The development of boron delivery agents for BNCT began in the early 1960s and is an ongoing and difficult task. A number of  boron-10  containing delivery agents have been synthesized for potential use in BNCT. [ 9 ] [ 20 ] [ 21 ]  The most important requirements for a successful boron delivery agent are:


However, as of 2021 no single boron delivery agent fulfills all of these criteria. With the development of new chemical synthetic techniques and increased knowledge of the biological and biochemical requirements needed for an effective agent and their modes of delivery, a wide variety of new boron agents has emerged (see examples in Table 1). However, only one of these compounds has ever been tested in large animals, and only boronophenylalanine (BPA) and sodium borocaptate (BSH), have been used clinically. [ 1 ]


a The delivery agents are not listed in any order that indicates their potential usefulness for BNCT. None of these agents have been evaluated in any animals larger than mice and rats, except for boronated porphyrin (BOPP) that also has been evaluated in dogs. However, due to the severe toxicity of BOPP in canines, no further studies were carried out.
 b See Barth, R.F., Mi, P., and Yang, W., Boron delivery agents for neutron capture therapy of cancer, Cancer Communications, 38:35 ( doi : 10.1186/s40880-018-0299-7),  2018 for an updated review.
 c The abbreviations used in this table are defined as follows: BNCT, boron neutron capture therapy; DNA, deoxyribonucleic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; MoAbs, monoclonal antibodies; VEGF, vascular endothelial growth factor.


The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting in order to achieve boron concentrations (20-50 μg/g tumor) sufficient to produce therapeutic doses of radiation at the site of the tumor with minimal radiation delivered to normal tissues. The selective destruction of infliltrative tumor (glioma) cells in the presence of normal brain cells represents an even greater challenge compared to malignancies at other sites in the body. Malignant gliomas are highly infiltrative of normal brain, histologically diverse, heterogeneous in their genomic profile and therefore it is very difficult to kill all of them. [ 6 ]


There also has been some interest in the possible use of  gadolinium -157 ( 157 Gd) as a capture agent for NCT for the following reasons: [ 22 ]   First , and foremost, has been its very high neutron capture cross section of 254,000  barns .  Second , gadolinium compounds, such as  Gd-DTPA  (gadopentetate dimeglumine Magnevist), have been used routinely as  contrast agents  for  magnetic resonance imaging  (MRI) of brain tumors and have shown high uptake by brain tumor cells in tissue culture ( in vitro ). [ 23 ]   Third , gamma rays and internal conversion and Auger electrons are products of the  157 Gd(n,γ) 158 Gd capture reaction ( 157 Gd + n th  (0.025eV) → [ 158 Gd] →  158 Gd + γ + 7.94 MeV). Though the gamma rays have longer pathlengths, orders of magnitude greater depths of penetration compared with alpha particles, the other radiation products (internal conversion and  Auger electrons ) have pathlengths of about one cell diameter and can directly damage  DNA . Therefore, it would be highly advantageous for the production of DNA damage if the  157 Gd were localized within the cell nucleus. However, the possibility of incorporating gadolinium into biologically active molecules is very limited and only a small number of potential delivery agents for Gd NCT have been evaluated. [ 24 ] [ 25 ]  Relatively few studies with Gd have been carried out in experimental animals compared to the large number with boron containing compounds (Table 1), which have been synthesized and evaluated in experimental animals ( in vivo ). Although  in vitro  activity has been demonstrated using the Gd-containing MRI contrast agent Magnevist as the Gd delivery agent, [ 26 ]  there are very few studies demonstrating the efficacy of Gd NCT in experimental animal tumor models, [ 25 ] [ 27 ]  and, as evidenced by a lack of citations in the literature, Gd NCT has not, as of 2019, been used clinically in humans.


Until 2014, neutron sources for NCT were limited to  nuclear reactors . [ 28 ]  Reactor-derived neutrons are classified according to their energies as thermal (E n  < 0.5 eV), epithermal (0.5 eV < E n  < 10 keV), or fast (E n  >10 keV). Thermal neutrons are the most important for BNCT since they usually initiate the  10 B(n,α) 7 Li capture reaction. However, because they have a limited depth of penetration, epithermal neutrons, which lose energy and fall into the thermal range as they penetrate tissues, are now preferred for clinical therapy, other than for skin tumors such as melanoma. [ 29 ]


A number of nuclear reactors with very good neutron beam quality have been developed and used clinically. These include: [ citation needed ]


As of May 2021, only the reactors in Argentina, China, and Taiwan are still being used clinically. It is anticipated that, beginning some time in 2022, clinical studies in Finland will utilize an accelerator neutron source designed and fabricated in the United States by Neutron Therapeutics, Danvers, Massachusetts.


It was not until the 1950s that the first clinical trials were initiated by Farr at the Brookhaven National Laboratory (BNL) in New York [ 7 ]  and by Sweet and Brownell at the Massachusetts General Hospital (MGH) using the Massachusetts Institute of Technology (MIT) nuclear reactor (MITR) [ 32 ]  and several different low molecular weight boron compounds as the boron delivery agent. [ 33 ]  However, the results of these studies were disappointing, and no further clinical trials were carried out in the United States until the 1990s.


Following a two-year Fulbright fellowship in Sweet's laboratory at the MGH, clinical studies were initiated by Hiroshi Hatanaka in Japan in 1967. He used a low-energy thermal neutron beam, which had low tissue penetrating properties, and sodium borocaptate (BSH) as the boron delivery agent, which had been evaluated as a boron delivery agent by Albert Soloway at the MGH. [ 34 ]  In Hatanaka's procedure, [ 35 ]  as much as possible of the tumor was surgically resected ("debulking"), and at some time thereafter, BSH was administered by a slow infusion, usually intra-arterially, but later intravenously. Twelve to 14 hours later, BNCT was carried out at one or another of several different nuclear reactors using low-energy thermal neutron beams. The poor tissue-penetrating properties of the thermal neutron beams necessitated reflecting the skin and raising a bone flap in order to directly irradiate the exposed brain, a procedure first used by Sweet and his collaborators.


Approximately 200+ patients were treated by Hatanaka, and subsequently by his associate, Nakagawa. [ 10 ]  Due to the heterogeneity of the patient population, in terms of the microscopic diagnosis of the tumor and its  grade , size, and the ability of the patients to carry out normal daily activities (Karnofsky  performance status ), it was not possible to come up with definitive conclusions about therapeutic efficacy. However, the survival data were no worse than those obtained by standard therapy at the time, and there were several patients who were long-term survivors, and most probably they were cured of their brain tumors. [ 10 ]


BNCT of patients with brain tumors was resumed in the United States in the mid-1990s by Chanana, Diaz, and Coderre [ 11 ]  and their co-workers at the Brookhaven National Laboratory using the Brookhaven Medical Research Reactor (BMRR) and at Harvard/Massachusetts Institute of Technology (MIT) using the  MIT Research Reactor (MITR) . [ 12 ]  For the first time, BPA was used as the boron delivery agent, and patients were irradiated with a collimated beam of higher energy epithermal neutrons, which had greater tissue-penetrating properties than thermal neutrons. A research group headed up by Zamenhof at the Beth Israel Deaconess Medical Center/Harvard Medical School and MIT was the first to use an epithermal neutron beam for clinical trials. Initially patients with cutaneous melanomas were treated and this was expanded to include patients with brain tumors, specifically melanoma metastatic to the brain and primary glioblastomas (GBMs). Included in the research team were Otto Harling at MIT and the Radiation Oncologist Paul Busse at the Beth Israel Deaconess Medical Center in Boston. A total of 22 patients were treated by the Harvard-MIT research group. Five patients with cutaneous melanomas were also treated using an epithermal neutron beam at the MIT research reactor (MITR-II) and subsequently patients with brain tumors were treated using a redesigned beam at the MIT reactor that possessed far superior characteristics to the original MITR-II beam and BPA as the capture agent. The clinical outcome of the cases treated at Harvard-MIT has been summarized by Busse. [ 12 ]  Although the treatment was well tolerated, there were no significant differences in the mean survival times (MSTs)of patients that had received BNCT compared to those who received conventional external beam X-irradiation. [ 12 ]


Shin-ichi Miyatake and Shinji Kawabata at Osaka Medical College in Japan [ 15 ] [ 16 ]  have carried out extensive clinical studies employing BPA (500 mg/kg) either alone or in combination with BSH (100 mg/kg), infused intravenously (i.v.) over 2 h, followed by neutron irradiation at Kyoto University Research Reactor Institute (KURRI). The Mean Survival Time (MST) of 10 patients with high grade gliomas in the first of their trials was 15.6 months, with one long-term survivor (>5 years). [ 16 ]  Based on experimental animal data, [ 36 ]  which showed that BNCT in combination with X-irradiation produced enhanced survival compared to BNCT alone, Miyatake and Kawabata combined BNCT, as described above, with an X-ray boost. [ 15 ]  A total dose of 20 to 30 Gy was administered, divided into 2 Gy daily fractions. The MST of this group of patients was 23.5 months and no significant toxicity was observed, other than hair loss (alopecia). However, a significant subset of these patients, a high proportion of which had small cell variant glioblastomas, developed cerebrospinal fluid dissemination of their tumors. [ 37 ]  Miyatake and his co-workers also have treated a cohort of 44 patients with recurrent high grade meningiomas (HGM) that were refractory to all other therapeutic approaches. [ 38 ]  The clinical regimen consisted of intravenous administration of boronophenylalanine two hours before neutron irradiation at the Kyoto University Research Reactor Institute in Kumatori, Japan. Effectiveness was determined using radiographic evidence of tumor shrinkage, overall survival (OS) after initial diagnosis, OS after BNCT, and radiographic patterns associated with treatment failure. The median OS after BNCT was 29.6 months and 98.4 months after diagnosis. Better responses were seen in patients with lower grade tumors. In 35 of 36 patients, there was tumor shrinkage, and the median progression-free survival (PFS) was  13.7 months. There was good local control of the patients' tumors, as evidenced by the fact that only 22.2% of them experienced local recurrence of their tumors. From these results, it was concluded that BNCT was effective in locally controlling tumor growth, shrinking tumors, and improving survival with acceptable safety in patients with therapeutically refractory HGMs.


In another Japanese trial, carried out by Yamamoto et al., BPA and BSH were infused over 1 h, followed by BNCT at the Japan Research Reactor (JRR)-4 reactor. [ 39 ]  Patients subsequently received an X-ray boost after completion of BNCT. The overall median survival time (MeST) was 27.1 months, and the 1 year and 2-year survival rates were 87.5 and 62.5%, respectively. Based on the reports of Miyatake, Kawabata, and Yamamoto, combining BNCT with an X-ray boost can produce a significant therapeutic gain. However, further studies are needed to optimize this combined therapy alone or in combination with other approaches including chemo- and immunotherapy, and to evaluate it using a larger patient population. [ 40 ]


The technological and physical aspects of the Finnish BNCT program have been described in considerable detail by Savolainen et al. [ 44 ]  A team of clinicians led by Heikki Joensuu and Leena Kankaanranta and nuclear engineers led by Iro Auterinen and Hanna Koivunoro at the Helsinki University Central Hospital and VTT Technical Research Center of Finland have treated approximately 200+ patients with recurrent malignant gliomas ( glioblastomas ) and head and neck cancer who had undergone standard therapy, recurred, and subsequently received BNCT at the time of their recurrence using BPA as the boron delivery agent. [ 13 ] [ 14 ]  The median time to progression in patients with gliomas was 3 months, and the overall MeST was 7 months. It is difficult to compare these results with other reported results in patients with recurrent malignant gliomas, but they are a starting point for future studies using BNCT as salvage therapy in patients with recurrent tumors. Due to a variety of reasons, including financial, [ 45 ]  no further studies have been carried out at this facility, which has been decommissioned. However, a new facility for BNCT treatment has been installed using an accelerator designed and fabricated by Neutron Therapeutics. [ 46 ]  This accelerator was specifically designed to be used in a hospital, and the BNCT treatment and clinical studies will be carried out there after dosimetric studies have been completed in 2021. Both Finnish and foreign patients are expected to be treated at the facility. [ 47 ] [ 48 ] [ 49 ]


To conclude this section on treating brain tumors with BNCT using reactor neutron sources, a clinical trial that was carried out by Stenstam, Sköld, Capala and their co-workers in Studsvik, Sweden, using an epithermal neutron beam produced by the Studsvik nuclear reactor, which had greater tissue penetration properties than the thermal beams originally used in the United States and Japan, will be briefly summarized. This study differed significantly from all previous clinical trials in that the total amount of BPA administered was increased (900 mg/kg), and it was infused i.v. over 6 hours. This was based on experimental animal studies in glioma bearing rats demonstrating enhanced uptake of BPA by infiltrating tumor cells following a 6-hour infusion. [ 34 ] [ 41 ] [ 42 ] [ 50 ]  The longer infusion time of the BPA was well tolerated by the 30 patients who were enrolled in this study. All were treated with 2 fields, and the average whole brain dose was 3.2–6.1 Gy (weighted), and the minimum dose to the tumor ranged from 15.4 to 54.3 Gy (w). There has been some disagreement among the Swedish investigators regarding the evaluation of the results. Based on incomplete survival data, the MeST was reported as 14.2 months and the time to tumor progression was 5.8 months. [ 41 ]  However, more careful examination [ 42 ]  of the complete survival data revealed that the MeST was 17.7 months compared to 15.5 months that has been reported for patients who received standard therapy of surgery, followed by radiotherapy (RT) and the drug  temozolomide  (TMZ). [ 51 ]  Furthermore, the frequency of adverse events was lower after BNCT (14%) than after radiation therapy (RT) alone (21%) and both of these were lower than those seen following RT in combination with TMZ. If this improved survival data, obtained using the higher dose of BPA and a 6-hour infusion time, can be confirmed by others, preferably in a  randomized clinical trial , it could represent a significant step forward in BNCT of brain tumors, especially if combined with a photon boost.


The single most important clinical advance over the past 15 years [ 52 ]  has been the application of BNCT to treat patients with recurrent tumors of the head and neck region who had failed all other therapy. These studies were first initiated by Kato et al. in Japan. [ 52 ] [ 53 ]  and subsequently followed by several other Japanese groups and by Kankaanranta, Joensuu, Auterinen, Koivunoro and their co-workers in Finland. [ 14 ]  All of these studies employed BPA as the boron delivery agent, usually alone but occasionally in combination with BSH. A very heterogeneous group of patients with a variety of histopathologic types of tumors have been treated, the largest number of which had recurrent squamous cell carcinomas. Kato et al. have reported on a series of 26 patients with far-advanced cancer for whom there were no further treatment options. [ 52 ]  Either BPA + BSH or BPA alone were administered by a 1 or 2 h i.v. infusion, and this was followed by BNCT using an epithermal beam. In this series, there were complete regressions in 12 cases, 10 partial regressions, and progression in 3 cases. The MST was 13.6 months, and the 6-year survival was 24%. Significant treatment related complications ("adverse" events) included transient mucositis, alopecia and, rarely, brain necrosis and osteomyelitis.


Kankaanranta et al. have reported their results in a prospective Phase I/II study of 30 patients with inoperable, locally recurrent squamous cell carcinomas of the head and neck region. [ 14 ]  Patients received either two or, in a few instances, one BNCT treatment using BPA (400 mg/kg), administered i.v. over 2 hours, followed by neutron irradiation. Of 29 evaluated patients, there were 13 complete and 9 partial remissions, with an overall response rate of 76%. The most common adverse event was oral mucositis, oral pain, and fatigue. Based on the clinical results, it was concluded that BNCT was effective for the treatment of inoperable, previously irradiated patients with head and neck cancer. Some responses were durable but progression was common, usually at the site of the previously recurrent tumor. As previously indicated in the section on neutron sources, all clinical studies have ended in Finland, for variety of reasons including economic difficulties of the two companies directly involved, VTT and Boneca. However, clinical studies using an accelerator neutron source designed and fabricated by Neutron Therapeutics and installed at the Helsinki University Hospital should be fully functional by 2022. [ 46 ]  Finally, a group in  Taiwan , led by Ling-Wei Wang and his co-workers at the Taipei Veterans General Hospital, have treated 17 patients with locally recurrent head and neck cancers at the Tsing Hua Open-pool Reactor (THOR) of the  National Tsing Hua University . [ 54 ]  Two-year overall survival was 47% and two-year loco-regional control was 28%. Further studies are in progress to further optimize their treatment regimen.


Other extracranial tumors that have been treated with BNCT include malignant  melanomas . The original studies were carried out in Japan by the late Yutaka Mishima and his clinical team in the Department of Dermatology at Kobe University [ 55 ]  using locally injected BPA and a thermal neutron beam. It is important to point out that it was Mishima who first used BPA as a boron delivery agent, and this approach subsequently was extended to other types of tumors based on the experimental animal studies of Coderre et al. at the Brookhaven National Laboratory. [ 56 ]  Local control was achieved in almost all patients, and some were cured of their melanomas. Patients with melanoma of the head and neck region, vulva, and extramammary Paget's disease of the genital region have been treated by Hiratsuka et al. with promising clinical results. [ 57 ]  The first clinical trial of BNCT in Argentina for the treatment of melanomas was performed in October 2003 [ 58 ]  and since then several patients with cutaneous melanomas have been treated as part of a Phase II clinical trial at the RA-6 nuclear reactor in Bariloche. The neutron beam has a mixed thermal-hyperthermal neutron spectrum that can be used to treat superficial tumors. [ 58 ]  The In-Hospital Neutron Irradiator (IHNI) in Beijing has been used to treat a small number of patients with cutaneous melanomas with a complete response of the primary lesion and no evidence of late radiation injury during a 24+-month follow-up period. [ 59 ]


Two patients with colon cancer, which had spread to the liver, have been treated by Zonta and his co-workers at the University of Pavia in Italy. [ 60 ]  The first was treated in 2001 and the second in mid-2003. The patients received an i.v. infusion of BPA, followed by removal of the liver (hepatectomy), which was irradiated outside of the body (extracorporeal BNCT) and then re-transplanted into the patient. The first patient did remarkably well and survived for over 4 years after treatment, but the second died within a month of cardiac complications. [ 61 ]  Clearly, this is a very challenging approach for the treatment of hepatic metastases, and it is unlikely that it will ever be widely used. Nevertheless, the good clinical results in the first patient established  proof of principle . Finally, Yanagie and his colleagues at Meiji Pharmaceutical University in Japan have treated several patients with recurrent rectal cancer using BNCT. Although no long-term results have been reported, there was evidence of short-term clinical responses. [ 62 ]


Accelerators now are the primary source of epithermal neutrons for clinical BNCT. The first papers relating to their possible use were published in the 1980s, and, as summarized by Blue and Yanch, [ 63 ]  this topic became an active area of research in the early 2000s. However, it was the Fukushima nuclear disaster in Japan in 2011 that gave impetus to their development for clinical use. Accelerators also can be used to produce epithermal neutrons. Today several accelerator-based neutron sources (ABNS) are commercially available or under development. Most existing or planned systems use either the lithium-7 reaction,  7 Li(p,n) 7 Be or the beryllium-9 reaction, 9 Be(p,n) 9 B, to generate neutrons, though other nuclear reactions also have been considered. [ 64 ]  The lithium-7 reaction requires a proton accelerator with energies between 1.9 and 3.0 MeV, while the beryllium-9 reaction typically uses accelerators with energies between 5 and 30 MeV. Aside from the lower proton energy that the lithium-7 reaction requires, its main benefit is the lower energy of the neutrons produced. This in turn allows the use of smaller moderators, "cleaner" neutron beams, and reduced neutron activation. Benefits of the beryllium-9 reaction include simplified target design and disposal, long target lifetime, and lower required proton beam current.


Since the proton beams for BNCT are quite powerful (~20-100 kW), the neutron generating target must incorporate cooling systems capable of removing the heat safely and reliably to protect the target from damage. In the case of the lithium-7, this requirement is especially important due to the low melting point and chemical volatility of the target material. Liquid jets, micro-channels and rotating targets have been employed to solve this problem.Several researchers have proposed the use of liquid lithium-7 targets in which the target material doubles as the coolant. [ 65 ] [ 66 ]  In the case of beryllium-9, "thin" targets, in which the protons come to rest and deposit much of their energy in the cooling fluid, can be employed. Target degradation due to beam exposure ("blistering") is another problem to be solved, either by using layers of materials resistant to blistering or by spreading the protons over a large target area. Since the nuclear reactions yield neutrons with energies ranging from < 100keV to tens of MeV, a Beam Shaping Assembly (BSA) [ 67 ]  must be used to moderate, filter, reflect and collimate the neutron beam to achieve the desired epithermal energy range, neutron beam size and direction. BSAs are typically composed of a range of materials with desirable nuclear properties for each function. A well-designed BSA should maximize neutron yield per proton while minimizing fast neutron, thermal neutron and gamma contamination. It should also produce a sharply delimited and generally forward directed beam enabling flexible positioning of the patient relative to the aperture. [ 68 ]
One key challenge for an ABNS is the duration of treatment time: depending on the neutron beam intensity, treatments can take up to an hour or more. Therefore, it is desirable to reduce the treatment time both for patient comfort during immobilization and to increase the number of patients that could be treated in a 24-hour period. Increasing the neutron beam intensity for the same proton current by adjusting the BSA is often achieved at the cost of reduced beam quality (higher levels of unwanted fast neutrons or gamma rays in the beam or poor beam collimation). Therefore, increasing the proton current delivered by ABNS BNCT systems remains a key goal of technology development programs.


The table below summarizes the existing or planned ABNS installations for clinical use (Updated November, 2024).


Product


Reaction


Accelerator Type


NeuCure


9 Be(p,n) 9 B


Cyclotron


Fukushima, Japan


7 Li(p,n) 7 Be


RFQ


NeuPex


Tandem Electrostatic


LINAC


iBNCT [ 73 ]


nuBeam


Single-ended electrostatic


Kanagawa, Japan


D-BNCT


Alphabeam


Treatment of Recurrent Malignant Gliomas


The single greatest advance in moving BNCT forward clinically has been the introduction of cyclotron-based neutron sources (c-BNS) in Japan. Shin-ichi Miyatake and Shinji Kawabata have led the way with the treatment of patients with recurrent glioblastomas (GBMs). [ 75 ] [ 76 ]  In their Phase II clinical trial, they used the Sumitomo Heavy Industries accelerator at the Osaka Medical College, Kansai BNCT Medical Center to treat a total of 24 patients. [ 75 ]  These patients ranged in age from 20 to 75 years, and all previously had received standard treatment consisting of surgery followed by chemotherapy with temozolomide (TMZ) and conventional radiation therapy. They were candidates for treatment with BNCT because their tumors had recurred and were progressing in size. They received an intravenous infusion of a proprietary formulation of  10 B-enriched boronophenylalanine ("Borofalan," StellaPharma Corporation, Osaka, Japan) prior to neutron irradiation. The primary endpoint of this study was the 1-year survival rate after BNCT, which was 79.2%, and the median overall survival rate was 18.9 months. Based on these results, it was concluded that c-BNS BNCT was safe and resulted in increased survival of patients with recurrent gliomas. Although there was an increased risk of brain edema due to re-irradiation, this was easily controlled. [ 75 ]  As a result of this trial, the Sumitomo accelerator was approved by the Japanese regulatory authority having jurisdiction over medical devices, and further studies are being carried out with patients who have recurrent, high-grade (malignant) meningiomas. However, further studies for the treatment of patients with GBMs have been put on hold pending additional analysis of the results.


Treatment of Recurrent or Locally Advanced Cancers of the Head and Neck


Katsumi Hirose and his co-workers at the Southern Tohoku BNCT Research Center in Koriyama, Japan, recently have reported on their results after treating 21 patients with recurrent tumors of the head and neck region. [ 77 ]  All of these patients had received surgery, chemotherapy, and conventional radiation therapy. Eight of them had recurrent squamous cell carcinomas (R-SCC), and 13 had either recurrent (R) or locally advanced (LA) non-squamous cell carcinomas (nSCC). The overall response rate was 71%, and the complete response and partial response rates were 50% and 25%, respectively, for patients with R-SCC and 80% and 62%, respectively, for those with R or LA SCC. The overall 2-year survival rates for patients with R-SCC or R/LA nSCC were 58% and 100%, respectively. The treatment was well tolerated, and adverse events were those usually associated with conventional radiation treatment of these tumors. These patients had received a proprietary formulation of  10 B-enriched boronophenylalanine (Borofalan), which was administered intravenously. Although the manufacturer of the accelerator was not identified, it presumably was the one manufactured by Sumitomo Heavy Industries, Ltd., which was indicated in the Acknowledgements of their report. [ 77 ]   Based on this Phase II clinical trial, the authors suggested that BNCT using Borofalan and c-BENS was a promising treatment for recurrent head and neck cancers, although further studies would be required to firmly establish this.


Clinical BNCT first was used to treat highly malignant brain tumors and subsequently for melanomas of the skin that were difficult to treat by surgery. Later, it was used as a type of "salvage" therapy for patients with recurrent tumors of the head and neck region. The clinical results were sufficiently promising to lead to the development of accelerator neutron sources, which will be used almost exclusively in the future. [ 46 ]  Challenges for the future clinical success of BNCT that need to be met include the following: [ 78 ] [ 79 ] [ 1 ] [ 2 ] [ 80 ] [ 81 ]


The  Pakistan Society of Neuro-Oncology  ( PASNO ) [ 1 ]  is Pakistan's first scientific society dedicated to  neuro-oncology . It was created to bring together experts from within and outside Pakistan to improve the care of patients with  tumors  of the brain and spinal cord, and provide a platform for research, teaching and training activities related to neuro-oncology in Pakistan. PASNO is chartered by the  Government of Pakistan  and is a non-profit society.


The society's inaugural  symposium  was attended by over 50 speakers from 13 countries. [ 2 ] [ 3 ] [ 4 ] [ 5 ] [ 6 ] [ 7 ]


This article about an organization in Pakistan is a  stub . You can help Wikipedia by  expanding it .


The  parietal bones  ( / p ə ˈ r aɪ . ɪ t əl /   pə- RY -it-əl ) are two bones in the  skull  which, when joined at a  fibrous joint  known as a  cranial suture , form the sides and roof of the  neurocranium . In  humans , each bone is roughly quadrilateral in form, and has two surfaces, four borders, and four angles. It is named from the Latin  paries  ( -ietis ), wall.


The external surface [Fig. 1] is convex, smooth, and marked near the center by an eminence, the  parietal eminence  ( tuber parietale ), which indicates the point where  ossification  commenced.


Crossing the middle of the bone in an arched direction are two curved lines, the superior and inferior  temporal lines ; the former gives attachment to the  temporal fascia , and the latter indicates the upper limit of the muscular origin of the  temporal muscle .


Above these lines the bone is covered by a tough layer of fibrous tissue – the  epicranial aponeurosis ; below them it forms part of the  temporal fossa , and affords attachment to the temporal muscle.


At the back part and close to the upper or sagittal border is the  parietal foramen  which transmits a vein to the  superior sagittal sinus , and sometimes a small branch of the  occipital artery ; it is not constantly present, and its size varies considerably.


The internal surface [Fig. 2] is concave; it presents depressions corresponding to the cerebral convolutions, and numerous furrows (grooves) for the ramifications of the  middle meningeal artery ; the latter run upward and backward from the sphenoidal angle, and from the central and posterior part of the squamous border.


Along the upper margin is a shallow groove, which, together with that on the opposite parietal, forms a channel, the  sagittal sulcus , for the  superior sagittal sinus ; the edges of the sulcus afford attachment to the  falx cerebri .


Near the groove are several depressions, best marked in the skulls of old persons, for the  arachnoid granulations  (Pacchionian bodies).


In the groove is the internal opening of the parietal foramen when that aperture exists.


The parietal bone is ossified in membrane from a single center, which appears at the  parietal eminence  about the eighth week of fetal development.


Ossification gradually extends in a radial manner from the center toward the margins of the bone; the angles are consequently the parts last formed, and it is here that the fontanelles exist.


Occasionally the parietal bone is divided into two parts, upper and lower, by an antero-posterior suture.


In non-human vertebrates, the parietal bones typically form the rear or central part of the  skull roof , lying behind the frontal bones. In many non-mammalian  tetrapods , they are bordered to the rear by a pair of  postparietal bones  that may be solely in the roof of the skull, or slope downwards to contribute to the back of the skull, depending on the species. In the living  tuatara  and some lizards, as well as in many fossil tetrapods, a small opening, the  parietal foramen  (also called the  pineal foramen ), is present between the two parietal bones at the midline of the skull. This opening is the location of the  parietal eye  (also called the pineal or third eye), which is much smaller than the two main eyes. [ 1 ] [ 2 ] [ 3 ]


The parietal bone is usually present in the posterior end of the skull and is near the midline.  This bone is part of the skull roof, which is a set of bones that cover the brain, eyes and nostrils. The parietal bones make contact with several other bones in the skull.  The anterior part of the bone articulates with the  frontal  bone and the  postorbital bone .  The posterior part of the bone articulates with the  squamosal bone , and less commonly the  supraoccipital  bone.  The bone-supported neck frills of ceratopsians were formed by extensions of the parietal bone.  These frills, which overhang the neck and extend past the rest of the skull is a diagnostic trait of ceratopsians.  The recognizable skull domes present in pachycephalosaurs were formed by the fusion of the frontal and parietal bones and the addition of thick deposits of bone to that unit. [ 4 ]


This article incorporates text in the  public domain  from  page 133  of the 20th edition of   Gray's Anatomy   (1918)


Pediatric Neurosurgery  is a subspecialty of  neurosurgery ; which includes  surgical  procedures that are related to the  nervous system ,  brain  and  spinal cord ; that treats  children  with operable  neurological disorders .


Boston Children's Hospital  was the first hospital in the  United States  with a specialized neurosurgical service for children, established in 1929 by  Harvey Cushing  and  Franc Ingraham . [ 1 ] [ 2 ]


As of 2009, there were fewer than 200 pediatric neurosurgeons in the United States. Approximately 80% of them were male. [ 3 ]  In the past 25 years, 391 doctors graduated from a pediatric neurosurgery program. Only 70% of them currently practice primarily pediatric rather than adult neurosurgery. Approximately 70% of them are in  academic medicine . [ 4 ]


This  pediatrics  article is a  stub . You can help Wikipedia by  expanding it .


Peripheral nerve tumors , also called tumors of peripheral nerves or tumors of the peripheral nervous system, are a diverse category with a range of morphological characteristics and biological potential. [ 1 ]  They are categorized as either benign or malignant peripheral nerve sheath tumors. [ 2 ] [ 3 ]


They vary from benign (soft tissue perineurioma and  schwannoma ) that can be completely removed to benign ( plexiform neurofibroma ) that may be locally aggressive to extremely malignant ( malignant peripheral nerve sheath tumors  [MPNST]). [ 1 ]  New and more precisely defined entities include malignant melanotic nerve sheath tumor (formerly known as melanotic schwannoma) and hybrid nerve sheath tumors. [ 4 ] [ 5 ]  The majority of peripheral nerve tumors are benign tumors of the nerve sheath (usually schwannomas); on rare occasions, they are metastatic tumors or originate from the nerve cells. [ 6 ] [ 7 ]


Most peripheral nerve tumors occur for unknown reasons. Some, including  schwannomatosis  and  neurofibromatosis  (types 1 and 2), are associated with recognized  hereditary disorders . Others may be caused by gene mutations. In the case of schwannomatosis and neurofibromatosis, tumors can grow on or close to nerves anywhere in the body. Frequently, there are several tumors. [ 8 ]


The typical symptoms involve a combination of  pain , loss of nerve function, and/or a palpable (or radiographically apparent) mass affecting a peripheral nerve. The etiology and importance of the last two symptoms should be apparent. For example, the presence of a severe nerve palsy is highly suggestive of malignancy as it is most likely the result of the tumor invading and destroying nerves. [ 7 ]


Methods used to identify tumors of the peripheral nervous system include a family history of any predisposition syndrome, including neurofibromatosis types 1 and 2, a targeted and comprehensive  physical examination , and radiological investigations, the primary one being  magnetic resonance imaging . [ 9 ] [ 10 ]  Other radiological investigations may include plain  radiographs ,  ultrasound  examination,  computed tomography , and  positron emission tomography . [ 11 ]  Definitive diagnosis is made by tumor  biopsy . [ 12 ]   Surgery  is the most common method of treating peripheral nerve sheath tumors. [ 11 ]  In malignant tumors, complete resection is the only known curative treatment (with a sufficiently wide margin or even amputation to improve prognosis). [ 12 ]  For larger lesions or those with a more aggressive histology,  adjuvant radiation  is recommended. Novel or combination therapies that are the focus of ongoing clinical trials are highly desirable. [ 13 ] [ 14 ]


Formally, the majority of these tumors lack a CNS WHO grade; instead, neoplasms should be graded within each category of tumor. [ 5 ]


(Localized, diffuse, plexiform subtype)


(Intraneural and soft tissue subtypes)


(epithelioid and perineural subtypes)


Phonemic neurological hypochromium therapy (PNHT)  is a technique that uses  insemination  devices to implement  chromium  (Cr3+) into the  hypothalamic  regions of the brain. It has been proposed by Dr. Nicole Kim to offset delayed  phonemic awareness  in children between the ages of 3 and 8. The causes of delayed phonemic awareness have been linked to an inability to break down chromium triastenitephosphate. PNHT has been successfully implemented into  in vivo  mice with some controversial side effects, including;  polydactyly ,  regurgitation ,  fatigue , and  nausea . While  Russia ,  Poland , and  Ukraine  have approved this procedure, the  United States Food and Drug Administration  (USFDA) has not yet granted its approval.


PNHT functions on the premise that the hypothalamic region of the  human brain  lacks the critical molecule  chromium picolinate , a molecule typically produced by cytochromase B7[1]. The hypothalamus of a developing child may lack cytochromase B7, thereby causing a delay in phonemic awareness. The PNHT process involves passing a chromium mixture (CrAt3PO4) dissolved in a "mobile phase" through a stationary phase, which separates the chromium picolinate to be measured from other molecules in the mixture based on differential partitioning between the mobile and stationary phases. Subtle differences in a compound's  partition coefficient  result in differential retention on the stationary phase and thus changing the separation.


In vitro  and animal studies[1 [ unreliable medical source? ] ,2] have shown chromium to have a positive effect on  insulin sensitivity . One of the intracellular proteins influencing the  insulin receptor  is the  oligopeptide   apolipoprotein , low  molecular weight , chromium-binding substance (apo-chromomodulin) [2]. In vitro, this peptide has the ability to increase  tyrosine kinase  activity eightfold, depending on the chromium concentration [3]. This in turn promotes insulin receptor activity, thus eliciting improved insulin sensitivity. Therefore, for some time now, chromium has been thought to play a beneficial role in  glucose metabolism  and, as early as 1957, was referred to as a “ glucose tolerance factor ” [4]. It has been marketed as such by some companies in the US.


There are studies that support this proposed effect. Anderson et al. [5] studied the effects of chromium treatment in a group of Chinese patients with  type 2 diabetes . They reported an average decrease in HbA1c (A1C) of almost 2 percentage points after only four months of treatment with 1,000 μg chromium daily. Since then, the effects of chromium on  glycemic control ,  lipid profile , weight, and  muscular strength  have been investigated, both in nondiabetic healthy subjects and in patients with type 2 diabetes.


2.	Shindea UA, Sharma G, Xu YJ, Dhalla NS, Goyal RK: Insulin sensitising action of chromium picolinate in various experimental models of diabetes mellitus. J Trace Elem Med Biol 18: 23–32, 2004


3.	Davis CM, Vincent JB: Chromium oligopeptide activates insulin receptor tyrosine kinase activity. Biochemistry 36: 4382–4385, 1997
4.	Sun Y, Ramirez J, Woski SA, Vincent JB: The binding of trivalent chromium to low-molecular-weight chromium-binding substance (LMWCr) and the transfer of chromium from transferrin and chromium picolinate to LMWCr. J Biol Inorg Chem 5: 129–136, 2000


5.	 Schwarz K, Mertz W: A glucose tolerance factor and its differentiation from factor 3. Arch Biochem Biophys 72: 515–518, 1957


Post-vagotomy diarrhea  is a form of  diarrhea  which occurs in 10% of people after a truncal  vagotomy , which can range from severe to debilitating in approximately 2% to 4% of patients. [ 1 ]  However, the occurrence of post-vagotomy diarrhea is significantly reduced after proximal selective vagotomy, specifically when  celiac  and  hepatic  branches of the  vagus  are retained. [ 1 ]


Surgical treatment for  refractory  post-vagotomy diarrhea is rarely needed and at least one year from the occurrence of  symptoms  should be allotted to ensure all non-surgical treatments have been appropriately explored. Under severe cases, where surgical intervention does become necessary, a 10 cm reverse  jejunal  interposition is usually the procedure of choice. [ 2 ]


Primary central nervous system lymphoma  ( PCNSL ), also termed  primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS) , [ 2 ]  is a  primary intracranial tumor  appearing mostly in patients with severe  immunodeficiency  (typically patients with  AIDS ). It is a subtype and one of the most aggressive of the  diffuse large B-cell lymphomas . [ 3 ]


PCNSLs represent around 20% of all cases of  lymphomas  in  HIV  infections. (Other types are  Burkitt's lymphomas  and immunoblastic lymphomas). Primary  CNS  lymphoma is highly associated with  Epstein-Barr virus  (EBV) infection (> 90%) in  immunodeficient  patients (such as those with AIDS and those  immunosuppressed ), [ 4 ]  and does not have a predilection for any particular age group. Mean  CD4 + count at time of diagnosis is ~50/μL. In immunocompromised patients, prognosis is usually poor.  In immunocompetent patients (that is, patients who do not have AIDS or some other acquired or secondary immunodeficiency), there is rarely an association with EBV infection or other  DNA viruses . In the immunocompetent population, PCNSLs typically appear in older patients in their 50s and 60s.


Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. [ 5 ] [ 6 ]   The cause for the increase in incidence of this disease in the immunocompetent population is unknown.


A primary CNS lymphoma usually presents with  seizure ,  headache , cranial nerve findings, altered mental status, or other focal neurological deficits typical of a  mass effect . [ 7 ] [ 8 ]   Systemic symptoms may include fever, night sweats, or weight loss. Other symptoms include


The current standard for diagnosis typically includes positive  CSF   cytology , vitreous biopsy, or brain/leptomeningeal biopsy. [ 10 ]  Histopathological confirmation is essential for definitive diagnosis. [ 11 ]


MRI  or contrast enhanced  CT  classically shows multiple  ring-enhancing lesions  in the deep  white matter . The major  differential diagnosis  (based on imaging) is cerebral  toxoplasmosis , which is also prevalent in AIDS patients and also presents with a ring-enhanced lesion, although toxoplasmosis generally presents with more lesions and the contrast enhancement is typically more pronounced.   Imaging techniques  cannot distinguish the two conditions with certainty, and cannot exclude other diagnoses.  Thus, patients undergo a  brain biopsy  or  vitreous  biopsy, if there is intraocular involvement. [ 10 ]


Most PCNSLs are diffuse large  B cell   non-Hodgkin lymphomas . [ 12 ] [ 13 ]


Surgical  resection  is usually ineffective because of the depth of the tumour. Treatment with  irradiation  and  corticosteroids  often only produces a partial response and tumour recurs in more than 90% of patients. Median survival is 10 to 18 months in  immunocompetent  patients, and less in those with AIDS. The addition of IV  methotrexate  and  folinic acid  (leucovorin)  may extend survival to a median of 3.5 years. If radiation is added to methotrexate, median survival time may increase beyond 4 years.  However, radiation is not recommended in conjunction with methotrexate because of an increased risk of  leukoencephalopathy  and  dementia  in patients older than 60. [ 14 ]   In AIDS patients, perhaps the most important factor with respect to treatment is the use of  highly active anti-retroviral therapy  (HAART), which affects the CD4+ lymphocyte population and the level of immunosuppression. [ 15 ]  The optimal treatment plan for patients with PCNSL has not been determined. Combination chemotherapy and radiotherapy at least doubles survival time, but causes dementia and leukoencephalopathy in at least 50% of patients who undergo it. The most studied chemotherapeutic agent in PCNSL is  methotrexate  (a folate analogue that interferes with  DNA  repair). Methotrexate therapy in patients with PCNSL typically requires hospitalization for close monitoring and intravenous fluids. Leucovorin is often given for the duration of the therapy. Standard chemotherapeutic regimens for lymphoma such as  CHOP  are ineffective in PCNSL, probably due to poor penetration of the agents through the  blood brain barrier . [ 15 ]


Newer treatments, such as high dose chemotherapy combined with autologous stem cell transplant are proving to increase survival by years. [ 16 ]  New research to increase permeability of the  blood brain barrier  with  NGR-hTNF  followed by  CHOP , produced responses in 75% cases.  [ 17 ]


A phase 1 clinical trial of  ibrutinib  – an inhibitor of  Bruton's tyrosine kinase  – in 13 patients reported responses in 10 (77%). [ 18 ]  Five of the responses were complete.


The initial response to radiotherapy is often excellent, and may result in a complete remission. However, the duration of response with radiotherapy alone remains short, with median survival after treatment with radiotherapy just 18 months. Methotrexate based chemotherapy markedly improves survival, with some studies showing median survival after methotrexate chemotherapy reaching 48 months. [ 15 ]


Patients with  AIDS  and PCNSL have a median survival of only 4 months with radiotherapy alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself. Extended survival has been seen, however, in a subgroup of AIDS patients with  CD4  counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either methotrexate monotherapy or  vincristine , procarbazine, or whole brain radiotherapy. These patients have a median survival of 10–18 months. Of course,  highly active antiretroviral therapy  (HAART) is critical for prolonged survival in any AIDS patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and PCNSL. [ 15 ]


aggressive:   Sézary disease


A  pseudomeningocele  is an abnormal collection of  cerebrospinal fluid  (CSF) that communicates with the CSF space around the  brain  or  spinal cord .  In contrast to a  meningocele , in which the fluid is surrounded and confined by  dura mater , in a pseudomeningocele, the fluid has no surrounding membrane, but is contained in a cavity within the  soft tissues .


Pseudomeningocele may result after  brain surgery ,  spine  surgery, or  brachial plexus   avulsion injury .


Treatment for pseudomeningocele is conservative or may involve neurosurgical repair.


A  pseudosubarachnoid hemorrhage  is an apparent increased  attenuation  on  CT scans  within the  basal cisterns  that mimics a true  subarachnoid hemorrhage . [ 1 ]  This occurs in cases of severe  cerebral edema , such as by  cerebral hypoxia . It may also occur due to  intrathecally administered   contrast material , [ 2 ]  leakage of high-dose  intravenous  contrast material into the  subarachnoid spaces , or in patients with  cerebral venous sinus thrombosis , severe  meningitis ,  leptomeningeal carcinomatosis , [ 3 ]   intracranial hypotension ,  cerebellar infarctions , or  bilateral   subdural hematomas . [ 4 ]


In a true  subarachnoid hemorrhage , there is higher attenuation on CT scans of the  basal cisterns , and blood that has leaked from a  vessel  or formed a  hematoma  is more highly attenuated due to the absorption of  plasma . [ 5 ]  Pseudosubarachnoid hemorrhages have been observed in as much as 20% of patients resuscitated from non-traumatic  cardiopulmonary arrest . Patients with pseudosubarachnoid hemorrhages may have worse  prognoses  than those with true subarachnoid hemorrhages because of underlying disease processes and decreased  cerebral perfusion  with elevated intracranial pressure. [ 6 ]  The identification of a pseudosubarachnoid hemorrhage as opposed to a true subarachnoid hemorrhage may therefore change a patient's treatment plan. [ citation needed ]


Psychosurgery , also called   neurosurgery for mental disorder  ( NMD ), is the  neurosurgical treatment  of  mental disorders . [ 1 ]  Psychosurgery has always been a controversial medical field. [ 1 ]  The modern  history of psychosurgery  begins in the 1880s under the Swiss psychiatrist  Gottlieb Burckhardt . [ 2 ] [ 3 ]  The first significant foray into psychosurgery in the 20th century was conducted by the Portuguese neurologist  Egas Moniz  who, during the mid-1930s, developed the operation known as leucotomy. The practice was enthusiastically taken up in the United States by the  neuropsychiatrist   Walter Freeman  and the  neurosurgeon   James W. Watts  who devised what became the standard prefrontal procedure and named their operative technique  lobotomy , although the operation was called leucotomy in the United Kingdom. [ 4 ]  In spite of the award of the  Nobel prize  to Moniz in 1949, the use of psychosurgery declined during the 1950s. By the 1970s the standard Freeman-Watts type of operation was very rare, but other forms of psychosurgery, although used on a much smaller scale, survived. Some countries have abandoned psychosurgery altogether; in others, for example the US and the UK, it is only used in a few centres on small numbers of people with  depression  or  obsessive-compulsive disorder  (OCD). [ 5 ]
In some countries it is also used in the treatment of  schizophrenia  and other disorders. [ 6 ] [ 7 ]


Psychosurgery is a collaboration between psychiatrists and neurosurgeons. During the operation, which is carried out under a  general anaesthetic  and using  stereotactic  methods, a small piece of  brain  is destroyed or removed. The most common types of psychosurgery in current or recent use are anterior capsulotomy,  cingulotomy ,  subcaudate tractotomy  and  limbic leucotomy . Lesions are made by radiation, thermo-coagulation, freezing or cutting. [ 1 ]  About a third of patients show significant improvement in their symptoms after operation. [ 1 ]  Advances in surgical technique have greatly reduced the incidence of death and serious damage from psychosurgery; the remaining risks include  seizures , incontinence, decreased drive and initiative, weight gain, and  cognitive  and  affective  problems. [ 1 ]


Currently, interest in the neurosurgical treatment of mental illness is shifting from  ablative  psychosurgery (where the aim is to destroy brain tissue) to  deep brain stimulation  (DBS) where the aim is to stimulate areas of the brain with implanted  electrodes . [ 8 ]


All the forms of psychosurgery in use today (or used in recent years) target the  limbic system , which involves structures such as the  amygdala ,  hippocampus , certain  thalamic  and  hypothalamic  nuclei,  prefrontal  and  orbitofrontal cortex , and  cingulate gyrus —all connected by fibre pathways and thought to play a part in the regulation of emotion. [ 9 ]  There is no international consensus on the best target site. [ 9 ]


Anterior cingulotomy  was first used by  Hugh Cairns  in the UK, and developed in the US by H.T. Ballantine Jr. [ 10 ]  In recent decades it has been the most commonly used psychosurgical procedure in the US. [ 9 ]  The target site is the anterior cingulate cortex; the operation disconnects the thalamic and posterior frontal regions and damages the anterior cingulate region. [ 9 ]


Anterior capsulotomy  was developed in Sweden, where it became the most frequently used procedure. It is also used in Scotland and Canada. The aim of the operation is to disconnect the orbitofrontal cortex and thalamic nuclei by inducing a lesion in the anterior limb of  internal capsule . [ 9 ] [ 11 ]


Subcaudate tractotomy  was the most commonly used form of psychosurgery in the UK from the 1960s to the 1990s. It targets the lower medial quadrant of the frontal lobes, severing connections between the limbic system and supra-orbital part of the frontal lobe. [ 9 ]


Limbic leucotomy   is a combination of subcaudate tractotomy and anterior cingulotomy. It was used at  Atkinson Morley Hospital  London in the 1990s [ 9 ]  and also at  Massachusetts General Hospital . [ 12 ]


Amygdalotomy , which targets the  amygdala , was developed as a treatment for aggression by Hideki Narabayashi in 1961 and is still used occasionally, for example at the  Medical College of Georgia . [ 13 ]


There is debate about whether  deep brain stimulation  (DBS) should be classed as a form of psychosurgery. [ 14 ]


Success rates for anterior capsulotomy, anterior cingulotomy, subcaudate tractotomy, and limbic leucotomy in treating depression and OCD have been reported as between 25 and 70 percent. [ 1 ]  The quality of outcome data is poor and the Royal College of Psychiatrists in their 2000 report concluded that there were no simple answers to the question of modern psychosurgery's clinical effectiveness; studies suggested improvements in symptoms following surgery but it was impossible to establish the extent to which other factors contributed to this improvement. [ 5 ]  Research into the effects of psychosurgery has not been able to overcome a number of methodological problems, including the problems associated with non-standardised diagnoses and outcome measurements, the small numbers treated at any one centre, and  positive publication bias . Controlled studies are very few in number and there have been no placebo-controlled studies. There are no systematic reviews or meta-analyses. [ 1 ] [ 15 ]


Modern techniques have greatly reduced the risks of psychosurgery, although risks of adverse effects still remain. Whilst the risk of death or vascular injury has become extremely small, there remains a risk of seizures, fatigue, and personality changes following operation. [ 5 ]


A 2012 follow-up study of eight depressed patients who underwent anterior capsulotomy in Vancouver, Canada, classified five of them as responders at two to three years after surgery. Results on neuropsychological testing were unchanged or improved, although there were isolated deficits and one patient was left with long-term frontal psychobehavioral changes and fatigue. One patient, aged 75, was left mute and  akinetic  for a month following surgery and then developed  dementia . [ 16 ]


In China, psychosurgical operations which make a lesion in the  nucleus accumbens  are used in the treatment of drug and alcohol dependence. [ 17 ] [ 18 ]  Psychosurgery is also used in the treatment of schizophrenia, depression, and other mental disorders. [ 6 ]  Psychosurgery is not regulated in China, and its use has been criticised in the West. [ 6 ]


India had an extensive psychosurgery programme until the 1980s, using it to treat addiction, and aggressive behaviour in adults and children, as well as depression and OCD. [ 19 ]
Cingulotomy and capsulotomy for depression and OCD continue to be used, for example at the BSES MG Hospital in Mumbai. [ 20 ]


In Japan the first lobotomy was performed in 1939 and the operation was used extensively in mental hospitals. [ 21 ]  However, psychosurgery fell into disrepute in the 1970s, partly due to its use on children with behavioural problems. [ 22 ]


In the 1980s there were 10–20 operations a year in Australia and New Zealand. [ 8 ]  The number had decreased to one or two a year by the 1990s. [ 8 ]  In Victoria, there were no operations between 2001 and 2006, but between 2007 and 2012 the Victoria Psychosurgery Review Board dealt with 12 applications, all them for DBS. [ 23 ]


In the 20-year period 1971–1991 the Committee on Psychosurgery in the Netherlands and Belgium oversaw 79 operations. [ 5 ]  Since 2000 there has been only one centre in Belgium performing psychosurgery, carrying out about 8 or 9 operations a year (some capsulotomies and some DBS), mostly for OCD. [ 8 ]


In France about five people a year were undergoing psychosurgery in the early 1980s. [ 24 ]
In 2005 the Health Authority recommended the use of ablative psychosurgery and DBS for OCD. [ 25 ]


In the early 2000s in Spain about 24 psychosurgical operations (capsulotomy, cingulotomy, subcaudate tractotomy, and hypothalamotomy) a year were being performed. OCD was the most common diagnosis, but psychosurgery was also being used in the treatment of anxiety and schizophrenia, and other disorders. [ 7 ]


In the UK between the late 1990s and 2009 there were just two centres using psychosurgery: a few stereotactic anterior capsulotomies are performed every year at the  University Hospital of Wales , Cardiff, while anterior cingulotomies are carried out by the Advanced Interventions Service at  Ninewells Hospital , Dundee. The patients have diagnoses of depression, obsessive-compulsive disorder, and anxiety. Ablative psychosurgery was not performed in England between the late 1990s and 2009, [ 5 ]  although a couple of hospitals have been experimenting with DBS. [ 26 ]  In 2010,  Frenchay Hospital  in Bristol performed an anterior cingulotomy on a woman who had previously undergone DBS. [ 27 ]


In Russia in 1998 the Institute of the Human Brain ( Russian Academy of Sciences ) started a programme of stereotactic cingulotomy for the treatment of drug addiction. About 85 people, all under the age of 35, were operated on annually. [ 28 ]  In the Soviet Union, leucotomies were used for the treatment of schizophrenia in the 1940s, but the practice was prohibited by the Ministry of Health in 1950. [ 29 ]


In the United States, the  Massachusetts General Hospital  has a psychosurgery program. [ 30 ]  Operations are also performed at a few other centres.


In Mexico, psychosurgery is used in the treatment of anorexia [ 31 ]  and aggression. [ 32 ]


In Canada, anterior capsulotomies are used in the treatment of depression and OCD. [ 16 ] [ 33 ]


Venezuela has three centres performing psychosurgery. Capsulotomies, cingulotomies and amygdalotomies are used to treat OCD and aggression. [ 34 ]


Evidence of  trepanning  (or trephining)—the practice of drilling holes in the skull—has been found in a skull from a Neolithic burial site in France, dated to about 5100 BC although it was also used to treat  brain cranial trauma . There have also been archaeological finds in South America, while in Europe trepanation was carried out in classical and medieval times. [ 35 ]
The first systematic attempt at psychosurgery is commonly attributed to the Swiss psychiatrist  Gottlieb Burckhardt . [ 36 ]  In December 1888 Burckhardt operated on the brains of six patients (one of whom died a few days after the operation) at the Préfargier Asylum, cutting out a piece of  cerebral cortex . He presented the results at the Berlin Medical Congress and published a report, but the response was hostile and he did no further operations. [ 37 ]
Early in the 20th century, Russian neurologist  Vladimir Bekhterev  and Estonian neurosurgeon  Ludvig Puusepp  operated on three patients with mental illness, with discouraging results. [ 37 ]


Although there had been earlier attempts to treat psychiatric disorders with brain surgery, it was Portuguese neurologist  Egas Moniz  who was responsible for introducing the operation into mainstream psychiatric practice. He also coined the term psychosurgery. [ 37 ]  Moniz developed a theory that people with mental illnesses, particularly "obsessive and melancholic cases", had a disorder of the  synapses  which allowed unhealthy thoughts to circulate continuously in their brains. Moniz hoped that by surgically interrupting pathways in their brain he could encourage new healthier synaptic connections. [ 38 ]  In November 1935, under Moniz's direction, surgeon Pedro Almeida Lima drilled a series of holes on either side of a woman's skull and injected  ethanol  to destroy small areas of subcortical white matter in the  frontal lobes . After a few operations using ethanol, Moniz and Almeida Lima changed their technique and cut out small cores of brain tissue. They designed an instrument which they called a leucotome and called the operation a  leucotomy  (cutting of the white matter). [ 38 ]  After twenty operations, they published an account of their work. The reception was generally not friendly but a few psychiatrists, notably in Italy and the US, were inspired to experiment for themselves. [ 38 ]


In the US, psychosurgery was taken up and zealously promoted by neurologist  Walter Freeman  and neurosurgeon  James Watts . [ 10 ]  They started a psychosurgery program at  George Washington University  in 1936, first using Moniz's method but then devised a method of their own in which the connections between the prefrontal lobes and deeper structures in the brain were severed by making a sweeping cut through a burr hole on either side of the skull. [ 10 ]  They called their new operation a  lobotomy . [ 38 ]


Freeman went on to develop a new form of lobotomy which could be dispensed without the need for a neurosurgeon. He hammered an ice pick-like instrument, an orbitoclast, through the eye socket and swept through the frontal lobes. The transorbital or "ice pick" lobotomy was done under  local anesthesia  or using  electroconvulsive therapy  to render the patient unconscious and could be performed in mental hospitals lacking surgical facilities. [ 39 ]  Such was Freeman's zeal that he began to travel around the nation in his own personal van, which he called his "lobotomobile", demonstrating the procedure in psychiatric hospitals. [ 40 ]  Freeman's patients included 19 children, one of whom was 4 years old. [ 41 ]


The 1940s saw a rapid expansion of psychosurgery, in spite of the fact that it involved a significant risk of death [ 42 ]  and severe personality changes. [ 43 ]  By the end of the decade, up to 5000 psychosurgical operations were being carried out annually in the US. [ 43 ]  In 1949, Moniz was awarded the  Nobel Prize for Physiology or Medicine .


Beginning in the 1940s various new techniques were designed in the hope of reducing the adverse effects of the operation. These techniques included  William Beecher Scoville 's  orbital undercutting , Jean Talairach's  anterior capsulotomy , and Hugh Cairn's  bilateral cingulotomy . [ 10 ]  Stereotactic techniques made it possible to place  lesions  more accurately, and experiments were done with alternatives to cutting instruments such as radiation. [ 10 ]  Psychosurgery nevertheless went into rapid decline in the 1950s, due to the introduction of new drugs and a growing awareness of the long-term damage caused by the operations, [ 10 ]  as well as doubts about its efficacy. [ 1 ]  By the 1970s, the standard or transorbital lobotomy had been replaced with other forms of psychosurgical operations.


During the 1960s and 1970s, psychosurgery became the subject of increasing public concern and debate, culminating in the US with congressional hearings. Particularly controversial in the United States was the work of Harvard neurosurgeon  Vernon Mark  and psychiatrist  Frank Ervin , who carried out amygdalotomies in the hope of reducing violence and "pathologic aggression" in patients with temporal lobe seizures and wrote a book entitled  Violence and the Brain  in 1970. [ 1 ]  The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research in 1977 endorsed the continued limited use of psychosurgical procedures. [ 1 ] [ 44 ]  Since then, a few facilities in some countries, such as the US, have continued to use psychosurgery on small numbers of patients. In the US and other Western countries, the number of operations has further declined over the past 30 years, [ timeframe? ]  a period during which there had been no major advances in ablative psychosurgery. [ 8 ]


Psychosurgery has a controversial history, and despite modifications, still raises serious questions about benefit, risks, and the adequacy with which consent is obtained.  Its continued use is defended by references to the "therapeutic imperative" to do something in the case of psychiatric patients who have not responded to other forms of treatment, and the evidence that some patients see improvement in their symptoms following surgery. There remain however problems concerning the rationale, indications and efficacy of psychosurgery, and the results of the operation raise questions of "identity, spirit, relationships, integrity and human flourishing". [ 45 ]


Radiosurgery  is  surgery  using  radiation , [ 1 ]  that is, the destruction of precisely selected areas of  tissue  using  ionizing radiation  rather than excision with a blade. Like other forms of  radiation therapy  (also called radiotherapy), it is usually used to treat  cancer . Radiosurgery was originally defined by the Swedish neurosurgeon  Lars Leksell  as "a single high dose fraction of radiation, stereotactically directed to an intracranial region of interest". [ 2 ]


In  stereotactic radiosurgery  ( SRS ), the word " stereotactic " refers to a three-dimensional  coordinate system  that enables accurate correlation of a virtual target seen in the patient's diagnostic images with the actual target position in the patient. Stereotactic radiosurgery may also be called  stereotactic body radiation therapy  (SBRT) or stereotactic ablative radiotherapy (SABR) when used outside the  central nervous system  (CNS). [ 3 ]


Stereotactic radiosurgery was first developed in 1949 by the Swedish neurosurgeon Lars Leksell to treat small targets in the brain that were not amenable to conventional surgery. The initial stereotactic instrument he conceived used probes and electrodes. [ 4 ]  The first attempt to supplant the electrodes with radiation was made in the early fifties, with  x-rays . [ 5 ]  The principle of this instrument was to hit the intra-cranial target with narrow beams of radiation from multiple directions. The beam paths converge in the target volume, delivering a lethal cumulative dose of radiation there, while limiting the dose to the adjacent healthy tissue. Ten years later significant progress had been made, due in considerable measure to the contribution of the physicists Kurt Liden and Börje Larsson. [ 6 ]   At this time, stereotactic  proton  beams had replaced the x-rays. [ 7 ]  The heavy particle beam presented as an excellent replacement for the surgical knife, but the  synchrocyclotron  was too clumsy. Leksell proceeded to develop a practical, compact, precise and simple tool which could be handled by the surgeon himself. In 1968 this resulted in the Gamma Knife, which was installed at the  Karolinska Institute  and consisted of several  cobalt-60   radioactive  sources placed in a kind of helmet with central channels for irradiation with gamma rays. [ 8 ]  This prototype was designed to produce slit-like radiation lesions for functional neurosurgical procedures to treat pain, movement disorders, or behavioral disorders that did not respond to conventional treatment. The success of this first unit led to the construction of a second device, containing 179 cobalt-60 sources. This second Gamma Knife unit was designed to produce spherical lesions to treat brain tumors and intracranial  arteriovenous malformations  (AVMs). [ 9 ]  Additional units were installed in the 1980s all with 201 cobalt-60 sources. [ 10 ]


In parallel to these developments, a similar approach was designed for a  linear particle accelerator  or Linac. Installation of the first 4  MeV  clinical linear accelerator began in June 1952 in the Medical Research Council (MRC) Radiotherapeutic Research Unit at the  Hammersmith Hospital , London. [ 11 ]  The system was handed over for physics and other testing in February 1953 and began to treat patients on 7 September that year. Meanwhile, work at the Stanford Microwave Laboratory led to the development of a 6 MeV accelerator, which was installed at Stanford University Hospital, California, in 1956. [ 12 ]  Linac units quickly became favored devices for conventional fractionated  radiotherapy  but it lasted until the 1980s before dedicated Linac radiosurgery became a reality. In 1982, the Spanish neurosurgeon J. Barcia-Salorio began to evaluate the role of cobalt-generated and then Linac-based photon radiosurgery for the treatment of AVMs and  epilepsy . [ 13 ]  In 1984, Betti and Derechinsky described a Linac-based radiosurgical system. [ 14 ]  Winston and Lutz further advanced Linac-based radiosurgical prototype technologies by incorporating an improved stereotactic positioning device and a method to measure the accuracy of various components. [ 15 ]  Using a modified Linac, the first patient in the United States was treated in Boston  Brigham and Women's Hospital  in February 1986. [ citation needed ]


Technological improvements in medical imaging and computing have led to increased clinical adoption of stereotactic radiosurgery and have broadened its scope in the 21st century. [ 16 ] [ 17 ]  The localization accuracy and precision that are implicit in the word "stereotactic" remain of utmost importance for radiosurgical interventions and are significantly improved via  image-guidance  technologies such as the  N-localizer [ 18 ]  and Sturm-Pastyr localizer [ 19 ]  that were originally developed for  stereotactic surgery .


In the 21st century the original concept of radiosurgery  expanded to include treatments comprising up to five  fractions , and stereotactic radiosurgery has been redefined as a distinct  neurosurgical  discipline that utilizes externally generated  ionizing radiation  to inactivate or eradicate defined targets, typically in the head or spine, without the need for a surgical incision. [ 20 ]  Irrespective of the similarities between the concepts of stereotactic radiosurgery and fractionated radiotherapy the mechanism to achieve treatment is subtly different, although both treatment modalities are reported to have identical outcomes for certain indications. [ 21 ]  Stereotactic radiosurgery has a greater emphasis on delivering precise, high doses to small areas, to destroy target tissue while preserving adjacent normal tissue. The same principle is followed in conventional radiotherapy although lower dose rates spread over larger areas are more likely to be used (for example as in  VMAT  treatments). Fractionated radiotherapy relies more heavily on the different  radiosensitivity  of the target and the surrounding normal tissue to the  total accumulated radiation dose . [ 20 ]  Historically, the field of fractionated radiotherapy evolved from the original concept of stereotactic radiosurgery following discovery of the principles of  radiobiology : repair, reassortment, repopulation, and reoxygenation. [ 22 ]  Today, both treatment techniques are complementary, as tumors that may be resistant to fractionated radiotherapy may respond well to radiosurgery, and tumors that are too large or too close to critical organs for safe radiosurgery may be suitable candidates for fractionated radiotherapy. [ 21 ]


Today, both Gamma Knife and Linac radiosurgery programs are commercially available worldwide. While the Gamma Knife is dedicated to radiosurgery, many Linacs are built for conventional fractionated radiotherapy and require additional technology and expertise to become dedicated radiosurgery tools. There is not a clear difference in efficacy between these different approaches. [ 23 ] [ 24 ]  The major manufacturers,  Varian  and  Elekta  offer dedicated radiosurgery Linacs as well as machines designed for conventional treatment with radiosurgery capabilities. Systems designed to complement conventional Linacs with beam-shaping technology, treatment planning, and image-guidance tools to provide. [ 25 ]  An example of a dedicated radiosurgery Linac is the  CyberKnife , a compact Linac mounted onto a robotic arm that moves around the patient and irradiates the tumor from a large set of fixed positions, thereby mimicking the Gamma Knife concept.


The fundamental principle of radiosurgery is that of selective  ionization  of tissue, by means of high-energy beams of radiation. Ionization is the production of  ions  and  free radicals  which are damaging to the  cells . These ions and radicals, which may be formed from the water in the cell or biological materials, can produce irreparable damage to DNA, proteins, and lipids, resulting in the cell's death. Thus, biological inactivation is carried out in a volume of tissue to be treated, with a precise destructive effect. The radiation dose is usually measured in  grays  (one gray (Gy) is the absorption of one  joule  of energy per kilogram of mass). A unit that attempts to take into account both the different organs that are irradiated and the type of radiation is the  sievert , a unit that describes both the amount of energy deposited and the biological effectiveness. [ citation needed ]


When used outside the CNS it may be called stereotactic body radiation therapy (SBRT) or stereotactic ablative radiotherapy (SABR). [ 3 ]


Radiosurgery is performed by a multidisciplinary team of  neurosurgeons ,  radiation oncologists  and medical  physicists  to operate and maintain highly sophisticated, highly precise and complex instruments, including medical linear accelerators, the Gamma Knife unit and the Cyberknife unit. The highly precise irradiation of targets within the brain and spine is planned using information from medical images that are obtained via  computed tomography ,  magnetic resonance imaging , and  angiography . [ citation needed ]


Radiosurgery is indicated primarily for the therapy of tumors, vascular lesions and functional disorders.  Significant clinical judgment must be used with this technique and considerations must include lesion type, pathology if available, size, location and age and general health of the patient.  General contraindications to radiosurgery include excessively large size of the target lesion, or lesions too numerous for practical treatment. Patients can be treated within one to five days as  outpatients . By comparison, the average hospital stay for a  craniotomy  (conventional neurosurgery, requiring the opening of the skull) is about 15 days. The radiosurgery outcome may not be evident until months after the treatment. Since radiosurgery does not remove the tumor but inactivates it biologically, lack of growth of the lesion is normally considered to be treatment success. General indications for radiosurgery include many kinds of brain tumors, such as  acoustic neuromas ,  germinomas ,  meningiomas ,  metastases , trigeminal neuralgia, arteriovenous malformations, and skull base tumors, among others.


Stereotatic radiosurgery of the spinal metastasis is efficient in controlling pain in up to 90% of the cases and ensures stability of the tumours on imaging evaluation in 95% of the cases, and is more efficient for spinal metastasis involving one or two segments. Meanwhile, conventional external beam radiotherapy is more suitable for multiple spinal involvement. [ 26 ]


SRS may be administered alone or in combination with other therapies. For brain metastases, these treatment options include  whole brain radiation therapy  (WBRT), surgery, and systemic therapies. However, a recent systematic review found no difference in the affects on overall survival or deaths due to brain metastases when comparing SRS treatment alone to SRS plus WBRT treatment or WBRT alone. [ 27 ]


Expansion of stereotactic radiotherapy to other lesions is increasing, and includes liver cancer, lung cancer, pancreatic cancer, etc. [ citation needed ]


The New York Times  reported in December 2010 that radiation overdoses had occurred with the linear accelerator method of radiosurgery, due in large part to inadequate safeguards in equipment retrofitted for stereotactic radiosurgery. [ 28 ]  In the U.S. the  Food and Drug Administration  (FDA) regulates these devices, whereas the Gamma Knife is regulated by the  Nuclear Regulatory Commission .


This is evidence that  immunotherapy  may be useful for treatment of radiation necrosis following stereotactic radiotherapy. [ 29 ]


The selection of the proper kind of radiation and device depends on many factors including lesion type, size, and location in relation to critical structures.  Data suggest that similar clinical outcomes are possible with all of the various techniques.  More important than the device used are issues regarding indications for treatment, total dose delivered, fractionation schedule and conformity of the treatment plan. [ citation needed ]


A Gamma Knife (also known as the Leksell Gamma Knife) is used to treat  brain tumors  by administering high-intensity gamma radiation therapy in a manner that concentrates the radiation over a small volume. The device was invented in 1967 at the Karolinska Institute in  Stockholm , Sweden, by  Lars Leksell , Romanian-born neurosurgeon Ladislau Steiner, and  radiobiologist  Börje Larsson from  Uppsala University , Sweden.


A Gamma Knife typically contains 201  cobalt-60  sources of approximately 30  curies  each (1.1  TBq ), placed in a hemispheric array in a heavily  shielded  assembly. The device aims  gamma radiation  through a target point in the patient's brain.  The patient wears a specialized helmet that is surgically fixed to the skull, so that the brain tumor remains stationary at the target point of the gamma rays. An  ablative  dose of radiation is thereby sent through the tumor in one treatment session, while surrounding brain tissues are relatively spared.


Gamma Knife therapy, like all radiosurgery, uses doses of radiation to kill cancer cells and shrink tumors, delivered precisely to avoid damaging healthy brain tissue. Gamma Knife radiosurgery is able to accurately focus many beams of gamma radiation on one or more tumors. Each individual beam is of relatively low intensity, so the radiation has little effect on intervening brain tissue and is concentrated only at the tumor itself.


Gamma Knife radiosurgery has proven effective for patients with benign or malignant brain tumors up to 4 cm (1.6 in) in size,  vascular  malformations such as an  arteriovenous malformation  (AVM), pain, and other functional problems. [ 30 ] [ 31 ] [ 32 ] [ 33 ]   For treatment of trigeminal neuralgia the procedure may be used repeatedly on patients.


Acute complications following Gamma Knife radiosurgery are rare, [ 34 ]  and complications are related to the condition being treated. [ 35 ] [ 36 ]


A linear accelerator (linac) produces x-rays from the impact of accelerated electrons striking a high  z  target, usually tungsten. The process is also referred to as "x-ray therapy" or "photon therapy."  The emission head, or " gantry ", is mechanically rotated around the patient in a full or partial circle. The table where the patient is lying, the "couch", can also be moved in small linear or angular steps. The combination of the movements of the gantry and of the couch allow the computerized planning of the volume of tissue that is going to be irradiated. Devices with a high energy of 6 MeV are commonly used for the treatment of the brain, due to the depth of the target. The diameter of the energy beam leaving the emission head can be adjusted to the size of the lesion by means of  collimators . They may be interchangeable orifices with different diameters, typically varying from 5 to 40 mm in 5 mm steps, or multileaf collimators, which consist of a number of metal leaflets that can be moved dynamically during treatment in order to shape the radiation beam to conform to the mass to be ablated. As of 2017 [update]  Linacs were capable of achieving extremely narrow beam geometries, such as 0.15 to 0.3 mm. Therefore, they can be used for several kinds of surgeries which hitherto had been carried out by open or endoscopic surgery, such as for trigeminal neuralgia. Long-term follow-up data has shown it to be as effective as radiofrequency ablation, but inferior to surgery in preventing the recurrence of pain. [ citation needed ]


The first such systems were developed by  John R. Adler , a  Stanford University  professor of neurosurgery and radiation oncology, and Russell and Peter Schonberg at Schonberg Research, and commercialized under the brand name CyberKnife.


Protons may also be used in radiosurgery in a procedure called  Proton Beam Therapy  (PBT) or  proton therapy . Protons are extracted from proton donor materials by a medical  synchrotron  or  cyclotron , and accelerated in successive transits through a circular, evacuated conduit or cavity, using powerful magnets to shape their path, until they reach the energy required to just traverse a human body, usually about 200 MeV. They are then released toward the region to be treated in the patient's body, the irradiation target. In some machines, which deliver protons of only a specific energy, a custom mask made of plastic is interposed between the beam source and the patient to adjust the beam energy to provide the appropriate degree of penetration. The phenomenon of the  Bragg peak  of ejected protons gives proton therapy advantages over other forms of radiation, since most of the proton's energy is deposited within a limited distance, so tissue beyond this range (and to some extent also tissue inside this range) is spared from the effects of radiation. This property of protons, which has been called the " depth charge  effect" by analogy to the explosive weapons used in anti-submarine warfare, allows for conformal dose distributions to be created around even very irregularly shaped targets, and for higher doses to targets surrounded or backstopped by radiation-sensitive structures such as the  optic chiasm  or brainstem. The development of "intensity modulated" techniques allowed similar conformities to be attained using linear accelerator radiosurgery. [ citation needed ]


As of 2013 [update]  there was no evidence that proton beam therapy is better than any other types of treatment in most cases, except for a "handful of rare pediatric cancers". Critics, responding to the increasing number of very expensive PBT installations, spoke of a "medical  arms race "  and "crazy medicine and unsustainable public policy". [ 37 ]


A  selective dorsal rhizotomy  ( SDR ), also known as a  rhizotomy ,  dorsal rhizotomy , or a  selective posterior rhizotomy , is a  neurosurgical  procedure that selectively cuts problematic  nerve roots  in the  spinal cord . [ 3 ] [ note 1 ]  This procedure has been well-established in the literature as a surgical intervention and is used to relieve negative symptoms of  neuromuscular  conditions such as  spastic diplegia  and other forms of  spastic cerebral palsy . [ 4 ]  The specific sensory nerves inducing spasticity are identified using  electromyographic  (EMG) stimulation and graded on a scale of 1 (mild) to 4 (severe spasticity). Abnormal nerve responses (usually graded a 3 or 4) are isolated and cut, thereby reducing symptoms of spasticity. [ 3 ]


Spasticity is defined as a velocity-dependent increase in muscle tone in response to a stretch. [ 5 ]   This  upper motor neuron  condition results from a lack of descending input from the brain that would normally release the inhibitory neurotransmitter  gamma amino butyric acid  (GABA), which serves to dampen neuronal excitability in the nervous system. [ 6 ]   Spasticity is thought to be caused by an excessive increase of excitatory signals from sensory nerves without proper inhibition by GABA. [ 7 ]   Two common conditions associated with this lack of descending input are cerebral palsy and  acquired brain injury . [ 6 ]


Selective dorsal rhizotomy (SDR), less often referred to as selective posterior rhizotomy (SPR), is the most widely used form of rhizotomy, and is today a primary treatment for  spastic diplegia , best done in the youngest years before bone and joint deformities from the pull of spasticity take place. Still, it can be performed safely and effectively on adults as well.


SDR is a permanent procedure that addresses the spasticity at its  neuromuscular  root: i.e., in the central nervous system that contains the misfiring nerves that cause the spasticity of those particular muscles in the first place. After SDR, the person's spasticity is usually eliminated, revealing the "real" strength (or lack thereof) of the muscles underneath. SDR's result is fundamentally unlike orthopedic surgical procedures, where spasticity is left untreated.


Because there is always temporary weakness after SDR, patients should work hard to strengthen the weak muscles with physical therapy and learn habits of movement and daily tasks in a body without spasticity.


SDR is usually performed on the  pediatric  spastic cerebral palsy population between the ages of 2 and 6. This is the age range where orthopedic deformities from spasticity have not yet occurred or are minimal. It is also variously claimed by clinicians that another advantage of doing the surgery so young is that it is inherently easier for these young children to restrengthen their muscles and to re-learn how to walk, often having the effect that later in life, they do not even remember the period when they lived with the spasticity at all. However, recent cases of successful SDR procedures among those with spastic diplegia across all age ranges (years 3–50) have proven its universal effectiveness and safety regardless of the age of the spastic diplegic patient. A counter-argument against the prevailing view concerning the younger years is that it may actually be quicker and easier to restrengthen an older patient's musculature, and regaining walking may happen faster with an older patient because the patient is fully matured and very aware of what is going on, and so may work harder and with more focus than might a young child. These two schools of thought have equally objectively valid bases for their formation and, thus, are each defended quite intensely by their respective proponents. [ citation needed ]


In 1913 Otfrid Foerster in Germany reported the results of dorsal root rhizotomy on patients with spastic cerebral palsy. Rhizotomy for spasticity purposes did indeed then proceed to take about a fifty-year hiatus. In 1967 Claude Gros and his colleagues at the neurosurgical hospital (CHU Gui de Chauliac) in  Montpellier  resurrected posterior rhizotomy for spasticity. Fasano of Italy in 1978 introduced 'selective' posterior rootlet rhizotomy for cerebral palsy patients and  Warwick Peacock [ 8 ]  developed the Gros technique in Cape Town, South Africa, by exposing the  cauda equina , rather than at the spinal cord level. Peacock moved to  Los Angeles  in 1986 and began widely campaigning for SDR's viability in cerebral palsy spasticity relief. Peacock and the surgeons he subsequently trained developed the procedure further using their own clinical-intellectual refinements and refinements in medical equipment and technology that occurred from the 1980s through the 2000s (decade).


Today,  St. Louis Children's Hospital  in  St. Louis, Missouri , has a "Center for Cerebral Palsy Spasticity" that is the only internationally known clinic in the world to have conducted concentrated first-hand clinical research on SDR over an extended period. Its chief neurosurgeon in the field, Doctor T.S. Park (who was initially trained by Peacock), has performed over five thousand SDR surgeries since 1987, some of them on adults, and is the originator of the L1- single-level laminectomy  modification to the SDR surgery in 1991, which sections the first  dorsal root  and enables the removal of significantly less spine-bone than in surgeries performed before 1991, as well as the inherent release of the  hip flexor  muscles specifically as a result of that particular sectioning—prior to that, total hip flexor release was not necessarily possible. That L1-laminectomy modification has since become the standard method, and SLCH has become internationally known as a major provider of SDR surgery to those in need. This clinic believes that patients with spastic diplegia, hemiplegia, or quadriplegia should have spasticity reduced first through SDR before undergoing muscle or tendon release procedures, and other surgeons today share this view. A major qualifier in the cases taken on at SLCH, however, is that all of its adults have had relatively mild  cases of spastic diplegia.


In September 2008, SDR was performed that 'closed the gap' on concerns regarding age of the patient in SDR:  Columbia-Presbyterian   Children's Hospital 's Richard C.E. Anderson performed an SDR surgery on a 28-year-old male with  moderate  spastic diplegia, which by the patient's own report has reduced his muscle tone nearly to the level of a "normal" person and enabled him to walk and exercise much more efficiently; also, Anderson in the past performed an SDR on a 16-year-old  wheelchair -using female with  severe  spastic diplegia. Reportedly, that particular SDR enabled the young woman to ambulate, whereas before the surgery, she was too tight to do so. In 2011, Anderson reported that another 16-year-old patient of his was considering undergoing the rhizotomy, but that patient subsequently decided to put her decision on hold  [ citation needed ] . And in July 2011, after offering her several months of consultation, the medical team at the Continuing Care department of  Gillette Children's Specialty Healthcare  performed an SDR procedure on a local young-adult Minnesota resident.Meanwhile, many countries such as the United Kingdom, Russia, and China adopted the dorsal rhizotomy to treat spastic cerebral palsy.


Not all people with spastic cerebral palsy benefit from SDR. For those under 18 years of age, rhizotomy requires that they be:


For adults between 19 and 50 years of age, rhizotomy requires:


The long-term effects of SDR have been reported. [ 10 ] [ 11 ]  Selective dorsal rhizotomy surgery has been performed routinely over the past several decades on children with spastic cerebral palsy, and the accumulated evidence indicates positive long-term outcomes. [ 12 ] [ 13 ]


All candidates for rhizotomy must have good muscle strength in the legs and trunk. There must also be evidence of adequate motor control or the ability to make reciprocal movements for crawling or walking and to move reasonably quickly from one posture to another. Chiefly, pediatric rhizotomy candidates are people with CP who have shown age-appropriate progression in motor development. Still, spasticity hampers the development of skills and/or causes gait patterns like the  scissors gait . In adults, the primary requirements are that the person is able to ambulate independently, but spasticity limits energy, flexibility, walking speed, and balance and sometimes causes pain/muscle spasms.


The criteria for patient eligibility from the St. Louis Children's Hospital are: [ 14 ]


After the surgery, all patients walking independently before surgery regained independent walking within a few weeks after surgery. Patients maintain independent walking for the long term; when others have more difficulty walking independently they may eventually need an assistive device. In nearly all cases, spasticity can be eliminated and the quality of independent walking improves, however, physical therapy and braces become unnecessary after SDR. Orthopedic surgery is rarely required after SDR.


In children who are 2–7 years old and walk with a walker or crutches before SDR, independent walking after the procedure is possible. Once they have achieved independent walking, they can maintain it.


In children who are older than 7 years and walk with crutches, independent walking (inside or outside house) is possible. If they walk with walker at the age, they will most likely walk with a walker or crutches after the procedure, though it improves the quality of assisted walking and transition movements, and alleviates deformities of the legs. Many of these patients will need orthopedic surgeries after SDR.


There are a few clinical situations in which, likely, someone may not be a candidate for the surgery. These situations include those who have had  severe   meningitis , a congenital (birth-originating) brain  infection , congenital  hydrocephalus  unrelated to the person's premature birth, a person who has had head trauma, or a person with some sort of  familial disease . Also precluded are people who have a "mixed" CP with predominant dystonia; and those who have severe  scoliosis . However, as with any procedure, an individual evaluation is needed to determine eligibility.


SDR begins with a 1- to 2-inch incision along the center of the lower back just above the waist. An L1  laminectomy  is then performed: a section of the spine's bone, the spinous processes together with a portion of the lamina, are removed, like a drain-cap, to expose the spinal cord and spinal nerves underneath. Ultrasound and an X-ray locate the tip of the spinal cord, where there is a natural separation between sensory and motor nerves. A rubber pad is then placed to separate the motor from the sensory nerves. The sensory nerve roots, each of which will be tested and selectively eliminated, are placed on top of the pad, while the motor nerves are beneath the pad, away from the operative field.


After the sensory nerves are exposed, each sensory nerve root is divided into 3–5 rootlets. Each rootlet is tested with electromyography, which records electrical patterns in muscles. Rootlets are ranked from 1 (mild) to 4 (severe) for spasticity. The severely abnormal rootlets are cut. This technique is repeated for rootlets between spinal nerves L2 and S2. Half of the L1 dorsal root fibers are cut without EMG testing.


The neurosurgical team at  Seattle Children's Hospital  has modified the surgical approach described above by tailoring the selection of nerve root sectioning to the individual patient.  This technique selectively analyzes each individual nerve root with  electromyography  to separate dorsal and ventral nerve roots through comparison of stimulus responses. Researchers have utilized objective feedback from the nerve root compared to the above-mentioned approach that relies on subjective visualization to identify motor versus sensory nerve roots, thus improving the likelihood of sectioning only those nerves of interest.  Another important difference between the two approaches is the location of the  laminectomy  to expose the nerve roots.  At Seattle Children's, the laminectomy is performed below the termination of the spinal cord ( conus ), potentially reducing the risk of injury. [ 15 ]


When testing and corresponding elimination are complete, the dura mater is closed, and fentanyl is given to bathe the sensory nerves directly. The other layers of tissue, muscle, fascia, and subcutaneous tissue are sewn. The skin is typically now closed with glue, but there are sometimes stitches to be removed from the back after 3 weeks. The surgery takes approximately 4 hours and typically involves one neurosurgeon, one anesthesiologist, and possibly an assortment of assisting physicians (as in the New York City September 2008 case). The patient then goes to the recovery room for 1–2 hours before being transferred to the intensive care unit overnight. Transfer from the ICU to a recovery room in the hospital is then done to enable direct post-surgical observation by the neurosurgeon and surgical team, but this usually lasts only about 3 days, during which the team performs range-of-motion tests that they record and compare to pre-surgery levels. After that short period, the patient, depending on circumstances and appropriateness, is either transferred to inpatient recovery or is linked to an intense outpatient exercise program and discharged from the hospital.


According to clinicians, it usually takes about one year from the date of surgery to achieve maximum results from SDR. However, videos from St. Louis Children's Hospital website have shown continued marked improvement as much as five years post-surgery, and presumably, if the person keeps exercising intensely, potential for continued improvement and strengthening is, just as in a person born with normal muscle tone and range of motion, unlimited.


Selective dorsal rhizotomy can alleviate  contractures  caused by spasticity from before the surgery takes place; also it prevents any more contractures or spasticity from occurring in the future. With or without rhizotomy, the only way contractures can ever be relieved is via  orthopaedic surgery . Fixed orthopaedic deformities of the legs caused by the previous years of intense spasticity are also not relieved by the SDR and must also be corrected surgically.


There is always abnormal sensitivity and tingling of the skin on the feet and legs after SDR because of the nature of the nerves that have been worked on, but this usually resolves within six weeks. There is no way to prevent the abnormal sensitivity in the feet. Transient change in bladder control may occur, but this also resolves within a few weeks.