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ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUuc3RhZ2luZy5tZWRzY2FwZS5jb20vYXJ0aWNsZS8xOTE2ODUyLW92ZXJ2aWV3\nAuthor: Edward C Jauch, MD, MS, FAHA, FACEP; Chief Editor: Helmi L Lutsep, MD more...\nSections Ischemic Stroke\nBrain Imaging With CT Scanning and MRI\nOther Imaging Studies in Ischemic Stroke\nBlood Studies\nEmergency Response and Transport\nAcute Management of Stroke\nFibrinolytic Therapy\nIntra-arterial Reperfusion\nAntiplatelet Agents\nBlood Pressure Control\nFever Control\nCerebral Edema Control\nSeizure Control\nAcute Decompensation\nAnticoagulation and Prophylaxis\nNeuroprotective Agents\nSpecialized Stroke Centers\nThrombolytics\nAnticonvulsants, Other\nAnticoagulants, Hematologic\nAnalgesics, Other\nBeta Blockers, Alpha Activity\nIschemic stroke (see the image below) is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Acute ischemic stroke is caused by thrombotic or embolic occlusion of a cerebral artery and is more common than hemorrhagic stroke.\nMaximum intensity projection (MIP) image from a computed tomography angiogram (CTA) demonstrates a filling defect or high-grade stenosis at the branching point of the right middle cerebral artery (MCA) trunk (red circle), suspicious for thrombus or embolus. CTA is highly accurate in detecting large- vessel stenosis and occlusions, which account for approximately one third of ischemic strokes.\nSee Acute Stroke, a Critical Images slideshow, for more information on incidence, presentation, intervention, and additional resources.\nConsider stroke in any patient presenting with acute neurologic deficit or any alteration in level of consciousness. Common stroke signs and symptoms include the following:\nAbrupt onset of hemiparesis, monoparesis, or (rarely) quadriparesis\nHemisensory deficits\nMonocular or binocular visual loss\nVisual field deficits\nFacial droop\nVertigo (rarely in isolation)\nSudden decrease in level of consciousness\nAlthough such symptoms can occur alone, they are more likely to occur in combination. No historical feature distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting, headache, and sudden change in level of consciousness are more common in hemorrhagic strokes. In younger patients, a history of recent trauma, coagulopathies, illicit drug use (especially cocaine), migraines, or use of oral contraceptives should be elicited.\nWith the availability of reperfusion options (fibrinolytic and endovascular therapies) for acute ischemic stroke in selected patients, the physician must be able to perform a brief but accurate neurologic examination on patients with suspected stroke syndromes. The goals of the neurologic examination include the following:\nConfirming the presence of stroke symptoms (neurologic deficits)\nDistinguishing stroke from stroke mimics\nEstablishing a neurologic baseline, should the patient's condition improve or deteriorate\nEstablishing stroke severity, using a structured neurologic exam and score (National Institutes of Health Stroke Scale [NIHSS]) to assist in prognosis and therapeutic selection\nEssential components of the neurologic examination include the following evaluations:\nMotor function\nSensory function\nCerebellar function\nDeep tendon reflexes\nLanguage (expressive and receptive capabilities)\nMental status and level of consciousness\nThe skull and spine also should be examined, and signs of meningismus should be sought.\nSee Clinical Presentation for more detail.\nEmergent brain imaging is essential for evaluation of acute ischemic stroke. Noncontrast computed tomography (CT) scanning is the most commonly used form of neuroimaging in the acute evaluation of patients with apparent acute stroke. The following neuroimaging techniques may also be used emergently:\nCT angiography and CT perfusion scanning\nCarotid duplex scanning\nDigital subtraction angiography\nLumbar puncture\nA lumbar puncture is required to rule out meningitis or subarachnoid hemorrhage when the CT scan is negative but the clinical suspicion remains high\nLaboratory tests performed in the diagnosis and evaluation of ischemic stroke include the following:\nComplete blood count (CBC): A baseline study that may reveal a cause for the stroke (eg, polycythemia, thrombocytosis, leukemia), provide evidence of concurrent illness, and ensure absence of thrombocytopenia when considering fibrinolytic therapy\nBasic chemistry panel: A baseline study that may reveal a stroke mimic (eg, hypoglycemia, hyponatremia) or provide evidence of concurrent illness (eg, diabetes, renal insufficiency)\nCoagulation studies: May reveal a coagulopathy and are useful when fibrinolytics or anticoagulants are to be used\nCardiac biomarkers: Important because of the association of cerebral vascular disease and coronary artery disease\nToxicology screening: May assist in identifying intoxicated patients with symptoms/behavior mimicking stroke syndromes or the use of sympathomimetics, which can cause hemorrhagic and ischemic strokes\nPregnancy testing: A urine pregnancy test should be obtained for all women of childbearing age with stroke symptoms; recombinant tissue-type plasminogen activator (rt-PA) is a pregnancy class C agent\nSee Workup for more detail.\nThe goal for the emergent management of stroke is to complete the following within 60 minutes or less of patient arrival: [1]\nAssess airway, breathing, and circulation (ABCs) and stabilize the patient as necessary\nComplete the initial evaluation and assessment, including imaging and laboratory studies\nInitiate reperfusion therapy, if appropriate\nCritical treatment decisions focus on the following:\nThe need for airway management\nOptimal blood pressure control\nIdentifying potential reperfusion therapies (eg, intravenous fibrinolysis with rt-PA (alteplase) or intra-arterial approaches)\nInvolvement of a physician with a special interest and training in stroke is ideal. Stroke care units with specially trained nursing and allied healthcare personnel have clearly been shown to improve outcomes.\nIschemic stroke therapies include the following:\nAntiplatelet agents [2, 3]\nTreatment of comorbid conditions may include the following:\nReduce fever\nCorrect hypotension/significant hypertension\nCorrect hypoxia\nCorrect hypoglycemia\nManage cardiac arrhythmias\nManage myocardial ischemia\nPrimary stroke prevention refers to the treatment of individuals with no previous history of stroke. Measures may include use of the following:\nPlatelet antiaggregants\nLifestyle interventions (eg, smoking cessation, alcohol moderation)\nSecondary prevention refers to the treatment of individuals who have already had a stroke. Measures may include use of the following:\nAntihypertensives\nSee Treatment and Medication for more detail.\nAcute ischemic stroke (AIS) is characterized by the sudden loss of blood circulation to an area of the brain, typically in a vascular territory, resulting in a corresponding loss of neurologic function. Also previously called cerebrovascular accident (CVA) or stroke syndrome, stroke is a nonspecific state of brain injury with neuronal dysfunction that has several pathophysiologic causes. Strokes can be divided into 2 types: hemorrhagic or ischemic. Acute ischemic stroke is caused by thrombotic or embolic occlusion of a cerebral artery. (See the image below.)\nNearly 800,000 people suffer strokes each year in the United States; 82–92% of these strokes are ischemic. Stroke is the fifth leading cause of adult death and disability, resulting in over $72 billion in annual cost. [4] Between 2012 and 2030, total direct medical stroke-related costs are projected to triple, to $184.1 billion, with the majority of the projected increase in costs arising from those 65 to 79 years of age. [5]\nIschemic and hemorrhagic stroke cannot be reliably differentiated on the basis of clinical examination findings alone. Further evaluation, especially with brain imaging tests (ie, computed tomography [CT] scanning or magnetic resonance imaging [MRI]), is required. (See Workup.)\nStroke categories\nThe system of categorizing stroke developed in the multicenter Trial of ORG 10172 in Acute Stroke Treatment (TOAST) divides ischemic strokes into the following 3 major subtypes: [2]\nLarge-artery\nSmall-vessel, or lacunar\nCardioembolic infarction\nLarge-artery infarctions often involve thrombotic in situ occlusions on atherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches; however, large-artery infarctions may also be cardioembolic.\nCardiogenic emboli are a common source of recurrent stroke. They may account for up to 20% of acute strokes and have been reported to have the highest 1-month mortality. [6] (See Pathophysiology.)\nSmall vessel or lacunar strokes are associated with small focal areas of ischemia due to obstruction of single small vessels, typically in deep penetrating arteries, that generate a specific vascular pathology.\nIn many patients the exact etiology of their stroke is not identified and these are classified as cryptogenic strokes.\nRecanalization strategies, including intravenous recombinant tissue-type plasminogen activator (alteplase or rt-PA) and intra-arterial approaches, attempt to establish revascularization so that cells within the ischemic penumbra (a metabolically active region, peripheral to the ischemic area, where blood flow is reduced and the cells are potentially viable) can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly.\nThe US Food and Drug Administration (FDA) has approved the use of rt-PA in patients who meet criteria set forth by the National Institute of Neurologic Disorders and Stroke (NINDS). In particular, rt-PA must be given within 3 hours of stroke onset and only after CT scanning has ruled out hemorrhagic stroke.\nOn the basis of recent European data, the American Heart Association and American Stroke Association recommended expanding the window of treatment from 3 hours to 4.5 hours, with more stringent exclusion criteria for the later period (see Treatment). The FDA has not approved rt-PA for this expanded indication, but this has become the community standard in many institutions.\nOther aspects of treatment for acute ischemic stroke include the following:\nOptimization of physiologic parameters and prevention of neurologic complications\nSupplemental oxygen as required (> 94% SaO2)\nOptimal blood pressure control (with consideration for reperfusion therapies)\nPrevention of hyperthermia\nSee also Hemorrhagic Stroke.\nThe brain is the most metabolically active organ in the body. While representing only 2% of the body's mass, it requires 15–20% of the total resting cardiac output to provide the necessary glucose and oxygen for its metabolism.\nKnowledge of cerebrovascular arterial anatomy and the territories supplied by the cerebral arteries is useful in determining which vessels are involved in acute stroke. Atypical patterns of brain ischemia that do not conform to specific vascular distributions may indicate a diagnosis other than ischemic stroke, such as venous infarction.\nArterial distributions\nIn a simplified model, the cerebral hemispheres are supplied by 3 paired major arteries, specifically, the anterior, middle, and posterior cerebral arteries.\nThe anterior and middle cerebral arteries carry the anterior circulation and arise from the supraclinoid internal carotid arteries. The anterior cerebral artery (ACA) supplies the medial portion of the frontal and parietal lobes and anterior portions of basal ganglia and anterior internal capsule. (See the image below.)\nLateral view of a cerebral angiogram illustrates the branches of the anterior cerebral artery (ACA) and Sylvian triangle. The pericallosal artery has been described to arise distal to the anterior communicating artery or distal to the origin of the callosomarginal branch of the ACA. The segmental anatomy of the ACA has been described as follows: the A1 segment extends from the internal carotid artery (ICA) bifurcation to the anterior communicating artery; A2 extends to the junction of the rostrum and genu of the corpus callosum; A3 extends into the bend of the genu of the corpus callosum; A4 and A5 extend posteriorly above the callosal body and superior portion of the splenium. The Sylvian triangle overlies the opercular branches of the middle cerebral artery (MCA), with the apex representing the Sylvian point.\nThe middle cerebral artery (MCA) supplies the lateral portions of the frontal and parietal lobes, as well as the anterior and lateral portions of the temporal lobes, and gives rise to perforating branches to the globus pallidus, putamen, and internal capsule. The MCA is the dominant source of vascular supply to the hemispheres. (See the images below.)\nThe supratentorial vascular territories of the major cerebral arteries are demonstrated superimposed on axial (left) and coronal (right) T2-weighted images through the level of the basal ganglia and thalami. The middle cerebral artery (MCA; red) supplies the lateral aspects of the hemispheres, including the lateral frontal, parietal, and anterior temporal lobes; insula; and basal ganglia. The anterior cerebral artery (ACA; blue) supplies the medial frontal and parietal lobes. The posterior cerebral artery (PCA; green) supplies the thalami and occipital and inferior temporal lobes. The anterior choroidal artery (yellow) supplies the posterior limb of the internal capsule and part of the hippocampus extending to the anterior and superior surface of the occipital horn of the lateral ventricle.\nFrontal view of a cerebral angiogram with selective injection of the left internal carotid artery (ICA) illustrates the anterior circulation. The anterior cerebral artery (ACA) consists of the A1 segment proximal to the anterior communicating artery, with the A2 segment distal to it. The middle cerebral artery (MCA) can be divided into 4 segments: the M1 (horizontal segment) extends to the anterior basal portion of the insular cortex (the limen insulae) and gives off lateral lenticulostriate branches, the M2 (insular segment), M3 (opercular branches), and M4 (distal cortical branches on the lateral hemispheric convexities).\nThe posterior cerebral arteries arise from the basilar artery and carry the posterior circulation. The posterior cerebral artery (PCA) gives rise to perforating branches that supply the thalami and brainstem and the cortical branches to the posterior and medial temporal lobes and occipital lobes. (See Table 1, below.)\nThe cerebellar hemispheres are supplied as follows:\nInferiorly by the posterior inferior cerebellar artery (PICA), arising from the vertebral artery (see the image below)\nFrontal projection from a right vertebral artery angiogram illustrates the posterior circulation. The vertebral arteries join to form the basilar artery. The posterior inferior cerebellar arteries (PICAs) arise from the distal vertebral arteries. The anterior inferior cerebellar arteries (AICAs) arise from the proximal basilar artery. The superior cerebellar arteries (SCAs) arise distally from the basilar artery prior to its bifurcation into the posterior cerebral arteries (PCAs).\nSuperiorly by the superior cerebellar artery\nAnterolaterally by the anterior inferior cerebellar artery (AICA), from the basilar artery\nTable 1. Vascular Supply to the Brain (Open Table in a new window)\nVASCULAR TERRITORY\nStructures Supplied\nAnterior Circulation (Carotid)\nAnterior Cerebral Artery\nCortical branches: medial frontal and parietal lobe\nMedial lenticulostriate branches: caudate head, globus pallidus, anterior limb of internal capsule\nMiddle Cerebral Artery\nCortical branches: lateral frontal and parietal lobes, lateral and anterior temporal lobe\nLateral lenticulostriate branches: globus pallidus and putamen, internal capsule\nAnterior Choroidal Artery\nOptic tracts, medial temporal lobe, ventrolateral thalamus, corona radiata, posterior limb of the internal capsule\nPosterior Circulation (Vertebrobasilar)\nPosterior Cerebral Artery\nCortical branches: occipital lobes, medial and posterior temporal and parietal lobes\nPerforating branches: brainstem, posterior thalamus and midbrain\nPosterior Inferior Cerebellar Artery\nInferior vermis; posterior and inferior cerebellar hemispheres\nAnterior Inferior Cerebellar Artery\nAnterolateral cerebellum\nSuperior Cerebellar Artery\nSuperior vermis; superior cerebellum\nAcute ischemic strokes result from vascular occlusion secondary to thromboembolic disease (see Etiology). Ischemia causes cell hypoxia and depletion of cellular adenosine triphosphate (ATP). Without ATP, there is no longer the energy to maintain ionic gradients across the cell membrane and cell depolarization. Influx of sodium and calcium ions and passive inflow of water into the cell lead to cytotoxic edema. [7, 8, 9]\nIschemic core and penumbra\nAn acute vascular occlusion produces heterogeneous regions of ischemia in the affected vascular territory. Local blood flow is limited to any residual flow in the major arterial source plus the collateral supply, if any.\nAffected regions with cerebral blood flow of lower than 10 mL/100 g of tissue/min are referred to collectively as the core. These cells are presumed to die within minutes of stroke onset. [10]\nZones of decreased or marginal perfusion (cerebral blood flow < 25 mL/100g of tissue/min) are collectively called the ischemic penumbra. Tissue in the penumbra can remain viable for several hours because of marginal tissue perfusion. [10]\nIschemic cascade\nOn the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and membrane ion-transport systems fail. Disruption of cellular metabolism also impairs normal sodium-potassium plasma membrane pumps, producing an intracellular increase in sodium, which in turns increases intracellular water content. This cellular swelling is referred to as cytotoxic edema and occurs very early in cerebral ischemia.\nCerebral ischemia impairs the normal sodium-calcium exchange protein also found on cell plasma membranes. The resulting influx of calcium leads to the release of a number of neurotransmitters, including large quantities of glutamate, which in turn activates N-methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons.\nThese neurons then become depolarized, causing further calcium influx, further glutamate release, and local amplification of the initial ischemic insult. This massive calcium influx also activates various degradative enzymes, leading to the destruction of the cell membrane and other essential neuronal structures. [11] Free radicals, arachidonic acid, and nitric oxide are generated by this process, which leads to further neuronal damage.\nIschemia also directly results in dysfunction of the cerebral vasculature, with breakdown of the blood-brain barrier occurring within 4-6 hours after infarction. Following the barrier’s breakdown, proteins and water flood into the extracellular space, leading to vasogenic edema. This produces greater levels of brain swelling and mass effect that peak at 3–5 days and resolve over the next several weeks with resorption of water and proteins. [12, 13]\nWithin hours to days after a stroke, specific genes are activated, leading to the formation of cytokines and other factors that, in turn, cause further inflammation and microcirculatory compromise. [11] Ultimately, the ischemic penumbra is consumed by these progressive insults, coalescing with the infarcted core, often within hours of the onset of the stroke.\nInfarction results in the death of astrocytes, as well as the supporting oligodendroglial and microglial cells. The infarcted tissue eventually undergoes liquefaction necrosis and is removed by macrophages, with the development of parenchymal volume loss. A well-circumscribed region of cerebrospinal fluid–like low density, resulting from encephalomalacia and cystic change, is eventually seen. The evolution of these chronic changes may be seen in the weeks to months following the infarction. (See the images below.)\nVascular distributions: Middle cerebral artery (MCA) infarction. Noncontrast computed tomography (CT) scanning demonstrates a large acute infarction in the MCA territory involving the lateral surfaces of the left frontal, parietal, and temporal lobes, as well as the left insular and subinsular regions, with mass effect and rightward midline shift. There is sparing of the caudate head and at least part of the lentiform nucleus and internal capsule, which receive blood supply from the lateral lenticulostriate branches of the M1 segment of the MCA. Note the lack of involvement of the medial frontal lobe (anterior cerebral artery [ACA] territory), thalami, and paramedian occipital lobe (posterior cerebral artery [PCA] territory).\nVascular distributions: Anterior cerebral artery (ACA) infarction. Diffusion-weighted image on the left demonstrates high signal in the paramedian frontal and high parietal regions. The opposite diffusion-weighted image in a different patient demonstrates restricted diffusion in a larger ACA infarction involving the left paramedian frontal and posterior parietal regions. There is also infarction of the lateral temporoparietal regions bilaterally (both middle cerebral artery [MCA] distributions), greater on the left indicating multivessel involvement and suggesting emboli.\nVascular distributions: Posterior cerebral artery (PCA) infarction. The noncontrast computed tomography (CT) images demonstrate PCA distribution infarction involving the right occipital and inferomedial temporal lobes. The image on the right demonstrates additional involvement of the thalamus, also part of the PCA territory.\nVascular distributions: Anterior choroidal artery infarction. The diffusion-weighted image (left) demonstrates high signal with associated signal dropout on the apparent diffusion coefficient (ADC) map involving the posterior limb of the internal capsule. This is the typical distribution of the anterior choroidal artery, the last branch of the internal carotid artery (ICA) before bifurcating into the anterior and middle cerebral arteries. The anterior choroidal artery may also arise from the middle cerebral artery (MCA).\nHemorrhagic transformation of ischemic stroke\nHemorrhagic transformation represents the conversion of an ischemic infarction into an area of hemorrhage. This is estimated to occur in 5% of uncomplicated ischemic strokes, in the absence of fibrinolytic treatment. Hemorrhagic transformation is not always associated with neurologic decline, with the conversion ranging from the development of small petechial hemorrhages to the formation of hematomas that produce neurologic decline and may necessitate surgical evacuation or decompressive hemicraniectomy.\nProposed mechanisms for hemorrhagic transformation include reperfusion of ischemically injured tissue, either from recanalization of an occluded vessel or from collateral blood supply to the ischemic territory or disruption of the blood-brain barrier. With disruption of the blood-brain barrier, red blood cells extravasate from the weakened capillary bed, producing petechial hemorrhage or more frank intraparenchymal hematoma. [7, 14, 15]\nSpontaneous hemorrhagic transformation of an ischemic infarct occurs within 2–14 days postictus, usually within the first week. It is more commonly seen following cardioembolic strokes and is more likely to occur with larger infarct volumes. [3, 7, 16] Hemorrhagic transformation is also more likely following administration of rt-PA in patients whose baseline noncontrast CT (NCCT) scans demonstrate areas of hypodensity. [17, 18, 19]\nPoststroke cerebral edema and seizures\nAlthough clinically significant cerebral edema can occur after anterior circulation ischemic stroke, it is thought to be somewhat rare (10-20%). [1] Edema and herniation are the most common causes of early death in patients with hemispheric stroke.\nSeizures occur in 2-23% of patients within the first days after ischemic stroke. [1] A fraction of patients who have experienced stroke develop chronic seizure disorders.\nIschemic strokes result from events that limit or stop blood flow, such as extracranial or intracranial thrombotic embolism, thrombosis in situ, or relative hypoperfusion. As blood flow decreases, neurons cease functioning. Although a range of thresholds has been described, irreversible neuronal ischemia and injury is generally thought to begin at blood flow rates of less than 18 mL/100 g of tissue/min, with cell death occurring rapidly at rates below 10 mL/100 g of tissue/min\nRisk factors for ischemic stroke include modifiable and nonmodifiable conditions. Identification of risk factors in each patient can uncover clues to the cause of the stroke and the most appropriate treatment and secondary prevention plan.\nNonmodifiable risk factors include the following (although there are likely many others):\nHistory of migraine headaches [20]\nFibromuscular dysplasia\nHeredity: Family history of stroke or transient ischemic attacks (TIAs)\nIn a prospective study of 27,860 women aged 45 years or older who were participating in the Women's Health Study, Kurth et al found that migraine with aura was a strong risk factor for any type of stroke. The adjusted incidence of this risk factor per 1000 women per year was similar to those of other known risk factors, including systolic blood pressure 180 mm Hg or higher, body mass index 35 kg/m2 or greater, history of diabetes, family history of myocardial infarction, and smoking. [21]\nFor migraine with aura, the total incidence of stroke in the study was 4.3 per 1000 women per year, the incidence of ischemic stroke was 3.4 per 1000 per year, and the incidence of hemorrhagic stroke was 0.8 per 1000 per year.\nModifiable risk factors include the following: [22]\nHypertension (the most important)\nCardiac disease: Atrial fibrillation, valvular disease, heart failure, mitral stenosis, structural anomalies allowing right-to-left shunting (eg, patent foramen ovale), and atrial and ventricular enlargement\nTransient ischemic attacks (TIA)\nHyperhomocystinemia\nLifestyle issues: Excessive alcohol intake, tobacco use, illicit drug use, physical inactivity [23]\nOral contraceptive use/postmenopausal hormone use\nIn 2014, the American Heart Association and the American Stroke Association issued guidelines for the reduction of stroke risk specifically in women. These gender-specific recommendations include the following: [24, 25]\nA stroke risk score should be developed specifically for women\nWomen with a history of high blood pressure before pregnancy should be considered for low-dose aspirin and/or calcium supplement treatment to reduce the risk of preeclampsia\nBlood pressure medication may be considered for pregnant women with moderately high blood pressure (150-159 mmHg/100-109 mmHg), and pregnant women with severe high blood pressure (160/110 mmHg or above) should be treated\nWomen should be screened for high blood pressure before they start using birth control pills because of an increased risk of stroke\nWomen with migraine headaches with aura should be encouraged to quit smoking to reduce the risk of stroke\nWomen over age 75 should be screened for atrial fibrillation\nGenetic and inflammatory mechanisms\nEvidence continues to accumulate that inflammation and genetic factors have important roles in the development of atherosclerosis and, specifically, in stroke. According to the current paradigm, atherosclerosis is not a bland cholesterol storage disease, as previously thought, but a dynamic, chronic, inflammatory condition caused by a response to endothelial injury.\nTraditional risk factors, such as oxidized low-density lipoprotein (LDL) cholesterol and smoking, contribute to this injury. It has been suggested, however, that infections may also contribute to endothelial injury and atherosclerosis.\nHost genetic factors, moreover, may modify the response to these environmental challenges, although inherited risk for stroke is likely multigenic. Even so, specific single-gene disorders with stroke as a component of the phenotype demonstrate the potency of genetics in determining stroke risk.\nA number of genes are known to increase susceptibility to ischemic stroke. Mutations to the F2 and F5 genes are relatively common in the general population and increase the risk of thrombosis. Mutations in the following genes also are known to increase the risk of stroke:\nNOS3: A nitric oxide synthetase gene; involved in vascular relaxation [26]\nALOX5AP: Involved in the metabolism of arachidonic acid [27]\nPRKCH: Involved in major signal transduction systems [28]\nHyperhomocysteinemia and homocystinuria\nHyperhomocysteinemia is implicated in the pathogenesis of ischemic stroke. The most common concern is mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene. In many populations, the mutant allele frequency reaches polymorphic proportions, and the risk factor for cerebrovascular disease is related to the serum level of homocysteine. Furthermore, in persons who are compound heterozygotes for MTHFR mutation, if elevated homocysteine is found it can be lowered with oral folic acid therapy.\nIn addition, hyperhomocysteinemia can be seen in cystathione beta synthetase (CBS) deficiency, which is generally referred to as homocystinuria. This disorder is inherited in an autosomal recessive manner. Symptoms usually manifest early in life. Patients have a marfanoid habitus, ectopia lentis, and myopia and generally have intellectual disability. [29]\nThromboembolic events are the most common cause of death for patients with homocystinuria and may be of any type, including myocardial infarction. The risk of having a vascular event in homocystinuria is 50% by age 30. [30] It was previously suggested that persons who are heterozygous for mutations in the CBS gene may have an increased risk of cerebrovascular disease as well, but several more recent studies on this subject failed to replicate this finding.\nAmyloid angiopathies\nAmyloid angiopathies are also known to increase risk for stroke and dementia. Mutations in the CST3 gene are causative and are inherited in an autosomal dominant manner. Sufferers will have diffuse deposition of amyloid, including in the brain. The onset of symptoms is typically in the third or fourth decade of life, with death occurring before age 60 years. These angiopathies appear to be most common in the Icelandic population. [31]\nCerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy (CADASIL), is caused by mutations in the NOTCH3 gene. It affects the small arteries of the brain. Strokelike episodes typically occur at a mean age of 46 years, with an age range of 19–67 years. White-matter changes in the brain are typically evident by young adulthood and progress over time. [32]\nMigraine headaches occur in 30–40% of people with CADASIL. Approximately 60% of symptomatic individuals have cognitive deficits, which can start as early as age 35 years, and many develop multi-infarct dementia. [33]\nOther mutations\nGenome-wide association studies have revealed additional loci that are commonly associated with ischemic stroke. Early onset ischemic stroke has been found to be associated with 2 single-nucleotide polymorphisms on 2q23.3. [34]\nLarge-vessel stroke has been associated with variations in HDAC9, PITX2, and ZFHX3. [35] HDAC9 is located on7p21.1, while PITX2 and ZFHX3 are located on 9p21. It is of note that the 9p21 locus has also been associated with cardiovascular disease.\nA polymorphism at 2q36.3 was found in which adenosine substitution conferred a lower risk of ischemic stroke in an additive fashion. [36] An additional study suggested an association between ischemic stroke and a locus on 12p13. [37]\nFor more information, see Genetic and Inflammatory Mechanisms in Stroke. In addition, complete information on the following metabolic diseases and stroke can be found in the following main articles:\nMethylmalonic Acidemia\nHomocystinuria/Homocysteinemia\nMELAS Syndrome\nHyperglycemia and Hypoglycemia in Stroke\nLarge-artery occlusion\nLarge-artery occlusion typically results from embolization of atherosclerotic debris originating from the common or internal carotid arteries or from a cardiac source. A smaller number of large-artery occlusions may arise from plaque ulceration and in situ thrombosis. Large-vessel ischemic strokes more commonly affect the MCA territory, with the ACA territory affected to a lesser degree. (See the images below.)\nNoncontrast computed tomography (CT) scan in a 52-year-old man with a history of worsening right-sided weakness and aphasia demonstrates diffuse hypodensity and sulcal effacement with mass effect involving the left anterior and middle cerebral artery territories consistent with acute infarction. There are scattered curvilinear areas of hyperdensity noted suggestive of developing petechial hemorrhage in this large area of infarction.\nMagnetic resonance angiogram (MRA) in a 52-year-old man demonstrates occlusion of the left precavernous supraclinoid internal carotid artery (ICA, red circle), occlusion or high-grade stenosis of the distal middle cerebral artery (MCA) trunk and attenuation of multiple M2 branches. The diffusion-weighted image (right) demonstrates high signal confirmed to be true restricted diffusion on the apparent diffusion coefficient (ADC) map consistent with acute infarction.\nLacunar strokes\nLacunar strokes represent 13–20% of all ischemic strokes. They result from occlusion of the penetrating branches of the MCA, the lenticulostriate arteries, or the penetrating branches of the circle of Willis, vertebral artery, or basilar artery. The great majority of lacunar strokes are related to hypertension. (See the image below.)\nAxial noncontrast computed tomography (CT) scan demonstrates a focal area of hypodensity in the left posterior limb of the internal capsule in a 60-year-old man with acute onset of right-sided weakness. The lesion demonstrates high signal on the fluid-attenuated inversion recovery (FLAIR) sequence (middle image) and diffusion-weighted magnetic resonance imaging (MRI) scan (right image), with low signal on the apparent diffusion coefficient (ADC) maps indicating an acute lacunar infarction. Lacunar infarcts are typically no more than 1.5 cm in size and can occur in the deep gray matter structures, corona radiata, brainstem, and cerebellum.\nCauses of lacunar infarcts include the following:\nMicroatheroma\nLipohyalinosis\nFibrinoid necrosis secondary to hypertension or vasculitis\nHyaline arteriosclerosis\nAmyloid angiopathy\nMicroemboli\nEmbolic strokes\nCardiogenic emboli may account for up to 20% of acute strokes. Emboli may arise from the heart, the extracranial arteries, including the aortic arch or, rarely, the right-sided circulation (paradoxical emboli) with subsequent passage through a patent foramen ovale. [38] Sources of cardiogenic emboli include the following:\nValvular thrombi (eg, in mitral stenosis or endocarditis or from use of a prosthetic valve)\nMural thrombi (eg, in myocardial infarction, atrial fibrillation, dilated cardiomyopathy, or severe congestive heart failure)\nAtrial myxoma\nAcute myocardial infarction is associated with a 2-3% incidence of embolic strokes, of which 85% occur in the first month after the infarction. [39] Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or may show calcific emboli.\nCardioembolic strokes may be isolated, multiple and in a single hemisphere, or scattered and bilateral; the latter 2 types indicate multiple vascular distributions and are more specific for cardioembolism. Multiple and bilateral infarcts can be the result of embolic showers or recurrent emboli. Other possibilities for single and bilateral hemispheric infarctions include emboli originating from the aortic arch and diffuse thrombotic or inflammatory processes that can lead to multiple small-vessel occlusions. (See the image below.) [40, 41]\nCardioembolic stroke: Axial diffusion-weighted images demonstrate scattered foci of high signal in the subcortical and deep white matter bilaterally in a patient with a known cardiac source for embolization. An area of low signal in the left gangliocapsular region may be secondary to prior hemorrhage or subacute to chronic lacunar infarct. Recurrent strokes are most commonly secondary to cardioembolic phenomenon.\nFor more information, see Cardioembolic Stroke.\nThrombotic strokes\nThrombogenic factors may include injury to and loss of endothelial cells; this loss exposes the subendothelium and results in platelet activation by the subendothelium, activation of the clotting cascade, inhibition of fibrinolysis, and blood stasis. Thrombotic strokes are generally thought to originate on ruptured atherosclerotic plaques. Arterial stenosis can cause turbulent blood flow, which can promote thrombus formation; atherosclerosis (ie, ulcerated plaques); and platelet adherence. All cause the formation of blood clots that either embolize or occlude the artery.\nIntracranial atherosclerosis may be the cause of thrombotic stroke in patients with widespread atherosclerosis. In other patients, especially younger patients, other causes should be considered, including the following: [7, 42]\nHypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency, pregnancy)\nArterial dissections\nVasoconstriction associated with substance abuse (eg, cocaine, amphetamines)\nWatershed infarcts\nVascular watershed, or border-zone, infarctions occur at the most distal areas between arterial territories. They are believed to be secondary to embolic phenomenon or to severe hypoperfusion, as occurs, for example, in carotid occlusion or prolonged hypotension. (See the image below.) [43, 44, 45]\nMagnetic resonance imaging (MRI) scan was obtained in a 62-year-old man with hypertension and diabetes and a history of transient episodes of right-sided weakness and aphasia. The fluid-attenuated inversion recovery (FLAIR) image (left) demonstrates patchy areas of high signal arranged in a linear fashion in the deep white matter, bilaterally. This configuration is typical for deep border-zone, or watershed, infarction, in this case the anterior and posterior middle cerebral artery (MCA) watershed areas. The left-sided infarcts have corresponding low signal on the apparent diffusion coefficient (ADC) map (right), signifying acuity. An old left posterior parietal infarct is noted as well.\nFlow disturbances\nStroke symptoms can result from inadequate cerebral blood flow because of decreased blood pressure (and specifically, decreased cerebral perfusion pressure) or as a result of hematologic hyperviscosity from sickle cell disease or other hematologic illnesses, such as multiple myeloma and polycythemia vera. In these instances, cerebral injury may occur in the presence of damage to other organ systems. For more information, see Blood Dyscrasias and Stroke.\nStroke is the leading cause of disability and the fifth leading cause of death in the United States. [46, 47] Each year, approximately 795,000 people in the United States experience new (610,000 people) or recurrent (185,000 people) stroke. [4] Epidemiologic studies indicate that 82–92% of strokes in the United States are ischemic.\nAccording to the World Health Organization (WHO), 15 million people suffer stroke worldwide each year. Of these, 5 million die, and another 5 million are left permanently disabled. [48]\nRace-, sex-, and age-related demographics\nIn the United States, blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites. [49] Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent lacunar strokes and stroke at an earlier age.\nMen are at higher risk for stroke than women; white men have a stroke incidence of 62.8 per 100,000, with death being the final outcome in 26.3% of cases, while women have a stroke incidence of 59 per 100,000 and a death rate of 39.2%.\nAlthough stroke often is considered a disease of elderly persons, one third of strokes occur in persons younger than 65 years. [47] Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur.\nIn the Framingham and Rochester stroke studies, the overall mortality rate at 30 days after stroke was 28%, the mortality rate at 30 days after ischemic stroke was 19%, and the 1-year survival rate for patients with ischemic stroke was 77%. However, the prognosis after acute ischemic stroke varies greatly in individual patients, depending on the stroke severity and on the patient’s premorbid condition, age, and poststroke complications. [2]\nA study utilizing the large national Get With The Guidelines - Stroke registry found that the baseline National Institutes of Health Stroke Scale (NIHSS) score was the strongest predictor of early mortality risk, even more so than currently used mortality prediction models incorporating multiple clinical data. [50] Cardiogenic emboli are associated with the highest 1-month mortality in patients with acute stroke.\nIn late 2018, a new clinical score was developed to identify patients with a high risk of early mortality after an ischemic stroke. Researchers examined data on 77,653 ischemic stroke patients from the Austrian national stroke unit registry, who were treated between 2006 and 2017. They analyzed a comprehensive list of variables on these patients and compared characteristics in patients who died within the first 7 days after the stroke to those who survived. Multivariate analysis was then performed to ascertain which factors were increasingly associated with early stroke death. Key factors included age, stroke severity measured by the National Institutes of Health Stroke Scale (NIHSS), pre-stroke functional disability (modified Rankin Scale > 0), pre-existing heart disease, diabetes mellitus, posterior circulation stroke syndrome, and non-lacunar stroke cause. Results showed that patients with a score ≥ 10 had a 35% risk of dying within the first few days at the stroke unit. [51]\nThe presence of computed tomography (CT) scan evidence of infarction early in presentation has been associated with poor outcome and with an increased propensity for hemorrhagic transformation after fibrinolytic therapy (see Pathophysiology). [3, 52, 53] Hemorrhagic transformation is estimated to occur in 5% of uncomplicated ischemic strokes in the absence of fibrinolytic therapy, although it is not always associated with neurologic decline. Indeed, hemorrhagic transformation ranges from the development of small petechial hemorrhages to the formation of hematomas requiring evacuation.\nAcute ischemic stroke has been associated with acute cardiac dysfunction and arrhythmia, which then correlate with worse functional outcome and morbidity at 3 months. Data suggest that severe hyperglycemia is independently associated with poor outcome and reduced reperfusion in fibrinolysis, as well as extension of the infarcted territory. [54, 55, 56]\nIn stroke survivors from the Framingham Heart Study, 31% needed help caring for themselves, 20% needed help when walking, and 71% had impaired vocational capacity in long-term follow-up. 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Avenues to reach an audience with a higher stroke risk could include local churches, employers, and senior organizations to promote stroke awareness.\nThe American Stroke Association (ASA) advises the public to be aware of the symptoms of stroke that are easily recognized, including the sudden onset of any of the following, and to call 911 immediately:\nNumbness or weakness of face, arm, or leg, especially on 1 side of the body\nDifficulty in speaking or understanding\nDeterioration of vision in 1 or both eyes\nDifficulty in walking, dizziness, and loss of balance or coordination\nSevere headache with no known cause\nIn the spring of 2013, the ASA launched a stroke public education campaign that uses the acronym FAST to teach the warning signs of stroke and the importance of calling 911, as follows:\nF: Face drooping\nA: Arm weakness\nS: Speech difficulty\nT: Time to call 911\nFor patient education information, see the Stroke Health Center and the Brain and Nervous System Health Center, as well as Stroke, Transient Ischemic Attack (TIA, Mini-stroke),and Stroke-Related Dementia.\n[Guideline] Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, et al. 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[Medline].\n[Guideline] Hughes S. New AHA/ASA Stroke Secondary Prevention Guidelines. Medscape Medical News. May 2 2014. [Full Text].\n[Guideline] Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2014 May 1. [Medline]. [Full Text].\nGeeganage CM, Diener HC, Algra A, Chen C, Topol EJ, Dengler R, et al. Dual or mono antiplatelet therapy for patients with acute ischemic stroke or transient ischemic attack: systematic review and meta-analysis of randomized controlled trials. Stroke. 2012 Apr. 43(4):1058-66. [Medline].\nHalkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006 May 20. 367(9523):1665-73. 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Accessed: November 7, 2016.\nAxial noncontrast computed tomography (NCCT) scan demonstrates diffuse hypodensity in the right lentiform nucleus with mass effect upon the frontal horn of the right lateral ventricle in a 70-year-old woman with a history of left-sided weakness for several hours.\nMagnetic resonance imaging (MRI) scan in a 70-year-old woman with a history of left-sided weakness for several hours. An axial T2 fluid-attenuated inversion recovery (FLAIR) image (left) demonstrates high signal in the lentiform nucleus with mass effect. The axial diffusion-weighted image (middle) demonstrates high signal in the same area, with corresponding low signal on the apparent diffusion coefficient (ADC) maps, consistent with true restricted diffusion and an acute infarction. Maximum intensity projection from a 3-dimensional (3-D) time-of-flight magnetic resonance angiogram (MRA, right) demonstrates occlusion of the distal middle cerebral artery (MCA) trunk (red circle).\nA 48-year-old man presented with acute left-sided hemiplegia, facial palsy, and right-sided gaze preference. Angiogram with selective injection of the right internal carotid artery demonstrates occlusion of the M1 segment of the right middle cerebral artery (MCA) and A2 segment of the right anterior cerebral artery (ACA; images courtesy of Concentric Medical).\nFollow-up imaging after mechanical embolectomy in 48-year-old man with acute left-sided hemiplegia, facial palsy, and right-sided gaze preference demonstrates complete recanalization of the right middle cerebral artery (MCA) and partial recanalization of the right A2 segment (images courtesy of Concentric Medical).\nCerebral angiogram performed approximately 4.5 hours after symptom onset in a 31-year-old man demonstrates an occlusion of the distal basilar artery (images courtesy of Concentric Medical).\nImage on the left demonstrates deployment of a clot retrieval device (older generation device) in a 31-year-old man. Followup angiogram after embolectomy demonstrates recanalization of the distal basilar artery with filling of the superior cerebellar arteries and posterior cerebral arteries. The patient had complete resolution of symptoms following embolectomy (images courtesy of Concentric Medical).\nRegions of interest are selected for arterial and venous input (image on left) for dynamic susceptibility-weighted perfusion magnetic resonance imaging (MRI). Signal-time curves (image on right) obtained from these regions of interest demonstrate transient signal drop following the administration of intravenous contrast. The information obtained from the dynamic parenchymal signal changes postcontrast is used to generate maps of different perfusion parameters.\nTable 1. Vascular Supply to the Brain\nTable 2. National Institutes of Health Stroke Scale\nlevel of consciousness (LOC)\nDrowsy\nStuporous\nLOC questions (month, age)\nAnswers both correctly\nAnswers 1 correctly\nIncorrect on both\nLOC commands (open and close eyes,\ngrip and release nonparetic hand)\nObeys both correctly\nObeys 1 correctly\nBest gaze (follow finger)\nPartial gaze palsy\nForced deviation\nBest visual (visual fields)\nNo visual loss\nPartial hemianopia\nComplete hemianopia\nBilateral hemianopia\nFacial palsy (show teeth, raise brows,\nsqueeze eyes shut)\nMotor arm left* (raise 90°, hold 10 seconds)\n(preferably with the palm facing up)\nNo drift\nCannot resist gravity\nNo effort against gravity\nMotor arm right* (raise 90°, hold 10 seconds)\nMotor leg left* (raise 30°, hold 5 seconds)\nMotor leg right* (raise 30°, hold 5 seconds)\nLimb ataxia (finger-nose, heel-shin)\nPresent in 1 limb\nPresent in 2 limbs\nSensory (pinprick to face, arm, leg)\nPartial loss\nSevere loss\nExtinction/neglect (double simultaneous testing)\nNo neglect\nPartial neglect\nComplete neglect\nDysarthria (speech clarity to \"mama,\nbaseball, huckleberry, tip-top, fifty-fifty\")\nNormal articulation\nMild to moderate dysarthria\nNear to unintelligible or worse\nBest language** (name items,\ndescribe pictures)\nNo aphasia\nMild to moderate aphasia\nSevere aphasia\n* For limbs with amputation, joint fusion, etc, score 9 and explain\n** For intubation or other physical barriers to speech, score 9 and explain. Do not add 9 to the total score. NIH Stroke Scale (PDF)\nEdward C Jauch, MD, MS, FAHA, FACEP Chief of System Research, Mission Research Institute, Mission Health; Adjunct Professor, Department of Bioengineering, Clemson University\nEdward C Jauch, MD, MS, FAHA, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Heart Association, American Medical Association, National Stroke Association, Society for Academic Emergency Medicine, South Carolina Medical Association\nDisclosure: Received grant/research funds from Genentech for site pi.\nSami Al Kasab, MD House Staff, Department of Neurology, Medical University of South Carolina College of Medicine\nSami Al Kasab, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians, American Heart Association\nBrian Stettler, MD Assistant Professor, Program Director, Emergency Medicine Residency Program, Department of Emergency Medicine, and Faculty Greater Cincinnati/Northern Kentucky Stroke Team, University of Cincinnati\nHelmi L Lutsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine; Associate Director, OHSU Stroke Center\nHelmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology, American Stroke Association\nDisclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Physician Advisory Board for Coherex Medical; National Leader and Steering Committee Clinical Trial, Bristol Myers Squibb.\nJeffrey L Arnold, MD, FACEP Chairman, Department of Emergency Medicine, Santa Clara Valley Medical Center\nJeffrey L Arnold, MD, FACEP is a member of the following medical societies: American Academy of Emergency Medicine and American College of Physicians\nJoseph U Becker, MD Fellow, Global Health and International Emergency Medicine, Stanford University School of Medicine\nJoseph U Becker, MD is a member of the following medical societies: American College of Emergency Physicians, Emergency Medicine Residents Association, Phi Beta Kappa, and Society for Academic Emergency Medicine\nSalvador Cruz-Flores, MD, MPH, FAHA, FCCM Professor of Neurology and Epidemiology, Sidney W Souers Endowed Chair, Director of Souers Stroke Institute, Cerebrovascular and Neurointensive Care Section, Director, Vascular Neurology Fellowship Training Program, Interim Chairman, Department of Neurology and Psychiatry, St Louis University School of Medicine; Director, Neuroscience Intensive Care Unit (5ICU), St Louis University Hospital\nSalvador Cruz-Flores, MD, MPH, FAHA, FCCM is a member of the following medical societies: American Academy of Hospice and Palliative Medicine, American Academy of Neurology, American College of Physicians, American Heart Association, American Society of Neuroimaging, American Stroke Association, National Stroke Association, Neurocritical Care Society, and Society of Critical Care Medicine\nDisclosure: Axio inc Honoraria Review panel membership; Roche Honoraria Review panel membership; Lilly Honoraria Review panel membership; Biotronik Honoraria Review panel membership\nJ Stephen Huff, MD Associate Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine\nJ Stephen Huff, MD is a member of the following medical societies: American Academy of Emergency Medicine, American Academy of Neurology, American College of Emergency Physicians, and Society for Academic Emergency Medicine\nRichard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University of Buffalo State University of New York School of Medicine and Biomedical Sciences\nRichard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine\nDisclosure: Medscape Salary Employment\nCharles R Wira III, MD Assistant Professor, Section of Emergency Medicine, Yale University School of Medicine; DEM Liaison and Attending Physician, Yale Acute Stroke Service, Department of Neurology, Yale-New Haven Hospital\nCharles R Wira III, MD is a member of the following medical societies: American College of Emergency Physicians, American Heart Association, American Stroke Association, Neurocritical Care Society, Society for Academic Emergency Medicine, and Society of Critical Care Medicine\nencoded search term (Ischemic Stroke) and Ischemic Stroke\nVertebrobasilar Stroke\nLaryngeal Manifestations of Stroke\nGenetic and Inflammatory Mechanisms in Stroke\nMagnetic Resonance Imaging in Acute Stroke\nMotor Recovery In Stroke\nScore Aids Treatment Decision in Mild Large-Vessel Stroke\nJan 15, 2021 This Week in Cardiology Podcast\nExercise at Midlife Linked to Better Brain Health in Late Life\nParkinsonism: Not Just a Motor Problem\nAccording to Neurologists\nCould RAS Dysfunction Explain COVID's Effects?\nInsomnia With Short Sleep Linked to Cognitive Impairment\nThe Cat’s Meow: Felines as Seizure Detectors?\nNeurologist as Patient: A Missed Diagnosis, Poor Communication, and Incompetent Care Could Have Led to Quadriplegia\nCannabis for Pain? An Expert's Guidance\nFDA Welcomes Sotagliflozin Data for Heart Failure in Diabetes\nWhat Is the Impact of the Current Pandemic on Stroke Care? 0.5 CME / CE / ABIM MOC Credits Clinical Review\nWhat Is the Impact of the Current Pandemic on Stroke Care?\nA 75-Year-Old Man With Left-Sided Facial Droop: Osmosis USMLE Study Question\nDiseases & Conditions Ischemic Stroke"

ERROR: type should be string, got "https://profreg.medscape.com/px/getpracticeprofile.do?method=getProfessionalProfile&urlCache=aHR0cHM6Ly9lbWVkaWNpbmUuc3RhZ2luZy5tZWRzY2FwZS5jb20vYXJ0aWNsZS84MDM2ODMtb3ZlcnZpZXc=\nReye Syndrome\nAuthor: Debra L Weiner, MD, PhD; Chief Editor: Kirsten A Bechtel, MD more...\nSections Reye Syndrome\nInvasive Procedures\nStage-Specific Management\nHyperammonemia Treatment Agents\nAlkalinizing Agents\nReye syndrome is characterized by acute noninflammatory encephalopathy and fatty degenerative liver failure. The syndrome was first described in 1963 in Australia by RDK Reye and described a few months later in the United States by GM Johnson. [17, 14] Cases with identical manifestations were described as early as 1929. In the United States, Reye syndrome became a reportable disease in 1973. Peak incidence was reported in 1979-80. [7, 8, 13]\nReye syndrome typically occurs after a viral illness, particularly an upper respiratory tract infection, influenza, varicella, or gastroenteritis, and is associated with the use of aspirin during the illness. A dramatic decrease in the use of aspirin among children, in combination with the identification of medication reactions, toxins, and inborn errors of metabolism (IEMs) that present with Reye syndrome–like manifestations, have made the diagnosis of Reye syndrome exceedingly rare.\nWith the recognition that Reye syndrome is rare, this condition should be considered in the differential diagnosis in any child with vomiting and altered mental status and classic laboratory findings. A high index of suspicion is essential. Given that manifestations of Reye syndrome are not unique to Reye syndrome but also are seen in a growing list of conditions, and given that no test is specific for Reye syndrome, the diagnosis must be one of exclusion.\nAll children with manifestations suggestive of Reye syndrome should be tested for IEM. Early recognition and treatment of Reye and Reye-like syndromes, including presumptive treatment for possible IEM (See Inborn Errors of Metabolism) is essential to prevent death and optimize the likelihood of recovery without neurologic impairment.\nSome have suggested the term Reye syndrome or Reye-like syndrome should be used to describe clinical manifestations of diseases states regardless of etiology, while causes still without a known etiology after diagnostic workup should be referred to as Reye disease.\nThe pathogenesis of Reye syndrome, while not precisely elucidated, appears to involve mitochondrial injury resulting in dysfunction that disrupts oxidative phosphorylation and fatty-acid beta-oxidation in a virus-infected, sensitized host potentially with an underlying occult inborn error of fatty acid oxidation, urea cycle or mitochondrial disorder. [2, 16] The host has usually been exposed to mitochondrial toxins, most commonly salicylates (>80% of cases).\nHistologic changes include cytoplasmic fatty vacuolization in hepatocytes, astrocyte edema and loss of neurons in the brain, and edema and fatty degeneration of the proximal lobules in the kidneys. All cells have pleomorphic, swollen mitochondria that are reduced in number, along with glycogen depletion and minimal tissue inflammation. Hepatic mitochondrial dysfunction results in hyperammonemia, which is thought to induce astrocyte edema, resulting in cerebral edema and increased intracranial pressure (ICP).\nInfluenza virus types A and B and varicella-zoster virus are the pathogens most commonly associated with Reye syndrome. Other pathogens include parainfluenza virus, adenovirus, coxsackievirus, measles, cytomegalovirus, Epstein-Barr virus, HIV, retrovirus, hepatitis virus types A and B, mycoplasma, chlamydia, pertussis, shigella, salmonella, and polio. Reye has occurred after immunization with live viral vaccines.\nThe association of Reye syndrome with salicylates, particularly aspirin, was demonstrated in several epidemiologic studies around the world. Less than 0.1% of children who took aspirin developed Reye syndrome, but more than 80% of patients diagnosed with Reye syndrome had taken aspirin in the past 3 weeks. A causal relation between Reye syndrome and salicylates has not been definitively established and has been questioned on the basis of biases and limitations in the studies, [1] but recommendations by government health agencies that children not be treated with salicylates led to an immediate and dramatic decrease in the incidence of Reye syndrome.\nResults of in vitro studies are contradictory on impact of aspirin on beta-oxidation metabolism. One study demonstrated that salicylates decrease beta-oxidation of the long-chain fatty acid palmitate by cultured fibroblasts from children who recovered from Reye syndrome as compared with control subjects. [2] Another study showed that in two different cell lines, aspirin increased mitochondrial long-chain fatty acid oxidation, did not change oxidation of medium chain fatty acids, and inhibited peroxisomal fatty acid oxidation, which suggest that aspirin impairs long-chain fatty acid transport into mitochondria. [18] Some have postulated that salicylates stimulate the expression of inducible nitric oxide synthase (iNOS) because of the findings of iNOS stimulation in African children with fatal malaria, a disease that causes symptoms similar to those of Reye syndrome and is often treated with aspirin.\nRecognition of the structural similarity between aspirin metabolites and enzyme substrates for the mitochondrial trifunctional enzyme important in beta-oxidation led to identification of the long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) component of the enzyme as the target of salicylate inhibition. [3] Absence of inhibition of beta-oxidation by salicylates in fibroblasts from patients with LCHAD deficiency substantiated the finding.\nOther agents\nAcetaminophen, outdated tetracycline, valproic acid, warfarin, zidovudine didanosine, and some neoplastic drugs have been associated with Reye syndrome or Reye-like syndrome. Nonsteroidal anti-inflammatory drugs, including sodium diclofenac and mefenamic acid, are thought to produce or worsen Reye syndrome. An association with antiemetics, such as phenothiazines, has been postulated but not substantiated. An association with acetaminophen was reported but has been refuted, although there may be a synergistic effect of acetaminophen and salicylates. [15]\nReye syndrome or Reye-like syndrome may also be associated with insecticides; herbicides; aflatoxins; isopropyl alcohol; paint; paint thinner; margosa (neem) oil; hepatotoxic mushrooms; hypoglycin in ackee fruit (Jamaican vomiting sickness); and herbal medications with atractyloside, a diterpenoid glycoside found in the extracts of the tuber of Callilepis laureola (impila poisoning). Bacillus cereus cereulide toxin has also been reported as producing Reye syndrome.\nIEMs that produce Reye-like syndromes include fatty-acid oxidation defects, particularly medium-chain acyl dehydrogenase (MCAD) and long-chain acyl dehydrogenase deficiency (LCAD) inherited and acquired forms, urea-cycle defects, amino and organic acidopathies, primary carnitine deficiency, and disorders of carbohydrate metabolism. Undoubtedly, other IEMs that cause Reye-like syndrome will be identified.\nThe percentage of patients with a previous diagnosis of Reye syndrome is 0.4%. The percentage of patients who have a sibling with a Reye syndrome history is 2.9%. It is likely that at least of some of these patients had an IEM rather than Reye syndrome.\nIEMs may account for the heterogeneity of disease manifestations in patients younger than 5 years who have received a diagnosis of Reye syndrome, especially those younger than 1 year. The possibility that IEMs are more likely than true Reye syndrome in patients younger than 5 years may also explain why decreases in salicylate use and decreases in the incidence of Reye syndrome have been greatest in patients older than 5 years.\nIEM is suggested by recurrence of symptoms, precipitating factors, including prolonged fasting, changes in diet, decompensation out of proportion to intercurrent illnesses, failure to thrive, neurologic abnormalities, neurologic dysfunction, and family members with similar symptoms and/or unexplained infant deaths.\nUnited States statistics\nIn the United States, national surveillance for Reye syndrome began in 1973. It is believed that before the 1970s, most of the cases that met the criteria for Reye syndrome were diagnosed as encephalitis or drug intoxication.\nThe peak annual incidence of 555 cases reported to the Centers for Disease Control and Prevention (CDC) was in 1979-1980. Between December 1, 1980, and November 30, 1997, 1207 cases of Reye syndrome in patients younger than 18 years were reported. [4] During that period, the incidence was 0.15-0.88 cases per 100,000 children per year and as high as 6 cases per 100,000 during regional outbreaks of influenza.\nCases of Reye syndrome declined in number after 1980, when the government began issuing warnings about the association between this syndrome and aspirin. Whereas an average of 100 cases per year were reported in 1985 and 1986, the maximum number of cases reported annually between 1987 and 1993 was 36, with a range of 0.03-0.06 cases per 100,000 per year. Since 1994, 2 or fewer cases have been reported every year. While Reye syndrome reporting to CDC is no longer mandated, many local/state health boards continue to require reporting.\nThe dramatic decrease in the frequency of Reye syndrome since the 1980s is largely attributable to reduced aspirin use in children, as well as to discoveries of and advances in the diagnosis of inborn errors of metabolism (IEMs) and identification of toxins and drugs capable of producing symptoms that mimic Reye syndrome. The decrease may also be partially attributable to overreporting of cases during the peak years that did not fully meet criteria and underreporting of cases in subsequent years by physicians who did not consider the diagnosis.\nSeasonal occurrence initially peaked from December to April, which correlated with the peak occurrence of viral respiratory infections, particularly influenza. Since 1990, the seasonal variation has been less pronounced than was suggested by this initial observation.\nInternational statistics\nIn the United Kingdom, 597 cases were reported between 1981 and 1996. After warnings of the association between Reye syndrome and aspirin were issued in 1986, the incidence of Reye syndrome decreased substantially, from a high of 0.63 per 100,000 children younger than 12 years in 1983-1984 to 0.11 cases per 100,000 in 1990-1991. Of the 597 cases, 155 were later reclassified, 76 of them as involving an IEM. [5] Similar rates have been reported from other countries.\nAge-, sex-, and race-related demographics\nBased on US CDC surveillance statistics for 1980-1997 for patients younger than 18 years, 1207 cases were reported in the United States. [4] Incidence peaks between age 5 and 14 years (median, 6 years; mean, 7 years); 13.5% were younger than 1 year. Reye syndrome rarely occurs in newborns or in children older than 18 years. Reye syndrome is equally distributed between the sexes. The racial distribution of Reye syndrome is 93% white and 5% African American, with the remaining percentage Asian, American Indian, and Native Alaskan. Of those younger than 1 year, 67% were African American and 12% were white.\nThe mortality rate has decreased from 50% to less than 20% as a result of early diagnosis, recognition of mild cases, and aggressive therapy. The 1980-1997 case review reports a mortality rate of 31.3%, 42.8% in those younger than 5 years and 24.2% in those older than 5 years, with a relative risk of 1.8% (95% confidence interval [CI], 1.5-2.1%). Decreased mortality also likely reflects an increase in diagnosis of inborn errors of metabolism (IEMs), which is critical for life-saving treatment of disease-specific metabolic derangements. Death is usually due to cerebral edema or increased intracranial pressure (ICP), but it may be due to myocardial dysfunction, cardiovascular collapse, respiratory failure, renal failure, gastrointestinal (GI) bleeding, status epilepticus, or sepsis.\nIncreased risk of mortality is associated with the following:\nAge younger than 5 years, with a relative risk of 1.8 (95% CI, 1.5-2.1)\nRapid progression from stage 1 to stage 3 and/or presentation with stage 4 or 5 (See Physical Examination) - The death rate by stage at the time of admission is 18% for patients in stage 0 and 90% for those in stage 5; meaningful survival beyond stage 3 is unlikely; full recovery is possible for patients in stages 0-2\nCentral venous pressure (CVP) less than 6 mm H2 0\nAmmonia level greater than 45 µg/dL (26 µmol/L), with a relative risk of 3.4 (95% CI, 1.9-6.2) [4]\nGlucose value less than 60 mg/dL\nHypoproteinemia unresponsive to fresh frozen vitamin K and fresh frozen plasma (FFP)\nAntecedent diarrheal illness\nPatients who survive may recover completely. The 1980-1997 US data indicate full recovery in 62% of the 1134 patients with known outcomes. Survivors are at increased risk for long-term neurologic sequelae if ammonia levels exceed 45 µg/dL, if they have stage 2-5 disease, or if they are younger than 5 years. Approximately 3% of patients have neurologic sequelae if ammonia levels are below 45 µg/dL, whereas nearly 11% have sequelae if levels are above 45 µg/dL, with a relative risk of 4.1 (95% CI, 1.2-14).\nSchrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs. 2007. 9(3):195-204. [Medline].\nGlasgow JF, Middleton B, Moore R, Gray A, Hill J. The mechanism of inhibition of beta-oxidation by aspirin metabolites in skin fibroblasts from Reye's syndrome patients and controls. Biochim Biophys Acta. 1999 May 31. 1454(1):115-25. [Medline].\nGosalakkal JA, Kamoji V. Reye syndrome and reye-like syndrome. Pediatr Neurol. 2008 Sep. 39(3):198-200. [Medline].\nBelay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999 May 6. 340(18):1377-82. [Medline].\nNew World Encyclopedia. Reye's Syndrome. Last updated September 5, 2008. Available at http://www.newworldencyclopedia.org/entry/Reye%27s_syndrome.\nLovejoy FH Jr, Smith AL, Bresnan MJ, Wood JN, Victor DI, Adams PC. Clinical staging in Reye syndrome. Am J Dis Child. 1974 Jul. 128(1):36-41. [Medline].\nCDC. Reye Syndrome 1990 Clinical Case Definition. Available at http://www.cdc.gov/ncphi/disss/nndss/casedef/reye_syndrome_current.htm.\nCDC. Reye syndrome surveillance--United States, 1989. MMWR Morb Mortal Wkly Rep. 1991 Feb 8. 40(5):88-90. [Medline].\nGallucci M, Smith JD, Limbucci N, Rossi A, Demaerel P, Krings T, et al. Pediatric Inflammatory Diseases. Part IV: Miscellaneous, Reye, PRES, Sarcoidosis. Neuroradiol J. 2012 Dec 20. 25(6):725-38. [Medline].\nChesnut RM. Medical management of severe head injury: present and future. New Horiz. 1995 Aug. 3(3):581-93. [Medline].\nBrenkert TE, Estrada CM, McMorrow SP, Abramo TJ. Intravenous hypertonic saline use in the pediatric emergency department. Pediatr Emerg Care. 2013 Jan. 29(1):71-3. [Medline].\nCag M, Saouli AC, Audet M, Wolf P, Cinqualbre J. Reye syndrome and liver transplantation. Turk J Pediatr. 2010 Nov-Dec. 52(6):662-4. [Medline].\nDiagnosis and treatment of Reye's syndrome. JAMA. 1981 Nov 27. 246 (21):2441-4. [Medline].\nJOHNSON GM, SCURLETIS TD, CARROLL NB. A STUDY OF SIXTEEN FATAL CASES OF ENCEPHALITIS- LIKE DISEASE IN NORTH CAROLINA CHILDREN. N C Med J. 1963 Oct. 24:464-73. [Medline].\nDinakaran D, Sergi CM. Co-ingestion of aspirin and acetaminophen promoting fulminant liver failure: A critical review of Reye syndrome in the current perspective at the dawn of the 21st century. Clin Exp Pharmacol Physiol. 2018 Feb. 45 (2):117-121. [Medline].\nPugliese A, Beltramo T, Torre D. Reye's and Reye's-like syndromes. Cell Biochem Funct. 2008 Oct. 26 (7):741-6. [Medline].\nREYE RD, MORGAN G, BARAL J. ENCEPHALOPATHY AND FATTY DEGENERATION OF THE VISCERA. A DISEASE ENTITY IN CHILDHOOD. Lancet. 1963 Oct 12. 2 (7311):749-52. [Medline].\nUppala R, Dudiak B, Beck ME, Bharathi SS, Zhang Y, Stolz DB, et al. Aspirin increases mitochondrial fatty acid oxidation. Biochem Biophys Res Commun. 2017 Jan 8. 482 (2):346-351. [Medline].\nSingh P, Goraya JS, Gupta K, Saggar K, Ahluwalia A. Magnetic resonance imaging findings in Reye syndrome: case report and review of the literature. J Child Neurol. 2011 Aug. 26 (8):1009-14. [Medline].\nTein I. Impact of fatty acid oxidation disorders in child neurology: from Reye syndrome to Pandora's box. Dev Med Child Neurol. 2015 Apr. 57 (4):304-6. [Medline].\nDebra L Weiner, MD, PhD Attending Physician, Division of Emergency Medicine, Children's Hospital, Boston; Assistant Professor, Department of Pediatrics, Harvard Medical School\nKirsten A Bechtel, MD Associate Professor of Pediatrics, Section of Pediatric Emergency Medicine, Yale University School of Medicine; Co-Director, Injury Free Coalition for Kids, Yale-New Haven Children's Hospital\nKirsten A Bechtel, MD is a member of the following medical societies: American Academy of Pediatrics\nRichard G Bachur, MD Associate Professor of Pediatrics, Harvard Medical School; Associate Chief and Fellowship Director, Attending Physician, Division of Emergency Medicine, Children's Hospital of Boston\nRichard G Bachur, MD is a member of the following medical societies: American Academy of Pediatrics, Society for Academic Emergency Medicine, and Society for Pediatric Research\nGarry Wilkes, MBBS, FACEM Director of Emergency Medicine, Bunbury Hospital; Medical Consultant, St John Ambulance, WA Ambulance Service; Adjunct Associate Professor, Edith Cowan University; Clinical Associate Professor, Rural Clinical School, University of Western Australia\nencoded search term (Reye Syndrome) and Reye Syndrome\nHyperammonemia\nPediatric Chickenpox\nDyspnea, Fever, Hemoptysis, and Diabetes in a Tobacco User\nConjugated Hyperbilirubinemia\nOutpatient Strategies for COVID-19 Therapy: Clinical Equipoise in Defense of Pascal\nInfluenza Vaccination Critical During Pandemic, CDC Says\nChikungunya Virus Vaccine Shows Promise in Early Clinical Trial\nDiseases & Conditions Reye Syndrome\nCOVID-19: The Influenza Vaccine Becomes Critical During Pandemic 0.25 CME / CE / ABIM MOC Credits Clinical Review\nCOVID-19: The Influenza Vaccine Becomes Critical During Pandemic\nClinical Case Dyspnea, Fever, Hemoptysis, and Diabetes in a Tobacco User\n2002 2054408-overview Laboratory Medicine\nLaboratory Medicine Ammonia"