Ischemic Stroke Stroke is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss

of neurologic function. Strokes are classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to stroke caused by thrombosis or embolism and is more common than hemorrhagic stroke. Essential update: New AHA/ASA guidelines for acute stroke treatment The American Heart Association (AHA) and American Stroke Association (ASA) released new guidelines for the early management of acute ischemic stroke in January 2013. New features of the guidelines include a focus on the importance of stroke systems of care, a recommendation for the use of tissue plasminogen activator (t-PA) in selected patients presenting within 3 to 4.5 hours of symptom onset, and a recommendation for door-to-needle times within 60 minutes of hospital arrival in patients eligible for thrombolysis.[1, 2] Signs and symptoms Although signs and symptoms of stroke can occur alone, they are more likely to occur in combination. Common stroke signs and symptoms include the following:

Abrupt onset of hemiparesis, monoparesis, or quadriparesis Acute hemisensory loss Complete or partial hemianopia, monocular or binocular visual loss, or diplopia Visual field deficits Diplopia Dysarthria Ataxia Vertigo Nystagmus Aphasia Sudden decrease in the level of consciousness In younger patients, a history of recent trauma, coagulopathies, illicit drug use (especially cocaine), migraines, or use of oral contraceptives should be elicited. See Clinical Presentation for more detail. Diagnosis With the availability of thrombolytic 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. Essential components of the neurologic examination include evaluations of the following:

Cranial nerves Motor function Sensory function Cerebellar function Gait Deep tendon reflexes Mental status level of consciousness The patients skull and spine also should be examined, and signs of meningismus should be sought.

Laboratory studies Laboratory tests performed in the diagnosis and evaluation of ischemic stroke include the following:

Complete blood cell count: The CBC count 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) Basic chemistry panel: The 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: Coagulation studies may reveal a coagulopathy and are useful when thrombolytics or anticoagulants are to be used Cardiac biomarkers: Cardiac biomarkers are important because of the association of cerebral vascular disease and coronary artery disease Toxicology screening: 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: Although infrequent in patients with suspected hypoxemia, arterial blood gas defines the severity of hypoxemia and may be used to detect acid-base disturbances Imaging studies Imaging in ischemic stroke can involve the following modalities:

Several types of magnetic resonance imaging Several types of computed tomography scanning Angiography Ultrasonography Radiology Echocardiography Nuclear imaging 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 See Workup for more detail. Management Ischemic stroke therapies include the following:

Thrombolytic therapy: Thrombolytics restore cerebral blood flow among some patients with acute ischemic stroke and may lead to improvement or resolution of neurologic deficits Antiplatelet agents: 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[3, 4] Mechanical thrombolysis: Involves the endovascular treatment of acute ischemic stroke 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 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins) Exercise Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures may include use of the following: Platelet antiaggregants Antihypertensives HMG-CoA reductase inhibitors (statins) Lifestyle interventions See Treatment and Medication for more detail. Image library Vascular distributions: 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 MCA distributions), greater on the left indicating multivessel involvement suggesting emboli. Background Stroke is characterized by the sudden loss of blood circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Also previously called cerebrovascular accident (CVA) or stroke syndrome, stroke is a nonspecific term encompassing a heterogeneous group of pathophysiologic causes. Broadly, however, strokes are classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to stroke caused by thrombosis or embolism and is more common than hemorrhagic stroke. (Prior literature indicated that only 8-18% of strokes are hemorrhagic, but a retrospective review from a stroke center found that 40.9% of 757 strokes included in the study were hemorrhagic.[5] ) Based on the system of categorizing stroke developed in the multicenter Trial of Org 10172 in Acute Stroke Treatment (TOAST), ischemic strokes may be divided into the following 3 major subtypes[6] :

Large artery infarction: Thrombotic strokes are caused by in situ occlusions on atherosclerotic lesions in the carotid, vertebrobasilar, and cerebral arteries, typically proximal to major branches. Small-vessel, or lacunar, infarction Cardioembolic infarction: 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. (See Pathophysiology.) The National Institute of Neurologic Disorders and Stroke (NINDS) recombinant tissue-type plasminogen activator (rt-PA) stroke study group first reported that the early administration of rt-PA benefited carefully selected patients with acute ischemic stroke.[7] The trials outcome led to the long-standing goal of t-PA administration within a 3-hour window for a patient deemed likely to benefit from thrombolytic intervention. Encouraged by this

breakthrough study and the subsequent approval by the US Food and Drug Administration (FDA) of the use of t-PA in acute ischemic stroke, many medical professionals now consider acute ischemic stroke to be a medical emergency that may be amenable to treatment. Thrombolytic therapy administered between 3 and 4.5 hours after the onset of symptoms was found to be efficacious in improving neurologic outcomes in the European Cooperative Acute Stroke Study III (ECASS III), suggesting a wider time window for the administration of thrombolytics.[8] Based on this and other data, in May 2009, the American Heart Association and the American Stroke Association guidelines for the administration of rt-PA were revised to expand the treatment window from 3 to 4.5 hours.[9] This indication has not yet been FDA approved. Understanding of the pathophysiology, clinical presentation, and evaluation of the stroke patient is essential, as is knowledge of the therapeutic armamentarium currently available to treat acute ischemic stroke, which includes supportive care, treatment of neurologic complications, antiplatelet therapy, glycemic control, blood pressure control, prevention of hyperthermia, and thrombolytic therapy. 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. See the Cardiac Output calculator. Knowledge of cerebrovascular arterial anatomy and the territories supplied by each is useful in determining which vessels are involved in acute stroke. Atypical patterns that do not conform to a vascular distribution may indicate a diagnosis other than ischemic stroke, such as venous infarction. Arterial distributions 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. 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 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. The cerebellar hemispheres are supplied inferiorly by the posterior inferior cerebellar artery (PICA) arising from the vertebral artery, superiorly by the superior cerebellar artery, and anterolaterally by the anterior inferior cerebellar artery (AICA) from the basilar artery. Pathophysiology Acute ischemic strokes are the result of vascular occlusion secondary to thromboembolic disease (see Etiology). Ischemia results in cell hypoxia and depletion of cellular adenosine triphosphate (ATP). Without ATP, energy failure results in an inability to maintain ionic

gradients across the cell membrane and cell depolarization. With an influx of sodium and calcium ions and passive inflow of water into the cell, cytotoxic edema results.[10, 11, 12] Ischemic core and penumbra An acute vascular occlusion produces heterogeneous regions of ischemia in the affected vascular territory. The quantity of local blood flow is made up of any residual flow in the major arterial source and the collateral supply, if any. Regions of the brain with CBF lower than 10 mL/100g of tissue/min are referred to collectively as the core, and these cells are presumed to die within minutes of stroke onset. Zones of decreased or marginal perfusion (CBF < 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. Ischemic cascade On the cellular level, the ischemic neuron becomes depolarized as ATP is depleted and membrane ion-transport systems fail. The resulting influx of calcium leads to the release of a number of neurotransmitters, including large quantities of glutamate, which in turn activates N -methyl-D-aspartate (NMDA) and other excitatory receptors on other neurons. 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.[13] 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. Vasogenic edema produces greater levels of brain swelling and mass effect that peaks at 3-5 days and resolves over the next several weeks with resorption of water and proteins.[14, 15] 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.[13] 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 oligodendroglia and microglia cells. The infarcted tissue eventually undergoes liquefaction necrosis and is removed by macrophages with the development of parenchymal volume loss. A wellcircumscribed region of cerebrospinal fluidlike low density is eventually seen, consisting of encephalomalacia and cystic change. The evolution of these chronic changes may be seen in the weeks to months following the infarction. Hemorrhagic transformation of ischemic stroke Hemorrhagic transformation represents the conversion of a bland infarction into an area of hemorrhage. This is estimated to occur in 5% of uncomplicated ischemic strokes, in the absence of thrombolytics. Hemorrhagic transformation is not always associated with neurologic decline and ranges from small petechial hemorrhages to hematomas requiring evacuation.

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.[10, 16, 17] Hemorrhagic transformation of an ischemic infarct occurs within 2-14 days post ictus, usually within the first week. It is more commonly seen following cardioembolic strokes and is more likely with larger infarct size.[10, 18, 7]Hemorrhagic transformation is also more likely following administration of t-PA, with noncontrast computed tomography (NCCT) scanning demonstrating areas of hypodensity.[19, 20, 21] Poststroke cerebral edema and seizures Although significant cerebral edema can occur after anterior circulation ischemic stroke, it is thought to be somewhat rare (10-20%).[22] 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 stroke.[22] 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 thrombosis embolism, thrombosis in situ, or relative hypoperfusion. As blood flow decreases, neurons cease functioning, and irreversible neuronal ischemia and injury begin at blood flow rates of less than 18 mL/100 g of tissue/min. Risk factors Risk factors for ischemic stroke include modifiable and nonmodifiable etiologies. 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:

Age Race Sex Ethnicity History of migraine headaches Sickle cell disease Fibromuscular dysplasia Heredity Modifiable risk factors include the following: Hypertension (the most important) Diabetes mellitus Cardiac disease - Atrial fibrillation, valvular disease, mitral stenosis, and structural anomalies allowing right to left shunting, such as a patent foramen ovale and atrial and ventricular enlargement Hypercholesterolemia Transient ischemic attacks (TIAs) Carotid stenosis Hyperhomocystinemia

Lifestyle issues - Excessive alcohol intake, tobacco use, illicit drug use, obesity, physical inactivity Oral contraceptive use Among the types of cardiac disease that increase stroke risk are atrial fibrillation, valvular disease, mitral stenosis, and structural anomalies allowing right-to-left shunting, such as a patent foramen ovale and atrial and ventricular enlargement. TIA is a transient neurologic deficit with no evidence of an ischemic lesion on neuroimaging. Roughly 80% resolve within 60 minutes.[23] TIA can result from the aforementioned mechanisms of stroke. Data suggest that roughly 10% of patients with TIA suffer stroke within 90 days and half of these patients suffer stroke within 2 days.[24, 25] Genetic and inflammatory mechanisms Evidence continues to accumulate to suggest important roles for inflammation and genetic factors in the process 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) 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. Flow disturbances Stroke symptoms can result from inadequate cerebral blood flow due to decreased blood pressure (and specifically, decreased cerebral perfusion pressure) or as a result of hematologic hyperviscosity due to 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. 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. Lacunar strokes Lacunar strokes represent 13-20% of all ischemic strokes. They occur when the penetrating branches of the MCA, the lenticulostriate arteries, or the penetrating branches of the circle of Willis, vertebral artery, or basilar artery become occluded. Causes of lacunar infarcts include the following:

Microatheroma Lipohyalinosis

Fibrinoid necrosis secondary to hypertension or vasculitis Hyaline arteriosclerosis Amyloid angiopathy The great majority are related to hypertension. Embolic strokes Cardiogenic emboli may account for up to 20% of acute strokes. Emboli may arise from the heart, the extracranial arteries, or, rarely, the right-sided circulation (paradoxical emboli) with subsequent passage through a patent foramen ovale. The 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 [MI], atrial fibrillation [AF], dilated cardiomyopathy, or severe congestive heart failure [CHF]) Atrial myxoma MI is associated with a 2-3% incidence of embolic strokes, of which 85% occur in the first month after MI.[26] Embolic strokes tend to have a sudden onset, and neuroimaging may demonstrate previous infarcts in several vascular territories or calcific emboli. Risk factors include atrial fibrillation and recent cardiac surgery. 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. Thrombotic strokes Thrombogenic factors may include injury to and loss of endothelial cells, exposing the subendothelium, and 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 increase the risk for 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 in patients with widespread atherosclerosis. In other patients, especially younger patients, other causes should be considered, including the following[29, 10] : Hypercoagulable states (eg, antiphospholipid antibodies, protein C deficiency, protein S deficiency, pregnancy)

Sickle cell disease Fibromuscular dysplasia Arterial dissections Vasoconstriction associated with substance abuse 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 due to severe hypoperfusion, such as in carotid occlusion or prolonged hypotension. Epidemiology Stroke is the leading cause of disability and the third leading cause of death in the United States.[33] More than 700,000 persons per year suffer a first-time stroke in the United States, with 20% of these individuals dying within the first year after the stroke. If current trends continue, this number is projected to reach 1 million per year by the year 2050.[34] The global incidence of stroke is unknown. Stroke incidence by race and sex In the United States, blacks have an age-adjusted risk of death from stroke that is 1.49 times that of whites.[35] 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 males 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%. Stroke and age Although stroke often is considered a disease of elderly persons, one third of strokes occur in persons younger than 65 years.[34] Risk of stroke increases with age, especially in patients older than 64 years, in whom 75% of all strokes occur. Prognosis The prognosis after acute ischemic stroke varies greatly, depending on the stroke severity and on the patients premorbid condition, age, and poststroke complications.[6] Some patients experience hemorrhagic transformation of their infarct (See Pathophysiology). This is estimated to occur in 5% of uncomplicated ischemic strokes, in the absence of thrombolytics. Hemorrhagic transformation is not always associated with neurologic decline and ranges from small petechial hemorrhages to hematomas requiring evacuation. 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%. In the United States, 20% of individuals die within the first year after a first-time stroke, as previously mentioned. Cardiogenic emboli are associated with the highest 1-month mortality in patients with acute stroke. 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 follow-up.

The presence of CT scan evidence of infarction early in presentation has been associated with poor outcome and with an increased propensity for hemorrhagic transformation after thrombolytics.[7, 36, 37] 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 thrombolysis, as well as extension of the infarcted territory.[38, 39, 40] To see complete information on Motor Recovery in Stroke, please go to the main article by clicking here. 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 include using local churches, employers, and senior organizations to promote stroke awareness. The American Stroke Association advises the public to be aware of the symptoms of stroke that are easily recognized and to call 911 immediately. These symptoms include the following:

Sudden numbness or weakness of face, arm, or leg, especially on 1 side of the body Sudden confusion Sudden difficulty in speaking or understanding Sudden deterioration of vision in 1 or both eyes Sudden difficulty in walking, dizziness, and loss of balance or coordination Sudden, severe headache with no known cause History A focused medical history for patients with ischemic stroke aims to identify risk factors for atherosclerotic and cardiac disease, including hypertension, diabetes mellitus, tobacco use, high cholesterol, and a history of coronary artery disease, coronary artery bypass, or atrial fibrillation (see Etiology). Consider stroke in any patient presenting with acute neurologic deficit or any alteration in level of consciousness. Common signs of stroke include the following:

Acute hemiparesis or hemiplegia Acute hemisensory loss Complete or partial hemianopia, monocular or binocular visual loss, or diplopia Dysarthria or aphasia Ataxia, vertigo, or nystagmus Sudden decrease in consciousness In younger patients, elicit a history of recent trauma, coagulopathies, illicit drug use (especially cocaine), migraines, or use of oral contraceptives. Establishing the time at which the patient was last without stroke symptoms is especially critical when thrombolytic therapy is an option. 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. 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 include detecting extracranial causes of stroke symptoms, distinguishing stroke from stroke mimics, determining and documenting for future comparison the degree of deficit, and localizing the lesion. The physical examination always includes a careful head and neck examination for signs of trauma, infection, and meningeal irritation. 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 change in level of consciousness are more common in hemorrhagic strokes. Common symptoms of stroke include the following:

Abrupt onset of hemiparesis, monoparesis, or quadriparesis Hemisensory deficits Monocular or binocular visual loss Visual field deficits Diplopia Dysarthria Ataxia Vertigo Aphasia Sudden decrease in the level of consciousness Although such symptoms can occur alone, they are more likely to occur in combination. A careful search for the cardiovascular causes of stroke requires examination of the ocular fundi (retinopathy, emboli, hemorrhage), heart (irregular rhythm, murmur, gallop), and peripheral vasculature (palpation of carotid, radial, and femoral pulses, auscultation for carotid bruit). Patients with a decreased level of consciousness should be assessed to ensure that they are able to protect their airway. The physical examination must encompass all of the major organ systems, starting with the airway, breathing, and circulation (ABC) and the vital signs. Patients with stroke, especially hemorrhagic stroke, can clinically deteriorate quickly; 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. Acutely lowering blood pressure has not proven to be beneficial in these stroke patients in the absence of signs and symptoms of associated malignant hypertension, acute myocardial infarction, CHF, or aortic dissection.

Head and neck 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 examination 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 CHF; thus, auscultation for murmurs and gallops is recommended. Examination of the extremities 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 thrombolytic 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 by cranial computed tomography [CT] scanning) Distinguishing stroke from stroke mimics Establishing a neurologic baseline should the patient's condition improve or deteriorate Essential components of the neurologic examination include the evaluation of cranial nerves, motor function, sensory function, cerebellar function, gait, and deep tendon reflexes, as well as of mental status and level of consciousness. The skull and spine also should be examined, and signs of meningismus should be sought. Central facial weakness from a stroke should be differentiated from the peripheral weakness of Bell palsy. With peripheral lesions (Bell palsy), the patient is unable to lift the eyebrows, wrinkle the forehead, or or close the eye on the affected side. A useful tool in quantifying neurological impairment is the National Institutes of Health Stroke Scale (NIHSS). The NIHSS (see Table 2, below and the NIH Stroke Score calculator) is used mostly by stroke teams. It enables the consultant to rapidly determine the severity and possible location of the stroke. A patient's score on the NIHSS is strongly associated with outcome, and it can help to identify those patients who are likely to benefit from thrombolytic therapy and those who are at higher risk of developing hemorrhagic complications of thrombolytic use. This scale is easily used and 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, with minor strokes usually being considered to have a score less than 5. An NIHSS score greater than 10 correlates with an 80% likelihood of visual flow deficits on angiography. However, discretion must be used in assessing the magnitude of the clinical deficit; for instance, if a patient's only deficit is being mute, the NIHSS score will be 3. Additionally, the scale does not measure some deficits associated with posterior circulation strokes (ie, vertigo, ataxia).

Middle cerebral artery stroke MCA occlusion commonly produces contralateral hemiparesis, contralateral hypesthesia, ipsilateral hemianopsia, and gaze preference toward the side of the lesion. Agnosia is common, and receptive or expressive aphasia may result if the lesion occurs in the dominant hemisphere. Neglect, inattention, and extinction of double simultaneous stimulation may occur in nondominant hemisphere lesions. Since the MCA supplies the upper extremity motor strip, weakness of the arm and face is usually worse than that of the lower limb. Anterior cerebral artery stroke ACA occlusions primarily affect frontal lobe function and can result in disinhibition and speech perseveration, producing primitive reflexes (eg, grasping, sucking reflexes), altered mental status, impaired judgment, contralateral weakness (greater in legs than arms), contralateral cortical sensory deficits gait apraxia, and urinary incontinence. Posterior cerebral artery stroke PCA occlusions affect vision and thought, producing contralateral homonymous hemianopsia, cortical blindness, visual agnosia, altered mental status, and impaired memory. Vertebrobasilar artery occlusions are notoriously difficult to detect because they 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 that there are crossed findings: ipsilateral cranial nerve deficits and contralateral motor deficits. This is contrasted to 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. Treatment Thrombolytic Therapy Thrombolytics restore cerebral blood flow among some patients with acute ischemic stroke and may lead to improvement or resolution of neurologic deficits. Unfortunately, thrombolytics can also cause symptomatic intracranial hemorrhage, defined as radiographic evidence of hemorrhage combined with escalation of the NIHSS score by 4 or more points (see the NIH Stroke Score calculator). Therefore, if the patient is a candidate for thrombolytic therapy, a thorough review of the inclusion and exclusion criteria must be performed. The exclusion criteria largely focus on identifying risk of hemorrhagic complication associated with thrombolytic use. While streptokinase and rt-PA have been shown to benefit patients with acute MI, only alteplase (rt-PA) has been shown to benefit selected patients with acute ischemic stroke. In May 2009, the American Heart Association/American Stroke Association (AHA/ASA) guidelines for the administration of rt-PA following acute stroke were revised to expand the window of treatment from 3 hours to 4.5 hours to provide more patients with an opportunity to receive benefit from this effective therapy.[8, 9, 61] Eligibility criteria for treatment in the 34.5 hours after acute stroke are similar to those for treatment at earlier time periods, with any 1 of the following additional exclusion criteria:

Patients older than 80 years All patients taking oral anticoagulants are excluded regardless of the international normalized ratio (INR) Patients with baseline NIHSS greater than 25 Patients with a history of stroke and diabetes Caution should be exercised in the administration of rt-PA to patients with major deficits. Patients with evidence of low attenuation (edema or ischemia) involving more than a third of the distribution of the MCA on their initial NCCT scan are less likely to have favorable outcome after thrombolytic therapy and are thought to be at higher risk for hemorrhagic transformation of their ischemic stroke.[36] In addition to the risk of symptomatic intracranial hemorrhage (6.4% in the NINDS trial), other complications include potentially hemodynamically significant hemorrhage and angioedema or allergic reactions.[22] Streptokinase has not been shown to benefit patients with acute ischemic stroke, but it has been shown to increase their risk of intracranial hemorrhage and death. Researchers have studied the use of transcranial ultrasound as a means of assisting rt-PA in thrombolysis. By delivering mechanical pressure waves to the thrombus, ultrasound can theoretically expose more of its surface to the circulating thrombolytic agent. Further research is necessary to determine the exact role of transcranial Doppler ultrasound in assisting thrombolytics in acute ischemic stroke. No human trials comparing the IV versus intra-arterial administration of thrombolytics exist. Theoretic advantages to intra-arterial delivery may include the possibility that higher local concentrations of thrombolytic would allow lower total doses of the agent (and theoretically less risk of systemic bleed) and a longer therapeutic window; however, the longer time to administration via the intra-arterial approach versus the IV approach may mitigate some of this advantage.

For more information, see Thrombolytic Therapy. For more information, see Reperfusion Injury in Stroke. Antiplatelet Agents 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 20,000 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 early stroke recurrence.[3, 4] CAST evaluated 21,106 patients and had a 4-week mortality reduction of 3.3% contrasted to 3.9%. A separate study also found that the combination of aspirin and lowmolecular-weight heparin did not significantly improve outcomes.[3] The early initiation of aspirin plus extended-release dipyridamole is likely to be as safe and effective in preventing disability as is later initiation after 7 days following stroke onset, according to a German study. The studys authors attempted to assess the precise time to initiate dipyridamole following ischemic stroke or TIA.[62] Patients from 46 stroke units who presented with an NIHSS score of 20 or less were randomly assigned to receive aspirin 25 mg plus extended-release dipyridamole 200 mg bid (early dipyridamole regimen) (n=283) or aspirin monotherapy (100 mg once daily) for 7 days (n=260). Therapy in either group was initiated within 24 hours of stroke onset. After 2 weeks, all patients received aspirin plus dipyridamole for up to 90 days. At day 90, 154 (56%) patients in the early dipyridamole group and 133 (52%) in the aspirin plus later dipyridamole group had no or mild disability (P = .45). Other antiplatelet agents are also under evaluation for use in the acute presentation of ischemic stroke. In a preliminary pilot study, abciximab was given within 6 hours to establish a safety profile. A trend toward improved outcome at 3 months for the treatment versus the placebo group was noted.[63] Further clinical trials are necessary. Neuroprotective Agents Despite very promising results in several animal studies, as of yet no single neuroprotective agent in ischemic stroke is supported by randomized, placebo-controlled human studies. Nevertheless, substantial research is underway evaluating different neuroprotective strategies, including hypothermia. For more information, see Neuroprotective Agents in Stroke. Mechanical Thrombolysis Studies have evaluated the efficacy of mechanical clot disruption in the setting of acute stroke. In most cases, these technologies were used in combination with thrombolysis. In an investigation by Berlis et al, mechanical disruption via an endovascular photoacoustic device was found to be more effective than thrombolysis alone in recanalization rates.[64] There are currently 2 FDA-approved devices for the endovascular treatment of acute ischemic stroke: the Concentric Retriever, which is mainly a grasping device, and the Penumbra device, which employs an aspiration function to remove clots.[65, 66, 67] The Penumbra trial demonstrated 82% recanalization in patients when using the aspiration function of the Penumbra device.

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.[68] In a second MERCI study, recanalization was achieved in 48% of those in which the device was deployed. Clot was successfully retrieved from all major cerebral arteries; however, the recanalization rate for the MCA was lowest. A further study of clot extraction, the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) study, identified a recanalization rate of 66%.[69, 70] 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 for whom t-PA was given in a group of patients with acute ischemic stroke presenting within 8 hours of onset of symptoms. Seventy-three percent of patients who failed IV t-PA therapy had recanalization following mechanical embolectomy.[71] However, based on these results, the FDA has cleared the use of the MERCI device in patients who are either ineligible for or who have failed IV thrombolytics. According to the 2011 AHA/ASA statement on CVT, evidence is insufficient to draw conclusions about the value of endovascular thrombolysis in patients with CVT. For that reason, the statement recommends this therapy only in patients with progressive neurological deterioration that persists despite medical treatment.[44] For more information, see Mechanical Thrombolysis in Acute Stroke. For more information, see Cerebral Revascularization. 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 I clinical trials.[72, 73, 74] High body temperature in the first 12-24 hours after stroke onset has been associated with poor functional outcome. Results from the Paracetamol (Acetaminophen) In Stroke (PAIS) trial did not support the routine use of high-dose acetaminophen in patients with acute stroke. The study assessed whether early treatment with paracetamol improves functional outcome in patients with acute stroke by reducing body temperature and preventing fever. Patients (n=1400) were randomly assigned to receive acetaminophen (6 g daily) or placebo within 12 hours of symptom onset. After 3 months, improvement on the modified Rankin scale was not beyond what was expected.[75] 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 NCCT scans are independent indicators of potential swelling and deterioration. Mannitol and other therapies to reduce 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.[22]

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 shown to decrease mortality and disability among patients with large hemispheric infarctions associated with life-threatening edema.[76, 77, 78, 79] Seizure Control Seizures occur in 2-23% of patients within the first days after stroke. Although seizure prophylaxis is not indicated, prevention of subsequent seizures with standard antiepileptic therapy is recommended.[22] The 2011 AHA/ASA CVT statement notes a lack of clinical trials on the use of anticonvulsants to control seizures, which occur in 37% of adults, 48% of children, and 71% of newborns who present with CVT. Therefore, opinions on their use vary greatly. However, because seizures increase the risk of anoxic damage, anticonvulsant treatment after even a single seizure is reasonable.[44] Post-ischemia strokes are usually focal, but they may be generalized. A fraction of patients who have experienced stroke develop chronic seizure disorders. Seizures secondary to ischemic stroke should be managed in the same manner as other seizure disorders that arise as a result of neurologic injury.[22] Acute Decompensation or Escalation In the case of the rapidly decompensating patient or the patient with deteriorating neurologic status, reassessment of 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. Some advocate resetting the time window to zero in this circumstance and encourage consideration of reperfusion strategies. Anticoagulation and Prophylaxis Heparin is known to prolong the lytic state caused by t-PA. Currently, data are inadequate to justify the utilization of heparin or other anticoagulants in the acute management of patients with ischemic stroke. Patients with embolic stroke who have another indication for anticoagulation (eg, atrial fibrillation) may be placed on anticoagulation therapy with the goal of preventing further embolic disease; however, the potential beneficial effects from that decision must be weighted against the risk of hemorrhagic transformation.[22] Immobilized stroke patients who are not receiving anticoagulants, such as IV heparin or an oral anticoagulant, may benefit from the administration of low-dose, subcutaneous unfractionated or lowmolecular-weight heparin, which reduces the risk of deep venous thrombosis.[22] For more information, see Stroke Anticoagulation and Prophylaxis. Induced Hypothermia Hypothermia is fast becoming the standard of care for the ongoing treatment of patients surviving cardiac arrest due to ventricular tachycardia or ventricular fibrillation. However, no major clinical study has demonstrated a role for hypothermia in the early treatment of ischemic stroke.[22] Carotid Endarterectomy

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 in acute stroke. Stroke Prevention Primary prevention refers to the treatment of individuals with no previous history of stroke. Measures may include the use of platelet antiaggregants; 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (ie, statins); and exercise. In February 2011, AHA/ASA guidelines for the primary prevention of stroke were published. The guideline emphasizes 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.[80] Secondary prevention refers to the treatment of individuals who have already had a stroke. Measures may include the use of platelet antiaggregants, antihypertensives, HMG-CoA reductase inhibitors (statins), and lifestyle interventions. 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. Written prescriptions for exercise and medications for smoking cessation (nicotine patch, bupropion, varenicline) increase the likelihood of success with these interventions. In addition to these well-documented factors, 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. The use of aspirin for primary stroke prevention is not recommended for persons at low risk. Aspirin is recommended for this purpose only in persons with at least a 6-10% risk of cardiovascular events over 10 years.[80] For patients with stroke risk due to 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 due to improvements in medical therapies. Therefore, individual patient comorbidities, life expectancy, and preferences should determine whether medical treatment alone or carotid revascularization is selected.[80] Atrial fibrillation is a major risk factor for stroke. The 2011 ACC Foundation (ACCF)/AHA/Heart Rhythm Society (HRS) atrial fibrillation guideline update on dabigatran states that the new anticoagulant dabigatran is useful as an alternative to warfarin in patients with atrial fibrillation who do not have a prosthetic heart valve or hemodynamically significant valve disease.[81] The 2011 AHA/ASA primary stroke prevention guideline recommends that EDs screen for AF and assess patients for anticoagulation therapy if AF is found.[80] For patients with atrial fibrillation after stroke or TIA, the 2010 AHA/ASA secondary stroke prevention guideline is 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 atrial fibrillation has not been established.[82]

The 2011 AHA/ASA guideline recommends ED-based smoking cessation interventions, and considers it reasonable for EDs to screen patients for hypertension and drug abuse.[80] Specialized Stroke Centers Given the multitude of factors that go into the care of a patient with acute stroke, the concept of the specialized stroke center has evolved. The Brain Attack Coalition provided recommendations for the establishment of 2 tiers of stroke centers: primary stroke centers (PSCs) and comprehensive stroke centers (CSCs).[22] The Joint Commission for the Accreditation of Hospital Organizations (JCAHO) now provides accreditation for PSC, and efforts to establish the requirements that distinguish CSC are currently ongoing. The PSC is designed to maximize the timely provision of stroke-specific therapy, including the administration of rt-PA, and is also capable of providing care to patients with uncomplicated stroke. The 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 and all patients with stroke requiring ICU level of care.[22] Once patients have been identified as potential stroke patients, their ED evaluation must be fast-tracked to allow for the completion of required laboratory tests and requisite noncontrast head CT scanning, as well as the notification and involvement of neurologic consultation. These requirements have led to the development of "stroke codes" or "stroke activations" in which EMS crews have been trained to identify possible stroke patients and arrange for their speedy, preferential transport to a PSC or CSC. Additionally, Stroke Centers should have personnel versed at monitoring stroke vital signs, which include the following:

Blood pressure Glucose levels Temperature Oxygenation Change in neurologic status Hospitals with specialized stroke teams have demonstrated significantly increased rates of thrombolytic 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 systems-based team approach requiring the cooperation of the ED, radiology, pharmacy, neurology, and 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, transport, treatment, and rehabilitation of stroke patients. For more information, see Stroke Team Creation and Primary Stroke Center Certification. 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 the most humane and appropriate therapeutic concern is the comfort of the patient. Some patients have advanced directives providing instructions for medical providers in the event of severe medical illness or injury. Consultations

Consultations are tailored to individual patient needs. An experienced professional who is sufficiently familiar with stroke or a stroke team should be available within 15 minutes of the patient's arrival in the ED. Often, occupational therapy, physical therapy, speech therapy, and physical medicine and rehabilitation experts are consulted within the first day of hospitalization. Consultation of cardiology and 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

Hemorrhagic Stroke 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 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] 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 Osler-Weber-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 EhlersDanlos vascular type from other forms of Ehlers-Danlos. Ehlers-Danlos vascular type is caused by mutations in the COL3A1 gene; it is inherited in an autosomal dominant manner. 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, 9, 17] (For more information, 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. 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. 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. 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 (ATACHII) 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 off-label 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 largevolume 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. 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 fourth-ventricle 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.