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. The cerebral vasculature is seen in the images below. The images after Table 1 demonstrate cerebral artery infarction.

Table 1. Vascular Supply to the Brain (Open Table in a new window)

VASCULAR TERRITORY Anterior Circulation (Carotid) Anterior Cerebral Artery Structures Supplied

Cortical branches: medial frontal and parietal lobe

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

Middle Cerebral Artery

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

Lateral lenticulostriate branches: globus pallidus and putamen, internal capsule

Anterior Choroidal Artery Posterior Circulation (Vertebrobasilar) Posterior Cerebral Artery

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

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

Perforating branches: brainstem, posterior thalamus and midbrain

Posterior Inferior Cerebellar Artery Anterior Inferior Cerebellar Artery Superior Cerebellar Artery

Inferior vermis; posterior and inferior cerebellar hemispheres Anterolateral cerebellum Superior vermis; superior cerebellum

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 well-circumscribed 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.

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 In a prospective study of 27,860 women aged 45 years or older who were participating in the Women's Health Study, Kurth et al found that migraine with aura was a strong risk factor for any type of stroke.[23] The adjusted incidence of this risk factor per 1000 women per year was similar to those of other known risk factors, including systolic blood pressure 180 mm Hg or higher, body mass index 35 kg/m2 or greater, history of diabetes, family history of myocardial infarction, and smoking.[23] For migraine with aura, the total incidence of stroke in the study was 4.3 per 1000 women per year, the incidence of ischemic stroke was 3.4 per 1000 per year, and the incidence of hemorrhagic stroke was 0.8 per 1000 per year. Modifiable risk factors for ischemic stroke 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.[24] 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.[25, 26] Antipsychotic medications An analysis of 14,584 stroke patients who had at least 1 antipsychotic

prescription during the year before their first hospitalization for stroke indicated that in the first few weeks of use, antipsychotics are associated with an increased stroke risk. Dosage size, older age and/or the presence of dementia, and the use of antipsychotics with a high binding affinity for alpha-2-adrenergic and M1-muscarinic receptors contributed to the stroke risk.[27] According to the investigators, the stroke risk in persons taking antipsychotic medications was 1.6-fold higher in the 2 weeks before the stroke occurred. However, this association was observed only in the initial 28 days of antipsychotic use, after which the drugs were no longer a contributing factor in stroke. 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. For more information, see Genetic and Inflammatory Mechanisms in Stroke. In addition, complete information on the following metabolic disease and stroke can be found in the main articles: Metabolic Disease and Stroke - Methylmalonic Acidemia Metabolic Disease and Stroke - Homocystinuria/Homocysteinemia Metabolic Disease and Stroke - Fabry Disease Metabolic Disease and Stroke MELAS Metabolic Disease and Stroke - Hyperglycemia/Hypoglycemia 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.

For more information, see Blood Dyscrasias and Stroke. Large-artery occlusion Large-artery occlusion typically results from embolization of atherosclerotic debris originating from the common or internal carotid arteries or from a cardiac source. A smaller number of large-artery occlusions may arise from plaque ulceration and in situ thrombosis. Large-vessel ischemic strokes more commonly affect the MCA territory with the ACA territory affected to a lesser degree. (See the images below.)

Noncontrast CT in this 52-year-old male with a history of worsening right-sided weakness and aphasia demonstrates diffuse hypodensity and sulcal effacement involving the left anterior and middle cerebral artery territories consistent with acute infarction. There are scattered curvilinear areas of hyperdensity noted suggestive of developing petechial hemorrhage in this large area of infarction.

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. (See the image below.) 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.[28] 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 smallFor more information, see Cardioembolic Stroke. 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[31, 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

The most frequent stroke mimics include the following: Seizure (17%) Systemic infection (17%) Brain tumor (15%) Toxic-metabolic cause, such as hyponatremia and hypoglycemia (13%) Positional vertigo (6%).

Approach Considerations
Laboratory evaluation of the patient with ischemic stroke should be driven by comorbid illnesses as well as the potential acute stroke. Additional laboratory tests are tailored to the individual patient. They may include rapid plasma reagent (RPR), toxicology screen, fasting lipid profile, sedimentation rate, pregnancy test, antinuclear antibody (ANA), rheumatoid factor, and homocysteine. CT is the most commonly used form of neuroimaging in the acute evaluation of patients with apparent acute stroke. MRI with magnetic resonance angiography (MRA) has been a major advance in the neuroimaging of stroke; MRI not only provides great structural detail but also can demonstrate impaired metabolism. Carotid duplex scanning is one of the most useful tests in evaluating patients with stroke. Increasingly, it is being performed earlier in the evaluation, not only to define the cause of the stroke but also to stratify patients for either medical management or carotid intervention if they have carotid stenoses. Digital subtraction angiography is considered the definitive method for demonstrating vascular lesions, including occlusions, stenoses, dissections, and aneurysms.

Complete Blood Cell Count

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

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. In patients who are not anticoagulated and in whom there is no suspicion for coagulation abnormality, administration of recombinant tissue-type plasminogen activator (rt-PA) should not be delayed awaiting laboratory studies.

Cardiac Biomarkers
Cardiac biomarkers are important because of the association of cerebral vascular disease and coronary artery disease. Additionally, several studies have indicated a link between elevations of cardiac enzyme levels and poor outcome in ischemic stroke.

Toxicology Screening
Toxicology screening may be useful in selected patients in order to assist in identifying intoxicated patients with symptoms/behavior mimicking stroke syndromes. Urine pregnancy test should be obtained for all women of childbearing age with stroke symptoms. The agent rtPA is Pregnancy Class C.

Arterial Blood Gas Analysis

Although infrequent in patients with suspected hypoxemia, arterial blood gas defines the severity of hypoxemia and may detect acid-base disturbances. If considering thrombolytics, arterial punctures should be avoided unless absolutely necessary.

Imaging in Stroke
Imaging in ischemic stroke can involve several types of MRI, several types of CT scanning, angiography, ultrasonography, radiology, echocardiography, and nuclear imaging studies.

Approach Considerations
Physician and nursing staff involved in the care of patients who have had a stroke, in the ED and in the hospital, should participate in scheduled stroke education. This will help them to maintain the skills required to treat stroke patients effectively and to remain current on medical advances for all stroke types.

Establishing the time at which stroke symptoms first occurred is of paramount importance when considering patients for possible thrombolytic therapy. An essential question is, "When was the patient last seen to be normal?" It is advisable for emergency clinicians to rapidly enlist the assistance of family members or relatives to establish time of symptom onset and to identify other pertinent components of the patient's presentation history. The central goal of therapy in acute ischemic stroke is to preserve the area of oligemia in the ischemic penumbra. The area of oligemia can be preserved by limiting the severity of ischemic injury (ie, neuronal protection) or by reducing the duration of ischemia (ie, restoring blood flow to the compromised area). Recanalization strategies, including IV recombinant tissue-type plasminogen activator (rt-PA) and intra-arterial approaches, attempt to establish revascularization so that cells in the penumbra can be rescued before irreversible injury occurs. Restoring blood flow can mitigate the effects of ischemia only if performed quickly. Neuroprotective strategies are intended to preserve the penumbral tissues and to extend the time window for revascularization techniques; however, at the present time, no neuroprotective agents are available and approved for use in ischemic stroke. The ischemic cascade offers many points at which such interventions could be attempted. Multiple strategies and interventions for blocking this cascade are currently under investigation. The timing of the restoration of cerebral blood flow appears to be a critical factor. Time may also prove to be a key factor in neuronal protection. It is expected that neuroprotective agents, which block the earliest stages of the ischemic cascade (eg, glutamate receptor antagonists, calcium channel blockers), will be effective only in the proximal phases of presentation. 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.[27, 3] A registry study involving 58,353 patients with acute ischemic stroke who underwent t-PA treatment within 4.5 hours of symptom onset confirmed that earlier treatment yielded better outcomes.[57, 58] For every 1000 patients, the investigators found that with each 15-minute reduction in time to therapy, an additional 18 patients had improved

ambulation at discharge, an additional 13 patients were discharged to a more independent environment, and an additional 4 patients survived to discharge.

Acute Management of Stroke

The goal for the acute management of patients with stroke is to stabilize the patient and to complete initial evaluation and assessment, including imaging and laboratory studies within 60 minutes of patient arrival.[22] A Finnish study demonstrated that time to treatment with thrombolytics can be decreased with changes in EMS and ED coordination and in ED procedures for treating acute stroke patients.[63] Critical decisions focus on blood pressure control, the need for intubation, and determination of risk-to-benefit profile for thrombolytic intervention. Referral to a physician with a special interest in stroke is ideal. Stroke care units exist and improve outcomes with specially trained personnel. Comorbid medical problems need to be addressed. Hypoglycemia and hyperglycemia need to be identified and treated early in the evaluation. Hyperthermia is infrequently associated with stroke but can increase morbidity. Administration of acetaminophen, by mouth or per rectum, is indicated in the presence of fever (temperature >100.4F). Supplemental oxygen is recommended when the patient has a documented oxygen requirement. In the small proportion of patients with stroke who are relatively hypotensive, pharmacologically increasing blood pressure may improve flow through critical stenoses. An area of continued interest in acute stroke is glucose management. A Cochrane review found that the use of intravenous insulin to maintain serum glucose within the first few hours of ischemic stroke did not improve functional outcome, death, or final neurological deficit and significantly increased the risk of hypoglycemia.[64] The 2011 AHA/ASA statement on CVT notes that appropriate acute therapy should focus on preventing complications and anticoagulation therapy. The recommended tests were MRI and MR venography (MRV) because they are the most sensitive. Blood workup should be performed later based on the underlying causes.[46]

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, 65] Eligibility criteria for treatment in the 3-4.5 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.[38] 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.

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.[66] 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.[67] 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.[68] 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.[69, 70, 71] 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.[72] 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%.[73, 74] 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.[75] 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.[46]

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.[76, 77, 78] 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.[79]

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.[80, 81, 82, 83]

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.[46]

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] .

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 low molecular-weight heparin, which reduces the risk of deep venous thrombosis.[22] For more information, see Stroke Anticoagulation and Prophylaxis.

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.[84] 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.[84] 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.[84] 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.[85] The 2011 AHA/ASA primary stroke prevention guideline recommends that EDs screen for AF and assess patients for anticoagulation therapy if AF is found.[84] 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.[86]

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.[84] Periprocedural use of antithrombotic medications In May 2013, the American Academy of Neurology issued guidelines on the periprocedural management of antithrombotic medications in patients with ischemic cerebrovascular disease.[87, 88] The guidelines list all the procedures for which there are data on stopping or continuing aspirin or warfarin and give recommendations. Key recommendations include the following: Stroke patients who are undergoing dental procedures should continue aspirin Stroke patients who are undergoing invasive ocular anesthesia, cataract surgery, dermatologic procedures, spinal/epidural procedures, transrectal ultrasound-guided prostate biopsy, or carpal tunnel surgery should probably continue aspirin Stroke patients receiving warfarin should routinely continue treatment when undergoing dental procedures and should probably continue treatment during dermatologic procedures Neurologists should counsel patients that bridging therapy is probably associated with increased bleeding risks, as compared with stopping warfarin; the risks compared with continuing warfarin are unknown