instruction stringlengths 34 186 | input stringlengths 2.02k 93.8k | output stringlengths 2 418 | meta_questiontype stringclasses 6
values | meta_inputlicense stringclasses 6
values | meta_pmid stringlengths 8 8 | meta_safetyreportid int64 9.51M 21M | meta_articlepubdate stringlengths 4 10 |
|---|---|---|---|---|---|---|---|
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Ewing-like sarcoma'. | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | CYCLOPHOSPHAMIDE, DACTINOMYCIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, TRABECTEDIN, VINCRISTINE | DrugsGivenReaction | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Impaired quality of life'. | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | CYCLOPHOSPHAMIDE, DACTINOMYCIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, TRABECTEDIN, VINCRISTINE | DrugsGivenReaction | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | CYCLOPHOSPHAMIDE, DACTINOMYCIN, DOXORUBICIN, ETOPOSIDE, IFOSFAMIDE, TRABECTEDIN, VINCRISTINE | DrugsGivenReaction | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
What was the dosage of drug 'DOXORUBICIN'? | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | OFF LABEL TREATMENT FOR EWING?LIKE SARCOMA | DrugDosageText | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
What was the dosage of drug 'ETOPOSIDE'? | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | OVER THE FIVE DAYS EVERY THREE WEEKS | DrugDosageText | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
What was the dosage of drug 'IFOSFAMIDE'? | Secondary CIC-rearranged sarcoma responsive to chemotherapy regimens for Ewing sarcoma: A case report.
Capicua transcriptional repressor (CIC)-rearranged sarcoma is an Ewing-like sarcoma with an aggressive clinical course and poor prognosis. No standard treatment has been established. The present study describes a case of CIC-rearranged sarcoma with lung metastases developing in a 24-year-old woman as a therapy-associated malignancy following chemotherapy for anaplastic large cell lymphoma at nine years old. This was treated with palliative regimens used for Ewing sarcoma. The patient achieved disease control for one year. Of note, ifosfamide and etoposide (IE), which were used as a second line treatment lead to a partial response. The case described in the present study indicated that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcoma, including those with a second malignant case.
Introduction
Undifferentiated small-cell sarcomas are soft tissue malignancies which are characterized by small, round to ovoid cytomorphology with a high nuclear/cytoplasmic ratio. The most frequent one is Ewing sarcoma, which is characterized by EWS RNA binding protein 1 (EWSR1)-erythroblast transformation-specific (ETS) gene fusions, and others without theses fusions are called ‘Ewing-like sarcomas’. Based on the discovery of novel molecular driving events, recent studies have enabled the identification of two distinct subgroups, these are, capicua transcriptional repressor (CIC)-rearranged sarcoma and BCL6 corepressor (BCOR)-rearranged sarcoma, within this previously uncharacterized group of Ewing-like sarcomas (1,2). In CIC-rearranged sarcoma, CIC is fused to double homeobox 4 (DUX4) with either t(4;19)(q35;q13.1) or t(10;19)(q26.3;q13) translocation, which are associated with oncogenesis, tumor development, and metastatic capability (1,3,4). On the other hand, BCOR is fused to mainly cyclin B3 (CCNB3) (5). These entities have different clinicopathological features. Of note, CIC-rearranged sarcomas are associated with an aggressive clinical course and poor prognosis compared to Ewing sarcoma (3). Median overall survival of patients with metastatic CIC-rearranged sarcoma is only 9-10 months (6,7). The efficacy of chemotherapy has not been prospectively evaluated, and no standard treatment has been established (7,8). Compared to CIC-rearranged sarcomas, BCOR-rearranged sarcomas have a much better prognosis (5,7), although no standard treatment for these tumors has been established either.
Here, we describe a case of metastatic CIC-rearranged sarcoma which developed years after chemotherapy for lymphoma that included alkylating agents and anthracycline, and was palliated with chemotherapy used for Ewing sarcoma.
Case report
The patient was a 24-year-old Japanese woman who had a past medical history of anaplastic large cell lymphoma at nine years old, treated with chemotherapy based on the ACLC99 protocol (9) and JACLS NHL-98 protocol (10), with subsequent autologous hematopoietic stem cell transplantation. These protocol regimens included cytotoxic drugs such as alkylating agents and anthracyclines. The cumulative dose of doxorubicin (DOX) was 150 mg/m2. She had been in long-term complete remission.
She was referred to our hospital after presenting with pain and swelling of the left shoulder in May 2018. A magnetic resonance imaging (MRI) scan of the left shoulder revealed a 5 cm soft tissue mass located between the deltoid and humerus (Fig. 1A-C). Open biopsy was performed. Small round atypical cells with a high nuclear/cytoplasmic ratio grew in sheets (Fig. 2A) and formed alveolar structures with necrosis and fibrosis. Immunohistochemically, tumor cells were positive for WT-1, calretinin and ETS variant transcription factor 4 (ETV4), and focally positive for CD99 (Fig. 2B and C). Fluorescence in situ hybridization demonstrated CIC rearrangement (Fig. 2D). Based on these findings, the tumor was diagnosed as CIC-rearranged sarcoma. Detail of fusion partner did not be studied. CT scan revealed multiple nodules in the lungs, which were consistent with metastases.
The clinical course is summarized in Fig. 3A. First-line palliative chemotherapy with DOX, vincristine (VCR), and cyclophosphamide (CPA) was initiated in June 2018 (Fig. 3B). After the first cycle, the lung metastases had shrunk, but the primary lesion had not changed. The patient underwent a wide resection of the primary lesion with replacement using artificial humeral head in July 2018 to improve her quality of life. Pathological response to initial chemotherapy was poor. DOX, VCR, and CPA were restarted. At the end of the third cycle, her cumulative lifetime exposure of DOX had reached 350 mg/m2. We substituted actinomycin-D (Act-D) for DOX beginning with the fourth cycle to avoid cardiotoxicity (11). The CIC-rearranged sarcoma was well-controlled during six cycles, although adverse events occurred, including grade 3 febrile neutropenia and septic arthritis requiring debridement. Six months from the beginning of therapy, progression of the lung metastases developed (Fig. 3C).
We administered ifosfamide and etoposide as second-line treatment. We planned 1,800 mg/m2 of ifosfamide per day for five days and 100 mg/m2 of etoposide per day over the same five days every three weeks. Two cycles of IE achieved a good response in the lung metastases as seen on CT scan; this response lasted for 4 months (Fig. 3D). However, persistent grade 2 anorexia due to chemotherapy impaired her quality of life. In addition, some evidences have suggested that pulmonary metastasectomy may be associated with clinical benefit (12,13). As extrapulmonary metastases had not appeared, after careful discussion among the multidisciplinary team and the patient, we planned a pneumonectomy for pulmonary oligometastases for improvement of prognosis and quality of life with subsequent chemotherapy holiday after 5 cycles of IE. Despite rapid progression of the lung metastases, with a left pleural effusion appearing right before surgery (Fig. 3E), pneumonectomy and maximum debulking of the pleural metastases were performed. However, not all residual disease could be resected.
Following surgery, an aggressive clinical course was maintained. As rapidly progressive malignant pleural effusion developed, pleurodesis was performed. Although we started trabectedin (TRB) as third-line therapy, no clinical benefit was observed. She died one month later. Her overall survival from diagnosis was 13 months.
Discussion
No molecular-based targeted therapy or cancer immunotherapy for the treatment of CIC-rearranged sarcomas has been reported, and chemotherapy with cytotoxic agents is still generally used. The available data on treatment for metastatic CIC-rearranged sarcoma come from small retrospective studies. Because of the low incidence and variations in treatment, some cases were formerly diagnosed and treated as other sarcomas without pathognomonic molecular analysis (6,7,14). Palmerini et al reported that in first-line settings for metastatic CIC-rearranged sarcoma, response rates to a Ewing regimen and another regimen (DOX and ifosfamide, unknown regimen) were 57% (n=8/14) and 0% (n=0/4), respectively (8). In addition, neoadjuvant chemotherapy with Ewing regimen achieved pathological response in 3 of 10 localized CIC-rearranged sarcoma (6). These findings suggest that chemotherapy with the Ewing regimens seems to be effective for patients newly diagnosed with metastatic CIC-rearranged sarcoma, albeit that further studies are warranted.
IE is an effective regimen for treatment of recurrent Ewing sarcoma (15). This regimen is not widely used in treatment for advanced soft tissue sarcoma (16,17), although minimum activity has been reported in small phase 2 trial (18). IE is commonly used with DOX, VCR, and CPA (VDC-IE) for treatment of localized Ewing sarcoma based on the results of a randomized phase 3 trial, but the same trial revealed that VDC-IE did not improve the outcome for patients with metastatic disease (19). Thus, we did not use VDC-IE in our first-line palliative treatment but did use it for second-line treatment. To our knowledge, this is the first case with a response to an IE regimen without DOX for refractory CIC-rearranged sarcoma. Unfortunately, the patients showed poor prognosis regardless palliative chemotherapy. However, Ewing regimens, especially IE regimen achieved clinically meaningful disease control in this case, considering to highly aggressive clinical course after IE regimen failure.
There is no established treatment for Ewing sarcoma refractory to both DOX, VCR, and CPA and to IE. TRB, a tetrahydroisoquinoline alkaloid, showed anti-tumor activity in CIC-rearranged sarcoma in a xenograft model (4). Preclinical and clinical studies have shown that TRB has an anti-tumor effect in several translocation-related sarcomas (20-22). Therefore, we used TRB as third-line palliative therapy based on these findings, but saw no clinical benefit. Interestingly, TRB did not demonstrate sufficient activity against relapsed Ewing sarcoma in a phase 2 trial (23). Of ten evaluable patients, there were no partial responses, one case of stable disease, and nine cases of progressive disease. Based on the above, the clinical response to chemotherapy in our case was concordant with the clinical chemosensitivity of Ewing sarcoma.
Our case is the first report of secondary CIC-rearranged sarcoma. Secondary sarcoma associated with prior chemotherapy is well known. Various treatment-related factors are associated with the development of secondary sarcoma, including exposure to alkylating agents and/or anthracyclines and a history of autologous hematopoietic stem cell transplantation (24,25). Most secondary sarcoma belong to the category with non-recurring genetic aberrations, including undifferentiated pleomorphic sarcoma, osteosarcoma, and malignant peripheral nerve sheath tumor (26). Ewing sarcoma accounts for only 5% of secondary sarcomas (24). However, CIC-rearranged sarcoma could have been overlooked in cases where pathognomonic molecular analysis was not performed. It is uncertain whether the clinical outcome differs between primary and secondary CIC-rearranged sarcoma. In our case, the previous treatment history restricted the use of DOX because of the patient's cumulative exposure.
In conclusion, we describe a case of metastatic CIC-rearranged sarcoma treated with palliative chemotherapy, beginning with an Ewing regimen, both VDC and IE. Our case and the best available clinical evidence suggest that treatment with Ewing regimens is a reasonable option for patients with metastatic CIC-rearranged sarcomas, including second malignant case.
Acknowledgements
The authors would like to thank Dr. Akihiko Yoshida (Department of Diagnostic Pathology, National Cancer Center Hospital) for his important contributions to the pathological diagnosis.
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
SK and YI made substantial contributions to the conception and design of the study. SK, YI, NK, HT, SM, TKo TH, MK, TKa, and HH substantial contributions to the acquisition of the data. SK and YI confirmed the authenticity of the raw data and drafted the manuscript. YFuj, YFun, MT and HM made substantial contributions to the analysis and interpretation of the data and were involved in revising the manuscript critically for important intellectual content. TH and MK contributed pathological diagnosis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Patient consent for publication
Written informed consent was obtained from the patient for publication of the clinical data and images.
Competing interests
The authors declare that they have no competing interests.
Figure 1 MRI of the tumor at presentation. A 5 cm long mass is isointense on (A) T1-weighted imaging, and (B) hyperintense on T2-weighted imaging and (C) short inversion time inversion recovery imaging.
Figure 2 Small round atypical cells with a high nuclear/cytoplasmic ratio grow in sheets. (A) Hematoxylin and eosin stains. Magnification, x100. (B) Tumor cells are focally positive for CD99 and show strong and diffuse positive staining for (C) ETV4. Magnification, x40. (D) Fluorescence in situ hybridization shows the rearrangement of CIC gene. Split of green (5' part) and orange (3' part) signals. ETV4, ETS variant transcription factor 4.
Figure 3 Summary of clinical course. (A) Course of treatment including chemotherapy and surgery. (B) Baseline CT scan in June 2018 shows small bilateral nodules. (C) A period of six months after the initiation of doxorubicin, vincristine and cyclophosphamide, progression of lung metastases is observed. (D) IE achieved a partial response confirmed in April 2019. (E) Disease progression was observed in June 2019. IE, ifosfamide and etoposide; VCR, vincristine; DOX, doxorubicin; CPA, cyclophosphamide; TRB, trabectedin. | FOR FIVE DAYS, EVERY THREE WEEK | DrugDosageText | CC BY-NC-ND | 33680459 | 19,217,525 | 2021-04 |
What was the dosage of drug 'DOXORUBICIN HYDROCHLORIDE'? | Postsurgical Diagnosis of an Unusual Case of Primary Hepatic Lymphoma Presenting as Liver Abscess with an Uncommon Complication: A Hepatogastric Fistula.
Primary hepatic lymphoma (PHL) is a very rare malignancy and constitutes 0.016% of all cases of non-Hodgkin's lymphoma and 0.4% of extranodal non-Hodgkin's lymphoma. We describe a rare case of primary hepatic lymphoma presenting as liver abscess which was complicated with the development of a hepatogastric fistula. A 58-year-old man presented with clinical signs of sepsis, high-grade fever, right upper abdominal pain, and weight loss which had progressed in the past 8 months. Noncontrast abdominal computed tomography (CT) revealed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within, which are seen to extend into the body of the stomach. The patient was initially misdiagnosed as a case of rupture of liver abscess into the stomach. Postoperative liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. Chemotherapy was initiated, but discontinued due to the patient's general condition. Finally, the patient succumbed to neutropenic fever following chemotherapy. Here, we present the exceptional case of a primary hepatic lymphoma with an unusual complication, a hepatogastric fistula, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
1. Introduction
PHL is a rare form of non-Hodgkin lymphoma (NHL), and it is a tumor confined to the liver without evidence of lymphomatous involvement of the lymph nodes, spleen, bone marrow, or other lymphoid structures. The vast majority of PHL is NHL, most often a diffuse large B-cell lymphoma type. PHL was often misdiagnosed as some other tumor and frequently diagnosed intra- or postoperatively. We report an interesting case of PHL that was difficult to discriminate from a liver abscess, with an unusual complication, hepatogastric fistula, diagnosed after postoperative biopsy report, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
2. Case Report
A 58-year-old male with no significant past medical history presented to our emergency department with fever, right upper abdominal pain, vomiting, hematemesis, anorexia, night sweats, and unexplained weight loss. Physical examination revealed an asthenic patient with mild mucocutaneous pallor, a temperature of 38°C, pulse rate of 110/min, blood pressure of 90/60 mmHg, and respiratory rate of 17/min. There was no clinical jaundice. Per abdominal examination revealed mild tenderness in the epigastric and right hypochondriac regions, with palpable liver extending one cm below the right subcostal margin, rounded margin. The spleen and superficial lymph nodes were not palpable. Initial investigations showed hemoglobin of 7.3 g/dl, total leukocyte count of 22,000 cells/mm3 (neutrophils 82%), and platelet counts (139,000 cells/mm3). Serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin levels were elevated, but the levels of other tumor markers, such as alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), were normal. Serology was negative for hepatitis B virus (HBV) surface antigen, HCV, and human immunodeficiency virus. An urgent noncontrast computed tomography (CT) examination of the abdomen and pelvis was performed which showed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within. The liver lesion was extending directly into the body of the stomach (Figure 1). The walls of the fundus and lesser curvature of the stomach could not be defined. These features were suggestive of rupture of left lobe liver abscess into the stomach. The spleen was remarkably normal, and the mesenteric, para-aortic, and retroperitoneal lymph nodes were not enlarged. Based on a presumptive diagnosis of liver abscess, the patient was initially treated with broad-spectrum antibiotics. The patient's clinical condition deteriorated, and a decision of surgical exploration was made. Intraoperative findings revealed dense adhesions of the left lobe of the liver with the anterior wall of the stomach and diaphragmatic surface. There was a 2 cm × 1 cm defect on the anterior wall of the stomach, and it was communicating with the abscess cavity in the left lobe of the liver. There was no peritoneal soiling. Necrosis tissues were removed from the liver, we drained the abscess cavity, and subhepatic drain was placed. The margins of the gastric perforation were freshened and primarily repaired (Figure 2). The patient was kept on nasojejunal tube for one week with broad-spectrum antibiotics and total parenteral nutrition. Histopathology of the surgical liver biopsy revealed a hepatic diffuse infiltration of large typical lymphoid B-cells, with necrosis. Immunohistochemistry was positive for CD20 and Ki-67 (80%) (Figure 3).
Postoperative investigations for disseminated non-Hodgkin lymphoma (NHL) by CT scan of the thorax did not reveal any lymphadenopathy or mass lesion. FDG-PET scan and bone marrow biopsy were negative. Thus, a diagnosis of primary non-Hodgkin lymphoma of the liver, large cell type, was confirmed. The patient condition did not allow additional complementary surgery, and he was managed with six cycles of R-CHOP regimen, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, a persistent fever occurred 1 month after three cycles of chemotherapy. The patient succumbed to neutropenic fever following chemotherapy.
3. Discussion
PHL and hepatogastric fistula are extremely rare. To our knowledge, this is the first report on a primary hepatic lymphoma invading the adjacent stomach, which was complicated with the development of a hepatogastric fistula. PHL was first described in 1965 by Ata and Kamel [1]. Some authors defined primary hepatic lymphoma as a very rare malignant tumor with the features of liver involvement and without involvement of other organs and tissues including the bone marrow, lymph nodes, spleen, and peripheral blood until at least 6 months after diagnosis [2, 3].
Primary hepatic lymphoma is very rare and constitutes about 0.0016% of all cases of non-Hodgkin's lymphoma (NHL) [4]. Extranodal lymphomas account for 10%–25% of non-Hodgkin's lymphomas, in which PHL is responsible for less than 1% [5].
PHL can occur at any age, and the average age of the reported patients is the fifth or sixth decade of life. It affects preferentially men with a male/female ratio of 2–3/1 [6]. PHL may be Hodgkin's or non-Hodgkin's; however, the latter is more common. Immunophenotypically, the B-cell is commoner than T-cell type [5]. The etiology of PHL is uncertain, and it may be associated with HIV, AIDS, hepatitis B and C, Epstein–Barr virus, liver cirrhosis, primary biliary cirrhosis, immunosuppressive therapy, and autoimmune diseases [7]. However, our case did not have any of the above conditions.
Symptoms are usually nonspecific and include hepatomegaly, gastrointestinal symptoms (abdominal pain, vomiting, and loss of appetite), right upper quadrant, and epigastric pain. Many cases are diffuse large B-cell lymphoma, and the patients show B-symptomatology of weight loss, fever, and night sweats, as well as fatigue and lethargy. Other rare clinical manifestations include pleural effusion, jaundice, thrombocytopenia, metabolic acidosis, and hypercalcemia [8]. Laboratory abnormalities associated with PHL include anaemia, neutropenia, hypercalcemia, and variably raised LDH, one serum alkaline phosphatase, b-microglobulin, and aminotransferase activities. The tumor markers AFP and CEA are found within normal range, in almost all cases of PHL [2].
On ultrasound imaging, majority are hypoechoic as compared to surrounding normal liver parenchyma. Radiological features of PHL are usually nonspecific, and the most common presentation on the computed tomography (CT) scan is a solitary hypoattenuating lesion, which may have a central area of low intensity indicating necrosis. Other less common radiological findings are multiple lesions and diffuse infiltration patterns [9]. On MRI, the lesion appears hypointense on T1-weighted and mildly hyperintense on T2-weighted images. However, it is often difficult to distinguish hepatic lymphoma from hepatocarcinoma or gastrointestinal tract metastasis because of the rarity of this disease and the nonspecific clinical presentation, laboratory, and radiologic features [10].
Diagnosis is often made upon histopathological and immunohistochemical investigation of the liver biopsy by using percutaneous needle aspiration, laparoscopy, or laparotomy [11]. In our case, liver biopsy was performed preoperatively because the lesion was profoundly symptomatic, and due to the rarity of the disease, we considered liver abscess with hepatogastric fistula in our first diagnosis.
Treatment modalities include surgical resection, chemotherapy, and radiotherapy alone or in combination. Most of the reported cases are diffuse large B-cell lymphomas, but this type is usually aggressive with a relatively poor prognosis [5]. Current literature favors combination chemotherapy as the frontline treatment owing to its noninvasive nature and improved survival outcomes. The standard treatment for patients with diffuse large B-cell lymphoma is CHOP. The addition of rituximab, a monoclonal antibody targeting the pan-B-cell antigenic marker CD20, to the CHOP regimen augments the complete response rate and prolongs overall survival [11, 12]. Optimal treatment is not yet defined. However, recent series reported favorable short and midterm outcomes and longer survival rates with the use of liver resection followed by adjuvant chemotherapy and/or radiation [13]. Surgery is a better option for localized disease with adequate normal liver volume, and preoperative chemotherapy can be tried with an attempt to reduce the tumor volume [5, 14]. However, because our patient's general condition did not permit, we did not proceed with a formal liver resection as indicated in this setting.
The clinical case we present is extremely unusual because there is a coincidence of two very rare features, primary hepatic lymphoma and hepatogastric fistula. Direct invasion to the gastric wall is the basis of the formation of a hepatogastric fistula. Nevertheless, a hepatogastric fistula is a rare complication, even more so for primary liver lymphoma. Such a fistula has been described following transarterial embolization, radiotherapy for hepatocellular carcinoma, percutaneous radiofrequency of hepatocellular carcinoma, pyogenic liver abscess, iatrogenic injury of the stomach, percutaneous catheter drainage of the liver abscess, or by direct infiltration of the stomach by hepatocellular carcinoma [15].
4. Conclusion
In conclusion, we have reported an exceptional case of PHL with an unusual complication that was difficult to discriminate from a liver abscess with a hepatogastric fistula. The preoperative diagnosis was difficult due to the rarity of the disease, the clinical and imaging manifestations of PHL were nonspecific, and levels of alpha-fetoprotein and carcinoembryonic antigen (CEA) were normal. The diagnosis of PHL should be strictly based on histopathology and immunophenotype. PHL should be considered in the differential diagnosis in a patient with space-occupying liver lesions. Favorable prognosis of PHL can be obtained by early surgery combined with chemotherapy in strictly selected patients.
Data Availability
The research article data used to support the findings of this study are available from the corresponding author upon request (mbarekyaka@yahoo.fr).
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Preoperative CT scan showing (a, b) liver cystic mass containing multiple air foci; (c, d) hepatogastric fistula.
Figure 2 Operative view of the anterior surface of the left lobe of the liver showing (a) necrotic area of liver lymphoma and (b) hepatogastric fistula.
Figure 3 Histopathological examination. (a) Diffuse proliferation of atypical lymphoid cells (HE, GX 40). (b) Large numbers of lymphocytes ranging in size from medium to large, with oval or round nuclei containing fine chromatin and scanty cytoplasm (HE, GX 200). (c) Immunohistochemical staining was positive for CD20 (a B-cell marker). (d) The Ki-67 index was positive in 80%. | R?CHOP | DrugDosageText | CC BY | 33680521 | 19,168,446 | 2021 |
What was the dosage of drug 'DOXORUBICIN'? | Postsurgical Diagnosis of an Unusual Case of Primary Hepatic Lymphoma Presenting as Liver Abscess with an Uncommon Complication: A Hepatogastric Fistula.
Primary hepatic lymphoma (PHL) is a very rare malignancy and constitutes 0.016% of all cases of non-Hodgkin's lymphoma and 0.4% of extranodal non-Hodgkin's lymphoma. We describe a rare case of primary hepatic lymphoma presenting as liver abscess which was complicated with the development of a hepatogastric fistula. A 58-year-old man presented with clinical signs of sepsis, high-grade fever, right upper abdominal pain, and weight loss which had progressed in the past 8 months. Noncontrast abdominal computed tomography (CT) revealed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within, which are seen to extend into the body of the stomach. The patient was initially misdiagnosed as a case of rupture of liver abscess into the stomach. Postoperative liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. Chemotherapy was initiated, but discontinued due to the patient's general condition. Finally, the patient succumbed to neutropenic fever following chemotherapy. Here, we present the exceptional case of a primary hepatic lymphoma with an unusual complication, a hepatogastric fistula, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
1. Introduction
PHL is a rare form of non-Hodgkin lymphoma (NHL), and it is a tumor confined to the liver without evidence of lymphomatous involvement of the lymph nodes, spleen, bone marrow, or other lymphoid structures. The vast majority of PHL is NHL, most often a diffuse large B-cell lymphoma type. PHL was often misdiagnosed as some other tumor and frequently diagnosed intra- or postoperatively. We report an interesting case of PHL that was difficult to discriminate from a liver abscess, with an unusual complication, hepatogastric fistula, diagnosed after postoperative biopsy report, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
2. Case Report
A 58-year-old male with no significant past medical history presented to our emergency department with fever, right upper abdominal pain, vomiting, hematemesis, anorexia, night sweats, and unexplained weight loss. Physical examination revealed an asthenic patient with mild mucocutaneous pallor, a temperature of 38°C, pulse rate of 110/min, blood pressure of 90/60 mmHg, and respiratory rate of 17/min. There was no clinical jaundice. Per abdominal examination revealed mild tenderness in the epigastric and right hypochondriac regions, with palpable liver extending one cm below the right subcostal margin, rounded margin. The spleen and superficial lymph nodes were not palpable. Initial investigations showed hemoglobin of 7.3 g/dl, total leukocyte count of 22,000 cells/mm3 (neutrophils 82%), and platelet counts (139,000 cells/mm3). Serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin levels were elevated, but the levels of other tumor markers, such as alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), were normal. Serology was negative for hepatitis B virus (HBV) surface antigen, HCV, and human immunodeficiency virus. An urgent noncontrast computed tomography (CT) examination of the abdomen and pelvis was performed which showed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within. The liver lesion was extending directly into the body of the stomach (Figure 1). The walls of the fundus and lesser curvature of the stomach could not be defined. These features were suggestive of rupture of left lobe liver abscess into the stomach. The spleen was remarkably normal, and the mesenteric, para-aortic, and retroperitoneal lymph nodes were not enlarged. Based on a presumptive diagnosis of liver abscess, the patient was initially treated with broad-spectrum antibiotics. The patient's clinical condition deteriorated, and a decision of surgical exploration was made. Intraoperative findings revealed dense adhesions of the left lobe of the liver with the anterior wall of the stomach and diaphragmatic surface. There was a 2 cm × 1 cm defect on the anterior wall of the stomach, and it was communicating with the abscess cavity in the left lobe of the liver. There was no peritoneal soiling. Necrosis tissues were removed from the liver, we drained the abscess cavity, and subhepatic drain was placed. The margins of the gastric perforation were freshened and primarily repaired (Figure 2). The patient was kept on nasojejunal tube for one week with broad-spectrum antibiotics and total parenteral nutrition. Histopathology of the surgical liver biopsy revealed a hepatic diffuse infiltration of large typical lymphoid B-cells, with necrosis. Immunohistochemistry was positive for CD20 and Ki-67 (80%) (Figure 3).
Postoperative investigations for disseminated non-Hodgkin lymphoma (NHL) by CT scan of the thorax did not reveal any lymphadenopathy or mass lesion. FDG-PET scan and bone marrow biopsy were negative. Thus, a diagnosis of primary non-Hodgkin lymphoma of the liver, large cell type, was confirmed. The patient condition did not allow additional complementary surgery, and he was managed with six cycles of R-CHOP regimen, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, a persistent fever occurred 1 month after three cycles of chemotherapy. The patient succumbed to neutropenic fever following chemotherapy.
3. Discussion
PHL and hepatogastric fistula are extremely rare. To our knowledge, this is the first report on a primary hepatic lymphoma invading the adjacent stomach, which was complicated with the development of a hepatogastric fistula. PHL was first described in 1965 by Ata and Kamel [1]. Some authors defined primary hepatic lymphoma as a very rare malignant tumor with the features of liver involvement and without involvement of other organs and tissues including the bone marrow, lymph nodes, spleen, and peripheral blood until at least 6 months after diagnosis [2, 3].
Primary hepatic lymphoma is very rare and constitutes about 0.0016% of all cases of non-Hodgkin's lymphoma (NHL) [4]. Extranodal lymphomas account for 10%–25% of non-Hodgkin's lymphomas, in which PHL is responsible for less than 1% [5].
PHL can occur at any age, and the average age of the reported patients is the fifth or sixth decade of life. It affects preferentially men with a male/female ratio of 2–3/1 [6]. PHL may be Hodgkin's or non-Hodgkin's; however, the latter is more common. Immunophenotypically, the B-cell is commoner than T-cell type [5]. The etiology of PHL is uncertain, and it may be associated with HIV, AIDS, hepatitis B and C, Epstein–Barr virus, liver cirrhosis, primary biliary cirrhosis, immunosuppressive therapy, and autoimmune diseases [7]. However, our case did not have any of the above conditions.
Symptoms are usually nonspecific and include hepatomegaly, gastrointestinal symptoms (abdominal pain, vomiting, and loss of appetite), right upper quadrant, and epigastric pain. Many cases are diffuse large B-cell lymphoma, and the patients show B-symptomatology of weight loss, fever, and night sweats, as well as fatigue and lethargy. Other rare clinical manifestations include pleural effusion, jaundice, thrombocytopenia, metabolic acidosis, and hypercalcemia [8]. Laboratory abnormalities associated with PHL include anaemia, neutropenia, hypercalcemia, and variably raised LDH, one serum alkaline phosphatase, b-microglobulin, and aminotransferase activities. The tumor markers AFP and CEA are found within normal range, in almost all cases of PHL [2].
On ultrasound imaging, majority are hypoechoic as compared to surrounding normal liver parenchyma. Radiological features of PHL are usually nonspecific, and the most common presentation on the computed tomography (CT) scan is a solitary hypoattenuating lesion, which may have a central area of low intensity indicating necrosis. Other less common radiological findings are multiple lesions and diffuse infiltration patterns [9]. On MRI, the lesion appears hypointense on T1-weighted and mildly hyperintense on T2-weighted images. However, it is often difficult to distinguish hepatic lymphoma from hepatocarcinoma or gastrointestinal tract metastasis because of the rarity of this disease and the nonspecific clinical presentation, laboratory, and radiologic features [10].
Diagnosis is often made upon histopathological and immunohistochemical investigation of the liver biopsy by using percutaneous needle aspiration, laparoscopy, or laparotomy [11]. In our case, liver biopsy was performed preoperatively because the lesion was profoundly symptomatic, and due to the rarity of the disease, we considered liver abscess with hepatogastric fistula in our first diagnosis.
Treatment modalities include surgical resection, chemotherapy, and radiotherapy alone or in combination. Most of the reported cases are diffuse large B-cell lymphomas, but this type is usually aggressive with a relatively poor prognosis [5]. Current literature favors combination chemotherapy as the frontline treatment owing to its noninvasive nature and improved survival outcomes. The standard treatment for patients with diffuse large B-cell lymphoma is CHOP. The addition of rituximab, a monoclonal antibody targeting the pan-B-cell antigenic marker CD20, to the CHOP regimen augments the complete response rate and prolongs overall survival [11, 12]. Optimal treatment is not yet defined. However, recent series reported favorable short and midterm outcomes and longer survival rates with the use of liver resection followed by adjuvant chemotherapy and/or radiation [13]. Surgery is a better option for localized disease with adequate normal liver volume, and preoperative chemotherapy can be tried with an attempt to reduce the tumor volume [5, 14]. However, because our patient's general condition did not permit, we did not proceed with a formal liver resection as indicated in this setting.
The clinical case we present is extremely unusual because there is a coincidence of two very rare features, primary hepatic lymphoma and hepatogastric fistula. Direct invasion to the gastric wall is the basis of the formation of a hepatogastric fistula. Nevertheless, a hepatogastric fistula is a rare complication, even more so for primary liver lymphoma. Such a fistula has been described following transarterial embolization, radiotherapy for hepatocellular carcinoma, percutaneous radiofrequency of hepatocellular carcinoma, pyogenic liver abscess, iatrogenic injury of the stomach, percutaneous catheter drainage of the liver abscess, or by direct infiltration of the stomach by hepatocellular carcinoma [15].
4. Conclusion
In conclusion, we have reported an exceptional case of PHL with an unusual complication that was difficult to discriminate from a liver abscess with a hepatogastric fistula. The preoperative diagnosis was difficult due to the rarity of the disease, the clinical and imaging manifestations of PHL were nonspecific, and levels of alpha-fetoprotein and carcinoembryonic antigen (CEA) were normal. The diagnosis of PHL should be strictly based on histopathology and immunophenotype. PHL should be considered in the differential diagnosis in a patient with space-occupying liver lesions. Favorable prognosis of PHL can be obtained by early surgery combined with chemotherapy in strictly selected patients.
Data Availability
The research article data used to support the findings of this study are available from the corresponding author upon request (mbarekyaka@yahoo.fr).
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Preoperative CT scan showing (a, b) liver cystic mass containing multiple air foci; (c, d) hepatogastric fistula.
Figure 2 Operative view of the anterior surface of the left lobe of the liver showing (a) necrotic area of liver lymphoma and (b) hepatogastric fistula.
Figure 3 Histopathological examination. (a) Diffuse proliferation of atypical lymphoid cells (HE, GX 40). (b) Large numbers of lymphocytes ranging in size from medium to large, with oval or round nuclei containing fine chromatin and scanty cytoplasm (HE, GX 200). (c) Immunohistochemical staining was positive for CD20 (a B-cell marker). (d) The Ki-67 index was positive in 80%. | SIX CYCLES OF R?CHOP REGIMEN | DrugDosageText | CC BY | 33680521 | 19,168,442 | 2021 |
What was the outcome of reaction 'Febrile neutropenia'? | Postsurgical Diagnosis of an Unusual Case of Primary Hepatic Lymphoma Presenting as Liver Abscess with an Uncommon Complication: A Hepatogastric Fistula.
Primary hepatic lymphoma (PHL) is a very rare malignancy and constitutes 0.016% of all cases of non-Hodgkin's lymphoma and 0.4% of extranodal non-Hodgkin's lymphoma. We describe a rare case of primary hepatic lymphoma presenting as liver abscess which was complicated with the development of a hepatogastric fistula. A 58-year-old man presented with clinical signs of sepsis, high-grade fever, right upper abdominal pain, and weight loss which had progressed in the past 8 months. Noncontrast abdominal computed tomography (CT) revealed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within, which are seen to extend into the body of the stomach. The patient was initially misdiagnosed as a case of rupture of liver abscess into the stomach. Postoperative liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. Chemotherapy was initiated, but discontinued due to the patient's general condition. Finally, the patient succumbed to neutropenic fever following chemotherapy. Here, we present the exceptional case of a primary hepatic lymphoma with an unusual complication, a hepatogastric fistula, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
1. Introduction
PHL is a rare form of non-Hodgkin lymphoma (NHL), and it is a tumor confined to the liver without evidence of lymphomatous involvement of the lymph nodes, spleen, bone marrow, or other lymphoid structures. The vast majority of PHL is NHL, most often a diffuse large B-cell lymphoma type. PHL was often misdiagnosed as some other tumor and frequently diagnosed intra- or postoperatively. We report an interesting case of PHL that was difficult to discriminate from a liver abscess, with an unusual complication, hepatogastric fistula, diagnosed after postoperative biopsy report, and try through the existing literature to show the difficulties involved in diagnosis and treatment.
2. Case Report
A 58-year-old male with no significant past medical history presented to our emergency department with fever, right upper abdominal pain, vomiting, hematemesis, anorexia, night sweats, and unexplained weight loss. Physical examination revealed an asthenic patient with mild mucocutaneous pallor, a temperature of 38°C, pulse rate of 110/min, blood pressure of 90/60 mmHg, and respiratory rate of 17/min. There was no clinical jaundice. Per abdominal examination revealed mild tenderness in the epigastric and right hypochondriac regions, with palpable liver extending one cm below the right subcostal margin, rounded margin. The spleen and superficial lymph nodes were not palpable. Initial investigations showed hemoglobin of 7.3 g/dl, total leukocyte count of 22,000 cells/mm3 (neutrophils 82%), and platelet counts (139,000 cells/mm3). Serum lactate dehydrogenase (LDH), C-reactive protein (CRP), and procalcitonin levels were elevated, but the levels of other tumor markers, such as alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA), were normal. Serology was negative for hepatitis B virus (HBV) surface antigen, HCV, and human immunodeficiency virus. An urgent noncontrast computed tomography (CT) examination of the abdomen and pelvis was performed which showed a heterogeneously hypodense lesion in the left lobe of the liver with multiple air foci within. The liver lesion was extending directly into the body of the stomach (Figure 1). The walls of the fundus and lesser curvature of the stomach could not be defined. These features were suggestive of rupture of left lobe liver abscess into the stomach. The spleen was remarkably normal, and the mesenteric, para-aortic, and retroperitoneal lymph nodes were not enlarged. Based on a presumptive diagnosis of liver abscess, the patient was initially treated with broad-spectrum antibiotics. The patient's clinical condition deteriorated, and a decision of surgical exploration was made. Intraoperative findings revealed dense adhesions of the left lobe of the liver with the anterior wall of the stomach and diaphragmatic surface. There was a 2 cm × 1 cm defect on the anterior wall of the stomach, and it was communicating with the abscess cavity in the left lobe of the liver. There was no peritoneal soiling. Necrosis tissues were removed from the liver, we drained the abscess cavity, and subhepatic drain was placed. The margins of the gastric perforation were freshened and primarily repaired (Figure 2). The patient was kept on nasojejunal tube for one week with broad-spectrum antibiotics and total parenteral nutrition. Histopathology of the surgical liver biopsy revealed a hepatic diffuse infiltration of large typical lymphoid B-cells, with necrosis. Immunohistochemistry was positive for CD20 and Ki-67 (80%) (Figure 3).
Postoperative investigations for disseminated non-Hodgkin lymphoma (NHL) by CT scan of the thorax did not reveal any lymphadenopathy or mass lesion. FDG-PET scan and bone marrow biopsy were negative. Thus, a diagnosis of primary non-Hodgkin lymphoma of the liver, large cell type, was confirmed. The patient condition did not allow additional complementary surgery, and he was managed with six cycles of R-CHOP regimen, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, a persistent fever occurred 1 month after three cycles of chemotherapy. The patient succumbed to neutropenic fever following chemotherapy.
3. Discussion
PHL and hepatogastric fistula are extremely rare. To our knowledge, this is the first report on a primary hepatic lymphoma invading the adjacent stomach, which was complicated with the development of a hepatogastric fistula. PHL was first described in 1965 by Ata and Kamel [1]. Some authors defined primary hepatic lymphoma as a very rare malignant tumor with the features of liver involvement and without involvement of other organs and tissues including the bone marrow, lymph nodes, spleen, and peripheral blood until at least 6 months after diagnosis [2, 3].
Primary hepatic lymphoma is very rare and constitutes about 0.0016% of all cases of non-Hodgkin's lymphoma (NHL) [4]. Extranodal lymphomas account for 10%–25% of non-Hodgkin's lymphomas, in which PHL is responsible for less than 1% [5].
PHL can occur at any age, and the average age of the reported patients is the fifth or sixth decade of life. It affects preferentially men with a male/female ratio of 2–3/1 [6]. PHL may be Hodgkin's or non-Hodgkin's; however, the latter is more common. Immunophenotypically, the B-cell is commoner than T-cell type [5]. The etiology of PHL is uncertain, and it may be associated with HIV, AIDS, hepatitis B and C, Epstein–Barr virus, liver cirrhosis, primary biliary cirrhosis, immunosuppressive therapy, and autoimmune diseases [7]. However, our case did not have any of the above conditions.
Symptoms are usually nonspecific and include hepatomegaly, gastrointestinal symptoms (abdominal pain, vomiting, and loss of appetite), right upper quadrant, and epigastric pain. Many cases are diffuse large B-cell lymphoma, and the patients show B-symptomatology of weight loss, fever, and night sweats, as well as fatigue and lethargy. Other rare clinical manifestations include pleural effusion, jaundice, thrombocytopenia, metabolic acidosis, and hypercalcemia [8]. Laboratory abnormalities associated with PHL include anaemia, neutropenia, hypercalcemia, and variably raised LDH, one serum alkaline phosphatase, b-microglobulin, and aminotransferase activities. The tumor markers AFP and CEA are found within normal range, in almost all cases of PHL [2].
On ultrasound imaging, majority are hypoechoic as compared to surrounding normal liver parenchyma. Radiological features of PHL are usually nonspecific, and the most common presentation on the computed tomography (CT) scan is a solitary hypoattenuating lesion, which may have a central area of low intensity indicating necrosis. Other less common radiological findings are multiple lesions and diffuse infiltration patterns [9]. On MRI, the lesion appears hypointense on T1-weighted and mildly hyperintense on T2-weighted images. However, it is often difficult to distinguish hepatic lymphoma from hepatocarcinoma or gastrointestinal tract metastasis because of the rarity of this disease and the nonspecific clinical presentation, laboratory, and radiologic features [10].
Diagnosis is often made upon histopathological and immunohistochemical investigation of the liver biopsy by using percutaneous needle aspiration, laparoscopy, or laparotomy [11]. In our case, liver biopsy was performed preoperatively because the lesion was profoundly symptomatic, and due to the rarity of the disease, we considered liver abscess with hepatogastric fistula in our first diagnosis.
Treatment modalities include surgical resection, chemotherapy, and radiotherapy alone or in combination. Most of the reported cases are diffuse large B-cell lymphomas, but this type is usually aggressive with a relatively poor prognosis [5]. Current literature favors combination chemotherapy as the frontline treatment owing to its noninvasive nature and improved survival outcomes. The standard treatment for patients with diffuse large B-cell lymphoma is CHOP. The addition of rituximab, a monoclonal antibody targeting the pan-B-cell antigenic marker CD20, to the CHOP regimen augments the complete response rate and prolongs overall survival [11, 12]. Optimal treatment is not yet defined. However, recent series reported favorable short and midterm outcomes and longer survival rates with the use of liver resection followed by adjuvant chemotherapy and/or radiation [13]. Surgery is a better option for localized disease with adequate normal liver volume, and preoperative chemotherapy can be tried with an attempt to reduce the tumor volume [5, 14]. However, because our patient's general condition did not permit, we did not proceed with a formal liver resection as indicated in this setting.
The clinical case we present is extremely unusual because there is a coincidence of two very rare features, primary hepatic lymphoma and hepatogastric fistula. Direct invasion to the gastric wall is the basis of the formation of a hepatogastric fistula. Nevertheless, a hepatogastric fistula is a rare complication, even more so for primary liver lymphoma. Such a fistula has been described following transarterial embolization, radiotherapy for hepatocellular carcinoma, percutaneous radiofrequency of hepatocellular carcinoma, pyogenic liver abscess, iatrogenic injury of the stomach, percutaneous catheter drainage of the liver abscess, or by direct infiltration of the stomach by hepatocellular carcinoma [15].
4. Conclusion
In conclusion, we have reported an exceptional case of PHL with an unusual complication that was difficult to discriminate from a liver abscess with a hepatogastric fistula. The preoperative diagnosis was difficult due to the rarity of the disease, the clinical and imaging manifestations of PHL were nonspecific, and levels of alpha-fetoprotein and carcinoembryonic antigen (CEA) were normal. The diagnosis of PHL should be strictly based on histopathology and immunophenotype. PHL should be considered in the differential diagnosis in a patient with space-occupying liver lesions. Favorable prognosis of PHL can be obtained by early surgery combined with chemotherapy in strictly selected patients.
Data Availability
The research article data used to support the findings of this study are available from the corresponding author upon request (mbarekyaka@yahoo.fr).
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Figure 1 Preoperative CT scan showing (a, b) liver cystic mass containing multiple air foci; (c, d) hepatogastric fistula.
Figure 2 Operative view of the anterior surface of the left lobe of the liver showing (a) necrotic area of liver lymphoma and (b) hepatogastric fistula.
Figure 3 Histopathological examination. (a) Diffuse proliferation of atypical lymphoid cells (HE, GX 40). (b) Large numbers of lymphocytes ranging in size from medium to large, with oval or round nuclei containing fine chromatin and scanty cytoplasm (HE, GX 200). (c) Immunohistochemical staining was positive for CD20 (a B-cell marker). (d) The Ki-67 index was positive in 80%. | Fatal | ReactionOutcome | CC BY | 33680521 | 19,168,446 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Darmok and Jalad at the Psych Ward: A Case Demonstration of How to Creatively Communicate with a 19-Year-Old Patient with Autism Spectrum Disorder.
Difficulties in communication often arise between individuals with autism spectrum disorder and their treating physicians because both sides struggle to find a common ground. The story of Darmok and Jalad at Tanagra from Star Trek: The Next Generation nicely exemplifies how two populations that spoke different languages were still able to find a creative way to communicate with each other. This story is used as a metaphor to illustrate how a novel connection was made with a 19-year-old patient with autism spectrum disorder who was admitted to the inpatient psychiatric unit.
1. Introduction
Patients with autism spectrum disorder have proven to be some of the most challenging populations to work with on inpatient psychiatric units. Difficulties arise between these patients and their treating physicians because both sides struggle to find a common ground ([1, 2]). Challenges in verbal communication skills, need for consistency, lack of reciprocity, and difficulty understanding theory of mind hinder these patients' ability to connect with their physician. For two-way communication to be effective, physicians also have a responsibility to meet these patients at their level. To accomplish this goal, physicians must make accommodations to facilitate reciprocity, identify patients' interests, and utilize those interests to ease communication [3]. The need arises for physicians to think outside of their own communicative methods and to learn those of their patients. The story of Darmok and Jalad at Tanagra from Star Trek: The Next Generation [4] nicely exemplifies how two populations that spoke different languages were able to find a creative way of communication. This story was used as a metaphor to help illustrate how an inpatient psychiatric treatment team was able to effectively communicate with a 19-year-old patient with autism spectrum disorder.
In the story of Darmok and Jalad, the Federation attempts to communicate with the Tamarians to establish diplomatic relations. However, the Tamarians speak a language incomprehensible to their universal translator who is supposed to interpret the aliens' language for the crew. In anticipation of the language barrier between the two populations, Picard from the Federation astutely points out that “communication is a matter of patience, imagination… these are qualities for which we have insufficient measure.” Picard and Dathon, a Tamarian, are transported from their respective ships to the surface of El-Adrel, where they initially struggle to communicate with each other. Dathon repeatedly remarks, “Darmok and Jalad at Tanagra,” which initially confuses Picard. Abiding by his words and using patience and imagination, Picard begins to comprehend Dathon's speech and eventually realizes, “that's how (the Tamarians) communicate, by citing example, by metaphor.” He begins to comprehend that “Darmok and Jalad at Tanagra” was an event that exemplified how a danger shared between two people can bring the two people together and that Dathon was applying that example to their current situation of Dathon and Picard here at El-Adrel. At that point, Picard has grasped Dathon's language enough to converse with him, the language once deemed incomprehensible.
The fictional case from Star Trek has rather practical implications for communication in clinical settings. Patience and imagination proved to be invaluable tools and the necessary measures to establishing a therapeutic alliance and effective communication with the patient in our case.
2. Case Presentation
The patient was a 19-year-old African American male with autism spectrum disorder and schizoaffective disorder. He was initially admitted for bizarre behavior, grandiose delusions, erotomania, depression, and suicidal ideation. He expressed grandiosity of saving the universe and delusions about being in a relationship with a female peer whom he had met in school and considered to be his “girlfriend.” He was stabilized on olanzapine for psychosis and fluoxetine for obsessional thoughts. His treatment team worked with him to let him know that he could think about this female peer but that he should not call or visit her. The patient agreed, albeit reluctantly. He was discharged once he was no longer suicidal and his psychosis had abated.
Within seven days of discharge, he was readmitted with continued erotomania and plans to visit this female peer. He also expressed some homicidal ideation towards his family for preventing him from seeing her. He was sexually preoccupied during the admission and acted inappropriately around female patients. Collateral information from his sister revealed that being discharged, and once again being near his “girlfriend's” home, may have triggered him. She noted that he had been compliant with his medications, so medication noncompliance was not a cause for his decompensation. Nevertheless, his medications were readjusted. He was cross-tapered from olanzapine to haloperidol and then to aripiprazole. Fluoxetine was discontinued in case it was having unwanted activating side effects. Medications proved beneficial for the patient's overall psychotic symptoms but did not address his inappropriate behaviors on the unit. However, a novel way of communication managed to fill that gap.
The patient frequently verbalized that an asteroid was going to hit the earth and that we would all die from the asteroid. He often expressed grandiose thoughts of needing to save the world from the asteroid. He loved to draw, and many of his drawings depicted an asteroid shooting towards the earth. Over several weeks, the treatment team expressed curiosity about his drawings and encouraged discussion about them. Eventually, he had enough spontaneity to discuss the past trauma of his mother's partner abusing him and his sisters. The treatment team then made the connection that his mother's partner, like the asteroid about to hit the earth, was an example of how one bad thing could make everyone suffer. The patient, who had never expressed much interest in the team's responses to him, exclaimed “Yeahhhh!” as he widened his eyes and smiled. He also offered a fist pump, which was the first time he initiated reciprocal communication with the team. With several weeks of patience and imagination, the treatment team began to learn how to speak to him on his own terms.
Patience and imagination also proved to be essential in addressing his inappropriate behaviors on the unit. The team had learned from his prior admission and previous attempts to redirect his behavior, that directly telling him not to engage in certain behaviors (e.g., keeping his hands to himself and not using offensive language) was rather futile. During the second admission, the team decided to take a different approach. It was apparent that the patient's drawings were a way of communication for him. While he typically responded with brief one- or two-word answers to routine psychiatric interview questions, he went into lengthy descriptions about his drawings when prompted. His drawings became a way for him to express his thoughts and emotions and to facilitate discussion with the treatment team.
Inspired by the patient's prior drawings, the team drew the Earth with a protective shield made of stick figures representing people on the unit and an asteroid coming towards the earth. The patient, who had previously exhibited distractibility and poor eye contact, suddenly paid very close attention to the picture being drawn. The team explained to him that the patient was a part of the protective shield and pointed out one of the stick figures to represent him. He was told that he was an important part of the shield and by maintaining appropriate boundaries along with everyone else who was a part of the shield, he could make others feel safe and prevent the asteroid from hitting the Earth. The patient expressed understanding and did not oppose. While his initial response was not totally affirmative, it was a more positive outcome than in the past when he had been given verbal instruction alone.
Several weeks after he was encouraged to engage in appropriate behavior by using pictures, the team was informed by a group therapy facilitator that the patient had said, “we need to be kind to everyone on this earth… so everyone will survive.” Not only did the patient understand the message the team was conveying at the time the picture was drawn but he also remembered and carried that message with him several weeks out. Incorporating pictorial communication with verbal communication was a way the team successfully modified its ways to meet his needs and to make communication more effective. Ultimately, he was able to be stabilized with no further instances of concerning behavior to a group home.
3. Discussion
This case parallels the story of Picard and Dathon in Star Trek. As stated by Picard, patience and imagination were virtues that enabled communication with those who speak a language different from their own. As Gernsbacher points out, “Successful healthcare interactions depend on provider's reciprocity, that is, their willingness and ability to modify their own behavior to meet patient needs and treat them with respect” [5] when working with autistic patients. The term reciprocity implies effort from both the patient and the physician. When the patient has barriers preventing them from fulfilling their end, the physician must go one step further to meet the patient where they are at. In the case described above, the patient exhibited reciprocal communication including expressive response, eye contact, and fist pump after the team took one step further to make a connection using a metaphor revolving around his interests.
Physicians' willingness to provide accommodations has shown to significantly impact the success of patient-physician interactions [6], and this case exemplifies how several modifications in communication facilitated the interactions—conveying understanding of the patient's life experiences by rephrasing it with his metaphors, recognizing that his expressions and drawings may seem repetitive and bizarre but carry deeper meaning once explored, understanding that his drawings offered additional insight to his thoughts, building rapport by expressing curiosity about his drawings, and offering alternative communication methods. While there are many well-known ways to accommodate communication with autistic patients such as simplifying sentences, reducing sensory stimulation, and communicating by writing, this case demonstrates some novel methods that required thinking outside the box on the physician's end.
4. Conclusions
In summary, individuals with autism spectrum disorder can be challenging to communicate with in clinical settings. Thinking outside the box and employing creative strategies to connect with such patients can be highly effective. Using the story of Darmok and Jalad at Tanagra from Star Trek: The Next Generation as a metaphor, the treatment team was able to very effectively connect to and communicate with a 19-year-old male with autism spectrum disorder. In general, this case highlights that certain populations of patients may require accommodations based on their individual life experiences, talents, and topics of interest.
Conflicts of Interest
The authors declare that they have no conflicts of interest. | ARIPIPRAZOLE, FLUOXETINE HYDROCHLORIDE, HALOPERIDOL, OLANZAPINE | DrugsGivenReaction | CC BY | 33680527 | 19,918,287 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dependence on respirator'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypertension'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Incorrect route of product administration'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Myoclonic epilepsy'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Pneumonia aspiration'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory rate increased'. | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | TRANEXAMIC ACID | DrugsGivenReaction | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Dependence on respirator'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Hypertension'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Incorrect route of product administration'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Myoclonic epilepsy'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Pneumonia aspiration'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Respiratory failure'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
What was the outcome of reaction 'Respiratory rate increased'? | Incorrect Route for Injection: Inadvertent Tranexamic Acid Intrathecal Injection.
Tranexamic acid has been increasingly used due to its safety and effectiveness. It has been associated with multiple reported cases of errors due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the incorrect route of injection and the associated catastrophic sequela. Here we report a case of wrong route injection of tranexamic acid during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery. It is reported that higher doses of tranexamic acid would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. Tranexamic acid induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model, with greater severity and duration of seizure with increasing doses.
Introduction
Tranexamic acid (TXA) is an antifibrinolytic; it is a lysine analogue, which exerts its effects through its interaction with plasmin and plasminogen in a dose-dependent manner. While at lower doses it is a competitive inhibitor of plasminogen into plasmin, at higher doses it is a non-competitive inhibitor of plasmin [1-2]. TXA, aprotinin, and aminocaproic acid have been used in multiple clinical procedures, including cardiovascular, obstetric, and orthopedic surgeries due to their effects in reducing blood losses [3]. TXA has been increasingly used due to its safety and effectiveness [3]. It has been associated with multiple reported cases of errors, due to lack of attention, incorrect labeling of the syringes, or look-alike with other medications leading to the wrong route of injection and the associated catastrophic sequela [3-4]. Here we report a case of wrong route injection of TXA during spinal anesthesia, leading to myoclonic seizures and eventually intensive care unit admission of a patient undergoing orthopedic surgery.
Case presentation
A 76-year-old male presented with a past medical history of atrial fibrillation, who was admitted to the hospital for an elective replacement of his knee after a diagnosis of end-stage osteoarthritis was made. On presentation, the patient was alert, awake, oriented, and gave informed consent to proceed with the elective procedure. The patient’s vital signs were as follows: temperature, 98.9°F; heart rate, 84 beats per minute; blood pressure, 122/71 mmHg; and SpO2 98% on room air. The patient was taken to the operating room, and the procedure was aborted due to inadvertent injection of TXA intrathecally while administering spinal anesthesia due to the similarity of the two ampoules and lack of warning sign or coloring. The patient was having myoclonic seizures, vital signs as follows: blood pressure, 216/113; pulse rate, 89; respiratory, 36; oxygen saturation, 99%; he was treated with levetiracetam intravenous injection 1000 mg, midazolam intravenous infusion, and was intubated; blood pressure improved with sedation only; then the patient was admitted to the neurological intensive care unit (NICU). Magnetic resonance imaging (MRI) showed no acute abnormalities. Electroencephalogram (EEG) study performed was limited due to the patient’s sedation. The patient ICU stay was complicated by aspiration pneumonia and then ventilator-dependent respiratory failure, with worsening oxygenation, and he failed multiple proning attempts. The patient eventually passed away due to respiratory failure. A morbidity and mortality conference was presented about this case. Some changes are being implemented to guarantee that this kind of preventable error does not occur in most settings where these two medications are used.
Discussion
TXA is an anti-fibrinolytic agent that forms a reversible complex that displaces plasminogen from fibrin resulting in inhibition of fibrinolysis; it also inhibits the proteolytic activity of plasmin. The majority of side effects are minimal and include mainly gastrointestinal upset [5], but neurotoxicity including seizures have been reported in post-marketing and in animal studies [6]. However, there is no information on using TXA intrathecally or reports of use to treat subarachnoid or intracranial hemorrhage in humans [6]. Few cases of accidental intrathecal injection have been reported regarding a wrong route injection of TXA. In a case reported by Wong et al., 1988, an 18-year-old patient undergoing appendectomy was injected with TXA intrathecally. The patient developed persistent sensory block of both lower extremities in addition to fever, myoclonus, urinary incontinence, and clonic convulsions, which then progressed to a generalized seizure that showed a good response to intravenous diazepam; the patient eventually fully recovered without residual neurological deficits [7].
In another case, an accidental intrathecal injection of TXA (75 mg) in a 30-year-old man was reported. The patient experienced a seizure, myoclonus, back pain, and hypertension that responded well to both clonazepam and phenobarbital. The patient got intubated due to refractory seizures and developed ventricular tachycardia, but eventually, symptoms resolved by day 4, and the patient was extubated [6]. A different case reported inadvertent intrathecal injection but a higher dose of TXA (500 mg) where the patient developed generalized convulsions and hypertension followed by refractory ventricular fibrillation and eventually cardiac arrest [8].
In our reported case, the patient presented with neurotoxicity due to the inadvertent intrathecal injection of TXA, which lead to myoclonus, seizures, and hypertension. The patient needed intubation and sedation to control the seizures; due to aspiration pneumonia, the patient remained ventilator-dependent and eventually passed away due to respiratory failure.
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge, as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient [8]. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global [9] or from neuronal hyperexcitability by blockage of inhibitory cortical-gamma aminobutyric acid (GABA)-A receptors [10]. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses [11].
Conclusions
In conclusion, the exact mechanism by which TXA induces seizures is not fully understood. It is reported that higher doses of TXA would cause massive sympathetic discharge as evidenced by the initial hypertensive response reported in our case report and also in some repeated patient. TXA induced seizures either from direct cerebral ischemia secondary to decreases in regional or global or from neuronal hyperexcitability by blockage of inhibitory cortical-GABA-A receptors. Some evidence has been shown for dose-related neurotoxicity in the animal model with greater severity and duration of seizure with increasing doses. An action is needed to make changes to the way in which ampoules are packaged to help reduce this major adverse event.
Human Ethics
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Fatal | ReactionOutcome | CC BY | 33680597 | 19,037,851 | 2021-02-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Asthenia'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Decreased appetite'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Dysgeusia'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypokalaemia'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hyponatraemia'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Nausea'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Weight decreased'. | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | AMLODIPINE BESYLATE, INDAPAMIDE, PAROXETINE, PERINDOPRIL | DrugsGivenReaction | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Asthenia'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Decreased appetite'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Dysgeusia'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Hypokalaemia'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Hyponatraemia'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Nausea'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
What was the outcome of reaction 'Weight decreased'? | Sweet Taste Dysgeusia in a Patient with Indapamide-Related Hyponatremia: Case Report and Review of the Literature.
Sweet taste dysgeusia is a rare symptom where patients experience all food as having a sweet taste. While its cause is still unknown, it has been increasingly reported in the setting of lung cancer and syndrome of inappropriate secretion of antidiuretic hormone-related hyponatremia. In this case report, we present what we believe to be the first case of sweet taste dysgeusia in a non-cancer context. We will briefly review and summarize all published cases describing this symptom and also reflect upon the nature of this condition focusing on the role of serum sodium levels in sweet taste receptor modulation.
Introduction
Dysgeusia is a distortion in taste perception, and, although uncommon, it is a well-recognized symptom of systemic conditions such as metabolic disorders (e.g., diabetes mellitus), ionic disturbances (e.g. zinc deficiency), and a secondary effect of some drugs (e.g., cisplatin) [1]. Such conditions tend to interfere with taste perception in a non-selective way, leading to the disturbance of more than one (usually all) types of taste [1]. Sweet taste dysgeusia is a rare type of partial dysgeusia where there is increased acuity for sweet perception only. This finding has been described in cases where hyponatremia developed in the setting of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and lung cancer [2-9], raising the question of whether it could represent an alerting sign for clinicians for this paraneoplastic phenomenon. Even though this triad appears to be unique, we have previously presented a case of this specific taste distortion in a woman with hyponatremia secondary to indapamide use and in whom no cancer was found after approximately one year of follow-up [10]. Here we represent the same case after three years of follow-up in order to analyze it from a possible pathophysiological point of view.
Case presentation
A 71-year-old woman presented to our medical ward with a three-week history of non-selective anorexia, asthenia, nausea, and weight loss (3 kg). She also complained of an unpleasant sweet taste in which all food was perceived as sweet. Her past medical history included essential hypertension and depression. She never smoked. Long-term medications included perindopril, amlodipine, and paroxetine. She was started on indapamide two weeks prior to the beginning of symptoms. On physical examination, she was slightly dehydrated, with no other relevant finding. Laboratory was as follow: occasional glucose of 171 mg/dL, serum urea of 37 mg/dL, serum creatinine of 1.2 mg/dL, sodium of 120 mmol/L, potassium of 2.2 mmol/L, zinc of 16.6 ug/dL, copper of 142 ug/dL, serum osmolality of 257 mOsmol/kg, and urinary osmolality of 133 mOsmol/kg. Chest X-ray did not show any finding, and the head and all body CT scans with intravenous contrast were unremarkable, with no signs of malignancy. Considering the diagnosis of iatrogenic hyponatremia and hypokalemia, indapamide and paroxetine were stopped, and electrolyte correction was started. Over the following days, the sweet taste sensation lessened as sodium concentration began to rise and finally disappeared when sodium concentration reached 130 mmol/L (Figure 1). In the following months, paroxetine was restarted. It has been three years of follow-up time. Until now, her serum sodium concentration remains at normal levels, and the sweet taste dysgeusia did not recur.
Figure 1 Evolution of symptoms in regard to renal function and sodium plasma concentration
Abbreviations: Cr, serum creatinine levels; Na, sodium concentration levels
Discussion
While the cause of the sweet taste dysgeusia remains largely unknown, sodium serum levels are likely to play a pivotal role in the pathophysiology of this intriguing symptom. The association between sweet taste dysgeusia and hyponatremia secondary to paraneoplastic SIADH was first brought to medical attention in 1995 when Panayiotou et al. [2] described three patients who were diagnosed with small cell carcinoma of the lung after the onset of sweet taste dysgeusia related to hyponatremia. Seven other patients have been reported since then and their clinical similarities are a striking feature [3-9].
Table 1 sums all 10 cases found in the literature.
Table 1 Characteristics from case series and case reports on cancer-related sweet taste dysgeusia
Abbreviations: F, female; M, male; Na, sodium plasma concentration; SIADH, syndrome of inappropriate secretion of antidiuretic hormone
Author, year Patient (sex/age in years) Clinical picture Duration of symptoms (weeks) Na (mmol/L) Diagnosis
Panayiotou et al. [2] M/63 Sweet dysgeusia 3 114 SIADH/small cell lung carcinoma
F/63 Sweet dysgeusia, nausea, and weight loss 4 116 SIADH/small cell lung carcinoma
M/60 Sweet dysgeusia, pulmonary mass 8 116 SIADH/small cell lung carcinoma
Croghan and Salik [3] F/59 Sweet dysgeusia, dyspnea, nausea, weight loss 12 118 SIADH/small cell lung carcinoma (with hepatic metastasis)
Karthik et al. [4] F/69 Sweet dysgeusia unknown 122 SIADH/lung adenocarcinoma
Nakazato et al. [5] F/56 Sweet dysgeusia, nausea, and weight loss 7 113 SIADH/lung neuroendocrine carcinoma
Ellison and Berl [6] M/62 Sweet dysgeusia unknown 122 SIADH/small cell lung carcinoma
Singh et al. [7] F/60 Sweet dysgeusia, loss of consciousness, nausea, and weight loss 10 days 111 SIADH/small cell lung carcinoma (with non-specified metastasis)
Eshuis et al. [8] F/70 Sweet dysgeusia, nausea, and weight loss 4 125 SIADH/small cell lung carcinoma (with hepatic metastasis)
Schuermann et al. [9] F/60 Sweet dysgeusia 8 110 SIADH/small cell lung carcinoma (with non-specified metastasis)
All patients described the sweet dysgeusia as an unpleasant sweet taste where most foods were perceived as sweet, and, most importantly, this complaint was the reason that led them to seek for a medical observation [2-9]. Small cell carcinoma was the most frequent histological type, whereas neuroendocrine large cell carcinoma and adenocarcinoma were reported in two patients only [4,5]. All patients had hyponatremia, which was clearly linked with the severity of the symptoms. All patients had their symptoms lessened upon hyponatremia correction [2-9], and, more importantly, some of them recurred during hyponatremia reappearance [4,5,7].
Pure sweet taste loss is described in anti-acetylcholine receptor antibody (AChRAb)-myasthenia gravis (MG) patients [11,12]. The progressive loss of sweet taste appears to follow the disease activity as dysgeusia evolved in parallel with MG composite score [12] and AChRAb titers [11]. Importantly, this sweet hypogeusia always coexists with thymoma in MG, suggesting a paraneoplastic autoimmune phenomenon targeting the G-protein coupled sweet receptor [12]. Therefore, it is reasonable to think that malignant neoplasms may produce unknown taste modifying substances that might induce structural changes in the sweet taste-receptor membrane [5].
Serotonin is an important neurotransmitter in taste reception signaling [13,14]. In healthy volunteers, the serotonin selective receptor inhibitor (SSRI) paroxetine significantly increases sweet taste sensitivity (p < 0.001) [15], and sertraline treated successfully an elderly patient with mild depression who described every food as having no taste [16].
The pathophysiology of this special type of dysgeusia is probably multifactorial since none of the aforementioned reasons explains it by itself. Hyponatremia is the most common electrolyte disturbance in hospitalized patients [17], and, yet, most patients will not develop taste perception abnormalities. Similarly, even though lung cancer is the most commonly diagnosed cancer worldwide [18], taste disturbances are uncommon prior to treatment [19].
In the present case, our patient described the same sweet taste dysgeusia as the cases mentioned before, but no malignant neoplasm was found, particularly lung cancer. In contrast to the reported cases where SIADH was the cause of hyponatremia [2-9], in our case, the variation in sodium concentration with indapamide introduction and withdrawal, the presence of hypokalemia, and the improvement of serum sodium concentration without water restriction favor the hypothesis of hyponatremia secondary to diuretic use. SSRI drugs are a well-known cause of hyponatremia, particularly in the elderly [20]. Our patient was on paroxetine for over 15 years. Despite this, she had never had this symptom before. We stopped paroxetine as a first attempt to assess our patient’s hyponatremia. Later on, paroxetine was restarted, and, until now, her serum sodium levels remain at normal range, and the sweet taste dysgeusia did not recur.
Overall, it appears that in order to develop sweet dysgeusia, one must have a combination of factors that potentiate the action of one another and would ultimately modulate the sweet taste receptor. Hyponatremia is the only common characteristic in the aforementioned cancer-related cases and ours. It is thus possible that our patient developed a sweet taste dysgeusia due to indapamide-related hyponatremia in the context of an already modulated sweet taste receptor environment by paroxetine. We could, herein, hypothesize that serum sodium concentrations not only have a modulating effect on the sweet taste receptor but also are the main driver of this particular sweet taste disturbance.
Conclusions
We present what we believe to be the first case report of sweet taste dysgeusia in a non-cancer context. In light of the literature, our case further underlines the particular role that sodium plasma levels have on the modulation of the sweet taste receptor. Even though we did not find any malignant neoplasm, we strongly consider that one should not be discouraged to pursue a cancer workout in the setting of this rare symptom.
Human Ethics
We are indebted to Professor Rui M. M. Victorino and Dr. João Meneses for fruitful discussions.
The authors have declared that no competing interests exist.
Consent was obtained or waived by all participants in this study | Recovered | ReactionOutcome | CC BY | 33680619 | 19,767,208 | 2021-02-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Bronchospasm'. | The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports.
Beta-blockers are key in the management of cardiovascular diseases but blocking airway β2-receptors can cause severe and sometimes fatal bronchoconstriction in people with asthma. Although cardioselective β1-blockers may be safer than non-selective β-blockers, they remain relatively contraindicated and under-prescribed. We review the evidence of the risk associated with cardioselective β1-blocker use in asthma.
We searched "asthma" AND "beta-blocker" in PubMed and EmbaseOvid from start to May 2020. The World Health Organization (WHO) global database of individual case safety reports (VigiBase) was searched for reports of fatal asthma or bronchospasm and listed cardioselective β1-blocker use (accessed February 2020). Reports were examined for evidence of pre-existing asthma.
PubMed and EmbaseOvid searches identified 304 and 327 publications, respectively. No published reports of severe or fatal asthma associated with cardioselective β1-blockers were found. Three large observational studies reported no increase in asthma exacerbations with cardioselective β1-blocker treatment. The VigiBase search identified five reports of fatalities in patients with pre-existing asthma and reporting asthma or bronchospasm during cardioselective β1-blocker use. Four of these deaths were unrelated to cardioselective β1-blocker use. The circumstances of the fifth death were unclear.
There were no published reports of cardioselective β1-blockers causing asthma death. Observational data suggest that cardioselective β1-blocker use is not associated with increased asthma exacerbations. We found only one report of an asthma death potentially caused by cardioselective β1-blockers in a patient with asthma in a search of VigiBase. The reluctance to use cardioselective β1-blockers in people with asthma is not supported by this evidence.
Introduction
Cardiovascular diseases are common among people with asthma with some adjusted models showing approximately double the risk of coronary heart disease and stroke [1–3]. In one prospective cohort study people with asthma had a 60% higher risk of cardiovascular events in a 10-year follow-up [4]. β2-agonist medications are fundamental in the current management of both asthma and other obstructive lung diseases such as COPD [5, 6]. On the other hand, β-antagonists, more commonly known as β-blockers, are a cornerstone of management of cardiovascular disease such as heart failure and after myocardial infarction [7]. Although these treatments primarily target different receptor subtypes (β1
versus β2), concern about the specificity of the available drugs for these receptor subtypes has led to uncertainty about the management of patients with both obstructive airways and cardiovascular diseases.
First-generation non-selective β-blockers caused alarm with reports of severe bronchospasm and fatalities, in some instances after only ocular administration [8, 9]. This led to β-blockers being absolutely contraindicated in asthma. “Cardioselective” β1-blockers were developed to preferentially block cardiac β1-adrenoceptors with less activity at airway β2-receptors. However, this selectivity is not complete, and concerns about the safety of cardioselective β1-blockers in patients with airways disease persist. Observational studies suggest that using cardioselective β1-blockers to treat cardiovascular disease is not associated with increased exacerbations in COPD [10, 11]. Guidelines support the use of cardioselective β1-blockers in COPD where there is a clear indication for their use [12, 13]. However, a recent randomised placebo-controlled trial of the cardioselective β1-blocker metoprolol in patients with COPD was stopped early due to concerns about a greater number of severe exacerbations in the metoprolol group [14]. The safety of cardioselective β1-blockers to treat cardiovascular disease in asthma remains unclear.
Many clinicians remain reluctant to use cardioselective β1-blockers in people with asthma [15, 16]. As a result, large numbers of people with asthma may be denied the cardiovascular benefits of β-blocker medications. It is also recognised that it can be difficult to distinguish between asthma and COPD and other comorbid disease in elderly people further adding to the challenges of appropriate medication prescribing [17, 18].
This narrative literature review first considers the pharmacology of cardioselective β1-blockers with respect to their use in asthma. We then review the published evidence of cardioselective β1-blocker use in asthma and also look at the WHO global database of individual case safety reports (VigiBase) for any details of reported asthma-related fatalities with cardioselective β1-blocker use [19].
Understanding the pharmacology
β-adrenoceptors
There are three known subtypes of β-adrenoceptor: β1-, β2- and β3-adrenoceptors. Beta1-adrenoceptors are found predominantly in the heart where the β1:β2 adrenoceptor ratio is around 7:3 and catecholamine stimulation leads to positive ionotropic and chronotropic effects [20]. Beta2-adrenoceptors are found predominantly in bronchial smooth muscle but also in heart, skeletal muscle and peripheral blood vessels [21]. Beta3-adrenoceptors are found primarily in adipose tissue and the bladder but are also found in the cardiac atria and peripheral vasculature where they are involved in mediation of metabolic effects [22]. The relevance of β3-blockade to cardiovascular and respiratory health is not clear but as β3-receptors do not seem be involved in airway smooth muscle function they will not be considered further in this review [22].
Relative β1-selectivity
Early “non-selective” β-blockers (such as propranolol, sotalol and timolol) bind and inhibit both β1- and β2-adrenoceptors. Cardioselective β1-blockers (such as metoprolol, bisoprolol and atenolol) have a greater inhibition of β1-adenoceptors than β2-adrenoceptors. Some cardioselective β1-blockers have less β2-blocking effect than others [23–25]. This has been quantified in vitro with the relative affinity for β1-adrenoceptors:β2-adrenoceptors ranging from 13.5 (bisoprolol) to 2.3 (metoprolol) (table 1) [26]. The selectivity of cardioselective β1-blockers is also dose dependent: with increasing doses of any cardioselective β1-blocker the selectivity becomes less marked [26, 27].
TABLE 1 Commonly used β-blockers and their relative β-adrenoceptor selectivity and partial agonist and inverse agonist properties
Cardioselective β1-blockers (relative selectivity of β1versus β2) Nonselective β-blockers (relative selectivity of β1versus β2)
Partial agonist/ISA Acebutolol (2.4#)
Practolol (>14.1#) Labetalol (2.5#)
Alprenolol (16.2#)
Inverse agonist Metoprolol (2.3#, 6.0¶)
Atenolol (4.7#, 5.7¶)
Bisoprolol (13.5#, 19.6¶)
Nebivolol (40.6¶) Carvedilol (4.5#)
Propranolol (8.3#)
Sotalol (12.0#)
Nadolol (23.4#)
Timolol (25.7#)
A relative selectivity ratio of 1 demonstrated equal activity at both β1- and β2-adrenoceptors. ISA: intrinsic sympathomimetic activity. #: according to Baker [26] using cell lines expressing human adrenoceptors; ¶: according to Ladage
et al. [49] in their review figure.
Intrinsic sympathomimetic activity and inverse agonism
Unoccupied β-adrenoceptors have a baseline level of activity. Most β-blockers not only prevent the binding of catecholamines, but also influence the baseline level of activity of the adrenoceptor [28]. β-blockers that cause an increase in baseline receptor activity on binding are described as having intrinsic sympathomimetic activity (ISA), also sometimes called weak partial agonist activity (figure 1) [29]. Examples of β-blockers with ISA include labetalol and acebutolol (table 1). A meta-analysis of β-blocker treatment after myocardial infarction found that β-blockers with ISA were associated with a higher all-cause mortality compared to β-blockers without ISA [30]. Current guidelines suggest avoiding β-blockers with ISA for treating cardiovascular disease [31].
FIGURE 1 Pictorial representation of β-adrenoceptor activity in the presence of background catecholamines, β-agonists and β-blockers. ISA: intrinsic sympathomimetic activity.
β-blockers that cause a decrease in baseline receptor activity are described as inverse agonists, also sometimes called negative intrinsic activity [28, 32, 33]. Examples of inverse agonists include metoprolol, bisoprolol, atenolol, nebivolol, carvedilol, nadolol, propranolol and timolol.
Temporal effect
A pharmacokinetic temporal phenomenon of β-blockers is well established in heart failure with initial negative inotropic effects causing lethargy and low blood pressure usually improving within a week of treatment. To avoid these unwanted symptoms, clinicians are advised to start with a low dose and slowly up-titrate β-blocker therapy (“start low, go slow” approach) [12]. In reactive airways disease, single doses of both cardioselective and non-selective β-blockers have been consistently found to decrease the forced expiratory volume in 1 s (FEV1) compared to placebo [34]. Pooled results in a meta-analysis by Salpeter
et al. [34] suggest that this initial drop in FEV1 resolves over a few days or weeks.
Interactions with β-agonist therapy
In a meta-analysis of people with asthma, the response to β-agonist therapy, as measured by FEV1 increase from baseline, showed a mean 16% increase after a single dose of a cardioselective β1-blocker compared to a 23% increase after placebo and a 1% decline after a non-selective β-blocker [24]. However, the bronchodilator response to β-agonist therapy is maintained during continuous treatment with cardioselective β1-blockers [35–37].
Methods
Review of cardioselective β1-blockers in asthma
We reviewed evidence of whether use of cardioselective β1-blockers altered safety outcomes among people with asthma, as defined by decrease in FEV1, asthma exacerbations, hospital admissions and fatalities. A search of the terms “asthma” AND “beta-blockers” was undertaken in the databases of biomedical published literature: PubMed and EmbaseOvid. In EmbaseOvid we used “asthma” with a focus AND “beta adrenergic receptor blocking agent” with a focus and “beta-blocker” as a keyword. In PubMed “asthma” AND “beta adrenergic blocking agent” were both recognised terms for medical subject headings, MeSH. Both searches were limited to results with abstracts and English language. PubMed and EmbaseOvid were searched on 24 May 2020, and 304 and 237 publications were identified, respectively. MB selected studies that were relevant for asthma and cardioselective β1-blocker use. The inclusion criteria included studies of clinical impact of an oral, intravenous or topical cardioselective β1-blocker on people with a clinical diagnosis of asthma. Exclusion criteria included cell-based studies, inhaled β-blocker use only and studies of non-selective β-blockers only. These studies were analysed along with further searching of the reference lists of these papers. The results are summarised in table 2 with individual studies detailed in the supplementary material. PRISMA is an evidenced-based minimum set of items for reporting in systematic reviews and meta-analyses; the PRISMA flow diagram is shown in figure 2. Data were collected on the type of study, the number of participants, the specific β1-blocker used, impact on FEV1, exacerbations and number of fatalities.
TABLE 2 Summary studies included in review
Type of study Publications found in the search and considered in the review
Meta-analysis or systematic review 4 (3 meta-analyses, 1 systematic review)
Randomised controlled trial 53 (765 participants in total of which 682 people with asthma and 83 with reversible airways disease)
Non-randomised trial 31 (106 915 participants in total of which 63 763 were asthma alone, 43 152 were asthma or COPD)
Literature review 12 (9 asthma, 1 obstructive lung disease, 1 reversible airways disease and 1 on adverse reactions to β-blockers)
Other 27 (8 case reports, 7 murine models, 7 guinea pig models, 4 opinion articles, 1 questionnaire)
Studies that could be allocated to two categories are included in the highest tier (for example, meta-analysis above non-randomised trial).
FIGURE 2 PRISMA flow diagram of articles considered in the literature review.
Search of World Health Organization global database for individual case safety reports
We also undertook a search of global pharmacovigilance safety reports. VigiBase holds reports of over 20 million suspected adverse drug reactions submitted from national pharmacovigilance centres since 1968 with currently 140 countries contributing [19]. VigiBase is held by the Uppsala Monitoring Centre. Any healthcare provider or patient can submit a report.
VigiBase (accessed February 2020) was interrogated for reports of asthma-related fatalities occurring in patients taking cardioselective β1-blockers up to December 2019. The anatomical, therapeutic, chemical classification was used to identify reports with cardioselective β1-blockers as suspect medicines. The Medical Dictionary for Drug Regulatory Authorities was used to identify reports that included as suspected adverse reactions categorised as asthma, bronchospasm and asthma crisis (table 3). From these reports, those with a fatal outcome were included for assessment. MB and RS independently reviewed the details of all 18 fatal cases. Reports with a documented history of asthma or COPD or concomitant medicines that suggested pre-existing asthma or COPD were identified (table 4).
TABLE 3 Summary of VigiBase total and fatal reports for cardioselective β1-blockers with asthma or bronchospasm as reported suspected adverse reactions from start to December 2019
Cardioselective β1-blockers Reactions coded as asthma Reactions coded as bronchospasm
Total Of which were fatal Total Of which were fatal
Metoprolol 286 4 322 6
Atenolol 141 1 385 3
Bisoprolol 95 0 108 1
Nebivolol 29 0 32 0
Betaxolol 18 0 86 0
Acebutolol 5 1 30 0
Celiprolol 6 0 41 1
Landiolol 1 0 0 0
Esmolol 1 0 11 1
Esatenolol 1 0 0 0
TABLE 4 VigiBase data: clinical details of all five reported fatalities with cardioselective β1-blocker use in patients with an adverse drug reaction of asthma or bronchospasm who had evidence of pre-existing asthma
Report Year Cardioselective β1-blockers Reported adverse drug reactions
Name Dose Duration Indication
1 1985 Metoprolol Not stated 1.1 years Not stated Asthma (general anaesthetic medications listed)
2 2017 Metoprolol 100 mg by mouth once daily Not stated Hypertension Asthma, sepsis, pneumonia, emphysema, decreased immune response, renal cancer
3 2018 Acebutolol 600 mg by mouth once daily Not stated Not stated Asthma, acute MI, cardiogenic shock, metastatic renal cancer
4 2009 Atenolol 50 mg once daily Not stated Not stated Bronchospasm, acute MI, cardiac failure, aspiration, sudden cardiac death
5 2019 Atenolol Not stated 11 years Hypertension Asthma, viral pneumonia (immunosuppressant medicines listed)
MI: myocardial infarction.
Results
Published reports
The 127 publications that were identified in this review are summarised in table 2 and detailed in the supplementary material. Key reports are discussed below.
A meta-analysis by Salpeter
et al. [34] (updated in 2011) included 19 single-dose and 10 continued-dose placebo-controlled randomised trials in reactive airways disease. They found no difference in FEV1, respiratory symptoms or incidence of inhaler use with continued cardioselective β1-blocker exposure [34].
Morales
et al. [38] undertook a meta-analysis and population-based study of topical β-blockers (delivered as eye drops) in people with asthma. The meta-analysis showed that eye drops have similar effects to systemic administration of β-blockers, with a drop in FEV1 from baseline for non-selective β-blockers (11% lower) and cardioselective β1-blockers (6% lower). The population-based nested case–control study, which included 4865 people with asthma and ocular hypertension, found a 4.8-fold increase in moderate asthma exacerbations after ocular single-dose non-selective β-blocker use. There was no significant increase in risk after continuous non-selective β-blocker administration or single or continuous cardioselective β1-blocker use.
Another systematic review by the same group included 32 studies of people with asthma given single doses of cardioselective β1-blockers (330 patient exposures) and also non-selective β-blockers (301 patient exposures) [24]. They found that FEV1 was decreased after a single dose of both cardioselective β1-blockers (7% lower than baseline) and non-selective β-blockers (10% lower than baseline). As mentioned above, the response to β-agonist after cardioselective β1-blockers (FEV1 16% increase from baseline) was better than the response after non-selective β-blockers (1% decrease) but lower than the response to β-agonist after placebo (23% increase).
A randomised placebo-controlled crossover trial of 19 adults with mild or moderate asthma given bisoprolol daily for a minimum of 2 weeks found no difference in exacerbations between the groups [37]. Rescue β-agonist therapy after a controlled bronchoconstriction was also non-inferior with bisoprolol treatment.
Non-randomised studies also did not find an association between cardioselective β1-blocker use and asthma exacerbations. A nested case–control study in a general practice database cohort of 35 502 patients with both asthma and cardiovascular disease found no evidence of a higher risk of moderate or severe asthma exacerbations among 5017 patients who had been prescribed cardioselective β1-blockers compared to controls matched for age, sex and duration of follow-up [39]. However, this study found a higher risk of exacerbations with the prescription of non-selective β-blockers [39]. Similar findings were made in another nested case–control study of 10 934 people admitted with a first asthma exacerbation requiring corticosteroids compared to 74 415 controls [40]. A 1-year cohort study of 8390 US army veterans who had asthma or COPD and concurrent heart disease found that there was no difference in hospital admissions related to asthma or COPD among the 2810 who had been treated with cardioselective β1-blockers compared to 5293 receiving only non-β-blocker heart medications [41]. Another observational study in the USA investigated 1062 Medicare beneficiaries aged over 65 with cardiovascular disease and COPD/asthma and found that half were on β-blockers but that their use did not appear to influence the occurrence of cardiac events, pulmonary events or death [42].
Nebivolol is a highly cardioselective β1-blocker with inverse agonist properties. A non-randomised study of patients with chronic heart failure with concomitant obstructive airways disease treated with nebivolol, up-titrated over 24 weeks, included 13 asthmatics who showed no significant decrease in FEV1 at the final 24-week visit [43].
In a slightly different clinical context, Sultana
et al. [44] suggested that the use of β-blockers was a risk factor for exacerbation related to thunderstorm asthma but grouped non-selective and cardioselective β1-blockers together. Among users of cardioselective β1-blockers there was no statistically significant increase in risk.
We found no published reports of fatalities or severe bronchospasm associated with use of cardioselective β1-blockers in asthma. By contrast we found six separate case reports of severe or fatal bronchospasm following non-selective β-blocker use in asthmatics.
The National Review of Asthma Deaths investigating the cause of 195 asthma deaths in the UK between 2012 and 2013 reported four deaths due to “Drugs (nonsteroidal anti-inflammatory drugs, aspirin or beta-blockers)” [45]. Unfortunately, this provided no details on whether any of these deaths were associated with cardioselective β1-blockers, and we have been unable to obtain this information from the authors of the report.
VigiBase reports
Table 3 shows the number of reports that included asthma or bronchospasm as an adverse reaction and a cardioselective β1-blocker as a suspect medicine. Of the 583 reports of asthma and 1015 reports of bronchospasm a total of six and 12 fatalities were identified. Five reports noted use of inhalers suggesting pre-existing obstructive lung disease (we could not adequately differentiate between asthma or COPD, but all have been included as potentially having asthma), four reported asthma as an adverse reaction and one referenced bronchospasm (table 4). Four of these cases listed other medicines that were suspected to have caused or contributed to the adverse reactions as well as the β-blocker. A range of concomitant conditions was reported including: sepsis, viral pneumonia, cardiac disorders and renal cancer. Bronchospasm did not appear to be the primary cause of death, and therefore these four deaths were deemed unlikely to be caused by cardioselective β1-blocker use. One report (Report 1 in table 4) included little information other than naming medications (salbutamol, beclomethasone, metoprolol and also general anaesthetic agents started on the same day), and the only clinical reaction reported was asthma. While the reaction could have been caused by the anaesthetic drugs, it is possible that this death may have been related to β-blocker use. Hence, we identified this as the single potential asthma fatality in VigiBase related to the use of a cardioselective β1-blocker in a patient with asthma.
There were also 13 fatalities without evidence of pre-existing asthma in the reports but with an adverse drug reaction coded as asthma (n=2) or bronchospasm (n=11) (table 3). It is possible that these people had undiagnosed asthma and only developed symptoms when they took β-blockers or simply that known pre-existing asthma was not recorded in the reports. Of these 13 fatalities four of these patients had respiratory-related deaths and all four were associated with metoprolol. Four of the 13 were considered non-respiratory. There was insufficient information in the reports for the remaining five patients to determine the likely cause of death.
Discussion
We found no evidence that treatment with cardioselective β1-blockers, given systemically or topically as eye drops, causes an increase in moderate or severe asthma exacerbations, and we found no reports of fatalities in people with asthma using cardioselective β1-blockers in the published literature. We found only one potential asthma death caused by cardioselective β1-blockers in the international pharmacovigilance database (VigiBase), and interpretation of the cause of death in this case was limited by insufficient information. These findings suggest that asthma-related deaths caused by cardioselective β1-blockers are likely to be very rare.
A major limitation of this review is publication and reporting bias. It is also possible that these adverse effects are so rare because clinicians have avoided cardioselective β-blockers in patients with asthma, in particular in those with severe or problematic asthma. We do not know how many asthmatics are prescribed cardioselective β1-blockers worldwide, but Morales
et al. [39] found that 14% of a UK population with diagnosed asthma and cardiovascular disease in a general practice database were prescribed cardioselective β1-blockers. Among a general practice data set of 1071 people with asthma and cardiovascular disease from the USA, 9% of those aged between 60 and 69 years had been prescribed β-blockers in the previous year [46]. In light of this, it seems that to have only one fatality that can potentially be linked to use of cardioselective β1-blockers in asthma in the VigiBase database is reassuringly low.
A strength of this review is the use of VigiBase data in addition to the published literature. Given that β-blockers have been available for many years, it is reasonable to expect that any major concerns would turn up on such a reporting system. However, as the VigiBase information comes from a variety of sources, the probability that a suspected adverse effect is drug-related is not the same in all cases. Reports can be submitted by any person – not necessarily a clinician – and most reports of fatal asthma or bronchospasm submitted to VigiBase had minimal clinical information making the correct assignment of the likely association between cardioselective β1-blocker use and asthma fatalities difficult. This variation in clinical information also limited the VigiBase analysis, as we were unable to explore other outcomes such as hospitalisation. Another limitation of the VigiBase data is that of under-reporting, which as a result of fear of litigation, lack of awareness of the reporting system or even the assumption that bronchospasm following β-blocker administration was expected, may prevent some cases from being reported.
Implications for clinical practice
Guidelines have shifted from previously stating that all β-blockers are contraindicated in asthma to recommending that prescription of cardioselective β1-blockers should be done under specialist supervision on a “case-by-case basis” [5]. Nevertheless, concerns over the safety of cardioselective β1-blockers in asthma persist, and this remains a difficult area for prescribers, resulting in underutilisation of β-blockers in people with asthma [47]. Clinically there must be a balance of risk and benefit behind each decision to treat a person with asthma with a β-blocker as outlined in the recent report from the Global Initiative for Asthma (GINA) [48]. If there is a clinical indication and perceived clinical benefit from a β-blocker for a person with asthma, this review suggests that using highly selective β1-blockers, such as bisoprolol, at the lowest effective dose, is likely to minimise the risk of problematic β2-blocking bronchospasm.
Future research
Major studies of the cardiovascular benefits of β-blockers have excluded patients with asthma – the cardiac benefits for these patients can only be extrapolated from studies from which they have been excluded. This should be addressed with future studies including these participants.
To support the safe and appropriate prescribing of cardioselective β1-blockers to a growing cohort of people with asthma and cardiovascular disease, research clarifying to what extent rescue β2-agonist therapy is affected by use of regular cardioselective β1-blocker therapy and understanding of the dose at which each drug becomes insufficiently selective is needed.
Conclusions
The pharmacology of cardioselective β1-blockers indicates that cardioselectivity is not complete. Small reductions in lung function have been observed after single doses in people with asthma, but this adverse effect appears to resolve with continued treatment. Observational studies have found no increase in moderate or severe asthma exacerbations in people with asthma taking regular cardioselective β1-blockers. We found no reports of asthma deaths caused by cardioselective β1-blockers in the published literature and only one possible death that was clearly in an asthmatic patient in the VigiBase data, for which there was insufficient detail to establish clear causality. Absence of evidence of fatal asthma is not necessarily evidence that it does not occur. However, these findings suggest that, despite widespread concerns, fatalities or serious asthma exacerbations due to cardioselective β1-blocker use are likely to be extremely rare. The reluctance to use cardioselective β1-blockers in people with asthma is not supported by this evidence.
Supplementary material
10.1183/23120541.00801-2020.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material 00801-2020.SUPPLEMENT
Acknowledgements
The authors are indebted to the national centres that make up the WHO Programme for International Drug Monitoring and contribute reports to VigiBase. The opinions and conclusions of this study are not necessarily those of the various centres, of the UMC or of the WHO.
This article has supplementary material available from openres.ersjournals.com.
Data availability: Data available from the corresponding author upon reasonable request.
Author contributions: M. Bennett, C. Chang and R. Hancox were involved in the design and review process. M. Tatley and R. Savage were involved in review and data collection from VigiBase.
Conflict of interest: M. Bennett reports grants from Waikato Medical Research Foundation during the conduct of the study.
Conflict of interest: C.L. Chang has nothing to disclose.
Conflict of interest: M. Tatley has nothing to disclose.
Conflict of interest: R. Savage has nothing to disclose.
Conflict of interest: R.J. Hancox reports a proposed research grant on a related topic and travel to meetings supported by GSK, and travel to meetings supported by Boehringer Ingelheim and AstraZeneca, outside the submitted work.
Support statement: This review was funded by the support of the Waikato Respiratory Research Fund and the University of Otago. Funding information for this article has been deposited with the Crossref Funder Registry. | ESMOLOL HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC | 33681344 | 19,904,699 | 2021-01 |
What was the outcome of reaction 'Bronchospasm'? | The safety of cardioselective β1-blockers in asthma: literature review and search of global pharmacovigilance safety reports.
Beta-blockers are key in the management of cardiovascular diseases but blocking airway β2-receptors can cause severe and sometimes fatal bronchoconstriction in people with asthma. Although cardioselective β1-blockers may be safer than non-selective β-blockers, they remain relatively contraindicated and under-prescribed. We review the evidence of the risk associated with cardioselective β1-blocker use in asthma.
We searched "asthma" AND "beta-blocker" in PubMed and EmbaseOvid from start to May 2020. The World Health Organization (WHO) global database of individual case safety reports (VigiBase) was searched for reports of fatal asthma or bronchospasm and listed cardioselective β1-blocker use (accessed February 2020). Reports were examined for evidence of pre-existing asthma.
PubMed and EmbaseOvid searches identified 304 and 327 publications, respectively. No published reports of severe or fatal asthma associated with cardioselective β1-blockers were found. Three large observational studies reported no increase in asthma exacerbations with cardioselective β1-blocker treatment. The VigiBase search identified five reports of fatalities in patients with pre-existing asthma and reporting asthma or bronchospasm during cardioselective β1-blocker use. Four of these deaths were unrelated to cardioselective β1-blocker use. The circumstances of the fifth death were unclear.
There were no published reports of cardioselective β1-blockers causing asthma death. Observational data suggest that cardioselective β1-blocker use is not associated with increased asthma exacerbations. We found only one report of an asthma death potentially caused by cardioselective β1-blockers in a patient with asthma in a search of VigiBase. The reluctance to use cardioselective β1-blockers in people with asthma is not supported by this evidence.
Introduction
Cardiovascular diseases are common among people with asthma with some adjusted models showing approximately double the risk of coronary heart disease and stroke [1–3]. In one prospective cohort study people with asthma had a 60% higher risk of cardiovascular events in a 10-year follow-up [4]. β2-agonist medications are fundamental in the current management of both asthma and other obstructive lung diseases such as COPD [5, 6]. On the other hand, β-antagonists, more commonly known as β-blockers, are a cornerstone of management of cardiovascular disease such as heart failure and after myocardial infarction [7]. Although these treatments primarily target different receptor subtypes (β1
versus β2), concern about the specificity of the available drugs for these receptor subtypes has led to uncertainty about the management of patients with both obstructive airways and cardiovascular diseases.
First-generation non-selective β-blockers caused alarm with reports of severe bronchospasm and fatalities, in some instances after only ocular administration [8, 9]. This led to β-blockers being absolutely contraindicated in asthma. “Cardioselective” β1-blockers were developed to preferentially block cardiac β1-adrenoceptors with less activity at airway β2-receptors. However, this selectivity is not complete, and concerns about the safety of cardioselective β1-blockers in patients with airways disease persist. Observational studies suggest that using cardioselective β1-blockers to treat cardiovascular disease is not associated with increased exacerbations in COPD [10, 11]. Guidelines support the use of cardioselective β1-blockers in COPD where there is a clear indication for their use [12, 13]. However, a recent randomised placebo-controlled trial of the cardioselective β1-blocker metoprolol in patients with COPD was stopped early due to concerns about a greater number of severe exacerbations in the metoprolol group [14]. The safety of cardioselective β1-blockers to treat cardiovascular disease in asthma remains unclear.
Many clinicians remain reluctant to use cardioselective β1-blockers in people with asthma [15, 16]. As a result, large numbers of people with asthma may be denied the cardiovascular benefits of β-blocker medications. It is also recognised that it can be difficult to distinguish between asthma and COPD and other comorbid disease in elderly people further adding to the challenges of appropriate medication prescribing [17, 18].
This narrative literature review first considers the pharmacology of cardioselective β1-blockers with respect to their use in asthma. We then review the published evidence of cardioselective β1-blocker use in asthma and also look at the WHO global database of individual case safety reports (VigiBase) for any details of reported asthma-related fatalities with cardioselective β1-blocker use [19].
Understanding the pharmacology
β-adrenoceptors
There are three known subtypes of β-adrenoceptor: β1-, β2- and β3-adrenoceptors. Beta1-adrenoceptors are found predominantly in the heart where the β1:β2 adrenoceptor ratio is around 7:3 and catecholamine stimulation leads to positive ionotropic and chronotropic effects [20]. Beta2-adrenoceptors are found predominantly in bronchial smooth muscle but also in heart, skeletal muscle and peripheral blood vessels [21]. Beta3-adrenoceptors are found primarily in adipose tissue and the bladder but are also found in the cardiac atria and peripheral vasculature where they are involved in mediation of metabolic effects [22]. The relevance of β3-blockade to cardiovascular and respiratory health is not clear but as β3-receptors do not seem be involved in airway smooth muscle function they will not be considered further in this review [22].
Relative β1-selectivity
Early “non-selective” β-blockers (such as propranolol, sotalol and timolol) bind and inhibit both β1- and β2-adrenoceptors. Cardioselective β1-blockers (such as metoprolol, bisoprolol and atenolol) have a greater inhibition of β1-adenoceptors than β2-adrenoceptors. Some cardioselective β1-blockers have less β2-blocking effect than others [23–25]. This has been quantified in vitro with the relative affinity for β1-adrenoceptors:β2-adrenoceptors ranging from 13.5 (bisoprolol) to 2.3 (metoprolol) (table 1) [26]. The selectivity of cardioselective β1-blockers is also dose dependent: with increasing doses of any cardioselective β1-blocker the selectivity becomes less marked [26, 27].
TABLE 1 Commonly used β-blockers and their relative β-adrenoceptor selectivity and partial agonist and inverse agonist properties
Cardioselective β1-blockers (relative selectivity of β1versus β2) Nonselective β-blockers (relative selectivity of β1versus β2)
Partial agonist/ISA Acebutolol (2.4#)
Practolol (>14.1#) Labetalol (2.5#)
Alprenolol (16.2#)
Inverse agonist Metoprolol (2.3#, 6.0¶)
Atenolol (4.7#, 5.7¶)
Bisoprolol (13.5#, 19.6¶)
Nebivolol (40.6¶) Carvedilol (4.5#)
Propranolol (8.3#)
Sotalol (12.0#)
Nadolol (23.4#)
Timolol (25.7#)
A relative selectivity ratio of 1 demonstrated equal activity at both β1- and β2-adrenoceptors. ISA: intrinsic sympathomimetic activity. #: according to Baker [26] using cell lines expressing human adrenoceptors; ¶: according to Ladage
et al. [49] in their review figure.
Intrinsic sympathomimetic activity and inverse agonism
Unoccupied β-adrenoceptors have a baseline level of activity. Most β-blockers not only prevent the binding of catecholamines, but also influence the baseline level of activity of the adrenoceptor [28]. β-blockers that cause an increase in baseline receptor activity on binding are described as having intrinsic sympathomimetic activity (ISA), also sometimes called weak partial agonist activity (figure 1) [29]. Examples of β-blockers with ISA include labetalol and acebutolol (table 1). A meta-analysis of β-blocker treatment after myocardial infarction found that β-blockers with ISA were associated with a higher all-cause mortality compared to β-blockers without ISA [30]. Current guidelines suggest avoiding β-blockers with ISA for treating cardiovascular disease [31].
FIGURE 1 Pictorial representation of β-adrenoceptor activity in the presence of background catecholamines, β-agonists and β-blockers. ISA: intrinsic sympathomimetic activity.
β-blockers that cause a decrease in baseline receptor activity are described as inverse agonists, also sometimes called negative intrinsic activity [28, 32, 33]. Examples of inverse agonists include metoprolol, bisoprolol, atenolol, nebivolol, carvedilol, nadolol, propranolol and timolol.
Temporal effect
A pharmacokinetic temporal phenomenon of β-blockers is well established in heart failure with initial negative inotropic effects causing lethargy and low blood pressure usually improving within a week of treatment. To avoid these unwanted symptoms, clinicians are advised to start with a low dose and slowly up-titrate β-blocker therapy (“start low, go slow” approach) [12]. In reactive airways disease, single doses of both cardioselective and non-selective β-blockers have been consistently found to decrease the forced expiratory volume in 1 s (FEV1) compared to placebo [34]. Pooled results in a meta-analysis by Salpeter
et al. [34] suggest that this initial drop in FEV1 resolves over a few days or weeks.
Interactions with β-agonist therapy
In a meta-analysis of people with asthma, the response to β-agonist therapy, as measured by FEV1 increase from baseline, showed a mean 16% increase after a single dose of a cardioselective β1-blocker compared to a 23% increase after placebo and a 1% decline after a non-selective β-blocker [24]. However, the bronchodilator response to β-agonist therapy is maintained during continuous treatment with cardioselective β1-blockers [35–37].
Methods
Review of cardioselective β1-blockers in asthma
We reviewed evidence of whether use of cardioselective β1-blockers altered safety outcomes among people with asthma, as defined by decrease in FEV1, asthma exacerbations, hospital admissions and fatalities. A search of the terms “asthma” AND “beta-blockers” was undertaken in the databases of biomedical published literature: PubMed and EmbaseOvid. In EmbaseOvid we used “asthma” with a focus AND “beta adrenergic receptor blocking agent” with a focus and “beta-blocker” as a keyword. In PubMed “asthma” AND “beta adrenergic blocking agent” were both recognised terms for medical subject headings, MeSH. Both searches were limited to results with abstracts and English language. PubMed and EmbaseOvid were searched on 24 May 2020, and 304 and 237 publications were identified, respectively. MB selected studies that were relevant for asthma and cardioselective β1-blocker use. The inclusion criteria included studies of clinical impact of an oral, intravenous or topical cardioselective β1-blocker on people with a clinical diagnosis of asthma. Exclusion criteria included cell-based studies, inhaled β-blocker use only and studies of non-selective β-blockers only. These studies were analysed along with further searching of the reference lists of these papers. The results are summarised in table 2 with individual studies detailed in the supplementary material. PRISMA is an evidenced-based minimum set of items for reporting in systematic reviews and meta-analyses; the PRISMA flow diagram is shown in figure 2. Data were collected on the type of study, the number of participants, the specific β1-blocker used, impact on FEV1, exacerbations and number of fatalities.
TABLE 2 Summary studies included in review
Type of study Publications found in the search and considered in the review
Meta-analysis or systematic review 4 (3 meta-analyses, 1 systematic review)
Randomised controlled trial 53 (765 participants in total of which 682 people with asthma and 83 with reversible airways disease)
Non-randomised trial 31 (106 915 participants in total of which 63 763 were asthma alone, 43 152 were asthma or COPD)
Literature review 12 (9 asthma, 1 obstructive lung disease, 1 reversible airways disease and 1 on adverse reactions to β-blockers)
Other 27 (8 case reports, 7 murine models, 7 guinea pig models, 4 opinion articles, 1 questionnaire)
Studies that could be allocated to two categories are included in the highest tier (for example, meta-analysis above non-randomised trial).
FIGURE 2 PRISMA flow diagram of articles considered in the literature review.
Search of World Health Organization global database for individual case safety reports
We also undertook a search of global pharmacovigilance safety reports. VigiBase holds reports of over 20 million suspected adverse drug reactions submitted from national pharmacovigilance centres since 1968 with currently 140 countries contributing [19]. VigiBase is held by the Uppsala Monitoring Centre. Any healthcare provider or patient can submit a report.
VigiBase (accessed February 2020) was interrogated for reports of asthma-related fatalities occurring in patients taking cardioselective β1-blockers up to December 2019. The anatomical, therapeutic, chemical classification was used to identify reports with cardioselective β1-blockers as suspect medicines. The Medical Dictionary for Drug Regulatory Authorities was used to identify reports that included as suspected adverse reactions categorised as asthma, bronchospasm and asthma crisis (table 3). From these reports, those with a fatal outcome were included for assessment. MB and RS independently reviewed the details of all 18 fatal cases. Reports with a documented history of asthma or COPD or concomitant medicines that suggested pre-existing asthma or COPD were identified (table 4).
TABLE 3 Summary of VigiBase total and fatal reports for cardioselective β1-blockers with asthma or bronchospasm as reported suspected adverse reactions from start to December 2019
Cardioselective β1-blockers Reactions coded as asthma Reactions coded as bronchospasm
Total Of which were fatal Total Of which were fatal
Metoprolol 286 4 322 6
Atenolol 141 1 385 3
Bisoprolol 95 0 108 1
Nebivolol 29 0 32 0
Betaxolol 18 0 86 0
Acebutolol 5 1 30 0
Celiprolol 6 0 41 1
Landiolol 1 0 0 0
Esmolol 1 0 11 1
Esatenolol 1 0 0 0
TABLE 4 VigiBase data: clinical details of all five reported fatalities with cardioselective β1-blocker use in patients with an adverse drug reaction of asthma or bronchospasm who had evidence of pre-existing asthma
Report Year Cardioselective β1-blockers Reported adverse drug reactions
Name Dose Duration Indication
1 1985 Metoprolol Not stated 1.1 years Not stated Asthma (general anaesthetic medications listed)
2 2017 Metoprolol 100 mg by mouth once daily Not stated Hypertension Asthma, sepsis, pneumonia, emphysema, decreased immune response, renal cancer
3 2018 Acebutolol 600 mg by mouth once daily Not stated Not stated Asthma, acute MI, cardiogenic shock, metastatic renal cancer
4 2009 Atenolol 50 mg once daily Not stated Not stated Bronchospasm, acute MI, cardiac failure, aspiration, sudden cardiac death
5 2019 Atenolol Not stated 11 years Hypertension Asthma, viral pneumonia (immunosuppressant medicines listed)
MI: myocardial infarction.
Results
Published reports
The 127 publications that were identified in this review are summarised in table 2 and detailed in the supplementary material. Key reports are discussed below.
A meta-analysis by Salpeter
et al. [34] (updated in 2011) included 19 single-dose and 10 continued-dose placebo-controlled randomised trials in reactive airways disease. They found no difference in FEV1, respiratory symptoms or incidence of inhaler use with continued cardioselective β1-blocker exposure [34].
Morales
et al. [38] undertook a meta-analysis and population-based study of topical β-blockers (delivered as eye drops) in people with asthma. The meta-analysis showed that eye drops have similar effects to systemic administration of β-blockers, with a drop in FEV1 from baseline for non-selective β-blockers (11% lower) and cardioselective β1-blockers (6% lower). The population-based nested case–control study, which included 4865 people with asthma and ocular hypertension, found a 4.8-fold increase in moderate asthma exacerbations after ocular single-dose non-selective β-blocker use. There was no significant increase in risk after continuous non-selective β-blocker administration or single or continuous cardioselective β1-blocker use.
Another systematic review by the same group included 32 studies of people with asthma given single doses of cardioselective β1-blockers (330 patient exposures) and also non-selective β-blockers (301 patient exposures) [24]. They found that FEV1 was decreased after a single dose of both cardioselective β1-blockers (7% lower than baseline) and non-selective β-blockers (10% lower than baseline). As mentioned above, the response to β-agonist after cardioselective β1-blockers (FEV1 16% increase from baseline) was better than the response after non-selective β-blockers (1% decrease) but lower than the response to β-agonist after placebo (23% increase).
A randomised placebo-controlled crossover trial of 19 adults with mild or moderate asthma given bisoprolol daily for a minimum of 2 weeks found no difference in exacerbations between the groups [37]. Rescue β-agonist therapy after a controlled bronchoconstriction was also non-inferior with bisoprolol treatment.
Non-randomised studies also did not find an association between cardioselective β1-blocker use and asthma exacerbations. A nested case–control study in a general practice database cohort of 35 502 patients with both asthma and cardiovascular disease found no evidence of a higher risk of moderate or severe asthma exacerbations among 5017 patients who had been prescribed cardioselective β1-blockers compared to controls matched for age, sex and duration of follow-up [39]. However, this study found a higher risk of exacerbations with the prescription of non-selective β-blockers [39]. Similar findings were made in another nested case–control study of 10 934 people admitted with a first asthma exacerbation requiring corticosteroids compared to 74 415 controls [40]. A 1-year cohort study of 8390 US army veterans who had asthma or COPD and concurrent heart disease found that there was no difference in hospital admissions related to asthma or COPD among the 2810 who had been treated with cardioselective β1-blockers compared to 5293 receiving only non-β-blocker heart medications [41]. Another observational study in the USA investigated 1062 Medicare beneficiaries aged over 65 with cardiovascular disease and COPD/asthma and found that half were on β-blockers but that their use did not appear to influence the occurrence of cardiac events, pulmonary events or death [42].
Nebivolol is a highly cardioselective β1-blocker with inverse agonist properties. A non-randomised study of patients with chronic heart failure with concomitant obstructive airways disease treated with nebivolol, up-titrated over 24 weeks, included 13 asthmatics who showed no significant decrease in FEV1 at the final 24-week visit [43].
In a slightly different clinical context, Sultana
et al. [44] suggested that the use of β-blockers was a risk factor for exacerbation related to thunderstorm asthma but grouped non-selective and cardioselective β1-blockers together. Among users of cardioselective β1-blockers there was no statistically significant increase in risk.
We found no published reports of fatalities or severe bronchospasm associated with use of cardioselective β1-blockers in asthma. By contrast we found six separate case reports of severe or fatal bronchospasm following non-selective β-blocker use in asthmatics.
The National Review of Asthma Deaths investigating the cause of 195 asthma deaths in the UK between 2012 and 2013 reported four deaths due to “Drugs (nonsteroidal anti-inflammatory drugs, aspirin or beta-blockers)” [45]. Unfortunately, this provided no details on whether any of these deaths were associated with cardioselective β1-blockers, and we have been unable to obtain this information from the authors of the report.
VigiBase reports
Table 3 shows the number of reports that included asthma or bronchospasm as an adverse reaction and a cardioselective β1-blocker as a suspect medicine. Of the 583 reports of asthma and 1015 reports of bronchospasm a total of six and 12 fatalities were identified. Five reports noted use of inhalers suggesting pre-existing obstructive lung disease (we could not adequately differentiate between asthma or COPD, but all have been included as potentially having asthma), four reported asthma as an adverse reaction and one referenced bronchospasm (table 4). Four of these cases listed other medicines that were suspected to have caused or contributed to the adverse reactions as well as the β-blocker. A range of concomitant conditions was reported including: sepsis, viral pneumonia, cardiac disorders and renal cancer. Bronchospasm did not appear to be the primary cause of death, and therefore these four deaths were deemed unlikely to be caused by cardioselective β1-blocker use. One report (Report 1 in table 4) included little information other than naming medications (salbutamol, beclomethasone, metoprolol and also general anaesthetic agents started on the same day), and the only clinical reaction reported was asthma. While the reaction could have been caused by the anaesthetic drugs, it is possible that this death may have been related to β-blocker use. Hence, we identified this as the single potential asthma fatality in VigiBase related to the use of a cardioselective β1-blocker in a patient with asthma.
There were also 13 fatalities without evidence of pre-existing asthma in the reports but with an adverse drug reaction coded as asthma (n=2) or bronchospasm (n=11) (table 3). It is possible that these people had undiagnosed asthma and only developed symptoms when they took β-blockers or simply that known pre-existing asthma was not recorded in the reports. Of these 13 fatalities four of these patients had respiratory-related deaths and all four were associated with metoprolol. Four of the 13 were considered non-respiratory. There was insufficient information in the reports for the remaining five patients to determine the likely cause of death.
Discussion
We found no evidence that treatment with cardioselective β1-blockers, given systemically or topically as eye drops, causes an increase in moderate or severe asthma exacerbations, and we found no reports of fatalities in people with asthma using cardioselective β1-blockers in the published literature. We found only one potential asthma death caused by cardioselective β1-blockers in the international pharmacovigilance database (VigiBase), and interpretation of the cause of death in this case was limited by insufficient information. These findings suggest that asthma-related deaths caused by cardioselective β1-blockers are likely to be very rare.
A major limitation of this review is publication and reporting bias. It is also possible that these adverse effects are so rare because clinicians have avoided cardioselective β-blockers in patients with asthma, in particular in those with severe or problematic asthma. We do not know how many asthmatics are prescribed cardioselective β1-blockers worldwide, but Morales
et al. [39] found that 14% of a UK population with diagnosed asthma and cardiovascular disease in a general practice database were prescribed cardioselective β1-blockers. Among a general practice data set of 1071 people with asthma and cardiovascular disease from the USA, 9% of those aged between 60 and 69 years had been prescribed β-blockers in the previous year [46]. In light of this, it seems that to have only one fatality that can potentially be linked to use of cardioselective β1-blockers in asthma in the VigiBase database is reassuringly low.
A strength of this review is the use of VigiBase data in addition to the published literature. Given that β-blockers have been available for many years, it is reasonable to expect that any major concerns would turn up on such a reporting system. However, as the VigiBase information comes from a variety of sources, the probability that a suspected adverse effect is drug-related is not the same in all cases. Reports can be submitted by any person – not necessarily a clinician – and most reports of fatal asthma or bronchospasm submitted to VigiBase had minimal clinical information making the correct assignment of the likely association between cardioselective β1-blocker use and asthma fatalities difficult. This variation in clinical information also limited the VigiBase analysis, as we were unable to explore other outcomes such as hospitalisation. Another limitation of the VigiBase data is that of under-reporting, which as a result of fear of litigation, lack of awareness of the reporting system or even the assumption that bronchospasm following β-blocker administration was expected, may prevent some cases from being reported.
Implications for clinical practice
Guidelines have shifted from previously stating that all β-blockers are contraindicated in asthma to recommending that prescription of cardioselective β1-blockers should be done under specialist supervision on a “case-by-case basis” [5]. Nevertheless, concerns over the safety of cardioselective β1-blockers in asthma persist, and this remains a difficult area for prescribers, resulting in underutilisation of β-blockers in people with asthma [47]. Clinically there must be a balance of risk and benefit behind each decision to treat a person with asthma with a β-blocker as outlined in the recent report from the Global Initiative for Asthma (GINA) [48]. If there is a clinical indication and perceived clinical benefit from a β-blocker for a person with asthma, this review suggests that using highly selective β1-blockers, such as bisoprolol, at the lowest effective dose, is likely to minimise the risk of problematic β2-blocking bronchospasm.
Future research
Major studies of the cardiovascular benefits of β-blockers have excluded patients with asthma – the cardiac benefits for these patients can only be extrapolated from studies from which they have been excluded. This should be addressed with future studies including these participants.
To support the safe and appropriate prescribing of cardioselective β1-blockers to a growing cohort of people with asthma and cardiovascular disease, research clarifying to what extent rescue β2-agonist therapy is affected by use of regular cardioselective β1-blocker therapy and understanding of the dose at which each drug becomes insufficiently selective is needed.
Conclusions
The pharmacology of cardioselective β1-blockers indicates that cardioselectivity is not complete. Small reductions in lung function have been observed after single doses in people with asthma, but this adverse effect appears to resolve with continued treatment. Observational studies have found no increase in moderate or severe asthma exacerbations in people with asthma taking regular cardioselective β1-blockers. We found no reports of asthma deaths caused by cardioselective β1-blockers in the published literature and only one possible death that was clearly in an asthmatic patient in the VigiBase data, for which there was insufficient detail to establish clear causality. Absence of evidence of fatal asthma is not necessarily evidence that it does not occur. However, these findings suggest that, despite widespread concerns, fatalities or serious asthma exacerbations due to cardioselective β1-blocker use are likely to be extremely rare. The reluctance to use cardioselective β1-blockers in people with asthma is not supported by this evidence.
Supplementary material
10.1183/23120541.00801-2020.Supp1Please note: supplementary material is not edited by the Editorial Office, and is uploaded as it has been supplied by the author.
Supplementary material 00801-2020.SUPPLEMENT
Acknowledgements
The authors are indebted to the national centres that make up the WHO Programme for International Drug Monitoring and contribute reports to VigiBase. The opinions and conclusions of this study are not necessarily those of the various centres, of the UMC or of the WHO.
This article has supplementary material available from openres.ersjournals.com.
Data availability: Data available from the corresponding author upon reasonable request.
Author contributions: M. Bennett, C. Chang and R. Hancox were involved in the design and review process. M. Tatley and R. Savage were involved in review and data collection from VigiBase.
Conflict of interest: M. Bennett reports grants from Waikato Medical Research Foundation during the conduct of the study.
Conflict of interest: C.L. Chang has nothing to disclose.
Conflict of interest: M. Tatley has nothing to disclose.
Conflict of interest: R. Savage has nothing to disclose.
Conflict of interest: R.J. Hancox reports a proposed research grant on a related topic and travel to meetings supported by GSK, and travel to meetings supported by Boehringer Ingelheim and AstraZeneca, outside the submitted work.
Support statement: This review was funded by the support of the Waikato Respiratory Research Fund and the University of Otago. Funding information for this article has been deposited with the Crossref Funder Registry. | Fatal | ReactionOutcome | CC BY-NC | 33681344 | 19,904,699 | 2021-01 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug ineffective'. | Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report.
Cryptococcosis is frequently found in immunosuppressed patients. It is also a significant opportunistic infection in non-immunocompromised individuals. In this study, we present a rare case of membranous nephropathy (MN) with pulmonary cryptococcosis. A 33-year-old man with MN was referred to our hospital because of dyspnea and weakness for 1 week. Before the above symptoms occurred, the dose of Cyclosporin A was increased again for relapse of MN. Multiple massive or patchy high-density shadows were present on computed tomography of the lung. Initially the patient underwent empirical anti-bacterial therapy, which turned out to be ineffective. As the results of serum cryptococcal latex agglutination tests were positive, the administration of anti-fungal drugs was prescribed. The results of fungal culture and pathologic examination of the lung tissue revealed the findings consistent with Cryptococcus neoformans. The patient was successfully treated with voriconazole followed by fluconazole with satisfactory result. Therefore, in patients with chronic kidney disease, lung lesions with poor bactericidal effects of cephalosporins need further examination to make sure whether there is pulmonary cryptococcosis. Early diagnosis and treatment might contribute to good results. It is a problem worthy of consideration that whether immunosuppressive agents need to be discontinued or not during antifungal therapy.
1 Introduction
Cryptococcosis is a potentially serious fungal disease associated with significant morbidity and mortality [1]. Clinical presentation of cryptococcosis varies from asymptomatic to life-threatening central nervous system (CNS) involvement. Previous large-scale retrospective analyses have shown that pulmonary cryptococcosis occurs predominantly in patients with HIV. Additional predisposing factors include underlying solid organ transplantation [2], aggressive cancer treatment, use of immunosuppressants or glucocorticoids, connective tissue diseases, or conditions that may damage immune function [3,4,5]. There are fewer cases that have been reported to present with chronic kidney disease with pulmonary cryptococcal infection. In this study, we report a case of membranous nephropathy (MN) with pulmonary cryptococcosis.
2 Case report
A 33-year-old man with MN was referred to our hospital in February 2018 because of worsening of dyspnea and weakness for 1 week, not accompanied by cough, sputum, or fever. The patient was given a renal biopsy for nephrotic syndrome and diagnosed with as idiopathic MN (IMN) in May 2008 after excluding tumors, hepatitis, and other factors. Treatment with 60 mg of prednisone daily was started after diagnosis of IMN. Because proteinuria continued, treatment was changed to prednisone 30 mg/day and tripterygium glycosides 60 mg/day in August 2008. Six months after prednisone treatment, the patient developed bilateral femoral head necrosis. Then the treatment regimen was adjusted to Cyclosporin A (CsA) 75 mg/12 h. The patient was treated successfully and then controlled with CsA 75 mg/day till 1 year later. Over the next few years, he experienced recurred albuminuria for several times. Even though he remained stable for about 4 years after his most recent discharge, he still required CsA 25 mg/12 h to control recurrence of his disease. Because proteinuria relapsed, treatment with 75 mg of CsA twice daily was increased again in January 2018 and, 1 month later, dyspnea and shortness of breath occurred. The lung computed tomography (CT) scan in local hospital showed nodules involving the left upper lobe (Figure 1). The dyspnea and shortness of breath worsened in the next days, and the patient was admitted to our hospital on February 8, 2018 for further examination.
Figure 1 Multiple massive or patchy high-density shadows in the left upper lobe of the lung before any treatment (red circle).
On admission, laboratory investigations were as follows: hemoglobin, 13.2 g/dL; hematocrit, 38.4%; platelets, 25.1 × 104/µL; massive proteinuria (5.2 g/day) without hematuria; leukocytes, 7,600/µL (72% neutrophils, 22% lymphocytes); total protein, 5.33 g/dL; albumin, 2.75 g/dL; total cholesterol, 0.27 g/dL; blood urea nitrogen (BUN), 31.7 mg/dL; Scr, 0.92 mg/dL; C3, 131 mg/dL; C4, 32 mg/dL; IgG, 794 mg/dL; IgA, 109 mg/dL; IgM, 165 mg/dL; erythrocyte sedimentation rate (ESR) 41 mm/h. C-reactive protein (CRP) and anti-HIV antibody were negative (Table 1).
Table 1 Laboratory test results before and after treatment
February 9, 2018 February 26, 2018 March 5, 2018
WBC (109/L) 7.6 8 8.8
NE (%) 72 59.3 55.3
LY (%) 22 29.4 31.6
HGB (g/dL) 13.2 12.4 12.7
HCT (%) 38.4 35 37.3
PLT (109/L) 251 297 295
CRP (mg/L) <1 <1 <1
ESR (mm/h) 41 30 6
Anti-HIV1 + 2 Negative — —
TP (g/L) 53.3 59 61.7
ALB (g/L) 27.5 31 32.6
CHOL (mmol/L) 7.01 — —
BUN (mg/dL) 31.7 77.4 84.6
Scr (mg/dL) 0.92 0.67 0.74
C3 (mg/dL) 131 — —
C4 (mg/dL) 32 — —
IgG (mg/dL) 794 — —
IgA (mg/dL) 109 — —
IgM (mg/dL) 165 — —
24 h urine protein (g) 5.2 — 0.336
Sputum bacterial culture Negative — —
Blood cryptococcal antigen — Positive Negative
Treatment with intravenous Piperacillin–Tazobactam was started at a dose of 3.375 g/8 h from February 8 for 1 week. Then chest CT scan was performed and presented no improvement of the nodules involving the left upper lobe (Figure 2a). At this time, serum cryptococcal antigen revealed positive. To confirm the diagnosis, a CT-guided lung biopsy was performed, and fresh lung tissue was submitted for fungal culture. Pathologic examination of the tissue biopsy revealed multiple round shape organisms. The capsules of the observed organisms could be visualized by periodic acid-Schiff (PAS) and periodic acid-silver methenamine (PASM) staining, which is compatible with Cryptococcus spp. (Figure 3). The tissue fungal culture showed Cryptococcus neoformans, and the chest abnormality was diagnosed as pulmonary cryptococcosis. Furthermore, lumbar puncture and examination of cerebrospinal fluid (CSF) were performed. CSF culture for fungus and cryptococcal antigen were all negative.
Figure 2 (a) Multiple massive or patchy high-density shadows in the left upper lobe of the lung. (b) The massive or patchy high-density shadows in the left upper lobe of the lung shrink after treatment for 2 weeks. (c) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for half year. (d) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for 9 months (red circle).
Figure 3 (a) PAS stain of patient’s lung tissue shows many yeast-like cells at 40× magnification (black arrow). (b) PAS-M stain of patient’s lung tissue shows yeast capsules stained in black at 60× magnification (blue arrow).
Voriconazole was administered intravenously at a dose of 200 mg/12 h from February 15 for 1 week, followed by fluconazole at a dose of 200 mg/day from February 22, 2018 for economical reason. Considering the massive proteinuria at this patient, the administration of oral CsA was maintained at a fixed dose of 75 mg/12 h as before hospitalization. On March 1, a second chest CT showed a decrease in the size of the nodule in the area of left upper lobe (Figure 2b) and serum cryptococcal antigen was negative. On the contrary, interestingly, the amount of proteinuria decreased after the initiation of anti-fungal administration, and subsequently normalized. The patient was discharged on March 5 and he took the oral fluconazole tablets at the same dose for 9 months with regular follow-up. The other two chest CT scans in September and December 2018, respectively, revealed complete remission of the lesion in the left upper lobe (Figure 2c and d). To date, relapse of pulmonary cryptococcosis has not been seen in the ambulatory patient.
Ethical approval: The research related to human use has complied with all the relevant national regulations and institutional policies, and is in accordance to the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board or equivalent committee.
Informed consent: Written informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the written consent is available for review by the editor of this journal.
3 Discussion
Cryptococcosis is an opportunistic infectious disease caused by encapsulated yeasts in the genus Cryptococcus. In humans, it is usually caused by the following two subspecies of the Cryptococcus spp. family: C. neoformans and C. gattii [6,7]. C. neoformans can cause cryptococcosis in both immunocompetent and immunocompromised patients, whereas C. gattii usually infects apparently immunocompetent. Once inhaled into the human host, it colonizes the pulmonary system. The infection can either localize or disseminate through blood to various organs, depending on patients’ immune status. In humans, C. neoformans can cause cryptococcal meningitis and wound or cutaneous cryptococcosis except for pulmonary cryptococcosis [8].
In the present case report, the patient was diagnosed as MN and presented with pulmonary cryptococcosis caused by C. neoformans without cryptococcal meningitis or cutaneous cryptococcosis. The reports of pulmonary fungal infection in patients with kidney disease are increasing in recent years, for example, kidney transplant patients [9]. The confirmed risk factors cited for fungal infection in kidney transplant patients include demographic (race and older age), medication-associated (immunosuppressive agents), and clinical data (diabetes, urinary tract infection, bacterial pneumonia, bacteremia, and leukopenia/pancytopenia), as well as organism-specific factors [9]. Wang et al. concluded that immunoglobulin G titer, plasma CsA concentration, serum creatinine level, CD4+/CD8+ ratio, and plasma albumin level were the risk factors of pulmonary infection in primary MN receiving CysA [10]. In recent years, there are some reports of fungal infection in dialysis patients [11] as well as in non-dialyzing uremia [12,13]. Abbott reported that diabetes, female patients, decreasedweight, serum creatinine at initial of dialysis, chronic obstructive lung disease, and AIDS were associated with fungal infection in dialysis patients [11]. Only a few reports have described the relationship between glomerular diseases with or without nephrotic syndrome and fungal infections, e.g., minor glomerular abnormality associated with pulmonary cryptococcosis [14], membranoproliferative glomerulonephritis with Candida endocrinopathy [15], crescentic glomerulonephritis with pulmonary aspergillosis [16], necrotizing glomerulonephritis with pulmonary cryptococcosis [17], and minimal change nephrotic syndrome with cutaneous cryptococcosis published in recent years [18]. In our case, the patient lived in the countryside near mountains, and 6 months before the onset of his chest tightness and shortness of breath, he hunted pheasants many times. His cryptococcosis may be related to this kind of wild bird. Besides, he had been taking oral immunosuppressive agents for more than 10 years, which may cause an immunocompromised host and can be associated with the infectious diseases. Combined with nephrotic syndrome and hypoproteinemia, the malnutrition may also contribute to the patient’s pathological condition. Accordingly, the patient’s definite cause of the development of pulmonary cryptococcosis remains unknown.
What needs to be mentioned is that the correlation between different immunosuppressive agents and cryptococcal infection is distinct. Some studies show that not all immunosuppressive agents would increase the incidence of cryptococcal infection. Mody et al. demonstrated that CsA treatment of mice enhanced survival after inoculation of Cryptococcus neoformans by both the intratracheal (IT) and intravenous (IV) routes [19]. Next year he demonstrated that CsA was effective for the treatment of extraneural cryptococcal infection in normal mice [20]. Odom et al. found that growth of the opportunistic fungal pathogen Cryptococcus neoformans was sensitive to CsA and FK506 at 37°C but not at 24°C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature [21]. These findings identify CsA as a potential antifungal drug. However, CsA was also reported to exacerbate cryptococcal meningitis in both mice and rabbits, most likely because CsA does not effectively penetrate the CNS [21,22]. Complex phenomena require more in-depth research to clarify. Leitheiser et al. assessed the risk factors associated with invasive fungal infections in kidney transplant patients, which suggested that CsA were not associated with increased risk for any patients, neither in Histoplasmosis and Aspergillosis groups nor in Candida, Cryptococcosis, and “Other” mycoses groups [9]. However, Wang and his colleagues reported that the plasma concentration of CsA was associated with pulmonary infections [10].
According to the related article for the management of pulmonary cryptococcosis in asymptomatic non-immunosuppressed patients, localized cryptococcal infection can be treated with fluconazole alone (200–400 mg/day orally) for 6 months [23]. For mild-to-moderate symptoms, administer fluconazole (400 mg/day orally) for 6–12 months. Persistently positive of serum cryptococcal antigen titers are not criteria for continuance of therapy. For severe disease, treatment is similar to disseminated cryptococcosis, as follows: the treatment is divided into induction therapy, consolidation therapy, and maintenance therapy. Induction therapy with amphotericin B deoxycholate (AmBD) 0.5–1.0 mg/kg/day plus flucytosine (100 mg/kg/day) for at least 4 weeks, followed by consolidation therapy with fluconazole (400 mg/day orally) for 8 weeks, and maintenance therapy with fluconazole (200 mg/day) for a total duration of 6–12 months [1]. We treated the patient with fluconazole alone (200 mg/day) for nearly 9 months and saw a rapid clinical response to fluconazole. Interestingly, the decrease in the severity of proteinuria was in parallel with improvement of pulmonary cryptococcosis.
In the case, the MN of this patient was a unique aspect. Proteinuria relapsed 1 month before the cryptococcal infection, and proteinuria remission almost coincided with the lung infection control. Whether some causal relationship exits is not clear. Probably, the relapse of nephrotic syndrome in this case is related to cryptococcal infection. It could not be demonstrated because the dose of CsA did not change in the whole course of antifungal treatment. Kidney biopsy puncture could be the useful method to clarify the causal relationship if cryptococcal antigens are found in kidney tissue. To provide the best treatment, more careful clinical consideration and study are needed when encountering similar problems in the future.
Acknowledgments
This work was supported by grants from National Natural Science Foundation of China (Dr Zhang, 81603572), Zhejiang Provincial Natural Science Foundation of China (Dr Xia, LQ19H290003), Project of Administration of Traditional Chinese Medicine of Zhejiang Province of China (Dr Xia, 2017ZA053), and Foundation of Zhejiang Chinese Medical University (Dr Xia, 2018ZG04).
Conflict of interest: The authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE | DrugsGivenReaction | CC BY | 33681469 | 19,379,027 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Osteonecrosis'. | Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report.
Cryptococcosis is frequently found in immunosuppressed patients. It is also a significant opportunistic infection in non-immunocompromised individuals. In this study, we present a rare case of membranous nephropathy (MN) with pulmonary cryptococcosis. A 33-year-old man with MN was referred to our hospital because of dyspnea and weakness for 1 week. Before the above symptoms occurred, the dose of Cyclosporin A was increased again for relapse of MN. Multiple massive or patchy high-density shadows were present on computed tomography of the lung. Initially the patient underwent empirical anti-bacterial therapy, which turned out to be ineffective. As the results of serum cryptococcal latex agglutination tests were positive, the administration of anti-fungal drugs was prescribed. The results of fungal culture and pathologic examination of the lung tissue revealed the findings consistent with Cryptococcus neoformans. The patient was successfully treated with voriconazole followed by fluconazole with satisfactory result. Therefore, in patients with chronic kidney disease, lung lesions with poor bactericidal effects of cephalosporins need further examination to make sure whether there is pulmonary cryptococcosis. Early diagnosis and treatment might contribute to good results. It is a problem worthy of consideration that whether immunosuppressive agents need to be discontinued or not during antifungal therapy.
1 Introduction
Cryptococcosis is a potentially serious fungal disease associated with significant morbidity and mortality [1]. Clinical presentation of cryptococcosis varies from asymptomatic to life-threatening central nervous system (CNS) involvement. Previous large-scale retrospective analyses have shown that pulmonary cryptococcosis occurs predominantly in patients with HIV. Additional predisposing factors include underlying solid organ transplantation [2], aggressive cancer treatment, use of immunosuppressants or glucocorticoids, connective tissue diseases, or conditions that may damage immune function [3,4,5]. There are fewer cases that have been reported to present with chronic kidney disease with pulmonary cryptococcal infection. In this study, we report a case of membranous nephropathy (MN) with pulmonary cryptococcosis.
2 Case report
A 33-year-old man with MN was referred to our hospital in February 2018 because of worsening of dyspnea and weakness for 1 week, not accompanied by cough, sputum, or fever. The patient was given a renal biopsy for nephrotic syndrome and diagnosed with as idiopathic MN (IMN) in May 2008 after excluding tumors, hepatitis, and other factors. Treatment with 60 mg of prednisone daily was started after diagnosis of IMN. Because proteinuria continued, treatment was changed to prednisone 30 mg/day and tripterygium glycosides 60 mg/day in August 2008. Six months after prednisone treatment, the patient developed bilateral femoral head necrosis. Then the treatment regimen was adjusted to Cyclosporin A (CsA) 75 mg/12 h. The patient was treated successfully and then controlled with CsA 75 mg/day till 1 year later. Over the next few years, he experienced recurred albuminuria for several times. Even though he remained stable for about 4 years after his most recent discharge, he still required CsA 25 mg/12 h to control recurrence of his disease. Because proteinuria relapsed, treatment with 75 mg of CsA twice daily was increased again in January 2018 and, 1 month later, dyspnea and shortness of breath occurred. The lung computed tomography (CT) scan in local hospital showed nodules involving the left upper lobe (Figure 1). The dyspnea and shortness of breath worsened in the next days, and the patient was admitted to our hospital on February 8, 2018 for further examination.
Figure 1 Multiple massive or patchy high-density shadows in the left upper lobe of the lung before any treatment (red circle).
On admission, laboratory investigations were as follows: hemoglobin, 13.2 g/dL; hematocrit, 38.4%; platelets, 25.1 × 104/µL; massive proteinuria (5.2 g/day) without hematuria; leukocytes, 7,600/µL (72% neutrophils, 22% lymphocytes); total protein, 5.33 g/dL; albumin, 2.75 g/dL; total cholesterol, 0.27 g/dL; blood urea nitrogen (BUN), 31.7 mg/dL; Scr, 0.92 mg/dL; C3, 131 mg/dL; C4, 32 mg/dL; IgG, 794 mg/dL; IgA, 109 mg/dL; IgM, 165 mg/dL; erythrocyte sedimentation rate (ESR) 41 mm/h. C-reactive protein (CRP) and anti-HIV antibody were negative (Table 1).
Table 1 Laboratory test results before and after treatment
February 9, 2018 February 26, 2018 March 5, 2018
WBC (109/L) 7.6 8 8.8
NE (%) 72 59.3 55.3
LY (%) 22 29.4 31.6
HGB (g/dL) 13.2 12.4 12.7
HCT (%) 38.4 35 37.3
PLT (109/L) 251 297 295
CRP (mg/L) <1 <1 <1
ESR (mm/h) 41 30 6
Anti-HIV1 + 2 Negative — —
TP (g/L) 53.3 59 61.7
ALB (g/L) 27.5 31 32.6
CHOL (mmol/L) 7.01 — —
BUN (mg/dL) 31.7 77.4 84.6
Scr (mg/dL) 0.92 0.67 0.74
C3 (mg/dL) 131 — —
C4 (mg/dL) 32 — —
IgG (mg/dL) 794 — —
IgA (mg/dL) 109 — —
IgM (mg/dL) 165 — —
24 h urine protein (g) 5.2 — 0.336
Sputum bacterial culture Negative — —
Blood cryptococcal antigen — Positive Negative
Treatment with intravenous Piperacillin–Tazobactam was started at a dose of 3.375 g/8 h from February 8 for 1 week. Then chest CT scan was performed and presented no improvement of the nodules involving the left upper lobe (Figure 2a). At this time, serum cryptococcal antigen revealed positive. To confirm the diagnosis, a CT-guided lung biopsy was performed, and fresh lung tissue was submitted for fungal culture. Pathologic examination of the tissue biopsy revealed multiple round shape organisms. The capsules of the observed organisms could be visualized by periodic acid-Schiff (PAS) and periodic acid-silver methenamine (PASM) staining, which is compatible with Cryptococcus spp. (Figure 3). The tissue fungal culture showed Cryptococcus neoformans, and the chest abnormality was diagnosed as pulmonary cryptococcosis. Furthermore, lumbar puncture and examination of cerebrospinal fluid (CSF) were performed. CSF culture for fungus and cryptococcal antigen were all negative.
Figure 2 (a) Multiple massive or patchy high-density shadows in the left upper lobe of the lung. (b) The massive or patchy high-density shadows in the left upper lobe of the lung shrink after treatment for 2 weeks. (c) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for half year. (d) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for 9 months (red circle).
Figure 3 (a) PAS stain of patient’s lung tissue shows many yeast-like cells at 40× magnification (black arrow). (b) PAS-M stain of patient’s lung tissue shows yeast capsules stained in black at 60× magnification (blue arrow).
Voriconazole was administered intravenously at a dose of 200 mg/12 h from February 15 for 1 week, followed by fluconazole at a dose of 200 mg/day from February 22, 2018 for economical reason. Considering the massive proteinuria at this patient, the administration of oral CsA was maintained at a fixed dose of 75 mg/12 h as before hospitalization. On March 1, a second chest CT showed a decrease in the size of the nodule in the area of left upper lobe (Figure 2b) and serum cryptococcal antigen was negative. On the contrary, interestingly, the amount of proteinuria decreased after the initiation of anti-fungal administration, and subsequently normalized. The patient was discharged on March 5 and he took the oral fluconazole tablets at the same dose for 9 months with regular follow-up. The other two chest CT scans in September and December 2018, respectively, revealed complete remission of the lesion in the left upper lobe (Figure 2c and d). To date, relapse of pulmonary cryptococcosis has not been seen in the ambulatory patient.
Ethical approval: The research related to human use has complied with all the relevant national regulations and institutional policies, and is in accordance to the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board or equivalent committee.
Informed consent: Written informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the written consent is available for review by the editor of this journal.
3 Discussion
Cryptococcosis is an opportunistic infectious disease caused by encapsulated yeasts in the genus Cryptococcus. In humans, it is usually caused by the following two subspecies of the Cryptococcus spp. family: C. neoformans and C. gattii [6,7]. C. neoformans can cause cryptococcosis in both immunocompetent and immunocompromised patients, whereas C. gattii usually infects apparently immunocompetent. Once inhaled into the human host, it colonizes the pulmonary system. The infection can either localize or disseminate through blood to various organs, depending on patients’ immune status. In humans, C. neoformans can cause cryptococcal meningitis and wound or cutaneous cryptococcosis except for pulmonary cryptococcosis [8].
In the present case report, the patient was diagnosed as MN and presented with pulmonary cryptococcosis caused by C. neoformans without cryptococcal meningitis or cutaneous cryptococcosis. The reports of pulmonary fungal infection in patients with kidney disease are increasing in recent years, for example, kidney transplant patients [9]. The confirmed risk factors cited for fungal infection in kidney transplant patients include demographic (race and older age), medication-associated (immunosuppressive agents), and clinical data (diabetes, urinary tract infection, bacterial pneumonia, bacteremia, and leukopenia/pancytopenia), as well as organism-specific factors [9]. Wang et al. concluded that immunoglobulin G titer, plasma CsA concentration, serum creatinine level, CD4+/CD8+ ratio, and plasma albumin level were the risk factors of pulmonary infection in primary MN receiving CysA [10]. In recent years, there are some reports of fungal infection in dialysis patients [11] as well as in non-dialyzing uremia [12,13]. Abbott reported that diabetes, female patients, decreasedweight, serum creatinine at initial of dialysis, chronic obstructive lung disease, and AIDS were associated with fungal infection in dialysis patients [11]. Only a few reports have described the relationship between glomerular diseases with or without nephrotic syndrome and fungal infections, e.g., minor glomerular abnormality associated with pulmonary cryptococcosis [14], membranoproliferative glomerulonephritis with Candida endocrinopathy [15], crescentic glomerulonephritis with pulmonary aspergillosis [16], necrotizing glomerulonephritis with pulmonary cryptococcosis [17], and minimal change nephrotic syndrome with cutaneous cryptococcosis published in recent years [18]. In our case, the patient lived in the countryside near mountains, and 6 months before the onset of his chest tightness and shortness of breath, he hunted pheasants many times. His cryptococcosis may be related to this kind of wild bird. Besides, he had been taking oral immunosuppressive agents for more than 10 years, which may cause an immunocompromised host and can be associated with the infectious diseases. Combined with nephrotic syndrome and hypoproteinemia, the malnutrition may also contribute to the patient’s pathological condition. Accordingly, the patient’s definite cause of the development of pulmonary cryptococcosis remains unknown.
What needs to be mentioned is that the correlation between different immunosuppressive agents and cryptococcal infection is distinct. Some studies show that not all immunosuppressive agents would increase the incidence of cryptococcal infection. Mody et al. demonstrated that CsA treatment of mice enhanced survival after inoculation of Cryptococcus neoformans by both the intratracheal (IT) and intravenous (IV) routes [19]. Next year he demonstrated that CsA was effective for the treatment of extraneural cryptococcal infection in normal mice [20]. Odom et al. found that growth of the opportunistic fungal pathogen Cryptococcus neoformans was sensitive to CsA and FK506 at 37°C but not at 24°C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature [21]. These findings identify CsA as a potential antifungal drug. However, CsA was also reported to exacerbate cryptococcal meningitis in both mice and rabbits, most likely because CsA does not effectively penetrate the CNS [21,22]. Complex phenomena require more in-depth research to clarify. Leitheiser et al. assessed the risk factors associated with invasive fungal infections in kidney transplant patients, which suggested that CsA were not associated with increased risk for any patients, neither in Histoplasmosis and Aspergillosis groups nor in Candida, Cryptococcosis, and “Other” mycoses groups [9]. However, Wang and his colleagues reported that the plasma concentration of CsA was associated with pulmonary infections [10].
According to the related article for the management of pulmonary cryptococcosis in asymptomatic non-immunosuppressed patients, localized cryptococcal infection can be treated with fluconazole alone (200–400 mg/day orally) for 6 months [23]. For mild-to-moderate symptoms, administer fluconazole (400 mg/day orally) for 6–12 months. Persistently positive of serum cryptococcal antigen titers are not criteria for continuance of therapy. For severe disease, treatment is similar to disseminated cryptococcosis, as follows: the treatment is divided into induction therapy, consolidation therapy, and maintenance therapy. Induction therapy with amphotericin B deoxycholate (AmBD) 0.5–1.0 mg/kg/day plus flucytosine (100 mg/kg/day) for at least 4 weeks, followed by consolidation therapy with fluconazole (400 mg/day orally) for 8 weeks, and maintenance therapy with fluconazole (200 mg/day) for a total duration of 6–12 months [1]. We treated the patient with fluconazole alone (200 mg/day) for nearly 9 months and saw a rapid clinical response to fluconazole. Interestingly, the decrease in the severity of proteinuria was in parallel with improvement of pulmonary cryptococcosis.
In the case, the MN of this patient was a unique aspect. Proteinuria relapsed 1 month before the cryptococcal infection, and proteinuria remission almost coincided with the lung infection control. Whether some causal relationship exits is not clear. Probably, the relapse of nephrotic syndrome in this case is related to cryptococcal infection. It could not be demonstrated because the dose of CsA did not change in the whole course of antifungal treatment. Kidney biopsy puncture could be the useful method to clarify the causal relationship if cryptococcal antigens are found in kidney tissue. To provide the best treatment, more careful clinical consideration and study are needed when encountering similar problems in the future.
Acknowledgments
This work was supported by grants from National Natural Science Foundation of China (Dr Zhang, 81603572), Zhejiang Provincial Natural Science Foundation of China (Dr Xia, LQ19H290003), Project of Administration of Traditional Chinese Medicine of Zhejiang Province of China (Dr Xia, 2017ZA053), and Foundation of Zhejiang Chinese Medical University (Dr Xia, 2018ZG04).
Conflict of interest: The authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PIPERACILLIN SODIUM\TAZOBACTAM SODIUM, PREDNISONE | DrugsGivenReaction | CC BY | 33681469 | 19,379,027 | 2021 |
What was the administration route of drug 'PIPERACILLIN SODIUM\TAZOBACTAM SODIUM'? | Membranous nephropathy with pulmonary cryptococcosis with improved 1-year follow-up results: A case report.
Cryptococcosis is frequently found in immunosuppressed patients. It is also a significant opportunistic infection in non-immunocompromised individuals. In this study, we present a rare case of membranous nephropathy (MN) with pulmonary cryptococcosis. A 33-year-old man with MN was referred to our hospital because of dyspnea and weakness for 1 week. Before the above symptoms occurred, the dose of Cyclosporin A was increased again for relapse of MN. Multiple massive or patchy high-density shadows were present on computed tomography of the lung. Initially the patient underwent empirical anti-bacterial therapy, which turned out to be ineffective. As the results of serum cryptococcal latex agglutination tests were positive, the administration of anti-fungal drugs was prescribed. The results of fungal culture and pathologic examination of the lung tissue revealed the findings consistent with Cryptococcus neoformans. The patient was successfully treated with voriconazole followed by fluconazole with satisfactory result. Therefore, in patients with chronic kidney disease, lung lesions with poor bactericidal effects of cephalosporins need further examination to make sure whether there is pulmonary cryptococcosis. Early diagnosis and treatment might contribute to good results. It is a problem worthy of consideration that whether immunosuppressive agents need to be discontinued or not during antifungal therapy.
1 Introduction
Cryptococcosis is a potentially serious fungal disease associated with significant morbidity and mortality [1]. Clinical presentation of cryptococcosis varies from asymptomatic to life-threatening central nervous system (CNS) involvement. Previous large-scale retrospective analyses have shown that pulmonary cryptococcosis occurs predominantly in patients with HIV. Additional predisposing factors include underlying solid organ transplantation [2], aggressive cancer treatment, use of immunosuppressants or glucocorticoids, connective tissue diseases, or conditions that may damage immune function [3,4,5]. There are fewer cases that have been reported to present with chronic kidney disease with pulmonary cryptococcal infection. In this study, we report a case of membranous nephropathy (MN) with pulmonary cryptococcosis.
2 Case report
A 33-year-old man with MN was referred to our hospital in February 2018 because of worsening of dyspnea and weakness for 1 week, not accompanied by cough, sputum, or fever. The patient was given a renal biopsy for nephrotic syndrome and diagnosed with as idiopathic MN (IMN) in May 2008 after excluding tumors, hepatitis, and other factors. Treatment with 60 mg of prednisone daily was started after diagnosis of IMN. Because proteinuria continued, treatment was changed to prednisone 30 mg/day and tripterygium glycosides 60 mg/day in August 2008. Six months after prednisone treatment, the patient developed bilateral femoral head necrosis. Then the treatment regimen was adjusted to Cyclosporin A (CsA) 75 mg/12 h. The patient was treated successfully and then controlled with CsA 75 mg/day till 1 year later. Over the next few years, he experienced recurred albuminuria for several times. Even though he remained stable for about 4 years after his most recent discharge, he still required CsA 25 mg/12 h to control recurrence of his disease. Because proteinuria relapsed, treatment with 75 mg of CsA twice daily was increased again in January 2018 and, 1 month later, dyspnea and shortness of breath occurred. The lung computed tomography (CT) scan in local hospital showed nodules involving the left upper lobe (Figure 1). The dyspnea and shortness of breath worsened in the next days, and the patient was admitted to our hospital on February 8, 2018 for further examination.
Figure 1 Multiple massive or patchy high-density shadows in the left upper lobe of the lung before any treatment (red circle).
On admission, laboratory investigations were as follows: hemoglobin, 13.2 g/dL; hematocrit, 38.4%; platelets, 25.1 × 104/µL; massive proteinuria (5.2 g/day) without hematuria; leukocytes, 7,600/µL (72% neutrophils, 22% lymphocytes); total protein, 5.33 g/dL; albumin, 2.75 g/dL; total cholesterol, 0.27 g/dL; blood urea nitrogen (BUN), 31.7 mg/dL; Scr, 0.92 mg/dL; C3, 131 mg/dL; C4, 32 mg/dL; IgG, 794 mg/dL; IgA, 109 mg/dL; IgM, 165 mg/dL; erythrocyte sedimentation rate (ESR) 41 mm/h. C-reactive protein (CRP) and anti-HIV antibody were negative (Table 1).
Table 1 Laboratory test results before and after treatment
February 9, 2018 February 26, 2018 March 5, 2018
WBC (109/L) 7.6 8 8.8
NE (%) 72 59.3 55.3
LY (%) 22 29.4 31.6
HGB (g/dL) 13.2 12.4 12.7
HCT (%) 38.4 35 37.3
PLT (109/L) 251 297 295
CRP (mg/L) <1 <1 <1
ESR (mm/h) 41 30 6
Anti-HIV1 + 2 Negative — —
TP (g/L) 53.3 59 61.7
ALB (g/L) 27.5 31 32.6
CHOL (mmol/L) 7.01 — —
BUN (mg/dL) 31.7 77.4 84.6
Scr (mg/dL) 0.92 0.67 0.74
C3 (mg/dL) 131 — —
C4 (mg/dL) 32 — —
IgG (mg/dL) 794 — —
IgA (mg/dL) 109 — —
IgM (mg/dL) 165 — —
24 h urine protein (g) 5.2 — 0.336
Sputum bacterial culture Negative — —
Blood cryptococcal antigen — Positive Negative
Treatment with intravenous Piperacillin–Tazobactam was started at a dose of 3.375 g/8 h from February 8 for 1 week. Then chest CT scan was performed and presented no improvement of the nodules involving the left upper lobe (Figure 2a). At this time, serum cryptococcal antigen revealed positive. To confirm the diagnosis, a CT-guided lung biopsy was performed, and fresh lung tissue was submitted for fungal culture. Pathologic examination of the tissue biopsy revealed multiple round shape organisms. The capsules of the observed organisms could be visualized by periodic acid-Schiff (PAS) and periodic acid-silver methenamine (PASM) staining, which is compatible with Cryptococcus spp. (Figure 3). The tissue fungal culture showed Cryptococcus neoformans, and the chest abnormality was diagnosed as pulmonary cryptococcosis. Furthermore, lumbar puncture and examination of cerebrospinal fluid (CSF) were performed. CSF culture for fungus and cryptococcal antigen were all negative.
Figure 2 (a) Multiple massive or patchy high-density shadows in the left upper lobe of the lung. (b) The massive or patchy high-density shadows in the left upper lobe of the lung shrink after treatment for 2 weeks. (c) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for half year. (d) The massive or patchy high-density shadows in the left upper lobe of the lung disappear after treatment for 9 months (red circle).
Figure 3 (a) PAS stain of patient’s lung tissue shows many yeast-like cells at 40× magnification (black arrow). (b) PAS-M stain of patient’s lung tissue shows yeast capsules stained in black at 60× magnification (blue arrow).
Voriconazole was administered intravenously at a dose of 200 mg/12 h from February 15 for 1 week, followed by fluconazole at a dose of 200 mg/day from February 22, 2018 for economical reason. Considering the massive proteinuria at this patient, the administration of oral CsA was maintained at a fixed dose of 75 mg/12 h as before hospitalization. On March 1, a second chest CT showed a decrease in the size of the nodule in the area of left upper lobe (Figure 2b) and serum cryptococcal antigen was negative. On the contrary, interestingly, the amount of proteinuria decreased after the initiation of anti-fungal administration, and subsequently normalized. The patient was discharged on March 5 and he took the oral fluconazole tablets at the same dose for 9 months with regular follow-up. The other two chest CT scans in September and December 2018, respectively, revealed complete remission of the lesion in the left upper lobe (Figure 2c and d). To date, relapse of pulmonary cryptococcosis has not been seen in the ambulatory patient.
Ethical approval: The research related to human use has complied with all the relevant national regulations and institutional policies, and is in accordance to the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board or equivalent committee.
Informed consent: Written informed consent was obtained from the patient for publication of this case report and all accompanying images. A copy of the written consent is available for review by the editor of this journal.
3 Discussion
Cryptococcosis is an opportunistic infectious disease caused by encapsulated yeasts in the genus Cryptococcus. In humans, it is usually caused by the following two subspecies of the Cryptococcus spp. family: C. neoformans and C. gattii [6,7]. C. neoformans can cause cryptococcosis in both immunocompetent and immunocompromised patients, whereas C. gattii usually infects apparently immunocompetent. Once inhaled into the human host, it colonizes the pulmonary system. The infection can either localize or disseminate through blood to various organs, depending on patients’ immune status. In humans, C. neoformans can cause cryptococcal meningitis and wound or cutaneous cryptococcosis except for pulmonary cryptococcosis [8].
In the present case report, the patient was diagnosed as MN and presented with pulmonary cryptococcosis caused by C. neoformans without cryptococcal meningitis or cutaneous cryptococcosis. The reports of pulmonary fungal infection in patients with kidney disease are increasing in recent years, for example, kidney transplant patients [9]. The confirmed risk factors cited for fungal infection in kidney transplant patients include demographic (race and older age), medication-associated (immunosuppressive agents), and clinical data (diabetes, urinary tract infection, bacterial pneumonia, bacteremia, and leukopenia/pancytopenia), as well as organism-specific factors [9]. Wang et al. concluded that immunoglobulin G titer, plasma CsA concentration, serum creatinine level, CD4+/CD8+ ratio, and plasma albumin level were the risk factors of pulmonary infection in primary MN receiving CysA [10]. In recent years, there are some reports of fungal infection in dialysis patients [11] as well as in non-dialyzing uremia [12,13]. Abbott reported that diabetes, female patients, decreasedweight, serum creatinine at initial of dialysis, chronic obstructive lung disease, and AIDS were associated with fungal infection in dialysis patients [11]. Only a few reports have described the relationship between glomerular diseases with or without nephrotic syndrome and fungal infections, e.g., minor glomerular abnormality associated with pulmonary cryptococcosis [14], membranoproliferative glomerulonephritis with Candida endocrinopathy [15], crescentic glomerulonephritis with pulmonary aspergillosis [16], necrotizing glomerulonephritis with pulmonary cryptococcosis [17], and minimal change nephrotic syndrome with cutaneous cryptococcosis published in recent years [18]. In our case, the patient lived in the countryside near mountains, and 6 months before the onset of his chest tightness and shortness of breath, he hunted pheasants many times. His cryptococcosis may be related to this kind of wild bird. Besides, he had been taking oral immunosuppressive agents for more than 10 years, which may cause an immunocompromised host and can be associated with the infectious diseases. Combined with nephrotic syndrome and hypoproteinemia, the malnutrition may also contribute to the patient’s pathological condition. Accordingly, the patient’s definite cause of the development of pulmonary cryptococcosis remains unknown.
What needs to be mentioned is that the correlation between different immunosuppressive agents and cryptococcal infection is distinct. Some studies show that not all immunosuppressive agents would increase the incidence of cryptococcal infection. Mody et al. demonstrated that CsA treatment of mice enhanced survival after inoculation of Cryptococcus neoformans by both the intratracheal (IT) and intravenous (IV) routes [19]. Next year he demonstrated that CsA was effective for the treatment of extraneural cryptococcal infection in normal mice [20]. Odom et al. found that growth of the opportunistic fungal pathogen Cryptococcus neoformans was sensitive to CsA and FK506 at 37°C but not at 24°C, suggesting that CsA and FK506 inhibit a protein required for C. neoformans growth at elevated temperature [21]. These findings identify CsA as a potential antifungal drug. However, CsA was also reported to exacerbate cryptococcal meningitis in both mice and rabbits, most likely because CsA does not effectively penetrate the CNS [21,22]. Complex phenomena require more in-depth research to clarify. Leitheiser et al. assessed the risk factors associated with invasive fungal infections in kidney transplant patients, which suggested that CsA were not associated with increased risk for any patients, neither in Histoplasmosis and Aspergillosis groups nor in Candida, Cryptococcosis, and “Other” mycoses groups [9]. However, Wang and his colleagues reported that the plasma concentration of CsA was associated with pulmonary infections [10].
According to the related article for the management of pulmonary cryptococcosis in asymptomatic non-immunosuppressed patients, localized cryptococcal infection can be treated with fluconazole alone (200–400 mg/day orally) for 6 months [23]. For mild-to-moderate symptoms, administer fluconazole (400 mg/day orally) for 6–12 months. Persistently positive of serum cryptococcal antigen titers are not criteria for continuance of therapy. For severe disease, treatment is similar to disseminated cryptococcosis, as follows: the treatment is divided into induction therapy, consolidation therapy, and maintenance therapy. Induction therapy with amphotericin B deoxycholate (AmBD) 0.5–1.0 mg/kg/day plus flucytosine (100 mg/kg/day) for at least 4 weeks, followed by consolidation therapy with fluconazole (400 mg/day orally) for 8 weeks, and maintenance therapy with fluconazole (200 mg/day) for a total duration of 6–12 months [1]. We treated the patient with fluconazole alone (200 mg/day) for nearly 9 months and saw a rapid clinical response to fluconazole. Interestingly, the decrease in the severity of proteinuria was in parallel with improvement of pulmonary cryptococcosis.
In the case, the MN of this patient was a unique aspect. Proteinuria relapsed 1 month before the cryptococcal infection, and proteinuria remission almost coincided with the lung infection control. Whether some causal relationship exits is not clear. Probably, the relapse of nephrotic syndrome in this case is related to cryptococcal infection. It could not be demonstrated because the dose of CsA did not change in the whole course of antifungal treatment. Kidney biopsy puncture could be the useful method to clarify the causal relationship if cryptococcal antigens are found in kidney tissue. To provide the best treatment, more careful clinical consideration and study are needed when encountering similar problems in the future.
Acknowledgments
This work was supported by grants from National Natural Science Foundation of China (Dr Zhang, 81603572), Zhejiang Provincial Natural Science Foundation of China (Dr Xia, LQ19H290003), Project of Administration of Traditional Chinese Medicine of Zhejiang Province of China (Dr Xia, 2017ZA053), and Foundation of Zhejiang Chinese Medical University (Dr Xia, 2018ZG04).
Conflict of interest: The authors state no conflict of interest.
Data availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681469 | 19,379,027 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'No adverse event'. | Altered Cholesterol Biosynthesis Affects Drug Metabolism.
The last step of cholesterol biosynthesis is the conversion of 7-dehydrocholesterol (7-DHC) into cholesterol, a reaction catalyzed by dehydrocholesterol reductase 7 (DHCR7). Investigation of the effect of Dhcr7 single-allele mutations on the metabolism of aripiprazole (ARI) and cariprazine (CAR) in maternally exposed transgenic pups revealed that ARI, CAR, and their active metabolites were decreased in the liver and brain of Dhcr7 . This difference in the drug and metabolite levels resulted in an increased turnover of ARI and CAR in tissues from Dhcr7 animals, indicating an enhanced metabolism, which was at least partially due to increased levels of Cyp2d6 in the liver of Dhcr7 mice. Finally, experiments with both WT and DHCR7 human fibroblasts revealed lower drug levels in DHCR7 heterozygous cells. Our findings have potential clinical implications, as DHCR7 heterozygosity is present in 1-3% in the human population, and these individuals might have reduced therapeutic levels of Cyp2d6-metabolized medications and are putatively more susceptible to unwanted side effects.
Introduction
Cholesterol biosynthesis is a complex process that makes cholesterol from acetyl-CoA.1 The last step of the pathway consists of the conversion of 7-dehydrocholesterol (7-DHC) into cholesterol, a step catalyzed by the enzyme dehydrocholesterol reductase 7 (DHCR7).1 It is estimated that 1–3% of the human population carries single-allele mutations in the DHCR7 gene.2 However, despite the high prevalence of DHCR7 heterozygous carriers in the human population, very little is known about the biological consequences of these single-allele mutations. It is known that Dhcr7+/– mice have higher 7-DHC levels than Dhcr7+/+ animals in all tissues and circulation.3−5 Similarly, 7-DHC is elevated in fibroblasts from DHCR7+/– when compared to DHCR7+/+, suggesting that animal observations translate to human physiology.6Dhcr7 heterozygosity has effects beyond biochemistry. Behavioral studies comparing the number and duration of ultrasonic vocalizations (USVs) between WT and Dhcr7+/– mice found that heterozygous animals made fewer and shorter USV calls than the WT animals.7
Many FDA-approved pharmaceuticals have a side effect of DHCR7 enzymatic activity inhibition.8−10 Aripiprazole (ARI) and cariprazine (CAR), two atypical antipsychotics, are among the most potent DHCR7 inhibitors, strongly elevating 7-DHC levels.10 This chemical inhibition of the DHCR7 enzyme can have profound consequences, as 7-DHC-derived oxysterols are cytotoxic. A 2016 review by Boland and Tatonetti demonstrates that first-trimester exposure to DHCR7 inhibitors results in outcomes similar to those of known teratogens and that DHCR7 activity should be considered during drug development and prenatal toxicity assessment.11 A set of recent studies revealed that Dhcr7+/– animals and DHCR7+/– human fibroblasts respond differently to inhibitors of the DHCR7 enzyme.3,4,6Dhcr7 heterozygosity by itself leads only to a small increase in 7-DHC levels,5 but a combination of both inhibitory insults (genetic and chemical) results in a robust elevation in 7-DHC. When subjected to the same dose of Dhcr7 inhibitors, heterozygous animals (or cells) have much higher 7-DHC elevation than those with a WT genotype, indicating a drug × gene interaction and a higher vulnerability of the Dhcr7+/– genotype to the inhibitors.3,4,6
This drug × gene interaction appears to be of particular importance during development. We recently evaluated sterol levels in the brains of offspring maternally exposed to ARI and CAR. We found that offsprings’ brains with a Dhcr7+/– genotype, when maternally exposed to CAR or ARI, have 7-DHC levels comparable to those detected in mild cases of the Smith–Lemli–Optiz Syndrome (SLOS), a neurodevelopmental disorder caused by mutations in both DHCR7 alleles.3,4 In addition, we observed that levels of CAR and its metabolites were significantly lower in Dhcr7+/– pups compared to their WT littermates, which suggests that WT and Dhcr7+/– mice may metabolize the drugs differently.
The metabolism and clearance of antipsychotics is complex and the entire mechanism is not fully understood. They are primarily cleared by hepatic metabolism with enzymes in the cytochrome P450 superfamily (CYPs).12,13 Most CYPs are abundantly expressed in the liver, with some isoforms present in other organs.13,14 ARI and CAR are cleared by multiple CYP isoforms (Figure 1).12,15−18 ARI is converted by CYP2D6 into D-ARI, which then undergoes N-dealkylation by CYP3A4 to generate 2,3-dichlorophenyl piperazine (2,3-DCPP).18,19 Similarly, CAR is converted into desmethyl-CAR (DCAR) and didesmethyl-CAR (DDCAR) by CYP2D6 and CYP3A4 or undergoes N-dealkylation to generate 2,3-DCPP.16
Figure 1 Simplified metabolism of ARI and CAR. (A) CYP2D6 catalyzes ARI’s dehydrogenation to generate D-ARI. Both ARI and D-ARI can undergo N-dealkylation by CYP3A4 to generate 2,3-DCPP. (B) CYP2D6 catalyzes the conversion of CAR into DCAR, which is then converted into DDCAR. CAR, DCAR, and DDCAR can undergo N-dealkylation to generate 2,3-DCPP.
In this current study, we investigated the influence of Dhcr7 heterozygosity on ARI, CAR, and their metabolites. The study was performed using WT and Dhcr7+/– human fibroblasts and transgenic animal models and assessed the expression of an ARI and CAR metabolizing enzyme.
Results
Dhcr7+/– Heterozygosity Influences Drug Levels across Multiple Tissues
In order to investigate the effect of a Dhcr7 heterozygosity on drug metabolism, we assessed the levels of ARI, CAR, and their active metabolites, across different tissues of WT and Dhcr7+/– mice. WT and Dhcr7+/– female mice were injected with ARI from E12 to E19 and the offspring tissue was collected at birth (P0). The levels of ARI and its metabolites (D-ARI and 2,3-DCPP) were measured in the liver of P0 animals (Figure 2). The analysis of medication levels with regards to embryonic genotype alone revealed that ARI levels in the livers of Dhcr7+/– pups were 52% lower than those of WT pups (Dhcr7+/– pups: 0.33 ± 0.05 ng/mg protein vs WT pups: 0.68 ± 0.06; p < 0.0001) (Figure 2A). D-ARI levels followed the same pattern as ARI and were found decreased in Dhcr7+/– pups compared to their WT littermates (Dhcr7+/– pups: 0.13 ± 0.02 ng/mg protein vs WT pups: 0.21 ± 0.02; p = 0.0095) (Figure 2B). A two-way ANOVA analysis accounting for the contribution of both genotypes is presented in Table 1. No significant differences were observed in 2,3-DCPP between WT and Dhcr7+/– pups (Figure 2C). Importantly, maternal genotype had no significant effect on the medication levels in the liver of pups, suggesting that the effect is primarily driven by the pup genotype.
Figure 2 Dhcr7+/– heterozygosity decreases ARI levels in the liver. Levels of ARI and its metabolites were determined in maternally exposed pups at an age of P0. Samples were grouped taking into account both the maternal and newborn mouse genotypes. WT and Dhcr7+/– pups are depicted in green or red, respectively. ARI (A), D-ARI (B), and 2,3-DCPP (C) were determined using LC–MS/MS. Bars correspond to the mean ± SEM; statistical significance: *p < 0.05; **p < 0.01. A two-way ANOVA analysis is presented in Table 1. Note the lower levels of ARI and D-ARI in Dhcr7+/– pups.
Table 1 ANOVA Analysis of ARI Levels in P0 Liversa
# Comparison ARI D-ARI 2,3-DCPP
1 embryonic genotype: Dhcr7+/+vs Dhcr7+/– 0.0002 0.0286 0.6585
2 maternal genotype: Dhcr7+/+vs Dhcr7+/– 0.0788 0.4764 0.2262
3 two-way interaction: maternal Dhcr7 vs embryonic Dhcr7 genotypes 0.7311 0.9987 0.9333
a Rows #1–2 denote statistical significance for single variables; #3 reports probability for the two interacting factors; values highlighted in bold denote p < 0.05. No statistical difference was observed between male and female animals.
Next, we were interested if this finding is also observed in response to CAR exposure and if this effect can be seen across multiple tissues. Developmental exposure (E12-E19) to 0.2 mg/kg CAR was followed by tissue harvest at birth and parent drug/metabolites (DCAR, DDCAR, and 2,3-DCPP) were measured in the liver, heart, lungs, and brain of offspring with the Dhcr7+/– and Dhcr7+/+ genotypes (Figure 3). Highest levels of CAR and its metabolites were observed in the liver, followed by the brain, lungs, and heart. Importantly, CAR levels were significantly lower in Dhcr7+/– pups when compared to their WT littermates in both the liver and brain (liver: Dhcr7+/– pups: 1.65 ± 0.12 ng/mg protein vs WT pups: 3.94 ± 0.23; p < 0.0001; brain: Dhcr7+/– pups: 0.36 ± 0.03 ng/mg protein vs WT pups: 0.98 ± 0.06; p < 0.0001) (Figure 3A). DCAR and DDCAR followed the same pattern, with lower levels detected in Dhcr7+/– pups compared to their WT littermates across all four investigated tissues, although only DDCAR levels reached significant difference between the two groups (Figure 3B,C, respectively). Levels of 2,3-DCPP were not significantly different between the two genotypes (Figure 3D).
Figure 3 Dhcr7+/– heterozygosity decreases CAR levels in the liver and brain. The levels of CAR and metabolites were determined at P0 in the brain, liver, lung, and heart. Samples were grouped taking into account the pups’ genotype. WT and Dhcr7+/– pups are depicted in green and red, respectively. CAR (A), DCAR (B), DDCAR (C), and 2,3-DCPP (D) were determined using LC–MS/MS. Opened symbols denote pups from WT mothers and filled symbols denote pups from Dhcr7+/– mothers. Bars correspond to the mean ± SEM; statistical significance: *p < 0.05; ****p < 0.0001. Note the decreased levels of CAR and DDCAR in both the liver and brain and the different CAR levels across the four investigated tissues.
To address the origin of these changes, we selected the two tissues with the highest drug levels (brain and liver) and reanalyzed the samples taking into account both maternal and embryonic genotypes. The liver data are depicted in Figure 4, and a two-way ANOVA analysis of our findings is presented in Table 2. The embryonic Dhcr7+/– genotype had a significant effect on CAR, DCAR, and DDCAR levels, with lower levels in heterozygous pups compared to their WT littermates. No effect on 2,3-DCPP was observed. Similarly, the levels of DCAR and DDCAR were also significantly decreased in pups born to Dhcr7+/– mothers, indicating that the maternal genotype also contributes to the decreased drug levels in the liver of heterozygous animals. Similar results were observed in the brain tissue, where the CAR, DCAR, and DDCAR levels were affected by both maternal and embryonic Dhcr7+/– genotypes (Figure 5 and Table 3). Furthermore, an analysis of the maternal serum revealed lower levels of CAR and its metabolites in the serum of Dhcr7+/– mothers when compared to their WT counterparts (Figure S1).
Figure 4 Levels of CAR and its metabolites in the liver depend on both maternal and embryonic genotypes. The levels of CAR and metabolites were determined in the livers of P0 pups. The data are presented taking into account both maternal and embryonic Dhcr7 genotypes. A two-way ANOVA analysis is presented in Table 2. Each symbol corresponds to a single pup. Bars correspond to the mean ± SEM; statistical significance: **p < 0.01; ****p < 0.0001. Note that for CAR, DCAR, and DDCAR, there is a summation effect between the maternal and pup Dhcr7 genotype, with the Dhcr7+/– pups born to Dhcr7+/– mothers showing the lowest levels.
Figure 5 Levels of CAR and its metabolites in the brain depend on both maternal and embryonic genotypes. The levels of CAR and metabolites were determined in the brains of P0 pups. The data are presented taking into account both the maternal and embryonic Dhcr7 genotypes. A two-way ANOVA analysis is presented in Table 3. Each symbol corresponds to a single pup. Bars correspond to the mean ± SEM; statistical significance: *p < 0.05; **p < 0.01; ***p < 0.001. Note that for CAR, DCAR, and DDCAR, there is a summation effect between the maternal and pup Dhcr7 genotype, with the Dhcr7+/– pups born to Dhcr7+/– mothers showing the lowest levels.
Table 2 ANOVA Analysis of CAR Levels in P0 Liversa
# Comparison CAR DCAR DDCAR 2,3-DCPP
1 embryonic genotype: Dhcr7+/+vs Dhcr7+/– <0.0001 0.0017 0.0380 0.8120
2 maternal genotype: Dhcr7+/+vs Dhcr7+/– 0.1782 <0.0001 0.0199 0.2030
3 two-way interaction: maternal Dhcr7 vs embryonic Dhcr7 genotypes 0.6421 0.3202 0.7388 0.9998
a Rows #1–2 denote statistical significance for single variables; #3 reports probability for the two interacting factors; values highlighted in bold denote p < 0.05. No statistical difference was observed between male and female animals.
Table 3 ANOVA Analysis of CAR Levels in P0 Brainsa
# Comparison CAR DCAR DDCAR 2,3-DCPP
1 embryonic genotype: Dhcr7+/+vs Dhcr7+/– 0.0525 0.0005 0.0039 0.3980
2 maternal genotype: Dhcr7+/+vs Dhcr7+/– <0.0001 0.0304 0.0018 0.2655
3 two-way interaction: maternal Dhcr7 vs embryonic Dhcr7 genotypes 0.0452 0.9414 0.1026 0.2885
a Rows #1–2 denote statistical significance for single variables; #3 reports probability for the two interacting factors; values highlighted in bold denote p < 0.05. No statistical difference was observed between male and female animals.
Dhcr7+/– Heterozygosity Increases Drug Turnover
Using data in Figures 2 and 3, we assessed drug turnover in the four investigated organs of both WT and Dhcr7+/–P0 mice by calculating the ratio of metabolites over the parent drug (Figure 6). While the overall drug metabolites’ levels were decreased by the pup Dhcr7+/– genotype, the metabolite/parent drug ratio was increased in the same samples. ARI turnover (D-ARI+2,3-DCPP)/ARI revealed a 40% higher turnover ratio in the liver of Dhcr7+/– animals when compared to their WT littermates, suggesting that the drug is metabolized at a higher rate in heterozygous animals (Dhcr7+/– pups: 0.21 ± 0.02 ng/mg protein vs WT pups: 0.13 ± 0.02; p = 0.0011) (Figure 6A). Similar results were obtained for CAR (DCAR + DDCAR + 2,3-DCPP)/CAR) with significantly higher turnover rates observed in Dhcr7+/– pups when compared to their WT littermates (Figure 6B). Drug turnover values for ARI and CAR grouped according to both maternal and embryonic genotypes are presented in Figures S2 and S3, respectively. Tables S1 and S2 depict the two-way ANOVA analysis assessing the contribution of both maternal and embryonic genotypes to the altered drug turnover. There are two possible explanations for these findings. First, the drug is metabolized independently across each tissue, and the higher turnover reflects tissue-specific metabolism. Alternatively, the turnover difference observed between WT and Dhcr7+/– animals is a result of hepatic activity, where the drug is converted into the metabolites in the liver and distributed by the systemic circulation to all tissues.
Figure 6 Dhcr7+/– mice metabolize ARI and CAR faster than WT mice. ARI (A) and CAR turnovers (B) were calculated by determining the ratio of drug metabolites over the parent drug. WT and Dhcr7+/– pups are depicted in green and red, respectively. Opened symbols denote pups from WT mothers and filled symbols denote pups from Dhcr7+/– mothers. Bars correspond to the mean ± SEM; statistical significance: **p < 0.01; ***p < 0.0001. Note that the parent drug/metabolite ratio was increased in Dhcr7+/– pups across all tissues.
Cyp2d6 Protein Expression is Increased in the Liver of Dhcr7+/– Animals
Cyp2d6 is a critical enzyme in the metabolism of both ARI and CAR (Figure 1).12,16,17 In order to determine if the increased metabolism of ARI and CAR was due to the increased level of the Cyp2d6 enzyme, Cyp2d6 protein expression was compared in WT and Dhcr7+/– livers of adult female mice (Figure 7). Three animals from each genotype were used for the western blot analysis. Cyp2d6 levels were normalized to the housekeeping protein DJ-1. We found that normalized Cyp2d6 levels were ∼40% higher in Dhcr7+/– animals when compared to WT (protein levels (a.u.): WT: 0.71 ± 0.06 versus Dhcr7+/–: 1.11 ± 0.07, p = 0.0075). Livers from adult male mice showed a similar pattern (Figure S4).
Figure 7 Cyp2d6 protein expression is increased in the liver of adult Dhcr7+/– mice. (A) Western blot for Cyp2d6. Expression of housekeeping protein DJ-1 was used as a loading control. Each lane corresponds to the liver samples from different animals. (B) Optical density quantification of bands, with Cyp2d6 normalized to DJ-1. The values on panel B are shown as averages ± SEM of three biological replicates. **p < 0.01.
Human Fibroblasts with a DHCR7+/– Genotype Have Lower Drug Levels than WT Cells
In order to gather an insight into the translational aspects of our transgenic animal observations, next, we treated five pairs of sex- and age-matched WT and DHCR7+/– human fibroblasts with ARI and CAR (Figure 8). After five days of treatment, ARI levels were lower in DHCR7+/– cells in comparison with WT (DHCR7+/– cells: 29.6 ± 3.8 ng/mg protein vs WT cells: 39.9 ± 5.3; p = 0.0757), although this difference did not reach statistical significance (Figure 8A). In contrast, CAR levels in DHCR7+/– cells were significantly lower than those detected in WT cells (DHCR7+/– cells: 34.6 ± 10.8 ng/mg protein vs WT cells: 72.8 ± 8.0; p = 0.0217) (Figure 8B). No sex or age differences were observed in the experiments with either ARI or CAR, but due to a limited sample size and statistical power, these findings cannot be considered conclusive.
Figure 8 Human fibroblasts with a DHCR7+/– genotype have lower drug levels than WT cells. Cells were treated for five days with either ARI (A) or CAR (B) and the drug levels were determined by LC–MS/MS. Drug metabolites were below the limit of quantitation and could not be determined. Blue and pink symbols denote cells from male and female human donors, respectively. Each symbol corresponds to cell cultures derived from a different individual. Bars correspond to the mean ± SEM; statistical significance: *p < 0.05.
Discussion
Our findings can be summarized as follows: (1) animals with a Dhcr7+/– genotype have lower drug levels than WT controls when exposed to the same levels of DHCR7 inhibiting medications; (2) drug turnover is higher in heterozygous animals, suggesting a faster metabolism of both ARI and CAR; (3) the differential drug and metabolite levels can be observed across multiple tissues, primarily in the liver and brain; (4) the embryonic Dhcr7+/– genotype is the primary contributing factor to the final drug levels and turnover observed in the offspring; (5) a critical enzyme in ARI and CAR metabolism, Cyp2d6, is expressed at higher levels in Dhcr7+/– animals; and (6) ARI- and CAR-exposed human fibroblasts from heterozygous individuals have lower drug levels than controls.
Brain cholesterol synthesis is critical for neurodevelopment. Our studies were designed to investigate the effects of a Dhcr7 heterozygosity on drug metabolism in utero at a time when intrinsic sterol synthesis starts in the developing brain. Interestingly, many medications that inhibit the DHCR7 enzyme are commonly prescribed to pregnant women, underscoring the public health relevance of our findings.20−22 Many medications with a DHCR7-inhibiting side effect have been associated with a wide range of negative pregnancy outcomes, including spontaneous abortions, intrauterine death, and major or minor fetal malformations.11
Our results suggest that the different metabolism and turnover of ARI and CAR is a stable effect of the DHCR7 genotype and does not depend on the age or pregnancy: the findings were consistent across multiple tissues, human and mouse models, and at least two different ages (P0 and adult pregnant females).
The altered drug levels and turnover observed between WT and Dhcr7+/– mice can be at least partially explained by higher Cyp2d6 levels detected in the heterozygous animals. This enzyme is responsible for the dehydrogenation of ARI into dehydro-ARI as well as the demethylation of CAR into DCAR and DDCAR. Therefore, more enzyme translates into a faster metabolism, leading to lower drug levels and higher turnover. Importantly, the effect of maternal and embryonic Dhcr7+/– genotypes appears to be summative, as heterozygous pups born to heterozygous mothers had the least amount of drugs and the highest drug turnover rate.
It is estimated that CYP2D6 constitutes ∼3% of the total hepatic CYP metabolism and is responsible for the metabolism of ∼20% of the drugs.23,24 Antipsychotics, antidepressants, beta-blockers, antiarrhythmics, and several opioids are all metabolized by CYP2D6.17,25−28 The above presented findings, using ARI and CAR, could be looked upon as a proof-of-concept study: it is plausible that our observations with ARI and CAR could be extrapolated to multiple DHCR7-inhibiting drugs cleared by CYP2D6. This raises the question if in DHCR7+/– individuals, the dosage of CYP2D6-metabolized, DHCR7-inhibiting medications should be adjusted.
However, should this adjustment be warranted at all for the 1–3% of the human population who carry single-allele DHCR7? Perhaps not. Increasing the dose might result in a more appropriate therapeutic level across the tissues but is also likely to increase the side effects, as higher medication doses will result in increased DHCR7 inhibition. This would further elevate unwanted 7-DHC levels which are already elevated at the baseline in DHCR7+/– individuals. In turn, as 7-DHC is the most reactive known sterol, it would spontaneously give rise to many oxysterols.29−33 These 7-DHC-derived oxysterols are known to be toxic, and their further elevation by drugs in DHCR7+/– individuals might not be a wise course of action.
Finally, it is interesting to consider our observations as a protective mechanism of the body against a toxic insult. Elevation of 7-DHC and 7-DHC-derived oxysterols disrupts cellular homeostasis and the body responds by increasing clearance to minimize the toxic side effects. Should this be true, the feedback mechanism by which a defensive increased CYP2D6 expression might occur should be further investigated.
Materials and Methods
Chemicals
Unless otherwise noted, all chemicals were purchased from Sigma-Aldrich Co (St. Louis, MO). HPLC-grade solvents were purchased from Thermo Fisher Scientific Inc. (Waltham, MA). CAR was obtained from Sigma-Aldrich and dissolved in 0.9% saline solution for the experiments. ARI and d8-ARI were obtained from Sigma-Aldrich (St. Louis, MO).
Mice Studies
Adult male and female B6.129P2(Cg)-Dhcr7tm1Gst/J stock # 007453 mice were purchased from Jackson Laboratories. Mice homozygous for the Dhcr7Ex8 allele lack the exon 8 coding sequence and flanking splice acceptor site of the targeted gene, resulting in the truncated DHCR7 mutation most frequently observed in SLOS patients (IVS8-1G > C). Homozygous mice die shortly after birth. Dhcr7+/– mice are well, fertile, and indistinguishable from control, wild-type mice. Mice were housed under a 12 h light–dark cycle at constant temperature (25 °C) and humidity with ad libitum access to food (Teklad LM-485 Mouse/Rat Irradiated Diet 7012) and water in Comparative Medicine at the UNMC, Omaha, NE. The time-pregnant female mice received i/p injections of vehicle (VEH) or CAR (0.2 mg/kg) from E12 to E19. 18 WT and thirteen Dhcr7+/– mothers were used in our study. WT mothers were mated with Dhcr7+/– fathers and Dhcr7+/– mothers were mated with WT fathers, as described previously.3,4 Time-pregnant female mice received i/p injections of VEH or ARI (5 mg/kg) from E12 to E19. Half of each genotype group was injected with VEH and the other half with CAR. Similarly, eight WT and seven Dhcr7+/– mothers were used in our study and half of each genotype was injected with VEH and the other half with ARI. The mouse colony was monitored three times a day and all newborn pups (P0) were collected for dissection shortly after birth. All pups were born naturally; thus, we had no access to placental tissue. Adult female mice were killed after pups’ delivery. Both ARI and CAR doses were determined based on bioequivalency, as described previously, according to the formula of the animal equivalent dose (AED in mg/kg) = human dose (mg/kg) × Km ratio.34 The E12-E19 exposure window was chosen based on the time point when de novo cholesterol biosynthesis starts in the mouse brain.35 After dissection, frozen tissue samples were sonicated in ice-cold PBS containing butylated hydroxytoluene (BHT) and triphenylphosphine (PPh3). The aliquots of homogenized tissue were used for drug extraction and protein measurements. The protein was measured using BCA assay (Pierce). All procedures were performed in accordance with the Guide for the Humane Use and Care of Laboratory Animals. The use of mice in this study was approved by the Institutional Animal Care and Use Committee of UNMC.
Human Fibroblasts
All WT and DHCR7+/– human fibroblasts were described previously.6 All cultured human fibroblasts used were passages 5–18. All cells were subcultured once a week, and the culture medium was changed every two days. All cell lines were maintained in Dulbecco’s modified Eagle’s medium (DMEM) with high glucose (25 mM), 1 mM l-glutamine, 10% fetal bovine serum, and penicillin/streptomycin at 37 °C and 5% CO2. For the drug exposure experiments, human fibroblasts were cultured in DMEM with 25 mM glucose, 1 mM l-glutamine, 10% delipidated fetal bovine serum (FBS), and penicillin/streptomycin. Medium was changed every 2 days during the course of the treatment. At the endpoint, cells were collected in ice-cold PBS and stored at −80 °C for further analyses.
LC–MS/MS (SRM) Analyses
Drug levels were determined as described previously.3,4 CAR and ARI levels were acquired in an Acquity UPLC system coupled to a Thermo Scientific TSQ Quantis mass spectrometer using an ESI source in the positive ion mode. A total of 5 μL of each sample was injected onto the column (Phenomenex Luna Omega C18, 1.6 μm, 100 Å, 2.1 mm × 50 mm) using water (0.1% v/v acetic acid) (solvent A) and acetonitrile (0.1% v/v acetic acid) (solvent B) as the mobile phase. The gradient was: 10–40% B for 0.5 min; 40–95% B for 0.4 min; 95% B for 1.5 min; 95–10% B for 0.1 min; and 10% B for 0.5 min. CAR and its metabolites were analyzed by selective reaction monitoring (SRM) using the following transitions: CAR 427 → 382, desmethyl-CAR (DCAR) 413 → 382, didesmethyl-CAR (DDCAR) 399 → 382 and 2,3-DCPP 230 → 187. The SRM for the internal standard (d8-ARI) was set to 456 → 293 and response factors were determined to accurately determine the drug levels. Similarly, ARI and its metabolites were analyzed by SRM using the following transitions: ARI 448 → 285, dehydroaripiprazole 446 → 285, 2,3-DCPP 230 → 187. The SRM for the internal standard (d8-ARI) was set to 456 → 293. Final drug levels are reported as ng/mg of protein.
Western Blot Analyses
Liver samples were homogenized by sonication in ice-cold RIPA lysis buffer (VWR International, Radnor, PA) plus phosphatase inhibitors (Sigma-Aldrich) and protease inhibitors (Thermo Fisher Scientific) and incubated on ice for 30 min. To clear the lysates, the samples were spun at 14,000 g at 4 °C for 5 min to pellet the debris. The protein concentration of the supernatant was quantified using the Bio-Rad BCA assay. Equal amounts of protein from each sample were mixed with the reducing reagent and loading buffer and heated to 70 °C for 10 min. Proteins were separated on NuPAGE 4–12% bis–tris protein gels (Thermo Fisher Scientific). Prestained protein ladder was used to evaluate the molecular weight. The Bio-Rad Mini Trans-Blot Electrophoretic Transfer Cell was used for the electrophoretic transfer using the polyvinylidene difluoride membranes (Immobilon-P PVDF Membrane, Sigma-Aldrich) and transfer buffer (25 mM Tris, 192 mM glycine and 20% (v/v) methanol (pH 8.3)). Following transfer, PVDF membranes were blocked in 5% milk in TBS (50 mM Tris-Cl, 150 mM NaCl, pH 7.5) with 0.05% Igepal (Spectrum Chemical, New Brunswick, NJ) and incubated in primary antibody overnight at +4 °C and secondary antibodies at room temperature for 1 h. Membranes were probed with the following primary antibodies: Cyp2d6 (Cell Signaling) and DJ-1 (Cell Signaling). Western blots were developed using Azure’s Radiance Substrate, imaged on Azure C300 with the cSeries Capture Software and saved as TIFF images (Azure Biosystems). The TIFF images were analyzed and quantified with AzureSpot.
Statistical Analyses
Statistical analyses were performed using Graphpad Prism 9 for Windows. Unpaired two-tailed t-tests were performed for individual comparisons between two groups. The Welch’s correction was employed when the variance between the two groups was significantly different. Two-way ANOVA analyses were performed to assess the contributions of the maternal and embryonic genotypes to drug metabolism and to test for any potential interactions between these variables. The p values for statistically significant differences are highlighted in the figure legends..
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c05817.Levels of CAR and its metabolites depend on maternal genotype; Dhcr7+/– mice metabolize ARI faster than WT mice; Dhcr7+/– mice metabolize CAR faster than WT mice; Cyp2d6 protein expression is increased in the liver of adult male Dhcr7+/– mice; ANOVA analysis of the ARI turnover in P0 livers; and ANOVA analysis of the CAR turnover in different tissues of P0 mice (PDF)
Supplementary Material
ao0c05817_si_001.pdf
Author Contributions
Experimental design and research concept: T.C.G.-M., Z.K., and K.M.; cell culture experiments: T.C.G.-M. and Z.K.; animal injections: A.A. and Z.K.; mouse dissections, sample preparation, and drug measurement: T.C.G.-M., Z.K., L.A., and A.A.; protein measurements: A.A., L.A., and Z.K.; mouse colony maintenance: A.A.; LC–MS/MS analyses: T.C.G.-M. and L.A.; western blot analyses: T.C.G.-M.; statistical analysis: T.C.G.-M. and K.M.; funding: K.M.; draft of the manuscript: T.C.G.-M., Z.K., and K.M., and the final version was approved by all authors.
The authors declare no competing financial interest.
Acknowledgments
This work was supported by The National Institutes of Health NIMH MH110636 (K.M.), MN067234 (K.M.), and NICHD HD064727 (Z.K.). The authors also would like to thank the human fibroblast donors. | ARIPIPRAZOLE | DrugsGivenReaction | CC BY-NC-ND | 33681590 | 19,918,173 | 2021-03-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardio-respiratory arrest'. | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | ACYCLOVIR, ANAKINRA, BORTEZOMIB, CARBAMAZEPINE, CLOBAZAM, CLONAZEPAM, CYCLOPHOSPHAMIDE, DEXAMETHASONE, ETOPOSIDE, FOSPHENYTOIN, HUMAN IMMUNOGLOBULIN G, INSULIN NOS, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LEVOCARNITINE, MAGNESIUM, MESNA, METHYLPREDNISOLONE, MIDAZOLAM, PERAMPANEL, PHENOBARBITAL SODIUM, RITUXIMAB, THIOPENTAL SODIUM, TOPIRAMATE | DrugsGivenReaction | CC BY | 33681644 | 19,141,129 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Febrile infection-related epilepsy syndrome'. | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | ACYCLOVIR, ANAKINRA, BORTEZOMIB, CARBAMAZEPINE, CLOBAZAM, CLONAZEPAM, CYCLOPHOSPHAMIDE, DEXAMETHASONE, ETOPOSIDE, FOSPHENYTOIN, HUMAN IMMUNOGLOBULIN G, INSULIN NOS, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LEVOCARNITINE, MAGNESIUM, MESNA, METHYLPREDNISOLONE, MIDAZOLAM, PERAMPANEL, PHENOBARBITAL SODIUM, RITUXIMAB, THIOPENTAL SODIUM, TOPIRAMATE | DrugsGivenReaction | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'ACYCLOVIR'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'ANAKINRA'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Subcutaneous | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'DEXAMETHASONE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'ETOPOSIDE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'HUMAN IMMUNOGLOBULIN G'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'LACOSAMIDE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'LEVETIRACETAM'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the administration route of drug 'METHYLPREDNISOLONE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Intravenous (not otherwise specified) | DrugAdministrationRoute | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'ACYCLOVIR'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 10 MILLIGRAM/KILOGRAM, 3X/DAY (TID) | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'ANAKINRA'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 100 MG | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'DEXAMETHASONE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 10 MILLIGRAM/SQ. METER, ONCE DAILY (QD) | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'ETOPOSIDE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 150 MILLIGRAM/SQ. METER, 2X/WEEK | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'HUMAN IMMUNOGLOBULIN G'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 2 G/KG ADMINISTERED OVER NEXT FIVE DAYS | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the dosage of drug 'METHYLPREDNISOLONE'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | 1 GRAM, ONCE DAILY (QD) | DrugDosageText | CC BY | 33681644 | 19,141,129 | 2021-03 |
What was the outcome of reaction 'Cardio-respiratory arrest'? | Super refractory status in a case of Febrile Infection-Related Epilepsy Syndrome due to hemophagocytic lymphocytic histiocytosis.
A 14-year-old boy presented with a prodromal respiratory infection followed by super refractory status epilepticus. A diagnosis of Febrile Infection-Related Epilepsy Syndrome (FIRES) was made. Initial MRI study and CSF analysis were normal. He required multiple anticonvulsants owing to the refractory nature of the seizures. The course of the illness was rather stormy, laced with various medical problems viz. hepatic dysfunction, sepsis, hemodynamic, and hematological abnormalities which posed several challenges in the management. Hemophagocytic lymphocytic histiocytosis (HLH) was identified as the etiology of the illness and was treated but without success. The case report highlights the several immunomodulatory strategies that were employed to treat the disease, despite which the outcome was unfavorable.
Key Points
Febrile Infection‐Related Epilepsy Syndrome (FIRES) presents as a super refractory status epilepticus (SRSE).
Management of FIRES may require multiple anticonvulsants and immunomodulatory strategies.
Multiple medical problems could be faced during the management of such a patient, related to both the presentation ie FIRES and its etiology, namely hemophagocytic lymphocytic histiocytosis (HLH).
Pursuit of etiology, as for instance HLH in this case, is important from the therapeutic point of view.
Early and aggressive management is of paramount importance in this difficult‐to‐treat disorder.
1 INTRODUCTION
Febrile Infection‐Related Epilepsy Syndrome or FIRES is a potentially devastating disease characterized by refractory status epilepticus that occurs following an apparently innocuous febrile illness in previously healthy people, usually children of school‐going age.
1
We report a patient with the syndrome in whom an unusual etiology was found, and the patient succumbed despite appropriate management strategies. We discuss here the potential difficulties faced during the management of the patient.
2 CASE REPORT
A 14‐year‐old boy was admitted with a seizure. He first experienced throat pain and rhinorrhea 9 days before this presentation and was treated with amoxicillin‐clavulanate. Seven days before this admission he started experiencing fever followed by headache and vomiting. Since six days, there was history of decline in food intake. He progressively worsened. A few hours before this admission, he experienced a seizure characterized by sudden alteration of sensorium followed by tonic posturing of neck, face, and hand with deviation of face to the right side. Seizure lasted less than a minute, and he remained in altered sensorium since. He had no comorbidities earlier. Birth, development, and immunization history were unremarkable and family history was negative for any similar or severe illnesses.
At admission, his vital parameters were as follows: pulse: 102/minute, BP: 110/80 mm Hg, respirations: 30 per minute, and temperature 98.4°F. Cardiorespiratory and per abdominal examinations were normal. Neurologically, he was drowsy and responding to pain. There was no word output. There were no meningeal signs or papilledema. Pupils were normal and reactive. Eye movements were normal. Stretch reflexes were normal, and plantars were flexors.
Levetiracetam (1.5 G stat, followed by 750 mg twice daily intravenously), acyclovir (10 mg/kg thrice a day intravenously), and supportive care measures were instituted.
Serum chemistry revealed transaminitis (aspartate aminotransferase, ie AST 466 i.u/L, alanine aminotransferase, ie ALT 360 i.u/L). Alkaline phosphatase was elevated (270 i.u/L). Bilirubin (0.8 mg%), renal functions, electrolytes, calcium, and phosphorous were normal. Hemogram revealed relative leucopenia (total WBC count 3700/cu.mm). ESR was 7 mm/hour. A contrast‐enhanced MRI of the brain was normal. He tested negative for malarial parasite, microfilaria, dengue, and leptospira. Initial blood and urine cultures were sterile. Widal test was negative. Lumbar puncture revealed clear CSF with normal opening pressure. CSF analysis revealed: total count: 5 cells, all lymphocytes, protein 62 mg%, and normal sugar. CSF virological studies were negative. Acyclovir was subsequently withdrawn.
On day 2, he experienced seizure again. Lacosamide (300 mg stat followed by 150 mg twice daily intravenously) was administered. Sensorium further worsened. Arterial blood gas analysis (ABG) revealed serial worsening with evolution of type II respiratory failure, warranting intubation, and ventilation. Serum ammonia was elevated (101 µmol/L, normal 12‐47 µmol/L). Levocarnitine was added. Continuous EEG monitoring was started and showed recurrent epileptiform activity arising from both fronto‐temporal regions, left more than right.
Subsequently, he started experiencing recurrent clinical seizures. Midazolam infusion (0.2 mg/kg stat followed by 0.5 mg/kg/hour infusion) was started. A drop in blood pressure warranted ionotropic support. He was now started on pulse methylprednisolone (1 g by intravenous infusion, once daily for 5 days). Hyperglycemia was noticed requiring administration of insulin. Seizures still recurred when ketamine infusion (3 mg/kg stat followed by 3 mg/kg/hour infusion) was started and burst suppression pattern was achieved.
On day 3, he was also started on intravenous immunoglobulin (IVIg) (2 g/kg administered over next five days). Ketogenic diet was instituted.
Multiple anticonvulsants were needed during the course of the disease, titrated based on metabolic and hemodynamic parameters, and are summarized in Figure 1. The various immunomodulatory strategies are summarized in Figure 2.
FIGURE 1 Figure showing the various anticonvulsants and the timelines
FIGURE 2 Figure showing the various immunomodulatory strategies and the timelines
Autoimmune workup revealed strongly positive anti‐nuclear antibodies on immunofluorescence with a homogenous nuclear pattern. Extractable nuclear antigen test was negative. Lupus anticoagulant test was weakly positive. Antithyroid antibody titers were strongly positive (serum antithyroid peroxidase‐O, ie TPO antibodies 112.23 IU/mL, normal: <5.61 IU/mL). All other tests of autoimmune panel including serum and CSF autoimmune antibody profile (anti NMDA, LGI‐1, CASPR‐2, GAD, GABA‐A, GABA‐B, AMPA antibodies in serum and CSF; serum anti‐ds‐DNA, beta‐2 glycoprotein, and cardiolipin antibodies, angiotensin‐converting enzyme levels, VDRL, p‐ANCA, and c‐ANCA, rheumatoid factor) were negative.
Bilirubin levels progressively increased (Table 1), predominantly the conjugated bilirubin levels. Ultrasound of the abdomen revealed mild ascites and bilateral pleural effusion. Repeat MRI of the brain showed T2/FLAIR hyperintensities in both mesial temporal lobes.
TABLE 1 showing the serial hematological and liver function parameters
Laboratory parameters Day 1 Day 8 Day11 Day13 Day 16 Day 21 Day 33
Hemoglobin (g/dL) 13.6 11.4 10.9 7.5 10.2 9.1 7.4
Total leukocyte count (×109/L) 3.7 7.8 2 5.7 23.7 9.4 2.9
Platelets (×109/L) 220 300 200 100 50 160 130
Total bilirubin (mg/dL) 0.6 3.7 11.9 13.2 9.6 18.7 28.7
Direct bilirubin (mg/dL) 0.5 3.4 10.4 11.2 8.9 15.1 22.3
Aspartate amino transferase (AST) (U/L) 466 139 208 104 67 79 66
Alanine amino transferase (ALT) (U/L) 635 96 131 104 67 53 47
Alkaline phosphatase (IU/L) 270 198 670 337 263 330 263
Total Protein (g/dL) 6.5 6.2 6 4.7 4.8 5.9 5.6
Albumin (g/dL) 4.2 3.2 3.3 2.6 1.9 2.4 3
John Wiley & Sons, LtdSerum ferritin levels were elevated on admission (2719 ng/mL, normal 7‐140 ng/mL) and progressively rose to 13 341 ng/mL on day 35. Serum triglyceride levels were elevated on admission (211 mg/dL, normal <150 mg/dL) and rose to 685 mg/dL on day 35. Bone marrow examination revealed features of hemophagocytic lymphocytic histiocytosis (HLH) with macrophage activate syndrome (Figure 3). Serum CD19 and 20 levels, soluble CD‐25, CXCL‐9, and IL‐18 levels, and NK cell function studies could not be tested. Whole‐genome exon sequencing did not reveal any evidence to suggest familial HLH.
FIGURE 3 (A, B, C‐ Bone marrow aspiration, D‐ Bone marrow biopsy) shows phagocytosis of hematopoietic elements by macrophages (Hematoxylin‐Eosin stain) (A, B, C‐ 100*10 × magnification, D‐ 40*10 × magnification)
Etoposide (150 mg/m2 intravenously, repeated twice weekly) and dexamethasone (10 mg/m2 intravenously daily) were administered. On day 34, owing to further recurrences of seizures, anakinra (100 mg subcutaneously) was started. He had multiple recurrences of seizures following this, and hence, anakinra was not continued.
He required multiple courses of antibiotics during the stay, administered based on culture‐sensitivity patterns on blood, urine, and endotracheal aspirate. He required administration of granulocyte‐monocyte colony‐stimulating factor (GM‐CSF) (175 micrograms subcutaneously) when the blood counts dropped after the immunomodulatory therapy (Table 1). He also received pneumocystis carinii prophylaxis (cotrimoxazole). He continued to experience multiple recurrences of seizures.
On day 40, he developed cardiorespiratory arrest and succumbed to the illness.
3 DISCUSSION
Our patient had super refractory status epilepticus on a background of recent febrile illness. Status epilepticus persisting despite two appropriately chosen anticonvulsants and including one benzodiazepine administered in therapeutic doses is considered as refractory in nature.
2
Status epilepticus lasting more than 24 hours after initiation of anesthesia or recurring following withdrawal/ tapering of anesthesia is called as super refractory status epilepticus.
3
Such a presentation occurring in a patient with no past history of epilepsy and without acute or active metabolic, toxic, or structural cause warrants consideration of the syndrome of NORSE ie new‐onset refractory status epilepticus.
4
NORSE may or may not be preceded by fever and when fever precedes the onset of such seizures by 2 weeks to 24 hours, it is referred to as FIRES ie Febrile Infection‐Related Epilepsy Syndrome.
1
Our patient fulfilled the consensus definitions of NORSE and FIRES.
5
Management of FIRES is challenging and can be classified into four categories: (i) general supportive measures, (ii) management of the seizures, (iii) immunotherapy, and (iv) Treatment of any identifiable etiology.
General supportive measures posed several challenges in our patient. He required prolonged ventilatory assistance with its attendant complications, importantly pneumonia, and required several courses of antibacterial and antifungal agents. Diarrhea associated with the use of antibiotics as well as ketogenic diet posed additional challenges. Maintenance of nutritional balance in the wake of need for ketogenic diet was particularly difficult. Additional measures included prevention of decubitus ulcers, prevention of skin excoriations despite the need for repeatedly cleaning the fecal‐soiled skin areas, especially in times of diarrhea, prevention of deep vein thrombosis, and passive physiotherapy measures. Parents and family members needed extensive counseling measures since the child required extended stay in the intensive care unit. In India, financial issues could pose additional challenges. Extensive evaluation, management in intensive care area, use of costly equipment like ventilator and infusion pumps, long‐term hospital stay, and the use of expensive medications like immunoglobulin, chemotherapeutic agents, and antibiotics can be demanding financially, especially in the absence of medical insurance.
The second pillar of management was anticonvulsants. It is well‐known that patients with FIRES respond poorly to anticonvulsants. Polytherapy is the rule as was seen in our patient. Levetiracetam was the first anticonvulsant used in our patient followed by lacosamide when he had a recurrence. When seizures subsequently recurred in clusters, FIRES was considered and midazolam was added and then ketamine. Abnormality of liver function tests in the form of anicteric transaminitis and hyperammonemia at admission and then the appearance and worsening of jaundice precluded the use of valproate. Anticipating the pharmacoresistant nature of the illness, we introduced ketogenic diet early in the course of the illness. Despite encouraging results reported in response to such a diet in literature, seizures were relentless in our patient.
6
We used several conventional anticonvulsants viz. levetiracetam, lacosamide, fos‐phenytoin, clobazam, clonazepam, phenobarbitone, topiramate, and perampanel and additional agents namely midazolam, ketamine, thiopentone, and magnesium. We maintained prolonged burst suppression with ketamine and thiopentone, yet when attempts were made to taper off the same, even with minimal reductions in the doses, generalized seizures recurred.
The third aspect of management of FIRES is immunotherapy. We aggressively instituted early immunomodulation in the form of intravenous methylprednisolone and immunoglobulin. When seizures recur beyond a week, status epilepticus is said to be “prolonged,” and hence, we added further immunomodulation.
7
These were in the form of the anti‐CD 20 monoclonal antibody, rituximab, and the chemotherapeutic agent cyclophosphamide that has been anecdotally used in the past in the treatment of FIRES. We also used anakinra, a recombinant modified version of human interleukin‐1 receptor antagonist protein which could be useful in severe refractory autoimmune encephalitis.
8
Peculiarly, our patient had a flurry of seizure upon administration of anakinra precluding further use of the same. Bortezomib is a 26‐S proteasome inhibitor used in the management of plasma cell dyscrasias such as multiple myeloma.
9
Although some evidence exists regarding the role in refractory autoimmune encephalitis, it did not benefit our patient.
10
A point of particular concern in our patient was the cytopenias that required additional therapy and also precluded timely administration of aggressive immunomodulatory therapy. Also, deranged liver functions precluded the use of tocilizumab in our patient.
The fourth aspect of management is the treatment of the etiology. The etiology of FIRES is identified in less than half of the patients and autoimmune and paraneoplastic causes are often implicated.
11
Autoimmune work up in our patient yielded positive anti‐nuclear and antithyroid antibodies. This warranted administration of conventional immunotherapy in the form of methylprednisolone and immunoglobulin. The patient had a progressive rise in bilirubin and also ferritin. Ferritin elevation warranted further evaluation when HLH was identified. Additional immunomodulation in the form of etoposide and dexamethasone were administered hence.
12
However, our patient did not respond to these measures and succumbed.
Hemophagocytic lymphocytic histiocytosis (HLH) is a rare life‐threatening hyperinflammatory hematological syndrome characterized by cytokine storm.
13
It can be primary or secondary to several conditions including autoimmune disorders, infections, and malignancy. The histiocytic society revised guidelines for the diagnosis of HLH, 2004 requires either molecular diagnosis consistent with HLH or the presence of five out of eight criteria, namely fever, splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow or other tissue, increase in sCD25 or reduced/absent NK cell function.
14
Our patient had persistent fever, cytopenia, hyperferritinemia, hypertriglyceridemia, and bone marrow evidence of hemophagocytosis. Whether FIRES and HLH are the underpinnings of an underlying immune dysfunction in a genetically susceptible individual which manifests with cytokine storm following a febrile illness or one leading to another is not clearly known. Farias‐Moeller et al described 3 patients with FIRES and HLH and suggested abnormal activation of innate immune system following a febrile illness that leads onto release of cytokines and chemokines resulting in neuronal hyperexcitability and manifesting as refractory seizures.
15
The defective NK cell function in HLH leads onto defective clearance of antigen‐presenting cells that results in a vicious cycle with further activation of macrophages and monocytes followed by phagocytosis of hematopoietic elements and tissue damage.
16
Serum ferritin in our patient at the time of admission was elevated and further increased during the course of the illness suggesting that HLH preceded the onset of FIRES.
The case highlights the multiple problems that could be faced by clinicians in the management of this difficult‐to‐treat disorder that resulted in an unfavorable outcome.
CONFLICT OF INTEREST
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. | Fatal | ReactionOutcome | CC BY | 33681644 | 19,141,129 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Hypotension'. | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | ACYCLOVIR, CANNABIDIOL, CEFTRIAXONE, IMMUNE GLOBULIN NOS, ISOFLURANE, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LIDOCAINE, MAGNESIUM, PENTOBARBITAL, PERAMPANEL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Multiple-drug resistance'. | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | ACYCLOVIR, CANNABIDIOL, CEFTRIAXONE, IMMUNE GLOBULIN NOS, ISOFLURANE, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LIDOCAINE, MAGNESIUM, PENTOBARBITAL, PERAMPANEL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Product use in unapproved indication'. | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | ACYCLOVIR, CANNABIDIOL, CEFTRIAXONE, IMMUNE GLOBULIN NOS, ISOFLURANE, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LIDOCAINE, MAGNESIUM, PENTOBARBITAL, PERAMPANEL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Renal failure'. | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | ACYCLOVIR, CANNABIDIOL, CEFTRIAXONE, IMMUNE GLOBULIN NOS, ISOFLURANE, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LIDOCAINE, MAGNESIUM, PENTOBARBITAL, PERAMPANEL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Respiratory failure'. | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | ACYCLOVIR, CANNABIDIOL, CEFTRIAXONE, IMMUNE GLOBULIN NOS, ISOFLURANE, KETAMINE, LACOSAMIDE, LEVETIRACETAM, LIDOCAINE, MAGNESIUM, PENTOBARBITAL, PERAMPANEL, VANCOMYCIN | DrugsGivenReaction | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
What was the dosage of drug 'IMMUNE GLOBULIN NOS'? | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | UNK, INTRAVENOUS | DrugDosageText | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
What was the outcome of reaction 'Respiratory failure'? | Proposal to optimize evaluation and treatment of Febrile infection-related epilepsy syndrome (FIRES): A Report from FIRES workshop.
Febrile infection-related epilepsy syndrome (FIRES) is a rare catastrophic epileptic encephalopathy that presents suddenly in otherwise normal children and young adults causing significant neurological disability, chronic epilepsy, and high rates of mortality. To suggest a therapy protocol to improve outcome of FIRES, workshops were held in conjunction with American Epilepsy Society annual meeting between 2017 and 2019. An international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with interest and expertise in FIRES convened to propose an algorithm for a standardized approach to the diagnosis and treatment of FIRES. The broad differential for refractory status epilepticus (RSE) should include FIRES, to allow empiric therapies to be started early in the clinical course. FIRES should be considered in all previously healthy patients older than two years of age who present with explosive onset of seizures rapidly progressing to RSE, following a febrile illness in the preceding two weeks. Once FIRES is suspected, early administrations of ketogenic diet and anakinra (the IL-1 receptor antagonist that blocks biologic activity of IL-1β) are recommended.
Key points
Consensus to optimize operational best practice on diagnosis and treatment of FIRES (febrile infectaion‐related epilpsy syndrome)
Recognize FIRES in a new explosive onset seizures progressing to status epilepticus following a febrile illness in the preceding two weeks
Once infectious, metabolic, toxic and structural etiologies excluded within the first 48 hours, consider immunomodulatory therapies
Targeted therapy for FIRES include anakinra, ketogenic diet, canabidiol and tocilizumab
1 INTRODUCTION
The first report of the acute encephalopathies of obscure origin in infants and children was in 1961. Previous names also include “devastating epileptic encephalopathy in school age children (DESC),” “Fever induced refractory encephalopathy in school age children” and “acute encephalitis with refractory repetitive partial seizures (AERRPS).” Now known as “febrile infection‐related epilepsy syndrome” (FIRES), FIRES is a subcategory of New‐Onset Refractory Status Epilepticus (NORSE) and affects previously healthy children and adults suddenly and explosively.
1
FIRES is rare with an estimated incidence of one per million and a prevalence of one per 100 000.
2
The historical mortality rate of FIRES during the acute phase is between 9%–18%. Additionally, only 18% of children retain normal cognitive function following the acute phase, and over 90% develop refractory epilepsy requiring lifelong treatment.
2
,
3
,
4
,
5
In an effort to unify clinicians and streamline research around the NORSE and FIRES, the consensus defining group convened and set standard definitions for NORSE and FIRES (funded by NORSE institute and endorsed by Critical Care EEG Monitoring Research Consortium (CCEMRC)).
6
NORSE was defined as a clinical presentation, not a specific diagnosis, in a patient without active epilepsy or other pre‐existing relevant neurological disorder, with new onset of refractory status epilepticus without a clear acute or active structural, toxic, or metabolic cause. FIRES is thus defined as a “subcategory of NORSE that requires a prior febrile infection, with fever starting between 2 weeks and 24 hours prior to onset of refractory SE, with or without fever at onset of SE.”
6
Unlike NORSE, FIRES affects slightly more male children, and the median age of onset is roughly 8 years.
4
,
6
,
7
Presentation of FIRES often begins with new‐onset intermittent or stuttering seizures that progress in a crescendo‐like pattern. Over a period of 2‐7 days, seizures generally increase in frequency and duration, and progress to refractory status epilepticus (RSE) with minimal response to conventional anti‐seizure medications (ASM). Some reported common features on the electroencephalograms (EEGs) of children with FIRES include 1) extreme delta brush, 2) a gradual increase in seizure burden and 3) focal seizure activity often with an onset low amplitude fast (>10 Hz) activity that evolves and shifts from one hemisphere of the brain to the other, eventually ending in the contralateral hemisphere.
8
Eventually, the seizure activity wanes in patients who survive, and there is progressive recovery of varying degrees of consciousness. Unfortunately, surviving patients are often left with significant cognitive deterioration and chronic intractable epilepsy.
3
,
9
Improved understanding of the underlying pathophysiology of FIRES may help guide treatment options and improve outcomes. Preliminary data suggest a dysregulated innate immune system activation in FIRES.
6
,
10
,
11
An unopposed pathological inflammatory state in the central nervous system (CNS) driven by over active proinflammatory cytokines and chemokines has been reported in children with this disorder.
12
This may contribute to seizure activity as these molecules have proconvulsant activity.
7
Additionally, a key role of interleukin‐1 (IL‐1) in epilepsy has been demonstrated in animal models.
13
Others have hypothesized that mesial temporal damage may contribute to the drug‐resistant epilepsy.
3
,
4
,
12
2 OBJECTIVES
Given the high morbidity and mortality in FIRES, and the potential role of inflammatory process that may allow for targeted therapy, an international group of pediatric epileptologists, pediatric neurointensivists, rheumatologists and basic scientists with clinical interest and expertise in FIRES was convened with a goal of:
Formulating a rational consensus driven approach for the evaluation of children with super‐refractory status epilepticus in order to increase the recognition of patients with FIRES
Developing a schema for early treatment of children meeting the current definition of FIRES with a goal of improving outcomes
Creating a collaboration of providers for potential future research or trials for patients with FIRES
3 METHODS
The FIRES workshops were held in conjunction with the 2017‐2019 American Epilepsy Society meeting. These were organized by Sookyong Koh, MD, PhD. Persons who had published or presented work in this area were invited and encouraged to invite colleagues who also had expertise in FIRES. Twenty‐five participants attended the first FIRES Workshop in 2017 and represented five countries (USA, UK, Sweden, Italy, and France). An initial draft protocol was outlined based on a group consensus at the initial meeting. Additional experts were invited and eventually included, resulting in this writing group. The group met annually at the American Epilepsy Society for the following two years to develop this final consensus document.
4 RESULTS
4.1 Pathogenesis of FIRES
The exact pathogenesis of FIRES remains elusive, but appears to involve a fulminant neurogenic inflammation in the brain.
2
,
10
Neurogenic inflammation has been proposed to describe an inflammatory response occurring in CNS cells, not only in neurons but also in glia and vascular cells of the blood‐brain barrier (BBB) which is evoked by enhanced levels of neuronal activity.
14
A nonspecific, febrile infectious process occurs within two weeks preceding presentation with RSE; however, a single, causative pathogenic agent has not been identified.
3
Rather, it is likely that a nonspecific infection, not causal to the syndrome, triggers an inflammatory cascade.
3
The hypothesis, supported by increased CSF levels of inflammatory molecules and the therapeutic response of unremitting seizures to anti‐cytokines treatments in FIRES patients, is that the progressive febrile infection primes the brain of a predisposed individual by inducing inflammatory response thereby reducing seizure threshold. Days to weeks after the febrile infection, the reduced threshold favors precipitation of seizures which in turn provoke a massive neurogenic inflammatory response. This neurogenic response contributes to seizure recurrence and status epilepticus.
Thus, FIRES may be considered a postinfectious immune system dysregulation in healthy, yet vulnerable individuals. While there have been no consistent single gene mutations reported in patients with FIRES, a genetic predisposition to inflammation may be important. In 2016, a potential link to the cytokine pathway was identified in patients with FIRES. Candidate gene analyses of 19 Japanese children with FIRES, focusing on polymorphisms of cytokine‐related genes, found a significant association between the frequency of tandem repeats of the RN2 allele of IL‐1RN and FIRES.
15
Variation in this allele results in higher levels of IL‐1β and lower levels of IL‐1Ra. A potential imbalance of intrinsic functional deficiency in endogenous IL‐1 receptor antagonist (IL1‐RA) and active IL‐1β could lead to an unopposed pathologic inflammatory state. Sakuma et al found proinflammatory cytokines and chemokines markedly elevated in FIRES patients while T‐cell associated and homeostatic cytokines were not.
10
,
12
Low rates of multiple autoantibodies, including GluR2, GluR3, glutamine decarboxylase (GAD), anti‐voltage‐gated potassium channel complex (VGKC), and neuropil, have been detected in FIRES cases. However, these rare positive findings likely reflect secondary epiphenomena due to breakdown of the BBB.
3
,
16
4.2 Preclinical and clinic evidence of IL‐1β‐IL‐1R1 axis as a therapeutic target
IL‐1 is a master cytokine of local and systemic inflammation. IL‐1Ra is the endogenous competitive antagonist of IL‐1 receptor type 1 (IL‐1R1); this receptor transduces the cellular signal upon agonist activation. It is well known that > 100‐fold molar excess of IL‐1Ra is needed to efficiently inhibit IL‐1 activity.
17
Anakinra is the human recombinant form of IL‐1Ra and was the first to be introduced in 1993. Anakinra currently has an established safety profile, known pharmakokinetics with short half‐life and is effective in CNS.
18
The availability of specific IL‐1‐targeting agents, such as anakinra, has revealed a pathological role of IL‐1‐mediated inflammation in a growing list of autoinflammatory diseases.
17
Anakinra is approved for use in various rheumatological disorders, including rheumatoid arthritis, neonatal onset multisystem inflammatory disease,
18
and other cryopyrin‐associated period fever syndromes. Anakinra is standard of care in systemic juvenile arthritis and macrophage activation syndrome. There have been two published phase II clinical studies evaluating the use of anakinra for neurological disease including patients with acute stroke and traumatic brain injury. In these studies, patients demonstrated the drug's tolerability even in exceptionally high doses.
19
,
20
There is established and growing evidence for the activation of the IL‐1β‐IL‐1R1 signaling pathway in human pharmacoresistant epilepsies in both children and adults, as shown by immunohistochemical and biochemical studies carried out in surgically resected epileptogenic foci.
21
,
22
,
23
,
24
,
25
Similar findings are reported in both immature and adult animal models of acute symptomatic seizures, febrile and non‐febrile SE, as well as in models of acquired epilepsies, absence epilepsy, and progressive myoclonic epilepsy.
26
,
27
,
28
,
29
Notably, the activation of this signaling in animals significantly contributes to seizure generation in both acute and chronic models
28
and is involved in epileptogenesis evoked by SE.
30
,
31
,
32
The activation of the IL‐1 signaling pathway, a pivotal part of the neuroinflammatory response, in chronic epileptogenic tissue
33
,
34
suggests that this signaling is inefficiently controlled. Indeed, IL‐1Ra, which is the key molecule modulating the effects of IL‐1β, is expressed to a lower extent than IL‐1β in epileptic foci from drug‐resistant epilepsy patients
22
and in animal models.
35
There is also a lower level of IL‐1Ra in blood of children with febrile seizures compared to children with fever without seizures.
36
Thus, the ratio IL‐1Ra:IL‐1β is likely to be involved in determining seizure threshold. Recent evidence showed that circulating IL‐1Ra in children with FIRES is less effective in blocking the IL‐1β‐signals as compared to native IL‐1Ra, as assessed in a cell‐based reporter system, denoting a functional inefficiency in IL‐1Ra inhibitory activity.
12
In support of the hypothesis that an imbalance between IL‐1β and IL‐1Ra contributes to recurrent seizure mechanisms, there are pharmacological studies in animal models showing that the intracerebral injection of IL‐1Ra blocks the ictogenic effects of IL‐1β
37
and is anticonvulsive per se by decreasing seizure number by 50% in kainate‐injected adult rats.
38
Additional studies have shown that adult mice overexpressing the human recombinant form of IL‐1Ra in astrocytes by 15‐fold were intrinsically more resistant to seizures.
39
Further studies of anakinra in adult rodent models have demonstrated an effect on the incidence, severity and duration of SE.
40
,
41
Anakinra also mediates neuroprotection
42
and inhibited seizures induced by bicuculline in an isolated guinea pig brain. Its anticonvulsive effect was associated with rescue of blood‐brain barrier (BBB) permeability dysfunction and decreased IL‐1β expression in astrocytes.
43
Inhibition of IL‐1β biosynthesis using the caspase‐1 inhibitor VX‐765 was also effective in reducing drug‐resistant recurrent seizures in adult epileptic mice.
44
Since FIRES affects mostly children, it is relevant to underscore that the activation of IL‐1‐IL‐1R1 axis has been demonstrated in forebrain astrocytes and neurons in immature rodent models of seizures, such as in postnatal day 14‐15 mice exposed to hyperthermia‐induced status epilepticus.
45
This axis was shown to contribute to both acute seizures and epiletogenesis in this model.
30
,
45
Another model incorporates an inflammatory challenge induced by the bacterial product lipopolysaccharide (LPS) in immature rats but seizure precipitation requires a concurrent convulsive agent at a subcovulsive dose: both the induction of the seizure and its long term neurological sequelae involve inflammatory processes.
46
Additionally, anakinra reduced kindling epileptogenesis in immature rats promoted by LPS,
47
and anakinra co‐administered with a COX‐2 antagonist to juvenile P21 rats after SE reduced the ensuing epilepsy severity since rats developed a milder form of epilepsy with strong reduction (up to 70%‐90%) of spontaneous seizure frequency, neuroprotection, and rescue of neurological comorbidities.
48
Notably, immature rats exposed to kainate‐induce seizures displayed age‐dependent seizure‐induced neuroinflammation in forebrain which occurs at about 2 weeks of age and approaches the adult pattern at P21.
49
This age‐dependent pattern may be ascribed to uncoupling between kainate‐seizures and activation of transcriptional factors promoting inflammation such as AP‐1 or NFkB. This evidence supports that the rodent brain becomes susceptible to seizure‐associated neuroinflammation at an age compatible with the occurence of FIRES in humans.
50
In summary, the experimental data show that the cytokine pathway, specifically mediated through IL‐1β is involved in both humans and animal models of epilepsy, including FIRES. Dysregulation of the balance of IL‐1β activation and inhibition influences epilepsy and epileptogenesis. These factors can be modified or targeted by therapeutics, including anakinra, which has evidence of potent anti‐seizure actions in a variety of experimental models of seizures, affords neuroprotection, and has potential anti‐epileptogenic effects.
4.3 Therapeutic options for FIRES
4.3.1 Anti‐seizure medications
Anti‐seizure medications (ASM) are poorly efficacious in FIRES.
3
Many children are treated with prolonged anesthetic coma given their seizure burden; however, there is concern that longer durations of barbiturate‐induced, burst suppression coma correlate with worse cognitive outcomes.
51
Cannabidiol (CBD) has been approved as Epidiolex® (GW Pharma) for the treatment epilepsy in patients with Dravet Syndrome or Lennox‐Gastaut Syndrome.
52
CBD may have an anti‐inflammatory effect. Small case series of patients with FIRES treated with CBD (mostly in the chronic phase) documented improvement in seizure frequency and duration in 6/7 cases after four weeks (90% reduction) and 48 weeks (65% reduction) of treatment.
4
4.3.2 Ketogenic diet
Several small case series suggest a benefit of ketogenic diet in children with FIRES,
53
,
54
with one study documenting efficacy in 7/9 children within 4‐6 days after diet onset.
53
Notably, the β‐hydroxybutyrate, one main ketone body generated by the KD, inhibits the proteolytic activity of caspase‐1 thereby reducing the release of biologically active IL‐1β.
55
The ketogenic diet exhibits anti‐inflammatory properties in animal studies, with animals showing less fever and lower proinflammatory cytokines after just 14 days of dietary therapy than controls.
56
4.3.3 Immunomodulatory/anti‐inflammatory therapies
Patients with FIRES are often treated with high‐dose steroids, intravenous immunoglobulin (IVIG), or both; however, there is little evidence of efficacy for such treatments. In a retrospective study of 29 patients given steroids for FIRES, most of whom were treated with pulse methylprednisolone, no significant benefit was seen in any subject.
3
Similarly, limited data support efficacy for plasmapheresis and no convincing benefit was noted in 30 patients given IVIG.
3
In one study of 8 children, IVIG was partially efficacious in 2 cases; however, both of these subjects had oligoclonal bands found in CSF electrophoresis, which is atypical for FIRES.
57
Therapeutic hypothermia is known to have anti‐inflammatory and neuroprotective property and has been shown to be beneficial in patients with FIRES.
7
The KD might also be active through an anti‐inflammatory mechanism as detailed above.
55
,
56
There are several case reports of children with FIRES treated with anakinra that showed significant reduction in seizures.
11
,
12
,
58
,
59
,
60
,
61
,
62
In a 32‐month old girl with FIRES, cytokine analysis was performed on both CSF and serum. While no significant abnormalities were detected in serum, both IL‐8 and IL‐6 were markedly increased in the CSF pretreatment but normalized on treatment. IL‐1β analysis was attempted but deemed unreliable.
There is little data on the use of other immunomodulatory therapies, although some of these also have a direct effect on the cytokine pathway. Canakinumab, a monoclonal antibody against IL‐1β has shown benefit in single report of a FIRES patient also treated with anakinra.
13
Tocilizumab blocks IL‐6‐mediated signaling and was reported to improve NORSE symptoms in one study; however, adverse events were reported following tocilizumab use in a fraction of patients within the study. Tocilizumab has a longer half‐life than anakinra and its CNS penetration is unclear.
63
Rituximab is an anti‐CD20 monoclonal antibody that depletes circulating B‐cells. It has shown no benefit in two reported cases of FIRES.
64
,
65
Tacrolimus inhibits T‐cell activation and proliferation and has been used in two cases with mixed results. Sato et al documented efficacy in a single patient who was also found to have anti‐glutamate receptor ε2 antibodies, suggesting this was probably not cryptogenic FIRES;
66
however, there was no benefit in one other case.
2
5 Proposed diagnostic heuristic and therapeutic considerations
FIRES is a devastating diagnosis that does not respond to treatment with conventional therapies and has a high rate of morbidity and mortality. New randomized trial data is unlikely to be feasible due to the low prevalence of FIRES. Given the available preclinical and case report data, we propose a shift in therapy toward early targeted immune therapy for FIRES, as our group no longer felt there was equipoise for treating FIRES without targeted therapies. To aid in the rapid identification of patients with FIRES and potential early targeted therapy, we compiled a typical case presentation of a child with FIRES (Box 1) as well as a diagnostic heuristic and approach to therapies (Figure 1). The recommendations made are expert opinion based on our experiences in treating children with FIRES, published case studies, and discussions with other clinicians in this field of study.
FIGURE 1 FIRES Recommended Diagnostics and Therapeutics ‡For cytokine assays, biorepository. EEG, electroencephalography; MRI, magnetic resonance imaging; CSF, cerebral spinal fluid; SE, status epilepticus; MP, methylprednisolone; CNS, central nervous system; ASM, anti‐seizure medications. Suspect diagnosis: New‐onset acute repetitive seizures and intermittent SE in a previously healthy, normal developing child older than 2 years of age; preceding febrile illness within 2 weeks of seizure onset. First 24 hours: First tier work up to exclude active bacterial and viral CNS infection via lumbar puncture. Confirm no other structural etiology via brain MRI. Continuous EEG monitoring needed. Save serum and CSF for autoimmune panel. Escalating ASM with benzodiazepines, fosphenytoin, phenobarbital, levitiracetam, valproic acid, midazolam drip followed by barbiturate coma—burst suppression. Day 2‐6: Establish FIRES determination—super‐refractory SE (SRSE); strongly consider FIRES by day 6. Start ketogenic diet. Tolerate brief breakthrough seizures; try lift or avoid barbiturate‐induced burst suppression. If suspicion of autoimmune encephalitis is high, then consider methylprednisolone (30 mg/kg daily, max 1 g, for 3 days) ± IVIG (2 g/kg divided over 2‐3 days). blood, serum, and CSF, if available, for cytokine assays including neopterin, Il‐6 and IL‐1β (see Table 1). Consider anakinra (subcutaneous injection 10 mg/kg divided twice to 4 times daily up to 400 mg/day). Consider other ASM including CBD Day 7‐21: Start ketogenic diet and anakinra if not done already. Avoid prolonged anesthetics, such as pentobarbital coma, propofol, lidocaine, isoflurane, or ketamine infusion. Extended trial of anakinra (3‐4 weeks) may be necessary before response is seen; alternatively, or if no response to anakinra after 4 weeks, consider other †immunomodulation such as tocilizumab (subcutaneous or intravenous injection 8‐12 mg/kg) or canakinumab (subcutaneous injection 2‐3 mg/kg) for patients weighing between 15‐40 kg. Continue immunomodulatory therapy if positive response noted. Consider alternate therapy, such as plasmapheresis, rituximab, cyclophosphamide, if autoimmune antibody detected. Resources: NORSE Institute (www.norseinstitute.com) NORSE Prospective Study
Nicolas.gaspart@erasme.ulb.ac.be
or
alrence.hirsch@yale.edu
Norse Family Resgistry
Teneille.gofton@lhsc.on.ca
Case Presentation
A previously healthy, developmentally normal 6‐year‐old girl initially presented to the emergency department (ED) with a 2‐week history of cough and rhinorrhea and a 24‐hour history of abdominal pain, dizziness, and fever, without headache, neck stiffness, or altered level of consciousness. A urinalysis in the ED was suggestive of a urinary tract infection, and she was prescribed an oral antibiotic and discharged. The prescription for the antibiotic was not filled because of a holiday weekend, and her mother brought her back to the ED the following day, where she was febrile to 39.4°C. She received an intramuscular dose of ceftriaxone and was again discharged home. Three days after her initial presentation, the patient again had a fever to 38.8°C, and her mother witnessed acute‐onset gaze deviation and head turn towards the left, progressing to generalized stiffness. Upon arrival to ED, the patient was awake and interactive; however, she was soon noted to have a decreased level of responsiveness with fluttering eyelid movements and oral automatisms. She was given intravenous lorazepam, and these movements stopped. She then became hypoxic and required emergent intubation with mechanical ventilation. Head computed tomography was unremarkable, and continuous video electroencephalogram (cvEEG) indicated subclinical SE, which persisted despite administration of 2 additional doses of intravenous lorazepam. She was given intravenous fosphenytoin (20 mg/kg), started on a midazolam infusion, and transferred to the pediatric intensive care unit (PICU).
In the 12 hours following patient’s arrival to the PICU, she had 9 multifocal onset electroclinical seizures, characterized by rhythmic twitching in the right face, arm, and leg. Midazolam infusion was discontinued and replaced by a pentobarbital infusion, which was titrated to a burst‐suppression EEG pattern. Empiric broad‐spectrum antibiotic coverage was initiated, including vancomycin, ceftriaxone, and acyclovir. A lumbar puncture (LP) was performed to rule out meningoencephalitis, and CSF analysis revealed 15 white blood cells (WBC)/mm3 with slightly elevated glucose and normal protein. CSF polymerase chain reactions for enterovirus, adenovirus, and herpes simplex virus were all negative. On hospital day 2, levetiracetam was initiated. Efforts to wean pentobarbital resulted in additional subclinical seizures, so this was continued, to target a burst‐suppression EEG pattern.
Additional investigation (see Appendix A) were unrevealing with negative infectious testing and a brain MRI with nonspecific findings of bilateral hippocampal and left thalamic T2 signal hyperintensity, with a loss of normal architecture in these regions. She received additional ASM including lacosamide, isoflurane, lidocaine infusion, perampanel, ketamine infusion, and cannabidiol oil. Additional therapies trialed included the ketogenic diet, hypothermia, magnesium infusion and intravenous immunoglobulin. Despite these aggressive therapies, the patient continued to have RSE. By hospital days 16, she developed many complications including refractory hypotension requiring continuous vasopressors and hydrocortisone, and anuria with renal failure requiring continuous venovenous hemofiltration (CVVH). The patient expired on hospital day 23 of respiratory failure.
5.1 How can FIRES be recognized early in the clinical course with reasonable certainty?
FIRES should be clinically suspected in any child presenting with new‐onset seizures, without a clear acute or active structural, toxic, or metabolic cause, which are rapidly increasing in frequency and severity following a nonspecific febrile illness in the last 2 weeks to 24 hours, consistent with the proposed definition approved by the CCEMRC.
6
The most critical differential diagnoses that must be excluded are central nervous system infections and autoimmune encephalitis. Common treatable infectious, metabolic, toxic, and structural etiologies can typically be excluded within the first 48 hours (Table 1).
TABLE 1 Diagnostic testing during evaluation for suspected FIRES
Blood/Serum CSF Other Testing
Infectious
Bacterial culture
Additional infectious testing based on travel and season
CSF cell count
Bacterial Culture
HSV PCR
Meningoencephalitis Panel (PCR)
CSF arboviral Panel (Immunoassay)
MRI with and without contrast
Continuous video EEG
Autoimmune
Autoimmune Encephalopathy Panel
ANA, SLE panel
ESR, CRP, Procalcitonin
Autoimmune Encephalopathy Panel
Autoinflammatory
B, T, NK cell number, ferritin
Immunoglobulins, IgE
Cytokine Panel (Cincinatti Children's Laboratory) Neopterins
Cytokine Panel (Cincinatti Children's Laboratory)
Neopterins
Metabolism
Based on history consider specific testing
Pre‐Ketogenic diet laboratories including:
electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels
John Wiley & Sons, LtdAs confirmation of specific antibodies that cause autoimmune encephalitis, such as anti‐NMDA receptor antibody, may be delayed for 1‐2 weeks, empiric treatment with IV methylprednisolone or IVIG is often undertaken after infectious causes are excluded, or in addition to empiric anti‐infective coverage. The common prodrome with behavior changes, mutism, and movement disorders may suggest that anti‐NMDA R encephalitis is a more likely etiology in the correct clinical context
67
and can help guide specific treatment for this diagnosis. Seizures are common (~ 70%), but rarely frequent, while the other two major symptoms, psychiatric features and movement disorders are even more prevalent (>90%).
67
,
68
Lack of clinical improvement after 2‐5 days of immunotherapy, including methylprednisolone, IVIG and plasmapheresis, should prompt increased clinical suspicion for FIRES. Unfortunately, there are no definitive confirmatory laboratory markers for FIRES. Laboratory evaluations are thus to exclude other identifiable etiology for RSE.
5.2 When to start empiric therapy for FIRES?
Once other potential common treatable causes are excluded with reasonable certainty, presumptive treatment for FIRES should be initiated, ideally, within one week of initial presentation. While research studies have demonstrated elevations in various inflammatory cytokines, such studies are very limited in the clinical sphere, and if performed, results are often available only after a significant delay. Our working group felt strongly that definitive treatment for FIRES should not be delayed given the lack of an established role in confirmatory cytokine testing.
5.3 What are potential therapeutic options in a child with SRSE, in whom FIRES is suspected?
Targeted therapy includes treatment with anakinra, initiation of the ketogenic diet where available, cannabidiol, and additional anti‐inflammatory therapies.
5.3.1 Anakinra considerations
As described above, preclinical data are compelling and early clinical data suggest that anakinra is beneficial in many FIRES patients. This is an established, effective medication used in rheumatologic disorders in children and is well‐tolerated and safe.
2
,
12
,
58
,
62
If seizures remain refractory after empiric treatment with corticosteroids and/or IVIG and if anesthetic agents are unable to be weaned, adding Anakinra for IL‐1 blockade should be considered within the first two weeks of presentation. Our group felt that there was not adequate therapeutic equipoise to justify a placebo‐controlled study, but that a well‐designed open‐label study should be done, comparing outcome in anakinra‐treated subjects to previously reported cases in the literature. Given that fulminant neurogenic inflammation is likely injurious to the brain, our group agreed that initiation of anakinra is likely time‐sensitive, with the potential for improved outcomes both regarding seizure control and neurocognitive function with earlier therapy. Thus, anakinra should optimally be started prior to or within the first two weeks (7‐14 days) after initial seizure presentation. Though rapid decreases in seizure burden have been experienced by our group (within 1‐2 days), extended trials of 3‐4 weeks may be needed particularly for patients with protracted courses. Several authors have identified and reported patients with increased seizures when anakinra is stopped and improved seizure control after re‐initiation. Extended therapy may be helpful during the chronic epilepsy phase of FIRES.
5.3.2 Ketogenic diet considerations
If it is possible to safely initiate the ketogenic diet at the patient's hospital, early initiation can start within the first week. As per each institution's ketogenic diet protocol in general, metabolic diseases should be excluded. Testing may include (based on clinical history): electrolytes, hepatic panel, amylase, lipase, NH3, lactic acid, pyruvic acid, amino acids, organic acids, carnitine, acyl‐carnitine, and beta‐hydroxybutyrate levels. If there is nothing suggestive of a metabolic disorder from the history or initial studies, the ketogenic diet can be initiated while testing is pending and stopped if metabolic parameters worsen. A metabolic disease is less likely the older the onset of FIRES.
3
5.3.3 CBD Considerations
Initiation of CBD may be considered at any time during the course of FIRES, but should not delay anakinra therapy, as there is limited data regarding the use of CBD in the acute phase of treatment.
5.3.4 Additional targeted anti‐inflammatory therapy
Tocilizumab and canakinumab may have therapeutic roles; however, the group felt they had lesser evidence and potentially greater side effects than anakinra and decreased CSF penetration, and thus should only be considered if anakinra is ineffective. Our group recommended caution combining tocilizumab and anakinra due to combined immune suppression and potential additive adverse effects.
6 DISCUSSION
FIRES is a devastating epilepsy syndrome that has significant associated morbidity and mortality necessitating early diagnosis and targeted treatment. Early administration of immune modulatory drugs, including the IL‐1 receptor antagonist, anakinra, that blocks biologic activity of IL‐1β, may be beneficial. Canakinumab, another IL‐1β inhibitor
13
and tocilizumab, an IL‐6 inhibitor,
63
have also been used with promising results in FIRES and NORSE cases, though more data are available with anakinra in children with FIRES at this time. Initiation of a ketogenic diet is strongly recommended due to established anti‐inflammatory effects; additionally, positive results in children with FIRES given a ketogenic diet have been reported.
6
,
53
CBD has been presented as a possible alternative therapy for uncontrolled seizures in a small case study in children with FIRES and is approved for other refractory epilepsy syndromes. This may be considered in conjunction with other therapies, although there is limited data regarding use in the acute phase of FIRES. Unfortunately, prolonged use of high‐dose barbiturates and anesthetics to induce coma may contribute to poor cognitive outcomes in patients with FIRES.
3
,
7
Tolerating brief breakthrough seizures or a low seizure burden may allow for weaning from continuous anesthetic anti‐seizure medications.
Though FIRES is a rare syndrome, its effect on children and their families is truly devastating. Randomized trials are not likely given the rarity and severity of this condition. Open communication among treating clinicians and establishment of a database and biorepository are underway to facilitate research into the underlying cause and pathogenesis of NORSE and FIRES (NORSE Institute www.norseinstitute.com). Delays in diagnostics and administration of appropriate therapeutics may contribute to poor prognoses.
7
We present these proposed expert recommendations and describe international collaborative efforts with the hope of helping future patients with FIRES and in memory of the children lost.
CONFLICT OF INTEREST
Sookyong Koh applied and received unrestricted educational grant from Sobi to hold FIRES Workshops. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
ACKNOWLEDGEMENTS
The authors wish to acknowledge the assistance and support of Sobi for unrestricted educational grant support; Dr Amy Brewster, Dr Kevin Chapman, Dr Jim Baumagartner, Dr Larry Hirsch, Ms Nora Wong and Dr Teresa Ravizza for their expert input; and Dr Ashley Bohn in manuscript development.
APPENDIX A Other Testing (Case Presentation)
Additional available data from the case presentation are listed below.
TSH low at 0.26, T4 low at 0.40, ANA‐negative, HIV‐negative, dsDNA‐negative, ANCA: neg, tissue transglutaminase IgA‐negative, issue transglutaminase IgG normal, TPO Ab‐negative, thyroglobulin‐negative, RPR nonreactive, ACE‐negative, arbovirus panel: negative, VRP: Adenovirus +. Repeat on 7/17 negative, adenovirus CSF: negative, CSF cytology: neg, NMDA serum: neg, Ehrlichia spp. titers: neg, Cat Scratch (Bartonella henselae) IgG/IgM: neg, genetic metabolic panel: Nonspecific changes not indicative of a metabolic disease. | Fatal | ReactionOutcome | CC BY-NC-ND | 33681649 | 19,147,763 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardio-respiratory arrest'. | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | BIOTIN, CARBAMAZEPINE, CLONAZEPAM, LEUCOVORIN, LEVETIRACETAM, OXCARBAZEPINE, PHENYTOIN, POTASSIUM BROMIDE, PYRIDOXINE, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33681650 | 19,124,536 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infantile spasms'. | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | BIOTIN, CLONAZEPAM, CORTICOTROPIN, LACOSAMIDE, LEUCOVORIN, LEVETIRACETAM, PHENOBARBITAL, POTASSIUM BROMIDE, PYRIDOXINE, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33681650 | 19,129,696 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Infection'. | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | BIOTIN, CARBAMAZEPINE, CLONAZEPAM, LEUCOVORIN, LEVETIRACETAM, OXCARBAZEPINE, PHENYTOIN, POTASSIUM BROMIDE, PYRIDOXINE, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33681650 | 19,124,536 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Sepsis'. | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | BIOTIN, CLONAZEPAM, CORTICOTROPIN, LACOSAMIDE, LEUCOVORIN, LEVETIRACETAM, PHENOBARBITAL, POTASSIUM BROMIDE, PYRIDOXINE, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33681650 | 19,129,696 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Somnolence'. | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | BIOTIN, CARBAMAZEPINE, CLONAZEPAM, LEUCOVORIN, LEVETIRACETAM, OXCARBAZEPINE, PHENYTOIN, POTASSIUM BROMIDE, PYRIDOXINE, VALPROIC ACID | DrugsGivenReaction | CC BY-NC-ND | 33681650 | 19,124,536 | 2021-03 |
What was the dosage of drug 'POTASSIUM BROMIDE'? | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | TITRATED AT 80 MG PER KG PER DAY | DrugDosageText | CC BY-NC-ND | 33681650 | 19,124,536 | 2021-03 |
What was the outcome of reaction 'Cardio-respiratory arrest'? | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33681650 | 19,124,536 | 2021-03 |
What was the outcome of reaction 'Sepsis'? | A novel possible familial cause of epilepsy of infancy with migrating focal seizures related to SZT2 gene variant.
Seizure threshold-2 (SZT2) gene variants have been associated with a decrease in seizure threshold resulting in variable phenotypic expressions ranging from mild-moderate intellectual disabilities without seizures, to an early-onset epileptic encephalopathy with severe cognitive impairment. In addition, hypotonia and distinctive facial dysmorphism, including a high forehead and to a lesser extent ptosis and down-slanting palpebral fissures, were present in the majority. We herein report a novel SZT2 variant in one of two siblings both diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). This report is the fourth to document a possible familial case in EIMFS, a condition that was not previously associated with SZT2 variant. This report expands the phenotypic expression of SZT2, corroborates the importance of genetic counseling in some cases of EIMFS, and highlights the efficacy of potassium bromide in controlling the seizures associated with this condition.
Key Points
Seizure threshold‐2 gene is highly expressed in the central nervous system and acts by regulating the mechanistic target of rapamycin (mTOR).
We are reporting a new possible familial case affecting two sisters harboring a SZT2 gene variant.
Both siblings were diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures.
Both sisters were highly pharmacoresistant and experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide.
1 INTRODUCTION
Seizure threshold‐2 (SZT2) gene, located on chromosome 1p34.2, is highly expressed in the central nervous system (CNS) and has been associated with a decrease in seizure threshold.
1
This gene that acts by regulating the mechanistic target of rapamycin (mTOR) activation was first identified in 2013 by Basel‐Vanagaite et al in two children diagnosed with an early‐onset refractory epileptic encephalopathy.
2
Subsequently, a few additional cases with variable phenotypic expressions were reported, although the majority manifested with an early‐onset pharmacoresistant epileptic encephalopathy associated with distinctive dysmorphic facial features.
We report a novel SZT2 gene variant in one of two siblings both diagnosed with the syndrome of epilepsy of infancy with migrating focal seizures (EIMFS). This is the first association between SZT2 variant and EIMFS and the possible fourth reported familial case of EIMFS.
2 CASES
Our two patients are sisters, born at 36 weeks of gestation to first degree cousins. They have an older brother, who is developmentally normal and with no history of seizures. Both had distinct dysmorphic facial features characterized by a high forehead, down‐slanting palpebral fissures and ptosis (Table 1). The siblings had remarkably similar neurological findings, seizure semiologies, EEG features and clinical courses (Table 1).
TABLE 1 Characteristics of the two siblings
Patient 1 Patient 2
Dysmorphic facial features High forehead, down‐slanting palpebral fissures and ptosis High forehead, down‐slanting palpebral fissures and ptosis
Psychomotor development
At 5 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone. At 6 months: complete head lag, axial and appendicular hypotonia, could not sit, did not reach for objects with absent visual tracking and no reactivity to auditory or visual stimuli. Never acquired any milestone.
Age at first seizure 1 mo 2 wk
Initial semiology Behavioral arrest, blinking and flushing Behavioral arrest, increased tone, grimacing and flushing
Stormy phase At 4 months: staring, blinking, flushing, increased tone, apnea and cyanosis with desaturation ± unilateral increased tone or clonic jerking
At 6 weeks: behavioral arrest, facial cyanosis, increased tone, apnea and desaturation
At 6 months: epileptic spasms
Seizure frequency Multiple times daily in clusters Multiple times daily in clusters
Seizure Duration 1‐2 min 1‐2 min
Initial EEG Multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from the right parasagittal, right posterior temporal, and left frontotemporal regions and sometimes migrating from one hemisphere to the other (at 5 months) Normal (at 2 wk)
Subsequent Worse EEG Same as initial EEG
Generalized slowing, multifocal independent spikes with ictal activity originating independently from the right frontotemporal, left temporal or bilateral temporal areas, and on occasions, the ictal discharge propagated from one hemisphere to the other (at 6 wk)
Hypsarrhythmia (at 6 mo)
Brain MRI Persistent cavum septum pellucidum and a short corpus callosum of normal thickness Persistent cavum septum pellucidum with a corpus callosum of normal length and thickness
Brain MRS Normal Normal
Metabolic workup Normal Normal
Immune workup Decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels
Decrease in cytotoxic T lymphocytes, T helper lymphocytes and natural killer cells. Normal B lymphocyte levels.
Low IgM with adequate levels of IgG and IgA
AEDs tried in multiple combinations Phenytoin, carbamazepine, oxcarbazepine, levetiracetam, clonazepam, valproate, potassium bromide Levetiracetam, valproate, phenobarbital, clonazepam, lacosamide, ACTH, potassium bromide
Other treatment Biotin, pyridoxine, folinic acid Biotin, pyridoxine, folinic acid
Outcome Death at 11 mo Death at 19 mo
John Wiley & Sons, LtdThe eldest sister (patient 1) started experiencing focal seizures characterized by behavioral arrest associated with blinking and flushing at 4 weeks of age. At the age of 4 months, the seizures recurred in clusters of 15‐30 episodes daily with each seizure lasting from 30 seconds to 2.5 minutes despite treatment with multiple combinations of antiseizure medications (Table 1). On her examination at 5 months of age, she was severely delayed (Table 1). A long‐term video/EEG recording revealed rare multifocal independent spikes with innumerable multifocal‐onset seizures originating independently from various cortical areas and sometimes migrating from one hemisphere to the other during the same seizure event (Table 1). Semiologically, the seizures were characterized by staring, blinking, flushing, increased tone, apnea, and cyanosis with the oxygen saturation sometimes dropping down to 75%. An epilepsy protocol brain MRI revealed a persistent cavum septum pellucidum and a short corpus callosum of normal thickness (Figure S1A).
3
MR spectroscopy (MRS) and metabolic investigations were normal. Her immune workup showed a decrease in all lymphocyte subsets and a decrease in all immunoglobulin levels (Table 1). At that time, potassium bromide was added to her regimen and titrated to a dose of 80 mg/kg/day, which resulted in mild somnolence relative to her baseline state. This drug, according to her parents, resulted in a dramatic and sustained reduction in the frequency of her seizures with only rare and isolated recurrences until her death at the age of 11 months from cardiorespiratory arrest secondary to an infection.
Her sister (patient 2) started to experience seizures at two weeks of age, characterized by behavioral arrest, increased tone, grimacing, and flushing. An EEG performed at day 21 of life was normal, although her typical spell was not captured (Table 1). At week 6 of life, the patient experienced a cluster of similar episodes along with apnea and cyanosis and associated on the surface EEG with ictal onsets originating independently from multiple brain regions with migration of the ictal discharge from one hemisphere to the other during the same seizure event (Figure 1A). A brain MRI showed a persistent cavum septum pellucidum with a corpus callosum of normal length and thickness (Figure S1B).
3
MRS and metabolic investigations were normal (Table 1). An immune profile revealed a reduction of lymphocytes and a low IgM level (Table 1). On examination, the patient had severe developmental delay and her seizures remained poorly controlled despite treatment with various combinations of antiseizure medications (Table 1). At the age of 6 months, she experienced flexor and tonic spasms in clusters associated with hypsarrhythmia (Figure 1B) that responded to ACTH. Subsequent serial video/EEG recordings documented slowing of the background, multifocal independent spikes, and focal seizures originating from multiple independent brain regions. An EEG performed at 15 months while maintained on phenobarbital, levetiracetam, clonazepam, lacosamide, and valproate depicts one of her innumerable recorded focal‐onset seizures (Figure 1C). Her seizures persisted and recurred in cluster multiple times daily until potassium bromide was introduced at 18 months of age, after which, according to her parents’ report, she remained seizure free till her death from sepsis one month later. While on potassium bromide, the child was more somnolent and sedated relative to her baseline state.
FIGURE 1 A, Consecutive EEG pages showing an ictal activity originating from the right hemisphere and migrating to the left hemisphere. B, Hypsarrhythmia with epileptic spasms in clusters seen on the EMG channel. C, Focal seizure that originated from the right temporal area and propagated 25 s later to the left temporal area
Whole exome sequencing revealed a SZT2 homozygous variant Chr1(GRCh37):g.43868902C > T; NM_015284.3:c.82C > T; p.(Arg28*), with homozygosity confirmed by parental testing who were both heterozygous for that variant. The SZT2 homozygous variant c.82C > T p. (Arg28*) creates a premature stop codon and is classified as likely pathogenic (Class 4) according to the ACMG guidelines. No other variants were found.
3 DISCUSSION
We present two siblings, one of whom had a documented novel homozygous nonsense variant in the SZT2 gene, c.82C > T p. (Arg28*), resulting in an early stop of protein translation. This variant was never reported hitherto and was not identified on the NHLBI Exome Sequencing Project (ESP) Exome Variant server (http://evs.gs.washington.edu/EVS). The population allele frequency of this variant was found to be 3.54e‐6 (using gnomAD database; https://gnomad.broadinstitute.org), which reflects the rarity and pathogenic likelihood of this nonsense variant.
SZT2 gene variant was first reported by Vanagaite et al in two unrelated children who shared common dysmorphic facial features, a distinctive early‐onset refractory epilepsy with encephalopathy and absent developmental milestones.
2
Since its original description, 19 additional cases were reported. Most were sporadic with only four families affected accounting for 9 of the 21 cases.
4
,
5
,
6
We are reporting a new possible familial case, the second of an Arabic descent,
5
harboring a SZT2 gene variant.
SZT2 loss‐of‐function variants alter the mechanistic target of rapamycin (mTOR) signalling.
7
This may explain the role of its variants in epileptogenesis.
1
It was recently shown that SZT2 dysfunction leads to a hyperactivation of the mTORC1 signaling pathway resulting in increased cell proliferation, disturbed connectivity of the brain and epileptogenesis.
1
,
8
,
9
SZT2 gene variants are associated with differing phenotypic expressions ranging from mild‐moderate intellectual disabilities without seizures,
10
to an early‐onset epileptic encephalopathy with severe cognitive impairment.
6
The severity of clinical manifestations varies according to the extent of residual protein function. As such, a biallelic truncating variant, as described in our patient, will result in a complete loss of SZT2 function and lead to a severe phenotype while the milder form is associated with homozygous in‐frame deletions of a single amino acid.
11
Characteristically, hypotonia and facial dysmorphism, including a high forehead and to a lesser extent ptosis and down‐slanting palpebral fissures, were present in the majority of reported patients including ours.
4
,
11
,
12
Although no genetic testing was done on the first child, as the WES was not available in our institution at the time, she was almost certainly affected by the same condition in view of her indistinguishable dysmorphic features, and essentially identical clinical course, EEG findings, and seizure semiology.
Most patients with an STZ2 variant (18/21; 86%) experienced seizures with a variable age at onset but mostly during the first 10 months of life.
6
,
11
The reported seizure types consisted of focal‐onset seizures, tonic seizures, and atypical absences.
6
,
13
Focal or multifocal epileptiform discharges were seen on the interictal EEG
6
,
13
while the ictal findings, described in only two previous cases originated from the temporal area.
6
We are the first to report that EIMFS can be secondary to a STZ2 variant. This condition, first described in 1995,
14
is a severe form of pharmacoresistant epilepsy characterized by recurrent seizures with an onset in the first 6 months of life, EEG documentation of seizures with multifocal ictal origins, and migration from one cortical region to another, in addition to profound developmental regression.
15
,
16
Focal motor seizure is the most frequent and characteristic seizure type encountered in this syndrome.
15
,
16
Although our two siblings did not have this particular seizure type, they both experienced recurrent daily clusters of focal impaired awareness seizures characterized by generalized stiffening and eye blinking associated with prominent autonomic manifestations, a semiology frequently described in this syndrome.
15
,
16
In addition, the co‐occurrence of infantile spasms in our second case associated with hypsarrhythmia has been described in infants with EIMFS.
16
Initially considered to be nonfamilial and of an unknown etiology, this condition was recently linked to several mutations most commonly affecting the KCNT1 and SCN2A genes.
17
All were de‐novo mutations except for three previous reports of familial EIMFS.
18
,
19
,
20
Our two patients were highly pharmacoresistant but both experienced a dramatic reduction in seizure frequency following the introduction of potassium bromide. Potassium bromide was reported to be effective in reducing seizure frequency in several cases diagnosed with EIMFS of various etiologies.
16
,
21
,
22
,
23
,
24
It was initially suggested that SZT2 variants are associated with two distinctive MRI findings consisting of a thick and shortened corpus callosum (CC) along with a persistent cavum septum pellucidum (CSP).
2
Subsequent accounts however failed to consistently describe those findings and reported normal imaging studies or different types of abnormalities including delayed myelination, dilated ventricles, atrophy, heterotopia, or subependymal nodules.
6
,
12
,
13
Both our patients had evidence of a persistent CSP on brain MRI with an abnormally short but not thickened CC in one of them. Interestingly, the detected CSP might not represent an incidental finding since it was reported to be a developmental anomaly that may contribute to epileptogenesis.
25
Basel‐Vanagaite et al (2013) published a very similar variant (early homozygous truncation of SZT2 at position 25) in a 10‐year‐old girl, the sixth child of nonconsanguineous parents of Iraqi Jewish descent. One of her brothers, probably affected by the same condition, died at the age of three years from a pulmonary infection. Like our two siblings, this girl had the same facial dysmorphic features (high forehead, down‐slanting palpebral fissures, and ptosis), severe developmental delay, hypotonia, and absence of developmental milestones.
2
Her seizures however started later at the age of 4 years (although the seizure onset in her affected brother was at the age of two months) and consisted of highly refractory focal impaired awareness seizures semiologically characterized by drooling and perioral cyanosis with occasional focal to bilateral tonic‐clonic seizures. Her interictal EEG was characterized by a slow background with multifocal epileptiform discharges, and her ictal EEG revealed focal 6 Hz or 12‐14 Hz discharges that secondarily generalized.
2
However, unlike our two siblings, there was no mention of ictal propagation from one hemisphere to the other.
Both siblings suffered from repeated infections and were found to have abnormalities in their immune workup. Whether SZT2 variants are associated with immunodeficiency will need to be confirmed in subsequent studies.
In summary, our findings expand the phenotypic spectrum of SZT2 variants and corroborate the importance of genetic counseling in some cases of EIMFS. In addition, they suggest that potassium bromide might be useful for the management of refractory seizures associated with SZT2 variants.
CONFLICTS OF INTERESTS
None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Supporting information
Fig S1
Click here for additional data file.
ACKNOWLEDGEMENTS
None. | Fatal | ReactionOutcome | CC BY-NC-ND | 33681650 | 19,129,696 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Cardiac arrest'. | Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.
The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated.
A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118).
Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group.
Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects.
Research Grants Council, Hong Kong.
Research in context
Evidence before this study
Rapid sedation via the intramuscular route is often preferred in patients with acute agitation in emergency settings. Whether intramuscular olanzapine is effective and safe compared to conventional treatment options (including benzodiazepines and first-generation antipsychotics) in emergency settings, where the aetiology of acute agitation is usually undifferentiated and clinical endpoints are urgent, is uncertain.
We searched PubMed from inception to July 22, 2020, without language restrictions, for randomised trials, systematic reviews, meta-analyses, and observational studies, using the terms “agitation or acute agitation or violence” and “parenteral or intramuscular” and “emergency”. During the study period, we identified four randomised trials (published in 2007, 2011, 2013, and 2016) conducted in psychiatry settings that evaluated the effectiveness and safety of intramuscular olanzapine. We did not find any randomised trials comparing intramuscular olanzapine with other sedatives for the treatment of acute agitation in emergency departments.
Added value of this study
We conducted a randomised, active-controlled trial in six Hong Kong emergency departments comparing time to sedation in patients receiving 5 mg of intramuscular midazolam, olanzapine or haloperidol. All three treatments provided adequate sedation at 60 min and midazolam resulted in faster sedation compared to the others. The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol. Overall adverse event rates were similar across the three arms while extrapyramidal syndrome (n = 1) and fatal cardiac arrest (n = 1) episodes were reported in the haloperidol arm.
Implications of all the available evidence
In patients with undifferentiated agitation admitted to emergency departments, intramuscular midazolam and olanzapine are preferred over haloperidol in view of haloperidol's slower time to sedation and the potential for cardiovascular and extrapyramidal side effects.
Alt-text: Unlabelled box
1 Introduction
Undifferentiated acute agitation presenting at the emergency department (ED) often stems from various aetiologies, including underlying mental illness, drug or alcohol intoxication, or a combination of diagnoses [1], [2], [3], [4]. Failed de-escalation strategies or oral medication necessitates parenteral sedation to prevent subsequent harm [5], with intramuscular sedation generally considered prior to intravenous cannulation [2].
A range of medications are currently used for rapid intramuscular sedation to manage acute agitation in the emergency setting, including benzodiazepines (e.g. midazolam [6], [7], [8], [9], [10], [11], [12], [13], lorazepam) [11,14,15], first-generation antipsychotics (e.g. haloperidol [[6], [7], [8],[11], [12], [13],[15], [16], [17], [18], [19], [20]], droperidol) [9,10,16,20], and second-generation antipsychotics (e.g. olanzapine [7,8,18], risperidone [17], ziprasidone) [7,8,10]. Recently, interest in second-generation antipsychotics to manage acute agitation has grown due to the lower incidence of extrapyramidal side effects (EPS) [7,8], over-sedation [8], and need for further rescue medications [10].
Intramuscular olanzapine and other sedatives have not been directly compared using randomised clinical trials in the general ED setting. Studies to date have used observational [21], [22], [23] or open-label study designs [18]. Previous randomised controlled trials have focused on intravenous olanzapine [4,24] or were conducted in psychiatric emergency settings [7,8,18]. The intravenous route provides rapid onset of action but may be inappropriate in some contexts as adequate staff and resources are required to manage potential emergencies. Our survey of emergency physicians in Hong Kong EDs reported a preference for intramuscular sedation over intravenous sedation, whereas the intravenous route was generally preferred in Australasia [25], suggesting regional differences in prescribing culture, and differences in the perceived need for aggressive management. Other studies investigated intramuscular olanzapine in psychiatric settings where patients with agitation were predominantly homogeneous with a history of mental illness [7,8,18] rather than “undifferentiated”, with an undiagnosed cause of agitation. Study results from psychiatric settings are not directly generalisable to inform acute ED practice due to differences in measured outcomes and perceived accept time to adequate sedation in different clinical contexts. To date, evidence of intramuscular olanzapine use in the general ED is scant as all have been observational studies [[21], [22], [23],26]. Therefore, comparing intramuscular olanzapine with haloperidol or midazolam, the two most commonly selected sedating agents in local setting [25], is important in determining a safe and effective choice of an initial agent for acute agitation in the ED setting. This study compares a second-generation antipsychotic (olanzapine) with a conventional antipsychotic (haloperidol) and a benzodiazepine (midazolam) in acute agitation management in the ED.
2 Methods
2.1 Study design
This was a multi-centre, double-blind, randomised, active-controlled pragmatic trial at EDs in six public hospitals under the Hong Kong Hospital Authority (Table S1 and S7). Between April 2014 to March 2019, patient attendances at these 24-h EDs comprised 39% of the Hospital Authority's overall ED visits. The Institutional Review Board or Clinical Research Ethics Committee approval was given at all study sites (Supplementary Table S1). An independent Data Safety and Monitoring Board for the study comprised a Biostatistician (BJC), Clinical Pharmacologist (BMYC), Toxicologist (MLT), Emergency Physician (HFH), Psychiatrist (CWL). This study was registered in ClinicalTrials.gov (NCT02380118).
2.2 Patients
Patients were enrolled from December 24, 2014 to September 6, 2019. Inclusion criteria were: patients aged 18–75 years; and requiring parenteral drug sedation for acute agitation at the treating physician's discretion. Patients who had received oral or parenteral sedative drug(s) within 12 h, either as usual medications or pre-hospital acute agitation management, were eligible. Exclusion criteria were known hypersensitivity or contraindication to any of the study drugs, immediately reversible aetiology for agitation (e.g. hypotension, hypoxia, hypoglycaemia), known pregnancy, or acute alcohol withdrawal (as it is amendable to benzodiazepines alone) [27]. All eligible patients were initially treated according to the study protocol (Appendix 1).
Written informed consent was secured from either the patient following recovery, if they had capacity to understand the study and give informed consent, or the patient's authorised representative. Inherent challenges in obtaining informed consent from highly agitated patients attending emergency settings have been acknowledged [3,10,11,22]. Application for patient consent waiver, as used in previous clinical trials internationally [1,3,4,10,11,19], was submitted but not approved. As requested by local ethics committees, patient consent was obtained after intervention or from an authorised representative.
2.3 Randomisation and masking
Eligible patients were assigned to the next sequential study pack pre-assembled by independent pharmacists (not involved in the patient's care during acute agitation episode) from the participating hospital's pharmacy department according to a computer-generated randomisation list. Study packs contained the assigned study drug, data collection tools, an unblinding envelope, and other necessary documents. All study packs and unblinding envelopes were opaque, sealed and tamper-proof. At each site, patients were randomised to “permuted blocks of six”, each containing two packs of haloperidol, olanzapine, and midazolam to ensure each arm had similar allocated numbers. Six randomisation lists were generated independently for each study site.
As the appearance of each study drug (midazolam/haloperidol: clear liquid ampule; olanzapine: yellow powder vial) could compromise double-blinding, an independent nurse (not involved in the participant's care) prepared and administered all study drugs. Blinding was maintained with all staff involved in patient care, monitoring, data collection, and statistical analysis.
2.4 Procedures
Patients were randomised to receive an initial 5 mg intramuscular injection of olanzapine, haloperidol, or midazolam with a ratio of 1:1:1, with an optional additional 5 mg dose of the same medication (maximum total dose=10 mg). Study drug selection and doses were based on local Hong Kong clinical practice and survey results [25] on prescribing preferences for acute agitation management, which reported haloperidol and midazolam monotherapy as the sedating agents most frequently selected for undifferentiated agitation in ED. The intramuscular route was the most common choice (63·9%) regardless of drug chosen; median initial and cumulative doses were 5 mg and 10 mg respectively. Although the product monograph recommends a starting dose of 10 mg intramuscular olanzapine, this is seldom prescribed in the local ED setting. Investigators concurred that both the initial (5 mg) and one additional dose (5 mg) would be included in each study pack to allow for flexibility in dosing escalation. To achieve initial or maintain adequate sedation, patients were eligible for alternative sedative drug(s) in addition to the assigned study drug according to clinical response and at the treating physician's discretion.
Agitation/sedation level was measured on a 6-point validated sedation scale: (5=highly aroused, violent; 4=highly aroused, possibly distressed, or fearful; 3=moderately aroused, unreasonable, or hostile; 2=mildly aroused, willing to talk reasonably; 1=minimal agitation; and 0=asleep) [28]. Adequate sedation was defined as a score ≤2. This scale was applied in previous clinical trials that studied sedation in ED [1,3,4,29]. Sedation scores and actual time of measurement were recorded at baseline (immediately before initial dose, t = 0), at first observed adequate sedation, and at 10, 20, 30, 45, and 60 min after the first dose regardless of observed time to sedation. Measurements were recorded by the treating physician, nurses (other than the independent nurse), or research staff. All study participants were given standard sedation care including 1:1 nursing and regular monitoring of sedation level, vital signs, cardiac rhythm, protocol-specified common adverse events, and any other untoward medical occurrence whether or not the occurrence is related to or considered to have a causal relationship with the study drug. Common adverse events related to study drugs were listed in the data collection tool, including airway management (jaw thrust, oral, nasal airway), need for assisted ventilation (bag & mask, intubation), oxygen desaturation <90%, systolic BP<90 mmHg, dystonic reactions, seizures, vomiting or aspiration. If possible, a 12-lead electrocardiogram (ECG) was obtained within 30 min of adequate sedation. However, ECGs are challenging to perform in highly agitated patients and therefore were not always obtained.
Other participant data, including sex, age, and medication history were collected on a standardised Case Report Form. ED presentation details were also collected at triage including perceived possible causes at current presentation such as drug/substance abuse, alcohol intoxication, underlying mental illness, non-compliance to usual medication, and suicidal ideation. Concurrent prescriptions of any antipsychotics, antidepressants, or hypnotics/anxiolytics were also retrieved from the Hospital Authority's computerised medical records system wherever possible.
2.5 Outcomes
The primary outcome measure was time to achieve adequate sedation. Three study arms were compared according to: 1) time required to achieve adequate sedation following drug administration; and 2) proportion of patients adequately sedated at 10, 20, 30, 45, and 60 min. Secondary outcome measures included: 1) proportion of patients requiring a second dose of study drug and/or alternative drug(s) to achieve initial adequate sedation; 2) proportion of patients with corrected QT interval (QTc) prolongation on the ECG (defined as QTc interval over 450 ms and 470 ms, respectively, for males and females) [30]; 3) adverse events reported after study drug administration; 4) the proportion of patients with a sedation score of 0 (observed asleep) after study drug administration [28]; and 5) ED length of stay (LOS).
2.6 Statistical analysis
Sample size calculation was based on Isbister et al., where intramuscular droperidol and midazolam were compared head-to-head in an Australian ED [9]. Assuming sedation times were similar to the Australian study and to demonstrate a difference in the mean time to sedation of 20 versus 25 min (standard deviation=12) between the two arms (haloperidol vs. midazolam), 91 patients were required in each arm (2-sided, statistical power 0·8). Thus, we aimed to enrol 282 patients (rounded up from 273 to account for patient loss).
The modified intention-to-treat principle was applied in the primary analysis. Thirty-six patients received treatment but were excluded due to lack of informed consent. As required by the IRB and stated in the protocol, a primary analysis of patients with informed consent was undertaken according to the allocated study arm, regardless of any unblinding or protocol deviations. The proportion of patients adequately sedated over time were plotted with Kaplan-Meier curves. Time from drug administration to adequate sedation was analysed based on the Kaplan-Meier estimate allowing for interval-censored data. Statistical tests for comparison of every two Kaplan-Meier curves were conducted with asymptotic two-sample log-rank tests. Median time to sedation was calculated for each arm with 95% confidence intervals (CI). Further, the relationship between drug exposure and time to sedation was investigated by fitting Weibull accelerated failure time models adjusted for sex, age, concurrent psychotropic medications, and perceived possible cause of agitation.
Differences in the median ED LOS from study drug administration to discharge/transfer were tested with the log-rank test. Differences in descriptive data of secondary outcomes were tested using Fisher's exact test/Chi-squared test (categorical variables) and log-rank test (continuous variables). A two-sided p-value <0·05 was considered statistically significant. Interim analysis was conducted at recruitment of 130 patients as detailed in Supplementary-Interim Analysis. Data was analysed using R version 3·4·3 (R Foundation for Statistical Computing, Vienna, Austria) by independent Data Safety and Monitoring Board member BJC and statistician VJF.
2.7 Role of the funding source
This study was funded by Research Grants Council, Hong Kong (789813). The study's funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author has full access to all data in the study and has final responsibility for the decision to submit for publication.
3 Results
3.1 Participants
During the study period 2423 patients were screened, of which 206 received study drugs and 167 provided informed consent (Fig. 1), provided by patients and representatives in 25·1% and 74·9% of cases, respectively. After receiving study drugs, 39 patients were excluded due to failure to consent (n = 36) or found out of age range (n = 3) (Fig. 1). Fifty-six patients were allocated to midazolam arm, 54 to olanzapine, and 57 to haloperidol. The actual sample size was less than planned as the study concluded prematurely due to factors detailed in Supplementary-Early Termination. Patient baseline characteristics were generally balanced, although the haloperidol arm (42%) had a lower proportion of males compared with the midazolam (61%) and olanzapine (70%) arms (Table 1). Use of any antidepressants, hypnotics, and anxiolytics were similar across all arms. Results of interim analysis are listed in Supplementary Table S2–5 and Figure S1.Fig. 1 Flow Diagram of Patient Inclusion (Modified CONSORT Diagram)
a, including other exclusion criteria, patients’ preference, profound risk of adverse event, and multiple exclusion reasons; b, the age of these 3 patients was unknown at recruitment, two patients were found to be over 75 years old, one below 18 years old after treatment; c. two patients were unconscious during the length of stay at Emergency Department and not accompanied by any representative; d, one dose of study drug was discarded due to contamination; e, one dose of study drug was given intravenously; f, allocation of two patients was unblinded due to protocol violation (intravenous route; n = 1) and for informing of the procedural sedation for endoscopy after transfer (5 mg given in Emergency Department; n = 1); g, allocation of three patients was unblinded due to adverse event (n = 2) and for informing of further sedation (10 mg given in Emergency Department; n = 1).
Fig. 1Table 1 Baseline characteristics of patients.
Table 1 Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Age (median, IQR) 44 (34, 54) 40 (30,54) 42 (33, 55)
Male 34 (61) 38 (70) 24 (42)
Perceived possible cause
Drug/substance abuse 16 (31) 14 (27) 19 (37)
Alcohol intoxication 15 (28) 12 (23) 13 (25)
Underlying mental illnesses 47 (87) 45 (83) 46 (84)
Non-compliance to usual medication 24 (47) 22 (43) 18 (35)
Suicidal ideation/attempt 18 (34) 17 (33) 18 (35)
Prior sedative drug 1a (2) 1b (2) 1c (2)
Concurrent psychotropic medications (any antipsychoticsd, antidepressantse, or hypnotics and anxiolyticsf) 19 (34) 17 (31) 13 (23)
Baseline sedation score
3 13 (23) 16 (30) 14 (25)
4 17 (30) 21 (39) 17 (30)
5 26 (46) 16 (30) 25 (44)
IQR, interquartile range; atramadol 50 mg; bhaloperidol 5 mg; chaloperidol 10 mg dantipsychotics were medications under the British National Formulary (BNF) category 4·2·1 and 4·2·2; eantidepressants were defined as medications under the BNF category 4·3; fhypnotics and anxiolytics were defined as medications under the BNF category 4·1.
3.2 Primary outcomes
The median time to sedation estimated by the Kaplan-Meier function was 8·5 (95% CI 8·5–59·5, IQR 8·0), 11·5 (95% CI 7·5–67·0, IQR 30·0), and 23·0 min (95% CI 6·0–53·5, IQR 21·0) for midazolam, olanzapine, and haloperidol, respectively. At 10 min after the initial dose, 52%, 34%, and 21% of patients were adequately sedated in the midazolam, olanzapine, and haloperidol arms, respectively. At 60 min, the proportion of patients sedated increased to 98%, 87%, and 97%, respectively (Table 2). The proportion of patients sedated by time was plotted on Kaplan-Meier curves (Fig. 2). Significant differences were detected in the Kaplan-Meier curves for midazolam compared with olanzapine (p = 0·03) and haloperidol (p = 0·002); however, this was not observed for haloperidol compared with olanzapine (p = 0·78).Table 2 Proportion of patients adequately sedated at each time point.
Table 2 Study group
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Proportion sedated, min
At 10 29·3 (52) 18·2 (34) 12·0 (21)
At 20 44·0 (79) 32·7 (60) 23·3 (41)
At 30 51·0 (91) 40·0 (74) 36·2 (63)
At 45 51·0 (91) 43·6 (81) 46·5 (82)
At 60 54·8 (98) 47·2 (87) 55·5 (97)
Interval-censored data was applied in this analysis.
Fig. 2 Proportion of Patients Adequately Sedated by Time in Kaplan-Meier Curve
No included patient was censored during observation. p-values derived by using asymptotic log-rank two-sample test for comparison of midazolam vs olanzapine, midazolam vs haloperidol, and haloperidol vs olanzapine were 0.03, 0.002 and 0.78, respectively.
Fig. 2
3.3 Secondary outcomes
The proportion of patients given the second dose of study drug or alternative sedative(s) was similar across all arms (Table 3). Fully-adjusted accelerated factors for olanzapine and haloperidol were compared with midazolam at 1·72 (95% CI 1·16–2·55) and 1·89 (95% CI 1·28–2·80), respectively (Supplementary Table S6), indicating significantly faster sedation for midazolam. The Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation with an accelerated factor of 0·96 (95% CI 0·49–1·88) for male (compared with female).Table 3 Patients given second dose of study drug or alternative sedatives, with adverse event report, and observed asleep.
Table 3 Study group P value
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Administered second dose of study drug or alternative sedatives 18 (32) 16 (30) 23 (40) 0·46
Administered second dose 13 (23) 15 (28) 18 (32) 0·61
Administered alternative sedatives 9a (16) 6 (11) 7b (12) 0·72
Midazolam 6 (67) 2 (33) 3 (43)
Haloperidol 2 (22) 4 (67) 2 (29)
Diazepam 3 (33) 0 – 2 (29)
Lorazepam 1 (11) 0 – 1 (14)
With adverse event 2 (4) 3 (6) 3 (5) 0·91
Oxygen desaturation (<90%) 2 (4) 1 (2) 1 (2)
Dry month 0 – 2 (4) 0 –
Dystonia 0 – 0 – 1 (2)
Cardiac arrest 0 – 0 – 1 (2)
ECG obtained (N = 52) (N = 52) (N = 56)
QTc prolongation 12 (23) 9 (17) 13 (23) 0·59
Fell asleep after treatment 28 (50) 10 (19) 17 (30) <0·01
*ECG, 12-lead electrocardiogram; QTc, corrected QT interval.
An adverse event is any untoward medical occurrence in a patient after administration of a medicinal product, which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug.
a Three patients were given two alternative sedative drugs.
b One patient was given two alternative sedative drugs.
Overall, the adverse event rate was similar for midazolam, olanzapine, and haloperidol at 4%, 6%, and 5%, respectively (Table 3). The most common adverse event was oxygen desaturation (midazolam, n = 2; olanzapine, n = 1; haloperidol, n = 1). Two patients in the olanzapine arm reported dry mouth. One patient reported dystonia after one dose of haloperidol (5 mg), which resolved fully with 2 mg intramuscular benztropine. In the single severe adverse event, the patient had a cardiac arrest three hours after two doses of intramuscular haloperidol (10 mg in total; second dose given 33 min after initial dose) and died 8 days later (see Supplementary-Severe Adverse Event).
Similar proportions of ECG completion and QTc prolongation were observed across the three arms (Table 3). The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol (p<0·01) (Table 3). LOS data was estimated as 4·52 (95% CI 2·63–8·69), 4·01 (95% CI 2·31–6·42), and 4·02 (95% CI 2·32–6·87) hours for midazolam, olanzapine and haloperidol, respectively. No significant difference in LOS was detected (p = 0·73).
4 Discussion
Intramuscular midazolam was more effective compared with antipsychotic drugs (olanzapine and haloperidol), as shown by the shorter time to adequate sedation and the higher proportion of patients sedated at any time point. No differences in outcomes were observed between olanzapine and haloperidol. All study drug dosages were effective in managing acute agitation in ED settings within 60 min.
No significant differences in adverse event rates were found across the three arms. One episode of extrapyramidal syndrome (dystonia) and one severe adverse event (fatal cardiac arrest) were reported in the haloperidol arm. Due to the low number of adverse events, the probability of type II error cannot be ruled out as the study was insufficiently powered to identify such differences. The high risk of extrapyramidal syndrome associated with haloperidol is well recognised and the event was considered to be causally associated with haloperidol [31]. The Data Safety Monitoring Board assessment concluded that the cause of death was associated with potential psychostimulants and unlikely to be solely associated with the study drug.
Additionally, significant differences were found in the proportion of patients asleep after study drug administration, with the highest percentage in the midazolam arm. Previous studies reported that midazolam posed a higher risk of over-sedation [9], considered as an undesirable clinical outcome [32]. Although no extended ED LOS was detected, patient assessment and referrals to other medical specialties may be delayed, requiring logistical considerations. Although no incident of respiratory depression was observed, midazolam is reported to cause respiratory depression [10] and careful monitoring of vital signs remains important, especially with high or rapidly escalating doses. Although differences in adverse event rate was not observed, intramuscular olanzapine was reported to be associated with a preferred safety profile compared to haloperidol [33]. Our times to sedation by midazolam and haloperidol were consistent with previously reported results. Intramuscular midazolam 2·5/5 mg was reported to achieve sedation within 5·1–18·3 min [6,10,11,13]. The mean time to sedation by intramuscular haloperidol 5 mg was reported to vary from 5 to 3 min [6,11,13]. Data exists concerning time to sedation in EDs by intramuscular olanzapine in randomised clinical trials and the product information suggests that the peak plasma concentration of 5 mg is expected within 15–45 min after administration. Raveendran et al. reported that 87% of violent patients with mental illnesses were sedated within 15 min with 10 mg intramuscular olanzapine in the psychiatry emergency setting [18].
Our recent study conducted in Australian EDs reported that after intravenous olanzapine 10 mg monotherapy (up to 20 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 11 min and 90·8%, respectively [4]. In the current study, after intramuscular olanzapine 5 mg was given (up to 10 mg in total as required), the median time to sedation and the proportion sedated at 60 min were 11·5 min and 87%, respectively. In our previous randomised clinical trial of intravenous olanzapine, we reported that following intravenous midazolam 2·5–5 mg monotherapy, the median time to sedation was 10 min, and proportion of patients sedated by 60 min was 87·0% [1]. In the current study, after intramuscular midazolam 5 mg (up to 10 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 8·5 min and 98%, respectively. These results suggest that the effectiveness of intramuscular olanzapine or midazolam (5 mg or 10 mg) in our predominantly Southern Chinese patient cohort might be comparable to intravenous administration of olanzapine or midazolam at similar doses. However, intramuscular sedation may provide more rapid initiation of emergency sedation, and potentially reduce the risk of injury to patients and staff, particularly during acute behavioural disturbance and in the context of mechanical restraint often being initially required. IV access in these circumstances may be fraught with difficulty and could be dangerous to both patients and staff members, so a less complex alternative route of administration (intramuscular) may provide many potential advantages if it is effective. The initial dose of intramuscular olanzapine (5 mg) may be considered relatively low compared to the manufacturer's recommendation (10 mg). In future studies, effectiveness and safety of higher doses of olanzapine in this clinical scenario could be further investigated.
The proportion of additional sedatives used in the haloperidol arm was numerically higher than the two other arms despite not reaching statistical significance. Consistently, higher proportions of additional sedative doses were required in patients treated with haloperidol vs. olanzapine as reported in observational studies by Klein et al. (18% vs. 11%)[26] and MacDonald et al. (43% vs. 29%), respectively [23].
Our study has several limitations. Firstly, the study concluded prematurely prior to attaining the full sample size mainly due to study fatigue and several episodes of social unrest in Hong Kong [34]. Early termination factors are detailed in Supplementary-Early Termination. The study period was extended from the initial planned 24 to 58 months. Despite the lower sample size, our study attained sufficient power to identify differences in the primary outcome measure among the three study drugs. Secondly, an imbalance in sex distribution was observed between the study arms, specifically, the haloperidol arm had more females than the other groups. However, the Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation given the accelerated factor by sex was close to one. Therefore, based on our results, the imbalance in sex distribution across the study arms is unlikely to affect the main results and conclusion. However, the possibility of imbalance in unmeasured baseline characteristics cannot be ruled out. Thirdly, while the sedation scale may introduce measurement bias due to subjectivity, it has been validated and applied in several studies conducted in similar settings [1,3,4]. Fourthly, patients were possibly excluded if physicians had a personal drug choice preference (e.g. antipsychotics preference for patients with known psychotic illness). However, exclusions of screened patients due to physician preference contributed only 1·2% of all excluded patients. Lastly, external validity may be impacted by the exclusion of some patients due to failure to obtain informed consent despite successful consent from 81·1% of those recruited. This discrepancy reflects immense challenges in undertaking pragmatic randomised clinical trials on acute agitation and behavioural emergencies in the ED setting and has been reported by researchers in ED settings elsewhere [22].
Our study indicates that intramuscular midazolam was more effective at 5–10 mg doses compared with olanzapine or haloperidol for acute agitation in ED settings, regardless of aetiology. Intramuscular midazolam's faster sedation time may deem it preferable as an initial sedation agent. Intramuscular midazolam, olanzapine, and haloperidol effectively sedated ED patients with acute agitation within 60 min. Although adverse event rates did not differ significantly, the potential risk of extrapyramidal side effects for haloperidol should be noted. Given the potential risk of adverse events, intramuscular midazolam or olanzapine should be considered over haloperidol for undifferentiated acute agitation in EDs. As this study includes only three of the most commonly prescribed sedatives in a local setting, further investigation to compare other sedatives is warranted.
Contributors
EWC, ICKW, and KSJL had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. EWC, KSJL, ICKW, CAG, JCK, DMT, DCMK, and LPL to developed the study design. EWC, KSJL, ICKW, BJC, JCK, DMT, DCMK, and SHT were responsible for the acquisition, analysis, and interpretation of data. EWC and KSJL drafted the manuscript. ICKW, CAG, JCK, DMT, and DCMK critically revised the manuscript. BJC and VJF contributed to statistical analysis. EWC, KSJL, LL, SHT, CTL, CPW, CAG, CHC, TSC, HFL, and SMT contributed in study site establishment and patient enrolment
Funding
This study was funded by Research Grants Council (Early Career Scheme), Hong Kong (789813).
Data sharing statement
Due to institutional review board restrictions associated with the trial, participant data is not available to external sources. Proposals to access the de-identified individual participant data (excluding any trial-specific participant opt-outs) that underlie the results reported in this article for secondary research purposes will be considered 12 months after publication. Proposal should be directed to the corresponding author, with approval by EWC and KSJL. Only proposals that are clearly in the public interest and compatible with the original purpose of the study will be considered. Qualified researchers will need to sign a data access agreement before data would be released.
Declaration of Competing Interest
All authors declare that no other support has been received from any organisation for the submitted work; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted study. Outside the submitted work, EWC has received honorarium from the Hospital Authority, research grants from Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA and Takeda outside the submitted work.. KSJL reports personal fees from MSD China, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. ICKW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire.
Appendix Supplementary materials
Image, application 1 Image, application 2
Acknowledgments
We thank all patients who participated in this trial. In addition to the authors, we express our appreciation to the following colleagues for their support and participation in this study: Queen Mary Hospital, Hong Kong, Tuen Mun Hospital, Hong Kong, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Prince of Wales Hospital, Hong Kong, Ruttonjee Hospital, Hong Kong, United Christian Hospital, Hong Kong; all pharmacists, physicians and nursing staff in participating sites; research associates and students who participated in this study: X Li, TY Ko, KY Yip, YT Hui, CY Ching, SY Kwok, C Tang, HK Tse, YK Ho, CY Lim, TY Leung, WH Chui, SY Ng, HW Chan, Y Chen, and all summer and exchange students who joined the team to learn about clinical trials. We express our thanks to members of Data Safety and Monitoring Board: BJ Cowling, HF Ho, ML Tse, BMY Cheung, CW Law; Statistician: VJ Fang; Proofreading: L Lam, J Blais, V Geall and KC Yan. Lastly, we are grateful for the support from Ms McShirley Leung who would have been pleased to know about our study findings.
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eclinm.2021.100751. | HALOPERIDOL | DrugsGivenReaction | CC BY-NC-ND | 33681744 | 19,870,551 | 2021-02 |
What was the administration route of drug 'HALOPERIDOL'? | Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.
The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated.
A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118).
Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group.
Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects.
Research Grants Council, Hong Kong.
Research in context
Evidence before this study
Rapid sedation via the intramuscular route is often preferred in patients with acute agitation in emergency settings. Whether intramuscular olanzapine is effective and safe compared to conventional treatment options (including benzodiazepines and first-generation antipsychotics) in emergency settings, where the aetiology of acute agitation is usually undifferentiated and clinical endpoints are urgent, is uncertain.
We searched PubMed from inception to July 22, 2020, without language restrictions, for randomised trials, systematic reviews, meta-analyses, and observational studies, using the terms “agitation or acute agitation or violence” and “parenteral or intramuscular” and “emergency”. During the study period, we identified four randomised trials (published in 2007, 2011, 2013, and 2016) conducted in psychiatry settings that evaluated the effectiveness and safety of intramuscular olanzapine. We did not find any randomised trials comparing intramuscular olanzapine with other sedatives for the treatment of acute agitation in emergency departments.
Added value of this study
We conducted a randomised, active-controlled trial in six Hong Kong emergency departments comparing time to sedation in patients receiving 5 mg of intramuscular midazolam, olanzapine or haloperidol. All three treatments provided adequate sedation at 60 min and midazolam resulted in faster sedation compared to the others. The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol. Overall adverse event rates were similar across the three arms while extrapyramidal syndrome (n = 1) and fatal cardiac arrest (n = 1) episodes were reported in the haloperidol arm.
Implications of all the available evidence
In patients with undifferentiated agitation admitted to emergency departments, intramuscular midazolam and olanzapine are preferred over haloperidol in view of haloperidol's slower time to sedation and the potential for cardiovascular and extrapyramidal side effects.
Alt-text: Unlabelled box
1 Introduction
Undifferentiated acute agitation presenting at the emergency department (ED) often stems from various aetiologies, including underlying mental illness, drug or alcohol intoxication, or a combination of diagnoses [1], [2], [3], [4]. Failed de-escalation strategies or oral medication necessitates parenteral sedation to prevent subsequent harm [5], with intramuscular sedation generally considered prior to intravenous cannulation [2].
A range of medications are currently used for rapid intramuscular sedation to manage acute agitation in the emergency setting, including benzodiazepines (e.g. midazolam [6], [7], [8], [9], [10], [11], [12], [13], lorazepam) [11,14,15], first-generation antipsychotics (e.g. haloperidol [[6], [7], [8],[11], [12], [13],[15], [16], [17], [18], [19], [20]], droperidol) [9,10,16,20], and second-generation antipsychotics (e.g. olanzapine [7,8,18], risperidone [17], ziprasidone) [7,8,10]. Recently, interest in second-generation antipsychotics to manage acute agitation has grown due to the lower incidence of extrapyramidal side effects (EPS) [7,8], over-sedation [8], and need for further rescue medications [10].
Intramuscular olanzapine and other sedatives have not been directly compared using randomised clinical trials in the general ED setting. Studies to date have used observational [21], [22], [23] or open-label study designs [18]. Previous randomised controlled trials have focused on intravenous olanzapine [4,24] or were conducted in psychiatric emergency settings [7,8,18]. The intravenous route provides rapid onset of action but may be inappropriate in some contexts as adequate staff and resources are required to manage potential emergencies. Our survey of emergency physicians in Hong Kong EDs reported a preference for intramuscular sedation over intravenous sedation, whereas the intravenous route was generally preferred in Australasia [25], suggesting regional differences in prescribing culture, and differences in the perceived need for aggressive management. Other studies investigated intramuscular olanzapine in psychiatric settings where patients with agitation were predominantly homogeneous with a history of mental illness [7,8,18] rather than “undifferentiated”, with an undiagnosed cause of agitation. Study results from psychiatric settings are not directly generalisable to inform acute ED practice due to differences in measured outcomes and perceived accept time to adequate sedation in different clinical contexts. To date, evidence of intramuscular olanzapine use in the general ED is scant as all have been observational studies [[21], [22], [23],26]. Therefore, comparing intramuscular olanzapine with haloperidol or midazolam, the two most commonly selected sedating agents in local setting [25], is important in determining a safe and effective choice of an initial agent for acute agitation in the ED setting. This study compares a second-generation antipsychotic (olanzapine) with a conventional antipsychotic (haloperidol) and a benzodiazepine (midazolam) in acute agitation management in the ED.
2 Methods
2.1 Study design
This was a multi-centre, double-blind, randomised, active-controlled pragmatic trial at EDs in six public hospitals under the Hong Kong Hospital Authority (Table S1 and S7). Between April 2014 to March 2019, patient attendances at these 24-h EDs comprised 39% of the Hospital Authority's overall ED visits. The Institutional Review Board or Clinical Research Ethics Committee approval was given at all study sites (Supplementary Table S1). An independent Data Safety and Monitoring Board for the study comprised a Biostatistician (BJC), Clinical Pharmacologist (BMYC), Toxicologist (MLT), Emergency Physician (HFH), Psychiatrist (CWL). This study was registered in ClinicalTrials.gov (NCT02380118).
2.2 Patients
Patients were enrolled from December 24, 2014 to September 6, 2019. Inclusion criteria were: patients aged 18–75 years; and requiring parenteral drug sedation for acute agitation at the treating physician's discretion. Patients who had received oral or parenteral sedative drug(s) within 12 h, either as usual medications or pre-hospital acute agitation management, were eligible. Exclusion criteria were known hypersensitivity or contraindication to any of the study drugs, immediately reversible aetiology for agitation (e.g. hypotension, hypoxia, hypoglycaemia), known pregnancy, or acute alcohol withdrawal (as it is amendable to benzodiazepines alone) [27]. All eligible patients were initially treated according to the study protocol (Appendix 1).
Written informed consent was secured from either the patient following recovery, if they had capacity to understand the study and give informed consent, or the patient's authorised representative. Inherent challenges in obtaining informed consent from highly agitated patients attending emergency settings have been acknowledged [3,10,11,22]. Application for patient consent waiver, as used in previous clinical trials internationally [1,3,4,10,11,19], was submitted but not approved. As requested by local ethics committees, patient consent was obtained after intervention or from an authorised representative.
2.3 Randomisation and masking
Eligible patients were assigned to the next sequential study pack pre-assembled by independent pharmacists (not involved in the patient's care during acute agitation episode) from the participating hospital's pharmacy department according to a computer-generated randomisation list. Study packs contained the assigned study drug, data collection tools, an unblinding envelope, and other necessary documents. All study packs and unblinding envelopes were opaque, sealed and tamper-proof. At each site, patients were randomised to “permuted blocks of six”, each containing two packs of haloperidol, olanzapine, and midazolam to ensure each arm had similar allocated numbers. Six randomisation lists were generated independently for each study site.
As the appearance of each study drug (midazolam/haloperidol: clear liquid ampule; olanzapine: yellow powder vial) could compromise double-blinding, an independent nurse (not involved in the participant's care) prepared and administered all study drugs. Blinding was maintained with all staff involved in patient care, monitoring, data collection, and statistical analysis.
2.4 Procedures
Patients were randomised to receive an initial 5 mg intramuscular injection of olanzapine, haloperidol, or midazolam with a ratio of 1:1:1, with an optional additional 5 mg dose of the same medication (maximum total dose=10 mg). Study drug selection and doses were based on local Hong Kong clinical practice and survey results [25] on prescribing preferences for acute agitation management, which reported haloperidol and midazolam monotherapy as the sedating agents most frequently selected for undifferentiated agitation in ED. The intramuscular route was the most common choice (63·9%) regardless of drug chosen; median initial and cumulative doses were 5 mg and 10 mg respectively. Although the product monograph recommends a starting dose of 10 mg intramuscular olanzapine, this is seldom prescribed in the local ED setting. Investigators concurred that both the initial (5 mg) and one additional dose (5 mg) would be included in each study pack to allow for flexibility in dosing escalation. To achieve initial or maintain adequate sedation, patients were eligible for alternative sedative drug(s) in addition to the assigned study drug according to clinical response and at the treating physician's discretion.
Agitation/sedation level was measured on a 6-point validated sedation scale: (5=highly aroused, violent; 4=highly aroused, possibly distressed, or fearful; 3=moderately aroused, unreasonable, or hostile; 2=mildly aroused, willing to talk reasonably; 1=minimal agitation; and 0=asleep) [28]. Adequate sedation was defined as a score ≤2. This scale was applied in previous clinical trials that studied sedation in ED [1,3,4,29]. Sedation scores and actual time of measurement were recorded at baseline (immediately before initial dose, t = 0), at first observed adequate sedation, and at 10, 20, 30, 45, and 60 min after the first dose regardless of observed time to sedation. Measurements were recorded by the treating physician, nurses (other than the independent nurse), or research staff. All study participants were given standard sedation care including 1:1 nursing and regular monitoring of sedation level, vital signs, cardiac rhythm, protocol-specified common adverse events, and any other untoward medical occurrence whether or not the occurrence is related to or considered to have a causal relationship with the study drug. Common adverse events related to study drugs were listed in the data collection tool, including airway management (jaw thrust, oral, nasal airway), need for assisted ventilation (bag & mask, intubation), oxygen desaturation <90%, systolic BP<90 mmHg, dystonic reactions, seizures, vomiting or aspiration. If possible, a 12-lead electrocardiogram (ECG) was obtained within 30 min of adequate sedation. However, ECGs are challenging to perform in highly agitated patients and therefore were not always obtained.
Other participant data, including sex, age, and medication history were collected on a standardised Case Report Form. ED presentation details were also collected at triage including perceived possible causes at current presentation such as drug/substance abuse, alcohol intoxication, underlying mental illness, non-compliance to usual medication, and suicidal ideation. Concurrent prescriptions of any antipsychotics, antidepressants, or hypnotics/anxiolytics were also retrieved from the Hospital Authority's computerised medical records system wherever possible.
2.5 Outcomes
The primary outcome measure was time to achieve adequate sedation. Three study arms were compared according to: 1) time required to achieve adequate sedation following drug administration; and 2) proportion of patients adequately sedated at 10, 20, 30, 45, and 60 min. Secondary outcome measures included: 1) proportion of patients requiring a second dose of study drug and/or alternative drug(s) to achieve initial adequate sedation; 2) proportion of patients with corrected QT interval (QTc) prolongation on the ECG (defined as QTc interval over 450 ms and 470 ms, respectively, for males and females) [30]; 3) adverse events reported after study drug administration; 4) the proportion of patients with a sedation score of 0 (observed asleep) after study drug administration [28]; and 5) ED length of stay (LOS).
2.6 Statistical analysis
Sample size calculation was based on Isbister et al., where intramuscular droperidol and midazolam were compared head-to-head in an Australian ED [9]. Assuming sedation times were similar to the Australian study and to demonstrate a difference in the mean time to sedation of 20 versus 25 min (standard deviation=12) between the two arms (haloperidol vs. midazolam), 91 patients were required in each arm (2-sided, statistical power 0·8). Thus, we aimed to enrol 282 patients (rounded up from 273 to account for patient loss).
The modified intention-to-treat principle was applied in the primary analysis. Thirty-six patients received treatment but were excluded due to lack of informed consent. As required by the IRB and stated in the protocol, a primary analysis of patients with informed consent was undertaken according to the allocated study arm, regardless of any unblinding or protocol deviations. The proportion of patients adequately sedated over time were plotted with Kaplan-Meier curves. Time from drug administration to adequate sedation was analysed based on the Kaplan-Meier estimate allowing for interval-censored data. Statistical tests for comparison of every two Kaplan-Meier curves were conducted with asymptotic two-sample log-rank tests. Median time to sedation was calculated for each arm with 95% confidence intervals (CI). Further, the relationship between drug exposure and time to sedation was investigated by fitting Weibull accelerated failure time models adjusted for sex, age, concurrent psychotropic medications, and perceived possible cause of agitation.
Differences in the median ED LOS from study drug administration to discharge/transfer were tested with the log-rank test. Differences in descriptive data of secondary outcomes were tested using Fisher's exact test/Chi-squared test (categorical variables) and log-rank test (continuous variables). A two-sided p-value <0·05 was considered statistically significant. Interim analysis was conducted at recruitment of 130 patients as detailed in Supplementary-Interim Analysis. Data was analysed using R version 3·4·3 (R Foundation for Statistical Computing, Vienna, Austria) by independent Data Safety and Monitoring Board member BJC and statistician VJF.
2.7 Role of the funding source
This study was funded by Research Grants Council, Hong Kong (789813). The study's funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author has full access to all data in the study and has final responsibility for the decision to submit for publication.
3 Results
3.1 Participants
During the study period 2423 patients were screened, of which 206 received study drugs and 167 provided informed consent (Fig. 1), provided by patients and representatives in 25·1% and 74·9% of cases, respectively. After receiving study drugs, 39 patients were excluded due to failure to consent (n = 36) or found out of age range (n = 3) (Fig. 1). Fifty-six patients were allocated to midazolam arm, 54 to olanzapine, and 57 to haloperidol. The actual sample size was less than planned as the study concluded prematurely due to factors detailed in Supplementary-Early Termination. Patient baseline characteristics were generally balanced, although the haloperidol arm (42%) had a lower proportion of males compared with the midazolam (61%) and olanzapine (70%) arms (Table 1). Use of any antidepressants, hypnotics, and anxiolytics were similar across all arms. Results of interim analysis are listed in Supplementary Table S2–5 and Figure S1.Fig. 1 Flow Diagram of Patient Inclusion (Modified CONSORT Diagram)
a, including other exclusion criteria, patients’ preference, profound risk of adverse event, and multiple exclusion reasons; b, the age of these 3 patients was unknown at recruitment, two patients were found to be over 75 years old, one below 18 years old after treatment; c. two patients were unconscious during the length of stay at Emergency Department and not accompanied by any representative; d, one dose of study drug was discarded due to contamination; e, one dose of study drug was given intravenously; f, allocation of two patients was unblinded due to protocol violation (intravenous route; n = 1) and for informing of the procedural sedation for endoscopy after transfer (5 mg given in Emergency Department; n = 1); g, allocation of three patients was unblinded due to adverse event (n = 2) and for informing of further sedation (10 mg given in Emergency Department; n = 1).
Fig. 1Table 1 Baseline characteristics of patients.
Table 1 Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Age (median, IQR) 44 (34, 54) 40 (30,54) 42 (33, 55)
Male 34 (61) 38 (70) 24 (42)
Perceived possible cause
Drug/substance abuse 16 (31) 14 (27) 19 (37)
Alcohol intoxication 15 (28) 12 (23) 13 (25)
Underlying mental illnesses 47 (87) 45 (83) 46 (84)
Non-compliance to usual medication 24 (47) 22 (43) 18 (35)
Suicidal ideation/attempt 18 (34) 17 (33) 18 (35)
Prior sedative drug 1a (2) 1b (2) 1c (2)
Concurrent psychotropic medications (any antipsychoticsd, antidepressantse, or hypnotics and anxiolyticsf) 19 (34) 17 (31) 13 (23)
Baseline sedation score
3 13 (23) 16 (30) 14 (25)
4 17 (30) 21 (39) 17 (30)
5 26 (46) 16 (30) 25 (44)
IQR, interquartile range; atramadol 50 mg; bhaloperidol 5 mg; chaloperidol 10 mg dantipsychotics were medications under the British National Formulary (BNF) category 4·2·1 and 4·2·2; eantidepressants were defined as medications under the BNF category 4·3; fhypnotics and anxiolytics were defined as medications under the BNF category 4·1.
3.2 Primary outcomes
The median time to sedation estimated by the Kaplan-Meier function was 8·5 (95% CI 8·5–59·5, IQR 8·0), 11·5 (95% CI 7·5–67·0, IQR 30·0), and 23·0 min (95% CI 6·0–53·5, IQR 21·0) for midazolam, olanzapine, and haloperidol, respectively. At 10 min after the initial dose, 52%, 34%, and 21% of patients were adequately sedated in the midazolam, olanzapine, and haloperidol arms, respectively. At 60 min, the proportion of patients sedated increased to 98%, 87%, and 97%, respectively (Table 2). The proportion of patients sedated by time was plotted on Kaplan-Meier curves (Fig. 2). Significant differences were detected in the Kaplan-Meier curves for midazolam compared with olanzapine (p = 0·03) and haloperidol (p = 0·002); however, this was not observed for haloperidol compared with olanzapine (p = 0·78).Table 2 Proportion of patients adequately sedated at each time point.
Table 2 Study group
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Proportion sedated, min
At 10 29·3 (52) 18·2 (34) 12·0 (21)
At 20 44·0 (79) 32·7 (60) 23·3 (41)
At 30 51·0 (91) 40·0 (74) 36·2 (63)
At 45 51·0 (91) 43·6 (81) 46·5 (82)
At 60 54·8 (98) 47·2 (87) 55·5 (97)
Interval-censored data was applied in this analysis.
Fig. 2 Proportion of Patients Adequately Sedated by Time in Kaplan-Meier Curve
No included patient was censored during observation. p-values derived by using asymptotic log-rank two-sample test for comparison of midazolam vs olanzapine, midazolam vs haloperidol, and haloperidol vs olanzapine were 0.03, 0.002 and 0.78, respectively.
Fig. 2
3.3 Secondary outcomes
The proportion of patients given the second dose of study drug or alternative sedative(s) was similar across all arms (Table 3). Fully-adjusted accelerated factors for olanzapine and haloperidol were compared with midazolam at 1·72 (95% CI 1·16–2·55) and 1·89 (95% CI 1·28–2·80), respectively (Supplementary Table S6), indicating significantly faster sedation for midazolam. The Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation with an accelerated factor of 0·96 (95% CI 0·49–1·88) for male (compared with female).Table 3 Patients given second dose of study drug or alternative sedatives, with adverse event report, and observed asleep.
Table 3 Study group P value
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Administered second dose of study drug or alternative sedatives 18 (32) 16 (30) 23 (40) 0·46
Administered second dose 13 (23) 15 (28) 18 (32) 0·61
Administered alternative sedatives 9a (16) 6 (11) 7b (12) 0·72
Midazolam 6 (67) 2 (33) 3 (43)
Haloperidol 2 (22) 4 (67) 2 (29)
Diazepam 3 (33) 0 – 2 (29)
Lorazepam 1 (11) 0 – 1 (14)
With adverse event 2 (4) 3 (6) 3 (5) 0·91
Oxygen desaturation (<90%) 2 (4) 1 (2) 1 (2)
Dry month 0 – 2 (4) 0 –
Dystonia 0 – 0 – 1 (2)
Cardiac arrest 0 – 0 – 1 (2)
ECG obtained (N = 52) (N = 52) (N = 56)
QTc prolongation 12 (23) 9 (17) 13 (23) 0·59
Fell asleep after treatment 28 (50) 10 (19) 17 (30) <0·01
*ECG, 12-lead electrocardiogram; QTc, corrected QT interval.
An adverse event is any untoward medical occurrence in a patient after administration of a medicinal product, which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug.
a Three patients were given two alternative sedative drugs.
b One patient was given two alternative sedative drugs.
Overall, the adverse event rate was similar for midazolam, olanzapine, and haloperidol at 4%, 6%, and 5%, respectively (Table 3). The most common adverse event was oxygen desaturation (midazolam, n = 2; olanzapine, n = 1; haloperidol, n = 1). Two patients in the olanzapine arm reported dry mouth. One patient reported dystonia after one dose of haloperidol (5 mg), which resolved fully with 2 mg intramuscular benztropine. In the single severe adverse event, the patient had a cardiac arrest three hours after two doses of intramuscular haloperidol (10 mg in total; second dose given 33 min after initial dose) and died 8 days later (see Supplementary-Severe Adverse Event).
Similar proportions of ECG completion and QTc prolongation were observed across the three arms (Table 3). The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol (p<0·01) (Table 3). LOS data was estimated as 4·52 (95% CI 2·63–8·69), 4·01 (95% CI 2·31–6·42), and 4·02 (95% CI 2·32–6·87) hours for midazolam, olanzapine and haloperidol, respectively. No significant difference in LOS was detected (p = 0·73).
4 Discussion
Intramuscular midazolam was more effective compared with antipsychotic drugs (olanzapine and haloperidol), as shown by the shorter time to adequate sedation and the higher proportion of patients sedated at any time point. No differences in outcomes were observed between olanzapine and haloperidol. All study drug dosages were effective in managing acute agitation in ED settings within 60 min.
No significant differences in adverse event rates were found across the three arms. One episode of extrapyramidal syndrome (dystonia) and one severe adverse event (fatal cardiac arrest) were reported in the haloperidol arm. Due to the low number of adverse events, the probability of type II error cannot be ruled out as the study was insufficiently powered to identify such differences. The high risk of extrapyramidal syndrome associated with haloperidol is well recognised and the event was considered to be causally associated with haloperidol [31]. The Data Safety Monitoring Board assessment concluded that the cause of death was associated with potential psychostimulants and unlikely to be solely associated with the study drug.
Additionally, significant differences were found in the proportion of patients asleep after study drug administration, with the highest percentage in the midazolam arm. Previous studies reported that midazolam posed a higher risk of over-sedation [9], considered as an undesirable clinical outcome [32]. Although no extended ED LOS was detected, patient assessment and referrals to other medical specialties may be delayed, requiring logistical considerations. Although no incident of respiratory depression was observed, midazolam is reported to cause respiratory depression [10] and careful monitoring of vital signs remains important, especially with high or rapidly escalating doses. Although differences in adverse event rate was not observed, intramuscular olanzapine was reported to be associated with a preferred safety profile compared to haloperidol [33]. Our times to sedation by midazolam and haloperidol were consistent with previously reported results. Intramuscular midazolam 2·5/5 mg was reported to achieve sedation within 5·1–18·3 min [6,10,11,13]. The mean time to sedation by intramuscular haloperidol 5 mg was reported to vary from 5 to 3 min [6,11,13]. Data exists concerning time to sedation in EDs by intramuscular olanzapine in randomised clinical trials and the product information suggests that the peak plasma concentration of 5 mg is expected within 15–45 min after administration. Raveendran et al. reported that 87% of violent patients with mental illnesses were sedated within 15 min with 10 mg intramuscular olanzapine in the psychiatry emergency setting [18].
Our recent study conducted in Australian EDs reported that after intravenous olanzapine 10 mg monotherapy (up to 20 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 11 min and 90·8%, respectively [4]. In the current study, after intramuscular olanzapine 5 mg was given (up to 10 mg in total as required), the median time to sedation and the proportion sedated at 60 min were 11·5 min and 87%, respectively. In our previous randomised clinical trial of intravenous olanzapine, we reported that following intravenous midazolam 2·5–5 mg monotherapy, the median time to sedation was 10 min, and proportion of patients sedated by 60 min was 87·0% [1]. In the current study, after intramuscular midazolam 5 mg (up to 10 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 8·5 min and 98%, respectively. These results suggest that the effectiveness of intramuscular olanzapine or midazolam (5 mg or 10 mg) in our predominantly Southern Chinese patient cohort might be comparable to intravenous administration of olanzapine or midazolam at similar doses. However, intramuscular sedation may provide more rapid initiation of emergency sedation, and potentially reduce the risk of injury to patients and staff, particularly during acute behavioural disturbance and in the context of mechanical restraint often being initially required. IV access in these circumstances may be fraught with difficulty and could be dangerous to both patients and staff members, so a less complex alternative route of administration (intramuscular) may provide many potential advantages if it is effective. The initial dose of intramuscular olanzapine (5 mg) may be considered relatively low compared to the manufacturer's recommendation (10 mg). In future studies, effectiveness and safety of higher doses of olanzapine in this clinical scenario could be further investigated.
The proportion of additional sedatives used in the haloperidol arm was numerically higher than the two other arms despite not reaching statistical significance. Consistently, higher proportions of additional sedative doses were required in patients treated with haloperidol vs. olanzapine as reported in observational studies by Klein et al. (18% vs. 11%)[26] and MacDonald et al. (43% vs. 29%), respectively [23].
Our study has several limitations. Firstly, the study concluded prematurely prior to attaining the full sample size mainly due to study fatigue and several episodes of social unrest in Hong Kong [34]. Early termination factors are detailed in Supplementary-Early Termination. The study period was extended from the initial planned 24 to 58 months. Despite the lower sample size, our study attained sufficient power to identify differences in the primary outcome measure among the three study drugs. Secondly, an imbalance in sex distribution was observed between the study arms, specifically, the haloperidol arm had more females than the other groups. However, the Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation given the accelerated factor by sex was close to one. Therefore, based on our results, the imbalance in sex distribution across the study arms is unlikely to affect the main results and conclusion. However, the possibility of imbalance in unmeasured baseline characteristics cannot be ruled out. Thirdly, while the sedation scale may introduce measurement bias due to subjectivity, it has been validated and applied in several studies conducted in similar settings [1,3,4]. Fourthly, patients were possibly excluded if physicians had a personal drug choice preference (e.g. antipsychotics preference for patients with known psychotic illness). However, exclusions of screened patients due to physician preference contributed only 1·2% of all excluded patients. Lastly, external validity may be impacted by the exclusion of some patients due to failure to obtain informed consent despite successful consent from 81·1% of those recruited. This discrepancy reflects immense challenges in undertaking pragmatic randomised clinical trials on acute agitation and behavioural emergencies in the ED setting and has been reported by researchers in ED settings elsewhere [22].
Our study indicates that intramuscular midazolam was more effective at 5–10 mg doses compared with olanzapine or haloperidol for acute agitation in ED settings, regardless of aetiology. Intramuscular midazolam's faster sedation time may deem it preferable as an initial sedation agent. Intramuscular midazolam, olanzapine, and haloperidol effectively sedated ED patients with acute agitation within 60 min. Although adverse event rates did not differ significantly, the potential risk of extrapyramidal side effects for haloperidol should be noted. Given the potential risk of adverse events, intramuscular midazolam or olanzapine should be considered over haloperidol for undifferentiated acute agitation in EDs. As this study includes only three of the most commonly prescribed sedatives in a local setting, further investigation to compare other sedatives is warranted.
Contributors
EWC, ICKW, and KSJL had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. EWC, KSJL, ICKW, CAG, JCK, DMT, DCMK, and LPL to developed the study design. EWC, KSJL, ICKW, BJC, JCK, DMT, DCMK, and SHT were responsible for the acquisition, analysis, and interpretation of data. EWC and KSJL drafted the manuscript. ICKW, CAG, JCK, DMT, and DCMK critically revised the manuscript. BJC and VJF contributed to statistical analysis. EWC, KSJL, LL, SHT, CTL, CPW, CAG, CHC, TSC, HFL, and SMT contributed in study site establishment and patient enrolment
Funding
This study was funded by Research Grants Council (Early Career Scheme), Hong Kong (789813).
Data sharing statement
Due to institutional review board restrictions associated with the trial, participant data is not available to external sources. Proposals to access the de-identified individual participant data (excluding any trial-specific participant opt-outs) that underlie the results reported in this article for secondary research purposes will be considered 12 months after publication. Proposal should be directed to the corresponding author, with approval by EWC and KSJL. Only proposals that are clearly in the public interest and compatible with the original purpose of the study will be considered. Qualified researchers will need to sign a data access agreement before data would be released.
Declaration of Competing Interest
All authors declare that no other support has been received from any organisation for the submitted work; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted study. Outside the submitted work, EWC has received honorarium from the Hospital Authority, research grants from Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA and Takeda outside the submitted work.. KSJL reports personal fees from MSD China, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. ICKW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire.
Appendix Supplementary materials
Image, application 1 Image, application 2
Acknowledgments
We thank all patients who participated in this trial. In addition to the authors, we express our appreciation to the following colleagues for their support and participation in this study: Queen Mary Hospital, Hong Kong, Tuen Mun Hospital, Hong Kong, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Prince of Wales Hospital, Hong Kong, Ruttonjee Hospital, Hong Kong, United Christian Hospital, Hong Kong; all pharmacists, physicians and nursing staff in participating sites; research associates and students who participated in this study: X Li, TY Ko, KY Yip, YT Hui, CY Ching, SY Kwok, C Tang, HK Tse, YK Ho, CY Lim, TY Leung, WH Chui, SY Ng, HW Chan, Y Chen, and all summer and exchange students who joined the team to learn about clinical trials. We express our thanks to members of Data Safety and Monitoring Board: BJ Cowling, HF Ho, ML Tse, BMY Cheung, CW Law; Statistician: VJ Fang; Proofreading: L Lam, J Blais, V Geall and KC Yan. Lastly, we are grateful for the support from Ms McShirley Leung who would have been pleased to know about our study findings.
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eclinm.2021.100751. | Intramuscular | DrugAdministrationRoute | CC BY-NC-ND | 33681744 | 19,870,551 | 2021-02 |
What was the outcome of reaction 'Cardiac arrest'? | Intramuscular midazolam, olanzapine, or haloperidol for the management of acute agitation: A multi-centre, double-blind, randomised clinical trial.
The safety and effectiveness of intramuscular olanzapine or haloperidol compared to midazolam as the initial pharmacological treatment for acute agitation in emergency departments (EDs) has not been evaluated.
A pragmatic, randomised, double-blind, active-controlled trial was conducted from December 2014 to September 2019, in six Hong Kong EDs. Patients (aged 18-75 years) with undifferentiated acute agitation requiring parenteral sedation were randomised to 5 mg intramuscular midazolam (n = 56), olanzapine (n = 54), or haloperidol (n = 57). Primary outcomes were time to adequate sedation and proportion of patients who achieved adequate sedation at each follow-up interval. Sedation levels were measured on a 6-level validated scale (ClinicalTrials.gov Identifier: NCT02380118).
Of 206 patients randomised, 167 (mean age, 42 years; 98 [58·7%] male) were analysed. Median time to sedation for IM midazolam, olanzapine, and haloperidol was 8·5 (IQR 8·0), 11·5 (IQR 30·0), and 23·0 (IQR 21·0) min, respectively. At 60 min, similar proportions of patients were adequately sedated (98%, 87%, and 97%). There were statistically significant differences for time to sedation with midazolam compared to olanzapine (p = 0·03) and haloperidol (p = 0·002). Adverse event rates were similar across the three arms. Dystonia (n = 1) and cardiac arrest (n = 1) were reported in the haloperidol group.
Midazolam resulted in faster sedation in patients with undifferentiated agitation in the emergency setting compared to olanzapine and haloperidol. Midazolam and olanzapine are preferred over haloperidol's slower time to sedation and potential for cardiovascular and extrapyramidal side effects.
Research Grants Council, Hong Kong.
Research in context
Evidence before this study
Rapid sedation via the intramuscular route is often preferred in patients with acute agitation in emergency settings. Whether intramuscular olanzapine is effective and safe compared to conventional treatment options (including benzodiazepines and first-generation antipsychotics) in emergency settings, where the aetiology of acute agitation is usually undifferentiated and clinical endpoints are urgent, is uncertain.
We searched PubMed from inception to July 22, 2020, without language restrictions, for randomised trials, systematic reviews, meta-analyses, and observational studies, using the terms “agitation or acute agitation or violence” and “parenteral or intramuscular” and “emergency”. During the study period, we identified four randomised trials (published in 2007, 2011, 2013, and 2016) conducted in psychiatry settings that evaluated the effectiveness and safety of intramuscular olanzapine. We did not find any randomised trials comparing intramuscular olanzapine with other sedatives for the treatment of acute agitation in emergency departments.
Added value of this study
We conducted a randomised, active-controlled trial in six Hong Kong emergency departments comparing time to sedation in patients receiving 5 mg of intramuscular midazolam, olanzapine or haloperidol. All three treatments provided adequate sedation at 60 min and midazolam resulted in faster sedation compared to the others. The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol. Overall adverse event rates were similar across the three arms while extrapyramidal syndrome (n = 1) and fatal cardiac arrest (n = 1) episodes were reported in the haloperidol arm.
Implications of all the available evidence
In patients with undifferentiated agitation admitted to emergency departments, intramuscular midazolam and olanzapine are preferred over haloperidol in view of haloperidol's slower time to sedation and the potential for cardiovascular and extrapyramidal side effects.
Alt-text: Unlabelled box
1 Introduction
Undifferentiated acute agitation presenting at the emergency department (ED) often stems from various aetiologies, including underlying mental illness, drug or alcohol intoxication, or a combination of diagnoses [1], [2], [3], [4]. Failed de-escalation strategies or oral medication necessitates parenteral sedation to prevent subsequent harm [5], with intramuscular sedation generally considered prior to intravenous cannulation [2].
A range of medications are currently used for rapid intramuscular sedation to manage acute agitation in the emergency setting, including benzodiazepines (e.g. midazolam [6], [7], [8], [9], [10], [11], [12], [13], lorazepam) [11,14,15], first-generation antipsychotics (e.g. haloperidol [[6], [7], [8],[11], [12], [13],[15], [16], [17], [18], [19], [20]], droperidol) [9,10,16,20], and second-generation antipsychotics (e.g. olanzapine [7,8,18], risperidone [17], ziprasidone) [7,8,10]. Recently, interest in second-generation antipsychotics to manage acute agitation has grown due to the lower incidence of extrapyramidal side effects (EPS) [7,8], over-sedation [8], and need for further rescue medications [10].
Intramuscular olanzapine and other sedatives have not been directly compared using randomised clinical trials in the general ED setting. Studies to date have used observational [21], [22], [23] or open-label study designs [18]. Previous randomised controlled trials have focused on intravenous olanzapine [4,24] or were conducted in psychiatric emergency settings [7,8,18]. The intravenous route provides rapid onset of action but may be inappropriate in some contexts as adequate staff and resources are required to manage potential emergencies. Our survey of emergency physicians in Hong Kong EDs reported a preference for intramuscular sedation over intravenous sedation, whereas the intravenous route was generally preferred in Australasia [25], suggesting regional differences in prescribing culture, and differences in the perceived need for aggressive management. Other studies investigated intramuscular olanzapine in psychiatric settings where patients with agitation were predominantly homogeneous with a history of mental illness [7,8,18] rather than “undifferentiated”, with an undiagnosed cause of agitation. Study results from psychiatric settings are not directly generalisable to inform acute ED practice due to differences in measured outcomes and perceived accept time to adequate sedation in different clinical contexts. To date, evidence of intramuscular olanzapine use in the general ED is scant as all have been observational studies [[21], [22], [23],26]. Therefore, comparing intramuscular olanzapine with haloperidol or midazolam, the two most commonly selected sedating agents in local setting [25], is important in determining a safe and effective choice of an initial agent for acute agitation in the ED setting. This study compares a second-generation antipsychotic (olanzapine) with a conventional antipsychotic (haloperidol) and a benzodiazepine (midazolam) in acute agitation management in the ED.
2 Methods
2.1 Study design
This was a multi-centre, double-blind, randomised, active-controlled pragmatic trial at EDs in six public hospitals under the Hong Kong Hospital Authority (Table S1 and S7). Between April 2014 to March 2019, patient attendances at these 24-h EDs comprised 39% of the Hospital Authority's overall ED visits. The Institutional Review Board or Clinical Research Ethics Committee approval was given at all study sites (Supplementary Table S1). An independent Data Safety and Monitoring Board for the study comprised a Biostatistician (BJC), Clinical Pharmacologist (BMYC), Toxicologist (MLT), Emergency Physician (HFH), Psychiatrist (CWL). This study was registered in ClinicalTrials.gov (NCT02380118).
2.2 Patients
Patients were enrolled from December 24, 2014 to September 6, 2019. Inclusion criteria were: patients aged 18–75 years; and requiring parenteral drug sedation for acute agitation at the treating physician's discretion. Patients who had received oral or parenteral sedative drug(s) within 12 h, either as usual medications or pre-hospital acute agitation management, were eligible. Exclusion criteria were known hypersensitivity or contraindication to any of the study drugs, immediately reversible aetiology for agitation (e.g. hypotension, hypoxia, hypoglycaemia), known pregnancy, or acute alcohol withdrawal (as it is amendable to benzodiazepines alone) [27]. All eligible patients were initially treated according to the study protocol (Appendix 1).
Written informed consent was secured from either the patient following recovery, if they had capacity to understand the study and give informed consent, or the patient's authorised representative. Inherent challenges in obtaining informed consent from highly agitated patients attending emergency settings have been acknowledged [3,10,11,22]. Application for patient consent waiver, as used in previous clinical trials internationally [1,3,4,10,11,19], was submitted but not approved. As requested by local ethics committees, patient consent was obtained after intervention or from an authorised representative.
2.3 Randomisation and masking
Eligible patients were assigned to the next sequential study pack pre-assembled by independent pharmacists (not involved in the patient's care during acute agitation episode) from the participating hospital's pharmacy department according to a computer-generated randomisation list. Study packs contained the assigned study drug, data collection tools, an unblinding envelope, and other necessary documents. All study packs and unblinding envelopes were opaque, sealed and tamper-proof. At each site, patients were randomised to “permuted blocks of six”, each containing two packs of haloperidol, olanzapine, and midazolam to ensure each arm had similar allocated numbers. Six randomisation lists were generated independently for each study site.
As the appearance of each study drug (midazolam/haloperidol: clear liquid ampule; olanzapine: yellow powder vial) could compromise double-blinding, an independent nurse (not involved in the participant's care) prepared and administered all study drugs. Blinding was maintained with all staff involved in patient care, monitoring, data collection, and statistical analysis.
2.4 Procedures
Patients were randomised to receive an initial 5 mg intramuscular injection of olanzapine, haloperidol, or midazolam with a ratio of 1:1:1, with an optional additional 5 mg dose of the same medication (maximum total dose=10 mg). Study drug selection and doses were based on local Hong Kong clinical practice and survey results [25] on prescribing preferences for acute agitation management, which reported haloperidol and midazolam monotherapy as the sedating agents most frequently selected for undifferentiated agitation in ED. The intramuscular route was the most common choice (63·9%) regardless of drug chosen; median initial and cumulative doses were 5 mg and 10 mg respectively. Although the product monograph recommends a starting dose of 10 mg intramuscular olanzapine, this is seldom prescribed in the local ED setting. Investigators concurred that both the initial (5 mg) and one additional dose (5 mg) would be included in each study pack to allow for flexibility in dosing escalation. To achieve initial or maintain adequate sedation, patients were eligible for alternative sedative drug(s) in addition to the assigned study drug according to clinical response and at the treating physician's discretion.
Agitation/sedation level was measured on a 6-point validated sedation scale: (5=highly aroused, violent; 4=highly aroused, possibly distressed, or fearful; 3=moderately aroused, unreasonable, or hostile; 2=mildly aroused, willing to talk reasonably; 1=minimal agitation; and 0=asleep) [28]. Adequate sedation was defined as a score ≤2. This scale was applied in previous clinical trials that studied sedation in ED [1,3,4,29]. Sedation scores and actual time of measurement were recorded at baseline (immediately before initial dose, t = 0), at first observed adequate sedation, and at 10, 20, 30, 45, and 60 min after the first dose regardless of observed time to sedation. Measurements were recorded by the treating physician, nurses (other than the independent nurse), or research staff. All study participants were given standard sedation care including 1:1 nursing and regular monitoring of sedation level, vital signs, cardiac rhythm, protocol-specified common adverse events, and any other untoward medical occurrence whether or not the occurrence is related to or considered to have a causal relationship with the study drug. Common adverse events related to study drugs were listed in the data collection tool, including airway management (jaw thrust, oral, nasal airway), need for assisted ventilation (bag & mask, intubation), oxygen desaturation <90%, systolic BP<90 mmHg, dystonic reactions, seizures, vomiting or aspiration. If possible, a 12-lead electrocardiogram (ECG) was obtained within 30 min of adequate sedation. However, ECGs are challenging to perform in highly agitated patients and therefore were not always obtained.
Other participant data, including sex, age, and medication history were collected on a standardised Case Report Form. ED presentation details were also collected at triage including perceived possible causes at current presentation such as drug/substance abuse, alcohol intoxication, underlying mental illness, non-compliance to usual medication, and suicidal ideation. Concurrent prescriptions of any antipsychotics, antidepressants, or hypnotics/anxiolytics were also retrieved from the Hospital Authority's computerised medical records system wherever possible.
2.5 Outcomes
The primary outcome measure was time to achieve adequate sedation. Three study arms were compared according to: 1) time required to achieve adequate sedation following drug administration; and 2) proportion of patients adequately sedated at 10, 20, 30, 45, and 60 min. Secondary outcome measures included: 1) proportion of patients requiring a second dose of study drug and/or alternative drug(s) to achieve initial adequate sedation; 2) proportion of patients with corrected QT interval (QTc) prolongation on the ECG (defined as QTc interval over 450 ms and 470 ms, respectively, for males and females) [30]; 3) adverse events reported after study drug administration; 4) the proportion of patients with a sedation score of 0 (observed asleep) after study drug administration [28]; and 5) ED length of stay (LOS).
2.6 Statistical analysis
Sample size calculation was based on Isbister et al., where intramuscular droperidol and midazolam were compared head-to-head in an Australian ED [9]. Assuming sedation times were similar to the Australian study and to demonstrate a difference in the mean time to sedation of 20 versus 25 min (standard deviation=12) between the two arms (haloperidol vs. midazolam), 91 patients were required in each arm (2-sided, statistical power 0·8). Thus, we aimed to enrol 282 patients (rounded up from 273 to account for patient loss).
The modified intention-to-treat principle was applied in the primary analysis. Thirty-six patients received treatment but were excluded due to lack of informed consent. As required by the IRB and stated in the protocol, a primary analysis of patients with informed consent was undertaken according to the allocated study arm, regardless of any unblinding or protocol deviations. The proportion of patients adequately sedated over time were plotted with Kaplan-Meier curves. Time from drug administration to adequate sedation was analysed based on the Kaplan-Meier estimate allowing for interval-censored data. Statistical tests for comparison of every two Kaplan-Meier curves were conducted with asymptotic two-sample log-rank tests. Median time to sedation was calculated for each arm with 95% confidence intervals (CI). Further, the relationship between drug exposure and time to sedation was investigated by fitting Weibull accelerated failure time models adjusted for sex, age, concurrent psychotropic medications, and perceived possible cause of agitation.
Differences in the median ED LOS from study drug administration to discharge/transfer were tested with the log-rank test. Differences in descriptive data of secondary outcomes were tested using Fisher's exact test/Chi-squared test (categorical variables) and log-rank test (continuous variables). A two-sided p-value <0·05 was considered statistically significant. Interim analysis was conducted at recruitment of 130 patients as detailed in Supplementary-Interim Analysis. Data was analysed using R version 3·4·3 (R Foundation for Statistical Computing, Vienna, Austria) by independent Data Safety and Monitoring Board member BJC and statistician VJF.
2.7 Role of the funding source
This study was funded by Research Grants Council, Hong Kong (789813). The study's funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author has full access to all data in the study and has final responsibility for the decision to submit for publication.
3 Results
3.1 Participants
During the study period 2423 patients were screened, of which 206 received study drugs and 167 provided informed consent (Fig. 1), provided by patients and representatives in 25·1% and 74·9% of cases, respectively. After receiving study drugs, 39 patients were excluded due to failure to consent (n = 36) or found out of age range (n = 3) (Fig. 1). Fifty-six patients were allocated to midazolam arm, 54 to olanzapine, and 57 to haloperidol. The actual sample size was less than planned as the study concluded prematurely due to factors detailed in Supplementary-Early Termination. Patient baseline characteristics were generally balanced, although the haloperidol arm (42%) had a lower proportion of males compared with the midazolam (61%) and olanzapine (70%) arms (Table 1). Use of any antidepressants, hypnotics, and anxiolytics were similar across all arms. Results of interim analysis are listed in Supplementary Table S2–5 and Figure S1.Fig. 1 Flow Diagram of Patient Inclusion (Modified CONSORT Diagram)
a, including other exclusion criteria, patients’ preference, profound risk of adverse event, and multiple exclusion reasons; b, the age of these 3 patients was unknown at recruitment, two patients were found to be over 75 years old, one below 18 years old after treatment; c. two patients were unconscious during the length of stay at Emergency Department and not accompanied by any representative; d, one dose of study drug was discarded due to contamination; e, one dose of study drug was given intravenously; f, allocation of two patients was unblinded due to protocol violation (intravenous route; n = 1) and for informing of the procedural sedation for endoscopy after transfer (5 mg given in Emergency Department; n = 1); g, allocation of three patients was unblinded due to adverse event (n = 2) and for informing of further sedation (10 mg given in Emergency Department; n = 1).
Fig. 1Table 1 Baseline characteristics of patients.
Table 1 Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Age (median, IQR) 44 (34, 54) 40 (30,54) 42 (33, 55)
Male 34 (61) 38 (70) 24 (42)
Perceived possible cause
Drug/substance abuse 16 (31) 14 (27) 19 (37)
Alcohol intoxication 15 (28) 12 (23) 13 (25)
Underlying mental illnesses 47 (87) 45 (83) 46 (84)
Non-compliance to usual medication 24 (47) 22 (43) 18 (35)
Suicidal ideation/attempt 18 (34) 17 (33) 18 (35)
Prior sedative drug 1a (2) 1b (2) 1c (2)
Concurrent psychotropic medications (any antipsychoticsd, antidepressantse, or hypnotics and anxiolyticsf) 19 (34) 17 (31) 13 (23)
Baseline sedation score
3 13 (23) 16 (30) 14 (25)
4 17 (30) 21 (39) 17 (30)
5 26 (46) 16 (30) 25 (44)
IQR, interquartile range; atramadol 50 mg; bhaloperidol 5 mg; chaloperidol 10 mg dantipsychotics were medications under the British National Formulary (BNF) category 4·2·1 and 4·2·2; eantidepressants were defined as medications under the BNF category 4·3; fhypnotics and anxiolytics were defined as medications under the BNF category 4·1.
3.2 Primary outcomes
The median time to sedation estimated by the Kaplan-Meier function was 8·5 (95% CI 8·5–59·5, IQR 8·0), 11·5 (95% CI 7·5–67·0, IQR 30·0), and 23·0 min (95% CI 6·0–53·5, IQR 21·0) for midazolam, olanzapine, and haloperidol, respectively. At 10 min after the initial dose, 52%, 34%, and 21% of patients were adequately sedated in the midazolam, olanzapine, and haloperidol arms, respectively. At 60 min, the proportion of patients sedated increased to 98%, 87%, and 97%, respectively (Table 2). The proportion of patients sedated by time was plotted on Kaplan-Meier curves (Fig. 2). Significant differences were detected in the Kaplan-Meier curves for midazolam compared with olanzapine (p = 0·03) and haloperidol (p = 0·002); however, this was not observed for haloperidol compared with olanzapine (p = 0·78).Table 2 Proportion of patients adequately sedated at each time point.
Table 2 Study group
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Proportion sedated, min
At 10 29·3 (52) 18·2 (34) 12·0 (21)
At 20 44·0 (79) 32·7 (60) 23·3 (41)
At 30 51·0 (91) 40·0 (74) 36·2 (63)
At 45 51·0 (91) 43·6 (81) 46·5 (82)
At 60 54·8 (98) 47·2 (87) 55·5 (97)
Interval-censored data was applied in this analysis.
Fig. 2 Proportion of Patients Adequately Sedated by Time in Kaplan-Meier Curve
No included patient was censored during observation. p-values derived by using asymptotic log-rank two-sample test for comparison of midazolam vs olanzapine, midazolam vs haloperidol, and haloperidol vs olanzapine were 0.03, 0.002 and 0.78, respectively.
Fig. 2
3.3 Secondary outcomes
The proportion of patients given the second dose of study drug or alternative sedative(s) was similar across all arms (Table 3). Fully-adjusted accelerated factors for olanzapine and haloperidol were compared with midazolam at 1·72 (95% CI 1·16–2·55) and 1·89 (95% CI 1·28–2·80), respectively (Supplementary Table S6), indicating significantly faster sedation for midazolam. The Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation with an accelerated factor of 0·96 (95% CI 0·49–1·88) for male (compared with female).Table 3 Patients given second dose of study drug or alternative sedatives, with adverse event report, and observed asleep.
Table 3 Study group P value
Midazolam (N = 56) Olanzapine (N = 54) Haloperidol (N = 57)
n (%) n (%) n (%)
Administered second dose of study drug or alternative sedatives 18 (32) 16 (30) 23 (40) 0·46
Administered second dose 13 (23) 15 (28) 18 (32) 0·61
Administered alternative sedatives 9a (16) 6 (11) 7b (12) 0·72
Midazolam 6 (67) 2 (33) 3 (43)
Haloperidol 2 (22) 4 (67) 2 (29)
Diazepam 3 (33) 0 – 2 (29)
Lorazepam 1 (11) 0 – 1 (14)
With adverse event 2 (4) 3 (6) 3 (5) 0·91
Oxygen desaturation (<90%) 2 (4) 1 (2) 1 (2)
Dry month 0 – 2 (4) 0 –
Dystonia 0 – 0 – 1 (2)
Cardiac arrest 0 – 0 – 1 (2)
ECG obtained (N = 52) (N = 52) (N = 56)
QTc prolongation 12 (23) 9 (17) 13 (23) 0·59
Fell asleep after treatment 28 (50) 10 (19) 17 (30) <0·01
*ECG, 12-lead electrocardiogram; QTc, corrected QT interval.
An adverse event is any untoward medical occurrence in a patient after administration of a medicinal product, which does not necessarily have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not considered related to study drug.
a Three patients were given two alternative sedative drugs.
b One patient was given two alternative sedative drugs.
Overall, the adverse event rate was similar for midazolam, olanzapine, and haloperidol at 4%, 6%, and 5%, respectively (Table 3). The most common adverse event was oxygen desaturation (midazolam, n = 2; olanzapine, n = 1; haloperidol, n = 1). Two patients in the olanzapine arm reported dry mouth. One patient reported dystonia after one dose of haloperidol (5 mg), which resolved fully with 2 mg intramuscular benztropine. In the single severe adverse event, the patient had a cardiac arrest three hours after two doses of intramuscular haloperidol (10 mg in total; second dose given 33 min after initial dose) and died 8 days later (see Supplementary-Severe Adverse Event).
Similar proportions of ECG completion and QTc prolongation were observed across the three arms (Table 3). The proportion of patients observed to be asleep after treatment with midazolam was higher compared with olanzapine and haloperidol (p<0·01) (Table 3). LOS data was estimated as 4·52 (95% CI 2·63–8·69), 4·01 (95% CI 2·31–6·42), and 4·02 (95% CI 2·32–6·87) hours for midazolam, olanzapine and haloperidol, respectively. No significant difference in LOS was detected (p = 0·73).
4 Discussion
Intramuscular midazolam was more effective compared with antipsychotic drugs (olanzapine and haloperidol), as shown by the shorter time to adequate sedation and the higher proportion of patients sedated at any time point. No differences in outcomes were observed between olanzapine and haloperidol. All study drug dosages were effective in managing acute agitation in ED settings within 60 min.
No significant differences in adverse event rates were found across the three arms. One episode of extrapyramidal syndrome (dystonia) and one severe adverse event (fatal cardiac arrest) were reported in the haloperidol arm. Due to the low number of adverse events, the probability of type II error cannot be ruled out as the study was insufficiently powered to identify such differences. The high risk of extrapyramidal syndrome associated with haloperidol is well recognised and the event was considered to be causally associated with haloperidol [31]. The Data Safety Monitoring Board assessment concluded that the cause of death was associated with potential psychostimulants and unlikely to be solely associated with the study drug.
Additionally, significant differences were found in the proportion of patients asleep after study drug administration, with the highest percentage in the midazolam arm. Previous studies reported that midazolam posed a higher risk of over-sedation [9], considered as an undesirable clinical outcome [32]. Although no extended ED LOS was detected, patient assessment and referrals to other medical specialties may be delayed, requiring logistical considerations. Although no incident of respiratory depression was observed, midazolam is reported to cause respiratory depression [10] and careful monitoring of vital signs remains important, especially with high or rapidly escalating doses. Although differences in adverse event rate was not observed, intramuscular olanzapine was reported to be associated with a preferred safety profile compared to haloperidol [33]. Our times to sedation by midazolam and haloperidol were consistent with previously reported results. Intramuscular midazolam 2·5/5 mg was reported to achieve sedation within 5·1–18·3 min [6,10,11,13]. The mean time to sedation by intramuscular haloperidol 5 mg was reported to vary from 5 to 3 min [6,11,13]. Data exists concerning time to sedation in EDs by intramuscular olanzapine in randomised clinical trials and the product information suggests that the peak plasma concentration of 5 mg is expected within 15–45 min after administration. Raveendran et al. reported that 87% of violent patients with mental illnesses were sedated within 15 min with 10 mg intramuscular olanzapine in the psychiatry emergency setting [18].
Our recent study conducted in Australian EDs reported that after intravenous olanzapine 10 mg monotherapy (up to 20 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 11 min and 90·8%, respectively [4]. In the current study, after intramuscular olanzapine 5 mg was given (up to 10 mg in total as required), the median time to sedation and the proportion sedated at 60 min were 11·5 min and 87%, respectively. In our previous randomised clinical trial of intravenous olanzapine, we reported that following intravenous midazolam 2·5–5 mg monotherapy, the median time to sedation was 10 min, and proportion of patients sedated by 60 min was 87·0% [1]. In the current study, after intramuscular midazolam 5 mg (up to 10 mg in total if required), the median time to sedation and the proportion sedated at 60 min were 8·5 min and 98%, respectively. These results suggest that the effectiveness of intramuscular olanzapine or midazolam (5 mg or 10 mg) in our predominantly Southern Chinese patient cohort might be comparable to intravenous administration of olanzapine or midazolam at similar doses. However, intramuscular sedation may provide more rapid initiation of emergency sedation, and potentially reduce the risk of injury to patients and staff, particularly during acute behavioural disturbance and in the context of mechanical restraint often being initially required. IV access in these circumstances may be fraught with difficulty and could be dangerous to both patients and staff members, so a less complex alternative route of administration (intramuscular) may provide many potential advantages if it is effective. The initial dose of intramuscular olanzapine (5 mg) may be considered relatively low compared to the manufacturer's recommendation (10 mg). In future studies, effectiveness and safety of higher doses of olanzapine in this clinical scenario could be further investigated.
The proportion of additional sedatives used in the haloperidol arm was numerically higher than the two other arms despite not reaching statistical significance. Consistently, higher proportions of additional sedative doses were required in patients treated with haloperidol vs. olanzapine as reported in observational studies by Klein et al. (18% vs. 11%)[26] and MacDonald et al. (43% vs. 29%), respectively [23].
Our study has several limitations. Firstly, the study concluded prematurely prior to attaining the full sample size mainly due to study fatigue and several episodes of social unrest in Hong Kong [34]. Early termination factors are detailed in Supplementary-Early Termination. The study period was extended from the initial planned 24 to 58 months. Despite the lower sample size, our study attained sufficient power to identify differences in the primary outcome measure among the three study drugs. Secondly, an imbalance in sex distribution was observed between the study arms, specifically, the haloperidol arm had more females than the other groups. However, the Weibull accelerated failure time model found a minimal effect of sex on time to adequate sedation given the accelerated factor by sex was close to one. Therefore, based on our results, the imbalance in sex distribution across the study arms is unlikely to affect the main results and conclusion. However, the possibility of imbalance in unmeasured baseline characteristics cannot be ruled out. Thirdly, while the sedation scale may introduce measurement bias due to subjectivity, it has been validated and applied in several studies conducted in similar settings [1,3,4]. Fourthly, patients were possibly excluded if physicians had a personal drug choice preference (e.g. antipsychotics preference for patients with known psychotic illness). However, exclusions of screened patients due to physician preference contributed only 1·2% of all excluded patients. Lastly, external validity may be impacted by the exclusion of some patients due to failure to obtain informed consent despite successful consent from 81·1% of those recruited. This discrepancy reflects immense challenges in undertaking pragmatic randomised clinical trials on acute agitation and behavioural emergencies in the ED setting and has been reported by researchers in ED settings elsewhere [22].
Our study indicates that intramuscular midazolam was more effective at 5–10 mg doses compared with olanzapine or haloperidol for acute agitation in ED settings, regardless of aetiology. Intramuscular midazolam's faster sedation time may deem it preferable as an initial sedation agent. Intramuscular midazolam, olanzapine, and haloperidol effectively sedated ED patients with acute agitation within 60 min. Although adverse event rates did not differ significantly, the potential risk of extrapyramidal side effects for haloperidol should be noted. Given the potential risk of adverse events, intramuscular midazolam or olanzapine should be considered over haloperidol for undifferentiated acute agitation in EDs. As this study includes only three of the most commonly prescribed sedatives in a local setting, further investigation to compare other sedatives is warranted.
Contributors
EWC, ICKW, and KSJL had full access to all the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. EWC, KSJL, ICKW, CAG, JCK, DMT, DCMK, and LPL to developed the study design. EWC, KSJL, ICKW, BJC, JCK, DMT, DCMK, and SHT were responsible for the acquisition, analysis, and interpretation of data. EWC and KSJL drafted the manuscript. ICKW, CAG, JCK, DMT, and DCMK critically revised the manuscript. BJC and VJF contributed to statistical analysis. EWC, KSJL, LL, SHT, CTL, CPW, CAG, CHC, TSC, HFL, and SMT contributed in study site establishment and patient enrolment
Funding
This study was funded by Research Grants Council (Early Career Scheme), Hong Kong (789813).
Data sharing statement
Due to institutional review board restrictions associated with the trial, participant data is not available to external sources. Proposals to access the de-identified individual participant data (excluding any trial-specific participant opt-outs) that underlie the results reported in this article for secondary research purposes will be considered 12 months after publication. Proposal should be directed to the corresponding author, with approval by EWC and KSJL. Only proposals that are clearly in the public interest and compatible with the original purpose of the study will be considered. Qualified researchers will need to sign a data access agreement before data would be released.
Declaration of Competing Interest
All authors declare that no other support has been received from any organisation for the submitted work; no other financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted study. Outside the submitted work, EWC has received honorarium from the Hospital Authority, research grants from Narcotics Division of the Security Bureau of HKSAR, National Health and Medical Research Council (NHMRC, Australia), National Natural Science Foundation of China (NSFC), Research Fund Secretariat of the Food and Health Bureau (HMRF, HKSAR), Research Grants Council (RGC, HKSAR), Wellcome Trust; Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Janssen, Pfizer, RGA and Takeda outside the submitted work.. KSJL reports personal fees from MSD China, outside the submitted work. ICKW received grants from the Research Grants Council (RGC, Hong Kong), Innovative Medicines Initiative (IMI), Shire, Janssen-Cilag, Eli-Lily, Pfizer, Bayer, European Union FP7 program. ICKW is a member of the National Institute for Health and Clinical Excellence (NICE) ADHD Guideline Group, the British Association for Psychopharmacology ADHD guideline group, and advisor to Shire.
Appendix Supplementary materials
Image, application 1 Image, application 2
Acknowledgments
We thank all patients who participated in this trial. In addition to the authors, we express our appreciation to the following colleagues for their support and participation in this study: Queen Mary Hospital, Hong Kong, Tuen Mun Hospital, Hong Kong, Pamela Youde Nethersole Eastern Hospital, Hong Kong, Prince of Wales Hospital, Hong Kong, Ruttonjee Hospital, Hong Kong, United Christian Hospital, Hong Kong; all pharmacists, physicians and nursing staff in participating sites; research associates and students who participated in this study: X Li, TY Ko, KY Yip, YT Hui, CY Ching, SY Kwok, C Tang, HK Tse, YK Ho, CY Lim, TY Leung, WH Chui, SY Ng, HW Chan, Y Chen, and all summer and exchange students who joined the team to learn about clinical trials. We express our thanks to members of Data Safety and Monitoring Board: BJ Cowling, HF Ho, ML Tse, BMY Cheung, CW Law; Statistician: VJ Fang; Proofreading: L Lam, J Blais, V Geall and KC Yan. Lastly, we are grateful for the support from Ms McShirley Leung who would have been pleased to know about our study findings.
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.eclinm.2021.100751. | Fatal | ReactionOutcome | CC BY-NC-ND | 33681744 | 19,870,551 | 2021-02 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Adverse drug reaction'. | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | LEVETIRACETAM, LORAZEPAM | DrugsGivenReaction | CC BY-NC-ND | 33681754 | 20,499,955 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Generalised tonic-clonic seizure'. | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | ARIPIPRAZOLE, CLONAZEPAM, DIAZEPAM, DIVALPROEX SODIUM, LACOSAMIDE, PYRIDOXINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Paroxysmal sympathetic hyperactivity'. | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | ARIPIPRAZOLE, CLONAZEPAM, DIAZEPAM, DIVALPROEX SODIUM, LACOSAMIDE, PYRIDOXINE, SERTRALINE HYDROCHLORIDE | DrugsGivenReaction | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the administration route of drug 'CLONAZEPAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the administration route of drug 'DIAZEPAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | Rectal | DrugAdministrationRoute | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the administration route of drug 'DIVALPROEX SODIUM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the administration route of drug 'PYRIDOXINE'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | Oral | DrugAdministrationRoute | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'ARIPIPRAZOLE'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 9 MILLILITER, 2X/DAY (BID) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'CLONAZEPAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 0.125 MILLIGRAM, 3X/DAY (TID) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'DIAZEPAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 10 MILLIGRAM, AS NEEDED (PRN) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'DIVALPROEX SODIUM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 125 MILLIGRAM, ONCE DAILY (QD) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'LACOSAMIDE'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 100 MILLIGRAM TABLET, 2X/DAY (BID) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'LEVETIRACETAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | UNKNOWN DOSE AND FREQUENCY | DrugDosageText | CC BY-NC-ND | 33681754 | 20,499,955 | 2021 |
What was the dosage of drug 'LORAZEPAM'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | UNKNOWN DOSE AND FREQUENCY | DrugDosageText | CC BY-NC-ND | 33681754 | 20,499,955 | 2021 |
What was the dosage of drug 'PYRIDOXINE'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 25 MILLIGRAM, ONCE DAILY (QD) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the dosage of drug 'SERTRALINE HYDROCHLORIDE'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | 100 MILLIGRAM, ONCE DAILY (QD) | DrugDosageText | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
What was the outcome of reaction 'Paroxysmal sympathetic hyperactivity'? | Paroxysmal sympathetic hyperactivity following status epilepticus in a 22-year-old with Juvenile Neuronal Ceroid Lipofuscinosis: A case report.
The Neuronal Ceroid Lipofuscinosis (NCL) refers to a group of rare neurolipidosis disorders characterized by progressive blindness, deterioration of speech and motor function, cognitive decline, behavior problems, seizures, and premature death. We report a case of a 22-year-old man with CLN3 variant, homozygous NCL (aka Juvenile Neuronal Ceroid Lipofuscinosis) complicated by epilepsy who presented with episodes of recurrent seizure-like activity following status epilepticus, but now without electrographic correlate. Episodes were accompanied by tachycardia, diaphoresis, hypertension, and a fearful facial expression likely representing paroxysmal sympathetic hyperactivity (PSH), and improved with administration of propranolol. It is possible that status epilepticus provoked these episodes of PSH.
1 Introduction
Neuronal Ceroid Lipofuscinoses (NCL) are a group of rare genetic metabolic neurodegenerative disorders caused by a buildup of ceroid lipofuscin in the brain [1]. NCL affects 2–4 in 100,000 births [2]. There are over thirteen genes (CLN 1–14, except CLN 9) containing 430 genetic mutations underlying NCL. These genes encode proteins found in the secretory, endosomal, and lysosomal pathways, but exact mechanisms of all gene mutations remain unclear. In most cases, the inheritance pattern of NCL is autosomal recessive, except for CLN4 which is autosomal dominant and gives rise to the adult onset form [3]. There is limited data on the clinical progression of the disorder due to its rare prevalence and the shortened lifespan of affected patients.
There are four subsets of JNCL characterized by age of onset: infantile, late-infantile, juvenile, and adult. Common features between the four subsets are visual decline, psychomotor regression, ataxia, myoclonus, and refractory epilepsy [1]. The prognosis is better as the age of onset increases, with infantile onset having the worse prognosis and adult onset having the best prognosis [1]. Juvenile NCL (JNCL) is seen in the described patient and most often presents between 4 and 7 years with rapidly progressive vision loss due to retinopathy. Between 10 to 12 years, increased seizures, behavioral issues, cognitive decline, and, sometimes, parkinsonism are common in JNCL [1], [4]. Death typically occurs by the third or fourth decade [4]. Given there are few people with JNCL who are in their third or fourth decade of life, little is known about the later manifestations of JNCL.
Paroxysmal sympathetic hyperactivity (PSH), a well-known complication of traumatic brain injuries due to dysregulation of sympathetic nervous system control [5], has been described in patients with JNCL at the time of infection or environmental triggers. In our patient, we observed PSH following status epilepticus, which has not previously been reported to our knowledge [6]. Although episodes may appear similar to seizures, clinical manifestations and continuous video electroencephalogram (cEEG) monitoring can differentiate the two entities and guide appropriate management.
2 Case description
A 22-year-old man with a history of CLN3 variant, homozygous NCL was transferred to our institution from an outside hospital for continuous EEG monitoring due to concern for nonconvulsive status epilepticus.
This patient was diagnosed with JNCL at age 5 after initially presenting with loss of color vision and central vision loss, which was followed over time by progressive intellectual impairment, seizures, dystonia, and spasticity. Now he is blind, severely intellectually impaired, and suffers from epilepsy, behavioral problems (aggression and irritability), hallucinations, dystonia, and spasticity. At baseline, he is aware of and can interact with his environment. He recognizes voices, follows simple commands, and communicates through one- to two-word phrases or hand motions. He ambulates with assistance and uses a wheelchair for long distances. His medication regimen at the time of presentation included clonazepam 0.125 mg tablet three times daily, divalproex sprinkle 7–125 mg capsules once daily, pyridoxine 25 mg tablet once daily, lacosimide 100 mg tablet twice daily, aripiprazole 1 mg/ml solution 9 mL twice daily, sertraline 100 mg once daily, and a rescue diazepam 10 mg gel suppository as needed. He previously had adverse reactions to levetiracetam and lorazepam. There had been no recent changes to his antiepileptic regimen or to other medications.
His typical seizure semiology is described as generalized tonic-clonic activity with 1 minute of tonic phase followed by 4 min of clonic phase. His seizures occur every 2–4 weeks. He rarely has clusters of seizures without returning to baseline. The last time a cluster occurred was 18 months prior to this presentation.
Two days prior to presentation to the outside hospital, the patient experienced a seizure and returned to baseline shortly after. The next day, he had 4 seizures, each 4 h apart, without return to baseline. His parents reported that the semiology of these seizures was consistent with his typical seizure semiology. He received multiple doses of clonazepam and midazolam and was brought to an outside hospital that night. No seizures were observed after arrival, but his mental status did not return to baseline. A noncontrast head CT showed no acute findings. Complete blood count, complete metabolic profile, and urinalysis showed no evidence of infection or metabolic derangement. EKG showed normal sinus rhythm. His daily total divalproex dose was increased from 875 mg to 1000 mg. He was transferred to our institution for continuous EEG monitoring due to concern for nonconvulsive status. He arrived at our institution approximately 60 h after the initial onset of seizure activity and approximately 18 h after the last observed seizure of his typical semiology. Six hours after admission to this hospital, the patient’s parents observed clinical events that were new and distinct from his typical seizures. His mental status still had not returned to baseline at this point.
During 48 h of cEEG, over 20 push-button events of varying lengths were captured. The following symptoms and observations of the episodes are listed here in no particular order: (1) fearful facial expression and calling for his father, (2) non-sustained multi-directional nystagmus, (3) body rolled to right side and right arm became hypertonic, flexed, adducted, and internally rotated, lower extremities held extended, with intermittent right leg shaking (not stereotyped episode to episode), (4) rocking back and forth with a quick frequency and low amplitude, (5) brief tachycardia to 140 beats/min, 6) hypertensive to 150/90 mmHg, (7) tachypnea to at least 25 breaths per min, (8) flushed skin and diaphoretic on forehead, arms, and palms, (9) decreased awareness from baseline, and (10) no electrographic correlate present concurrently. When each episode ceased, his muscles relaxed, heart rate and blood pressure normalized, diaphoresis resolved, and the patient verbalized that he felt better. These episodes lasted from 10 s to 5 min and occurred as frequently as every 10 s during some clusters. No inciting triggers could be identified. The EEG showed mild diffuse slowing and mildly increased beta activity during wakefulness, as well as rare frontopolar predominant sharp waveforms during the first day of monitoring. On the second day, eye leads were added. During the awake state, the background again showed mild slowing with excess beta activity and left > right frontal activity appearing to correspond with the eye leads. During sleep, intermittent interictal discharges were observed, sometimes broad right or maximal at F8/T2/T4/T6, broad discharges from the left hemisphere, and some with a more generalized, frontal predominant field. No electrographic correlate was found for any of the events (Fig. 1).Fig. 1 EEG tracings during admission. A) Longitudinal bipolar montage demonstrating baseline awake EEG; B & C) Longitudinal bipolar montage EEG demonstrating representative, sporadic interictal discharges, seen predominantly during sleep; D) Longitudinal bipolar montage EEG recording at the time of a typical clinical event. There was no clear change in the EEG from baseline seen with events.
Given the presentation of abrupt tachycardia, hypertension, diaphoresis, abnormal posturing, and the lack of electrographic correlate to these events, PSH was clinically suspected. Focal status was thought to be less likely given the recurrent presence of autonomic features, the lack of clear stereotyped movements, and lack of response to benzodiazepines. Due to the high suspicion for PSH, propranolol was initiated at 10 mg by mouth every 6 h. The episodes decreased in frequency and severity immediately. He did not have any episodes in the first 5 h after taking propranolol. Approximately six hours following each dose, he had minor, but similar, episodes that could be intentionally shortened with deep breathing. This pattern continued and was observed consistently over the next few days. The correlation between propranolol initiation and resolution of the episodes supported the suspected diagnosis of PSH. Over the next few days, the episodes dissipated, and mental status returned to baseline. Propranolol was continued, and the patient was discharged to an acute neurologic rehabilitation hospital.
3 Discussion
The patient’s episodes of increased muscle tone and hyperadrenergic state without evidence of seizure activity on cEEG likely represented PSH. Using the PSH Assessment Measure (PSH-AM) outlined in Meyfroidt et al., this patient scored 18, with any score ≥ 17 meaning PSH is the probable diagnosis (Fig. 2) [5]. The main features that differentiated this patient’s episodes from those of typical PSH are multi-directional nystagmus and the rocking and shaking movements, which made this presentation more difficult to discern clinically from seizure (Table 1). Given that the episodes were not stereotyped, were not consistent with his typical seizure semiology, had no EEG correlate, did not respond to benzodiazepines, and immediately abated with the administration of propranolol, PSH was the suspected diagnosis. Supportive ancillary testing was not feasible for our patient but could be considered in some cases. Ictal SPECT could be used during an episode to exclude evidence of a seizure focus not seen on scalp EEG, though would require careful coordination of isotrope injection and imaging, as well as consistent patient cooperation. Autonomic testing could also be pursued on an outpatient basis.Fig. 2 PSH Assessment Measure. This is the PSH-AM found in Meyfroidt et al. [5]. The patient described had a CFS subtotal of 11 and a DLT subtotal of 7, giving him an PSH-AM score of 18. This makes PSH a probable diagnosis. * Indicates the symptoms present in the patient described.
Table 1 Comparison of PSH and Focal Seizures. While there are some similarities in the presentation, the key differences are the sympathetic features like tachycardia, tachypnea, hypertension, and diaphoresis in PSH as compared to focal seizures. Also, response to treatment can differentiate the two with beta blockade resolving PSH and antiepileptic drugs resolving focal seizures.
Paroxysmal sympathetic Hyperactivity Focal Seizures
Definition “Simultaneous, paroxysmal transient increases in sympathetic (elevated heart rate, blood pressure, respiratory rate, temperature, sweating) and motor (posturing) activity.” [7] Seizure activity initiated in a single area of the brain
Presentation Tachycardia, tachypnea hypertension, diaphoresis, posturing Aura, automatisms, lateralizing motor features, vocalizations, post-ictal confusion, hyperadrenergic state, tachycardia if mesial temporal lobe seizure
Stereotyped No Yes
Diagnostic Tool PSH Assessment Measure (PSH-AM), autonomic testing EEG
Treatment Beta-blocker Anti-epileptic drugs
Response to beta-blockade Responsive Not responsive
There is limited information regarding the incidence of PSH in JNCL. Ostergaard (2018) reported five cases of patients with JNCL who presented with PSH in late adolescence [6]. Mild episodes were evoked by environmental stimuli, such as moving from bed to chair, brushing teeth, and loud noises. More severe episodes, which required ICU admission, were primarily associated with underlying infections as inciting factors. When the inciting factors of the PSH episodes were resolved, the episodes of PSH abated.
Further, the patients with JNCL that Ostergaard (2018) followed over fifteen years were found to have age-related significant decrease in parasympathetic activity leading to autonomic imbalance and sympathetic predominance by the late adolescent period [6]. About 80% of PSH cases are found in patients after a traumatic brain injury (TBI). The pathophysiology is felt to involve injury to the brainstem causing disruption of descending inhibitory pathways, resulting in spinal circuit excitation [5]. Lesions in the midbrain, pons, periventricular gray matter, corpus callosum, and deep gray nuclei due to brain injuries (anoxic brain injury, stroke, tumors, infections, unspecified) have an increased risk of resulting in PSH [8]. The etiology of PSH in JNCL is unknown, but it has been suggested that there is a loss of inhibitory control over excitatory autonomic centers [5]. Sympathetic outflow may also have reduced manifestations in a pediatric patient given the variation in insular structure connectivity at a younger age [9]. This reasoning could contribute to why episodes of PSH present later in adolescence with JNCL.
There is an ongoing effort to better understand how status epilepticus affects long term brain function. It is evident that prolonged convulsive status epilepticus is associated with high morbidity and mortality because irreversible neuronal activity may occur [10], [11]. Neuronal damage occurs in 10 to 50 percent of people with status epilepticus lasting over 30 min, which can lead to neurologic deficits [12]. Given the patient’s status epilepticus lasted for at least 12 h without returning to baseline, there is a high likelihood of neuronal injury, and possibly within the pathway mediating autonomic function. Given this patient’s previous diagnosis of JNCL, it is also possible that having a neurodegenerative disease could increase the likelihood of neuronal injury during status epilepticus, causing neuronal deficits which potentiate or unmask the presentation of sympathetic excitation.
This report is unique because relatively few patients with JNCL survive into or beyond their early 20 s, and no identical presentation of PSH following status epilepticus has been reported. It is unknown whether this presumed PSH is due to progression of the disease independently or was a consequence of the antecedent status epilepticus. The patient’s parents were able to concretely explain and demonstrate video of the differences between the new episodes and the patient’s typical seizures. Furthermore, the patient’s longstanding child neurologist confirmed that these episodes, as described, were new. Patients with JNCL and other neurodegenerative and neurodevelopmental disorders with associated epilepsy tend to have consistent seizure semiology. When semiology differs, it is important to explore the possibility of a new condition in the context of patient history.
While there are significant limitations to proposing the diagnosis of PSH following status epilepticus in this single instance, this case report aims to make physicians and caregivers aware of the variety of symptoms that can present as a result of an extended lifespan of patients with JNCL. Patients may have further complications from the progression of JNCL with age, which are still unknown given the low prevalence of patients in their third decade of life. It is difficult, yet important, to differentiate if complications arise from the pathophysiology of JNCL or from associated conditions, like status epilepticus [7].
4 Conclusion
This patient’s unique presentation suggests that the pathophysiologic underpinnings of paroxysmal sympathetic hyperactivity following status epilepticus may share commonality with those seen following other types of brain injury. Awareness of various presentations of neurologic symptoms in JNCL typically seen in other neurologic disorders remains crucial for understanding later manifestations of JNCL and associated conditions.
5 Declarations of interest
None. | Recovering | ReactionOutcome | CC BY-NC-ND | 33681754 | 19,789,164 | 2021 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Drug resistance'. | Very rare case of Graves' disease with resistance to methimazole: a case report and literature review.
BACKGROUND
Methimazole (MMI) is used to treat hyperthyroidism in Graves' disease. It is rare to encounter patients in whom hyperthyroidism cannot be controlled using high doses of MMI.Case presentation: A 21-year-old woman was referred to our hospital because of MMI-resistant Graves' disease. Although her MMI dose had been increased to 120 mg/day, her serum thyroid hormone concentration was too high to be measured. Additional therapy with lithium carbonate, and then with dexamethasone and inorganic iodine, was initiated. After 14 days, the patient's serum thyroid hormone concentration normalized, while she was taking 150 mg/day MMI, 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, and total thyroidectomy was then performed. The patient was discharged 8 days after the thyroidectomy and experienced no major complications.
CONCLUSIONS
We have presented a rare case of Graves' disease that was resistant to high-dose MMI. Combination therapy of MMI with lithium carbonate, dexamethasone and inorganic iodine may represent a therapeutic option for the preoperative preparation of patients with MMI-resistant Graves' disease.
Background
Graves’ disease is the most common cause of thyrotoxicosis, and the lifetime risk of developing this disease is approximately 3% and 0.5% for women and men, respectively.1 Graves’ disease is caused by autoimmunity targeting thyroid-stimulating hormone (TSH) receptors in the thyroid glands, which induce thyrotoxicosis and a diffuse goitre.1,2 The principal means of managing Graves’ disease is the inhibition of excess thyroid hormone production using anti-thyroid drugs, radioiodine ablation or thyroidectomy.1,2 Among these treatment modalities, an anti-thyroid agent, methimazole (MMI), is the most widely used option for the initial treatment of Graves’ disease, because of its efficacy, convenience and low cost.3 However, thyroidectomy should be considered for patients with large thyroid glands, especially when anti-thyroid agents are not effective or tolerated. However, the patient’s hyperthyroidism should be adequately controlled before they undergo thyroidectomy; otherwise, the risk of thyroid storm during the perioperative period is higher.4,5 Furthermore, no definitive guidelines exist regarding the preoperative management for patients with Graves’ disease with severe hyperthyroidism because of resistance to MMI.
We recently encountered a rare case of Graves’ disease with resistance to extremely high doses of MMI. A previous clinical study showed that a high dose of MMI (120 mg/day) reduces thyroid hormone concentration more rapidly than standard doses of MMI (30 to 40 mg/day) in patients with hyperthyroidism. However, such a high dose of MMI may increase the risks of severe adverse effects, such as skin rashes and agranulocytosis.6 Nevertheless, a case report suggested that 150 mg/day MMI was effective at controlling hyperthyroidism in a patient with Graves’ disease who was resistant to standard doses of MMI.7 Although we carefully increased the doses of MMI (to 120 mg/day) administered to the patient we describe, her serum thyroid hormone concentration remained too high to be measured . However, she became euthyroid when combination therapy of 150 mg/day MMI with lithium carbonate, dexamethasone and inorganic iodine was instituted, and total thyroidectomy was then performed. The patient experienced no major complications and was discharged from the hospital post-operatively.
Case presentation
A 14-year-old girl initially presented with symptoms of general fatigue, palpitations, and excessive sweating. The patient did not have any significant medical history and had never consumed tobacco or alcohol. However, her grandmother had Graves’ disease. The patient was diagnosed as having Graves’ disease on the basis of the following laboratory findings: positivity for TSH receptor autoantibody (TRAb) (first generation assay, 47.8% [normal range, <10%]), high free triiodothyronine (T3) (39.86 pmol/L [normal range, 3.54–6.62 pmol/L]) and free thyroxine (T4) (57.14 pmol/L [normal range, 11.58–21.88 pmol/L]) concentrations, and low TSH concentration (<0.005 μIU/mL [normal range, 0.50–5.00 μIU/mL]). Fifteen mg/day of MMI was administered as the initial treatment. The patient became euthyroid after 3 months and her thyroid hormone concentration remained stable thereafter, while she administered 5 to 10 mg/day MMI. The patient wished to undergo definitive therapy for Graves’ disease, using radioiodine ablation or thyroidectomy, but she was not able to do so at the time because of financial constraints. Therefore, MMI treatment was continued. When the patient was 19 years old, her serum thyroid hormone concentration began to increase, and her attending physician increased the MMI dose to 40 mg/day and recommended the patient to undergo radioiodine ablation or thyroidectomy to control her hyperthyroidism. However, the patient declined the attending physician’s recommendation because the financial constraints remained. When the patient was 21 years old, her hyperthyroidism became uncontrollable, even at a dose of 90 mg/day MMI, which is above the standard dose range.3 She also required hospitalisation for 2 weeks because of severe insomnia. The hospital staff confirmed that the patient took her medication as prescribed during her hospitalisation. However, the patient’s thyroid hormone concentration did not improve. Her TRAb titre had not been assessed since her first measurement. The patient was referred to our hospital for further treatment of her hyperthyroidism.
Clinical course: The patient’s height, body mass, and body mass index were 165 cm, 50 kg, and 18.4 kg/m2, respectively. Physical examination revealed that she had characteristic signs of hyperthyroidism, including diffuse large goitre with bruit, tremors, sweating, and sinus tachycardia (106 beats/minute); however, no ophthalmopathy was observed. Blood tests confirmed hyperthyroidism (free T3, 24.78 pmol/L; free T4, 42.99 pmol/L, TSH <0.005 μIU/mL) and there was a moderate TRAb titre (second generation assay, 5.6 IU/L [normal range, <1.0 IU/L]).7 Ultrasound and computed tomography scans showed a large thyroid gland with high blood flow, but no internal nodule was identified (Figure 1). All these findings were compatible with Graves’ disease. We did not consider changing the anti-thyroid therapy from MMI to propylthiouracil (PTU), because MMI is more effective than PTU for the control of hyperthyroidism.8,9
Figure 1. Images of the ultrasound (A, B) and computed tomography (C, D) scans of the patient’s thyroid glands. A and B: Colour-flow Doppler images of the right and left lobe, respectively. C and D: Coronal and transverse sections, respectively, showing both thyroid lobes and the isthmus. Thyroid gland size was determined on the ultrasonographic images (thickness × width): right lobe, 24.2 × 22.8 mm; left lobe, 23.3 × 22.1 mm; isthmus, 8-mm thickness. The length of each thyroid lobe could not be measured.
First, we evaluated the patient’s drug compliance. We asked the patient’s family to monitor her drug compliance without notifying the patient, and they confirmed that the patient did take her medication and that the number of empty tablet containers matched the prescription. Therefore, we judged that she was resistant to high doses of MMI and that thyroidectomy would be necessary to treat her hyperthyroidism effectively. Next, we cooperated with medical social workers to seek financial support for the patient, and we were able to overcome her financial constraints regarding surgery.
Hyperthyroidism should be adequately controlled before thyroidectomy is performed;4,5 therefore, we treated the patient’s disease with 120 mg/day MMI,7 which is a much higher dose than the standard dose range for MMI,3 but her serum thyroid hormone concentration remained too high to be measured (Figure 2). Therefore, we initiated additional therapy with 200 mg/day lithium carbonate, followed by 800 mg/day lithium carbonate,11 4 mg/day dexamethasone12 and 153 mg/day inorganic iodine.12 However, the patient’s thyroid hormone concentration remained high; therefore, the thyroidectomy was postponed. After further intensifying the drug therapy to 150 mg/day MMI,7 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, the patient’s serum thyroid hormone concentration normalized. Therefore, total thyroidectomy was performed 7 days after hospitalisation. The patient’s thyroid gland weighed 86 g, which is approximately six-to-seven times heavier than a normal thyroid gland.13 Histopathological assessment of the excised thyroid gland showed diffuse follicular hyperplasia without autonomous thyroid nodules, which is compatible with Graves’ disease. Hormone replacement therapy with levothyroxine was initiated after the surgery, and the MMI, lithium carbonate, dexamethasone and inorganic iodine were tapered off. No surgical complications developed, except for moderate hypocalcaemia that lasted a few days. The patient was discharged 8 days after thyroidectomy.
Figure 2. Clinical course of the patient in our hospital. The values shown are in mg/day for MMI, PRL, Li, I and Dex; and μg/day for L-T4.
MMI, methimazole; PRL, propranolol; Li, lithium carbonate, I, inorganic iodine; Dex, dexamethasone; L-T4, levothyroxine.
Discussion
Here, we report a rare case of Graves’ disease that was resistant to an extremely high dose (150 mg/day) of MMI. Some cases of Graves’ disease occur in which high doses of anti-thyroid agents, such as 150 mg/day of MMI or 60 to 90 mg/day of carbimazole (equivalent to 36 to 54 mg/day MMI), are needed to control the hyperthyroidism.7,15–19 However, to the best of our knowledge, this is the first case of Graves’ disease to be reported that showed no response to a very high dose of MMI and in which the patient’s uncontrolled hyperthyroidism was corrected by the addition of lithium carbonate, dexamethasone and inorganic iodine to the therapeutic regimen. For the present case, we had to increase the dose of MMI beyond the standard range to control the patient’s hyperthyroidism prior to thyroidectomy.3 However, a previous clinical study showed that a very high dose of MMI is associated with a higher risk of severe adverse effects.6 In this study, patients with hyperthyroidism were treated with 120 mg/day MMI, and eight of the 25 experienced severe adverse effects. Skin rash was the most common adverse effect, but two patients showed agranulocytosis.6 In addition, other clinical studies have shown that high doses of MMI are associated with higher risks of adverse effects.20–22 Therefore, very high doses of MMI should not be considered to represent a standard treatment option for Graves’ disease; instead, this treatment strategy should only be reserved for the very few patients for whom other treatment options are not available.
MMI inhibits thyroid hormone synthesis by preventing the iodination of tyrosine residues in thyroglobulin by thyroid peroxidase.3 Although some previous cases of Graves’ disease have been reported that involved resistance to standard doses of MMI, the underlying mechanisms of this resistance remain unclear.7,15–19 For several years after the onset of the disease, the patient’s hyperthyroidism was well controlled using relatively low doses of MMI, which excluded the possibility that the resistance to MMI was caused by genetic factors. After rapid and efficient absorption from the intestine,23 MMI is metabolized in the liver24 and is principally excreted through the bile and urine.25 A previous clinical study showed that the peak plasma concentration and half-life of MMI after oral administration are comparable in healthy individuals and patients with hyperthyroidism.23 In addition, the patient reported herein did not show any symptoms or signs of comorbid gastrointestinal or liver disease, which may have affected the pharmacokinetics of MMI. Therefore, it is unlikely that the MMI resistance documented herein was the result of defects in the absorption, metabolism or excretion of MMI. After its absorption, MMI accumulates at high concentrations in the thyroid gland, to levels approximately two-to-five times higher than those in the plasma.26 Therefore, it is probable that the concentration of MMI in the thyroid gland, rather than in the circulation, has the largest impact on its anti-thyroid effect.3 Indeed, in a patient who needed a high dose (150 mg/day) of MMI to control their hyperthyroidism, the concentration of MMI in their thyroid tissue was lower than that in the thyroid of MMI-sensitive patients.7
Given that large thyroids are associated with resistance to MMI in patients with Graves’ disease,27 the substantial thyroid gland hypertrophy may have caused impaired uptake or greater metabolism and excretion of MMI in the present case. Another possibility is atypical iodine intake, which affects the absorption and oxidation of MMI in the thyroid gland.28 Because the Japanese diet has been reported to contain many iodine-rich foods, such as seaweed and seafood,29 high dietary intake of iodine may have affected the sensitivity of the patient to MMI. However, because the plasma and intra-thyroidal MMI concentrations and urinary iodine excretion were not evaluated in the patient, we cannot comment on these possible causes of the MMI resistance in the present case. However, the evaluation of these factors should be considered in future cases of MMI resistance to elucidate the underlying mechanisms. Finally, poor drug compliance should be suspected initially in patients with Graves’ disease whose disease is resistant to MMI. We confirmed that the patient’s drug compliance was high, on the basis of a report from her family. In addition, the hospital staff confirmed that the patient took her medication as prescribed during her hospitalisation for severe insomnia, although the evaluation of drug compliance was not the principal aim of this period of hospitalisation. Furthermore, the patient’s circulating thyroid hormone concentration rapidly decreased after the initiation of lithium carbonate, inorganic iodine and corticosteroid therapy, which suggests that the patient did take these medications. Therefore, low drug compliance was unlikely to be the explanation for the MMI resistance in the present case.
The present patient responded to treatment with lithium carbonate, inorganic iodine and corticosteroid, in addition to MMI. Lithium carbonate and inorganic iodine ameliorate hyperthyroidism by inhibiting the release of thyroid hormone from the thyroid gland,30,31 and corticosteroids principally work by suppressing the conversion of T4 to T3 in peripheral tissues,32 whereas MMI blocks thyroid hormone synthesis within the thyroid gland.3 Therefore, we speculate that these drugs were effective at controlling the hyperthyroidism in the present patient because their mechanisms of action differ to that of MMI. Although lithium carbonate is not recommended as a first-line therapy for Graves’ disease because of a relatively high risk of adverse effects, several clinical studies have shown that lithium carbonate represents an alternative therapy for patients who do not tolerate MMI or PTU.11,24,33 We found that the addition of lithium carbonate (200 mg/day) to basal MMI treatment reduced the thyroid hormone concentration of the present patient. Because anti-thyroid effects of lithium carbonate have been reported at doses of 600 to 900 mg/day,11,33,34 we increased her lithium carbonate dose to 800 mg/day. However, inorganic iodine and corticosteroid were simultaneously administered; therefore, we do not know whether the escalation of the dose of lithium carbonate was the key change in therapy in the present case. Combination therapy of MMI with corticosteroid and inorganic iodine is a strategy that is commonly used for the management of thyroid storm; 8 mg/day dexamethasone and up to 200 mg/day inorganic iodine are recommended in the guidelines for the management of thyroid storm published by the Japan Thyroid Association and the Japan Endocrine Society.12 However, the optimal doses of these drugs for use in MMI-resistant Graves’ disease remain unclear. We found that the combination of inorganic iodine, which was initiated at 153 mg/day and increased to 306 mg/day, and dexamethasone, which was initiated at 4 mg/day and increased to 6 mg/day, normalized the very high thyroid hormone concentration of the patient within 14 days.
In conclusion, we encountered a rare case of Graves’ disease with resistance to an extremely high dose of MMI. We found that combination therapy with lithium carbonate, inorganic iodine and corticosteroid is an effective alternative means of preparing MMI-resistant patients with Graves’ disease for surgery.
Ethics statement
The patient provided her written consent for her treatment publication of the findings of this case study. We have de-identified all the patient’s details in this case report to comply with the CAse REport (CARE) guidelines.14 The approval of the Institutional Review Body was not required because of the nature of this study (a case report).
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: YM received financial support from Boehringer Ingelheim JP Co., Ltd. and Ono Pharmaceutical Co., Ltd.
Author contributions: YM treated the patient, and wrote, revised and finalized the paper. MH, MT, HK, MO, TF, YT, and SY supervised the treatment of the patient, contributed to the discussion and revised the manuscript. All the authors read and approved the final version of the manuscript.
ORCID iD: Yusaku Mori https://orcid.org/0000-0002-1734-0605 | METHIMAZOLE | DrugsGivenReaction | CC BY-NC | 33682498 | 19,253,298 | 2021-03 |
What is the weight of the patient? | Very rare case of Graves' disease with resistance to methimazole: a case report and literature review.
BACKGROUND
Methimazole (MMI) is used to treat hyperthyroidism in Graves' disease. It is rare to encounter patients in whom hyperthyroidism cannot be controlled using high doses of MMI.Case presentation: A 21-year-old woman was referred to our hospital because of MMI-resistant Graves' disease. Although her MMI dose had been increased to 120 mg/day, her serum thyroid hormone concentration was too high to be measured. Additional therapy with lithium carbonate, and then with dexamethasone and inorganic iodine, was initiated. After 14 days, the patient's serum thyroid hormone concentration normalized, while she was taking 150 mg/day MMI, 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, and total thyroidectomy was then performed. The patient was discharged 8 days after the thyroidectomy and experienced no major complications.
CONCLUSIONS
We have presented a rare case of Graves' disease that was resistant to high-dose MMI. Combination therapy of MMI with lithium carbonate, dexamethasone and inorganic iodine may represent a therapeutic option for the preoperative preparation of patients with MMI-resistant Graves' disease.
Background
Graves’ disease is the most common cause of thyrotoxicosis, and the lifetime risk of developing this disease is approximately 3% and 0.5% for women and men, respectively.1 Graves’ disease is caused by autoimmunity targeting thyroid-stimulating hormone (TSH) receptors in the thyroid glands, which induce thyrotoxicosis and a diffuse goitre.1,2 The principal means of managing Graves’ disease is the inhibition of excess thyroid hormone production using anti-thyroid drugs, radioiodine ablation or thyroidectomy.1,2 Among these treatment modalities, an anti-thyroid agent, methimazole (MMI), is the most widely used option for the initial treatment of Graves’ disease, because of its efficacy, convenience and low cost.3 However, thyroidectomy should be considered for patients with large thyroid glands, especially when anti-thyroid agents are not effective or tolerated. However, the patient’s hyperthyroidism should be adequately controlled before they undergo thyroidectomy; otherwise, the risk of thyroid storm during the perioperative period is higher.4,5 Furthermore, no definitive guidelines exist regarding the preoperative management for patients with Graves’ disease with severe hyperthyroidism because of resistance to MMI.
We recently encountered a rare case of Graves’ disease with resistance to extremely high doses of MMI. A previous clinical study showed that a high dose of MMI (120 mg/day) reduces thyroid hormone concentration more rapidly than standard doses of MMI (30 to 40 mg/day) in patients with hyperthyroidism. However, such a high dose of MMI may increase the risks of severe adverse effects, such as skin rashes and agranulocytosis.6 Nevertheless, a case report suggested that 150 mg/day MMI was effective at controlling hyperthyroidism in a patient with Graves’ disease who was resistant to standard doses of MMI.7 Although we carefully increased the doses of MMI (to 120 mg/day) administered to the patient we describe, her serum thyroid hormone concentration remained too high to be measured . However, she became euthyroid when combination therapy of 150 mg/day MMI with lithium carbonate, dexamethasone and inorganic iodine was instituted, and total thyroidectomy was then performed. The patient experienced no major complications and was discharged from the hospital post-operatively.
Case presentation
A 14-year-old girl initially presented with symptoms of general fatigue, palpitations, and excessive sweating. The patient did not have any significant medical history and had never consumed tobacco or alcohol. However, her grandmother had Graves’ disease. The patient was diagnosed as having Graves’ disease on the basis of the following laboratory findings: positivity for TSH receptor autoantibody (TRAb) (first generation assay, 47.8% [normal range, <10%]), high free triiodothyronine (T3) (39.86 pmol/L [normal range, 3.54–6.62 pmol/L]) and free thyroxine (T4) (57.14 pmol/L [normal range, 11.58–21.88 pmol/L]) concentrations, and low TSH concentration (<0.005 μIU/mL [normal range, 0.50–5.00 μIU/mL]). Fifteen mg/day of MMI was administered as the initial treatment. The patient became euthyroid after 3 months and her thyroid hormone concentration remained stable thereafter, while she administered 5 to 10 mg/day MMI. The patient wished to undergo definitive therapy for Graves’ disease, using radioiodine ablation or thyroidectomy, but she was not able to do so at the time because of financial constraints. Therefore, MMI treatment was continued. When the patient was 19 years old, her serum thyroid hormone concentration began to increase, and her attending physician increased the MMI dose to 40 mg/day and recommended the patient to undergo radioiodine ablation or thyroidectomy to control her hyperthyroidism. However, the patient declined the attending physician’s recommendation because the financial constraints remained. When the patient was 21 years old, her hyperthyroidism became uncontrollable, even at a dose of 90 mg/day MMI, which is above the standard dose range.3 She also required hospitalisation for 2 weeks because of severe insomnia. The hospital staff confirmed that the patient took her medication as prescribed during her hospitalisation. However, the patient’s thyroid hormone concentration did not improve. Her TRAb titre had not been assessed since her first measurement. The patient was referred to our hospital for further treatment of her hyperthyroidism.
Clinical course: The patient’s height, body mass, and body mass index were 165 cm, 50 kg, and 18.4 kg/m2, respectively. Physical examination revealed that she had characteristic signs of hyperthyroidism, including diffuse large goitre with bruit, tremors, sweating, and sinus tachycardia (106 beats/minute); however, no ophthalmopathy was observed. Blood tests confirmed hyperthyroidism (free T3, 24.78 pmol/L; free T4, 42.99 pmol/L, TSH <0.005 μIU/mL) and there was a moderate TRAb titre (second generation assay, 5.6 IU/L [normal range, <1.0 IU/L]).7 Ultrasound and computed tomography scans showed a large thyroid gland with high blood flow, but no internal nodule was identified (Figure 1). All these findings were compatible with Graves’ disease. We did not consider changing the anti-thyroid therapy from MMI to propylthiouracil (PTU), because MMI is more effective than PTU for the control of hyperthyroidism.8,9
Figure 1. Images of the ultrasound (A, B) and computed tomography (C, D) scans of the patient’s thyroid glands. A and B: Colour-flow Doppler images of the right and left lobe, respectively. C and D: Coronal and transverse sections, respectively, showing both thyroid lobes and the isthmus. Thyroid gland size was determined on the ultrasonographic images (thickness × width): right lobe, 24.2 × 22.8 mm; left lobe, 23.3 × 22.1 mm; isthmus, 8-mm thickness. The length of each thyroid lobe could not be measured.
First, we evaluated the patient’s drug compliance. We asked the patient’s family to monitor her drug compliance without notifying the patient, and they confirmed that the patient did take her medication and that the number of empty tablet containers matched the prescription. Therefore, we judged that she was resistant to high doses of MMI and that thyroidectomy would be necessary to treat her hyperthyroidism effectively. Next, we cooperated with medical social workers to seek financial support for the patient, and we were able to overcome her financial constraints regarding surgery.
Hyperthyroidism should be adequately controlled before thyroidectomy is performed;4,5 therefore, we treated the patient’s disease with 120 mg/day MMI,7 which is a much higher dose than the standard dose range for MMI,3 but her serum thyroid hormone concentration remained too high to be measured (Figure 2). Therefore, we initiated additional therapy with 200 mg/day lithium carbonate, followed by 800 mg/day lithium carbonate,11 4 mg/day dexamethasone12 and 153 mg/day inorganic iodine.12 However, the patient’s thyroid hormone concentration remained high; therefore, the thyroidectomy was postponed. After further intensifying the drug therapy to 150 mg/day MMI,7 800 mg/day lithium carbonate, 6 mg/day dexamethasone and 306 mg/day inorganic iodine, the patient’s serum thyroid hormone concentration normalized. Therefore, total thyroidectomy was performed 7 days after hospitalisation. The patient’s thyroid gland weighed 86 g, which is approximately six-to-seven times heavier than a normal thyroid gland.13 Histopathological assessment of the excised thyroid gland showed diffuse follicular hyperplasia without autonomous thyroid nodules, which is compatible with Graves’ disease. Hormone replacement therapy with levothyroxine was initiated after the surgery, and the MMI, lithium carbonate, dexamethasone and inorganic iodine were tapered off. No surgical complications developed, except for moderate hypocalcaemia that lasted a few days. The patient was discharged 8 days after thyroidectomy.
Figure 2. Clinical course of the patient in our hospital. The values shown are in mg/day for MMI, PRL, Li, I and Dex; and μg/day for L-T4.
MMI, methimazole; PRL, propranolol; Li, lithium carbonate, I, inorganic iodine; Dex, dexamethasone; L-T4, levothyroxine.
Discussion
Here, we report a rare case of Graves’ disease that was resistant to an extremely high dose (150 mg/day) of MMI. Some cases of Graves’ disease occur in which high doses of anti-thyroid agents, such as 150 mg/day of MMI or 60 to 90 mg/day of carbimazole (equivalent to 36 to 54 mg/day MMI), are needed to control the hyperthyroidism.7,15–19 However, to the best of our knowledge, this is the first case of Graves’ disease to be reported that showed no response to a very high dose of MMI and in which the patient’s uncontrolled hyperthyroidism was corrected by the addition of lithium carbonate, dexamethasone and inorganic iodine to the therapeutic regimen. For the present case, we had to increase the dose of MMI beyond the standard range to control the patient’s hyperthyroidism prior to thyroidectomy.3 However, a previous clinical study showed that a very high dose of MMI is associated with a higher risk of severe adverse effects.6 In this study, patients with hyperthyroidism were treated with 120 mg/day MMI, and eight of the 25 experienced severe adverse effects. Skin rash was the most common adverse effect, but two patients showed agranulocytosis.6 In addition, other clinical studies have shown that high doses of MMI are associated with higher risks of adverse effects.20–22 Therefore, very high doses of MMI should not be considered to represent a standard treatment option for Graves’ disease; instead, this treatment strategy should only be reserved for the very few patients for whom other treatment options are not available.
MMI inhibits thyroid hormone synthesis by preventing the iodination of tyrosine residues in thyroglobulin by thyroid peroxidase.3 Although some previous cases of Graves’ disease have been reported that involved resistance to standard doses of MMI, the underlying mechanisms of this resistance remain unclear.7,15–19 For several years after the onset of the disease, the patient’s hyperthyroidism was well controlled using relatively low doses of MMI, which excluded the possibility that the resistance to MMI was caused by genetic factors. After rapid and efficient absorption from the intestine,23 MMI is metabolized in the liver24 and is principally excreted through the bile and urine.25 A previous clinical study showed that the peak plasma concentration and half-life of MMI after oral administration are comparable in healthy individuals and patients with hyperthyroidism.23 In addition, the patient reported herein did not show any symptoms or signs of comorbid gastrointestinal or liver disease, which may have affected the pharmacokinetics of MMI. Therefore, it is unlikely that the MMI resistance documented herein was the result of defects in the absorption, metabolism or excretion of MMI. After its absorption, MMI accumulates at high concentrations in the thyroid gland, to levels approximately two-to-five times higher than those in the plasma.26 Therefore, it is probable that the concentration of MMI in the thyroid gland, rather than in the circulation, has the largest impact on its anti-thyroid effect.3 Indeed, in a patient who needed a high dose (150 mg/day) of MMI to control their hyperthyroidism, the concentration of MMI in their thyroid tissue was lower than that in the thyroid of MMI-sensitive patients.7
Given that large thyroids are associated with resistance to MMI in patients with Graves’ disease,27 the substantial thyroid gland hypertrophy may have caused impaired uptake or greater metabolism and excretion of MMI in the present case. Another possibility is atypical iodine intake, which affects the absorption and oxidation of MMI in the thyroid gland.28 Because the Japanese diet has been reported to contain many iodine-rich foods, such as seaweed and seafood,29 high dietary intake of iodine may have affected the sensitivity of the patient to MMI. However, because the plasma and intra-thyroidal MMI concentrations and urinary iodine excretion were not evaluated in the patient, we cannot comment on these possible causes of the MMI resistance in the present case. However, the evaluation of these factors should be considered in future cases of MMI resistance to elucidate the underlying mechanisms. Finally, poor drug compliance should be suspected initially in patients with Graves’ disease whose disease is resistant to MMI. We confirmed that the patient’s drug compliance was high, on the basis of a report from her family. In addition, the hospital staff confirmed that the patient took her medication as prescribed during her hospitalisation for severe insomnia, although the evaluation of drug compliance was not the principal aim of this period of hospitalisation. Furthermore, the patient’s circulating thyroid hormone concentration rapidly decreased after the initiation of lithium carbonate, inorganic iodine and corticosteroid therapy, which suggests that the patient did take these medications. Therefore, low drug compliance was unlikely to be the explanation for the MMI resistance in the present case.
The present patient responded to treatment with lithium carbonate, inorganic iodine and corticosteroid, in addition to MMI. Lithium carbonate and inorganic iodine ameliorate hyperthyroidism by inhibiting the release of thyroid hormone from the thyroid gland,30,31 and corticosteroids principally work by suppressing the conversion of T4 to T3 in peripheral tissues,32 whereas MMI blocks thyroid hormone synthesis within the thyroid gland.3 Therefore, we speculate that these drugs were effective at controlling the hyperthyroidism in the present patient because their mechanisms of action differ to that of MMI. Although lithium carbonate is not recommended as a first-line therapy for Graves’ disease because of a relatively high risk of adverse effects, several clinical studies have shown that lithium carbonate represents an alternative therapy for patients who do not tolerate MMI or PTU.11,24,33 We found that the addition of lithium carbonate (200 mg/day) to basal MMI treatment reduced the thyroid hormone concentration of the present patient. Because anti-thyroid effects of lithium carbonate have been reported at doses of 600 to 900 mg/day,11,33,34 we increased her lithium carbonate dose to 800 mg/day. However, inorganic iodine and corticosteroid were simultaneously administered; therefore, we do not know whether the escalation of the dose of lithium carbonate was the key change in therapy in the present case. Combination therapy of MMI with corticosteroid and inorganic iodine is a strategy that is commonly used for the management of thyroid storm; 8 mg/day dexamethasone and up to 200 mg/day inorganic iodine are recommended in the guidelines for the management of thyroid storm published by the Japan Thyroid Association and the Japan Endocrine Society.12 However, the optimal doses of these drugs for use in MMI-resistant Graves’ disease remain unclear. We found that the combination of inorganic iodine, which was initiated at 153 mg/day and increased to 306 mg/day, and dexamethasone, which was initiated at 4 mg/day and increased to 6 mg/day, normalized the very high thyroid hormone concentration of the patient within 14 days.
In conclusion, we encountered a rare case of Graves’ disease with resistance to an extremely high dose of MMI. We found that combination therapy with lithium carbonate, inorganic iodine and corticosteroid is an effective alternative means of preparing MMI-resistant patients with Graves’ disease for surgery.
Ethics statement
The patient provided her written consent for her treatment publication of the findings of this case study. We have de-identified all the patient’s details in this case report to comply with the CAse REport (CARE) guidelines.14 The approval of the Institutional Review Body was not required because of the nature of this study (a case report).
Declaration of conflicting interest: The authors declare that there is no conflict of interest.
Funding: YM received financial support from Boehringer Ingelheim JP Co., Ltd. and Ono Pharmaceutical Co., Ltd.
Author contributions: YM treated the patient, and wrote, revised and finalized the paper. MH, MT, HK, MO, TF, YT, and SY supervised the treatment of the patient, contributed to the discussion and revised the manuscript. All the authors read and approved the final version of the manuscript.
ORCID iD: Yusaku Mori https://orcid.org/0000-0002-1734-0605 | 50 kg. | Weight | CC BY-NC | 33682498 | 19,253,298 | 2021-03 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Erythema'. | Dermatological manifestations during COVID-19 infection: a case series and discussion on the problem of differential diagnosis.
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. As of 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two million related deaths. SARS-CoV-2 causes bilateral interstitial pneumonia, which can responsible of respiratory failure in the most severe cases, but the virus has also a wide range of other manifestations, including gastrointestinal, cardiovascular, neurological, and cutaneous signs and symptoms. Cutaneous manifestations are an important matter of study for allergy specialists, as they can be specific signs of the infection, but also manifestations of adverse reactions to the medical therapy in use. In this case series, we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients and two in patients with mild disease, treated at home. The first case reported is a woman, who develops urticaria while being treated at home with mild COVID-infection; the second and the third one case reported are drug- hypersensivity reaction to remdesevir and low molecular weight heparin. The last case reported is a man with mild covid with vasculitic sacral lesions. Key words: COVID pandemic, SARS-CoV-2, dermatological manifestation in covid infections, remdesevir hypersensitivity, covid and urticaria, covid and vasculitic lesions.
Introduction
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. Until 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two millions related deaths (1).
SARS-CoV-2, a novel coronavirus first reported in December 2019 in the city of Wuhan in the Hubei province of China (2), infects human cells through the bond of its surface protein, the so-called spike (S) protein, to the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein expressed mainly by the lung type II alveolar cells, but also by other cellular lines like endothelial cells, small intestinal epithelial cells and nasal epithelia(3).
Clinical features of SARS-CoV-2 infections are extremely variable: some patients can remain completely asymptomatic or have a fever for a few days, in some cases associated with the characteristic feature of anosmia and ageusia (loss of smell and taste), while others could develop interstitial pneumonia, ranging from mild to severe grade, requiring oxygen-therapy or mechanical ventilation.
While the initial reports of the infections did not mention COVID-related dermatologic manifestations or defined them as very rare, more recent studies defined the incidence of these manifestation between 5 and 20%(4, 5).
The most characteristic are the vasculitic lesions, such as chill-blade like lesions on hands and foots, livedo reticularis and truncal or acral petechiae or purpura; less common are the reports of urticaria, maculopapular erythema and vesicular eruption (6, 7).
Urticaria accounts for almost 20% of the dermatologic manifestations of COVID-19, and affects patients with respiratory involvement as patients with no pulmonary symptoms; it usually appears at the same time as the other symptoms, but it can also be later, while less frequently is the onset symptom of the infection. It usually affects the trunk eventually in association with arms and legs, while the head, hands and feet are commonly spared (8).
Maculopapular rash represent over 40% of cutaneous manifestations in COVID-19 patients; the erythematous lesions, which sometimes flows into larger erythematous patches, are usually located in the trunk and limbs, usually sparing palmoplantar skin and mucosa. This condition is commonly associated with a more severe course of the disease (8).
Vesicular rash, accounting for less than 10% of COVID-19 manifestations, tend to appear in the early stages of the infection, sometimes before all the other symptoms. The typical lesions, affecting mainly the trunk and the limbs, are monomorphic and can have haemorrhagic content. It seems to be associated with intermedium severity of the disease (8).
While vasculitic manifestations are caused by the pro-thrombotic effects of the viral infection, remains to be clarified how the virus can cause the other cutaneous manifestations. It is known that any viral infections can be a trigger for urticarial (9), but in the case of COVID-19 the immune upregulation, typical of this infection, could lead to an aberrant activation and degranulation of the dormant mast cells caused by the activated complement system and the altered cytokine-chemokine activity.
As of today, none of the dermatological manifestations of COVID has a specific treatment; they seem to respond well to steroid therapy, which has become one of the main treatment in COVID patients, and for urticaria the response the antihistamine therapy is similar to other causes of urticarial (10, 11).
Since all of the mentioned manifestations can develop before, in conjunction or after the beginning of the respiratory symptoms and possibly after the administration of medical therapy, a differential diagnosis between dermatological manifestation of COVID-19 and adverse reaction to drugs must be evaluated.
In this case series we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients, and the other in patients with mild disease, treated at home.
First case
A woman with fever, asthenia and cough for three days, subsequently developing anosmia and ageusia. The general practitioner (GP) prescribed COVID swab, which resulted positive. Because the symptoms were mild and the peripheral saturation was steadily over 95-96%, the GP started at home therapy with paracetamol and low molecular weight heparin. A couple of days later, as the woman reported feeling of shortness of breath, steroid therapy with methylprednisolone was prescribed. After four days of steroid therapy the fever was gone, and the dyspnea had improved, but the woman called the GP, reporting acute onset of urticaria, with itching hives on the belly and the back. The GP replaced methylprednisolone with prednisone, deeming urticaria as an allergic reaction to the steroid therapy. After a couple of days of antihistamine therapy, the woman reported complete resolution of urticaria, which eventually relapsed after a couple of days, urticaria, this time affecting all over the trunk, arms and legs. The GP did not change the medications, carrying on the steroid therapy and prescribing a longer antihistamine therapy, which was enough to treat the acute presentation of urticaria without another relapse. After a total of twelve days since the beginning of the therapy, the women was apyretic and regained the sense of taste; after three weeks the COVID swab became negative. The antihistamine therapy was suspended after a total of two consecutive weeks, with no subsequent episodes of urticaria.
Figure 1. Hives during the first day of urticaria
Figure 2 and 3. Hives during the relapse of urticaria
Figure 4. Maculopapular rash after one hour of remdersivir administration.
Figure 5. Maculopapular rash the day after.
Second case
Allergological consultation was requested for a man hospitalized for bilateral interstitial pneumonia COVID-related, with moderate acute respiratory distress syndrome (PaO2/FiO2 < 200 mmHg), treated HFNOT (high-flow nasal oxygen therapy).
The patient was obese, smoker and suffering from arterial hypertension. After two days of therapy with dexamethasone 6 mg/die and low molecular weight heparin with no improvement in the PaO2/FiO2 ratio, antiviral therapy with remdesevir was started. One hour after the administration of the first dose of the drug, he developed an itching maculo-papular rash under the neck, which later expanded on the upper trunk. Subsequent blood test revealed no eosinophilia nor elevated tryptase; the consultant decided to withdraw remdesevir therapy and prescribed antihistamine therapy with intramuscular chlorphenamine, continuing steroid and LMWH therapy. The rash did not expand further, and disappeared in the subsequent days.
Third case
A woman, overweight, smoker and suffering from diabetes was hospitalized with a diagnosis of bilateral interstitial pneumonia with severe respiratory failure, initially treated with HFNOT and then with c-PAP. Initial medical therapy included azithromycin, lopinavir/ritonavir and LMWH, followed by tocilizumab. During the 35th day of hospitalization, the patient developed a fixed erythema on the trunk and the limbs; since antiviral and the anti-IL6 mAb have been suspended from more than ten days, the reaction was attributed to enoxaparin. The doctors decided to stop the treatment with enoxaparin, replacing it with fondaparinux, as the patient had important thrombotic risk factor. A brief course of methylprednisolone 40 mg/die was done, with subsequent resolution of the rash in the course of a few days.
Figure 6 and 7. Fixed erythema on the trunk and belly.
Fourth case
Man, 45 years of age, overweight (99 kg), non-smoker, with a positive COVID-19 swab, with episodes of dyspnea and desaturation (91-92%). The man was treated at home after refusal of hospitalization, with steroid therapy (desamethasone 6 mg/die), azithromycin 500 mg/die and LMWH (enoxaparin 6000 UI/die).
After twelve days since the diagnosis of SARS-CoV-2 infection, the man developed sacral vasculitic lesions, without pain or itching; as the respiratory symptoms was improving and no other vasculitic lesion were found, the general practitioner decided not to modify the treatment. After an initial increase in the extension of the lesion, in two weeks the doctor observed a complete spontaneous resolution.
Figure 8. Sacral vasculitic manifestations.
Discussion and conclusions
Dermatological and allergic manifestation during COVID-19 infection are not very common, but not as rare as the first studies have reported. As of today, the presence of dermatological manifestations of COVID-19 has not been related to more severe disease or has been defined as a clinical subtype of the disease.
Vascular and thrombotic lesion are more characteristic of the SARS-CoV-2 infection and they are more easily recognisable, but the early use of heparin in hospitalized patient and in patients treated at home with known risk factors for thrombotic events may have lowered their global frequency since the initial reports. In the case of our patient, it is possible that the daily dose of heparin was too low to prevent the development of thrombotic lesions.
Less typical cutaneous rash, such as urticarial, vesicular or maculo-papular rash, can also appear in these patients, in some cases associated with more common symptoms, such as cough, dyspnea and fever, but also as one of the main features of the infection, in patients without respiratory symptoms. In these time of pandemic is therefore important for clinicians to be familiar with these cutaneous manifestations and, in regards to urticaria, to evaluate unusual cases of acute onset in subjects without previous history of urticaria, as it can be the first symptom of the infection. An early diagnosis is important not only for a timely treatment of the patients, but also to limit the viral spread. In these patients urticaria is as important to be properly treated as the other symptoms, as it can be bothersome or cause of concern. As the response to antihistamine therapy is good, a normal route of antihistamine therapy is always recommended as these drugs are usually well tolerated, while in patients with concomitant respiratory symptoms, a brief cycle of steroid therapy can have a positive impact on the cutaneous manifestation as on the respiratory ones. These patients have to be re-evaluated in the long term after the infection’s resolution, to define any cases of chronic urticaria if the symptoms last longer than six weeks.
It is also important to keep in mind that in COVID patients multiple drugs are often used in the same time. They include antibiotics, usually azithromycin or a beta-lactam, associated with low molecular weight heparin, sometimes with concomitant steroid therapy and/or an antiviral drug and eventually with monoclonal antibodies. In case of an adverse dermatological reaction, is therefore important the presence of an allergy consultant, not only to treat the acute cutaneous manifestation, but also to define a follow up path to complete the eventual diagnosis of drug hypersensitivity; in the case we reported of fixed erythema associated to enoxaparin, the woman was referred to allergist consultation to better defined the diagnosis of drug hypersensitivity.
Conflict of Interest:
Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article | AZITHROMYCIN ANHYDROUS, ENOXAPARIN, LOPINAVIR\RITONAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-SA | 33682815 | 19,169,148 | 2021-02-09 |
Give an alphabetized list of all active substances of drugs taken by the patient who experienced 'Off label use'. | Dermatological manifestations during COVID-19 infection: a case series and discussion on the problem of differential diagnosis.
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. As of 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two million related deaths. SARS-CoV-2 causes bilateral interstitial pneumonia, which can responsible of respiratory failure in the most severe cases, but the virus has also a wide range of other manifestations, including gastrointestinal, cardiovascular, neurological, and cutaneous signs and symptoms. Cutaneous manifestations are an important matter of study for allergy specialists, as they can be specific signs of the infection, but also manifestations of adverse reactions to the medical therapy in use. In this case series, we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients and two in patients with mild disease, treated at home. The first case reported is a woman, who develops urticaria while being treated at home with mild COVID-infection; the second and the third one case reported are drug- hypersensivity reaction to remdesevir and low molecular weight heparin. The last case reported is a man with mild covid with vasculitic sacral lesions. Key words: COVID pandemic, SARS-CoV-2, dermatological manifestation in covid infections, remdesevir hypersensitivity, covid and urticaria, covid and vasculitic lesions.
Introduction
On March 11, 2019 the World Health Organization (WHO) declared Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, as a pandemic. Until 15/01/2021, more than ninety million cases of infections have been confirmed, with almost two millions related deaths (1).
SARS-CoV-2, a novel coronavirus first reported in December 2019 in the city of Wuhan in the Hubei province of China (2), infects human cells through the bond of its surface protein, the so-called spike (S) protein, to the angiotensin-converting enzyme 2 (ACE2), a transmembrane protein expressed mainly by the lung type II alveolar cells, but also by other cellular lines like endothelial cells, small intestinal epithelial cells and nasal epithelia(3).
Clinical features of SARS-CoV-2 infections are extremely variable: some patients can remain completely asymptomatic or have a fever for a few days, in some cases associated with the characteristic feature of anosmia and ageusia (loss of smell and taste), while others could develop interstitial pneumonia, ranging from mild to severe grade, requiring oxygen-therapy or mechanical ventilation.
While the initial reports of the infections did not mention COVID-related dermatologic manifestations or defined them as very rare, more recent studies defined the incidence of these manifestation between 5 and 20%(4, 5).
The most characteristic are the vasculitic lesions, such as chill-blade like lesions on hands and foots, livedo reticularis and truncal or acral petechiae or purpura; less common are the reports of urticaria, maculopapular erythema and vesicular eruption (6, 7).
Urticaria accounts for almost 20% of the dermatologic manifestations of COVID-19, and affects patients with respiratory involvement as patients with no pulmonary symptoms; it usually appears at the same time as the other symptoms, but it can also be later, while less frequently is the onset symptom of the infection. It usually affects the trunk eventually in association with arms and legs, while the head, hands and feet are commonly spared (8).
Maculopapular rash represent over 40% of cutaneous manifestations in COVID-19 patients; the erythematous lesions, which sometimes flows into larger erythematous patches, are usually located in the trunk and limbs, usually sparing palmoplantar skin and mucosa. This condition is commonly associated with a more severe course of the disease (8).
Vesicular rash, accounting for less than 10% of COVID-19 manifestations, tend to appear in the early stages of the infection, sometimes before all the other symptoms. The typical lesions, affecting mainly the trunk and the limbs, are monomorphic and can have haemorrhagic content. It seems to be associated with intermedium severity of the disease (8).
While vasculitic manifestations are caused by the pro-thrombotic effects of the viral infection, remains to be clarified how the virus can cause the other cutaneous manifestations. It is known that any viral infections can be a trigger for urticarial (9), but in the case of COVID-19 the immune upregulation, typical of this infection, could lead to an aberrant activation and degranulation of the dormant mast cells caused by the activated complement system and the altered cytokine-chemokine activity.
As of today, none of the dermatological manifestations of COVID has a specific treatment; they seem to respond well to steroid therapy, which has become one of the main treatment in COVID patients, and for urticaria the response the antihistamine therapy is similar to other causes of urticarial (10, 11).
Since all of the mentioned manifestations can develop before, in conjunction or after the beginning of the respiratory symptoms and possibly after the administration of medical therapy, a differential diagnosis between dermatological manifestation of COVID-19 and adverse reaction to drugs must be evaluated.
In this case series we report four different cases of dermatological manifestations in COVID patients, two in hospitalised patients, and the other in patients with mild disease, treated at home.
First case
A woman with fever, asthenia and cough for three days, subsequently developing anosmia and ageusia. The general practitioner (GP) prescribed COVID swab, which resulted positive. Because the symptoms were mild and the peripheral saturation was steadily over 95-96%, the GP started at home therapy with paracetamol and low molecular weight heparin. A couple of days later, as the woman reported feeling of shortness of breath, steroid therapy with methylprednisolone was prescribed. After four days of steroid therapy the fever was gone, and the dyspnea had improved, but the woman called the GP, reporting acute onset of urticaria, with itching hives on the belly and the back. The GP replaced methylprednisolone with prednisone, deeming urticaria as an allergic reaction to the steroid therapy. After a couple of days of antihistamine therapy, the woman reported complete resolution of urticaria, which eventually relapsed after a couple of days, urticaria, this time affecting all over the trunk, arms and legs. The GP did not change the medications, carrying on the steroid therapy and prescribing a longer antihistamine therapy, which was enough to treat the acute presentation of urticaria without another relapse. After a total of twelve days since the beginning of the therapy, the women was apyretic and regained the sense of taste; after three weeks the COVID swab became negative. The antihistamine therapy was suspended after a total of two consecutive weeks, with no subsequent episodes of urticaria.
Figure 1. Hives during the first day of urticaria
Figure 2 and 3. Hives during the relapse of urticaria
Figure 4. Maculopapular rash after one hour of remdersivir administration.
Figure 5. Maculopapular rash the day after.
Second case
Allergological consultation was requested for a man hospitalized for bilateral interstitial pneumonia COVID-related, with moderate acute respiratory distress syndrome (PaO2/FiO2 < 200 mmHg), treated HFNOT (high-flow nasal oxygen therapy).
The patient was obese, smoker and suffering from arterial hypertension. After two days of therapy with dexamethasone 6 mg/die and low molecular weight heparin with no improvement in the PaO2/FiO2 ratio, antiviral therapy with remdesevir was started. One hour after the administration of the first dose of the drug, he developed an itching maculo-papular rash under the neck, which later expanded on the upper trunk. Subsequent blood test revealed no eosinophilia nor elevated tryptase; the consultant decided to withdraw remdesevir therapy and prescribed antihistamine therapy with intramuscular chlorphenamine, continuing steroid and LMWH therapy. The rash did not expand further, and disappeared in the subsequent days.
Third case
A woman, overweight, smoker and suffering from diabetes was hospitalized with a diagnosis of bilateral interstitial pneumonia with severe respiratory failure, initially treated with HFNOT and then with c-PAP. Initial medical therapy included azithromycin, lopinavir/ritonavir and LMWH, followed by tocilizumab. During the 35th day of hospitalization, the patient developed a fixed erythema on the trunk and the limbs; since antiviral and the anti-IL6 mAb have been suspended from more than ten days, the reaction was attributed to enoxaparin. The doctors decided to stop the treatment with enoxaparin, replacing it with fondaparinux, as the patient had important thrombotic risk factor. A brief course of methylprednisolone 40 mg/die was done, with subsequent resolution of the rash in the course of a few days.
Figure 6 and 7. Fixed erythema on the trunk and belly.
Fourth case
Man, 45 years of age, overweight (99 kg), non-smoker, with a positive COVID-19 swab, with episodes of dyspnea and desaturation (91-92%). The man was treated at home after refusal of hospitalization, with steroid therapy (desamethasone 6 mg/die), azithromycin 500 mg/die and LMWH (enoxaparin 6000 UI/die).
After twelve days since the diagnosis of SARS-CoV-2 infection, the man developed sacral vasculitic lesions, without pain or itching; as the respiratory symptoms was improving and no other vasculitic lesion were found, the general practitioner decided not to modify the treatment. After an initial increase in the extension of the lesion, in two weeks the doctor observed a complete spontaneous resolution.
Figure 8. Sacral vasculitic manifestations.
Discussion and conclusions
Dermatological and allergic manifestation during COVID-19 infection are not very common, but not as rare as the first studies have reported. As of today, the presence of dermatological manifestations of COVID-19 has not been related to more severe disease or has been defined as a clinical subtype of the disease.
Vascular and thrombotic lesion are more characteristic of the SARS-CoV-2 infection and they are more easily recognisable, but the early use of heparin in hospitalized patient and in patients treated at home with known risk factors for thrombotic events may have lowered their global frequency since the initial reports. In the case of our patient, it is possible that the daily dose of heparin was too low to prevent the development of thrombotic lesions.
Less typical cutaneous rash, such as urticarial, vesicular or maculo-papular rash, can also appear in these patients, in some cases associated with more common symptoms, such as cough, dyspnea and fever, but also as one of the main features of the infection, in patients without respiratory symptoms. In these time of pandemic is therefore important for clinicians to be familiar with these cutaneous manifestations and, in regards to urticaria, to evaluate unusual cases of acute onset in subjects without previous history of urticaria, as it can be the first symptom of the infection. An early diagnosis is important not only for a timely treatment of the patients, but also to limit the viral spread. In these patients urticaria is as important to be properly treated as the other symptoms, as it can be bothersome or cause of concern. As the response to antihistamine therapy is good, a normal route of antihistamine therapy is always recommended as these drugs are usually well tolerated, while in patients with concomitant respiratory symptoms, a brief cycle of steroid therapy can have a positive impact on the cutaneous manifestation as on the respiratory ones. These patients have to be re-evaluated in the long term after the infection’s resolution, to define any cases of chronic urticaria if the symptoms last longer than six weeks.
It is also important to keep in mind that in COVID patients multiple drugs are often used in the same time. They include antibiotics, usually azithromycin or a beta-lactam, associated with low molecular weight heparin, sometimes with concomitant steroid therapy and/or an antiviral drug and eventually with monoclonal antibodies. In case of an adverse dermatological reaction, is therefore important the presence of an allergy consultant, not only to treat the acute cutaneous manifestation, but also to define a follow up path to complete the eventual diagnosis of drug hypersensitivity; in the case we reported of fixed erythema associated to enoxaparin, the woman was referred to allergist consultation to better defined the diagnosis of drug hypersensitivity.
Conflict of Interest:
Each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article | AZITHROMYCIN ANHYDROUS, ENOXAPARIN, LOPINAVIR\RITONAVIR, TOCILIZUMAB | DrugsGivenReaction | CC BY-NC-SA | 33682815 | 19,169,148 | 2021-02-09 |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.