1.

OVERVIEW

Practice Essentials Ischemic stroke 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. Essential update: Antihypertensive treatment found not beneficial in acute ischemic stroke In the single-blind, randomized China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) study, which included 4,071 patients with acute ischemic stroke and elevated blood pressure, immediate blood pressure reduction with antihypertensive medication within 48 hours of symptom onset did not reduce the risk for death or major disability. CATIS excluded patients who received thrombolytic therapy. Mean systolic blood pressure was reduced from 166.7 to 144.7 mm Hg within 24 hours in the antihypertensive treatment group.[1, 2] Among the 2,038 patients who received antihypertensive treatment, 683 reached the primary endpoint of death or major disability at 14 days or hospital discharge, compared with 681 of the 2,033 patients who received no antihypertensive treatment. At 3-month follow-up, 500 patients in the antihypertensive treatment group and 502 patients in the control group reached the secondary endpoint of death or major disability.[1, 2] Signs and symptoms Consider stroke in any patient presenting with acute neurologic deficit or any alteration in level of consciousness. Common stroke signs and symptoms include the following:

Abrupt onset of hemiparesis, monoparesis, or (rarely) quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia

Dysarthria Facial droop Ataxia Vertigo (rarely in isolation) Nystagmus Aphasia Sudden decrease in level of consciousness

Although 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. With the availability of fibrinolytic therapy 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:

Confirming the presence of a stroke syndrome Distinguishing stroke from stroke mimics Establishing a neurologic baseline, should the patient's condition improve or deteriorate Establishing stroke severity, using a structured neurologic exam and score (National Institutes of Health Stroke Scale [NIHSS]) to assist in prognosis and therapeutic selectionEssential components of the neurologic examination include the following evaluations:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Language (expressive and receptive capabilities) Mental status and level of consciousness

The skull and spine also should be examined, and signs of meningismus should be sought. Diagnosis Emergent brain imaging is essential for confirming the diagnosis of 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 are also used:

CT angiography and CT perfusion scanning Magnetic resonance imaging (MRI) Carotid duplex scanning Digital subtraction angiography Lumbar puncture A lumbar puncture is required to rule out meningitis or subarachnoid hemorrhage when the CT scan is negative but the clinical suspicion remains high Laboratory studies Laboratory tests performed in the diagnosis and evaluation of ischemic stroke include the following:

Complete blood count (CBC): A baseline study that may reveal a cause for the stroke (eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide evidence of concurrent illness (eg, anemia)

Basic chemistry panel: A baseline study that may reveal a stroke mimic (eg, hypoglycemia, hyponatremia) or provide evidence of concurrent illness (eg, diabetes, renal insufficiency)

Coagulation studies: May reveal a coagulopathy and are useful when fibrinolytics or anticoagulants are to be used

Cardiac biomarkers: Important because of the association of cerebral vascular disease and coronary artery disease

Toxicology screening: May assist in identifying intoxicated patients with symptoms/behavior mimicking stroke syndromes

Pregnancy 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

Arterial blood gas analysis: In selected patients with suspected hypoxemia, arterial blood gas defines the severity of hypoxemia and may be used to detect acid-base disturbances See Workup for more detail. Management The goal for the emergent management of stroke is to complete the following within 60 minutes of patient arrival[3] :

Assess airway, breathing, and circulation (ABCs) and stabilize the patient as necessary Complete the initial evaluation and assessment, including imaging and laboratory studies Initiate reperfusion therapy, if appropriate

Critical treatment decisions focus on the following:

The need for airway management Optimal blood pressure control Identifying potential reperfusion therapies (eg, intravenous fibrinolysis with rt-PA or intraarterial approaches) Involvement of a physician with a special interest in stroke is ideal. Stroke care units with specially trained personnel exist and improve outcomes. Ischemic stroke therapies include the following:

Fibrinolytic therapy Antiplatelet agents[4, 5] Mechanical thrombectomy Treatment of comorbid conditions may include the following:

Reduce fever

Correct hypotension/significant hypertension Correct hypoxia Correct hypoglycemia Manage cardiac arrhythmias Manage myocardial ischemia

Stroke prevention Primary stroke prevention refers to the treatment of individuals with no previous history of stroke. Measures may include use of the following:

Platelet antiaggregants Statins Exercise Lifestyle interventions (eg, smoking cessation, alcohol moderation) Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures may include use of the following:

Platelet antiaggregants Antihypertensives Statins Lifestyle interventions See Treatment and Medication for more detail. Image library

Maximum 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. Background Acute 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.)

Maximum 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.

Nearly 800,000 people suffer strokes each year in the United States; 82-92% of these strokes are ischemic. Stroke is the fourth leading cause of adult death and disability, resulting in over $72 billion in annual cost.[6] Ischemic 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.) Stroke categories The 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[4] :

Large-artery Small-vessel, or lacunar Cardioembolic infarction Large-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. Cardiogenic 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.[7] (See Pathophysiology.) Treatment Recanalization strategies, including intravenous recombinant tissue-type plasminogen activator (rt-PA) and intra-arterial approaches, attempt to establish revascularization so that cells in the ischemic penumbra (a metabolically active region, peripheral to the ischemic area, where blood flow is reduced) can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. The 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. On 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 yet approved rt-PA for this expanded indication, but this has become the community standard in many institutions. Other aspects of treatment for acute ischemic stroke include the following: Treatment of neurologic complications

Supplemental oxygen as required Antiplatelet therapy Glycemic control Optimal blood pressure control Prevention of hyperthermia See also Hemorrhagic Stroke. Anatomy The 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. Knowledge 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. Arterial distributions In a simplified model, the cerebral hemispheres are supplied by 3 paired major arteries, specifically, the anterior, middle, and posterior cerebral arteries.

The 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.)

Lateral 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. The 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.)

The 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.

Frontal 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). The 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.) The cerebellar hemispheres are supplied as follows:

Inferiorly by the posterior inferior cerebellar artery (PICA), arising from the vertebral artery

(see the image below)

Frontal 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 (SICAs) arise distally from the basilar artery prior to its bifurcation into the posterior cerebral arteries (PCAs).

Superiorly by the superior cerebellar artery Anterolaterally by the anterior inferior cerebellar artery (AICA), from the basilar artery Table 1. Vascular Supply to the Brain (Open Table in a new window)

VASCULAR TERRITORY

Structures Supplied

Anterior Circulation (Carotid)

Anterior Cerebral Artery Cortical

branches: medial

frontal

and

parietal

lobe

Medial lenticulostriate branches: caudate head, globus pallidus, anterior limb of internal capsule

Middle Cerebral Artery

Cortical branches: lateral frontal and parietal lobes lateral and anterior temporal lobe

Lateral lenticulostriate branches: globus pallidus and putamen, internal capsule

Anterior Artery

Choroidal Optic tracts, medial temporal lobe, ventrolateral thalamus, corona radiata, posterior limb of the internal capsule

Posterior Circulation (Vertebrobasilar)

Posterior Artery

Cerebral Cortical branches: occipital lobes, medial and posterior temporal and parietal lobes

Perforating midbrain

branches: brainstem,

posterior

thalamus

and

Posterior

Inferior Inferior vermis; posterior and inferior cerebellar hemispheres

Cerebellar Artery

Anterior

Inferior Anterolateral cerebellum

Cerebellar Artery

Superior Artery

Cerebellar Superior vermis; superior cerebellum

Pathophysiology Acute 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.[8, 9, 10] Ischemic core and penumbra An 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. Affected 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.[11] Zones 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.[11] Ischemic cascade On 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. Cerebral 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-Daspartate (NMDA) and other excitatory receptors on other neurons. These 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.[12] Free radicals, arachidonic acid, and nitric oxide are generated by this process, which leads to further neuronal damage. Ischemia 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 barriers 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.[13, 14] Within 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.[12] Ultimately, the ischemic penumbra is consumed by these progressive insults, coalescing with the infarcted core, often within hours of the onset of the stroke. Infarction 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 fluidlike 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.)

Vascular 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).

Vascular 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.The 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.Vascular 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). Hemorrhagic transformation of ischemic stroke Hemorrhagic 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. Proposed 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.[8, 15, 16] 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.[5, 8, 17] Hemorrhagic transformation is also more likely following administration of rt-PA in patients whose noncontrast CT (NCCT) scans demonstrate areas of hypodensity.[18, 19, 20] Poststroke cerebral edema and seizures Although clinically significant cerebral edema can occur after anterior circulation ischemic stroke, it is thought to be somewhat rare (10-20%).[3] Edema and herniation are the most common causes of early death in patients with hemispheric stroke. Seizures occur in 2-23% of patients within the first days after ischemic stroke.[3] A fraction of patients who have experienced stroke develop chronic seizure disorders. Etiology Ischemic 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 Risk factors Risk 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. Nonmodifiable risk factors include the following (although there are likely many others):

Age

Race Sex Ethnicity History of migraine headaches Fibromuscular dysplasia Heredity: Family history of stroke or transient ischemic attacks (TIAs) In 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] For 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. Modifiable risk factors include the following[22] :

Hypertension (the most important) Diabetes mellitus Cardiac 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

Hypercholesterolemia TIAs Carotid stenosis Hyperhomocystinemia Lifestyle issues: Excessive alcohol intake, tobacco use, illicit drug use, physical inactivity[23] Obesity Oral contraceptive use/postmenopausal hormone use Sickle cell disease

Genetic and inflammatory mechanisms Evidence 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. Traditional 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. Host 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. A 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:

NOS3: A nitric oxide synthetase gene; involved in vascular relaxation[24] ALOX5AP: Involved in the metabolism of arachidonic acid[25] PRKCH: Involved in major signal transduction systems[26] Hyperhomocysteinemia and homocystinuria Hyperhomocysteinemia 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. In 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.[27] Thromboembolic 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.[28] 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. Amyloid angiopathies Amyloid 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.[29] CADASIL Cerebral 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.[30] Migraine 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.[31] Other mutations Genome-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 singlenucleotide polymorphisms on 2q23.3.[32]

Large-vessel

stroke

has

been

associated

with

variations

in HDAC9, PITX2,

andZFHX3.[33] 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. A polymorphism at 2q36.3 was found in which adenosine substitution conferred a lower risk of ischemic stroke in an additive fashion.[34] An additional study suggested an association between ischemic stroke and a locus on 12p13.[35] For 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:

Methylmalonic Acidemia Homocystinuria/Homocysteinemia Fabry Disease MELAS Syndrome Hyperglycemia and Hypoglycemia in Stroke Large-artery occlusion Large-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.)

Noncontrast 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.

Magnetic 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.

Maximum intensity projection (MIP)

image from a computed tomography angiogram (CTA) demonstrates a filling defect or highgrade 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. Lacunar strokes Lacunar 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.)

Axial 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 fluidattenuated 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. Causes of lacunar infarcts include the following:

Microatheroma Lipohyalinosis

Fibrinoid necrosis secondary to hypertension or vasculitis Hyaline arteriosclerosis Amyloid angiopathy Microemboli Embolic strokes Cardiogenic 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.[36] Sources of cardiogenic emboli include the following:

Valvular thrombi (eg, in mitral stenosis or endocarditis or from use of a prosthetic valve) Mural thrombi (eg, in myocardial infarction, atrial fibrillation, dilated cardiomyopathy, or severe congestive heart failure)

Atrial myxoma Acute myocardial infarction is associated with a 2-3% incidence of embolic strokes, of which 85% occur in the first month after the infarction.[37] Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or may show calcific emboli. Cardioembolic 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.)[38, 39]

Cardioembolic 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. For more information, see Cardioembolic Stroke. Thrombotic strokes Thrombogenic 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. Intracranial 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[8, 40] :

Hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency, pregnancy)

Sickle cell disease Fibromuscular dysplasia Arterial dissections Vasoconstriction associated with substance abuse (eg, cocaine, amphetamines) Watershed infarcts Vascular 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.)[41, 42, 43]

Magnetic resonance imaging (MRI) scan was obtained in a 62year-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. Flow disturbances Stroke 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. Epidemiology Stroke is the leading cause of disability and the fourth leading cause of death in the United States.[44,
45]

Each year, approximately 795,000 people in the United States experience new

(610,000 people) or recurrent (185,000 people) stroke.[6]Epidemiologic studies indicate that 8292% of strokes in the United States are ischemic. According 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.[46] Race-, sex-, and age-related demographics

In the United States, blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites.[47] Hispanics have a lower overall incidence of stroke than whites and blacks but more frequent lacunar strokes and stroke at an earlier age. Men 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%. Although stroke often is considered a disease of elderly persons, one third of strokes occur in persons younger than 65 years.[45] Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur. Prognosis In 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 patients premorbid condition, age, and poststroke complications.[4] A 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.[48] Cardiogenic emboli are associated with the highest 1-month mortality in patients with acute stroke. The 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).[5,
49, 50]

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.

Acute 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.[51, 52, 53] In 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 followup. For more information, see the Medscape Reference article Motor Recovery in Stroke. Patient Education Public education must involve all age groups. Incorporating stroke into basic life support (BLS) and cardiopulmonary resuscitation (CPR) curricula is just one way to reach a younger audience. Avenues to reach an audience with a higher stroke risk could include local churches, employers, and senior organizations to promote stroke awareness. The 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: Numbness or weakness of face, arm, or leg, especially on 1 side of the body

Confusion Difficulty in speaking or understanding Deterioration of vision in 1 or both eyes Difficulty in walking, dizziness, and loss of balance or coordination Severe headache with no known cause In 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:

F: Face drooping A: Arm weakness S: Speech difficulty

T: Time to call 911

BAB II PRESENTATION History A focused medical history for patients with ischemic stroke aims to identify risk factors for atherosclerotic and cardiac disease, including the following (see Etiology):

Hypertension Diabetes mellitus Tobacco use High cholesterol History of coronary artery disease, coronary artery bypass, or atrial fibrillation In younger patients, elicit a history of the following:

Recent trauma Coagulopathies Illicit drug use (especially cocaine) Migraines Oral contraceptive use Stroke should be considered in any patient presenting with an acute neurologic deficit (focal or global) or altered level of consciousness. No historical feature distinguishes ischemic from hemorrhagic stroke, although nausea, vomiting, headache, and a sudden change in the patients level of consciousness are more common in hemorrhagic strokes. Consider stroke in any patient presenting with acute neurologic deficit or any alteration in level of consciousness. Common signs and symptoms of stroke include the abrupt onset of any of the following:

Hemiparesis, monoparesis, or (rarely) quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia Dysarthria

Facial droop Ataxia Vertigo (rarely in isolation) Aphasia Sudden decrease in the level of consciousness Although such symptoms can occur alone, they are more likely to occur in combination. Establishing the time at which the patient was last without stroke symptoms, or last known to be normal, is especially critical when fibrinolytic therapy is an option. Unfortunately, the median time from symptom onset to emergency department (ED) presentation ranges from 4-24 hours in the United States.[3] Multiple factors contribute to delays in seeking care for symptoms of stroke. Many strokes occur while patients are sleeping and are not discovered until the patient wakes (this phenomenon is also known as "wake-up" stroke). Stroke can leave some patients too incapacitated to call for help. Occasionally, a stroke goes unrecognized by patients or their caregivers.[6, 54] If the patient awakens with symptoms, then the time of onset is defined as the time at which the patient was last seen to be without symptoms. Input from family members, coworkers, and bystanders may be required to help establish the exact time of onset, especially in right hemispheric strokes accompanied by neglect or left hemispheric strokes with aphasia. Physical Examination The goals of the physical examination are as follows:

Detect extracranial causes of stroke symptoms Distinguish stroke from stroke mimics Determine and document for future comparison the degree of deficit Localize the lesion Identify comorbidities Identify conditions that may influence treatment decisions (eg, trauma, active bleeding, active infection)

The physical examination always includes a careful head and neck examination for signs of trauma, infection, and meningeal irritation. A careful search for the cardiovascular causes of stroke requires examination of the following:

Ocular fundi (retinopathy, emboli, hemorrhage) Heart (irregular rhythm, murmur, gallop) Peripheral vasculature (palpation of carotid, radial, and femoral pulses; auscultation for carotid bruit) The physical examination must encompass all of the major organ systems, starting with airway, breathing, and circulation (ABCs) and the vital signs. Patients with a decreased level of consciousness should be assessed to ensure that they are able to protect their airway. Patients with stroke, especially hemorrhagic stroke, can suffer quick clinical deterioration; therefore, constant reassessment is critical. Ischemic strokes, unless large or involving the brainstem, do not tend to cause immediate problems with airway patency, breathing, or circulation compromise. On the other hand, patients with intracerebral or subarachnoid hemorrhage frequently require intervention for airway protection and ventilation. Vital signs, while nonspecific, can point to impending clinical deterioration and may assist in narrowing the differential diagnosis. Many patients with stroke are hypertensive at baseline, and their blood pressure may become more elevated after stroke. While hypertension at presentation is common, blood pressure decreases spontaneously over time in most patients. Head and neck, cardiac, and extremities examination A careful examination of the head and neck is essential. Contusions, lacerations, and deformities may suggest trauma as the etiology for the patient's symptoms. Auscultation of the neck may elicit a bruit, suggesting carotid disease as the cause of the stroke. Cardiac arrhythmias, such as atrial fibrillation, are found commonly in patients with stroke. Similarly, strokes may occur concurrently with other acute cardiac conditions, such as acute myocardial infarction and acute heart failure; thus, auscultation for murmurs and gallops is recommended.

Carotid or vertebrobasilar dissections and, less commonly, thoracic aortic dissections may cause ischemic stroke. Unequal pulses or blood pressures in the extremities may reflect the presence of aortic dissections. Neurologic examination With the availability of fibrinolytic therapy 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:

Confirming the presence of a stroke syndrome (to be defined further with cranial CT scanning) Distinguishing stroke from stroke mimics Establishing a neurologic baseline should the patient's condition improve or deteriorate Establishing stroke severity to assist in prognosis and therapeutic selection Essential components of the neurologic examination include the following evaluations:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Language (expressive and receptive capabilities) Mental status and level of consciousness The skull and spine also should be examined, and signs of meningismus should be sought. National Institutes of Health Stroke Scale A useful tool in quantifying neurologic impairment is the National Institutes of Health Stroke Scale (NIHSS) (see Table 2, below). The NIHSS enables the healthcare provider to rapidly determine the severity and possible location of the stroke. NIHSS scores are strongly associated with outcome and can help to identify those patients who are likely to benefit from fibrinolytic therapy and those who are at higher risk of developing hemorrhagic complications of fibrinolytic use.

The NIHSS is easily performed; it focuses on the following 6 major areas of the neurologic examination:

level of consciousness Visual function Motor function Sensation and neglect Cerebellar function Language The NIHSS is a 42-point scale. Patients with minor strokes usually have a score of less than 5. An NIHSS score of greater than 10 correlates with an 80% likelihood of proximal vessel occlusions (as identified on CT or standard angiograms). However, discretion must be used in assessing the magnitude of the clinical deficit and resulting disability; for instance, if a patient's only deficit is mutism, the NIHSS score will be 3. Additionally, the scale does not measure some deficits associated with posterior circulation strokes (ie, vertigo, ataxia).[55] Table 2. National Institutes of Health Stroke Scale (Open Table in a new window)

Category

Description

Score

1a

level of consciousness (LOC)

Alert

Drowsy

Stuporous

Coma

1b

LOC questions (month, age)

Answers

both

correctly 0

Answers

correctly 1

Incorrect

on

both 2

1c

LOC

commands

(open

and

close

eyes, Obeys

both

correctly 0

grip

and

release

nonparetic

hand) Obeys

correctly 1

Incorrect

on

both 2

Best gaze (follow finger)

Normal

Partial

gaze

palsy 1

Forced

deviation 2

Best visual (visual fields)

No

visual

loss 0

Partial

hemianopia 1

Complete

hemianopia 2

Bilateral

hemianopia 3

Facial

palsy

(show

teeth,

raise

brows, Normal

squeeze

eyes

shut) Minor

Partial

Complete

Motor arm left* (raise 90, hold 10 seconds)

No

drift 0

Drift

Cannot

resist

gravity 2

No

effort

against

gravity 3

No

movement 4

Motor arm right* (raise 90, hold 10 seconds)

No

drift 0

Drift

Cannot

resist

gravity 2

No

effort

against

gravity 3

No

movement 4

Motor leg left* (raise 30, hold 5 seconds)

No

drift 0

Drift

Cannot

resist

gravity 2

No

effort

against

gravity 3

No

movement 4

Motor leg right* (raise 30, hold 5 seconds)

No

drift 0

Drift

Cannot

resist

gravity 2

No

effort

against

gravity 3

No

movement 4

Limb ataxia (finger-nose, heel-shin)

Absent

Present

in

limb 1

Present

in

limbs 2

10

Sensory (pinprick to face, arm, leg)

Normal

Partial

loss 1

Severe

loss 2

11

Extinction/neglect

(double

simultaneous No

neglect 0

testing)

Partial

neglect 1

Complete

neglect 2

12

Dysarthria

(speech

clarity

to

"mama, Normal

articulation 0

baseball,

huckleberry,

tip-top,

fifty-fifty") Mild to moderate dysarthria 1

Near to unintelligible or worse 2

13

Best

language**

(name

items, No

aphasia 0

describe

pictures) Mild

to

moderate

aphasia 1

Severe

aphasia 2

Mute

Total

0-42

For

limbs

with

amputation,

joint

fusion,

etc,

score

and

explain.

** For intubation or other physical barriers to speech, score 9 and explain. Do not add 9 to the total score. NIH Stroke Scale (PDF)

Middle cerebral artery stroke Middle cerebral artery (MCA) occlusions commonly produce the following:

Contralateral hemiparesis Contralateral hypesthesia Ipsilateral hemianopsia Gaze preference toward the side of the lesion Agnosia Receptive or expressive aphasia, if the lesion occurs in the dominant hemisphere

Neglect, inattention, and extinction of double simultaneous stimulation, with some nondominant hemisphere lesions The MCA supplies the upper extremity motor strip. Consequently, weakness of the arm and face is usually worse than that of the lower limb. Anterior cerebral artery stroke Anterior cerebral artery (ACA) occlusions primarily affect frontal lobe function. Findings in ACA stroke may include the following:

Disinhibition and speech perseveration Primitive reflexes (eg, grasping, sucking reflexes) Altered mental status Impaired judgment Contralateral weakness (greater in legs than arms) Contralateral cortical sensory deficits Gait apraxia Urinary incontinence Posterior cerebral artery stroke Posterior cerebral artery (PCA) occlusions affect vision and thought. Manifestations include the following:

Contralateral homonymous hemianopsia Cortical blindness Visual agnosia Altered mental status Impaired memory Vertebrobasilar artery occlusions are particularly difficult to localize, because they may cause a wide variety of cranial nerve, cerebellar, and brainstem deficits. These include the following:

Vertigo Nystagmus Diplopia

Visual field deficits Dysphagia Dysarthria Facial hypesthesia Syncope Ataxia A hallmark of posterior circulation stroke is the presence of crossed findings: ipsilateral cranial nerve deficits and contralateral motor deficits. This contrasts with anterior stroke, which produces only unilateral findings. Lacunar stroke Lacunar strokes result from occlusion of the small, perforating arteries of the deep subcortical areas of the brain. The infarcts are generally from 2-20 mm in diameter. The most common lacunar syndromes include pure motor, pure sensory, and ataxic hemiparetic strokes. By virtue of their small size and well-defined subcortical location, lacunar infarcts do not lead to impairments in cognition, memory, speech, or level of consciousness.

BAB III Diagnostic Considerations Stroke mimics commonly confound the clinical diagnosis of stroke. One study reported that 19% of patients diagnosed with acute ischemic stroke by neurologists before cranial CT scanning actually had non-cerebrovascular causes for their symptoms. The most frequent stroke mimics include the following:

Seizure (17%) Systemic infection (17%) Brain tumor (15%) Toxic-metabolic disorders, such as hyponatremia and hypoglycemia (13%) Positional vertigo (6%) Conversion disorder In the prehospital and emergency department (ED) settings, hypoglycemia is a common stroke mimic and is particularly important to consider, since it can be readily detected and corrected.[56,
57]

For more information, see Hyperglycemia and Hypoglycemia in Stroke.

Ischemic versus hemorrhagic stroke Although the definitive distinction of ischemic stroke from hemorrhagic stroke requires neuroimaging, a meta-analysis found that the following clinical findings increase the probability of hemorrhagic stroke[58] :

Coma (likelihood ratio [LR] 6.2) Neck stiffness (LR 5.0) Seizures accompanying the neurologic deficit (LR, 4.7) Diastolic blood pressure >110 mm Hg (LR, 4.3) Vomiting (LR, 3.0) Findings that decrease the probability of hemorrhage include cervical bruit (LR 0.12) and prior transient ischemic attack (LR, 0.34). Transient ischemic attack

Transient ischemic attack (TIA) is an acute episode of temporary neurologic dysfunction that results from focal cerebral, spinal cord, or retinal ischemia and is not associated with acute tissue infarction. Roughly 80% of TIAs resolve within 60 minutes.[59] TIA can result from the same mechanisms as ischemic stroke. Data suggest that roughly 10% of patients with TIA suffer stroke within 90 days and of those, half suffer stroke within 2 days.[60, 61] The classic definition of TIA included symptoms lasting as long as 24 hours. With advances in neuroimaging, however, it now appears that many such cases represent minor strokes with resolved symptoms rather than true TIAs. Thus, the current definition of TIA is based on tissue pathophysiology rather than symptom duration.[59] Cerebral venous thrombosis Diagnosis and management of a rare form of stroke, cerebral venous thrombosis (CVT), was the subject of a 2011 American Heart Association/American Stroke Association (AHA/ASA) statement for healthcare professionals. According to the statement, diagnosing CVT requires a high degree of clinical suspicion. Most people diagnosed with CVT present with headache, often of increasing severity and usually accompanied by focal neurologic signs.[48] Differentials Bell Palsy Brain Neoplasms Conversion Disorder in Emergency Medicine Hemorrhagic Stroke Hypoglycemia Migraine Headache Seizure Assessment in the Emergency Department Emergent Management of Subarachnoid Hemorrhage

Syncope Transient Global Amnesia

Bells palsy Practice Essentials Bell palsy, also termed idiopathic facial paralysis (IFP), is the most common cause of unilateral facial paralysis and the most common cause of facial paralysis worldwide. It is one of the most common neurologic disorders of the cranial nerves. In the great majority of cases, Bell palsy gradually resolves over time, and its cause is unknown. Essential update: New Bell palsy guidelines issued by the The American Academy of OtolaryngologyHead and Neck Surgery Foundation The American Academy of OtolaryngologyHead and Neck Surgery Foundation has issued updated guidelines for the diagnosis and management of Bell palsy that recommend the use of corticosteroids within 72 hours after the onset of symptoms in patients 16 years of age and older.

Antiviral agents (eg, acyclovir, valacyclovir) may be considered if a viral etiology is suspected, but only in combination with corticosteroids.[1] Additional recommendations include the following[1] :

Patients with acute-onset unilateral facial paralysis should be assessed to exclude other possible identifiable causes (eg, herpes zoster, Lyme disease, sarcoidosis)

Diagnostic imaging and routine lab testing are not recommended for patients with new-onset disease

Electrodiagnostic testing is not recommended in patients with incomplete facial paralysis; however, it may be offered to those patients with complete facial paralysis

If there is impaired eye closure, appropriate eye protection should be implemented Referral to a facial nerve specialist should occur in cases of new or worsening neurologic symptoms, developing ocular symptoms, or incomplete facial recovery after 3 months

These guidelines concur with the American Academy of Neurology guidelines issued in 2012.[2] Signs and symptoms Signs and symptoms of Bell palsy include the following:

Acute onset of unilateral upper and lower facial paralysis (over a 48-hr period) Posterior auricular pain Decreased tearing Hyperacusis Taste disturbances Otalgia Weakness of the facial muscles Poor eyelid closure Aching of the ear or mastoid Tingling or numbness of the cheek/mouth Epiphora Ocular pain Blurred vision Flattening of forehead and nasolabial fold on the side affected by palsy

When patient raises eyebrows, palsy-affected side of forehead remains flat When patient smiles, face becomes distorted and lateralizes to side opposite the palsy

See Clinical Presentation for more specific information on the signs and symptoms of Bell palsy. Diagnosis Examination for Bell palsy includes the following:

Otologic examination: Pneumatic otoscopy and tuning fork examination, particularly if evidence of acute or chronic otitis media

Ocular examination: Patient often unable to completely close eye on affected side Oral examination: Taste and salivation often affected Neurologic examination: All cranial nerves, sensory and motor testing, cerebellar testing

Grading The grading system developed by House and Brackmann categorizes Bell palsy on a scale of I to VI,[3, 4, 5] as follows: Grade I: normal facial function Grade II: mild dysfunction Grade III: moderate dysfunction Grade IV: moderately severe dysfunction Grade V: severe dysfunction Grade VI: total paralysis See Clinical Presentation for more specific information on patient history and physical examination for Bell palsy. Testing Although there are no specific diagnostic tests for Bell palsy, the following may be useful for identifying or excluding other disorders:

Rapid plasma reagin and/or venereal disease research laboratory test or fluorescent treponemal antibody absorption test

HIV screening by enzyme-linked immunosorbent assay and/or Western blot Complete blood count Erythrocyte sedimentation rate Thyroid function Serum glucose CSF analysis Blood glucose Hemoglobin A1c Antineutrophil cytoplasmic antibody levels Salivary flow Schirmer blotting test Nerve excitability test Computed tomography Magnetic resonance imaging

See Workup for more specific information on testing and imaging modalities for Bell palsy. Management Goals of treatment: (1) improve facial nerve (seventh cranial nerve) function; (2) reduce neuronal damage; (3) prevent complications from corneal exposure Treatment includes the following:

Corticosteroid therapy (prednisone)[6, 7] Antiviral agents[6, 8] Eye care: Topical ocular lubrication is usually sufficient in most cases to prevent corneal drying, abrasion, and ulcers[9]

Surgical options Surgical treatment options include the following:

Facial nerve decompression Subocularis oculi fat lift

Implantable devices (eg, gold weights) placed into the eyelid Tarsorrhaphy Transposition of the temporalis muscle Facial nerve grafting Direct brow lift

See Treatment and Medication for more specific information regarding pharmacologic and other therapies for Bell palsy. Image library

Left-sided Bell palsy.

Background Bell palsy, more appropriately termed idiopathic facial paralysis (IFP), is the most common cause of unilateral facial paralysis. Bell palsy is an acute, unilateral, peripheral, lower-motorneuron facial nerve paralysis that gradually resolves over time in 80-90% of cases. Controversy surrounds the etiology and treatment of Bell palsy. The cause of Bell palsy remains unknown, though the disorder appears to be a polyneuritis with possible viral, inflammatory, autoimmune, and ischemic etiologies. Increasing evidence implicates herpes simplex type I and herpes zoster virus reactivation from cranial-nerve ganglia.[10] (See Etiology.)

Bell palsy is one of the most common neurologic disorders affecting the cranial nerves, and it is the most common cause of facial paralysis worldwide. It is thought to account for approximately 60-75% of cases of acute unilateral facial paralysis. Bell palsy is more common in adults, in people with diabetes, and in pregnant women. (See Epidemiology.) Diagnosis Determining whether facial nerve paralysis is peripheral or central is a key step in the diagnosis. A lesion involving the central motor neurons above the level of the facial nucleus in the pons causes weakness of the lower face alone. Thorough history taking and examination, including the ears, nose, throat, and cranial nerves, must be performed. (See Presentation.) The minimum diagnostic criteria include paralysis or paresis of all muscle groups on one side of the face, sudden onset, and absence of central nervous system (CNS) disease. Note that the diagnosis of IFP can be made only after other causes of acute peripheral palsy have been excluded. (See DDx.) If the clinical findings are doubtful or if paralysis lasts longer than 6-8 weeks, further investigations, including gadolinium-enhanced magnetic resonance imaging (MRI) of the temporal bones and pons, should be considered.[11] Electrodiagnostic tests (eg, stapedius reflex test, evoked facial nerve electromyography [EMG], audiography) may help to improve the accuracy of prognosis in difficult cases. (See Workup.)

Treatment Treatment of Bell palsy should be conservative and guided by the severity and probable prognosis in each particular case. Studies have shown the benefit of high-dose corticosteroids for acute cases.[12, 13] Although antiviral treatment has also come into use, evidence is now available indicating that it may not be beneficial.[12] (See Treatment and Medication.) Topical ocular therapy is useful in most cases, with the exception of those in which the condition is severe or prolonged. In these cases, surgical management is best. Several procedures are aimed at protecting the cornea from exposure and achieving facial symmetry. These procedures reduce

the need for constant use of lubrication drops or ointments, may improve cosmesis, and may be needed to preserve vision on the affected side. (See Treatment.) Patient education To prevent corneal abrasions, patients should be instructed about eye care. They also should be encouraged to do facial muscle exercises using passive range of motion, as well as actively close their eyes and smile. For patient education information, see the Brain and Nervous System Center, as well as Bells Palsy. Anatomy In 1550, Fallopius noted the narrow foramen in the temporal bone through which a part of the seventh cranial nerve (facial nerve) passes; this feature is now sometimes called the fallopian canal or the facial canal. In 1828, Charles Bell made the distinction between the fifth and seventh cranial nerves; he noted that the seventh nerve was involved mainly in the motor function of the face and that the fifth nerve primarily conducted sensation from the face. The facial nerve contains parasympathetic fibers to the nose, palate, and lacrimal glands. Its course is tortuous, both centrally and peripherally. The facial nerve travels a 30-mm intraosseous course through the internal auditory canal (with the eighth cranial nerve) and through the internal fallopian canal in the petrous temporal bone. This bony confinement limits the amount that the nerve can swell before it becomes compressed. The nucleus of the facial nerve lies within the reticular formation of the pons, adjacent to the fourth ventricle. The facial nerve roots include fibers from the motor, solitary, and salivatory nuclei. The preganglionic parasympathetic fibers that originate in the salivatory nucleus join the fibers from nucleus solitarius to form the nervus intermedius. The nervus intermedius is composed of sensory fibers from the tongue, mucosa, and postauricular skin, as well as parasympathetic fibers to the salivary and lacrimal glands. These fibers then synapse with the submandibular ganglion, which has fibers that supply the sublingual and submandibular glands. The fibers from the nervus intermedius also supply the

pterygopalatine ganglion, which has parasympathetic fibers that supply the nose, palate, and lacrimal glands. The fibers of the facial nerve then course around the sixth cranial nerve nucleus and exit the pons at the cerebellopontine angle. The fibers go through the internal auditory canal along with the vestibular portion of the eighth cranial nerve. The facial nerve passes through the stylomastoid foramen in the skull and terminates into the zygomatic, buccal, mandibular, and cervical branches. These nerves serve the muscles of facial expression, which include the frontalis, orbicularis oculi, orbicularis oris, buccinator, and platysma muscles. Other muscles innervated by the facial nerve include the stapedius, stylohyoid, posterior belly of the digastric, occipitalis, and anterior and posterior auricular muscles. All muscles innervated by the facial nerve are derived from the second branchial arch. See the images below.

The facial nerve.

Pathophysiology The precise pathophysiology of Bell palsy remains an area of debate. The facial nerve courses through a portion of the temporal bone commonly referred to as the facial canal. A popular theory proposes that edema and ischemia result in compression of the facial nerve within this bony canal. The cause of the edema and ischemia has not yet been established. This compression has been seen in MRI scans with facial nerve enhancement.[14]

The first portion of the facial canal, the labyrinthine segment, is the narrowest; the meatal foramen in this segment has a diameter of only about 0.66 mm. This is the location that is thought to be the most common site of compression of the facial nerve in Bell palsy. Given the tight confines of the facial canal, it seems logical that inflammatory, demyelinating, ischemic, or compressive processes may impair neural conduction at this site. Injury to the facial nerve in Bell palsy is peripheral to the nerves nucleus. The injury is thought to occur near, or at, the geniculate ganglion. If the lesion is proximal to the geniculate ganglion, the motor paralysis is accompanied by gustatory and autonomic abnormalities. Lesions between the geniculate ganglion and the origin of the chorda tympani produce the same effect, except that they spare lacrimation. If the lesion is at the stylomastoid foramen, it may result in facial paralysis only. Etiology Herpes simplex virus In the past, situations that produced cold exposure (eg, chilly wind, cold air conditioning, or driving with the car window down) were considered to be the only triggers for Bell palsy. Several authors now believe, however, that the herpes simplex virus (HSV) is a common cause of Bell palsy, though a definitive causal relationship of HSV to Bell palsy may be difficult to prove because of the ubiquitous nature of HSV. The hypothesis that HSV is the etiologic agent in Bell palsy holds that after causing primary infection on the lips (ie, cold sores), the virus travels up the axons of the sensory nerves and resides in the geniculate ganglion. At times of stress, the virus reactivates and causes local damage to the myelin. This hypothesis was first suggested in 1972 by McCormick.[15] Autopsy studies have since shown HSV in the geniculate ganglion of patients with Bell palsy. Murakami et al performed polymerase chain reaction (PCR) assay testing on the endoneural fluid of the facial nerve in patients who underwent surgery for Bell palsy and found HSV in 11 of 14 cases.[16] Additional support for a viral etiology was seen when intranasal, inactivated influenza vaccine was strongly linked to the development of Bell palsy.[17, 18] With those cases, however, it is not

clear whether another component of the vaccine caused the paresis, which was then accompanied by a reactivation of HSV infection. Additional causes Besides HSV infection, possible etiologies for Bell palsy include other infections (eg, herpes zoster, Lyme disease, syphilis, Epstein-Barr viral infection, cytomegalovirus, human immunodeficiency virus [HIV], mycoplasma); inflammation alone; and microvascular disease (diabetes mellitus and hypertension). Bell palsy has also been known to follow recent upper respiratory infection (URI).[19, 20, 21, 22, 23, 24] Bell palsy may be secondary to viral and/or autoimmune reactions that cause the facial nerve to demyelinate, resulting in unilateral facial paralysis. A family history of Bell palsy has been reported in approximately 4% of cases. Inheritance in such cases may be autosomal dominant with low penetration; however, which predisposing factors are inherited is unclear.[25] The family history may also be positive for other nerve, nerve root, or plexus disorders (eg, trigeminal neuralgia) in siblings.[26] In addition, there are isolated reports of familial Bell palsy with neurologic deficits, including ophthalmoplegia[27] and essential tremor.[28] A rare form of familial Bell palsy has a predilection for juvenile females.[29] Because there is a strong environmental predisposition to Bell palsy, due to the common viral etiology, a positive family history may or may not indicate a true genetic etiology. Epidemiology In the United States, the annual incidence of Bell palsy is approximately 23 cases per 100,000 persons.[7] Very few cases are observed during the summer months. Internationally, the highest incidence was found in a study in Seckori, Japan, in 1986, and the lowest incidence was found in Sweden in 1971. Most population studies generally show an annual incidence of 15-30 cases per 100,000 population. Bell palsy is thought to account for approximately 60-75% of cases of acute unilateral facial paralysis, with the right side affected 63% of the time. It can also be recurrent, with a reported recurrence range of 4-14%.[20]

Though bilateral simultaneous Bell palsy can develop, it is rare. It accounts for only 23% of bilateral facial paralysis and has an occurrence rate that is less than 1% of that for unilateral facial nerve palsy.[30, 31] The majority of patients with bilateral facial palsy have Guillain-Barr syndrome, sarcoidosis, Lyme disease, meningitis (neoplastic or infectious), or bilateral neurofibromas (in patients with neurofibromatosis type 2). Persons with diabetes have a 29% higher risk of being affected by Bell palsy than do persons without diabetes. Thus, measuring blood glucose levels at the time of diagnosis of Bell palsy may detect undiagnosed diabetes. Diabetic patients are 30% more likely than nondiabetic patients to have only partial recovery; recurrence of Bell palsy is also more common among diabetic patients.[32] Bell palsy is also more common in people who are immunocompromised or in women with preeclampsia.[33] Sex- and age-related demographics Bell palsy appears to affect the sexes equally. However, young women aged 10-19 years are more likely to be affected than are men in the same age group. Pregnant women have a 3.3 times higher risk of being affected by Bell palsy than do nonpregnant women; Bell palsy occurs most frequently in the third trimester. In general, Bell palsy occurs more commonly in adults. A slightly higher predominance is observed in patients older than 65 years (59 cases per 100,000 people), and a lower incidence rate is observed in children younger than 13 years (13 cases per 100,000 people). The lowest incidence is found in persons younger than 10 years, and the highest incidence is in persons aged 60 years or older. Peak ages are between 20 and 40 years. The disease also occurs in elderly persons aged 70-80 years.[34] Prognosis The natural course of Bell palsy varies from early complete recovery to substantial nerve injury with permanent sequelae (eg, persistent paralysis and synkinesis). Prognostically, patients fall into 3 groups:

Group 1 - Complete recovery of facial motor function without sequelae

Group 2 - Incomplete recovery of facial motor function, but with no cosmetic defects that are apparent to the untrained eye

Group 3 - Permanent neurologic sequelae that are cosmetically and clinically apparent

Approximately 80-90% of patients with Bell palsy recover without noticeable disfigurement within 6 weeks to 3 months. Use of the Sunnybrook grading scale for facial nerve function at 1 month has been suggested as a means of predicting probability of recovery.[35] Most patients who suffer from Bell palsy have neurapraxia or local nerve conduction block. These patients are likely to have a prompt and complete recovery of the nerve. Patients with axonotmesis, with disruption of the axons, have a fairly good recovery, but it is usually not complete. The risk factors thought to be associated with a poor outcome in patients with Bell palsy include (1) age greater than 60 years, (2) complete paralysis, and (3) decreased taste or salivary flow on the side of paralysis (usually 10-25% compared with the patients normal side). Other factors thought to be associated with poor outcome include pain in the posterior auricular area and decreased lacrimation. Patients aged 60 years or older have an approximately 40% chance of complete recovery and have a higher rate of sequelae. Patients younger than 30 years have only a 10-15% chance of less than complete recovery and/or long-term sequelae. The sooner the recovery, the less likely are the chances that sequelae will develop, as summarized below:

If some restoration of function is noted within 3 weeks, then the recovery is most likely to be complete

If the recovery begins between 3 weeks and 2 months, then the ultimate outcome is usually satisfactory

If the recovery does not begin until 2-4 months from the onset, likelihood of permanent sequelae, including residual paresis and synkinesis, is higher

If no recovery occurs by 4 months, then the patient is more likely to have sequelae from the disease, which include synkinesis, crocodile tears, and (rarely) hemifacial spasm

Bell palsy recurs in 4-14% of patients, with one source suggesting a recurrence rate of 7%. It may recur on the same or opposite side of the initial palsy. Recurrence usually is associated with a family history of recurrent Bell palsy. Higher recurrence rates among patients were reported in the past; however, many of these patients were found to have an underlying etiology for the recurrence, eliminating the diagnosis of Bell palsy, an idiopathic disease.[36] Patients with recurrent ipsilateral facial palsy should undergo MRI or high-resolution computed tomography (CT) scanning to rule out a neoplastic or inflammatory (eg, multiple sclerosis, sarcoidosis) cause of recurrence. Recurrent or bilateral disease should suggest myasthenia gravis. Sequelae Most patients with Bell palsy recover without any cosmetically obvious deformities. Approximately 30% of patients, however, experience long-term symptoms following the paralysis, and approximately 5% are left with an unacceptably high degree of sequelae. Bell palsy sequelae include incomplete motor regeneration, incomplete sensory regeneration, and aberrant reinnervation of the facial nerve. Incomplete motor regeneration The largest portion of the facial nerve is composed of efferent fibers that stimulate muscles of facial expression. Suboptimal regeneration of this portion results in paresis of all or some of these facial muscles. This manifests as (1) oral incompetence, (2) epiphora (excessive tearing), and (3) nasal obstruction. Incomplete sensory regeneration Dysgeusia or ageusia (impairment or loss of taste, respectively) may occur with incomplete regeneration of the chorda tympani. Incomplete regeneration of other afferent branches may result in dysesthesia (impairment of sensation or disagreeable sensation to normal stimuli). Aberrant reinnervation of the facial nerve During regeneration and repair of the facial nerve, some neural fibers may take an unusual course and connect to neighboring muscle fibers. This aberrant reconnection produces unusual neurologic pathways. When voluntary movements are initiated, they are accompanied by involuntary movements (eg, eye closure associated with lip pursing or mouth grimacing that

occurs during blinking of the eye). The condition in which involuntary movements accompany voluntary movements is termed synkinesis. History The diagnosis of Bell palsy must be made on the basis of a thorough history and physical examination, as well as the use of diagnostic testing when necessary. Bell palsy is a diagnosis of exclusion. Clinical features of the disorder that may help to distinguish it from other causes of facial paralysis include the sudden onset of unilateral facial paralysis and the absence of signs and symptoms of CNS, ear, and cerebellopontine angle disease. Symptoms of Bell palsy include the following:

Acute onset of unilateral upper and lower facial paralysis (over a 48-h period) Posterior auricular pain Decreased tearing Hyperacusis Taste disturbances Otalgia

Early symptoms include the following:

Weakness of the facial muscles poor eyelid closure Aching of the ear or mastoid (60%) Alteration of taste (57%) Hyperacusis (30%) Tingling or numbness of the cheek/mouth Epiphora Ocular pain Blurred vision

Onset The onset of Bell palsy is typically sudden, and symptoms tend to peak in less than 48 hours. This sudden onset can be frightening for patients, who often fear they have had a stroke or have a tumor and that the distortion of their facial appearance will be permanent. See the image below.

Left-sided Bell palsy. Because the condition appears so rapidly, patients with Bell palsy frequently present to the emergency department (ED) before seeing any other health care professional. More people first notice paresis in the morning. Because the symptoms require several hours to become evident, most cases of paresis likely begin during sleep. Facial paralysis The paralysis must include the forehead and lower aspect of the face. The patient may report the inability to close the eye or smile on the affected side. He or she also may report increased salivation on the side of the paralysis. If the paralysis involves only the lower portion of the face, a central cause should be suspected (ie, supranuclear). If the patient complains of contralateral weakness or diplopia in conjunction with the supranuclear facial palsy, a stroke or intracerebral lesion should be strongly suspected. If a patient has gradual onset of facial paralysis, weakness of the contralateral side, or a history of trauma or infection, other causes of facial paralysis must be strongly considered. Progression of the paresis is possible, but it usually does not progress beyond 7-10 days. A progression beyond this point suggests a different diagnosis. Patients who have bilateral facial palsy must be evaluated for Guillain-Barr syndrome, Lyme disease, and meningitis. Many patients report numbness on the side of the paralysis. Some authors believe that this is secondary to involvement of the trigeminal nerve, whereas other authors argue that this symptom is probably from lack of mobility of the facial muscles and not lack of sensation.

Ocular manifestations Early ocular complications include the following:

Lagophthalmos (inability to close the eye completely) Paralytic ectropion of the lower lid Corneal exposure Brow droop Upper eyelid retraction Decreased tear output/poor tear distribution Loss of the nasolabial fold Corneal erosion, infection, and ulceration (rare)

Late ocular manifestations include the following:

Mild, generalized mass contracture of the facial muscles, rendering the affected palpebral fissure narrower than the opposite one (after several months)

Aberrant regeneration of the facial nerve with motor synkinesis Reversed jaw winking (ie, contracture of the facial muscles with twitching of the corner of the mouth or dimpling of the chin occurring simultaneously with each blink) Autonomic synkinesis (ie, crocodile tearstearing with chewing) Permanent, disfiguring facial paralysis (rare)

Two thirds of patients complain about tear flow.[10] This results from the reduced function of the orbicularis oculi in transporting the tears. Fewer tears arrive at the lacrimal sac, and overflow occurs. The production of tears is not accelerated.

Posterior auricular pain Half of the patients affected with Bell palsy may complain of posterior auricular pain. [10] The pain frequently occurs simultaneously with the paresis, but pain precedes the paresis by 2-3 days in about 25% of patients. Ask the patient if he or she has experienced trauma, which may account for the pain and facial paralysis.

One third of patients may experience hyperacusis in the ear ipsilateral to the paralysis, which is secondary to weakness of the stapedius muscle. Taste disorders While only one third of patients report taste disorders,[10] 80% of patients show a reduced sense of taste. Patients may fail to note reduced taste, because of normal sensation in the uninvolved side of the tongue. Early recovery of the sense of taste suggests that the patient will experience a complete recovery. Facial spasm Facial spasm, a very rare complication of Bell palsy, occurs as tonic contraction of 1 side of the face. Spasms are more likely to occur during times of stress or fatigue and may be present during sleep. This condition may occur secondary to compression of the root of the seventh nerve by an aberrant blood vessel, tumor, or demyelination of the nerve root. Facial spasm occurs most commonly in patients in the fifth and sixth decades of life. Sometimes the etiology is not found. The presence of progressive facial hemispasm with other cranial nerve findings indicates the possibility of a brainstem lesion. Synkinesis is an abnormal contracture of the facial muscles while smiling or closing the eyes. It may be mild and result in slight movement of the mouth or chin when the patient blinks or in eye closure with smiling. Crocodile tears can be observed; patients shed tears while they eat. Cranial neuropathies Some believe that other cranial neuropathies may also be present in Bell palsy; however, this is not uniformly accepted. The symptoms in question include the following:

Hyperesthesia or dysesthesia of the glossopharyngeal or trigeminal nerves Dysfunction of the vestibular nerves Hyperesthesia of the cervical sensory nerves Vagal or trigeminal motor weakness

Physical Examination

Weakness and/or paralysis from involvement of the facial nerve affects the entire face (upper and lower) on the affected side. A careful examination of the head, ears, eyes, nose, and throat must be carried out in all patients with facial paralysis. Time must also be taken to examine the patients skin for signs of squamous cell carcinoma, which can invade the facial nerve, and parotid gland disease. Focus attention on the voluntary movement of the upper part of the face on the affected side; in supranuclear lesions, such as occur in a cortical stroke (upper motor neuron; above the facial nucleus in the pons), the upper third of the face is spared in the majority of cases, while the lower two thirds are paralyzed. The orbicularis, frontalis, and corrugator muscles are innervated bilaterally at the level of the brainstem, which explains the pattern of facial paralysis in these cases.[31] Initial inspection of the patient demonstrates flattening of the forehead and nasolabial fold on the side affected by the palsy. When the patient is asked to raise his or her eyebrows, the side of the forehead with the palsy will remain flat. When the patient is asked to smile, the face will become distorted and lateralize to the side opposite the palsy. Otologic examination An otologic examination includes pneumatic otoscopy and tuning fork examination. An otologic cause should be considered if the history or physical examination demonstrates evidence of acute or chronic otitis media, including a tympanic membrane perforation, otorrhea, cholesteatoma, or granulation tissue, or if a history of ear surgery is noted. Concurrent rash or vesicles along the ear canal, pinna, and mouth should raise the suspicion for Ramsay Hunt syndrome (herpes zoster oticus). The external auditory canal must be inspected for vesicles, injection or erythema, infection, or trauma. The patient may have decreased sensation to pinprick in the posterior auricular area. Tympanic membranes should be normal; the presence of inflammation, vesicles, or other signs of infection raises the possibility of complicated otitis media. The patient who has paralysis of the stapedius muscle will report hyperacusis. This can be tested clinically using the stethoscope loudness test. In this, the patient wears a stethoscope, and an

activated tuning fork is placed at its bell. The loud sound will lateralize to the side of the paralyzed stapedius muscle. Ocular examination With weakness/paralysis of the orbicularis oculi muscle (facial nerve innervation) and normal function of the levator muscle (oculomotor nerve innervation) and Mueller muscle (sympathetic innervation), the patient frequently is not able to close the eye completely on the affected side. On attempted eye closure, the eye rolls upward and inward on the affected side. (This is known as Bell phenomenon and is considered a normal response to eye closure.) In addition, the tear reflex is absent in many cases of Bell palsy. For these reasons, the patient may have decreased tearing and susceptibility to corneal abrasion and dryness of the eye. The patient may appear to have loss of corneal reflex on the affected side; however, the contralateral eye blinks when testing the corneal reflex on the affected side. Oral examination A careful oral examination must be performed. Taste and salivation are affected in many patients with Bell palsy. Taste may be assessed by holding the tongue with gauze and testing each side of the tongue independently with salt, sugar, and vinegar. The mouth must be washed after testing with different substances. The affected side has decreased taste compared with the normal side. Neurologic examination Careful neurologic examination is necessary in patients with facial paralysis. This includes complete examination of all of the cranial nerves, sensory and motor testing, and cerebellar testing. A neurologic abnormality warrants neurologic referral and further testing, such as MRI of the brain, lumbar puncture, and EMG where appropriate. Grading The grading system developed by House and Brackmann categorizes Bell palsy on a scale of I to VI.[3, 4, 5] Grade I is normal facial function. Grade II is mild dysfunction. Characteristics include the following:

Slight weakness is noted on close inspection

Slight synkinesis may be present Normal symmetry and tone are noted at rest Forehead motion is moderate to good Complete eye closure is achieved with minimal effort Slight mouth asymmetry is noted

Grade III is moderate dysfunction. The following characteristics are found:

An obvious, but not disfiguring, difference is noted between the 2 sides A noticeable, but not severe, synkinesis, contracture, or hemifacial spasm is present Normal symmetry and tone are noted at rest Forehead movement is slight to moderate Complete eye closure is achieved with effort A slightly weak mouth movement is noted with maximal effort

Grade IV is moderately severe dysfunction. Signs include the following:

An obvious weakness and/or disfiguring asymmetry is noted Symmetry and tone are normal at rest No forehead motion is observed Eye closure is incomplete An asymmetrical mouth is noted with maximal effort

Grade V is severe dysfunction. Characteristics include the following:

Only a barely perceptible motion is noted Asymmetry is noted at rest No forehead motion is observed Eye closure is incomplete Mouth movement is only slight.

Grade VI is total paralysis. The following are noted:

Gross asymmetry No movement In this system, grades I and II are considered good outcomes, grades III and IV represent moderate dysfunction, and grades V and VI describe poor results. Grade VI is defined as

complete facial paralysis; all of the other grades are defined as incomplete. An incomplete facial paralysis denotes an anatomically and, to some degree, functionally intact nerve. The degree of facial nerve function should be noted in the chart at the patients initial visit. Diagnostic Considerations In most cases, the diagnosis of Bell palsy is straightforward as long as the patient has undergone a thorough history and physical examination. Failure to recognize structural, infectious, or vascular lesions leading to seventh cranial (facial) nerve damage may result in further deterioration of the patients condition. For example, if other cranial nerve, motor, or sensory symptoms are present, then other neurologic diseases should be considered (eg, stroke, GuillainBarr syndrome, basilar meningitis, cerebellar pontine angle tumor). Symptoms associated with seventh nerve neoplasm include slowly progressive paralysis, facial hyperkinesis, severe pain, recurrent palsy, and other cranial nerve involvement. Cerebellopontine tumors may affect the seventh, eighth, and fifth cranial nerves simultaneously. Patients with a progressive paralysis of the facial nerve lasting longer than 3 weeks should be evaluated for neoplasm. Recurrent ipsilateral facial paralysis must raise the suspicion of a tumor of the facial nerve or parotid gland. Tumors in the temporal bone, such as facial nerve neuromas, meningiomas, hemangiomas, and malignant primary and metastatic lesions, should be considered as well. If a patient is from the Northeast United States, Lyme disease should be considered as a cause of facial paralysis, and serologic testing should be performed. Approximately 5-10% of untreated Lyme patients may have a peripheral facial nerve palsy. If a patient reports the sudden onset of hearing loss and severe pain with the onset of facial paralysis, Ramsay Hunt syndrome must be considered. Typically, these patients will also have an erythematous vesicular rash involving the ear canal, auricle, and/or oropharynx. Other problems to be considered include the following:

Acoustic neuroma and other cerebellopontine angle lesions Acute or chronic otitis media Amyloidosis

Aneurysm of vertebral artery, basilar artery, or carotid arteries Autoimmune syndromes Botulism Carcinomatosis Carotid disease and stroke - Including embolic phenomenon Cholesteatoma of the middle ear Congenital malformation Facial nerve schwannoma Geniculate ganglion infection Glomus tumors Guillain-Barr syndrome Herpes zoster Human immunodeficiency virus (HIV) infection Leukemia/lymphoma Leukemic meningitis Malignant otitis externa Melkersson-Rosenthal syndrome Meningitis Mycoplasma pneumonia Nasopharyngeal carcinoma Osteomyelitis of the skull base Otitis media Parotid gland disease or tumor Pontine lesions Sarcoma Skull base tumor Teratoma Tuberculosis Viral syndromes Wegener granulomatosis Wegener vasculitis

In the setting of an appropriate history, additional considerations include the following:

Alcoholic neuropathy Anesthesia nerve blocks Basal skull fractures Barotrauma Benign intracranial hypertension Birth trauma Carbon monoxide exposure Diphtheria Facial injuries Facial trauma (blunt, penetrating, iatrogenic) Forceps delivery Iatrogenic - As in otologic, neurotologic, skull base, or parotid surgery Infectious mononucleosis Kawasaki disease Leprosy Metastatic disease Mumps Polyneuritis Temporal bone fracture Tetanus Thalidomide exposure Toxic

Bilateral cases Bilateral simultaneous Bell palsy is a rare occurrence; the rate of such cases is less than 1% of that of unilateral facial nerve palsy,[30, 31] and it accounts for only 23% of bilateral facial paralysis cases. The majority of patients with bilateral facial palsy have Guillain-Barr syndrome, sarcoidosis, Lyme disease, meningitis (neoplastic or infectious), or bilateral neurofibromas (in patients with neurofibromatosis type 2). Differential Diagnoses

Anterior Circulation Stroke Benign Skull Tumors Brainstem Gliomas Cerebral Aneurysms Intracranial Hemorrhage Lyme Disease in Emergency Medicine Meningioma Neurosyphilis Sarcoidosis Tuberculous Meningitis

Bells Palsy Work Up In many cases, the history and physical examination of the patient establish the diagnosis of Bell palsy. If the clinical findings are doubtful or if paralysis lasts longer than 6-8 weeks, further investigations should be considered.[11] No specific diagnostic tests are available for Bell palsy, though the following may be useful for identifying or excluding other disorders:

Rapid plasma reagin (RPR) and/or venereal disease research laboratory (VDRL) test or fluorescent treponemal antibody absorption (FTA-ABS) test

HIV screening by means of enzyme-linked immunosorbent assay (ELISA) and/or Western blot Complete blood cell (CBC) count Erythrocyte sedimentation rate measurement Thyroid function studies Serum glucose level Cerebrospinal fluid analysis In addition to the above tests, blood glucose or hemoglobin A1c levels may be obtained to determine if the patient has undiagnosed diabetes. Persons with diabetes have a 29% higher risk of being affected by Bell palsy than do persons without diabetes.

Serum titers for herpes simplex virus (HSV) may be obtained. However, this test is usually not helpful, owing to the ubiquitous nature of this virus. Antineutrophil cytoplasmic antibody (cANCA) levels are indicated, if applicable, to exclude Wegener granulomatosis. In areas where Lyme disease is endemic, serum titers (immunoglobulin M [IgM] and IgG) for Borrelia burgdorferi should be obtained. Serum titers (IgM and IgA) for Mycoplasma pneumoniae may be obtained. A study in Germany measured titers in patients with Bell palsy and found that several patients had elevated titers for M pneumoniae, though only 2 of those who tested positive had respiratory symptoms.[37] Salivary flow test Salivary flow also may be tested. The physician places a small catheter into the paralyzed and normal submandibular glands. The patient is then asked to suck on a lemon, and the salivary flow is compared between the 2 sides. The normal side is the control. Schirmer blotting test The Schirmer blotting test may be used to assess tearing function. The use of benzene will stimulate the nasolacrimal reflex, and the degree of tearing can be compared between the paralyzed and normal sides. Nerve excitability test The nerve excitability test determines the threshold of the electrical stimulus needed to produce visible muscle twitching. This test is technically challenging and has very limited clinical availability. Imaging considerations If the history and physical examination lead to a diagnosis of Bell palsy, then immediate imaging is not necessary, because most patients with Bell palsy improve within 8-10 weeks. If the paralysis does not improve or worsens, imaging may be useful. If the patient has a palpable parotid mass, imaging may be necessary. CT Scanning and MRI for Bells Palsy

Imaging with CT scanning or other methods is indicated if there are other associated physical findings or if the paresis is progressive and unremitting. CT scanning demonstrates the architecture of the temporal bone and may be used if some other pathology is suspected. MRI is useful as a means of excluding other pathologies as the cause of paralysis and is preferred for imaging the cerebellopontine angle. MRI in patients with Bell palsy may show enhancement of the seventh cranial nerve (facial nerve) at or near the geniculate ganglion. Alternatively, MRI may demonstrate a neoplasm compressing the facial nerve. Tumors that compress or involve the facial nerve include schwannoma (most common), hemangioma, meningioma, and sclerosing hemangioma. Perform gadolinium-enhanced MRI when findings are atypical or when the facial nerve paralysis appears central, to rule out a tumor or vascular compression.[38]Increased signal intensity of the premeatal or intratemporal segment of the facial nerve after administration of gadolinium has been noted in patients with Bell palsy.[39, 40] Attempts to correlate outcome with quantification of signal intensity increases have yielded contradictory results. Conduction Testing and EMG for Bells Palsy Useful tests for evaluation of the function of the facial nerve include nerve conduction testing and EMG. Nerve conduction velocities and EMG produce a graphic readout of the electrical currents, displayed by stimulating the facial nerve and recording the excitability of the facial muscles it supplies. These tests may aid in assessing the outcome of a patient who has persistent and severe Bell palsy. This testing is not part of the acute workup; the tests are most useful when performed 3-10 days after the onset of paralysis. Note that most electromyographic/nerve conduction studies do not show an abnormality for 3 weeks following a peripheral nerve injury. Comparison to the contralateral side helps to demonstrate the extent of nerve injury and has prognostic implications. Nerve conduction responses are abnormal if a difference of 50% in amplitude between the paralyzed and normal side is detected; a difference of 90% between the 2 sides suggests a poorer prognosis.

May et al demonstrated that prognosis may be favorable if the motor amplitude of the affected side is greater than 25% of that of the normal side. An incomplete recovery was observed in patients whose results demonstrated less than 25% amplitude on the paralyzed side.[41] Blink reflexes can be used to measure conduction across the involved segment, but they are commonly absent in Bell palsy. Electroneurography for Bells Palsy Electroneurography is a physiologic test that uses EMG to objectively measure the difference between potentials generated by the facial musculature on both sides of the face in response to a supramaximal electrical stimulation of the facial nerve. Because all electrodiagnostic testing is performed on the nerve distal to the proposed site of injury, sufficient time is needed for wallerian degeneration to occur, usually 48-72 hours. Testing should begin 3 days from the onset of complete paralysis. Electrodiagnostic testing measures the facial nerve degeneration indirectly. If a patient does not reach 90% degeneration within the first 3 weeks of the onset of paralysis, some studies suggest that the prognosis is excellent, with over 80-100% of the patients recovering with excellent function. The patients who reach over 90% degeneration within the first 3 weeks of the onset of paralysis have a much more guarded prognosis, with only 50% having good recovery of facial motion. The rate of degeneration also predicts the prognosis. Patients who have 90% degeneration by 5 days have a worse prognosis than those with 90% degeneration at 14 days. Brainstem Auditory Evoked Response and Audiometry Brainstem auditory evoked response (BAER) may be obtained in patients with peripheral facial nerve lesions and other neurologic involvement. This test measures the transmission of response through the brainstem and is effective in detecting, notably, retrocochlear lesions. Hendrix and Melnick evaluated the BAER of 17 patients with Bell palsy and found no evidence of retrocochlear lesions of the auditory system in any of the patients.[42] In study by Shannon et al, BAER was recorded in 27 patients with Bell palsy; only 6 patients had prolonged brainstem transmission but normal auditory function.[43]

These studies were small and do not support routine use of BAER in patients with Bell palsy. However, when a patient presents with multiple cranial neuropathies (eg, of the seventh and eighth cranial nerves), BAER may be useful. If hearing loss is suspected, audiography and auditory evoked potentials (AEPs) should be pursued once an underlying structural lesion has been excluded. Typically, the hearing threshold is not affected by Bell palsy. Impedance testing may reveal an absent or diminished stapedial reflex because of paresis of the stapedial branch of the facial nerve. Blepharokymographic Analysis for Bells Palsy Blepharokymographic analysis, a high-speed eyelid motion-analysis system, has been used to evaluate movement of the eyelids. Computer-based analysis may prove helpful in diagnosing Bell palsy, predicting prognosis, and evaluating response to therapeutic measures such as placement of a gold weight in the affected upper eyelid (used in cases in which spontaneous recovery has been limited). Histologic Findings in Bells Palsy In a review of 12 autopsy cases of patients with Bell palsy, most cases showed inflammatory changes around the mastoid cells and walls of the arteries.[44] The most common site of involvement was the geniculate ganglion. Surgical findings described constriction of the nerve at the stylomastoid foramen, with swelling of the nerve itself. Microscopic findings showed an inflammatory reaction with infiltration of macrophages on the nerve TREATMENT for Bells Palsy Because persons with true Bell palsy generally have an excellent prognosis, and because spontaneous recovery is fairly common, treatment of Bell palsy is still controversial. The goals of treatment are to improve facial nerve (seventh cranial nerve) function and reduce neuronal damage. Many issues must be addressed in treating patients with Bell palsy. The most important is the onset of symptoms. Treatment may be considered for patients who present within 1-4 days of the onset of paralysis.

Patients with Bell palsy frequently present to the emergency department (ED). The role of the ED clinician consists of the following:

Initiate appropriate treatment Protect the eye Arrange appropriate medical follow-up care The American Academy of Neurology (AAN) published a practice parameter in 2001 stating that steroids are probably effective and acyclovir (with prednisone) is possibly effective for the treatment of Bell palsy. There was insufficient evidence for recommendations on facial decompression surgery.[45] In 2012, the AAN released guidelines stating that steroids are highly likely to be effective and increase the likelihood of recovery of facial nerve function in new-onset Bell palsy[6, 8] A variety of nonpharmacologic measures have been used to treat Bell palsy, including physical therapy (eg, facial exercises,[46] neuromuscular retraining[47] ) and acupuncture.[48] No adverse effects of these treatments have been reported. Reviews suggest that physical therapy may result in faster recovery and reduced sequelae, but further randomized, controlled trials are needed to confirm any benefit. Surgical options Surgical options for Bell palsy include the following:

Facial nerve decompression Subocularis oculi fat (SOOF) lift Implantable devices (eg, gold weights) placed into the eyelid Tarsorrhaphy Transposition of the temporalis muscle Facial nerve grafting Direct brow lift Anecdotal evidence suggests that surgical repair by using a combination of procedures tailored to the patients clinical findings works well for improving symptoms and exposure. Most patients who have had severe corneal exposure from lagophthalmos with or without paralytic ectropion have received a combination of lateral tarsal strip placement, SOOF lift, and gold-weight

implantation. Patients without severe exposure have received a single procedure or combinations of procedures. Pharmacologic Therapy for Bells Palsy The most widely accepted treatment for Bell palsy is corticosteroid therapy. However, the use of steroids is still controversial because most patients recover without treatment. Antiviral agents have also been studied in this setting, as have combinations of the 2 types of drugs. Corticosteroids As previously mentioned, 2012 guidelines from the AAN state that steroids are highly likely to be effective and increase the likelihood of recovery of facial nerve function in new-onset Bell palsy[6, 8] Guidelines from the American Academy of OtolaryngologyHead and Neck Surgery Foundation (AAO-HNSF) were issued in November 2013 that also support the AAN guidelines. The guidelines recommend use of corticosteroids within 72 hours from the onset of symptoms. Antiviral agents (eg, acyclovir, valacyclovir) may be considered if a viral etiology is suspected, but only in combination with corticosteroids.[49] Many trials have been carried out to study the efficacy of prednisone in Bell palsy. In 1972, for example, Adour et al conducted a large, controlled clinical trial that found that 89% of patients treated with prednisone had full recovery, compared with 64% of patients treated with placebo.[50] This trial and other early studies, however, showed conflicting results for steroid use in treating Bell palsy,[51] and they were limited in their size. However, 3 subsequent randomized, controlled trials showed significant improvement in outcomes when prednisolone was started within 72 hours of symptom onset.[12, 13, 52] Based on these 3 studies, steroids should be strongly considered to optimize outcomes. Once the decision to use steroids is made, the consensus is that this treatment should be started immediately. One of the 3 studiesa double-blind, randomized trial from Scotland involving 551 patients with Bell palsy who were recruited within 72 hours of symptom onsetdemonstrated that early

treatment with prednisolone can significantly improve the chances of complete recovery at 3 and 9 months.[12] In contrast, acyclovir given alone did not show any significant difference in the rate of facial recovery compared with placebo, and there was no additional benefit from combining acyclovir and prednisolone compared with prednisolone alone. A larger double-blind, controlled trial showed that prednisolone significantly shortened the time to complete recovery, while valacyclovir did not affect facial recovery compared with placebo.[13] Further analysis showed that patients treated with prednisolone within 48 hours had significantly higher rates of complete recovery than did those who were not treated, whereas no significant difference in recovery rate was seen between patients treated at 49-72 hours and untreated patients.[53] The recommended dose of prednisone for the treatment of Bell palsy is 1 mg/kg or 60 mg/day for 6 days, followed by a taper, for a total of 10 days. Caution should be used in patients with any of the following:

Tuberculosis Immunocompromise Pregnancy Active infection Sarcoidosis Sepsis Peptic ulcer disease Diabetes mellitus Renal or hepatic dysfunction Malignant hypertension High-dose steroids (>120 mg/day of prednisone) have been safely used to treat Bell palsy in patients with diabetes[54, 55] ; however, optimal dosing has not been established. Caution should be used in these cases because of the risk of hyperglycemia. Antiviral agents Evaluation of the use of antiviral medicines in Bell palsy has shown limited benefit from these drugs,[38, 56] with 3 randomized, controlled trials having demonstrated no benefit from them.[12, 13,

52]

However, given the evidence suggesting that a large percentage of Bell palsy cases may result

from a viral infection,[24, 57] the use of antiviral agents may be reasonable in certain situations. The 2001 AAN practice perameter suggested that the use of acyclovir for the treatment of Bell palsy is only possibly effective and that therapy with this agent alone is not effective in facial recovery.[45] According to the academy's 2012 guidelines, benefit from antivirals has not been established and, at best, is likely to be modest.[6, 8] The Scottish study cited earlier suggested that prednisolone, and not acyclovir, is useful for facial recovery in Bell palsy.[12] A Cochrane review found no significant benefit to the use of antivirals over placebo in reducing the rate of incomplete recovery from Bell palsy.[58] This meta-analysis looked at 7 studies involving a total of 1987 patients treated between 1966 and 2008. Acyclovir (Zovirax) is administered at a dosage of 400 mg orally 5 times daily for 10 days. Evidence supports HSV as a major cause of Bell palsy; if varicella zoster virus (VZV) is suspected, higher doses may be needed (800 mg orally 5 times daily). Valacyclovir (Valtrex), taken orally in doses of 500 mg twice daily for 5 days, may be used instead of acyclovir. Although it is more expensive, it may be associated with better compliance. If VZV is the cause of Bell palsy, higher doses may be needed (1000 mg orally 3 times daily). Because of the increased cost and greater risk of side effects with higher doses, however, valacyclovir cannot be routinely recommended for the treatment of Bell palsy at this time. Corticosteroid-antiviral combinations A prospective randomized trial with 101 patients comparing prednisone with acyclovir demonstrated that the prednisone group had better clinical recovery.[59]In another prospective, randomized trial, with 99 patients, the combination of prednisone and acyclovir was more effective than prednisone monotherapy in preventing nerve degeneration, as measured by electrodiagnostic tests.[60] A Japanese randomized, prospective study of 221 patients with Bell palsy showed significant improvement in facial function using a combination of prednisone and valacyclovir therapy

versus using prednisone alone. This improvement was noted in patients who had severe to complete facial palsy.[57] Quant et al conducted a meta-analysis of published studies from 1984 to January 2009 that showed no improved benefit (with respect to degree of facial muscle recovery in patients with Bell palsy) from the use of corticosteroids plus antiviral agents as compared with corticosteroid therapy alone.[61] Six trials (representing pooled data from 1145 patients) were examined and included 574 patients who received corticosteroids alone and 571 patients who received corticosteroids and antiviral agents. Quant et al suggest that the routine use of antiviral agents is not warranted; however, future studies should improve diagnostic efforts to identify herpes virus as a potential etiology. Additionally, newer antiviral agents may prove more beneficial than older antiviral agents used in the studies analyzed to date.[61] Contrary to the meta-analyses by Quant et al and Cochrane, de Almeida and colleagues found that antiviral agents, when combined with corticosteroids, were associated with greater risk reduction of borderline significance than were corticosteroids alone.[62] Their meta-analysis examined 18 trials involving a total of 2786 patients. If antiviral agents are used, they should be initiated in conjunction with corticosteroids. Future studies will be needed to determine which population will most benefit from antiviral therapy. Local Treatment for Bells Palsy It is universally accepted that eye care is imperative in Bell palsy. The patients eye is at risk for drying, corneal abrasion, and corneal ulcers. In most cases, topical ocular lubrication (with artificial tears during the day and lubricating ophthalmic ointment at night, or occasionally ointment day and night) is sufficient to prevent the complications of corneal exposure.[9] Punctal plugs may be helpful if dryness of the cornea is a persistent problem. Occluding the eyelids by using tape or by applying a patch for 1 or 2 days may help to heal corneal erosions. Care must be taken to prevent worsening the abrasion with the tape or patch by

ensuring that the eyelid is securely closed. Clear plastic wrap, cut to 8 X 10 cm and applied with generous amounts of ointment as a nighttime occlusive bandage, may be required. External eyelid weights are available to improve mechanical blink. The weights are attached to the upper lid with an adhesive and are available in different skin tones. Lower-lid ectropion or droop can temporarily be helped by applying tape below the lid margin in the center of the lower lid; the lid is pulled laterally and upward to anchor on the orbital rim. Botulinum toxin can be injected transcutaneously or subconjunctivally at the upper border of the tarsus and aimed at the levator muscle to produce complete ptosis and to protect the cornea.[4] Botulinum toxin may help in relaxing the facial muscles after they have developed mass contraction, though the results are not as satisfying in patients with Bell palsy as in patients with idiopathic hemifacial spasm. Facial Nerve Decompression Surgery to decompress the facial nerve is controversial. Patients with a poor prognosis, identified by facial nerve testing or persistent paralysis, appear to benefit the most from surgical intervention. However, studies have been mixed as far as benefit from surgery.[45] Surgery may be considered in patients with complete Bell palsy that has not responded to medical therapy and with greater than 90% axonal degeneration, as shown on facial nerve EMG within 3 weeks of the onset of paralysis.[63,
31]

The problem must be localized with MRI. The

surgeon can then decide if the maxillary segment should be decompressed externally or if the labyrinthine segment and geniculate ganglion should be decompressed with a middle fossa craniotomy. A study in patients with greater than 90% degeneration demonstrated superior results in the cohort that underwent middle fossa decompression, compared with the cohort that chose not to pursue surgical decompression. In the surgical group, 91% of cases exhibited a postoperative House-Brackmann grade of I or II. In the nonsurgical group, 58% of the patients had a poor result, with a House-Brackmann grade of III or IV at 7 months. The best surgical results were obtained when the procedure was done within 14 days after the onset of paralysis.[64]

Subocularis Oculi Fat Lift The SOOF is deep to the orbicularis oculi muscle and superficial to the periosteum below the inferior orbital rim. An SOOF lift is designed to lift and suspend the midfacial musculature. The procedure may also elevate the upper lip and the angle of the mouth to improve facial symmetry. Lateral tarsal strip procedure An SOOF lift is commonly performed in conjunction with a lateral tarsal strip procedure to correct horizontal lower-lid laxity and to improve apposition of the lid to the globe.[65] First, lateral canthotomy and cantholysis is performed. Then, the anterior lamella is removed, and the lateral tarsal strip is shortened and attached to the periosteum at the lateral orbital rim.

Implants in Eyelid Implantable devices have been used to restore dynamic lid closure in cases of severe, symptomatic lagophthalmos. These procedures are best for patients with poor Bell phenomenon and decreased corneal sensation. Gold or platinum weights, a weight-adjustable magnet, or palpebral springs can be inserted into the eyelids. Pretarsal gold-weight implantation is most commonly performed. The implants are inert and composed of 99.99% pure gold or platinum. Sizes range from 0.6-1.8 g. The weight allows the upper eyelid to close with gravity when the levator palpebrae are relaxed. Therefore, patients must sleep with their head slightly elevated. The implants are easily removed if nerve function returns. Complications include migration of the implant, inflammation, allergic reaction, and extrusion.

Tarsorrhapy Tarsorrhaphy decreases horizontal lid opening by fusing the eyelid margins together, increasing support of the precorneal lake of tears and improving coverage of the eye during sleep. The procedure can be done in the office and is particularly suitable for patients who are unable or

unwilling to undergo other surgery. It can be completed as either a temporary or a permanent measure. Permanent tarsorrhaphy is performed if nerve recovery is not expected. Tarsorrhaphy can be performed laterally, centrally, or medially. The lateral procedure is the most common; however, it can restrict the monocular temporal visual field. Central tarsorrhaphy offers good corneal protection, but it occludes vision and can be cosmetically unacceptable. Medial or paracentral tarsorrhaphy is performed lateral to the lacrimal puncta and can offer good lid closure without substantially affecting the visual field

Muscle Transposition, Nerve Grafting, nd Brow Lift Transposition of temporalis Transposition of the temporalis muscle can be used to reanimate the face and to provide lid closure by using the fifth cranial nerve. Strips from the muscle and fascia are placed in the upper and lower lids as an encircling sling. Patients initiate movement by chewing or clenching their teeth. Facial nerve grafting or hypoglossal-facial nerve anastomosis Reinnervation of the facial nerve by means of facial nerve grafting or hypoglossal-facial nerve anastomosis can be used in cases of clinically significant permanent paralysis to help restore relatively normal function to the orbicularis oculi muscle or eyelids. Direct brow lift Brow ptosis is repaired with a direct brow lift. Care should be taken in the presence of corneal decompensation because lifting the brow can cause worsening of lagophthalmos, especially if lid closure is poor. A gold-weight implant can be placed or lower-lid resuspension can be performed simultaneously to prevent this complication.

Conultations and Monitoring Consultations

If the patients paralysis is not resolving or is progressing to complete paralysis, a thorough neurologic assessment and an examination of the head, eyes, ears, nose, and throat should be performed to rule out neoplastic causes of facial nerve palsy. If the initial diagnostic impression based on the history and physical examination of the patient is not Bell palsy, then consultation with a neurologist or otolaryngologist is needed. For example, consultation with an otolaryngologist should be made for the patient who has facial palsy and pain and in whom the ear, nose, and throat examination does not show auricular vesicles (as in Ramsay Hunt syndrome). These patients should be evaluated for malignancy or other structural lesions of the facial nerve. Consultation with a neurologist or otolaryngologist should also be sought if the paralysis persists for several months. An evaluation by an otolaryngologist may be indicated for patients with a prolonged course, for the consideration of surgical decompression of the facial nerve. Patients who report persistent dry eye or painful eye should be referred to an ophthalmologist. An evaluation by a specialist in infectious disease may be indicated if results of laboratory studies are positive for Lyme disease, syphilis, or HIV infection. The patient should be monitored if the initial EMG shows that the function of the involved facial muscles is less than 25% of the normal sides facial muscle function. If the residual paralysis is severe, the patient should be referred for counseling.

Medication for Bells Palsy The goals of pharmacotherapy are to reduce morbidity and prevent complications. Agents used in cases of Bell palsy include corticosteroids and antiviral agents. Early treatment with corticosteroids is the most widely accepted treatment, but it remains controversial because most patients recover without treatment. The literature offers less support for the use of antiviral agents in either monotherapy or combination therapy, although treatment with combinations of corticosteroids and antiviral agents is somewhat better supported.

Corticoteroids Prednisone can be used in the treatment of Bell palsy but has many adverse effects, including the following:

Fluid retention Hypokalemia Myopathy Peptic ulcer Headache (pseudotumor) Menstrual irregularities Cataracts Glaucoma Manifestation of latent diabetes mellitus In addition, signs of infection may be masked in patients taking prednisone. Physicians should use caution when using prednisone in patients with the aforementioned conditions. View full drug information Prednisone (Deltasone, Orasone, Sterapred)

Prednisone, the standard drug used in Bell palsy, is a glucocorticoid that is absorbed readily from the gastrointestinal tract. It has anti-inflammatory and immune-modulating effects, as well as profound and varied metabolic effects. For best outcome, prednisone treatment should be initiated within 72 hours of symptom onset. Antivirals Acyclovir and valacyclovir have been administered in the treatment of Bell palsy in combination with prednisone or have been used alone in patients who cannot take prednisone. The use of antivirals has proved most beneficial in patients with severe to complete facial palsy.[57] Acyclovir (Zovirax)

Acyclovir is a prodrug activated by phosphorylation, by way of virus-specific thymidine kinase (TK), that inhibits viral replication. Herpes virus TK, but not host cell TK, uses acyclovir as a purine nucleoside, converting it into acyclovir monophosphate, a nucleotide analogue. Guanylate kinase converts the monophosphate form into diphosphate and triphosphate analogues that inhibit viral DNA replication. Acyclovir has an affinity for viral TK and, once phosphorylated, causes DNA chain termination when acted on by DNA polymerase. The drug inhibits the activity of HSV-1 and HSV-2. Patients experience less pain and faster resolution of cutaneous lesions when acyclovir is used within 48 hours after rash onset. Acyclovir may also prevent recurrent outbreaks. Early initiation of therapy is imperative. Valacyclovir (Valtrex)

Valacyclovir is a prodrug that is rapidly converted to acyclovir. It is more expensive than acyclovir, but it has a more convenient dosing regimen.

Brain Neoplasms Practice Essentials Brain tumors may originate from neural elements within the brain, or they may represent spread of distant cancers. Gliomas, metastases, meningiomas, pituitary adenomas, and acoustic

neuromas account for 95% of all brain tumors. Essential update: FDA approves new contrast agent for CNS imaging In March 2013, the US Food and Drug Administration (FDA) approved gadoterate meglumine (Dotarem), a gadolinium-based contrast agent (GBCA), for use in magnetic resonance imaging (MRI) of the brain, spine, and associated tissues in patients aged 2 years and older. In a study of 245 adult and 38 pediatric patients with suspected central nervous system (CNS) abnormalities, the use of gadoterate meglumine resulted in improved detection and analysis of CNS lesions. Similar results were seen in another study in patients with known CNS abnormalities. Gadoterate meglumine is the seventh GBCA approved by the FDA for CNS MRI.[1] Signs and Symptoms

Presenting complaints of patients with an intracranial neoplasm tend to be similar for primary brain tumors and intracranial metastases. The onset of symptoms usually is insidious, but an acute episode may occur with bleeding into the tumor, or when an intraventricular tumor suddenly occludes the third ventricle. Manifestations may be nonspecific and include the following:

Headache Altered mental status Ataxia Nausea Vomiting Weakness Gait disturbance CNS neoplasms also may manifest as follows:

Focal seizures Fixed visual changes Speech deficits Focal sensory abnormalities Headache associated with intracranial neoplasms have the following characteristics:

Often is a late complaint Usually not an isolated finding The worst symptom in only one half of patients Usually nonspecific and resembles tension-type headaches[2, 3, 4] In patients with established headache, may manifest as a change in the headache pattern New onset of headaches in middle-aged or older patients is worrisome The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor

Headaches are more common with posterior fossa tumors Headache is a more frequent symptom of intracranial tumor in pediatric patients Prevailing inaccurate portrayals of a tumor headache include the following:

Pain that is worse in the early morning than at other times Accompanying vomiting (with or without nausea) Exacerbation with Valsalva maneuvers, bending over, or rising from a recumbent position No physical finding or pattern of findings unmistakably identifies a patient with a CNS neoplasm. Based on their location, intracranial tumors may produce a focal or generalized deficit, but signs may be lacking (especially if the tumor is confined to the frontal lobe) or even falsely localizing. Findings may include the following:

Papilledema, which is more prevalent with pediatric brain tumors, reflects an increase in intracranial pressure (ICP) of several days or longer

Diplopia may result from displacement or compression of the sixth cranial nerve at the base of the brain

Impaired upward gaze, called Parinaud syndrome, may occur with pineal tumors Tumors of the occipital lobe specifically may produce homonymous hemianopia or partial visual field deficits

Anosmia may occur with frontal lobe tumors Brainstem and cerebellar tumors induce cranial nerve palsies, ataxia, incoordination, nystagmus, pyramidal signs, and sensory deficits on one or both sides of the body See Clinical Presentation for more detail. Diagnosis With clinical suspicion of cancer, obtain routine laboratory studies on admission, including the following:

Complete blood cell count (CBC) Coagulation studies Electrolyte levels Comprehensive metabolic panel Obtain neuroimaging studies in patients with symptoms suggestive of an intracranial neoplasm, such as the following:

Acute mental status changes New-onset seizures

Focal motor or sensory deficits, including gait disturbance Suspicious headache Signs of elevated ICP (eg, papilledema) Generally, CT is the imaging modality of choice for the ED physician. Although some tumors exhibit a characteristic appearance, do not make an unequivocal diagnosis based solely on radiologic findings. Generally, computed tomography (CT) is the imaging modality of choice for the emergency department physician. CT findings are as follows:

Most tumors demonstrate enhancement with contrast material administration Tumors may appear hypodense, isodense, or hyperdense or have mixed density Metastases to the brain tend to be multiple, but certain tumors (eg, renal cell carcinomas) tend to produce solitary metastatic brain lesions As magnetic resonance imaging (MRI) becomes increasingly available, it may supplant CT as the imaging procedure of choice. Features of MRI for imaging intracranial neoplasms are as follows:

MRI is most helpful for identifying tumors in the posterior fossa (including acoustic neuromas) and hemorrhagic lesions

MRI is useful in patients with an allergy to iodinated contrast material or renal insufficiency Drawbacks to MRI include incompatibility with certain medical equipment, longer imaging times (increased risk of motion artifact), and poor visualization of the subarachnoid space

Neither CT nor MRI can be used to differentiate tumor recurrence from radionecrosis See Workup for more detail. Management Acute treatment for cerebral edema from intracranial neoplasms is as follows:

Corticosteroids may dramatically reduce signs and symptoms, bringing relief within a few hours

Dexamethasone is the agent of choice Recommended doses generally range from 4-24 mg daily Definitive treatment is as follows:

Generally, care of patients with a brain tumor is multidisciplinary, requiring assistance from a neurosurgeon, an oncologist, a radiologist, and an expert in radiation therapy

Management varies greatly depending on tumor location, tissue type, and comorbid conditions Surgical treatment options may include tumor removal or debulking, installation of a ventricular shunt, and placement of radioactive implants See Treatment and Medication for more detail. Image library

Neoplasms, brain. CT images of several tumor types. Slide courtesy of UMASS Continuing Education Office.

Background Brain tumors may originate from neural elements within the brain, or they may represent spread of distant cancers. Primary brain tumors arise from CNS tissue and account for roughly half of all cases of intracranial neoplasms. The remainder of brain neoplasms are caused by metastatic lesions. In adults, two thirds of primary brain tumors arise from structures above the tentorium (supratentorial), whereas in children, two thirds of brain tumors arise from structures below the tentorium (infratentorial). Gliomas, metastases, meningiomas, pituitary adenomas, and acoustic neuromas account for 95% of all brain tumors. Classification by tumor cell type is irrelevant to the emergency physician because emergent treatment is the same regardless of the tumor type.

Neoplasms, brain. CT images of several tumor types. Slide courtesy of UMASS Continuing Education Office. Many review articles have been written on brain tumors, and this discussion at times draws from the consensus of these reviews.

Patophisiology Tumors of the brain produce neurologic manifestations through a number of mechanisms. Small, critically located tumors may damage specific neural pathways traversing the brain. Tumors can invade, infiltrate, or supplant normal parenchymal tissue, disrupting normal function. Because the brain dwells in the limited volume of the cranial vault, growth of intracranial tumors with accompanying edema may cause increased intracranial pressure. Tumors adjacent to the third and fourth ventricles may impede the flow of cerebrospinal fluid, leading to obstructive hydrocephalus. In addition, tumors generate new blood vessels (ie, angiogenesis), disrupting the normal blood-brain barrier and promoting edema.

Neoplasms, brain. Colloid cyst of the third ventricle with obstructive hydrocephalus.Image courtesy of Peter Ferrera, MD. The cumulative effects of tumor invasion, edema, and hydrocephalus may elevate the intracranial pressure (ICP) and impair cerebral perfusion. Intracranial compartmental rise in ICP may

provoke shifting or herniation of tissue under the falx cerebri, through the tentorium cerebelli, or through the foramen magnum. Slow-growing tumors, particularly tumors expanding in the so-called silent areas of the brain, such as the frontal lobe, may be associated with a more insidious clinical course. These tumors tend to be larger at detection. Most primary brain tumors do not metastasize, but if they do metastasize, intracranial spread generally precedes distant dissemination. Metastatic brain tumors from non-CNS primary tumors may be the first sign of malignancy, or they may herald a relapse. Nonetheless, the signs and symptoms of brain metastases simulate those of primary brain tumors. Leptomeningeal infiltration may present with dysfunction of multiple cranial nerves.

Frequency United States Estimates of the annual incidence rate of primary brain tumors range from 7-19.1 cases per 100,000 population. Metastatic tumors to the brain are more common with more than 200,000 patients per year in the United States with a new diagnosis of intracranial metastases. An increase in the prevalence of HIV infection corresponds to an increase in the occurrence of primary CNS lymphoma. Pituitary adenomas are exceptionally common, and they are frequent incidental findings on autopsy. Autopsy series of patients with systemic cancer show that intracranial metastases are present in 18-24% of patients. International The international incidence is not known, but it is thought to parallel that of the United States.

Mortality/Morbidity

In the United States in 1999, primary cancers of the central nervous system were the cause of death in approximately 13,100 people.

Brain tumors are the second most common cancer in children, comprising 15-25% of all pediatric malignancies.

Perhaps no other cancer is as feared as brain tumor since severe disability, including paralysis, seizures, gait disturbances, and impairment of intellectual capacity may occur. Race Differences are seen between ethnic groups within the same country, and a 3-fold difference in incidence has been reported between countries worldwide. Developed countries appear to have the highest rates, but this may reflect better registration systems. Sex Meningiomas and pituitary adenomas are slightly more common in women than in men. Males are more likely to be diagnosed with brain tumors than females, with a male-to-female ratio of 1.5:1. Age

Tumors in the posterior fossa predominate in preadolescent children, with the incidence of supratentorial tumors increasing from adolescence to adulthood.

Low-grade gliomas, such as astrocytomas, are more common in younger people than in older people. High-grade gliomas, such as anaplastic astrocytoma andglioblastoma multiforme, tend to originate in the fourth or fifth decade or beyond.

In children, brain tumors are the most prevalent solid tumor, second only to leukemia as a cause of pediatric cancer. The incidence rate of primary CNS neoplasms is 3.6 cases per 100,000 children each year.

History Presenting complaints of patients with an intracranial neoplasm tend to be similar for primary brain tumors and intracranial metastases. Manifestations depend on the cause of the symptoms:

an increase in ICP, direct compression of essential gray or white matter, shifting of intracranial contents, or secondary cerebral ischemia. Symptoms may be nonspecific and include headache, altered mental status, ataxia, nausea, vomiting, weakness, and gait disturbance. CNS neoplasms also may manifest as focal seizures, fixed visual changes, speech deficits, or focal sensory abnormalities. The onset of symptoms usually is insidious, but an acute episode may occur with bleeding into the tumor, or when an intraventricular tumor suddenly occludes the third ventricle. In one study of children with brain tumors, time from symptom onset to diagnosis of a brain tumor was found to be 3.3 months. Head tilt, cranial nerve palsies, endocrine and growth abnormalities and reduced visual acuity were associated with a longer symptom interval. Headache was the number one symptom experienced in more than half of patients.[13]

Although headache is the symptom customarily associated with an intracranial neoplasm, it often is a late complaint. Usually, headache is not an isolated finding.
o o

Headache is the worst symptom in only one half of patients. Most headaches in patients with brain tumors are nonspecific and resemble tension-type headaches.[2, 3, 4]

o o o

A change in any patient's headache pattern may be cause for concern. New onset of headaches in middle-aged or older patients is worrisome. The location of the headache reliably indicates the side of the head affected, but it does not indicate the precise site of the tumor.

o o o

Headaches are more common with posterior fossa tumors. Headache is a more frequent symptom of intracranial tumor in pediatric patients. Prevailing inaccurate portrayals of a tumor headache include pain that is worse in the early morning than at other times; vomiting (with or without nausea); and exacerbation with Valsalva maneuvers, bending over, or rising from a recumbent position.

Mental status changes, especially memory loss and decreased alertness, may be subtle clues of a frontal lobe tumor. Complaints may be as mundane as sleeping longer, appearing preoccupied while awake, and apathy.
o

Temporal lobe neoplasms may lead to depersonalization, emotional changes, and behavioral disturbances.

o o

Vision, smell, and other sensory disturbances may be caused by a brain tumor. An acoustic neuroma may present as intermittent (then progressive) hearing loss, disequilibrium, and tinnitus.

Symptoms of pediatric posterior fossa tumors include increased irritability, unsteadiness, ataxia, headache, vomiting, and progressive obtundation.

Supratentorial tumors in children are more commonly associated with seizures, hemiparesis, visual field cuts, speech difficulties, and intellectual disturbance.

Pituitary adenomas may be divided into 2 broad categories: nonfunctional and hypersecretory. Nonfunctional pituitary adenomas remain asymptomatic until they are large enough to encroach the optic chiasm and disturb normal vision. Most hypersecretory pituitary adenomas secrete prolactin, with affected women noting an amenorrhea-galactorrhea syndrome. Men with prolactin pituitary adenomas more commonly complain of headache, visual problems, and impotence.

Seizures, focal or generalized, may be the earliest expression of a brain tumor. A Jacksonian pattern, ie, one in which a focal seizure begins in one extremity and then progresses until it becomes generalized, is distinctive in suggesting a focal structural lesion of the cortex.
o

Depending on the rate of growth of the tumor, seizures may be present for months to years before a brain tumor is diagnosed.

Any middle-aged or elderly patients presenting with a first seizure should have CNS tumor high in the differential diagnosis.

Patients with a brain tumor may present with acute neurologic changes mimicking those associated with stroke.

Physical No physical finding or pattern of findings unmistakably identifies a patient with a CNS neoplasm.

Based on their location, intracranial tumors may produce a focal or generalized deficit, but signs may be lacking (especially if the tumor is confined to the frontal lobe) or even falsely localizing.

Papilledema, which is more prevalent with pediatric brain tumors, reflects an increase in ICP of several days or longer. Papilledema usually does not cause visual loss. Not all patients with CNS tumors develop papilledema.

Diplopia may result from displacement or compression of the sixth cranial nerve at the base of the brain.

Impaired upward gaze, called Parinaud syndrome, may occur with pineal tumors. Tumors of the occipital lobe specifically may produce homonymous hemianopia or partial

visual field deficits. with surrounding edema.

Neoplasms, brain. Occipital lobe glioblastoma

Anosmia may occur with frontal lobe tumors. Brainstem and cerebellar tumors induce cranial nerve palsies, ataxia, incoordination, nystagmus, pyramidal signs, and sensory deficits on one or both sides of the body.
o

Three cranial nerves run through the cerebellopontine angle: facial, cochlear, and vestibular. Masses in these regions may impair the functions of these nerves.

Acoustic neuromas most commonly originate from the vestibular nerve (part of cranial nerve VIII).

Causes Although few factors are unequivocally associated with an increased risk of brain cancer, some are consequential.

Most CNS neoplasms are thought to arise from individual cell mutations.

A prior history of irradiation to the head for reasons other than treatment of the present tumor may increase the chance of primary brain tumor.

A few inherited diseases, such as neurofibromatosis, tuberous sclerosis, multiple endocrine neoplasia (type 1), and retinoblastoma, increase the predilection to develop CNS tumors.

The most common tumors originating from the cerebellopontine angle are acoustic neuroma and meningioma.

Primary CNS lymphoma is a relatively frequent occurrence in HIV patients. Metastatic tumors reach the brain via hematogenous dissemination through the arterial system. Lung cancer is by far the most common solid tumor disseminating to the brain, followed by breast, melanoma, and colon cancer.
o

Less common sources of metastasis are malignant melanoma,testicular cancer, and renal cell cancer.

Prostate, uterine, and ovarian cancers are unlikely sources of brain metastasis.

Laboratory Studies

Patients with cancer are predisposed to medical complications, including bleeding disturbances (hyperviscosity), metabolic disorders (hypercalcemia), and production of excessive hormones (syndrome of inappropriate antidiuretic hormone secretion).

With clinical suspicion of cancer, obtain routine laboratory studies on admission, including a CBC, coagulation studies, and analysis of electrolytes and comprehensive metabolic panel.

Imaging Studies

Obtain neuroimaging studies in patients with symptoms suggestive of an intracranial neoplasm (eg, acute mental status changes; new-onset seizures; focal, motor, or sensory deficits, including gait disturbance; suspicious headache; signs of elevated ICP, such as papilledema).

Although some tumors exhibit a characteristic appearance, do not make an unequivocal diagnosis based solely on radiologic findings.

Generally, CT is the imaging modality of choice for the ED physician. Intravenous contrast material assists in tumor identification. Most tumors demonstrate enhancement with contrast material administration.

Tumors may appear hypodense, isodense, or hyperdense, or they may have mixed density. Metastases to the brain tend to be multiple, but certain tumors, such as renal cell carcinomas, tend to be solitary metastatic brain lesions.

With increasing availability, MRIs may supplant CTs as the imaging procedures of choice. An MRI is most helpful for identifying tumors in the posterior fossa (including acoustic neuromas), hemorrhagic lesions. It is useful in patients with an allergy to iodinated contrast material or renal insufficiency.

Drawbacks to MRI include incompatibility with certain medical equipment, longer imaging times (increased risk of motion artifact), and poor visualization of the subarachnoid space.

Neither CT nor MRI can be used to differentiate tumor recurrence from radionecrosis. On plain skull radiographs, large pituitary adenomas are associated with a large sella turcica.

Procedures

Lumbar puncture is not indicated in the ED in the patient with suspected CNS neoplasms.

Treatment Prehospital Care Prehospital care is supportive and directed to the presenting symptom complex. For example, treat seizures in the usual manner. Airway disturbance, breathing difficulty, signs of pronounced elevation in ICP, and notable impairment of consciousness may necessitate definitive airway control with endotracheal intubation and, possibly, hyperventilation.

Emergency Department Care ED treatment of the patient with an intracerebral neoplasm depends on both the nature of the tumor and the general condition of the patient. Decisions regarding surgical resection, initiation of radiation treatment, and chemotherapy are beyond the scope of practice of the ED physician.

Corticosteroids may dramatically reduce signs and symptoms related to cerebral edema. Affected patients may experience relief within the first few hours of steroid therapy.
o

Dexamethasone is the agent of choice because of its minimal salt-retaining properties. Recommended doses generally range from 4-24 mg daily. For patients with impaired consciousness or signs of increased intracranial pressure, 10 mg IV[8] or 10-24 mg IV are recommended as the first dose. Side effects, notably proximal muscle weakness, are dosedependent. Often, corticosteroids can be tapered or discontinued after definitive therapy. The final dose of steroids should be the lowest necessary to control the patient's neurologic symptoms.

For patients with signs or symptoms of impending herniation and airway compromise, consider use of adjunctive medications for rapid sequence intubation. These might include lidocaine and medication for rapid-onset neuromuscular blockade, with precautions to diminish fasciculations. Induction agents, such as thiopental, may be used.

After definitive control of the airway, consider gentle hyperventilation. Discuss the use of mannitol with the appropriate consultant. Although mannitol may reduce transiently lower ICP, concern about rebound increases in ICP makes its use problematic.

Consultations Local practice patterns govern requests for consultations.

Generally, care of patients with a brain tumor is multidisciplinary, requiring assistance from a neurosurgeon, an oncologist, a radiologist, and an expert in radiation therapy.

Management varies greatly depending on tumor location, tissue type, and comorbid conditions. Surgical treatment options may include tumor removal or debulking, installation of a ventricular shunt, and placement of radioactive implants.

Medication Summary Practice parameters from the American Academy of Neurology discourage prophylactic use of anticonvulsants for seizures in patients with newly diagnosed brain tumors and suggest that it is

appropriate to taper and discontinue anticonvulsant use postoperatively in patients without seizures.[14] Anticonvulsant use may be reserved for patients with clinical seizures, but some physicians prescribe prophylactic anticonvulsants in patients with cortical tumors

Corticosteroids Class Summary Steroids are thought to stabilize cell membranes and diminish the vasogenic edema associated with tumors. Dexamethasone (Decadron)

Used in treatment of vasogenic cerebral edema; improves endothelial integrity.

Hyperosmolar agents Class Summary These agents may reduce ICP and cerebral edema by creating an osmotic gradient across an intact blood-brain barrier. As water diffuses from the brain into the intravascular compartment, ICP decreases. View full drug information Mannitol (Osmitrol)

May reduce subarachnoid space pressure by creating osmotic gradient between cerebrospinal fluid in arachnoid space and plasma. Not for long-term use.

Further Inpatient Care

Further inpatient care is complex and may involve multiple consultants, depending on the tumor type and overall prognosis.

Definitive diagnosis requires tissue biopsy performed by a qualified neurosurgeon. Additional neurosurgical options include resection or debulking and placement of a ventricular shunt with obstructive hydrocephalus.

The admitting physician should coordinate oncologic or radiation oncology consultations.

Further Outpatient Care

The patient's primary physician best manages coordination of consultants, but the responsible neurosurgeon should direct the treatment of specific postoperative complications or care.

A common problem confronting the ED physician is a patient with a known brain neoplasm complaining of a headache or worsening other symptoms. This scenario always raises the possibility of tumor recurrence or worsening cerebral edema. Obtain a CT scan or MRI to rule out life-threatening events, such as hemorrhage or herniation.

Radiation therapy for gliomas usually is performed on an outpatient basis.

Inpatient & Outpatient Medications

Steroids or anticonvulsants may be used. Provide medications for patient comfort and pain control.

Transfer

New occurrence of CNS tumor may require transfer to a facility with appropriate neurosurgical staff.

Speak directly to the consultant prior to transfer to address initiation of steroid or anticonvulsant treatment.

Complications

Acute symptoms in a patient with a brain tumor, particularly when signs and symptoms simulate the presentation of a cerebrovascular accident, suggest the possibility of acute hemorrhage into a

tumor. Brain neoplasms predisposed to hemorrhage include lung cancer, melanoma, and choriocarcinoma.

Lesions near the third ventricle can cause paroxysmal symptoms of headache, syncope, or mental status change. Additionally, vomiting, ataxia, memory changes, visual disturbances, or personality changes may occur.

Episodic increases in ICP secondary to pressure arising from blockage of cerebrospinal fluid outflow cause transient symptoms.

Sudden death is a reported complication from obstruction of outflow drainage from the third ventricle.

Sudden increases in ICP may lead to life-threatening brain herniation, which shifts the brain parenchyma in the direction of least resistance: caudally through the foramen magnum (posterior fossa tumors) or transtentorial apertures.

Some pituitary tumors are hormonally active and capable of producing acromegaly or galactorrhea. Pituitary apoplexy, an unusual complication arising from pituitary adenomas, describes hemorrhage into the tumor, leading to headache, deterioration of vision, oculomotor palsies, and shock secondary to acute adrenal insufficiency.

Although radiation therapy rarely causes acute toxicity with modern dosing schedules and concomitant use of steroids, subacute or chronic effects may occur.

Subacute encephalopathy occurs 6-16 weeks after radiation therapy and is characterized by somnolence and headaches.

Chronic effects of prolonged radiation treatment tend to be more serious and range from impairment of intellectual capacity to complete incapacity

Prognosis

Tumor resectability, tumor location, age of the patient, and tumor histology are the primary determinants of survival.

Without radiation therapy, the mean life expectancy of a patient with brain metastases is 1 month. Radiation therapy may extend survival to 4-6 months.

Patients with seizures secondary to a brain tumor generally experience obvious neurologic deterioration over a 6-month course.

Most patients with brain metastases die from progression of their primary malignancy rather than from brain damage.

Conversion Disorder in Emergency Medicine Background Conversion disorder (functional neurological symptom disorder) is classified as one of the somatic symptom and related disorders in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association, Fifth Edition, DSM-5.[1,
2]

(These were

formerly known as somatoform disorders inDSM-IV-TR).[3] Although defined as a condition that presents as an alteration or loss of a physical function suggestive of a physical disorder, conversion disorder is presumed to be the expression of an underlying psychological conflict or need. The critical psychological conflict or stress may not be apparent initially, but it becomes evident in the course of obtaining a patients history: ideally, it is a psychological factor related symbolically and temporally to symptom onset. Conversion symptoms are presumed to result from an unconscious process. (Conscious/intentional production of physical symptoms is classified as factitious disorder or malingering.) Conversion symptoms are not considered to be under voluntary control, and, should not be explained by any physical disorder or known pathological mechanism (after appropriate medical evaluation). Though classified with somatic symptom/somatoform disorders in DSM-III throughDSM-5, conversion disorder is classified as a dissociative disorder in ICD-10, keeping its long association with hysteria (Dissociative Disorders in DSM).[4, 5]Clinical descriptions of conversion disorder date to almost 4000 years ago; the Egyptians attributed symptoms to a "wandering uterus." In the 19th century, Paul Briquet described the disorder as a dysfunction of the CNS.[6,
7]

Freud first used the term conversion to refer to the development of a somatic symptom to help

bind anxiety around a repressed conflict.[8] In current practice, the term has made it into the popular press.[9]

Pathophysiology Presenting symptoms can range far across the field of clinical neurology. Conversion reactions usually approximate lesions in the nervous systems voluntary motor or sensory pathways. Symptoms most commonly reported are weakness, paralysis, pseudoseizures, involuntary

movements (eg, tremors), and sensory disturbances. These losses or distortions of neurologic function cannot adequately be accounted for by organic disease. Functional MRI (fMRI) and transcranial magnetic stimulation (TMS) studies have shown different activation patterns in patients with conversion symptoms and healthy control subjects; this is in keeping with the "involuntary" nature of conversion symptoms.[10, 11, 12, 13] Patient's whose symptoms are limited to pain or sexual functioning are not classified under conversion disorder; likewise, patients already classified as demonstrating somatization disorder or schizophrenia are also not classified under conversion disorder. Diagnostic criteria for conversion disorder changes little from DSM-IV to DSM-5. The DSMIV criteria are as follows[3] :

One or more symptoms or deficits are present that affect voluntary motor or sensory function that suggest a neurologic or other general medical condition.

Psychologic factors are judged to be associated with the symptom or deficit because conflicts or other stressors precede the initiation or exacerbation of the symptom or deficit.

The symptom or deficit is not intentionally produced or feigned (as in factitious disorder or malingering).

The symptom or deficit, after appropriate investigation, cannot be explained fully by a general medical condition, the direct effects of a substance, or as a culturally sanctioned behavior or experience.

The symptom or deficit causes clinically significant distress or impairment in social, occupational, or other important areas of functioning or warrants medical evaluation.

The symptom or deficit is not limited to pain or sexual dysfunction, does not occur exclusively during the course of somatization disorder, and is not better accounted for by another mental disorder. According to psychodynamic theory, conversion symptoms develop to defend against unacceptable impulses.[8] The primary gain, that is to say the purpose of a conversion symptom is to bind anxiety and keep a conflict internal. A fairly transparent example would be leg paralysis after an equestrian competitor is thrown from his or her horse. The symptom has a symbolic

value that is a representation and partial solution of a deep-seated psychological conflict: to avoid running away like a coward, and yet to avoid being thrown again. According to learning theory, conversion disorder symptoms are a learned maladaptive response to stress. Patients achieve secondary gain by avoiding activities that are particularly offensive to them, thereby gaining support from family and friends, which otherwise may not be offered.[14]

Epidemiology Frequency United States True conversion reaction is rare.[15, 16] Predisposing factors include extreme psychosocial stress, and perhaps, rural upbringing. Some psychiatrists suspect that western society has incorporated Freudian notions of unconscious motivations and conflicts: conversion reactions have become too obvious to serve their purpose.

Incidence has been reported to be 11-300 cases per 100,000 people. Cultural factors may play a significant role.[17] Symptoms that might be considered a conversion disorder in the US may be a normal expression of anxiety in other cultures.

One study reports that conversion disorder accounts for 1.2-11.5% of psychiatric consultations for hospitalized medical and surgical patients. International At the National Hospital in London, the diagnosis was made in 1% of inpatients.[18] Iceland's incidence of conversion disorder is reported to be 15 cases per 100,000 persons. Mortality/Morbidity Patients diagnosed with conversion disorder may go on to demonstrate serious, traditional medical illness. This has been happening less and less often over the years (29% in 1950s down to 4% in 1990s). Unfortunately, emergency physicians may find themselves sorting out new neurologic symptoms in settings of terrible time pressure: populations statistics may be of little reassurance for any specific individual. Sex

Sex ratio is not known although it has been estimated that women patients outnumber men by 6:1. This is of little help when evaluating an individual patient. Age Conversion disorder may present at any age but is rare in children younger than 10 years or in persons older than 35 years.[19] In a University of Iowa study of 32 patients with conversion disorder, however, the mean age was 41 years with a range of 23-58 years.[20] In pediatric patients, incidence of conversion is increased after physical or sexual abuse. Incidence also increases in those children whose parents are either seriously ill or have chronic pain.[21]

History Degree of impairment usually is marked and interferes with daily life activities. Prolonged loss of function may produce organic complications such as disuse atrophy or contractures. Weakness, paralysis, pseudoseizures, involuntary movements (eg, tremors), and sensory disturbances (eg, aphonia, deafness, blindness) are the most frequent complaints. Symptoms often enable patients to avoid an unpleasant situation at home or work, attract attention, or gain support from others. This may become evident through careful questioning. The symptom must not be under voluntary control. Determining the symptom may be difficult, since it usually cannot be identified by observation. Features suggestive of voluntary control consist of variability, inconsistency, obvious and immediate benefit, as well as a personality that may suggest dishonesty and opportunism. Symptoms, if voluntary, tend to be self-limited and of brief duration. La belle indiffrence was considered a classic feature of conversion disorder. It is characterized by the inappropriate and paradoxical absence of distress despite the presence of an unpleasant symptom. Patients often deny emotional difficulty. Unfortunately, la belle indiffrence, histrionic personality, and secondary gain are clinical features that appear to have no diagnostic

significance. They can easily be absent in patients with conversion disorder; they can be easily be present in patients with traditional neurologic disorder. One study reported 5 patients with hysterical conversion reactions after injury or infarction to the left cerebral hemisphere.[22]

Physical Absence of a physical disorder is an important diagnostic feature. Individuals with conversion disorder often have physical signs but lack objective neurological signs to substantiate their symptoms. Weakness Weakness usually involves whole movements rather than muscle groups. Weakness affects the extremities more often than ocular, facial, or cervical movements. With the use of various clinical techniques, weakness of one limb can be demonstrated to cause contraction of opposing muscle groups. Discontinuous resistance during testing of power or give-way weakness may exist. Muscle wasting is absent, and reflexes are normal. Sensory symptoms Sensory loss or distortion often is inconsistent when tested on more than one occasion and is incompatible with peripheral nerve or root distribution. Discrete patches of anesthesia or hemisensory loss that stop in the midline may be present. Classic dermatomes in patients with numbness usually are not followed. Visual symptoms Visual symptoms include monocular diplopia, triplopia, field defects, tunnel vision, and bilateral blindness associated with intact pupillary reflexes. Optokinetic nystagmus may be observed in patients with apparent blindness when exposed to a rotating striped drum.

Gait disturbances Astasia-abasia is a motor coordination disorder characterized by the inability to stand despite normal ability to move legs when lying down or sitting. Patients walk normally if they think they are not being observed. Occasionally, while being observed, patients actively attempt to fall. This contrasts with those patients with organic disease who attempt to support themselves. Pseudoseizures During an attack, marked involvement of the truncal muscles with opisthotonos and lateral rolling of the head or body is present. All 4 limbs may exhibit random thrashing movements, which may increase in intensity if restraint is applied. Cyanosis is rare unless patients deliberately hold their breath. Reflexes (eg, pupillary, corneal) are retained but may be difficult to test due to tightly closed lids. Tongue biting and incontinence are rare unless the patient has some degree of medical knowledge about the natural course of the disease. In contrast to true seizures, pseudoseizures primarily occur in the presence of other people and not when the patient is alone or asleep.

Causes

True etiology is unknown. Most clinicians presume conversion reactions are caused by previous severe stress, emotional conflict, or an associated psychiatric disorder.

Many studies confirm high incidence of depression in patients with conversion disorder. As many as half of these patients have personality disorders or display hysterical traits.[23]

In children, conversion disorder often is observed following physical or sexual abuse.

Children who have family members with a history of conversion reactions are more likely to suffer from conversion disorder. In addition, if family members are seriously ill or in chronic pain, children are more likely to be affected.

Laboratory Studies Carefully consider the possibility of an organic etiology. Some authors have suggested that unnecessary, painful, or invasive testing can result in reinforcement and fixation of symptoms and should be avoided when possible. Consider laboratory testing to exclude the following clinical entities:

Electrolyte disturbances Hypoglycemia Hyperglycemia Renal failure Systemic infection Toxins Other drugs

Imaging Studies

A chest x-ray (CXR) may be considered to diagnose an occult neoplasm. CT scan or MRI may be performed to exclude a stroke or a space-occupying lesion in the brain or spinal cord.

Other Tests

An electroencephalograph may help distinguish pseudoseizures from a true seizure disorder.

Procedures

Spinal fluid may be diagnostic in ruling out infectious or other causes of neurologic symptoms

Prehospital Care Treat patients as if their symptoms have an organic origin. Prehospital personnel most often cannot distinguish a conversion reaction from an organic illness.

Emergency Department Care Emergency physicians must be aware that the diagnosis of conversion disorder does not exclude the presence of underlying disease, and diagnosis should not be made solely on the basis of negative workup results. Approach each patient as if their symptoms had an organic basis, and treat them accordingly.

Consultations Consultation is often necessary and should be considered during ED discharge planning for any patients without previous histories of conversion reaction.

Consultation may be a cost-effective method to eliminate unnecessary hospitalization by streamlining these patients to appropriate outpatient psychiatric follow-up.[15]

Neurologic consultation may help if the neurological examination is equivocal. Psychiatric consultation may be necessary if an organic cause is virtually excluded. Thoughtful questioning may elicit the underlying stressor.

Another treatment technique is suggestive therapy: an authoritative, not confrontative, pronouncement that "this problem usually resolves in a few hours" is often successful, especially with children. Appropriate attention, for example, repeated vital signs plus adjunctive antianxiety medication, can increase odds of success with adults.[18,
24]

Other

suggestive therapies for symptom removal include hypnosis and amobarbital interviews.[15]

Behavior-oriented treatment strategies may be helpful.[25,

26]

The goals are to unlearn

maladaptive responses and to learn more appropriate responses. Attempt to eliminate the patient's belief that the extremity is paralyzed by telling the patient (1) that all tests indicate the muscles and nerves are functioning normally, (2) the brain is communicating with the nerves

and muscles, and (3) this apparent lost ability is recoverable. Although confronting the patient with the fact that the symptoms are not organic is counterproductive, a strategic/paradoxical behavioral intervention around the possibility of psychiatric diagnosis may help.[27]

Medication Summary Drug therapy has not proven reliable. However, a number of psychiatrists recommend a sedative or antianxiety agent. It is usually easiest to give a benzodiazepine, eg, lorazepam 0.5-1 mg (along with a suggestion that symptoms are likely to remit in an hour or so). Amobarbital is falling out of favor as a sedative, or for an Amytal interview, but has been a traditional medication.[15]

Further Outpatient Care

Any patient diagnosed with a conversion reaction in the ED should be encouraged to pursue psychiatric follow-up. This can be suggested as a way to reduce and manage stress and mitigate exacerbation of physical symptoms (side-stepping arguments about etiology of symptoms). Psychiatric follow-up is especially helpful for rare cases of more serious psychiatric syndromes presenting to an emergency department with physical symptoms.

Many patients have spontaneous remission after outpatient psychotherapy or suggestive therapy. As of yet, there are no well-established treatment regimens for conversion disorder. There has been more success with the other somatoform disorders

Complications

Errors in diagnosis of conversion disorder are not uncommon. With newer diagnostic testing, instances of false-positive diagnoses of conversion disorder in which a neurological disease is later identified are around 4%.

Authors have reported various organic diseases in patients who were initially diagnosed with conversion disorder. In one case report, a woman reporting leg weakness and back pain was subsequently diagnosed with sporadic Creutzfeldt-Jakob disease.[28] Other patients with underlying psychiatric illnesses were found to have disk herniations, epidural abscesses, or cerebral hemorrhages.[29, 30] In another case series, 5 patients were identified as having sarcoma-

induced osteomalacia, cerebellar medulloblastoma, Huntington chorea, transverse myelitis, and lower extremity dystonia.[31] Although these case reports were rare, the initial diagnosis of conversion disorder without a complete neurologic examination, appropriate imaging, and other diagnostic testing should be discouraged.[32]

Prognosis

Prognostic studies differ in outcome, with recovery rates ranging from 15-74%. Factors associated with favorable outcomes are male gender, acute onset of symptoms, precipitation by a stressful event, good premorbid health, and an absence of organic or psychiatric disorder.[33]

Many patients with conversion reactions have spontaneous remission or demonstrate marked or complete recovery after brief psychotherapy

Background The terms intracerebral hemorrhage and hemorrhagic stroke are used interchangeably in this article and are regarded as separate entities from hemorrhagic transformation of ischemic stroke. Hemorrhagic stroke is less common than ischemic stroke (ie, stroke caused by thrombosis or embolism); epidemiologic studies indicate that only 8-18% of strokes are hemorrhagic.[1]However, hemorrhagic stroke is associated with higher mortality rates than is ischemic stroke. (See Epidemiology.)[2] Patients with hemorrhagic stroke present with focal neurologic deficits similar to those of ischemic stroke but tend to be more ill than are patients with ischemic stroke. However, though patients with intracerebral bleeds are more likely to have headache, altered mental status, seizures, nausea and vomiting, and/or marked hypertension, none of these findings reliably distinguishes between hemorrhagic and ischemic stroke. (See Presentation.)[3] Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be obtained on an emergent basis (see the image below). Brain imaging aids in excluding ischemic stroke, and it may identify complications of hemorrhagic stroke such as intraventricular hemorrhage, brain edema, and hydrocephalus. Either noncontrast computed tomography (NCCT)

scanning or magnetic resonance imaging (MRI) is the modality of choice. For more information, see Ischemic Stroke in Emergency Medicine. (See Workup.)

Axial noncontrast computed tomography scan of the brain of a 60-yearold man with a history of acute onset of left-sided weakness. Two areas of intracerebral hemorrhage are seen in the right lentiform nucleus, with surrounding edema and effacement of the adjacent cortical sulci and right sylvian fissure. Mass effect is present upon the frontal horn of the right lateral ventricle, with intraventricular extension of the hemorrhage. The treatment of patients with acute stroke depends on the cause and severity of the bleeding. Basic life support, as well as control of bleeding, seizures, blood pressure (BP), and intracranial pressure, are critical. Surgical evacuation of the hematoma is a potential therapeutic option, but it remains controversial. (See Treatment.) For patient education information, see the Stroke Health Center, as well asStroke.

Anatomy Knowledge of cerebrovascular arterial anatomy and the brain regions supplied by the arteries is useful in determining which vessels are involved in acute stroke. Atypical patterns that do not conform to a vascular distribution may indicate another diagnosis, such as venous infarction. The cerebral hemispheres are supplied by 3 paired major arteries: the anterior, middle, and posterior cerebral arteries. The anterior and middle cerebral arteries are responsible for the anterior circulation and arise from the supraclinoid internal carotid arteries. The posterior cerebral arteries arise from the basilar artery and form the posterior circulation, which also

supplies the thalami, brainstem, and cerebellum. The angiograms in the images below demonstrate some portions of the circulation involved in hemorrhagic strokes.

Frontal view of a cerebral angiogram with selective injection of the left internal carotid artery illustrates the anterior circulation. The anterior cerebral artery consists of the A1 segment proximal to the anterior communicating artery with the A2 segment distal to it. The middle cerebral artery can be divided into 4 segments: the M1 (horizontal segment) extends to 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).

Lateral view of a cerebral angiogram illustrates the branches of the anterior cerebral artery (ACA) and sylvian triangle. The pericallosal artery has been described as arising 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: (1) the A1 segment extends from the internal carotid artery (ICA) bifurcation to the anterior communicating artery, (2) A2 extends to the junction of the rostrum and genu of the corpus callosum, (3) A3 extends into the bend of the genu of the corpus callosum, and (4) 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, with the apex

representing the sylvian point.

Frontal 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 (PICA) arise from the distal vertebral arteries. The anterior inferior cerebellar arteries (AICA) arise from the proximal basilar artery. The superior cerebellar arteries (SCA) arise distally from the basilar artery before its bifurcation into the posterior cerebral arteries.

Pathophysiology In intracerebral hemorrhage, bleeding occurs directly into the brain parenchyma. The usual mechanism is thought to be leakage from small intracerebral arteries damaged by chronic hypertension. Other mechanisms include bleeding diatheses, iatrogenic anticoagulation, cerebral amyloidosis, and cocaine abuse. Intracerebral hemorrhage has a predilection for certain sites in the brain, including the thalamus, putamen, cerebellum, and brainstem. In addition to the area of the brain injured by the hemorrhage, the surrounding brain can be damaged by pressure produced by the mass effect of the hematoma. A general increase in intracranial pressure may occur. Subarachnoid hemorrhage The pathologic effects of subarachnoid hemorrhage (SAH) on the brain are multifocal. SAH results in elevated intracranial pressure and impairs cerebral autoregulation. These effects can occur in combination with acute vasoconstriction, microvascular platelet aggregation, and loss of microvascular perfusion, resulting in profound reduction in blood flow and cerebral ischemia.[4]See the images below.

Noncontrast computed tomography (CT) scanning was performed emergently in a 71-year-old man who presented with acute onset of severe headache and underwent rapid neurologic deterioration requiring intubation. The noncontrast CT scan (left image) demonstrates diffuse, high-density subarachnoid hemorrhage in the basilar cisterns and both Sylvian fissures. There is diffuse loss of gray-white differentiation. The fluid-attenuated inversion-recovery (FLAIR) image (right) demonstrates high signal throughout the cortical sulci and in the basilar cisterns, as well as in the dependent portions of the ventricles. FLAIR is highly sensitive to acute subarachnoid hemorrhage; the suppression of high cerebrospinal fluid signal aids in making subarachnoid hemorrhage more conspicuous than do conventional magnetic

resonance

imaging

sequences.

Computed

tomographic

angiography examination and subsequent cerebral angiography were performed in 71-year-old man who presented with acute onset of severe headache and underwent rapid neurologic deterioration. Multiple aneurysms were identified, including a 9-mm aneurysm at the junction of the anterior cerebral and posterior communicating arteries seen on this lateral view of an internal carotid artery injection. Balloon-assisted coil embolization was performed.

Lateral view of a selective injection of the left internal carotid artery demonstrates a microcatheter passing distal to the aneurysm neck. This lateral view from

an angiogram performed during balloon-assisted coil embolization demonstrates significantly diminished filling of the aneurysm

Etiology The etiologies of stroke are varied, but they can be broadly categorized into ischemic or hemorrhagic. Approximately 80-87% of strokes are from ischemic infarction caused by thrombotic or embolic cerebrovascular occlusion. Intracerebral hemorrhages account for most of the remainder of strokes, with a smaller number resulting from aneurysmal subarachnoid hemorrhage.[5, 6, 7, 8] In 20-40% of patients with ischemic infarction, hemorrhagic transformation may occur within 1 week after ictus.[9, 10] Differentiating between the different types of stroke is an essential part of the initial workup of patients with stroke, as the subsequent management of each disorder will be vastly different. Risk factors The risk of hemorrhagic stroke is increased with the following factors:

Advanced age Hypertension (up to 60% of cases) Previous history of stroke Alcohol abuse Use of illicit drugs (eg, cocaine, other sympathomimetic drugs) Causes of hemorrhagic stroke include the following[8, 9, 11, 12, 13] :

Hypertension Cerebral amyloidosis Coagulopathies Anticoagulant therapy Thrombolytic therapy for acute myocardial infarction (MI) or acute ischemic stroke (can cause iatrogenic hemorrhagic transformation)

Arteriovenous malformation (AVM), aneurysms, and other vascular malformations (venous and cavernous angiomas)

Vasculitis Intracranial neoplasm Amyloidosis Cerebral amyloidosis affects people who are elderly and may cause up to 10% of intracerebral hemorrhages. Rarely, cerebral amyloid angiopathy can be caused by mutations in the amyloid precursor protein and is inherited in an autosomal dominant fashion. Coagulopathies Coagulopathies may be acquired or inherited. Liver disease can result in a bleeding diathesis. Inherited disorders of coagulation such as factor VII, VIII, IX, X, and XIII deficiency can predispose to excessive bleeding, and intracranial hemorrhage has been seen in all of these disorders. Anticoagulant therapy Anticoagulant therapy is especially likely to increase hemorrhage risk in patients who metabolize warfarin inefficiently. Warfarin metabolism is influenced by polymorphism in

the CYP2C9 genes. Three known variants have been described.CYP2C9*1 is the normal variant and is associated with typical response to dosage of warfarin. Variations *2 and *3 are relatively common polymorphisms that reduce the efficiency of warfarin metabolism.[14] Atrioventricular malformations Numerous genetic causes may predispose to AVMs in the brain, although AVMs are generally sporadic. Polymorphisms in the IL6 gene increase susceptibility to a number of disorders, including AVM. Hereditary hemorrhagic telangiectasia (HHT), previously known as OslerWeber-Rendu syndrome, is an autosomal dominant disorder that causes dysplasia of the vasculature. HHT is caused by mutations inENG, ACVRL1, or SMAD4 genes. Mutations in SMAD4 are also associated with juvenile polyposis, so this must be considered when obtaining the patients history.

HHT is most frequently diagnosed when patients present with telangiectasias on the skin and mucosa or with chronic epistaxis from AVMs in the nasal mucosa. Additionally, HHT can result in AVMs in any organ system or vascular bed. AVM in the gastrointestinal tract, lungs, and brain are the most worrisome, and their detection is the mainstay of surveillance for this disease. Hypertension The most common etiology of primary hemorrhagic stroke (intracerebral hemorrhage) is hypertension. At least two thirds of patients with primary intraparenchymal hemorrhage are reported to have preexisting or newly diagnosed hypertension. Hypertensive small-vessel disease results from tiny lipohyalinotic aneurysms that subsequently rupture and result in intraparenchymal hemorrhage. Typical locations include the basal ganglia, thalami, cerebellum, and pons. Aneurysms and subarachnoid hemorrhage The most common cause of atraumatic hemorrhage into the subarachnoid space is rupture of an intracranial aneurysm. Aneurysms are focal dilatations of arteries, with the most frequently encountered intracranial type being the berry (saccular) aneurysm. Aneurysms may less commonly be related to altered hemodynamics associated with AVMs, collagen vascular disease, polycystic kidney disease, septic emboli, and neoplasms. Nonaneurysmal perimesencephalic subarachnoid hemorrhage may also be seen. This phenomenon is thought to arise from capillary or venous rupture. It has a less severe clinical course and, in general, a better prognosis. Berry aneurysms are most often isolated lesions whose formation results from a combination of hemodynamic stresses and acquired or congenital weakness in the vessel wall. Saccular aneurysms typically occur at vascular bifurcations, with more than 90% occurring in the anterior circulation. Common sites include the following:

The junction of the anterior communicating arteries and anterior cerebral arteriesmost commonly, the middle cerebral artery (MCA) bifurcation

The supraclinoid internal carotid artery at the origin of the posterior communicating artery The bifurcation of the internal carotid artery (ICA)

Genetic causes of aneurysms Intracranial aneurysms may result from genetic disorders. Although rare, several families have been described that have a predispositioninherited in an autosomal dominant fashionto intracranial berry aneurysms. A number of genes, all categorized as ANIB genes, are associated with this predisposition. Presently,ANIB1 through ANIB11 are known. Autosomal dominant polycystic kidney disease (ADPKD) is another cause of intracranial aneurysm. Families with ADPKD tend to show phenotypic similarity with regard to intracranial hemorrhage or asymptomatic berry aneurysms.[15] Loeys-Dietz syndrome (LDS) consists of craniofacial abnormalities, craniosynostosis, marked arterial tortuosity, and aneurysms and is inherited in an autosomal dominant manner. Although intracranial aneurysms occur in LDS of all types, saccular intracranial aneurysms are a prominent feature of LDS type IC, which is caused by mutations in the SMAD3 gene.[16] Ehlers-Danlos syndrome is a group of inherited disorders of the connective tissue that feature hyperextensibility of the joints and changes to the skin, including poor wound healing, fragility, and hyperextensibility. However, Ehlers-Danlos vascular type (type IV) also is known to cause spontaneous rupture of hollow viscera and large arteries, including arteries in the intracranial circulation. Patients with Ehlers-Danlos syndrome may also have mild facial findings, including lobeless ears, a thin upper lip, and a thin, sharp nose. The distal fingers may appear prematurely aged (acrogeria). In the absence of a suggestive family history, it is difficult to separate Ehlers-Danlos vascular type from other forms of Ehlers-Danlos. Ehlers-Danlos vascular type is caused by mutations in theCOL3A1 gene; it is inherited in an autosomal dominant manner. See Genetic and Inflammatory Mechanisms in Stroke, as well as Blood Dyscrasias and Stroke. Information on metabolic diseases and stroke can be found in the following articles:

Methylmalonic Acidemia Homocystinuria/Homocysteinemia Fabry Disease MELAS Mitochondrial Encephalomyopathy, Lactic Acidosis, Strokelike Episodes

Hyperglycemia/Hypoglycemia Hemorrhagic transformation of ischemic stroke Hemorrhagic transformation represents the conversion of a bland infarction into an area of hemorrhage. Proposed 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 frank intraparenchymal hematoma.[8, see Reperfusion Injury in Stroke.) 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 with larger infarct size.[8, 10, 18]Hemorrhagic transformation is also more likely following administration of tissue plasminogen activator (tPA) in patients whose noncontrast computed tomography (CT) scans demonstrate areas of hypodensity.[19, 20, 17] See the image below.
9, 17]

(For more information,

Noncontrast computed tomography scan (left) obtained in a 75year-old man who was admitted for stroke demonstrates a large right middle cerebral artery distribution infarction with linear areas of developing hemorrhage. These become more confluent on day 2 of hospitalization (middle image), with increased mass effect and midline shift. There is massive hemorrhagic transformation by day 6 (right), with increased leftward midline shift and subfalcine herniation. Obstructive hydrocephalus is also noted, with dilatation of the lateral ventricles, likely due to compression of the foramen of Monroe. Intraventricular hemorrhage is also noted layering in the left occipital horn. Larger infarctions are more likely to undergo hemorrhagic transformation and are one contraindication to thrombolytic therapy.

Epidemiology Occurrence in the United States

Each year in the United States, approximately 795,000 people experience new or recurrent stroke. Of these, approximately 610,000 represent initial attacks, and 185,000 represent recurrent strokes. Epidemiologic studies indicate that approximately 87% of strokes in the United States are ischemic, 10% are secondary to intracerebral hemorrhage, and another 3% may be secondary to subarachnoid hemorrhage.[5, 21] A 2010 retrospective review from a stroke center found that 40.9% of the 757 patients in the study had suffered hemorrhagic strokes.[22] The researchers speculate that improved availability and implementation of computed tomography (CT) scanning may have unmasked a previous underestimation of the actual percentage of hemorrhagic strokes, or increased use of antiplatelet agents and warfarin may have led to a higher incidence of hemorrhage. Alternatively, this higher rate may represent referral bias of patients with intracerebral hemorrhages to medical centers with neurosurgical capabilities. The incidence of stroke varies with age, sex, ethnicity, and socioeconomic status. For example, American Heart Association (AHA) researchers found that rates of intracerebral hemorrhage are higher in Mexican Americans, Latin Americans, blacks, Native Americans, Japanese people, and Chinese people than they are in whites.[5] Flaherty et al found that excess risk of intracranial hemorrhage in African Americans is largely attributable to higher hemorrhage rates in young and middle-aged persons, particularly for deep cerebral and brainstem locations. Hypertension is the predominant risk factor.[23] International occurrence According 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.[24] The global incidence of stroke has at least a modest variation from nation to nation, suggesting the importance of genetics and environmental factors, such as disparities in access to health care in developing countries. The age-adjusted incidence of total strokes per 1000 person-years for people 55 years or older has been reported in the range of 4.2 to 6.5. The highest incidences have been reported in Russia, Ukraine, and Japan.

In a prospective, population-based registry study from Italy, the crude annual incidence rate of intracerebral hemorrhage was 36.9 per 100,000 population. When standardized to the 2006 European population, the rate was 32.9 per 100,000 population; standardized to the world population, the rate was 15.9 per 100,000 population.[25] Overall, the incidence of acute stroke has demonstrated a constant decline over the past several decades, most notably during the 1970s-1990s, although in recent years the rate trend has begun to plateau. However, the increased survival among stroke victims will place an increased demand on health-care systems globally.[8, 26] Stroke subtypes also vary greatly in different parts of the world and between different races. For example, the proportion of hemorrhagic strokes may be higher in certain populations, such as the Chinese population, in which it has been reported to be up to 39.4%, and the Japanese, in which it is reportedly up to 38.7%.[26, 1]

Prognosis The prognosis in patients with hemorrhagic stroke varies depending on the severity of stroke and the location and the size of the hemorrhage. Lower Glasgow Coma Scale (GCS) scores are associated with poorer prognosis and higher mortality rates. A larger volume of blood at presentation is also associated with a poorer prognosis. Growth of the hematoma volume is associated with a poorer functional outcome and increased mortality rate. The intracerebral hemorrhage score is the most commonly used instrument for predicting outcome in hemorrhagic stroke. The score is calculated as follows:

GCS score 3-4: 2 points GCS score 5-12: 1 point GCS score 13-15: 0 points Age 80 years: Yes, 1 point; no, 0 points Infratentorial origin: Yes, 1 point; no, 0 points Intracerebral hemorrhage volume 30 cm3: 1 point Intracerebral hemorrhage volume < 30 cm3: 0 points

Intraventricular hemorrhage: Yes, 1 point; no, 0 points In a study by Hemphill et al, all patients with an Intracerebral Hemorrhage Score of 0 survived, and all of those with a score of 5 died; 30-day mortality increased steadily with the Score.[27] Other prognostic factors include the following:

Nonaneurysmal perimesencephalic stroke has a less severe clinical course and, in general, a better prognosis

The presence of blood in the ventricles is associated with a higher mortality rate; in one study, the presence of intraventricular blood at presentation was associated with a mortality increase of more than 2-fold

Patients with oral anticoagulation-associated intracerebral hemorrhage have higher mortality rates and poorer functional outcomes In studies, withdrawal of medical support or issuance of Do Not Resuscitate (DNR) orders within the first day of hospitalization predict poor outcome independent of clinical factors. Because limiting care may adversely impact outcome, American Heart Association/American Stroke Association (AHA/ASA) guidelines suggest that new DNR orders should probably be postponed until at least the second full day of hospitalization. Patients with DNRs should be given all other medical and surgical treatment, unless the DNR explicitly says otherwise.[28] For more information, see Motor Recovery in Stroke.

History Obtaining an adequate history includes determining the onset and progression of symptoms, as well as assessing for risk factors and possible causative events. Such risk factors include the following:

Previous transient ischemic attack (TIA) and stroke Hypertension Diabetes Smoking Arrhythmia and valvular disease

Illicit drug use Use of anticoagulants Risk factors for thrombosis A history of trauma, even if minor, may be important, as extracranial arterial dissections can result in ischemic stroke. Hemorrhagic versus ischemic stroke Symptoms alone are not specific enough to distinguish ischemic from hemorrhagic stroke. However, generalized symptoms, including nausea, vomiting, and headache, as well as an altered level of consciousness, may indicate increased intracranial pressure and are more common with hemorrhagic strokes and large ischemic strokes. Seizures are more common in hemorrhagic stroke than in the ischemic kind. Seizures occur in up to 28% of hemorrhagic strokes, generally at the onset of the intracerebral hemorrhage or within the first 24 hours. Focal neurologic deficits The neurologic deficits reflect the area of the brain typically involved, and stroke syndromes for specific vascular lesions have been described. Focal symptoms of stroke include the following:

Weakness or paresis that may affect a single extremity, one half of the body, or all 4 extremities

Facial droop Monocular or binocular blindness Blurred vision or visual field deficits Dysarthria and trouble understanding speech Vertigo or ataxia Aphasia Subarachnoid hemorrhage Symptoms of subarachnoid hemorrhage may include the following:

Sudden onset of severe headache Signs of meningismus with nuchal rigidity

Photophobia and pain with eye movements Nausea and vomiting Syncope - Prolonged or atypical The most common clinical scoring systems for grading aneurysmal subarachnoid hemorrhage are the Hunt and Hess grading scheme and the World Federation of Neurosurgeons (WFNS) grading scheme, which incorporates the Glasgow Coma Scale. The Fisher Scale incorporates findings from noncontrast computed tomography (NCCT) scans.

Physical Examination The assessment in patients with possible hemorrhagic stroke includes vital signs; a general physical examination that focuses on the head, heart, lungs, abdomen, and extremities; and a thorough but expeditious neurologic examination.[28]However, intracerebral hemorrhage may be clinically indistinguishable from ischemic stroke. (Though stroke is less common in children, the clinical presentation is similar.) Hypertension (particularly systolic blood pressure [BP] greater than 220 mm Hg) is commonly a prominent finding in hemorrhagic stroke. Higher initial BP is associated with early neurologic deterioration, as is fever.[28] An acute onset of neurologic deficit, altered level of consciousness/mental status, or coma is more common with hemorrhagic stroke than with ischemic stroke. Often, this is caused by increased intracranial pressure. Meningismus may result from blood in the subarachnoid space. Examination results can be quantified using various scoring systems. These include the Glasgow Coma Scale (GCS), the Intracerebral Hemorrhage Score (which incorporates the GCS; see Prognosis), and the National Institutes of Health Stroke Scale. Focal neurologic deficits The type of deficit depends upon the area of brain involved. If the dominant hemisphere (usually the left) is involved, a syndrome consisting of the following may result:

Right hemiparesis Right hemisensory loss

Left gaze preference Right visual field cut Aphasia Neglect (atypical) If the nondominant (usually the right) hemisphere is involved, a syndrome consisting of the following may result:

Left hemiparesis Left hemisensory loss Right gaze preference Left visual field cut Nondominant hemisphere syndrome may also result in neglect when the patient has left-sided hemi-inattention and ignores the left side. If the cerebellum is involved, the patient is at high risk for herniation and brainstem compression. Herniation may cause a rapid decrease in the level of consciousness and may result in apnea or death. Specific brain sites and associated deficits involved in hemorrhagic stroke include the following:

Putamen - Contralateral hemiparesis, contralateral sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, aphasia, neglect, or apraxia

Thalamus - Contralateral sensory loss, contralateral hemiparesis, gaze paresis, homonymous hemianopia, miosis, aphasia, or confusion

Lobar - Contralateral hemiparesis or sensory loss, contralateral conjugate gaze paresis, homonymous hemianopia, abulia, aphasia, neglect, or apraxia

Caudate nucleus - Contralateral hemiparesis, contralateral conjugate gaze paresis, or confusion Brainstem - Quadriparesis, facial weakness, decreased level of consciousness, gaze paresis, ocular bobbing, miosis, or autonomic instability Cerebellum Ipsilateral ataxia, facial weakness, sensory loss; gaze paresis, skew deviation, miosis, or decreased level of consciousness Other signs of cerebellar or brainstem involvement include the following:

Gait or limb ataxia

Vertigo or tinnitus Nausea and vomiting Hemiparesis or quadriparesis Hemisensory loss or sensory loss of all 4 limbs Eye movement abnormalities resulting in diplopia or nystagmus Oropharyngeal weakness or dysphagia Crossed signs (ipsilateral face and contralateral body) Many other stroke syndromes are associated with intracerebral hemorrhage, ranging from mild headache to neurologic devastation. At times, a cerebral hemorrhage may present as a new-onset seizure

Diagnostic Considerations Intracerebral hemorrhage may be clinically indistinguishable from ischemic stroke, and a thorough history and physical examination are important. An acute onset of neurologic deficit, altered level of consciousness/mental status, or coma is more common with hemorrhagic stroke than with ischemic stroke. A history of trauma, even if minor, may be important, as extracranial arterial dissections can result in ischemic stroke. Seizures are more common in hemorrhagic stroke than in ischemic stroke and occur in up to 28% of hemorrhagic strokes, generally at the onset of the intracerebral hemorrhage or within the first 24 hours. Postictal (Todd) paralysis and hyperosmolality should also be considered. Other problems to consider are as follows:

Hyponatremia or hypernatremia Migraine headache Hyperosmolar hyperglycemic nonketotic coma Differential Diagnoses

Encephalitis Headache, Migraine Hypernatremia Hyperosmolar Hyperglycemic Nonketotic Coma

Hypertensive Emergencies Hypoglycemia Hyponatremia Labyrinthitis Ossificans Meningitis Neoplasms, Brain Stroke, Ischemic Subarachnoid Hemorrhage Subdural Hematoma Transient Ischemic Attack

Approach Considerations Laboratory tests should include a complete blood count, a metabolic panel, andparticularly in patients taking anticoagulantscoagulation studies (ie, prothrombin time or international normalized ratio [INR] and an activated partial thromboplastin time).[28] Brain imaging is a crucial step in the evaluation of suspected hemorrhagic stroke and must be obtained on an emergent basis. Brain imaging aids diagnosing hemorrhage, and it may identify complications such as intraventricular hemorrhage, brain edema, or hydrocephalus. Either noncontrast computed tomography (NCCT) scanning or magnetic resonance imaging (MRI) is the modality of choice. Computed tomography (CT)-scan studies can also be performed in patients who are unable to tolerate a magnetic resonance examination or who have contraindications to MRI, including pacemakers, aneurysm clips, or other ferromagnetic materials in their bodies. Additionally, CTscan examination is more easily accessible for patients who require special equipment for life support. See the image below.

Noncontrast computed tomography scan of the brain (left) demonstrates an acute hemorrhage in the left gangliocapsular region, with surrounding white

matter hypodensity consistent with vasogenic edema. T2-weighted axial magnetic resonance imaging scan (middle image) again demonstrates the hemorrhage, with surrounding high-signal edema. The coronal gradient-echo image (right) demonstrates susceptibility related to the hematoma, with markedly low signal adjacent the left caudate head. Gradient-echo images are highly sensitive for blood products. CT angiography and contrast-enhanced CT scanning may be considered for helping identify patients at risk for hematoma expansion. Extravasation of contrast within the hematoma indicates high risk. When clinical or radiologic findings suggest an underlying structural lesion, useful techniques include CT angiography, CT venography, contrast-enhanced CT scanning, contrast-enhanced MRI, magnetic resonance angiography (MRA), or magnetic resonance venography.[28] Conventional angiography is the gold standard in evaluating for cerebrovascular disease and for providing less-invasive endovascular interventions. This modality can be performed to clarify equivocal findings or to confirm and treat disease seen on MRA, CTA, transcranial Doppler, or neck ultrasonograms. However, Zhu et al found that in patients with spontaneous intracranial hemorrhage, angiographic yield was significantly lower in patients older than 45 years and those who had preexisting hypertension.[29] Although the traditional approach to excluding underlying vascular abnormalities in patients with spontaneous intracerebral hemorrhage is to use digital subtraction angiography (DSA) in the acute and subacute phases, Wong et al found that MRA was able to detect most structural vascular abnormalities in the subacute phase in most patients. Consequently, they recommend MRA as the screening test.

Treatment The treatment and management of patients with acute intracerebral hemorrhage depends on the cause and severity of the bleeding. Basic life support, as well as control of bleeding, seizures, blood pressure (BP), and intracranial pressure, are critical. Medications used in the treatment of acute stroke include the following:

Anticonvulsants - To prevent seizure recurrence Antihypertensive agents - To reduce BP and other risk factors of heart disease Osmotic diuretics - To decrease intracranial pressure in the subarachnoid space Management begins with stabilization of vital signs. Perform endotracheal intubation for patients with a decreased level of consciousness and poor airway protection. Intubate and hyperventilate if intracranial pressure is elevated, and initiate administration of mannitol for further control. Rapidly stabilize vital signs, and simultaneously acquire an emergent computed tomography (CT) scan. Glucose levels should be monitored, with normoglycemia recommended.[28]Antacids are used to prevent associated gastric ulcers. Currently, no effective targeted therapy for hemorrhagic stroke exists. Studies of recombinant factor VIIa (rFVIIa) have yielded disappointing results. Evacuation of hematoma, either via open craniotomy or endoscopy, may be a promising ultra-early-stage treatment for intracerebral hemorrhage that may improve long-term prognosis.

Management of Seizures Early seizure activity occurs in 4-28% of patients with intracerebral hemorrhage; these seizures are often nonconvulsive.[30,
31]

According to American Heart Association/American Stroke

Association (AHA/ASA) 2010 guidelines for the management of spontaneous intracerebral hemorrhage, patients with clinical seizures or electroencephalographic (EEG) seizure activity accompanied by a change in mental status should be treated with antiepileptic drugs.[28] Patients for whom treatment is indicated should immediately receive a benzodiazepine, such as lorazepam or diazepam, for rapid seizure control. This should be accompanied by phenytoin or fosphenytoin loading for longer-term control. Prophylaxis The utility of prophylactic anticonvulsant medication remains uncertain. In prospective and population-based studies, clinical seizures have not been associated with worse neurologic outcome or mortality. Indeed, 2 studies have reported worse outcomes in patients who did not have a documented seizure but who received antiepileptic drugs (primarily phenytoin).[28]

The 2010 AHA/ASA guidelines do not offer recommendations on prophylactic anticonvulsants, but suggest that continuous EEG monitoring is probably indicated in patients with intracranial hemorrhage whose mental status is depressed out of proportion to the degree of brain injury Prophylactic anticonvulsant therapy has been recommended in patients with lobar hemorrhages to reduce the risk of early seizures. One large, single-center study showed that prophylactic antiepileptic drugs significantly reduced the number of clinical seizures in these patients.[30] In addition, AHA/ASA guidelines from 2012 suggest that prophylactic anticonvulsants may be considered for patients with aneurysmal subarachnoid hemorrhage. In such cases, however, anticonvulsant use should generally be limited to the immediate post-hemorrhagic period. Routine long-term use is not recommended, but it may be considered in patients with a prior seizure history, intracerebral hematoma, intractable hypertension, or infarction or aneurysm at the middle cerebral artery.[32]

Blood Pressure Control No controlled studies have defined optimum BP levels for patients with acute hemorrhagic stroke, but greatly elevated BP is thought to lead to rebleeding and hematoma expansion. Stroke may result in loss of cerebral autoregulation of cerebral perfusion pressure. Suggested agents for use in the acute setting are beta blockers (eg, labetalol) and angiotensinconverting enzyme inhibitors (ACEIs) (eg, enalapril). For more refractory hypertension, agents such as nicardipine and hydralazine are used. Avoid nitroprusside because it may raise intracranial pressure. The 2010 AHA/ASA guidelines acknowledge that evidence for the efficacy of managing BP in hemorrhagic stroke is currently incomplete. With that caveat, the AHA/ASA recommendations for treating elevated BP are as follows[28] :

If systolic BP is over 200 mm Hg or mean arterial pressure (MAP) is over 150 mm Hg, then consider aggressive reduction of BP with continuous IV infusion; check BP every 5 minutes

If systolic BP is over 180 mm Hg or MAP is over 130 mm Hg and intracranial pressure may be elevated, then consider monitoring intracranial pressure and reducing BP using intermittent or

continuous intravenous medications, while maintaining a cerebral perfusion pressure of 60 mm Hg or higher

If systolic BP is over 180 or MAP is over 130 mm Hg and there is no evidence of elevated intracranial pressure, then consider modest reduction of BP (target MAP of 110 mm Hg or target BP of 160/90 mm Hg) using intermittent or continuous intravenous medications to control it, and perform clinical reexamination of the patient every 15 minutes

In patients presenting with a systolic BP of 150 to 220 mm Hg, acute lowering of systolic BP to 140 mm Hg is probably safe For patients with aneurysmal subarachnoid hemorrhage, the 2012 AHA/ASA guidelines recommend lowering BP below 160 mmHg acutely to reduce rebleeding.[32] The ongoing Antihypertensive Treatment in Acute Cerebral Hemorrhage-II (ATACH-II) phase 3 randomized clinical trial is designed to determine whether the likelihood of death or disability at 3 months after spontaneous supratentorial intracerebral hemorrhage is lower when systolic BP has been reduced to 180 mm Hg or below or to 140 mm Hg or below. In ATACH-II, intravenous nicardipine is started within 3 hours of stroke onset and continued for the next 24 hours.

Intracranial Pressure Control Elevated intracranial pressure may result from the hematoma itself, from surrounding edema, or from both. The frequency of increased intracranial pressure in patients with intracerebral hemorrhage is not known. Elevate the head of the bed to 30. This improves jugular venous outflow and lowers intracranial pressure. The head should be midline and not turned to the side. Provide analgesia and sedation as needed. Antacids are used to prevent gastric ulcers associated with intracerebral hemorrhage. More aggressive therapies, such as osmotic therapy (ie, mannitol, hypertonic saline), barbiturate anesthesia, and neuromuscular blockage, generally require concomitant monitoring of intracranial pressure and BP with an intracranial pressure monitor to maintain adequate cerebral perfusion pressure of greater than 70 mm Hg. A randomized, controlled study of mannitol in intracerebral hemorrhage failed to demonstrate any difference in disability or death at 3 months.[33]

Hyperventilation (partial pressure of carbon dioxide [PaCO2] of 25 to 30-35 mm Hg) is not recommended, because its effect is transient, it decreases cerebral blood flow, and it may result in rebound elevated intracranial pressure.[2]Glucocorticoids are not effective and result in higher rates of complications with poorer outcomes

Hemostatic Therapy The use of hemostatic therapy with rFVIIa to stop ongoing hemorrhage or prevent hematoma expansion has generated much interest. However, research to date has failed to support this offlabel use of rFVIIa.[34, 35, 36] A preliminary study of treatment rFVIIa demonstrated reduced mortality and improved functional outcomes. Unfortunately, the results of a subsequent randomized trial that was larger than the preliminary study revealed no overall benefit from treatment; hemostatic therapy with rFVIIa reduced growth of the hematoma but did not improve survival or functional outcome.[37] Diringer et al found that a higher dose of rFVIIa was associated with a small increase in the risk of arterial thromboembolic events in patients who presented less than 3 hours after spontaneous intracerebral hemorrhage. Arterial events were also associated with the presence of cardiac or cerebral ischemia at presentation, with advanced age, and with antiplatelet use.[38] The investigators also found that with the use of 20 or 80 mcg/kg rFVIIa, the rates of venous events were similar to those with placebo

Treatment of Anticoagulation-associated Intracranial Hemorrhage Patients on warfarin have an increased incidence of hemorrhagic stroke. Morbidity and mortality for warfarin-associated bleeding is high, with over one half of patients dying within 30 days. Most episodes occur with a therapeutic international normalized ratio (INR), but overanticoagulation is associated with an even greater risk of bleeding.

The need to reverse warfarin anticoagulation is a true medical emergency, and reversal must be accomplished as quickly as possible to prevent further hematoma expansion. Options for reversal therapy include the following:

Intravenous vitamin K Fresh frozen plasma (FFP) Prothrombin complex concentrates (PCC) rFVIIa FFP versus PCC Because vitamin K requires more than 6 hours to normalize the INR, it should be administered with either FFP or PCC. FFP is the standard of care in the United States[39] ; however, FFP needs to be given in a dose of 15-20 mL/kg and therefore requires a large-volume infusion. PCC contains high levels of vitamin K-dependent cofactors and thus involves a smaller-volume infusion than FFP and more rapid administration.[40, 41] However, PCC is associated with high rates of thrombotic complications. No randomized, controlled trial has studied the safety and efficacy of FFP versus PCC for reversing the effects of warfarin in patients with intracranial hemorrhage. The International Normalised ratio normalisation in patients with Coumarin-related intracranial Haemorrhages (INCH) trial, a prospective, randomized, controlled, multicenter trial comparing the 2 agents, began recruiting subjects in 2009.[42] FVIIa Based upon the available medical evidence, the use of FVIIa is currently not recommended over other agents. The PCC available in the United States contains only low levels of FVII, however, and Sarode et al have described successful, rapid reversal of vitamin K antagonist related coagulopathy using a combination of low-dose FVIIa with PCC, although they note the need for caution in patients at high risk for thrombosis.[39] Patients on heparin (either unfractionated or low molecular weight heparin [LMWH]) who develop a hemorrhagic stroke should immediately have anticoagulation reversed with protamine.[2] The dose of protamine is dependent upon the dose of heparin that was given and the time elapsed since that dose.

Patients with severe deficiency of a specific coagulation factor who develop spontaneous intracerebral hemorrhage should receive factor replacement therapy.[28] Reversal of antiplatelet therapy and platelet dysfunction There is controversy about whether patients on antiplatelet medications (eg, aspirin, aspirin/dipyridamole [Aggrenox], clopidogrel) should be given desmopressin (DDAVP) and/or platelet transfusions. Patients with renal failure and platelet dysfunction may also benefit from the administration of desmopressin (DDAVP). The 2010 AHA/ASA guideline for management of spontaneous intracerebral hemorrhage recommends platelet transfusions only when such hemorrhaging complicates severe thrombocytopenia.[28]

Invasive Therapy A potential treatment for hemorrhagic stroke is surgical evacuation of the hematoma. However, the role of surgical treatment for supratentorial intracranial hemorrhage remains controversial. Outcomes in published studies are conflicting. The international multicenter Trial in Intracerebral Haemorrhage (STICH), which compared early surgery with initial conservative treatment, failed to demonstrate a surgery-related benefit.[43] In contrast, a meta-analysis of trials for surgical treatment of spontaneous supratentorial intracerebral hemorrhage found evidence for improved outcome with surgery if any of the following applied[44] :

Surgery undertaken within 8 hours of ictus Volume of the hematoma 20-50 mL Glasgow coma score 9-12 Patient age 50-69 years In addition, evidence suggests that a subset of patients with lobar hematoma but no intraventricular hemorrhage may benefit from intervention.[45] A study in this group of patients (STICH II) has been completed, but results are still pending.[46]

In patients with cerebellar hemorrhage, surgical intervention has been shown to improve outcome if the hematoma is greater than 3 cm in diameter. It can be lifesaving in the prevention of brainstem compression. Endovascular treatment of aneurysms Endovascular therapy using coil embolization, as an alternative to surgical clipping, has been increasingly employed in recent years with great success (see the following images), although controversy still exists over which treatment is ultimately superior.

A cerebral angiogram was performed in a 57-year-old man with a family history of subarachnoid hemorrhage and who was found on previous imaging to have a left distal internal carotid artery (ICA) aneurysm. The lateral projection from this angiogram demonstrates a narrow-necked aneurysm arising off the posterior aspect of the distal supraclinoid left ICA, with an additional nipplelike projection off the inferior aspect of the dome of the aneurysm. There is also a mild, lobulated dilatation of the cavernous left ICA.

Follow-up cerebral angiogram after coil embolization in a 57year-old man with a left distal internal carotid artery aneurysm. Multiple coils were placed with sequential occlusion of the aneurysm, including the nipple at its inferior aspect. A small amount of residual filling is noted at the proximal neck of the aneurysm, which may thrombose over time.

The International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling reported that independent survival was higher at 1 year with endovascular coiling and that the survival benefit continued for at least 7 years.[47] This randomized, multicenter, international trial included 2143 patients. The investigators also noted that the risk of late rebleeding was small in both groups but higher in the endovascular coiling group, reconfirming the higher long-term anatomic cure rate of surgery.[47, 48] More recently, the Barrow Ruptured Aneurysm Trial (BRAT), which included 358 patients, demonstrated superior functional outcome at 1 year with endovascular coil embolization than with microsurgical clipping for acutely ruptured intracerebral aneurysm. Further, in contrast to the ISAT results, no patient in the endovascular embolization group suffered a recurrent hemorrhage.[49] Outcomes at 3-year follow-up of the BRAT patients continued to favor coil embolization, though the difference no longer reached statistical significance.[50] Endovascular treatment of aneurysms may be favored over surgical clipping under the following circumstances[51] :

The aneurysm is in a location that is difficult to access surgically, such as the cavernous internal carotid artery (ICA) or the basilar terminus

The aneurysm is small-necked and located in the posterior fossa The patient is elderly The patient has a poor clinical grade The following factors militate against endovascular treatment:

Wide-based aneurysms or those without an identifiable neck Aneurysms with a vessel extending off the aneurysm dome Severely atherosclerotic or tortuous vessels that limit the endovascular approach Although vasospasm may be treated with intra-arterial pharmaceutical agents, such as verapamil or nicardipine, balloon angioplasty can be used for opening larger vessels (see the images below). The combination of the 2 treatments appears to provide safe and long-lasting therapy for severe, clinically significant vasospasm.[52]

Frontal view from a cerebral angiogram in a 41-year-man who presented 7 days earlier with subarachnoid hemorrhage from a ruptured anterior communicating artery (ACA) aneurysm (which was treated with surgical clipping). There is significant narrowing of the proximal left ACA, left M1 segment, and left supraclinoid internal carotid

artery, indicating vasospasm.

Angiographic view in a 41-year-man

who presented 7 days earlier with subarachnoid hemorrhage from a ruptured anterior communicating artery (ACA) aneurysm (which was treated with surgical clipping). Superimposed road map image demonstrates placement of a wire across the left M1 segment and balloon angioplasty. The left proximal ACA and supraclinoid internal carotid artery (ICA) were also angioplastied, and intra-arterial verapamil was administered. Follow-up image on the right after treatment demonstrates resolution of the left M1 segment and distal ICA, which are now widely patent. Residual narrowing is seen in the left proximal ACA. Ventriculostomy Placement of an intraventricular catheter for cerebrospinal fluid drainage (ie, ventriculostomy) is often used in the setting of obstructive hydrocephalus, which is a common complication of thalamic hemorrhage with third-ventricle compression and of cerebellar hemorrhage with fourthventricle compression. Ventriculostomies are associated with a risk of infection, including bacterial meningitis

Prevention of Hemorrhagic Stroke Antihypertensives The 2010 AHA/ASA guidelines for spontaneous ICH recommend that after acute intracerebral hemorrhage, patients without medical contraindications should have BP well controlled, especially for hemorrhage in typical hypertensive vasculopathy locations.[28] In addition, the guidelines strongly recommend maintenance of BP below 140/90 mm Hg to prevent a first stroke. In patients with hypertension plus either diabetes or renal disease, the treatment goal is BP below 130/80 mm Hg.[53] BP-lowering medications include thiazide diuretics, calcium channel blockers, angiotensinconverting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs). For patients with diabetes, the use of ACEIs and ARBs to treat hypertension is a class I-A recommendation (strongest and best-documented), according to the 2011 AHA/ASA primary prevention guidelines.[28] Beta blockers are considered second-line agents given their inferiority in preventing vascular events, despite producing similar reductions in BP. (Adverse effects of ACEIs include cough [10%], which is less common with ARBs.) Although statin therapy is recommended for primary prevention of ischemic stroke (class I-A recommendation),[53] especially if other risk factors are present, some studies have found an increased risk of intracerebral hemorrhage with statin use. However, a meta-analysis of 31 randomized, controlled trials of statin therapy found that active statin therapy was not associated with a significant increase in intracerebral hemorrhage.[54] In the Heart Outcomes Prevention Evaluation (HOPE) study, the addition of the ACEI ramipril to all other medical therapy, including antiplatelet agents, reduced the relative risk of stroke, death, and myocardial infarction by 32% compared with placebo.[55] Only 40% of the efficacy of ramipril could be attributed to its BP-lowering effects. Other postulated mechanisms included endothelial protection. Whether the beneficial effect of ramipril represents a class effect of ACEIs or whether it is a property unique to ramipril is unclear.

In the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), a regimen based on perindopril, an ACEI, was superior to placebo.[56] Although this drug alone was not superior to placebo, the combination of perindopril with indapamide (a thiazide diuretic) substantially reduced the recurrence of stroke.[56]Much of the effect in reducing stroke recurrence was attributable to the lowering of BP, in contrast to findings for ramipril from the HOPE study. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) showed slight superiority of chlorthalidone (a thiazide diuretic) over lisinopril (an ACEI) in terms of stroke occurrence.[57] The Losartan Intervention for Endpoint Reduction in Hypertension Study (LIFE) demonstrated that an ARB (losartan) was superior to a beta blocker (atenolol) in reducing the occurrence of stroke.[58] The Morbidity and Mortality after Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES) study found that the ARB eprosartan was superior to the calcium channel blocker nitrendipine in the secondary prevention of stroke and transient ischemic attack (TIA).[59] This was true despite comparable BP reductions. The absolute annual difference in stroke and TIA risk was approximately 4%. The study was relatively small, and most events were TIAs. Lifestyle interventions Smoking cessation, a low-fat diet (eg, Dietary Approaches to Stop Hypertension [DASH] or Mediterranean diets), weight loss, and regular exercise should be encouraged as strongly as pharmacologic treatment. Written prescriptions for exercise and medications for smoking cessation (ie, nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions. Reducing sodium intake and increasing consumption of foods high in potassium to reduce BP may also help in primary prevention.[53] High alcohol intake should be reduced, as drinking more than 30 drinks per month has been tied to increased risk of intracerebral hemorrhage. Exercise

A Finnish study showed that the likelihood of stroke in men with the lowest degree of physical fitness (maximal oxygen uptake [VO2max] < 25.2 mL/kg/min) was more than 3 times greater than in men with the highest degree of physical fitness (VO2max >35.3 mL/kg/min).[60] level of physical fitness was a more powerful risk factor than low-density lipoprotein cholesterol level, body mass index, and smoking, and it was nearly comparable to hypertension as a risk factor. The 2011 AHA/ASA guidelines for the primary prevention of stroke, which address hemorrhagic and ischemic stroke, emphasize exercise and other lifestyle modifications. The guidelines endorse the 2008 Physical Activity Guidelines for Americans, which include a recommendation of at least 150 minutes per week of moderate-intensity aerobic physical activity.[53]

Consultations Emergent neurosurgical or neurologic consultation is often indicated; local referral patterns may vary. The need for invasive intracranial pressure monitoring and for emergent cerebral angiography should be assessed by the neurosurgeon. Patients in whom the hemorrhages cause is unclear and who would otherwise be candidates for surgery should be considered for angiographic evaluation. Also seeStroke Team Creation and Primary Stroke Center Certification.

Medication Summary Medications used in the treatment of acute stroke include anticonvulsants such as diazepam, to prevent seizure recurrence; antihypertensive agents such as labetalol, to reduce blood pressure (BP) and other risk factors for heart disease; and osmotic diuretics such as mannitol, to decrease intracranial pressure in the subarachnoid space. As previously mentioned, the treatment and management of patients with acute intracerebral hemorrhage depends on the cause and severity of the bleeding. However, there is currently no effective targeted therapy for hemorrhagic stroke.

Anticonvulsants, Other

Class Summary Benzodiazepines are commonly used to control seizure activity and recurrence. Agents such as lorazepam and diazepam are often used acutely, in combination with either phenytoin or fosphenytoin loading. Diazepam (Diastat, Diazemuls, Valium)

Diazepam controls active seizures by modulating the postsynaptic effects of gammaaminobutyric acid type A (GABA-A) transmission, resulting in an increase in presynaptic inhibition. It appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect. It also acts as an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders. Diazepam should be augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital, because it rapidly distributes to other body fat stores. Lorazepam (Ativan)

Lorazepam is a short-acting acting benzodiazepine with a moderately long half-life. It has become the drug of choice in many centers for treating active seizures.

Anticonvulsants, Hydantoins Class Summary Anticonvulsants prevent seizure recurrence and terminate clinical and electrical seizure activity. These agents are used routinely to avoid seizures that may be induced by cortical damage. According to the American Heart Association/American Stroke Association (AHA/ASA) 2010 guidelines for management of spontaneous intracranial hemorrhage, treatment with antiepileptic drugs is indicated for those patients with clinical seizures or with electroencephalographic (EEG)

seizure activity accompanied by a change in mental status.[28] Prophylactic use of anticonvulsants is controversial and should be used judiciously, if at all. Phenytoin (Dilantin) Phenytoin may act in the motor cortex, where it may inhibit spread of seizure activity, as well as in the brainstem centers responsible for the tonic phase of grand mal seizures. All doses should be individualized. The antiepileptic effect of phenytoin is not immediate. Concomitant administration of an intravenous benzodiazepine will usually be necessary to control status epilepticus. In addition, a larger dose before retiring should be administered if the dose cannot be divided equally. Fosphenytoin (Cerebyx) Fosphenytoin is a diphosphate ester salt of phenytoin that acts as water-soluble prodrug of phenytoin. Phenytoin, in turn, stabilizes neuronal membranes and decreases seizure activity. To avoid the need to perform molecular-weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses, express the dose as phenytoin sodium equivalents. Although fosphenytoin can be administered intravenously or intramuscularly, the intravenous route is the route of choice and should be used in emergency situations. The antiepileptic effect of phenytoin, whether given as fosphenytoin or parenteral phenytoin, is not immediate. Concomitant administration of an intravenous benzodiazepine will usually be necessary to control status epilepticus.

Beta Blockers, Alpha Activity Class Summary Beta blockers are used to reduce BP and risk factors for heart disease. They are first-line agents for acute BP reduction in hemorrhagic stroke, but they are second-line agents for stroke prevention. Selective beta blockers obstruct access to beta-1 receptors more than they do to beta2 receptors; nonselective beta blockers obstruct access to beta-1 and beta-2 receptors. Labetalol (Trandate)

Labetalol blocks beta1-, alpha-, and beta2-adrenergic receptor sites to decrease BP. It is administered as a 5-20 mg intravenous bolus over 2 minutes, then as a continuous infusion at 2 mg/min (not to exceed 300 mg/dose).

Beta Blockers, Beta-1 Selective Class Summary Beta blockers are used to reduce BP and risk factors for heart disease. They are first-line agents for acute BP reduction in hemorrhagic stroke, but they are second-line agents for stroke prevention. Selective beta blockers obstruct access to beta-1 receptors more than they do to beta2 receptors; nonselective beta blockers obstruct access to beta-1 and beta-2 receptors. Esmolol (Brevibloc) Esmolol is an ultra-short-acting agent that selectively blocks beta-1 receptors with little or no effect on beta-2 receptor types. This drug is particularly useful in patients with elevated arterial pressure, especially if surgery is planned, and its short half-life of 8 minutes allows for titration and quick discontinuation, if necessary. Esmolol is also useful in patients at risk for experiencing complications from beta blockade, particularly those with reactive airway disease, mild to moderate left-ventricular dysfunction, and/or peripheral vascular disease.

Vasodilators Class Summary Vasodilators lower BP through direct vasodilation and relaxation of the vascular smooth muscle. They are used more for BP lowering in refractory situations. Hydralazine (Apresoline)

Hydralazine decreases systemic resistance through direct vasodilation of arterioles and is used to treat hypertensive emergencies. The use of a vasodilator will reduce the stroke volume ratio (SVR), which, in turn, may allow forward flow, improving cardiac output. Hydralazine is typically not a first-line agent, because of its side-effect profile.

Calcium Channel Blockers Class Summary Calcium channel blockers are used to lower BP by relaxing the blood vessels and increasing the amount of blood and oxygen that is delivered to the heart, while reducing the hearts workload. In acute situations, intravenous calcium channel blockers are frequently used to control BP. These are first-line agents for long-term BP control in stroke patients (along with thiazides, ACEIs, and angiotensin receptor blockers [ARBs]). Nicardipine (Cardene, Cardene IV, Cardene SR) Nicardipine relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery and reduces myocardial oxygen consumption.

Angiotensin-converting Enzyme Inhibitors Class Summary ACEIs prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. These are first-line agents for emergent and long-term BP control in hemorrhagic stroke patients. Enalapril (Vasotec) Enalapril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. It helps to control BP and proteinuria. Ramipril (Altace)

Ramipril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in increased levels of plasma renin and a reduction in aldosterone secretion. Lisinopril (Zestril) Lisinopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.

Angiotensin Receptor Blockers Class Summary ARBs may be used as an alternative to ACEIs in patients who develop adverse effects, such as a persistent cough. Losartan (Cozaar) Losartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACEIs do. In addition, it does not affect the response to bradykinin and is less likely to be associated with cough and angioedema. Candesartan (Atacand) Candesartan blocks vasoconstriction and the aldosterone-secreting effects of angiotensin II. It may induce a more complete inhibition of the renin-angiotensin system than ACEIs do. In addition, it does not affect response to bradykinin and is less likely to be associated with cough and angioedema. Valsartan (Diovan) Valsartan produces direct antagonism of angiotensin II receptors. It displaces angiotensin II from the AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses.

Diuretics, Thiazide Class Summary Thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubules of the kidney, resulting in increased urinary excretion of sodium and water. Hydrochlorothiazide (Microzide) Hydrochlorothiazide inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions. Chlorthalidone (Diuril) Chlorthalidone inhibits the reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as potassium and hydrogen ions.

Diuretics, Osmotic Agents Class Summary Osmotic diuretics, such as mannitol, may be used to decrease intracranial pressure in the subarachnoid space. As water diffuses from the subarachnoid space into the intravascular compartment, pressure in the subarachnoid compartment may decrease. Mannitol (Osmitrol) Mannitol reduces cerebral edema with the help of osmotic forces. It also decreases blood viscosity, resulting in reflex vasoconstriction and lowering of intracranial pressure.

Analgesics, Other Class Summary Because hyperthermia may exacerbate neurologic injury, these agents may be given to reduce fever and relieve pain. Acetaminophen (Tylenol, FeverAll, Aspirin Free Anacin)

Acetaminophen reduces fever, maintains normothermia, and reduces headache.

Hemostatics Class Summary Vitamin K is used to promote the formation of clotting factors. Phytonadione can overcome the competitive block produced by warfarin and other related anticoagulants. A fresh frozen plasma (FFP) infusion followed by oral vitamin K should be given without delay in the emergency department to manage warfarin-related intracranial hemorrhage. Vitamin K1 (phytonadione; vitamin K, Mephyton, AquaMephyton) Phytonadione can overcome the competitive block produced by warfarin and other related anticoagulants. Vitamin K3 (menadione) is not effective for this purpose. There is a delay of the clinical effect for several hours while liver synthesis of the clotting factors is initiated and plasma levels of clotting factors II, VII, IX, and X are gradually restored. Phytonadione should not be administered prophylactically and is used only if evidence of anticoagulation exists. The required dose varies with the clinical situation, including the dose and duration of action of the anticoagulant ingested. Intravenous phytonadione is recommended for life-threatening bleeding, including intracerebral hemorrhage complicating warfarin therapy, although it carries a small risk of anaphylaxis.

Blood Components Class Summary These agents are indicated for the correction of abnormal hemostatic parameters. Fresh frozen plasma Plasma, the fluid component of blood, contains the blood's soluble clotting factors. FFP is created by separating plasma from a unit of blood and freezing it for use in patients with bloodproduct deficiencies.

Platelets Platelets are fragments of large bone marrow cells found in the blood that play a role in blood coagulation. A single random donor unit of platelets per 10 kg is administered in adults when the platelet count drops below 50,000/L. Prothrombin complex concentrate (Bebulin VH, Profilnine SD) Prothrombin complex concentrate (PCC) is a mixture of vitamin K-dependent clotting factors found in normal plasma that replaces deficient clotting factors, provides an increase in plasma levels of factor IX, and can temporarily correct a coagulation defect in patients with factor IX deficiency. PCC is usually reserved for situations in which volume overload is a concern.

Antidotes, Other Class Summary Protamine is used to neutralize the effects of anticoagulants. Protamine Protamine sulfate forms a salt with heparin and neutralizes its effects. The dosage administered is dependent on the amount of time that has passed since heparin was given.

Vasopressin-Related Class Summary These agents improve bleeding time and hemostasis. Desmopressin acetate (DDAVP, Stimate) Desmopressin releases von Willebrand protein from endothelial cells. It improves bleeding time and hemostasis in patients with mild and moderate von Willebrand disease without abnormal molecular forms of von Willebrand protein. It is effective in uremic bleeding. Tachyphylaxis usually develops after 48 hours, but the drug can be effective again after several days.

Hypoglicemia Practice Essentials Hypoglycemia is characterized by a reduction in plasma glucose concentration to a level that may induce symptoms or signs such as altered mental status and/or sympathetic nervous system stimulation. This condition typically arises from abnormalities in the mechanisms involved in glucose homeostasis. The most common cause of hypoglycemia in patients with diabetes is injecting a shot of insulin and skipping a meal or overdosing insulin. Essential update: Severe hypoglycemia and risk of cardiovascular disease in type 2 diabetes In patients with type 2 diabetes, having episodes of severe hypoglycemia may increase their risk of developing cardiovascular disease. In a recent meta-analysis of 6 observational studies involving 903,510 patients, from 0.6% to 5.8% of patients experienced severe hypoglycemia during 1 to 5 years of follow-up. Severe hypoglycemia was strongly associated with a higher risk for cardiovascular disease (relative risk, 2.05). Comorbid severe illness alone did not explain the association between hypoglycemia and cardiovascular disease in the studies.[1, 2] Signs and symptoms The glucose level at which an individual becomes symptomatic is highly variable (threshold generally at < 50 mg/dL). Carefully review the patient's medication and drug history for potential causes of hypoglycemia (eg, new medications, insulin usage or ingestion of an oral hypoglycemic agent, possible toxic ingestion). The patients medical and/or social history may reveal the following:

Diabetes mellitus, renal insufficiency/failure, alcoholism, hepatic cirrhosis/failure, other endocrine diseases, or recent surgery

Central nervous system: Headache, confusion, personality changes Ethanol intake and nutritional deficiency Weight reduction, nausea and vomiting Fatigue, somnolence

Neurogenic or neuroglycopenic symptoms of hypoglycemia may be categorized as follows:

Neurogenic (adrenergic) (sympathoadrenal activation) symptoms: Sweating, shakiness, tachycardia, anxiety, and a sensation of hunger

Neuroglycopenic symptoms: Weakness, tiredness, or dizziness; inappropriate behavior (sometimes mistaken for inebriation), difficulty with concentration; confusion; blurred vision; and, in extreme cases, coma and death

Reactive hypoglycemic include the following features:

More common in overweight and obese people who are insulin-resistant May be a frequent precursor to type 2 diabetes Possible higher risk in patients with a family history of type 2 diabetes or insulin-resistance syndrome

True loss of consciousness is highly suggestive of an etiology other than reactive hypoglycemia. Gestational hypoglycemia may have the following features[3] :

More frequent in women younger than 25 years More frequent in women with a preexisting medical condition Less frequent in women whose prepregnancy body mass index was 30 kg/m2 Greater risk of preeclampsia/eclampsia in affected women

Diagnosis Rapid diagnosis and treatment is essential in any patient with suspected hypoglycemia, regardless of the cause. The Whipple triad is characteristically present: documentation of low blood sugar, presence of symptoms, and reversal of these symptoms when the blood glucose level is restored to normal. Physical findings, however, are nonspecific in hypoglycemia and are generally related to the central and autonomic nervous systems. Examination includes the following:

Vital signs Head, eyes, ears, nose, and throat Cardiovascular

Neurologic Pulmonary Gastrointestinal Dermatologic

Elderly persons exhibit fewer symptoms of hypoglycemia, and their threshold of plasma glucose is lower at presentation than in younger persons. Laboratory studies Patients with no previous history of hypoglycemia require a complete workup to find a potentially treatable disease. Laboratory studies that should be obtained include the following:

Glucose and electrolyte levels (including calcium, magnesium) Oral glucose tolerance test and/or 72-hour fasting plasma glucose Complete blood count

Other tests that may be helpful including the following:

Blood cultures Urinalysis Serum insulin, cortisol levels, and thyroid hormone levels C-peptide levels Insulin radioimmunoassay

Imaging studies Imaging modalities to evaluate insulinomas may include the following:

CT scanning MRI Octreotide scanning

Procedures Selective percutaneous transhepatic venous sampling may be performed to localize an insulinoma to the pancreatic head, body, or tail. Selective arteriography is also often helpful in localizing insulin-secreting lesions. Management

Pharmacotherapy The mainstay of therapy for hypoglycemia is glucose. Other medications may be administered based on the underlying cause or the accompanying symptoms. Medications used in the treatment of hypoglycemia include the following:

Glucose supplements (eg, dextrose) Glucose-elevating agents (eg, glucagon) Inhibitors of insulin secretion (eg, diazoxide, octreotide) Antineoplastic agents (eg, streptozocin)

Other therapies

Fasting hypoglycemia: Dietary therapy (frequent meals/snacks preferred, especially at night, with complex carbohydrates); IV glucose infusion; IV octreotide

Reactive hypoglycemia: Dietary therapy (restriction of refined carbohydrates, avoidance of simple sugars, increased meal frequency, increased protein and fiber)

Surgery Definitive treatment for fasting hypoglycemia caused by a tumor is surgical resection. The success rate is good for benign islet-cell adenomas, and the success rate for malignant islet-cell tumors can be as high as 50%. Background Hypoglycemia is a clinical situation characterized by a reduction in plasma glucose concentration to a level that may induce symptoms or signs such as altered mental status and/or sympathetic nervous system stimulation. The glucose level at which an individual becomes symptomatic is highly variable, although a plasma glucose level less than 50 mg/dL is generally considered the threshold. Hypoglycemia typically arises from abnormalities in the mechanisms involved in glucose homeostasis. To diagnose hypoglycemia, the Whipple triad is characteristically present. This triad includes the documentation of low blood sugar, presence of symptoms, and reversal of these symptoms when the blood sugar level is restored to normal. See a diagnostic algorithm for hypoglycemia, below.

Phatophysiology Hypoglycemic symptoms are related to sympathetic activation and brain dysfunction secondary to decreased levels of glucose. Stimulation of the sympathoadrenal nervous system leads to sweating, palpitations, tremulousness, anxiety, and hunger. Reduction in cerebral glucose availability (ie, neuroglycopenia) can manifest as confusion, difficulty with concentration, irritability, hallucinations, focal impairments (eg, hemiplegia), and, eventually, coma and death. The adrenergic symptoms often precede the neuroglycopenic symptoms and, thus, provide an early warning system for the patient. Studies have shown that the primary stimulus for the release of catecholamines is the absolute level of plasma glucose; the rate of decrease of glucose is less important. Previous blood sugar levels can influence an individual's response to a particular level of blood sugar. However, it is important to note that a patient with repeated hypoglycemia can have almost no symptoms (hypoglycemic unawareness). The threshold at which a patient feels the hypoglycemic symptoms decreases with repeated episodes of hypoglycemia. Etiology Causes of hypoglycemia are varied, but it is seen most often in diabetic patients. Hypoglycemia may result from medication changes or overdoses, infection, diet changes, metabolic changes over time, or activity changes; however, no acute cause may be found. Other causes include alimentary problems, idiopathic causes, fasting, insulinoma, endocrine problems, extrapancreatic causes, hepatic disease, post bariatric surgery, and miscellaneous causes. 1. Fasting hypoglycemia Nesidioblastosis it is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adult. This condition is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells. Causes of fasting hypoglycemia usually diagnosed in infancy or childhood include inherited liver enzyme deficiencies that restrict hepatic glucose release (deficiencies of glucose-6phosphatase, fructose-1,6-diphosphatase, phosphorylase, pyruvate carboxylase,

phosphoenolpyruvate carboxykinase, or glycogen synthetase). Inherited defects in fatty acid oxidation, including that resulting from systemic carnitine deficiency and inherited defects in

ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency) cause fasting hypoglycemia by restricting the extent to which nonneural tissues can derive their energy from plasma free fatty acids (FFA) and ketones during fasting or exercise. This results in an abnormally high rate of glucose uptake by nonneural tissues under these conditions. Several cases of nesidioblastosis were reported recently after gastric bypass surgery. 2. Drugs Ethanol (including propranolol plus ethanol), haloperidol, pentamidine, quinine, salicylates, and sulfonamides ("sulfa drugs") have been associated with hypoglycemia. Other drugs that may be related to this condition include oral hypoglycemics, phenylbutazone, insulin, bishydroxycoumarin, carbamate p-aminobenzoic disopyramide, acid, propoxyphene, methanol, stanozolol, hypoglycin, tricyclic

insecticide,

isoniazid,

methotrexate,

antidepressants, cytotoxic agents, organophosphates, didanosine, chlorpromazine, fluoxetine, sertraline, fenfluramine, trimethoprim, 6-mercaptopurine, thiazide diuretics, thioglycolate, tremetol, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA), clofibrate, angiotensin converting enzyme (ACE) inhibitors, and lithium. 3. Surreptitious sulfonylurea use/abuse Factitious hypoglycemia or self-induced hypoglycemia can be seen in healthcare workers or in relatives who care for diabetic family members at home. 4. Exogenous insulin Sources of exogenous insulin include insulin-producing tumors of pancreas and nonbetacell tumors.

Insulin-producing tumors of pancreas Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually curable cause of fasting hypoglycemia and is most often diagnosed in adults. It may occur as an isolated abnormality or as a component of the multiple endocrine neoplasia type I (MEN) syndrome.

Carcinomas account for only 10% of insulin-secreting islet cell tumors. Hypoglycemia in patients with islet cell adenomas results from uncontrolled insulin secretion, which may be clinically determined during fasting and exercise. Approximately 60% of patients with insulinoma are female. Insulinomas are uncommon in persons younger than 20 years and are rare in those younger than 5 years. The median age at diagnosis is about 50 years, except in patients with MEN syndrome, in which the median age is in the mid 20s. Ten percent of patients with insulinoma are older than 70 years. Nonbeta-cell tumors Hypoglycemia may also be caused by large noninsulin-secreting tumors, most commonly retroperitoneal or mediastinal malignant mesenchymal tumors. The tumor secretes abnormal insulinlike growth factor (large IGF-II), which does not bind to its plasma binding proteins. This increase in free IGF-II exerts hypoglycemia through the IGF-I or the insulin receptors. The hypoglycemia is corrected when the tumor is completely or partially removed and usually recurs when the tumor regrows. 5. Reactive hypoglycemia Reactive hypoglycemia can be idiopathic, due to alimentary problems, or a result of congenital enzyme deficiencies. Alimentary hypoglycemia is another form of reactive hypoglycemia that occurs in patients who have had previous upper gastrointestinal (GI) surgical procedures (gastrectomy, gastrojejunostomy, vagotomy, pyloroplasty) and allows rapid glucose entry and absorption in the intestine, provoking excessive insulin response to a meal. This may occur within 1-3 hours after a meal. Very rare cases of idiopathic alimentary hypoglycemia occur in patients who have not had GI operations. Congenital enzyme deficiencies include hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood. In hereditary fructose intolerance and galactosemia, an inherited deficiency of a hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or galactose is ingested. Leucine provokes an exaggerated insulin secretory response to a meal and reactive hypoglycemia in patients with leucine sensitivity of childhood.

Other causes of hypoglycemia include the following, singly or in combination (eg, chronic renal failure and sulfonylurea ingestion):

Autoimmune hypoglycemia: Insulin antibodies and insulin receptor antibodies Hormonal deficiencies: Hypoadrenalism (cortisol), hypopituitarism (growth hormone) (in children), glucagons deficiency (rare), and epinephrine (very rare)

Critical illnesses: Cardiac, hepatic, and renal diseases; sepsis with multiorgan failure Exercise (in patients with diabetes treated with diabetes medications) Pregnancy Renal glycosuria Ketotic hypoglycemia of childhood Adrenal insufficiency Hypopituitarism Starvation Artifact

Epidemiology The incidence of hypoglycemia in a population is difficult to ascertain. Patients and physicians frequently attribute symptoms (eg, anxiety, irritability, hunger) to hypoglycemia without documenting the presence of low blood sugar. The true prevalence of hypoglycemia, with blood sugar levels below 50 mg/dL, generally occurs in 5-10% of people presenting with symptoms suggestive of hypoglycemia. Hypoglycemia is also a known complication of several medications, and the incidence is difficult to determine with any certainty. In addition, this condition is a known complication of many therapies for diabetes; therefore, the incidence of hypoglycemia in a population of people with diabetes is very different from that in a population of people without diabetes.[4, 5, 6, 7, 8, 9] Insulin-producing tumors are a rare but important treatable cause of hypoglycemia, with an annual US incidence of 1-2 cases per million persons per year. Reactive hypoglycemia is reported most frequently by women aged 25-35 years; however, other causes of hypoglycemia are not associated with a sex predilection. The average age of a patient

diagnosed with an insulinoma is the early 40s, but cases have been reported in patients ranging from birth to age 80 years.[10] Prognosis The prognosis of hypoglycemia depends on the cause of this condition, its severity, and its duration. If the cause of fasting hypoglycemia is identified and treated early, the prognosis is excellent. If the problem is not curable, such as an inoperable malignant tumor, the long-term prognosis is poor. However, note that these tumors may progress rather slowly. Severe and prolonged hypoglycemia can be life threatening and may be associated with increased mortality in patients with diabetes. If the patient has reactive hypoglycemia, symptoms often spontaneously improve over time, and the long-term prognosis is very good. Reactive hypoglycemia is often treated successfully with dietary changes and is associated with minimal morbidity. Mortality is not observed. Untreated reactive hypoglycemia may cause significant discomfort to the patient, but long-term sequelae are not likely. A study by Boucai et al found that drug-associated hypoglycemia was not associated with increased mortality risk among patients admitted to general wards. This suggests that hypoglycemia may be a marker of disease burden and not a direct cause of death.[11]

Migrain Headache Practice Essentials Migraine is a complex disorder characterized by recurrent episodes of headache, most often unilateral and in some cases associated with visual or sensory symptomscollectively known as an aurathat arise most often before the head pain but that may occur during or afterward. Migraine is most common in women and has a strong genetic component.

Essential update: FDA approves first device to relieve migraine headache with aura In December 2013, the FDA approved the Cerena Transcranial Magnetic Stimulator (Cerena TMS), the first deviceto relieve pain caused by migraine headache with aura for use in patients age 18 years and older.[1, 2] Users hold the device with both hands to the back of the head and press a button to release a pulse of magnetic energy that stimulates the occipital cortex. The recommended daily usage of the device is not to exceed one treatment in 24 hours. Approval for the Cerena TMS was based on a randomized study of 201 patients with moderate to strong migraine headaches in which nearly 38% of the patients using the device were pain-free 2 hours following its use relative to 17% of control patients.[1,
2]

At 24 hours, nearly 34% of

patients treated with the device were pain-free compared with 10% of the control group. Contraindications and precautions regarding the use of the Cerena TMS include the following[1,
2]

: Do not use for patients with metals in the head, neck, or upper body that are attracted by a magnet

Do not use for patients with an active implanted medical device (eg, pacemaker, deep brain stimulator)

This device should not be used in patients with suspected/diagnosed epilepsy or who have a personal or family history of seizures

Signs and symptoms Typical symptoms of migraine include the following:

Throbbing or pulsatile headache, with moderate to severe pain that intensifies with movement or physical activity

Unilateral and localized pain in the frontotemporal and ocular area, but the pain may be felt anywhere around the head or neck

Pain builds up over a period of 1-2 hours, progressing posteriorly and becoming diffuse Headache lasts 4-72 hours Nausea (80%) and vomiting (50%), including anorexia and food intolerance, and lightheadedness

Sensitivity to light and sound

Features of migraine aura are as follows:

May precede or accompany the headache phase or may occur in isolation Usually develops over 5-20 minutes and lasts less than 60 minutes Most commonly visual but can be sensory, motor, or any combination of these Visual symptoms may be positive or negative The most common positive visual phenomenon is the scintillating scotoma, an arc or band of absent vision with a shimmering or glittering zigzag border

Physical findings during a migraine headache may include the following:

Cranial/cervical muscle tenderness Horner syndrome (ie, relative miosis with 1-2 mm of ptosis on the same side as the headache)

Conjunctival injection Tachycardia or bradycardia Hypertension or hypotension Hemisensory or hemiparetic neurologic deficits (ie, complicated migraine) Adie-type pupil (ie, poor light reactivity, with near dissociation from light)

Diagnosis The diagnosis of migraine is based on patient history. International Headache Society diagnostic criteria are that patients must have had at least 5 headache attacks that lasted 4-72 hours (untreated or unsuccessfully treated) and that the headache must have had at least 2 of the following characteristics[3] :

Unilateral location

Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

In addition, during the headache the patient must have had at least 1 of the following:

Nausea and/or vomiting Photophobia and phonophobia

Finally, these features must not have been attributable to another disorder. Classification of migraine is as follows:

Migraine without aura (formerly, common migraine) Probable migraine without aura Migraine with aura (formerly, classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine Complications of migraine Migrainous disorder not fulfilling above criteria

Migraine variants include the following:

Childhood periodic syndromes Late-life migrainous accompaniments Basilar-type migraine Hemiplegic migraine Status migrainosus Ophthalmoplegic migraine Retinal migraine

A migraine variant may be suggested by focal neurologic findings, such as the following, that occur with the headache and persist temporarily after the pain resolves:

Unilateral paralysis or weakness - Hemiplegic migraine Aphasia, syncope, and balance problems - Basilar-type migraine Third nerve palsy with ocular muscle paralysis and ptosis, including or sparing the pupillary response - Ophthalmoplegic migraine

Testing and imaging studies Selection of laboratory and/or imaging studies to rule out conditions other than migraine headache is determined by the individual presentation (eg, erythrocyte sedimentation rate and Creactive protein levels may be appropriate to exclude temporal/giant cell arteritis). Neuroimaging is not necessary in patients with a history of recurrent migraine headaches and a normal neurologic examination. The American Headache Society released a list of 5 commonly performed tests or procedures that are not always necessary in the treatment of migraine and headache, as part of the American Board of Internal Medicine (ABIM) Foundation's Choosing Wisely campaign. The recommendations include[4, 5] :

Don't perform neuroimaging studies in patients with stable headaches that meet criteria for migraine.

Don't perform computed tomography imaging for headache when magnetic resonance imaging is available, except in emergency settings.

Don't recommend surgical deactivation of migraine trigger points outside of a clinical trial. Don't prescribe opioid or butalbital-containing medications as first-line treatment for recurrent headache disorders.

Don't recommend prolonged or frequent use of over-the-counter pain medications for headache.

Management Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive). Acute/abortive medications Acute treatment aims to reverse, or at least stop the progression of, a headache. It is most effective when given within 15 minutes of pain onset and when pain is mild.[6] Abortive medications include the following:

Selective serotonin receptor (5-hydroxytryptamine1, or 5-HT1) agonists (triptans) Ergot alkaloids (eg, ergotamine, dihydroergotamine [DHE]) Analgesics Nonsteroidal anti-inflammatory drugs (NSAIDs) Combination products Antiemetics

Preventive/prophylactic medications The following may be considered indications for prophylactic migraine therapy:

Frequency of migraine attacks is greater than 2 per month Duration of individual attacks is longer than 24 hours The headaches cause major disruptions in the patient's lifestyle, with significant disability that lasts 3 or more days

Abortive therapy fails or is overused Symptomatic medications are contraindicated or ineffective Use of abortive medications more than twice a week Migraine variants such as hemiplegic migraine or rare headache attacks producing profound disruption or risk of permanent neurologic injury[7]

Prophylactic medications include the following:

Antiepileptic drugs Beta blockers Tricyclic antidepressants Calcium channel blockers Selective serotonin reuptake inhibitors (SSRIs) NSAIDs Serotonin antagonists Botulinum toxin

Other measures Treatment of migraine may also include the following:

Reduction of migraine triggers (eg, lack of sleep, fatigue, stress, certain foods) Nonpharmacologic therapy (eg, biofeedback, cognitive-behavioral therapy) Integrative medicine (eg, butterbur, riboflavin, magnesium, feverfew, coenzyme Q10)

Image library

Migraine headache.Example of a visual migraine aura as described by a person who experiences migraines. This patient reported that these visual auras preceded her headache by 20-30 minutes. Background Migraine headache is a complex, recurrent headache disorder that is one of the most common complaints in medicine. In the United States, more than 30 million people have 1 or more migraine headaches per year. Approximately 75% of all persons who experience migraines are women (see Epidemiology). The term migraine is derived from the Greek word hemikrania. This term was corrupted into low Latin as hemigranea, the French translation of which was migraine. Causes of migraine Migraine was previously considered to be a vascular phenomenon that resulted from intracranial vasoconstriction followed by rebound vasodilation. Currently, however, the neurovascular theory describes migraine as primarily a neurogenic process with secondary changes in cerebral perfusion associated with a sterile neurogenic inflammation (see Pathophysiology). A genetic component to migraine is indicated by the fact that approximately 70% of patients have a first-degree relative with a history of migraine. In addition, a variety of environmental and behavioral factors may precipitate migraine attacks in persons with a predisposition to migraine (see Etiology). Migraine characteristics and treatment Migraine is characterized most often by unilateral head pain that is moderate to severe, throbbing, and aggravated by activity. It may also be associated with various visual or sensory symptoms, which occur most often before the headache component but which may occur during or after the headache; these are collectively known as an aura. Most commonly, the aura consists of visual manifestations, such as scotomas, photophobia, or visual scintillations (eg, bright zigzag lines) (see Presentation). The head pain may also be associated with weakness. This form of migraine is termed hemiplegic migraine.

In practice, however, migraine headaches may be unilateral or bilateral and may occur with or without an aura. In the current International Headache Society categorization, the headache previously described as classic migraine is now known as migraine with aura, and the headache that was described as common migraine is now termed migraine without aura. Migraines without aura are the most common, accounting for more than 80% of all migraines. The diagnosis of migraine is clinical in nature, based on criteria established by the International Headache Society. A full neurologic examination should be performed during the first visit, to exclude other disorders; the findings are usually normal in patients with migraine. Neuroimaging is not necessary in a typical case, but other diagnostic investigations may be indicated to guide management (see Workup). Migraine treatment involves acute (abortive) and preventive (prophylactic) therapy. Patients with frequent attacks usually require both. Measures directed toward reducing migraine triggers are also generally advisable. Acute treatment aims to eliminate, or at least prevent the progression of, a headache. Preventive treatment, which is given even in the absence of a headache, aims to reduce the frequency and severity of migraine attacks, to make acute attacks more responsive to abortive therapy, and perhaps also to improve the patient's quality of life (see Treatment). Migraine classification The second edition of the International Classification of Headache Disorders(ICHD)[8] lists the following types of migraine:

Migraine without aura (formerly, common migraine) Probable migraine without aura Migraine with aura (formerly, classic migraine) Probable migraine with aura Chronic migraine Chronic migraine associated with analgesic overuse Childhood periodic syndromes that may not be precursors to or associated with migraine Complications of migraine Migrainous disorder not fulfilling above criteria

Diagnostic criteria According to the International Headache Society, the diagnosis of migraine requires that the patient has experienced at least 5 attacks that fulfill the following 3 criteria and that are not attributable to another disorder.[3] First, the headache attacks must have lasted 4-72 hours (untreated or unsuccessfully treated). Second, the headache must have had at least 2 of the following characteristics:

Unilateral location Pulsating quality Moderate or severe pain intensity Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs)

Third, during the headache the patient experiences at least 1 of the following:

Nausea and/or vomiting Photophobia and phonophobia

In June 2013, the International Classification of Headache Disorders, Third Edition(ICHD-III, beta version) was published and is available for field testing, which will take place for several years before the final version is published.

Changes from the previous edition include the following[9] :

The addition of chronic migraines: Those that occur on at least 15 days of the month for more than 3 months

For a diagnosis of migraine with aura, the following criteria must be met: One or more visual, sensory, speech, motor, brainstem, or retinal symptoms, as well as at least 2 of the following 4 criteria: (1) at least 1 aura symptom spreading gradually over 5 or more minutes and/or 2 or more symptoms occurring in succession; (2) each aura symptom lasting 5-60

minutes; (3) at least 1 aura symptom being unilateral; and (4) the aura being accompanied by or followed shortly by headache

Under headaches associated with sexual activity, the subtypes of preorgasmic and orgasmic headache have been eliminated

For thunderclap headaches, the headache must last at least 5 minutes, but the criterion of not recurring regularly during subsequent weeks or months has been discarded

Hypnic headaches no longer have to first occur after age 50 years A number of pain characteristics under the new daily persistent headaches section have been eliminated

For secondary headaches, it is not required that the causative agent be removed before a diagnosis

Migraine guidelines In April 2000, the US Headache Consortium, a multispecialty group that includes the American College of Emergency Physicians, released evidence-based guidelines for the diagnosis, treatment, and prevention of migraine headaches. Guidelines are also available from the American Academy of Neurology, the National Headache Foundation, and the Canadian Association of Emergency Physicians.[6, 10, 11] Phatophysiology The mechanisms of migraine remain incompletely understood. However, new technologies have allowed formulation of current concepts that may explain parts of the migraine syndrome.

1. Vascular theory In the 1940s and 1950s, the vascular theory was proposed to explain the pathophysiology of migraine headache. Wolff et al believed that ischemia induced by intracranial vasoconstriction is responsible for the aura of migraine and that the subsequent rebound vasodilation and activation of perivascular nociceptive nerves resulted in headache. This theory was based on the following 3 observations:

Extracranial vessels become distended and pulsatile during a migraine attack Stimulation of intracranial vessels in an awake person induces headache Vasoconstrictors (eg, ergots) improve the headache, whereas vasodilators (eg, nitroglycerin) provoke an attack

However, this theory did not explain the prodrome and associated features. Nor did it explain the efficacy of some drugs used to treat migraines that have no effect on blood vessels and the fact that most patients do not have an aura. Moreover, with the advent of newer imaging technologies, researchers found that intracranial blood flow patterns were inconsistent with the vascular theory. No consistent flow changes have been identified in patients suffering from migraine headache without aura. Regional cerebral blood flow (rCBF) remains normal in the majority of patients. However, bilateral decrease in rCBF, beginning at the occipital cortex and spreading anteriorly, has been reported. More recently, Perciaccante has shown that migraine is characterized by a cardiac autonomic dysfunction.[12] As a result of these anomalous findings, the vascular theory was supplanted by the neurovascular theory. 2. Neurovascular theory The neurovascular theory holds that a complex series of neural and vascular events initiates migraine.[13] According to this theory, migraine is primarily a neurogenic process with secondary changes in cerebral perfusion.[14] At baseline, a migraineur who is not having any headache has a state of neuronal hyperexcitability in the cerebral cortex, especially in the occipital cortex.[15] This finding has been demonstrated in studies of transcranial magnetic stimulation and with functional magnetic resonance imaging (MRI). This observation explains the special susceptibility of the migrainous brain to headaches.[16] One can draw a parallel with the patient with epilepsy who similarly has interictal neuronal irritability. 3. Cortical spreading depression In 1944, Leao proposed the theory of cortical spreading depression (CSD) to explain the mechanism of migraine with aura. CSD is a well-defined wave of neuronal excitation in the cortical gray matter that spreads from its site of origin at the rate of 2-6 mm/min.

This cellular depolarization causes the primary cortical phenomenon or aura phase; in turn, it activates trigeminal fibers, causing the headache phase. The neurochemical basis of the CSD is the release of potassium or the excitatory amino acid glutamate from neural tissue. This release depolarizes the adjacent tissue, which, in turn, releases more neurotransmitters, propagating the spreading depression. Oligemia Positron emission tomography (PET) scanning demonstrates that blood flow is moderately reduced during a migrainous aura, but the spreading oligemia does not correspond to vascular territories. The oligemia itself is insufficient to impair function. Instead, the flow is reduced because the spreading depression reduces metabolism. Although CSD is the disturbance that presumably results in the clinical manifestation of migraine aura, this spreading oligemia can be clinically silent (ie, migraine without aura). Perhaps a certain threshold is required to produce symptoms in patients having aura but not in those without aura. A study of the novel agent tonabersat, which inhibits CSD, found that the agent helped to prevent migraine attacks with aura only, suggesting that CSD may but not be involved in attacks without aura.[17] Trigeminovascular system Activation of the trigeminovascular system by CSD stimulates nociceptive neurons on dural blood vessels to release plasma proteins and pain-generating substances such as calcitonin generelated peptide, substance P, vasoactive intestinal peptide, and neurokinin A. The resultant state of sterile inflammation is accompanied by further vasodilation, producing pain. The initial cortical hyperperfusion in CSD is partly mediated by the release of trigeminal and parasympathetic neurotransmitters from perivascular nerve fibers, whereas delayed meningeal blood flow increase is mediated by a trigeminal-parasympathetic brainstem connection. According to Moulton et al, altered descending modulation in the brainstem has been postulated to contribute to the headache phase of migraine; this leads to loss of inhibition or enhanced facilitation, resulting in trigeminovascular neuron hyperexcitability.[18] Metalloproteinases

In addition, through a variety of molecular mechanisms, CSD upregulates genes, such as those encoding for cyclo-oxygenase 2 (COX-2), tumor necrosis factor alpha (TNF-alpha), interleukin1beta, galanin, and metalloproteinases. The activation of metalloproteinases leads to leakage of the blood-brain barrier, allowing potassium, nitric oxide, adenosine, and other products released by CSD to reach and sensitize the dural perivascular trigeminal afferent endings.[19] Increased net activity of matrix metalloproteinase2 (MMP-2) has been demonstrated in migraineurs. Patients who have migraine without aura seem to have an increased ratio of matrix metalloproteinase9 (MMP-9) to tissue inhibitors of metalloproteinase1 (TIMP-1), in contrast to a lower MMP-9/TIMP-1 ratio in patients who have migraine with aura.[20] Measured levels of MMP-9 alone are the same for migraine patients with or without aura.[21] Hypoxia In an experimental study, acute hypoxia was induced by a single episode of CSD. This was accompanied by dramatic failure of brain ion homeostasis and prolonged impairment of neurovascular and neurometabolic coupling.[22] Vasoactive substances and neurotransmitters Perivascular nerve activity also results in release of substances such as substance P, neurokinin A, calcitonin gene-related peptide, and nitric oxide, which interact with the blood vessel wall to produce dilation, protein extravasation, and sterile inflammation. This stimulates the trigeminocervical complex, as shown by induction of c-fos antigen by PET scan. Information then is relayed to the thalamus and cortex for registering of pain. Involvement of other centers may explain the associated autonomic symptoms and affective aspects of this pain. Neurogenically induced plasma extravasation may play a role in the expression of pain in migraine, but it may not be sufficient by itself to cause pain. The presence of other stimulators may be required. Although some drugs that are effective for migraine inhibit neurogenic plasma extravasation, substance P antagonists and the endothelin antagonist bosentan inhibit neurogenic plasma extravasation but are ineffective as antimigraine drugs. Also, the pain process requires not only

the activation of nociceptors of pain-producing intracranial structures but also reduction in the normal functioning of endogenous pain-control pathways that gate the pain. Migraine center A potential "migraine center" in the brainstem has been proposed, based on PET-scan results showing persistently elevated rCBF in the brainstem (ie, periaqueductal gray, midbrain reticular formation, locus ceruleus) even after sumatriptan-produced resolution of headache and related symptoms. These were the findings in 9 patients who had experienced spontaneous attack of migraine without aura. The increased rCBF was not observed outside of the attack, suggesting that this activation was not due to pain perception or increased activity of the endogenous antinociceptive system. The fact that sumatriptan reversed the concomitant increased rCBF in the cerebral cortex but not the brainstem centers suggests dysfunction in the regulation involved in antinociception and vascular control of these centers. Thalamic processing of pain is known to be gated by ascending serotonergic fibers from the dorsal raphe nucleus and from aminergic nuclei in the pontine tegmentum and locus ceruleus; the latter can alter brain flow and blood-brain barrier permeability. Because of the set periodicity of migraine, linkage to the suprachiasmatic nucleus of the hypothalamus that governs circadian rhythm has been proposed. Discovering the central trigger for migraine would help to identify better prophylactic agents.

Brainstem activation PET scanning in patients having an acute migraine headache demonstrates activation of the contralateral pons, even after medications abort the pain. Weiler et al proposed that brainstem activation may be the initiating factor of migraine. Once the CSD occurs on the surface of the brain, H+ and K+ ions diffuse to the pia mater and activate C-fiber meningeal nociceptors, releasing a proinflammatory soup of neurochemicals (eg,

calcitonin generelated peptide) and causing plasma extravasation to occur. Therefore, a sterile, neurogenic inflammation of the trigeminovascular complex is present. Once the trigeminal system is activated, it stimulates the cranial vessels to dilate. The final common pathway to the throbbing headache is the dilatation of blood vessels. Cutaneous allodynia Burstein et al described the phenomenon of cutaneous allodynia, in which secondary pain pathways of the trigeminothalamic system become sensitized during a migrainous episode.[23] This observation demonstrates that, along with the previously described neurovascular events, sensitization of central pathways in the brain mediates the pain of migraine. Dopamine pathway Some authors have proposed a dopaminergic basis for migraine.[24] In 1977, Sicuteri postulated that a state of dopaminergic hypersensitivity is present in patients with migraine. Interest in this theory has recently been renewed. Some of the symptoms associated with migraine headaches, such as nausea, vomiting, yawning, irritability, hypotension, and hyperactivity, can be attributed to relative dopaminergic stimulation. Dopamine receptor hypersensitivity has been shown experimentally with dopamine agonists (eg, apomorphine). Dopamine antagonists (eg, prochlorperazine) completely relieve almost 75% of acute migraine attacks.

Magnesium deficiency Another theory proposes that deficiency of magnesium in the brain triggers a chain of events, starting with platelet aggregation and glutamate release and finally resulting in the release of 5hydroxytryptamine, which is a vasoconstrictor. In clinical studies, oral magnesium has shown benefit for preventive treatment and intravenous magnesium may be effective for acute treatment, particularly in certain subsets of migraine patients.[25]

Endothelial dysfunction Vascular smooth muscle cell dysfunction may involve impaired cyclic guanosine monophosphate and hemodynamic response to nitric oxide.[26] Nitric oxide released by microglia is a potentially cytotoxic proinflammatory mediator, initiating and maintaining brain inflammation through activation of the trigeminal neuron system. Nitric oxide levels continue to be increased even in the headache-free period in migraineurs.[27] In premenopausal women with migraine, particularly in those with migraine aura, increased endothelial activation, which is a component of endothelial dysfunction, is evident.[28] Serotonin and migraine The serotonin receptor (5-hydroxytryptamine [5-HT]) is believed to be the most important receptor in the headache pathway. Immunohistochemical studies have detected 5hydroxytryptamine1D (5-HT1D) receptors in trigeminal sensory neurons, including peripheral projections to the dura and within the trigeminal nucleus caudalis (TNC) and solitary tract, while 5-HT1B receptors are present on smooth muscle cells in meningeal vessels; however, both can be found in both tissues to some extent and even in coronary vessels. All the currently available triptans (see Medication) are selective 5-HT1B/D full agonists. These agents may decrease headache by abolishing neuropeptide release in the periphery and blocking neurotransmission by acting on second-order neurons in the trigeminocervical complex. Migraine risk factors Predisposing vascular risk factors for migraine include the following[29] :

Increased levels of C-reactive protein Increased levels of interleukins Increased levels of TNF-alpha and adhesion molecules (systemic inflammation markers) Oxidative stress and thrombosis Increased body weightHigh blood pressure Hypercholesterolemia Impaired insulin sensitivity

High homocysteine levels Stroke Coronary heart disease

Transformed migraine/medication overuse headache In some patients, migraine progresses to chronic migraine. Acute overuse of symptomatic medication is considered one of the most important risk factors for migraine progression. Medication overuse headache can occur with any analgesic, including acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and aspirin. In addition, Bigal and Lipton identified the following associations of medication with progression to chronic migraine[30] :

Opiates - Critical dose of exposure is around 8 days per month; the effect is more pronounced in men

Barbiturates - Critical dose of exposure is around 5 days per month; the effect is more pronounced in women

Triptans - Migraine progression is seen only in patients with high frequency of migraine at baseline (10-14 days/mo)

In the study, the effect of anti-inflammatory medications varied with headache frequency. These agents were protective in patients with fewer than 10 days of headache at baseline but induced migraine progression in patients with a high frequency of headaches at baseline.[30]

Etiology Migraine has a strong genetic component. Approximately 70% of migraine patients have a firstdegree relative with a history of migraine. The risk of migraine is increased 4-fold in relatives of people who have migraine with aura.[31] Nonsyndromic migraine headache with or without aura generally shows a multifactorial inheritance pattern, but the specific nature of the genetic influence is not yet completely

understood. Certain rarer syndromes with migraine as a clinical feature generally show an autosomal dominant inheritance pattern.[32] However, recent genome-wide association studies have suggested 4 regions in which singlenucleotide polymorphisms influence the risk of developing migraine headache.[33,
34, 35]

Other

associations have been found in individual studies but could not be replicated in other populations. Familial hemiplegic migraine Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is preceded or followed by hemiplegia, which typically resolves. FHM may be associated with cerebellar ataxia, which is also linked to the 19p locus. Evidence suggests that the 19p locus for FHM may also be involved in patients with other forms of migraine. Three genes have thus far been identified as being causative for FHM. FHM type 1 is characterized clinically by episodes that commonly include nystagmus and cerebellar signs. This disorder is caused by mutations in theCACNA1A gene located on 19p13, which codes for a brain-specific calcium channel. Mutations in CACNA1A were previously thought to account for 50% of cases of FHM,[36] but a Danish study showed that only 7% of patients with a clinical diagnosis of FHM had a mutation in that gene.[37] FHM type 2 occurs in patients who also have a seizure disorder. This condition has been attributed to mutations in the ATP1A2 gene, located on 1q21q23, which encodes a sodium/potassium pump.[38,
39]

However, the Danish study found mutations in ATP1A2 in only

7% of patients with a clinical diagnosis of FHM.[37] FHM type 3 is caused by mutations in the SCN1A gene, located on 2q24. Mutations in SCN1A are also known to cause familial febrile seizure disorders and infantile epileptic encephalopathy.[40] Although SCN1A mutation has been reported in several unrelated families, it is felt to be a rare cause of FHM.[41] Migraine in other inherited disorders Migraine occurs with increased frequency in patients with mitochondrial disorders, such as MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike

episodes). CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is a genetic disorder that causes migraine with aura, strokes before the age of 60, progressive cognitive dysfunction, and behavioral changes. CADASIL is inherited in an autosomal dominant fashion, and most patients with the disorder have an affected parent. Approximately 90% of cases result from mutations of the <inotch3< i="">gene, located on chromosome 19. Patients with CADASIL have significant morbidity from their ailment, and life expectancy is approximately 68 years.[42]</inotch3<> Migraine is also a common symptom in other genetic vasculopathies, including 2 autosomal dominant disorders: (1) RVCL (retinal vasculopathy with cerebral leukodystrophy), which is caused by mutations in the TREX1 gene,[43] and (2) HIHRATL (hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy), which is suggested to be caused by mutations in theCOL4A1 gene.[44] The mechanisms by which these genetic vasculopathies give rise to migraine are still unclear.[45] Migraine precipitants Various precipitants of migraine events have been identified, as follows:

Hormonal changes, such as those accompanying menstruation (common),[46] pregnancy, and ovulation

Stress Excessive or insufficient sleep Medications (eg, vasodilators, oral contraceptives[47] ) Smoking Exposure to bright or fluorescent lighting Strong odors (eg, perfumes, colognes, petroleum distillates) Head trauma Weather changes Motion sickness Cold stimulus (eg, ice cream headaches) Lack of exercise Fasting or skipping meals

Red wine

Certain foods and food additives have been suggested as potential precipitants of migraine, including the following:

Caffeine Artificial sweeteners (eg, aspartame, saccharin) Monosodium glutamate (MSG) Citrus fruits Foods containing tyramine (eg, aged cheese) Meats with nitrites

However, large epidemiologic studies have failed to substantiate most of these as triggers,[48] and no diets have been shown to help migraine. Nevertheless, patients who identify particular foods as triggers should avoid these foods. Although chocolate has been considered a migraine trigger, data from the PAMINA study do not support this contention.[48] Instead, it has been hypothesized that ingestion of chocolate may be in response to a craving brought on at the start of a migraine, as a result of hypothalamic activation. Migraine and other vascular disease People who suffer from migraine headaches are more likely to also have cardiovascular or cerebrovascular disease (ie, stroke, myocardial infarction).[49]Reliable evidence comes from the Women's Health Study, which found that migraine with aura raised the risk of myocardial infarction by 91% and ischemic stroke by 108% and that migraine without aura raised both risks by approximately 25%.[50] Migraines during pregnancy are also linked to stroke and vascular diseases.[51] Migraine with aura for women in midlife has a statistically significant association with late-life vascular disease (infarcts) in the cerebellum. This association is not seen in migraine without aura.[52] Migraine and iron

In a population-based MRI study by Kruit et al, migraineurs had increased local iron deposits in the putamen, globus pallidus, and red nucleus, compared with controls.[53] This increase in iron deposits may be explained as a physiologic response induced by repeated activation of nuclei involved in central pain processing or by damage to these structures secondary to the formation of free radicals in oxidative stress (possibly the cause of the disease becoming chronic).[54] Migraine and sensory perception In a study by Nguyen et al, quantitative sensory testing found significant differences in the perception of vibrotactile stimulation in patients with migraine compared with controls, including stimulus amplitude discrimination, temporal order judgment, and duration discrimination.[55] Epidemiology In the United States, more than 30 million people have 1 or more migraine headaches per year. This corresponds to approximately 18% of females and 6% of males.[56] Migraine accounts for 64% of severe headaches in females and 43% of severe headaches in males. Approximately 75% of all persons who experience migraines are women. Currently, 1 in 6 American women has migraine headaches. (The reported incidence of migraine in females of reproductive age has increased over the last 20 years, but this change probably reflects greater awareness of the condition.) The incidence of migraine with aura peaks in boys at around age 5 years and in girls at around age 12-13 years. The incidence of migraine without aura peaks in boys at age 10-11 years and in girls at age 14-17 years.[57] Before puberty, the prevalence and incidence of migraine are higher in boys than in girls. After age 12 years, the prevalence increases in males and females, reaching a peak at age 30-40 years. The female-to-male ratio increases from 2.5:1 at puberty to 3.5:1 at age 40 years. Attacks usually decrease in severity and frequency after age 40 years, except for women in perimenopause. A study by Hsu et al suggests that women aged 40-50 years are also more susceptible to migrainous vertigo.[58] Onset of migraine after age 50 years is rare. Race-related differences in prevalence

The prevalence of migraine appears to be lower among African Americans and Asian Americans than among whites. One study showed that among women, 20.4% of whites, 16.2% of African Americans, and 9.2% of Asian Americans met International Classification of Headache Disorders (ICHD) criteria for migraine. Similarly, in males, 8.6% of whites, 7.2% of African Americans, and 4.8% of Asian Americans were considered to have migraine. Economic impact of migraine The economic cost resulting from migraine-related loss of productive time in the US workforce is more than $13 billion per year, most of which is in the form of reduced work productivity. In the American Migraine Study, more than 85% of women and 82% of men with severe migraine had some headache-related disability. Migraineur men required 3.8 bed-rest days per year, whereas women required 5.6 bed-rest days per year.[59] International statistics The World Health Organization (WHO) estimates the worldwide prevalence of current migraine to be 10% and the lifetime prevalence to be 14%. The adjusted prevalence of migraine is highest in North America, followed by South and Central America, Europe, Asia, and Africa.[25] Approximately 3000 migraine attacks per million persons worldwide occur every day. According to the WHO, migraine is 19th among all causes of years lived with disability. In the United States, migraine prevalence is inversely correlated with household income and level of education. Internationally, however, a relationship between migraine and socioeconomic status is not present.

Prognosis Migraine is a chronic condition, but prolonged remissions are common. One study showed that among persons who had migraine during childhood, 62% were migraine free for more than 2 years during puberty and as young adults but that only 40% were still migraine free at age 30 years.[60]

The severity and frequency of migraine attacks tend to diminish with increasing age. After 15 years of suffering migraines, approximately 30% of men and 40% of women no longer have migraine attacks. Migraine and vascular disorders Migraine and ischemic strokes reportedly occur in 1.4-3.3 per 100,000 population and account for 0.8% of total strokes. Milhaud et al showed that in young patients (< 45 y) with active migraine who had suffered ischemic stroke, risk factors such as patent foramen ovale, female gender, and oral contraceptive use were much more likely to be present; posterior circulation stroke was characteristic. Surprisingly, older patients characteristically lacked vascular risk factors (ie, previous hypertension, ischemic heart disease, cigarette smoking).[61] Even in patients older than 45 years, women with migraine are more likely to suffer from ischemic stroke. Migraineurs, male and female, have a 2.5-fold increased risk of subclinical cerebellar stroke and those with migraines with aura and increased headache frequency are at the highest risk.[62] Migraineurs also have a higher incidence of adverse cardiovascular profiles (including diabetes and hypertension), and they are more likely to be smokers, have a family history of early heart attacks, and have an unfavorable cholesterol profile. The odds of an elevated Framingham risk score of coronary artery disease are doubled with migraine with aura, and women who have migraine with aura are more likely to be using oral contraceptives.[63, 64] The Women's Health Study, which included professional women older than 45 years, showed that any history of migraine is associated with a higher incidence of major cardiovascular disease and that the highest risk is associated with migraine with aura, with a 2.3-fold risk of cardiovascular death and a 1.3-fold risk of coronary vascularization.[65] However, those who have migraine without aura have the same risks as the general population. These findings have been confirmed in a population-based study by Bigal et al.[66]Similarly, a study by Gudmundsson et al found that men and women who have migraine with aura are at a higher risk for cardiovascular and all-cause mortality than are those without headache.[67]

Seizure Assessment in the Emergency Department Overview A seizure is an episode of neurologic dysfunction caused by abnormal neuronal activity that results in a sudden change in behavior, sensory perception, or motor activity. The clinical spectrum of seizures includes simple and complex focal or partial seizures and generalized seizures. The term epilepsy refers to recurrent, unprovoked seizures from known or unknown causes. The term ictus describes the period in which the seizure occurs, and the term postictal refers to the period after the seizure has ended but before the patient has returned to his or her baseline mental status. A focal or partial seizure consists of abnormal neuronal firing that is limited to 1 hemisphere or area of the brain and that manifests itself as seizure activity on 1 side of the body or one extremity. These seizures are classified as simple partial if there is no change in mental status or complex partial if there is some degree of impaired consciousness. A generalized seizure consists of abnormal electrical activity involving both cerebral hemispheres that causes an alteration in mental status. Traditionally, the patient with 30 minutes of continuous seizure activity or a series of seizures without a return to full consciousness is defined as being in status epilepticus(SE). Newer definitions suggest that SE is defined by duration of 5 continuous minutes of generalized seizure activity or 2 or more separate seizure episodes without return to baseline.[1] This article focuses on the emergency department (ED) evaluation, management, and disposition of adult patients presenting for evaluation of seizure. Febrile seizures in children are a distinct entity and are discussed in a separate article. Phatophysiology A seizure results when abnormal neuronal firing manifests clinically by changes in motor control, sensory perception, behavior, or autonomic function.

This sudden biochemical imbalance between excitatory neurotransmitters and the N-methyl D aspartate (NMDA) receptor and inhibitory forces (eg, gamma-aminobutyric acid [GABA]) at the neuronal cell membrane results in repeated, abnormal electrical discharges that may stay within a certain area of the brain or they may propagate throughout the brain resulting in generalized seizures. For example, in the event that these neuronal discharges are confined to the visual cortex, the seizure manifests itself with visual phenomena. Seizures also produce a number of physiologic changes. Many of these systemic responses are thought to be a result of the catecholamine surge that accompanies seizures.[2] During a generalized seizure, there can be a period of transient apnea and subsequent hypoxia. In a physiologic effort to maintain appropriate cerebral oxygenation, the patient may become hypertensive. Additionally, transient hyperthermia may occur in up to 40% of patients and is thought to result from vigorous muscle activity that occurs in a seizure.[3]Hyperglycemia and lactic acidosis occur within minutes of a convulsive episode and usually resolve within 1 hour.[4] Transient leukocytosis may also be seen but is not accompanied by bandemia (unless infection is present). In the setting of prolonged convulsive seizure activity or status epilepticus (SE), there is pronounced systemic decompensation, including hypoxemia, hypercarbia, hypertension followed by hypotension, hyperthermia, depletion of cerebral glucose and oxygen, cardiac dysrhythmias, and rhabdomyolysis. These changes may even take place despite adequate oxygenation and ventilation. In extremis, pulmonary edema and disseminated intravascular coagulation (DIC) have also been reported.[5]

Etiology For patients with known seizure disorder, the most likely cause is subtherapeutic levels of antiepileptic medications, which usually occur for 1 of the following reasons:

Medical noncompliance Systemic derangement that may disrupt absorption, distribution, and metabolism of medication (infection)

In addition, multiple other factors, including stress, lack of sleep, and caffeine use, may contribute to seizures in patients with known seizure disorder, but these are diagnoses of exclusion. For patients presenting with new-onset seizure disorder, the list of possible causes is longer and includes the following:

Central nervous system (CNS) pathologies (stroke, neoplasm, trauma, hypoxia, vascular abnormality)

Metabolic

abnormalities

(hypoglycemia

hyperglycemia,

hyponatremia

hypernatremia, hypercalcemia, hepatic encephalopathy)

Toxicologic etiologies (alcohol withdrawal, cocaine, isoniazid, theophylline) Infectious etiologies (meningitis, encephalitis, brain abscess)

Neurocysticercosis and malaria are very common causes of seizures in the developing world and should be considered in patients with a history of travel and in immigrants.

Epidemiology Epilepsy and seizures affect more than 3 million American of all ages. Approximately 200,000 new cases occur each year, of which 40-50% will recur be classified as epilepsy.[6] Overall, approximately 50,000-150,000 cases will reach status epilepticus (SE). Incidence is highest in those younger than 2 years and in those older than 65 years. Males are slightly more likely to develop epilepsy than females. History of head trauma, history of stroke, and family history of epilepsy are all independent risk factors for first seizures in adults.[7] After the first seizure, overall recurrence risk in adults is 3040% (greatest in the first 6 months). This risk drops to less than 10% in 2 years.[7] Clinical Presentation Patient history A history of epilepsy is often noted (if the patient is unconscious, family, friends, or prehospital personnel can be questioned). Other history findings may include the following:

Recent noncompliance with medications History of central nervous system (CNS) pathology (stroke, neoplasms, recent surgery) History of systemic neoplasms, infections, metabolic disorders, or toxic ingestions Recent trauma or fall Alcohol abuse Recent travel or immigration to the United States Pregnancy Focal symptoms (partial seizure activity) that then progressed to a generalized seizure

Physical examination A generalized seizure is recognizable at the bedside when tonic-clonic activity is present. If the patient is actively seizing, attempt to observe motor activity, as posturing

(decerebrate/decorticate) and eye deviation may provide clues to the epileptic focus. A partial seizure may present as isolated seizure activity with or without loss of consciousness. The workup for partial seizures is more extensive and requires neurologic consultation. Identifying a partial seizure that then generalizes to a full tonic-clonic seizure may be difficult, as this may be missed as the initial presentation of a generalized seizure. In a generalized, tonic-clonic seizure, accurate vital signs are difficult to obtain. Low-grade fever may be present initially, but prolonged fever may be an indication of infectious etiology. Mental status examination is important. As noted (see Overview), any seizure with loss of consciousness is considered a complex seizure . Focal deficits on neurologic examination may be evidence of an old lesion, new pathology, or Todds paralysis (transient, < 24 h paralysis that mimics stroke). Hyperreflexia and extensor plantar responses are indicative of a recent seizure but should resolve during the postictal period. Special concerns Special concerns in patients with seizures in the ED include the following:

Eclampsia Trauma

Intracranial hemorrhage (ICH) Alcohol withdrawal or medication withdrawal Drug-induced seizures

Seizures in pregnancy are a complication of severe, untreated preeclampsia. In fact, eclampsia can occur up to 4 weeks after delivery.[8] Seizing pregnant patients should be treated just as nonpregnant patients are because the risk of complications from the seizure outweighs the risk of toxicity from the antiepileptics. Fortunately, eclamptic seizures are usually short in duration. Magnesium sulfate is the treatment of choice for eclamptic seizures because it is the most effective medication for prevention of recurrent seizures.[9] In addition, patients with postpartum eclampsia, especially those with late postpartum eclampsia, have a higher incidence of cerebral venous thrombosis, intracranial hemorrhage, and acute ischemic stroke than do eclamptic patients diagnosed prepartum. Although most women with typical eclampsia do not need brain imaging, postpartum eclamptic patients and those with focal neurological deficits, persistent visual disturbances, and symptoms refractory to magnesium and antihypertensive treatment should undergo thorough diagnostic testing, preferably including MRI.[10] Seizures after trauma can be due to a variety of injuries, and intracranial pathology must be ruled out. The risk of posttraumatic seizures with an obvious underlying injury is directly related to the severity of the injury but is not significantly affected by early use of antiepileptic medications. [11,
12]

Stroke related to ICH may predispose the patient to seizures. Deep, small intraparenchymal bleeds are thought to be low risk unless they involve the temporal regions. Larger bleeds that cause mass effects pose a higher risk of seizures. Common practice is to consider a prophylactic loading dose of an antiepileptic medication (typically phenytoin or fosphenytoin). Alcohol withdrawal can occur anywhere from 6 to 48 hours after cessation of drinking and can occur at any blood alcohol level. Benzodiazepines are the mainstay of therapy, and large doses may be necessary to control the withdrawal and prevent or control seizures.[13]

Barbiturate or benzodiazepine withdrawal may cause seizure. With certain agents, symptoms may not develop for days or even weeks after cessation of use. Tricyclic antidepressant (TCA) overdose and isoniazid (INH) therapy/overdose are 2 of the more common causes of drug-induced seizures. An electrocardiogram (ECG) will show a widened QRS and prominent R wave in lead aVR. Treatment of TCA overdose consists of bicarbonate infusion and supportive care. Pyridoxine is the treatment of choice for known INH ingestion.

Emergent Management of Subarachnoid Hemorrhage Overview Emergent management of subarachnoid hemorrhage (SAH), including prehospital care, is critical: An estimated 10-15% of patients die before reaching the hospital. Moreover, mortality rate reaches as high as 40% within the first week, and about 50% die in the first 6 months.[1, 2] The common medical use of the term subarachnoid hemorrhage (SAH) refers to the nontraumatic presence of blood within the subarachnoid space from some pathologic process, usually from rupture of a berry aneurysm or arteriovenous malformation (AVM) (see the following image).

Brain computed tomography (CT) scan showing subtle finding of blood at the area of the circle of Willis consistent with acute subarachnoid hemorrhage. Image courtesy of Dana Stearns, MD, Massachusetts General Hospital. SAH classification Subarachnoid hemorrhage (SAH) is classified according to 5 grades, as follows:

Grade I: Mild headache with or without meningeal irritation Grade II: Severe headache and a nonfocal examination, with or without mydriasis Grade III: Mild alteration in neurologic examination, including mental status Grade IV: Obviously depressed level of consciousness or focal deficit\Grade V: Patient either posturing or comatose

Prehospital Care Advances in the management of subarachnoid hemorrhage (SAH) have resulted in a relative reduction in mortality rate that exceeds 25%. However, more than one third of survivors have major neurologic deficits. Mortality and morbidity rates increase with age and poorer overall health of the patient. Prehospital care is critical and includes the following:

Address the patient's airway, breathing, and circulatory status (ABCs) Triage and transport patients with altered level of consciousness or an abnormal neurologic examination to the closest medical center with a computed tomography (CT) scan and neurosurgical backup

Ideally, avoid sedating these patients en route

Emergency Department Care Grade I or II SAH In patients with a suspected grade I or II subarachnoid hemorrhage (SAH), emergency department (ED) care essentially is limited to diagnosis and supportive therapy. Early identification of sentinel headaches is key to reduced mortality and morbidity rates. Use sedation judiciously. Secure intravenous access, and closely monitor the patient's neurologic status. Grade III, IV, or V SAH In patients with a grade III, IV, or V subarachnoid hemorrhage (SAH) (ie, altered neurologic examination), ED care is more extensive.

Address the patient's airway, breathing, and circulatory status (ABCs). In addition, reliable neurologic examinations before and after initial treatment are critically important to optimizing management and to deciding on the appropriate neurosurgical intervention. Intubation Endotracheal (ET) intubation of obtunded patients protects them from aspiration caused by depressed airway protective reflexes. Also intubate to hyperventilate patients with signs of herniation. Thiopental and etomidate are the optimal induction agents in subarachnoid hemorrhage (SAH) during an intubation. Thiopental is short-acting and has a barbiturate cytoprotective effect. It should be used only in hypertensive patients because of its propensity to drop systolic blood pressure (SBP), which is the leading cause of secondary brain injury. In hypotensive and normotensive patients, use etomidate. Use rapid sequence intubation if possible. In the process, to blunt intracranial pressure (ICP) increase, ideally use sedation, defasciculation, short-acting neuromuscular blockade, and other agents with ICP-blunting properties (such as intravenous lidocaine). Precautions Avoid excessive or inadequate hyperventilation. Target the partial pressure of carbon dioxide (pCO2) at 30-35 mm Hg to reduce elevated ICP. Excessive hyperventilation may be harmful to areas of vasospasm. Avoid excessive sedation. It makes serial neurologic exams more difficult and has been reported to increase ICP directly. However, avoid any increase in ICP due to excessive agitation from pain and discomfort. Use the following interventions early and judiciously to decrease elevated ICP when herniation is suspected:

Use osmotic agents, such as mannitol, which reduces ICP 50% in 30 minutes, peaks after 90 minutes, and lasts 4 hours

Loop diuretics, such as furosemide, also decrease ICP without increasing serum osmolality

intravenous steroid therapy to control brain edema is controversial and debated

Provide supplemental oxygen for all patients with central nervous system (CNS) impairment. Consultations Obtain emergent neurosurgical consultation for definitive treatment of subarachnoid hemorrhage (SAH). Interventional radiology may be needed when surgical intervention is deemed necessary by the neurosurgical consultant (eg, a large clot causing a mass effect is present and needs to be evacuated emergently). Monitoring Monitor the patient's cardiac activity, oximetry, automated blood pressure (BP), and end-tidal carbon dioxide, when applicable. End-tidal carbon dioxide monitoring of intubated patients enables the clinician to avoid excessive or inadequate hyperventilation. Target the partial pressure of carbon dioxide (pCO2) at about 30-35 mm Hg to reduce elevated intracranial pressure (ICP). Invasive arterial line monitoring is indicated when dealing with labile BP (common in highgrade subarachnoid hemorrhage). Antihypertensive agents were previously advocated for a systolic blood pressure (SBP) greater than 160 mm Hg or a diastolic BP (DBP) greater than 90 mm Hg. Keep systolic blood pressure 90-140 mm Hg before aneurysm treatment, then allow hypertension to keep the SBP less than 200 mm Hg.[5] Use medications that can be titrated rapidly. Vasopressors may be indicated to keep the SBP over 120 mm Hg; this avoids central nervous system (CNS) damage in the ischemic penumbra from the reactive vasospasm seen in subarachnoid hemorrhage (SAH). Consult critical care providers who will be involved in ongoing care of the patient, as individual practices vary. Adjunctive Therapies and Measures

Keep the patient's core body temperature at 37.2C; administer oral (PO)acetaminophen (325650 mg q4-6h), and use cooling devices if necessary.[5] Consider antiemetics for nausea or vomiting. Elevate the head of the bed 30 to facilitate intracranial venous drainage. Emergent ventricular drainage by the neurosurgeon may be necessary. Maintain the patient's serum glucose level at 80-120 mg/dL; use sliding or continuous infusion of insulin if necessary.[5] Fluids and hydration Maintain euvolemia (central venous pressure [CVP], 5-8 mm Hg); if cerebral vasospasm is present, maintain hypervolemia (CVP of 8-12 mm Hg, or pulmonary capillary wedge pressure [PCWP] of 12-16 mm Hg).[5, 6] Do not overhydrate patients because of the risks of hydrocephalus. Patients with subarachnoid hemorrhage (SAH) may also have hyponatremia from cerebral salt wasting. Seizure prevention Prophylactic use of anticonvulsants does not acutely prevent seizures after subarachnoid hemorrhage (SAH), but use anticonvulsants in patients who have had a seizure or if local practice dictates routine use. Begin with anticonvulsants that do not change the level of consciousness (ie,phenytoin first; use barbiturates or benzodiazepines only to stop active seizures). Controversial measures A randomized study of patients in an intensive care unit (ICU) demonstrated fewer ischemic events after aneurysmal subarachnoid hemorrhage (SAH) when high-dose magnesium was given for 10 days. The presumed mechanism was decreased cerebral vasospasm.[7] A meta-analysis demonstrated similar findings.[8] However, other studies have shown no benefit from magnesium.[9] Clearly, further study is indicated.

Use of antifibrinolytics, such as epsilon aminocaproic acid, to prevent rebleeding is controversial. These agents competitively inhibit plasminogen activation and have been reported to reduce the incidence of rebleeding. Other reports warn of their detrimental vasospastic effect and increased occurrence of hydrocephalus. Consult a neurosurgeon concerning their use. Hospitalization and Transfer Admit patients with suspected subarachnoid hemorrhage (SAH) to an intensive care unit (ICU) for serial neurologic examinations and for hemodynamic monitoring. Emergent imaging and intervention may be necessary if mass effect or rebleeding develops. Patients with possible ruptured or leaking subarachnoid hemorrhage (SAH) should be transferred emergently to the closest center with computed tomography (CT) scanning and neurosurgical staff. Stabilize patients promptly for transfer in an advanced cardiac life support (ACLS)monitored unit. Address airway and the possible need for intubation or other emergent interventions, such as mannitol and hyperventilation, prior to transfer.

Practice Essentials Syncope is defined as a transient, self-limited loss of consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. This definition excludes seizures, coma, shock, or other states of altered consciousness. Although most causes of syncope are benign, this symptom presages a life-threatening event in a small subset of patients. Essential update: Differentiating cardiac from vasovagal syncope In a retrospective study of 89 patients with vasovagal syncope and 17 patients with cardiac syncope, Tretter and Kavey found a number of differences in presentation. Patients with cardiac syncope, compared with those with vasovagal syncope, presented more often with the following[1] :

Syncope surrounding activity (65% vs 18%) Family history of cardiac disease or sudden cardiac death (41% vs 25%)

Abnormal physical examination findings supporting a cardiac diagnosis (29% vs 0%) Abnormal ECG findings (76% vs 0%) Signs and symptoms History and physical examination are the most specific and sensitive ways of evaluating syncope. These measures, along with 12-lead electrocardiography (ECG), are the only current level A recommendations listed in the 2007 American College of Emergency Physicians (ACEP) Clinical Policy on Syncope.[2] A detailed account of the event must be obtained from the patient, including the following:

Precipitant factors Activity the patient was involved in before the event Position the patient was in when the event occurred The following questions should be asked:

Was loss of consciousness complete? Was loss of consciousness with rapid onset and short duration? Was recovery spontaneous, complete, and without sequelae? Was postural tone lost? If the answers are positive, syncope is highly likely; if 1 or more are negative, other forms of loss of consciousness should be considered.[3] Presyncopal symptoms reported may include the following:

Prior faintness, dizziness, or light-headedness (70% of cases of true syncope) Prior vertigo, weakness, diaphoresis, epigastric discomfort, nausea, blurred or faded vision, pallor, or paresthesias

Red flag symptoms: Exertional onset, chest pain, dyspnea, low back pain, palpitations, severe headache, focal neurologic deficits, diplopia, ataxia, or dysarthria Other information that should be obtained includes the following:

Detailed account of the event from any available witnesses (eg, whether patient experienced postevent confusion) Patients medication history

Patients personal or familial medical history of cardiac disease A complete physical examination is required, with particular attention to the following:

Analysis of vital signs Measurement of the glucose level by rapid fingerstick Detailed cardiopulmonary examination Detailed neurologic examination Assessment for signs of trauma Stool guaiac examination Bedside examinations to help elucidate the origin of syncope (eg, Hallpike maneuver) See Clinical Presentation for more detail. Diagnosis No specific laboratory testing has sufficient power to be absolutely indicated for evaluation of syncope. Research-based and consensus guideline recommendations are as follows:

Serum glucose Complete blood count Serum electrolytes Cardiac enzymes Total creatine kinase Urinalysis/dipstick Imaging studies that may be helpful include the following:

Chest radiography: May serve to identify pneumonia, congestive heart failure (CHF), lung mass, effusion, or widened mediastinum

Computed tomography (CT) of the head (noncontrast): Has a low diagnostic yield in syncope but may be clinically indicated in patients with new neurologic deficits or in patients with head trauma secondary to syncope

CT of the chest and abdomen: Indicated only in select cases (eg, suspected aortic dissection, ruptured abdominal aortic aneurysm, or pulmonary embolism [PE])

Magnetic resonance imaging (MRI) of the brain and magnetic resonance arteriography (MRA): May be required in select cases to evaluate vertebrobasilar vasculature

Ventilation-perfusion (V/Q) scanning: Appropriate for suspected PE Echocardiography: The test of choice for evaluating suspected mechanical cardiac causes of syncope A standard 12-lead ECG is a level A recommendation in the 2007 ACEP consensus guidelines for syncope.[2] The following considerations are relevant:

Normal ECG findings are a good prognostic sign ECG can be diagnostic for acute myocardial infarction or myocardial ischemia and can provide objective evidence of preexisting cardiac disease or dysrhythmia

Bradycardia, sinus pauses, nonsustained ventricular tachycardia and sustained ventricular tachycardia, and atrioventricular conduction defects are truly diagnostic only when they coincide with symptoms

Loop recorders have a higher diagnostic yield than Holter monitor evaluation, with a marginal cost savings[4] Ambulatory monitoring appears to have a higher negative than positive diagnostic yield[5] Other diagnostic tests and procedures include the following:

Head-up tilt-table test: Useful for confirming autonomic dysfunction and can generally be safely arranged on an outpatient basis

Electroencephalography (EEG): Can be performed at the discretion of a neurologist if seizure is considered a likely alternative diagnosis

Stress test: A cardiac stress test is appropriate for patients in whom cardiac syncope is suspected and who have risk factors for coronary atherosclerosis

Carotid sinus massage (to diagnose carotid sinus syncope) See Workup for more detail. Management Prehospital management of syncope may require the following:

Intravenous access Oxygen administration Advanced airway techniques Glucose administration

Pharmacologic circulatory support Pharmacologic or mechanical restraints Defibrillation or temporary pacing Advanced triage decisions, such as direct transport to multispecialty tertiary care centers, may be required in select cases. In patients brought to the emergency department with a presumptive diagnosis of syncope, appropriate initial interventions include the following:

IV access, oxygen administration, and cardiac monitoring ECG and rapid blood glucose evaluation The treatment choice for syncope depends on the cause or precipitant of the syncope, as follows: Situational syncope: Patient education regarding the condition

Orthostatic syncope: Patient education; additional therapy in the form of thromboembolic disease (TED) stockings, mineralocorticoids, and other drugs (eg, midodrine); elimination of drugs associated with hypotension; intentional oral fluid consumption

Cardiac arrhythmic syncope: Antiarrhythmic drugs or pacemaker placement Cardiac mechanical syncope: Beta blockade; if valvular disease is present, surgical correction

Background Syncope is defined as a transient, self-limited loss of consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. The term syncope excludes seizures, coma, shock, or other states of altered consciousness. Syncope is a prevalent disorder, accounting for 1-3% of emergency department (ED) visits and as many as 6% of hospital admissions each year in the United States. As much as 50% of the population may experience a syncopal event during their lifetime. Although many etiologies for syncope are recognized, categorization into reflex (neurally mediated), orthostatic, and cardiac (cardiovascular) may be helpful during the initial evaluation. Cardiac syncope is associated with increased mortality, whereas noncardiac syncope is not. Syncope may result in significant

morbidity due to falls or accidents that occur as a result. In the United States alone, an estimated $2 billion annually is spent on patients hospitalized with syncope. Although most causes of syncope are benign, this symptom presages a life-threatening event in a small subset of patients. It is unclear whether hospital inpatient admission of asymptomatic patients after syncope affects outcomes. No current criterion standard exists for diagnosing undifferentiated syncope. Many physicians continue to admit patients because of perceived risk. Recent reviews of the 2001 American College of Emergency Physician (ACEP) clinical policy suggest that evidence-based criteria may decrease admission rates by nearly half by identifying cardiac causes of syncope. Inpatient admission should be reserved for patients in whom identification of specific immediate risk, such as those with structural heart disease or history of ventricular arrhythmia, is needed. Outpatient management can be used for patients who are low risk for a cardiac etiology in order to define a precise cause in order to effect mechanism-specific treatment.

Pathophysiology Syncope occurs due to global cerebral hypoperfusion. Brain parenchyma depends on adequate blood flow to provide a constant supply of glucose, the primary metabolic substrate. Brain tissue cannot store energy in the form of high-energy phosphates found elsewhere in the body; therefore, a cessation of cerebral perfusion lasting only 3-5 seconds can result in syncope. Cerebral perfusion is maintained relatively constant by an intricate and complex feedback system involving cardiac output, systemic vascular resistance, arterial pressure, intravascular volume status, cerebrovascular resistance with intrinsic autoregulation, and metabolic regulation. A clinically significant defect in any one of these or subclinical defects in several of these systems may cause syncope. Cardiac output (CO) can be diminished secondary to mechanical outflow obstruction, pump failure, hemodynamically significant arrhythmias, or conduction defects. Systemic vascular resistance (SVR) can drop secondary to vasomotor instability, autonomic failure, or vasodepressor/vasovagal response. Mean arterial pressure (MAP) decreases with all causes of hypovolemia. Medications can affect CO, SVR, or MAP.

Other conditions can mimic syncope. A CNS event, such as a hemorrhage or an unwitnessed seizure, can present as syncope. Syncope can occur without reduction in cerebral blood flow in patients who have severe metabolic derangements (eg, hypoglycemia, hyponatremia, hypoxemia, hypercarbia).

Frequency United States Framingham data demonstrate a first occurrence rate of 6.2 cases per 1000 patient-years.[6,
7]

Syncope reoccurs in 3% of affected individuals, and approximately 10% of affected individuals

have a cardiac etiology. International Data from Europe and Japan suggest a similar occurrence rate to the United States, accounting for 1-3.5% of ED visits.

Mortality/Morbidity Data suggest that patients with cardiac syncope are more likely to experience a poor outcome. Patients who have a significant cardiac history and those who seem to have a cardiac syncope (because of associated chest pain, dyspnea, cardiac murmur, signs of congestive heart failure [CHF], or ECG abnormalities) should be considered to be at increased risk. Most published methods of risk stratification take into account cardiac symptoms and risk factors. Morbidity from syncope includes recurrent syncope, which occurs in 20% of patients within one year of the initial episode. Lacerations, extremity fractures, head injuries, and motor vehicle accidents can occur secondary to syncope. Syncope in a patient with poor baseline cardiac function portends a poor prognosis irrespective of etiology. Middlekauff et al studied 491 patients with New York Heart Association (NYHA) functional class III or IV disease and noted that, regardless of the cause, 45% of those with

syncope died within 1 year, whereas 12% of those without syncope died during the same interval.[8] Patients with cardiac syncope appear to do worse than patients with noncardiac syncope. Soteriades et al followed 7814 patients with syncope for 17 years and found a higher mortality rate for patients with cardiac syncope compared with noncardiac syncope.[9] Suzuki et al studied 912 patients with syncope for an average of 3 years and found the same result.[10] Risk of serious outcome and death in patients with syncope increases with higher peak troponin concentrations, according to a prospective cohort study of 338 patients who had plasma troponin I levels measured 12 hours after syncope, using a sensitive assay.[11] The percentage of patients with a serious outcome increased across patients divided into quintiles on the basis of peak troponin concentration at 1 month (0%, 9%, 13%, 26%, 70%) and at 1 year (10%, 22%, 26%, 52%, 85%).[11] Decision rules may assist in identifying patients who are at risk. Martin et al describes a risk stratification system that predicts an increased incidence of death at 1 year based on the presence of abnormal ECG findings, a history of ventricular arrhythmia, a history of CHF, and age older than 45 years.[12] Sarasin et al demonstrates a risk of arrhythmia that is proportional to the number of cardiac risk factors, including abnormal ECG findings, history of CHF, and age older than 65 years.[13] The San Francisco Syncope Rule identifies patients who are at immediate risk for serious outcomes within 7 days, with a 96% sensitivity based on the presence of abnormal ECG findings, a history of CHF, dyspnea, a hematocrit level of less than 30, and hypotension. [14] The presence of these findings should prompt serious consideration for hospital admission. In an external retrospective review, validation of the San Francisco Syncope Rule in a Canadian emergency department was undertaken. The rule performed with a sensitivity of 90% (44/49 outcomes; 95% confidence interval [CI] 79-96%) and a specificity of 33%, which was much lower than previously reported. Based on results of this study, implementation of this rule would have significantly increased admission rates. These authors concluded further study is needed.[15] Another study was also unable to validate the rule, with sensitivity of 74% and specificity of 57% reported.[16]

The Risk stratification Of Syncope in the Emergency department, or ROSE, criteria suggest that an elevated B-type natriuretic peptide (BNP), Hemoccult positive stool, anemia, low oxygen saturation, and presence of Q waves on ECG predict serious outcomes at 30 days.[17] These rules had a 87% sensitivity and a 98.5% negative predictive value to help risk stratify patients. In this study, the isolated finding of BNP greater than 300 pg/mL was a major predictor of serious outcomes and was present in 89% of patients who died within 30 days. Constantino et al discovered that 6.1% of patients had severe outcomes within 10 days of syncope evaluation.[18] The mortality rate was 0.7%, and 5.4% of patients were readmitted or experienced major therapeutic intervention. Risk factors associated with severe short-term outcomes included abnormal ECG, history of CHF, age older than 65 years, male gender, history of chronic obstructive pulmonary disease (COPD), structural heart disease, presence of trauma, and lack of prodromal symptoms. The Evaluation of Guidelines in SYncope Study 2 (EGSYS 2) prospectively followed nearly 400 patients at 1 month and 2 years. The death rate was 2% at 1 month and 9% at 2 years. Patients with advancing age, presence of structural heart disease, and/or abnormal ECG had higher risk.[19] Clinical judgement, Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) score, and San Francisco Syncope Rule all have relatively low sensitivities individually for predicting severe short-term outcomes. Some evidence suggests that combining various risk stratification tools may increase sensitivity and reduce unnecessary admissions.[20] A review and meta-analysis by Serrano et al assessed the methodological quality and prognostic accuracy of the San Francisco Syncope Rule and the OESIL risk score.[21] The analysis of 18 eligible studies determined that the quality and accuracy of both sets of clinical decision rules are limited. Race, sex, and age No significant differences regarding race are observed with respect to syncope risk. Larger prospective studies fail to show clinically significant differences between men and women. National Hospital Ambulatory Medical Care Survey (NHAMCS) data show that syncope occurs in all age groups but is most common in adult populations. Noncardiac causes tend to be more

common in young adults, whereas cardiac syncope becomes increasingly more frequent with advancing age. Syncope is relatively uncommon in pediatric populations. One small retrospective study by Pratt and Fleisher reported a prevalence of less than 0.1% in children.[22]Pediatric syncope warrants prompt detailed evaluation. Advancing age is an independent risk factor for both syncope and death. Various studies suggest categorizing patients older than 45 years, 65 years, and 80 years as "higher risk." Advancing age correlates with increasing frequency of coronary artery and myocardial disease, arrhythmia, vasomotor instability, autonomic failure, polyneuropathy, and use of polypharmacy.

TRANSIENT GLOBAL AMNESIA Transient global amnesia (TGA) has been a well-described phenomenon for more than 40 years. Clinically, it manifests with a paroxysmal, transient loss of memory function. Immediate recall ability is preserved, as is remote memory; however, patients experience striking loss of memory for recent events and an impaired ability to retain new information. In some cases, the degree of retrograde memory loss is mild. Many patients are anxious or agitated and may repeatedly ask questions concerning transpiring events. Upon mental status examination, language function is preserved, which indicates a preservation of semantic and syntax memory. Attention is spared, visual-spatial skills are intact, and social skills are retained. Symptoms typically last less than 24 hours. As the syndrome resolves, the amnesia improves, but the patient may be left with a distinct lapse of recollection for events during the attack.

Generally, TGA is solitary event, however, patients can experience more than one event with very similar symptoms and recovery.

Pathophysiology The precise pathophysiology of transient global amnesia is not clear. The findings reported with positron emission tomography (PET), diffusion-weighted MRI (DWI), single photon emission computed tomography (SPECT) and MR spectroscopy (MRS) have indicated various brain regions that are affected in TGA.

On PET and DWI, blood flow to specific brain areas that involve memory appears to be disrupted transiently during TGA. This includes the thalamus and/or mesial temporal structures (in particular the amygdala and hippocampus).

Hakan et al demonstrated tiny increases in signal in the left parahippocampal gyrus and splenium of the corpus callosum on DWI in one patient. This method of imaging allows detection of hyperacute ischemic change. Liang et al and Yang et al have also recently used DWI to document tiny lesions in the hippocampus of patients with acute TGA.[1, 2] However, Eustache et al reported a PET study consistent with a spreading depression in the left lateral frontal cortex. This case also featured oligemia in the left occipital cortex.[3] Strupp et al found mainly medial temporal changes on DWI in 7 of 10 patients with TGA. They suggested that cellular edema or spreading depression could be responsible, not just ischemia.[4]

Winbeck et al found a significant incidence (10/28) of acute DWI changes in patients with TGA, which is comparable to the TIA group (21/74). Although the patients who presented with a TIA had a higher prevalence of vascular risk factors, those in the TGA group (who had DWI changes) were found to have significantly more carotid atherosclerosis.[5]

Nakada et al demonstrated via high-resolution T2-reversed MRI a high incidence of hippocampal cavities compared with their normal or disease controls. The authors conclude that their findings may indicate that TGA can be associated with neuronal loss in the CA1 region of the hippocampus.[6]

Generally, the territory of the vertebrobasilar system is most often rendered ischemic and dysfunctional. However, since ischemia typically does not progress to infarction, symptoms are expected to resolve completely.

Yamane et al reported rather diffuse cerebral hypoperfusion on SPECT that improved months later upon repeating the test in a patient with TGA.[7] Yang et al also reported hypoperfusion in the cerebellar vermis that recovered by the time of follow-up examination.[1]

Bartsch et al found that in 7 patients with TGA, 4 had a diffusion abnormality corresponding with a T2 lesion in the CA-1 sector of the hippocampus. In 3 of these patients, MRS revealed a lactate peak. The authors suggest that this represents an acute stress reaction of this particular area and indicates the pathological substrate of TGA.[8] Overall, the variety of findings on functional imaging studies may support the notion that TGA is a syndrome with not only a variety of precipitating causes but also of differing mechanisms.

Epidemiology Frequency United States Based on data from Rochester, Minnesota, Miller et al determined an incidence of 5.2 cases per 100,000 population. However, among individuals older than 50 years, the incidence was 23.5 cases per 100,000 population per year.[9] International Estimates vary, but Matiea-Guiu et al found a lower incidence in Alcoi, Spain, of 2.9 cases per 100,000 population.[10] On the other hand, Lauria et al found an incidence of 10 cases per 100,000 population in Belluno, Italy.[11] Mortality/Morbidity

As the name implies, transient global amnesia symptoms are transient. The mean annual recurrence rate is thought to be low (approximately 4-5%). However, in the study by Miller et al, the calculated recurrence rate could be as high as 24% over a lifetime depending on inclusion criteria.[9] These occasional recurrences usually involve no long-term morbidity or death.

If transient ischemic attack (TIA) is suspected, then the patient should be evaluated for stroke risk factors. Likewise, if a seizure is suspected, appropriate testing should be initiated.

Race No consistent racial predilection is known. Sex No sex predilection has been observed. However, one study found that particular triggers may be associated with men and women. For men, transient global amnesia occurs more often after a physical precipitating event. In women, episodes may be more associated with emotional precipitating events, a history of anxiety, or pathological personality. Age The typical age of occurrence is older than 50 years.

BAB 4 Approach Considerations Imaging studies Emergent brain imaging is essential for confirming the diagnosis of ischemic stroke. Noncontrast CT scanning is the most commonly used form of neuroimaging in the acute evaluation of patients with apparent acute stroke. Alumbar puncture is required to rule out meningitis or subarachnoid hemorrhage when the CT scan is negative but the clinical suspicion remains high. MRI with magnetic resonance angiography (MRA) has been a major advance in the neuroimaging of stroke. MRI not only provides great structural detail but also can demonstrate early cerebral edema. In addition, MRI has proved to be sensitive for detection of acute intracranial hemorrhage. However, MRI is not as available as CT scanning is in emergencies, many patients have contraindications to MRI imaging (eg, pacemakers, implants), and interpretation of MRI scans may be more difficult. Carotid duplex scanning is one of the most useful tests in evaluating patients with stroke. Increasingly, it is being performed earlier in the evaluation, not only to define the cause of the stroke but also to stratify patients for either medical management or carotid intervention if they have carotid stenoses. Digital subtraction angiography is considered the definitive method for demonstrating vascular lesions, including occlusions, stenoses, dissections, and aneurysms. For more information, see Cerebral Revascularization Imaging. Laboratory studies Extensive laboratory testing is not routinely required before decisions are made regarding fibrinolysis. Testing can often be limited to blood glucose, plus coagulation studies if the patient is on warfarin, heparin, or one of the newer antithrombotic agents (eg, dabigatran, rivaroxaban). A complete blood count (CBC) and basic chemistry panel can be useful baseline studies.

Additional laboratory tests are tailored to the individual patient and may include the following:

Cardiac biomarkers Toxicology screen Fasting lipid profile Erythrocyte sedimentation rate Pregnancy test Antinuclear antibody (ANA) Rheumatoid factor Homocysteine level Rapid plasma reagent (RPR) A urine pregnancy test should be obtained for all women of childbearing age with stroke symptoms. The safety of the fibrinolytic agent recombinant tissue-type plasminogen activator (rtPA) in pregnancy has not been studied in humans (ie, the agent is in the FDA pregnancy category C). Brain Imaging With CT Scanning and MRI CT scanning Imaging with CT scanning has multiple logistic advantages for patients with acute stroke. Image acquisition is faster with CT scanning than with MRI, allowing for assessment with an examination that includes noncontrast CT scanning, CT angiography (CTA), and CT perfusion scanning in a short amount of time. Expedient acquisition is of the utmost importance in acute stroke imaging because of the narrow window of time available for definitive ischemic stroke treatment with pharmacologic agents and mechanical devices. CT scanning can also be performed in patients who are unable to tolerate an MR examination or who have contraindications to MRI, including implantable pacemakers, some aneurysm clips, or other ferromagnetic materials in their bodies. Additionally, CT scanning is more easily accessible for patients who require special equipment for monitoring and life support.[62, 63] MRI

Conventional (spin echo) MRI may take hours to produce discernible findings in acute ischemic stroke. Diffusion-weighted imaging (DWI) is highly sensitive to early cellular edema, which correlates well with the presence of cerebral ischemia. For this reason, many centers include DWI in their standard brain MRI protocol. DWI MRI can detect ischemia much earlier than standard CT scanning or spin echo MRI can and provides useful data in patients with stroke or transient ischemic attack (TIA). (See the image below.)[3, 64, 65, 66]

Magnetic 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 3dimensional (3-D) time-of-flight magnetic resonance angiogram (MRA, right) demonstrates occlusion of the distal middle cerebral artery (MCA) trunk (red circle). The most commonly used technique for perfusion MRI is dynamic susceptibility, which involves generating maps of brain perfusion by monitoring the first pass of a rapid bolus injection of contrast through the cerebral vasculature. Susceptibility-related T2 effects create signal loss in capillary blood vessels and parenchyma perfused by contrast. For more information on MRI and MRA in this setting, see Magnetic Resonance Imaging in Acute Stroke. Based on the central volume principle, dynamic brain perfusion data can be obtained. Cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time (MTT) can be calculated using either perfusion MRI or CT scanning. (See the image below.)

Regions 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. An evidence-based guideline from the American Academy of Neurology advises that DWI is more useful than noncontrast CT scanning for the diagnosis of acute ischemic stroke within 12 hours of symptom onset and should be performed for the most accurate diagnosis of acute ischemic stroke (level A). No recommendations were made regarding the use of perfusionweighted imaging (PWI) in diagnosing acute ischemic stroke, as evidence to support or refute its value in this setting is insufficient.[67] Intra-arterial contrast enhancement may be seen secondary to slow flow during the first or second day after onset of infarction. This finding has been correlated with increased infarct volume size.[68] Other Imaging Studies in Ischemic Stroke Transcranial Doppler ultrasonography is useful for evaluating more proximal vascular anatomyincluding the middle cerebral artery (MCA), intracranial carotid artery, and vertebrobasilar arterythrough the infratemporal fossa.[69]Echocardiography is obtained in all patients with acute ischemic stroke in whom cardiogenic embolism is suspected. Chest radiography has potential utility for patients with acute stroke. However, obtaining a chest radiograph should not delay the administration of rt-PA, as radiographs have not been shown to alter the clinical course or decision-making in most cases.[70]

The use of single-photon emission CT (SPECT) scanning in stroke is still experimental and is available only at select institutions. Theoretically, it can define areas of altered regional blood flow.[71] Conventional angiography is the gold standard in evaluating for cerebrovascular disease as well as for disease involving the aortic arch and great vessels in the neck. Conventional angiography can be performed to clarify equivocal findings or to confirm and treat disease seen on MRA, CTA, transcranial Doppler, or ultrasonography of the neck. (See the images below.)

A 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).

Follow-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). Cerebral 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).

Image on the left demonstrates deployment of a clot

retrieval 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). Blood Studies A CBC serves as a baseline study and may reveal a cause for the stroke (eg, polycythemia, thrombocytosis, thrombocytopenia, leukemia) or provide evidence of concurrent illness (eg, anemia). The basic chemistry panel serves as a baseline study and may reveal a stroke mimic (eg, hypoglycemia, hyponatremia) or provide evidence of concurrent illness (eg, diabetes, renal insufficiency). Coagulation studies may reveal a coagulopathy and are useful when fibrinolytics or anticoagulants are to be used. In patients who are not taking anticoagulants or antithrombotics and in whom there is no suspicion for coagulation abnormality, administration of rt-PA should not be delayed while awaiting laboratory results. Cardiac biomarkers are important because of the association of cerebral vascular disease and coronary artery disease. Additionally, several studies have indicated a link between elevations of cardiac enzyme levels and poor outcome in ischemic stroke.

Toxicology screening may be useful in selected patients in order to assist in identifying intoxicated patients with symptoms/behavior mimicking stroke syndromes. In patients with suspected hypoxemia, arterial blood gas studies define the severity of hypoxemia and may detect acid-base disturbances. However, arterial punctures should be avoided unless absolutely necessary in patients being considered for fibrinolytic therapy.

Bab 5 treatment Approach Considerations The central goal of therapy in acute ischemic stroke is to preserve tissue in the ischemic penumbra, where perfusion is decreased but sufficient to stave off infarction. Tissue in this area of oligemia can be preserved by restoring blood flow to the compromised area and optimizing collateral flow. Recanalization strategies, including the administration of intravenous (IV) recombinant tissuetype plasminogen activator (rt-PA) and intra-arterial approaches, attempt to establish

revascularization so that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. Many surgical and endovascular techniques have been studied in the treatment of acute ischemic stroke. Carotid endarterectomy has been used with some success in the acute management of internal carotid artery occlusions, but no evidence supports its use acutely in ischemic stroke. In addition to limiting the duration of ischemia, an alternative strategy is to limit the severity of ischemic injury (ie, neuronal protection). Neuroprotective strategies are intended to preserve the penumbral tissues and to extend the time window for revascularization techniques. At the present time, however, no neuroprotective agents have been shown to impact outcomes in ischemic stroke. Palliative care Palliative care is an important component of comprehensive stroke care. Some stroke patients will simply not recover, and others will be in a state of debilitation such that their comfort is the most humane and appropriate therapeutic concern. Some patients have advance directives providing instructions for medical providers in the event of severe medical illness or injury. Clinical education Prehospital care providers are essential to timely stroke care. Course curricula for prehospital care providers are beginning to include more information on stroke than ever before. Through certification and Acute Cardiac Life Support (ACLS) instruction, as well as continuing medical education classes, prehospital care providers can remain current on stroke warning signs, prehospital stroke tools, and triage protocols in their region, and can promote stroke awareness in their own communities. Physician and nursing staff involved in the care of stroke patients, in the emergency department (ED) and in the hospital, should participate in scheduled stroke education. This will help them to maintain the skills required to treat stroke patients effectively and to remain current on medical advances for all stroke types.

Emergency Response and Transport Recognition that a stroke may have occurred, activation of 911, and rapid transport to the appropriate receiving facility are necessary to provide stroke patients with the best chance for acute interventions. Of patients with signs or symptoms of stroke, 29-65% utilize some facet of the emergency medical services (EMS) system.[72, 73] Most of the patients who call EMS are those who present within 3 hours of symptom onset. Calls to 911 and the use of EMS are associated with shorter time periods from symptom onset to hospital arrival.[74, 75] Stroke should be a priority dispatch with prompt EMS response. EMS responders should provide advance notice to their ED destination in as timely a manner as possible so as to allow preparation and marshaling of personnel and resources. With the development of stroke center designation, which is currently in progress, such centers would then become the preferred destination for patients with acute stroke symptoms who utilize EMS. Data supporting the use of emergency air transport for patients with acute stroke symptoms are limited. Further evaluation of this transportation modality is necessary to minimize the potentially high number of stroke mimics and to maximize the appropriate use of transport resources. Telemedicine is also a technology that has the potential to provide timely expert advice to rural and underserved clinics and hospitals.[3] Acute Management of Stroke The goal for the emergent management of stroke is to assess the patients airway, breathing, and circulation (ABCs); stabilize the patient as necessary; and complete initial evaluation and assessment, including imaging and laboratory studies, within 60 minutes of patient arrival.[3] A Finnish study demonstrated that time to treatment with fibrinolytics can be decreased with changes in EMS and ED coordination and in ED procedures for treating acute stroke patients.[76] A US study in which a multidisciplinary team used value stream analysis to assess the steps required to treat acute ischemic stroke with IV rt-PA found several inefficiencies in the protocol (eg, in patient routing) that were slowing treatment. Use of a revised protocol that targeted those

inefficiencies reduced door-to-needle times from 60 to 39 minutes and increased the percentage of patients treated in 60 minutes or less after hospital arrival from 52% to 78%, with no change in symptomatic hemorrhage rate.[77] Critical decisions focus on the need for airway management, establishment of optimal blood pressure control, and identification of potential reperfusion therapies (IV fibrinolysis with rt-PA or intra-arterial approaches). Involvement of a physician with a special interest in stroke is ideal. Stroke care units with specially trained personnel exist and improve outcomes. Comorbidities Comorbid medical conditions also need to be addressed. Hyperthermia is infrequently associated with stroke but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is indicated in the presence of fever (temperature >100.4F). Oxygen supplementation Supplemental oxygen is recommended when the patient has a documented oxygen requirement (ie, oxygen saturation < 95%). In the small proportion of patients with stroke who are relatively hypotensive, administration of IV fluid, vasopressor therapy, or both may improve flow through critical stenoses. Hypoglycemia and hyperglycemia Hypoglycemia needs to be identified and treated early in the evaluation. In contrast, the management of hyperglycemia in acute stroke remains an area of uncertainty.[78] Hyperglycemia is common after acute ischemic stroke, even in patients without diabetes. A Cochrane review found that the use of IV insulin to maintain serum glucose in the range of 4-7.5 mmol/L (72-135 mg/dL) in the first 24 hours of ischemic stroke did not improve functional outcome, death rates, or final neurologic deficit and significantly increased the risk of hypoglycemia.[79] Fibrinolytic Therapy

The only fibrinolytic agent that has been shown to benefit selected patients with acute ischemic stroke is rt-PA. While streptokinase may benefit patients with acute MI, in patients with acute ischemic stroke it has been shown to increase the risk of intracranial hemorrhage and death. Fibrinolytics (ie, rt-PA) restore cerebral blood flow in some patients with acute ischemic stroke and may lead to improvement or resolution of neurologic deficits. Unfortunately, fibrinolytics may also cause symptomatic intracranial hemorrhage. Other complications include potentially hemodynamically significant hemorrhage and angioedema or allergic reactions.[3] Inclusion/exclusion criteria Therefore, if the patient is a candidate for fibrinolytic therapy, a thorough review of the inclusion and exclusion criteria must be performed. The exclusion criteria largely focus on identifying risk of hemorrhagic complications associated with fibrinolytic use. The American Heart Association/American Stroke Association (AHA/ASA) inclusion guidelines for the administration of rt-PA are as follows[3] :

Diagnosis of ischemic stroke causing measurable neurologic deficit Neurologic signs not clearing spontaneously to baseline Neurologic signs not minor and isolated Symptoms not suggestive of subarachnoid hemorrhage No head trauma or prior stroke in past 3 months No myocardial infarction (MI) in past 3 months No gastrointestinal/genitourinary hemorrhage in previous 21 days No arterial puncture in a noncompressible site during the past 7 days No major surgery in past 14 days No history of prior intracranial bleeding Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg No evidence of acute trauma or bleeding Not taking an oral anticoagulant, or if so, international normalized ratio (INR) under 1.7 If taking heparin within 48 hours, a normal activated prothrombin time (aPT) Platelet count of more than 100,000/L Blood glucose greater than 50 mg/dL (2.7 mmol)

No seizure with residual postictal impairments CT scan does not show evidence of multilobar infarction (hypodensity over one third hemisphere) or intracerebral hemorrhage

The patient and family understand the potential risks and benefits of therapy Whereas these inclusion/exclusion criteria are from the original FDA approval, subsequent data and experience have allowed some patients with what were previously considered relative contraindications to be safely treated. Involvement of a physician with stroke expertise is critical for assessing the risk/benefit consideration for these groups of patients. Time to therapy An rt-PA stroke study group from the National Institute of Neurologic Disorders and Stroke (NINDS) first reported that the early administration of rt-PA benefited carefully selected patients with acute ischemic stroke.[5] The FDA subsequently approved the use of rt-PA in patients who met NINDS criteria. In particular, rt-PA had to be given within 3 hours of stroke onset and only after CT scanning had ruled out hemorrhagic stroke. Subsequently, fibrinolytic therapy administered 3-4.5 hours after symptom onset was found to improve neurologic outcomes in the European Cooperative Acute Stroke Study III (ECASS III), suggesting a wider time window for fibrinolysis.[80] On the basis of these and other data, in May 2009 the AHA/ASA revised the guidelines for the administration of rt-PA after acute stroke, expanding the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to benefit from this therapy.[80, 81, 82, 83] Eligibility criteria for treatment during this later period are similar to those for earlier treatment but are more stringent, with any 1 of the following serving as an additional exclusion criterion:

Age older than 80 years Use of oral anticoagulants, regardless of the INR Baseline score on the National Institutes of Health Stroke Scale (NIHSS) greater than 25 History of stroke and diabetes A 10-center European study of nearly 6900 patients found IV rt-PA to be most effective when given within 90 minutes of the onset of stroke symptoms.[84, 85]Patients scoring in the 7-12 range

on the NIHSS had better outcomes when thrombolytic therapy was provided within 90 minutes of symptom onset than when it was provided 90-270 minutes after onset. For patients with minor stroke or moderate-to-severe stroke, however, treatment within the initial 90-minute window provided no additional advantage. Hemorrhage risk Although antiplatelet therapy may increase the risk for symptomatic intracerebral hemorrhage with fibrinolysis, a study by Diedler et al that included 3782 patients who had received 1 or 2 antiplatelet drugs found that the risk of intracerebral hemorrhage was small compared with the documented benefit of fibrinolysis.[86]These researchers concluded that antiplatelet treatment should not be considered a contraindication to fibrinolysis, although caution is warranted in patients receiving the combination of aspirin and clopidogrel. Data regarding the safety of fibrinolytic therapy in patients taking dabigatran, rivaroxaban, or apixaban are not available. Extreme caution should be used when considering fibrinolytic therapy in such patients. Caution should also be exercised in the administration of rt-PA to patients with evidence of low attenuation (edema or ischemia) involving more than a third of the distribution of the middle cerebral artery (MCA) on their initial noncontrast CT scan; such patients are less likely to have a favorable outcome after fibrinolytic therapy and are at higher risk for hemorrhagic transformation of their ischemic stroke.[49] Ultrasound therapy Researchers have studied the use of transcranial ultrasound as a means of assisting rt-PA in fibrinolysis.[87,
88]

By delivering mechanical pressure waves to the thrombus, ultrasound can

theoretically expose more of the thrombuss surface to the circulating fibrinolytic agent. Further research is necessary to determine the exact role of transcranial Doppler ultrasound in assisting fibrinolytics in acute ischemic stroke. For more information, see Thrombolytic Therapy in Stroke and Reperfusion Injury in Stroke.

Intra-arterial Reperfusion There have been no completed human trials comparing intravenous versus intra-arterial administration of fibrinolytics. Theoretically, intra-arterial delivery may produce higher local concentrations of the fibrinolytic agent at lower total doses (and thus possibly lower the risk of a systemic bleed) and allow a longer therapeutic window. However, the longer time for initiating intra-arterial administration may mitigate some of this advantage.[3] The Interventional Management of Acute Stroke Study (IMS-III) was halted for futility after showing no additional benefit from intra-arterial therapies (rt-PA, mechanical thrombectomy, or both) compared with intravenous rt-PA in patients with large-vessel occlusions. Additional analyses of the IMS III data are under way to better understand the results and potentially identity subsets of patients who may benefit from the combined approach.[89] Intra-arterial fibrinolysis has been the traditional approach for patients with stroke from basilar artery occlusion. However, results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry study in 592 patients, did not support unequivocal superiority of intra-arterial fibrinolysis over intravenous fibrinolysis.[90] A meta-analysis of case studies involving a total of 420 patients with basilar artery occlusion did indicate that recanalization was achieved more frequently with intra-arterial fibrinolysis than with intravenous fibrinolysis (65% vs 53%), but the report also found that death and long-term disability were equally common with the 2 techniques.[91] These researchers concluded that intravenous fibrinolysis represents probably the best treatment that can be offered to these patients in hospitals without a 24-hour interventional neuroradiologic service.[91] Antiplatelet Agents AHA/ASA guidelines recommend giving aspirin, 325 mg orally, within 24-48 hours of ischemic stroke onset. The benefit of aspirin is modest but statistically significant and appears principally to involve the reduction of recurrent stroke.[83] The International Stroke Trial and the Chinese Acute Stroke Trial (CAST) demonstrated modest benefit from the use of aspirin in the setting of acute ischemic stroke. The International Stroke

Trial randomized 19,435 patients within 48 hours of stroke onset to treatment with aspirin 325 mg, subcutaneous heparin in 2 different dose regimens, aspirin with heparin, and a placebo. The study found that aspirin therapy reduced the risk of stroke recurrence within 14 days (2.8% vs 3.9%), with no significant excess of hemorrhagic strokes.[92, 93] In CAST, which included 21,106 patients, aspirin treatment (160 mg/day) that was started within 48 hours of the onset of suspected acute ischemic stroke and was continued in hospital for up to 4 weeks reduced mortality to 3.3%, compared with 3.9% with placebo. A separate study also found that the combination of aspirin and lowmolecular-weight heparin did not significantly improve outcomes.[92] Other antiplatelet agents have also been under evaluation for use in the acute presentation of ischemic stroke. In a preliminary pilot study, abciximab given within 6 hours showed a trend toward improved outcome at 3 months.[94] However, the phase 3 Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II) was terminated prematurely after 808 patients because of lack of efficacy and an increased rate of symptomatic or fatal intracranial hemorrhage in patients receiving abciximab.[95] Blood Pressure Control Although hypertension is common in acute ischemic stroke and is associated with poor outcome, studies of antihypertensive treatment in this setting have produced conflicting results. A theoretical drawback of blood pressure reduction is that elevated blood pressure may counteract dysfunctional cerebral autoregulation from stroke, but limited evidence suggests that antihypertensive treatment in acute stroke does not change cerebral perfusion.[96] Calcium channel blockers did not alter outcome after ischemic stroke in some trials. Possible adverse effects of antihypertensive treatment have been reported in certain trials, especially those using intravenous calcium channel blockers or oral beta blockers. In the Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS) trial, early lowering of blood pressure with labetalol and lisinopril slightly improved outcome and did not increase serious adverse events. However, CHHIPS had a small sample size.[97]

A study in 339 patients with ischemic stroke found that oral candesartan reduced combined vascular events but had no effect on disability.[96] However, the Scandinavian Candesartan Acute Stroke Trial (SCAST), a randomized, placebo-controlled, double-blind study involving 2029 patients, found no indication of benefit from candesartan but did find some suggestion of harm.[98] For patients who are not candidates for fibrinolytic therapy, current guidelines recommend permitting moderate hypertension in most patients with acute ischemic stroke. Most patients will experience spontaneous reduction in blood pressure over the first 24 hours without treatment.[83] The exceptions would be patients who have comorbidities (eg, aortic dissection, acute myocardial infarction [MI], decompensated heart failure, hypertensive emergency) that require emergent blood pressure management. Thresholds for antihypertensive treatment in acute ischemic stroke patients who are not fibrinolysis candidates, according to the 2013 ASA guidelines, are systolic blood pressure higher than 220 mm Hg or diastolic blood pressure above 120 mm Hg.[83] In those patients, a reasonable goal is to lower blood pressure by 15% during the first 24 hours after onset of stroke. Care must be taken to not lower blood pressure too quickly or aggressively, since this could worsen perfusion in the penumbra. Mechanical Thrombectomy Mechanical clot disruption is an alternative for patients in whom fibrinolysis is ineffective or contraindicated. Currently, 4 devices are approved by the FDA for the endovascular treatment of acute ischemic stroke, as follows:

Merci Retriever (Concentric Medical, Mountain View, CA): Corkscrew-shaped device that captures and engages clots

Penumbra System (Penumbra, Alameda, CA): Employs both aspiration and extraction Solitaire FR Revascularization Device (Covidien, Dublin, Ireland): Stent-retriever system; combines the ability to restore blood flow and retrieve clot

Trevo (Concentric Medical, Mountain View, CA): Stent-retriever system

Successful recanalization occurred in 12 of 28 patients in the Mechanical Embolus Retrieval in Cerebral Ischemia (MERCI) 1 pilot trial, a study of the Merci Retrieval System. [99] In a second MERCI study, recanalization was achieved in 48% of patients in whom the device was deployed. Clot was successfully retrieved from all major cerebral arteries; however, the recanalization rate for the MCA was lowest.[100] The Multi MERCI trial used the newer-generation Concentric retrieval device (L5). Recanalization was demonstrated in approximately 55% of patients who did not receive t-PA and in 68% of those to whom t-PA was given. Seventy-three percent of patients who failed intravenous t-PA therapy had recanalization following mechanical embolectomy.[101] On the basis of these results, the FDA cleared the use of the MERCI device in patients who are either ineligible for or who have failed intravenous fibrinolytics. In a trial of the Penumbra System in 23 patients who presented within 8 hours of symptom onset, revascularization to a Thrombolysis in Myocardial Infarction (TIMI) grade of 2 or 3 was accomplished in all 21 treated vessels. Vessel tortuosity prevented access by the device in 3 patients.[102] More recent trials of the stent-retriever systems demonstrated superiority in reperfusion over the original Merci systems. In the Solitaire Flow Restoration Device Versus the Merci Retriever in Patients with Acute Ischaemic Stroke (SWIFT) study, which enrolled 113 subjects with moderate or severe strokes within 8 hours after symptom onset, the Solitaire FR system demonstrated successful revascularization (TIMI 2-3 flow) in 61% of patients, compared with 24% of patients treated with the Merci system. Patients in the Solitaire FR group also had a higher rate of good 90-day clinical outcomes than did those in the Merci group (58% versus 33%, respectively).[103] A similar study, the Trevo Versus Merci Retrievers for Thrombectomy Revascularisation of Large Vessel Occlusions in Acute Ischaemic Stroke (TREVO 2) trial, reported successful reperfusion (TIMI 2-3 flow) in 86% of patients using the Trevor stent retriever, compared with 60% in the Merci group. The rate of good clinical outcomes at 90 days was also higher in the Trevo group than in the Merci group (40% vs 22%, respectively).[104] Ongoing studies will better define the role of intra-arterial therapies with and without intravenous fibrinolysis.

Long-term results of the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) study confirm the superiority of aggressive medical management alone to aggressive medical management with stenting in patients with a stroke or transient ischemic attack resulting from stenosis of a major intracranial artery.[105, 106,
107]

Long-term follow-up results were available for 227 patients in the medical management

group and 224 patients in the stenting group. Occurrence rates for primary endpoint events (stroke or death within 30 days after enrollment or after either a revascularization procedure for the qualifying lesion during follow-up or a stroke in the territory of the qualifying artery beyond 30 days) in the medical group and the stenting group were 14.1% and 20.6%, respectively, at year 2 and 14.9% and 23.9% at year 3.[106] Rates of any stroke and of any major hemorrhage were also significantly lower in the medical group than in the stenting group. For more information, see Mechanical Thrombolysis in Acute Stroke. Fever Control Antipyretics are indicated for febrile stroke patients, since hyperthermia accelerates ischemic neuronal injury. Substantial experimental evidence suggests that mild brain hypothermia is neuroprotective. The use of induced hypothermia is currently being evaluated in phase II clinical trials.[108, 109, 110] High body temperature in the first 12-24 hours after stroke onset has been associated with poor functional outcome. However, results from the Paracetamol (Acetaminophen) in Stroke (PAIS) trial did not support the routine use of high-dose acetaminophen (6 g daily) in patients with acute stroke, although post-hoc analysis suggested a possible beneficial effect on functional outcome in patients admitted with a body temperature of 37-39 C.[111] Cerebral Edema Control Significant cerebral edema after ischemic stroke is thought to be somewhat rare (10-20%). Maximum severity of edema is reached 72-96 hours after the onset of stroke.

Early indicators of ischemia on presentation and on noncontrast CT (NCCT) scans are independent indicators of potential swelling and deterioration (see the image below). Mannitol and other therapies to reduce intracranial pressure (ICP) may be used in emergency situations, although their usefulness in swelling secondary to ischemic stroke is unknown. No evidence exists supporting the use of corticosteroids to decrease cerebral edema in acute ischemic stroke. Prompt neurosurgical assistance should be sought when indicated.[3]

Axial 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. Patient position, hyperventilation, hyperosmolar therapy, and, rarely, barbiturate coma may be used, as in patients with increased ICP secondary to closed head injury. Hemicraniectomy has been shown to decrease mortality and disability among patients with large hemispheric infarctions associated with life-threatening edema.[112, 113, 114, 115] Seizure Control Seizures occur in 2-23% of patients within the first days after ischemic stroke. These seizures are usually focal, but they may be generalized. Although primary prophylaxis for poststroke seizures is not indicated, secondary prevention of subsequent seizures with standard antiepileptic therapy is recommended.[3] A fraction of patients who have experienced stroke develop chronic seizure disorders. Seizure disorders secondary to ischemic stroke should be managed in the same manner as other seizure disorders that arise as a result of neurologic injury.[3]

Acute Decompensation In the case of the rapidly decompensating patient or the patient with deteriorating neurologic status, reassessment of the ABCs as well as hemodynamics and reimaging are indicated. Many patients who develop hemorrhagic transformation or progressive cerebral edema will demonstrate acute clinical decline. Rarely, a patient may have escalation of symptoms secondary to increased size of the ischemic penumbra. Careful observation for hemorrhagic transformation (especially in the first 24 hours postreperfusion) and cerebral edema in patients with hemispheric or posterior fossa strokes in the first 24-36 hours is warranted. Anticoagulation and Prophylaxis Currently, data are inadequate to justify the routine use of heparin or other anticoagulants in the acute management of ischemic stroke.[116] Patients with embolic stroke who have another indication for anticoagulation (eg, atrial fibrillation) may be placed on anticoagulation therapy nonemergently, with the goal of preventing further embolic disease; however, the potential benefits of that intervention must
[3]

be weighed

against

the risk of hemorrhagic

transformation. For more information, see Stroke Anticoagulation and Prophylaxis. Immobilized stroke patients in particular are at increased risk of developing deep venous thrombosis (DVT) and should receive early efforts to reduce the occurrence of DVT. The use of low-dose, subcutaneous unfractionated or lowmolecular-weight heparin may be appropriate in these cases.[3] The CLOTS (Clots in Legs Or sTockings after Stroke) trial demonstrated that intermittent pneumatic compression of the lower extremities, started in the first 3 hospital days, reduced the risk of DVT in immobile patients with acute stroke.[117] Neuroprotective Agents The rationale for the use of neuroprotective agents is that reducing the release of excitatory neurotransmitters by neurons in the ischemic penumbra may enhance the survival or these neurons. Despite very promising results in several animal studies, however, no single neuroprotective agent in ischemic stroke has as yet been supported by randomized, placebocontrolled human studies. Nevertheless, substantial research is under way evaluating different neuroprotective strategies.

Hypothermia is fast becoming the standard of care for the ongoing treatment of patients surviving cardiac arrest from ventricular tachycardia or ventricular fibrillation. However, no major clinical study has demonstrated a role for hypothermia in the early treatment of ischemic stroke.[3] For more information, see Neuroprotective Agents in Stroke. Stroke Prevention Primary prevention refers to the treatment of individuals with no history of stroke. Measures may include the use of platelet antiaggregants, statins, and exercise. The 2011 AHA/ASA guidelines for the primary prevention of stroke emphasize the importance of lifestyle changes to reduce well-documented modifiable risk factors, citing an 80% lower risk of a first stroke in people who follow a healthy lifestyle compared with those who do not.[22] Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures may include the use of platelet antiaggregants,[118]antihypertensives, statins,[119] and lifestyle interventions. A study by the Warfarin-Aspirin Symptomatic Intracranial Disease Trial Investigators concluded that in stroke patients who have significant intracranial arterial stenosis, aspirin should be used in preference to warfarin for secondary prevention.[120] Smoking cessation, blood pressure control, diabetes control, a low-fat diet, weight loss, and regular exercise should be encouraged as strongly as the medications described above. The 2011 AHA/ASA guidelines recommend ED-based smoking cessation interventions, and consider it reasonable for EDs to screen patients for hypertension and drug abuse.[22] Written prescriptions for exercise and medications for smoking cessation (ie, nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions. In addition, the 2011 AHA/ASA guidelines for primary stroke prevention indicate that it is reasonable to avoid exposure to environmental tobacco smoke, despite a lack of stroke-specific data. Aspirin for primary prevention

Overall, the value of aspirin in primary prevention appears uncertain,[121] and its use for this purpose is not recommended for patients at low risk. Aspirin is recommended for primary prevention only in persons with at least a 6-10% risk of cardiovascular events over 10 years.[22] On the other hand, low-dose aspirin may be beneficial for primary prevention of stroke in women. A randomized, placebo-controlled trial in 39,876 initially healthy women aged 45 years or older demonstrated that 100 mg of aspirin on alternate days resulted in a 24% reduction in the risk of ischemic stroke, with a nonsignificant increase in the risk of hemorrhagic stroke.[122] Dual antiplatelet therapy for secondary prevention A systematic review and meta-analysis of 12 randomized trials involving 3766 patients concluded that, compared with aspirin alone, dual antiplatelet therapy with aspirin plus either dipyridamole or clopidogrel appears to be safe and effective in reducing stroke recurrence and other vascular events (ie, transient ischemic attack [TIA], acute coronary syndrome, MI), in patients with acute ischemic stroke or TIA.[123] Dual therapy was also associated with a nonsignificant trend toward increased major bleeding. The European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) showed that the combination of aspirin and dipyridamole was preferable to aspirin alone as antithrombotic therapy for cerebral ischemia of arterial origin.[124] In ESPRIT, secondary prevention was started within 6 months of a TIA or minor stroke of presumed arterial origin. The addition of extended-release dipyridamole to aspirin therapy appears to be equally safe and effective whether started early or late after stroke. A German study in 543 patients found no significant difference in disability at 90 days, regardless of whether dipyridamole was started within 24 hours of stroke or TIA onset or after 7 days of aspirin monotherapy.[125] In contrast, the Management of AtheroThrombosis with Clopidogrel in High-risk patients with recent transient ischaemic attack or ischaemic stroke (MATCH) trial, which included 7599 patients, found that adding aspirin to clopidogrel did not significantly reduce major vascular events. However, the risk of life-threatening or major bleeding was increased by the addition of aspirin.[126]

Carotid artery stenosis For patients at risk for stroke from asymptomatic carotid artery stenosis, the 2011 AHA/ASA primary prevention guidelines state that older studies that showed revascularization surgery as more beneficial than medical treatment may now be obsolete because of improvements in medical therapies. Therefore, individual patient comorbidities, life expectancy, and preferences should determine whether medical treatment alone or carotid revascularization is selected.[22] Atrial fibrillation Atrial fibrillation (AF) is a major risk factor for stroke. The 2011 AHA/ASA primary stroke prevention guideline recommends that EDs screen for AF and assess patients for anticoagulation therapy if AF is found.[22] In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W), oral anticoagulation with warfarin proved superior to clopidogrel plus aspirin for prevention of vascular events in patients with AF who were at high risk of stroke.[127] The study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. Interestingly, in ACTIVE W, the rate of vascular events was significantly higher in patients who switched from warfarin to clopidogrel plus aspirin as a result of randomization than in patients who had been on warfarin before study enrollment and remained on warfarin during the study. The benefit of anticoagulation therapy over dual antiplatelet therapy was much more modest in patients who had not been on warfarin before study initiation and were then randomized to warfarin. The 2011 ACC Foundation (ACCF)/AHA/Heart Rhythm Society (HRS) AF guideline update states that the new anticoagulant dabigatran is useful as an alternative to warfarin in patients with AF who do not have a prosthetic heart valve or hemodynamically significant valve disease.[128] However, a 2012 meta-analysis found an increased risk for MI or acute coronary syndrome with dabigatran.[129] For patients with AF after stroke or TIA, the 2010 AHA/ASA secondary stroke prevention guidelines are in accord with the standard recommendation of warfarin, with aspirin as an

alternative for patients who cannot take oral anticoagulants. However, clopidogrel should not be used in combination with aspirin for such patients, because the bleeding risk of the combination is comparable to that of warfarin. The guideline states that the benefit of warfarin after stroke or TIA in patients without AF has not been established.[130] Specialized Stroke Centers The concept of the specialized stroke center has evolved in response to the multitude of factors involved in the care of patients with acute stroke. The Brain Attack Coalition provided recommendations for the establishment of 2 tiers of stroke centers: primary stroke centers (PSCs) and comprehensive stroke centers (CSCs).[3] The Joint Commission for the Accreditation of Hospital Organizations (JCAHO) now provides accreditation for PSCs and CSCs. These centers are characterized as follows:

PSC: Designed to maximize the timely provision of stroke-specific therapy, including the administration of rt-PA; the center is also capable of providing care to patients with uncomplicated stroke

CSC: Shares the commitment that the PSC has to acute delivery of rt-PA and also provides care to patients with hemorrhagic stroke and intracranial hemorrhage, as well as to all patients with stroke who require emergent advanced imaging, intra-arterial therapies, neurosurgical interventions, and management in a neurosurgical intensive care unit (NSICU) PSCs and CSCs work most effectively when integrated into a regional stroke system of care so that patients are treated at the most appropriate hospital based on factors such as severity, comorbidities, and timing. Integrating regional prehospital services (911 and EMS) into this system of care ensures the most appropriate triage from the field. Additionally, stroke centers should have personnel versed in the monitoring of stroke vital signs, which include the following:

Blood pressure Glucose levels Temperature Oxygenation

Change in neurologic status A further tier, acute stroke ready hospitals, is being defined as hospitals in which most of the necessary resources are in place to emergently evaluate patients and potentially treat them with fibrinolytics, with the assistance of remote stroke expertise, typically by telemedicine. Key to the optimal function of these stroke centers is their interactions within a regional stroke system of care. Coordination of care Once patients have been identified as potential stroke patients, their ED evaluation must be fasttracked to allow for the completion of required laboratory tests and requisite noncontrast head CT scanning, as well as for the notification and involvement of neurologic consultants. These requirements have led to the development of "code stroke" protocols for the ED. In addition, EMS personnel are trained to identify possible stroke patients and arrange for their speedy, preferential transport to a PSC or CSC.[77] Hospitals with specialized stroke teams have demonstrated significantly increased rates of fibrinolytic administration and decreased mortality. Cumulatively, the center should identify performance measures and include mechanisms for evaluating the effectiveness of the system, as well as its component parts. The acute care of the stroke patient is more than anything a systemsbased team approach requiring the cooperation of the ED, radiology, pharmacy, neurology, and intensive care unit (ICU) staff. A stroke system should ensure effective interaction and collaboration among the agencies, services, and people involved in providing prevention and the timely identification, triage to the most appropriate hospital, rapid transport, treatment, and rehabilitation of stroke patients. For more information, see Stroke Team Creation and Primary Stroke Center Certification. Consultations A stroke team or an experienced professional who is sufficiently familiar with stroke should be available within 15 minutes of the patient's arrival in the ED. Other consultations are tailored to individual patient needs. Often, occupational therapy, physical therapy, speech therapy, and physical medicine and rehabilitation experts are consulted within the first day of hospitalization.

Consultation of cardiology, vascular surgery, or neurosurgery may be warranted based on the results of carotid duplex scanning , neuroimaging, transthoracic and transesophageal echocardiography, and clinical course. During hospitalization, additional useful consultations include the following:

Home health care coordinator Rehabilitation coordinator Social worker Psychiatrist (commonly for depression) Dietitian

BAB 6 MEDICATION Medication Summary

While only 1 drug, recombinant tissue-type plasminogen activator (rt-PA), has demonstrated efficacy and effectiveness in treating acute ischemic stroke and is approved by the FDA, other medications are equally important. National consensus panels have included the use of antihypertensives, anticonvulsants, and osmotic agents in their recommendations. Additional agents may be required for comorbid illnesses in many patients with stroke. Medications for the management of ischemic stroke can be distributed into the following categories:

Anticoagulation Reperfusion Antiplatelet Neuroprotective Thrombolytics Class Summary Thrombolyticmore accurately, fibrinolyticagents convert entrapped plasminogen to plasmin and initiate local fibrinolysis by binding to fibrin in a clot. Alteplase (Activase) Alteplase is a t-PA used in management of acute myocardial infarction (MI), acute ischemic stroke, and pulmonary embolism. Safety and efficacy with concomitant administration of heparin or aspirin during the first 24 hours after symptom onset have not been investigated. Anticonvulsants, Other Class Summary While seizures associated with stroke are relatively uncommon, recurrent seizures may be life threatening. Generally, agents used for treating recurrent convulsive seizures are also used in patients with seizures after stroke. Benzodiazepines, typically diazepam and lorazepam, are the first-line drugs for ongoing seizures. Diazepam (Valium)

Diazepam acts on the gamma-aminobutyric acid (GABA) receptor complex in the limbic system and thalamus, producing a calming effect. The drug is useful in controlling active seizures and should be augmented by longer-acting anticonvulsants, such as phenytoin or phenobarbital. Lorazepam (Ativan) Lorazepam is a short-acting benzodiazepine with a moderately long half-life. It has become the drug of choice in many centers for treating active seizures. Antiplatelet Agents Class Summary Although antiplatelet agents have proved useful for preventing recurrent stroke or stroke after transient ischemic attacks (TIAs), efficacy in the treatment of acute ischemic stroke has not been demonstrated. Early aspirin therapy is recommended within 48 hours of the onset of symptoms but should be delayed for at least 24 hours after rt-PA administration. Aspirin should not be considered as an alternative to intravenous fibrinolysis or other therapies aimed at improving outcomes after stroke. Aspirin (ASA) Aspirin blocks prostaglandin synthetase action, which in turn inhibits prostaglandin synthesis and prevents the formation of platelet-aggregating thromboxane A2. It also acts on the hypothalamic heat-regulating center to reduce fever. Dipyridamole and aspirin (Aggrenox) The combination of extended-release dipyridamole and aspirin reduces the relative risk of stroke, death, and myocardial infarction (MI). It is used for the secondary prevention of ischemic stroke and TIAs. Clopidogrel (Plavix) Clopidogrel inhibits platelet aggregation and is used for secondary stroke prevention. It is indicated for the reduction of atherothrombotic events following a recent stroke.

Anticoagulants, Hematologic Class Summary Anticoagulants such as warfarin are used for secondary stroke prevention. Warfarin (Coumadin, Jantoven) Warfarin is an anticoagulant used to reduce the risk of death, recurrent MI, and thromboembolic events such as stroke or systemic embolization after MI. Dabigatran (Pradaxa) Dabigatran is a competitive, direct inhibitor of thrombin that can prevent thrombus development. This agent inhibits free and clot-bound thrombin and thrombin-induced platelet aggregation. It may be used as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent atrial fibrillation and risk factors for stroke or systemic embolization. Rivaroxaban (Xarelto) Rivaroxaban is a Factor Xa inhibitor indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. The dose is adjusted according to estimated creatinine clearance. Apixaban (Eliquis) Apixaban is a factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It inhibits free and clot-bound factor Xa and prothrombinase activity. Although this agent has no direct effect on platelet aggregation, it does indirectly inhibit platelet aggregation induced by thrombin. Apixaban is indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation. Analgesics, Other Class Summary

Hyperthermia in acute stroke is potentially harmful and should be treated. Agents with potential bleeding risk should be avoided, if possible. Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)

Acetaminophen reduces fever by acting directly on hypothalamic heat-regulating centers, which increases the dissipation of body heat via vasodilation and sweating. Beta Blockers, Alpha Activity Class Summary Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters depend largely on whether the patient is a candidate for fibrinolytic therapy. While the target blood pressures may differ, the therapeutic agents are primarily the same. Labetalol (Normodyne, Trandate) Labetalol is an adrenergic receptor-blocking agent with nonselective beta-adrenergic and selective alpha1 competitive receptor-blocking actions. It produces dose-related decreases in blood pressure without inducing reflex tachycardia. ACE Inhibitors Class Summary Angiotensin-converting enzyme (ACE) inhibitors prevent the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion. Enalapril (Vasotec)

An ACE inhibitor, enalapril decreases circulating angiotensin II levels and suppresses the reninangiotensin-aldosterone system, lowering overall blood pressure. Calcium Channel Blockers

Class Summary Optimal blood pressure management in acute stroke remains subject to some debate. Treatment parameters depend largely on whether the patient is a candidate for fibrinolytic therapy. While the target blood pressures may differ, the therapeutic agents are largely the same.

Nicardipine (Cardene)

A calcium channel blocker, nicardipine inhibits calcium ion influx into vascular smooth muscle and myocardium.[87] Vasodilators Class Summary Vasodilators lower blood pressure through direct vasodilation and relaxation of the vascular smooth muscle. They are used more for blood pressure lowering in severe or refractory situations and should be used with caution.

Nitroprusside sodium (Nipride, Nitropress, Sodium Nitroprusside) Nitroprusside sodium is a vasodilator that decreases peripheral vascular resistance by relaxing arteriolar smooth muscle. It also decreases venous return through venous dilation.