Ischemic Stroke in Emergency Medicine 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.

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 subtype.

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.

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. [3] The trial’s 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.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. 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.

Axial noncontrast computed tomography (NCCT) demonstrates diffuse hypodensity in the right lentiform nucleus with mass effect upon the frontal horn of the right lateral ventricle in this 70-year-old female with history of left-sided weakness for several hours duration.

Magnetic Resonance Imaging (MRI) was subsequently obtained in the same patient as in the above image. An axial T2 FLAIR image (left) demonstrates high signal in the lentiform nucleus with mass effect. The axial diffusion weighted image (middle) demonstrates high signal in the same area with corresponding low signal on the apparent diffusion coefficient (ADC) maps, consistent with true restricted diffusion and an acute infarction. Maximum intensity projection from a 3D time-of-flight magnetic resonance angiogram (MRA, right) demonstrates occlusion of the distal middle cerebral artery (MCA) trunk (red circle).

Anatomy

The brain is the most metabolically active organ in the body. While representing only 2% of the body's mass, it requires 15-20% of the total resting cardiac output to provide the necessary glucose and oxygen for its metabolism.

Knowledge of cerebrovascular arterial anatomy and the territories supplied by 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.

Frontal view of a cerebral angiogram with selective injection of the left internal carotid artery illustrates the anterior circulation. The anterior cerebral artery consists of the A1 segment proximal to the anterior communicating artery with the A2 segment distal to it. The MCA can be divided into 4 segments: the M1 (horizontal segment) extends to the limen insulae and gives off lateral lenticulostriate branches, the M2 (insular segment), M3 (opercular branches) and M4 (distal cortical branches on the lateral hemispheric

convexities).

Lateral view of a cerebral angiogram illustrates the branches of the anterior cerebral artery and Sylvian triangle. The pericallosal artery has been described to arise distal to the anterior communicating artery or distal to the origin of the callosomarginal branch of the ACA. The segmental anatomy of the ACA has been described as follows: the A1 segment extends from the ICA bifurcation to the anterior communicating artery; A2 extends to the junction of the rostrum and genu of the corpus callosum; A3 extends into the bend of the genu of the corpus callosum; A4 and A5 extend posteriorly above the callosal body and superior portion of the splenium. The Sylvian triangle overlies the opercular branches of the MCA with the apex representing the Sylvian point.

Table 1. Vascular Supply to the Brain

VASCULAR TERRITORY Structures Supplied

Anterior Circulation (Carotid)

Anterior Cerebral Artery Cortical branches: medial frontal and parietal lobe

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

Middle Cerebral Artery Cortical branches: lateral frontal and parietal lobes lateral and anterior temporal lobe

Lateral lenticulostriate branches: globus pallidus and putamen, internal capsule

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

Posterior Circulation (Vertebrobasilar)

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

Perforating branches: brainstem, posterior thalamus and midbrain

Posterior Inferior Cerebellar Artery

Inferior vermis; posterior and inferior cerebellar hemispheres

Anterior Inferior Cerebellar Artery

Anterolateral cerebellum

Superior Cerebellar Artery Superior vermis; superior cerebellum

The supratentorial vascular territories of the major cerebral arteries are demonstrated superimposed on axial (left) and coronal (right) T2-weighted images through the level of the basal ganglia and thalami. The MCA (red) supplies the lateral aspects of the hemispheres, including the lateral frontal, parietal and anterior temporal lobes, insula and basal ganglia. The ACA (blue) supplies the medial frontal and parietal lobes. The PCA (green) supplies the thalami and occipital and inferior temporal lobes. The anterior choroidal artery (yellow) supplies the posterior limb of the internal capsule and part of the hippocampus extending to the anterior and superior surface of the occipital horn of the lateral ventricle.

Vascular distributions: MCA infarction. Noncontrast CT demonstrates a large acute infarction in the MCA territory involving the lateral surfaces of the left frontal, parietal, and temporal lobes, as well as the left insular and subinsular regions, with mass effect and rightward midline shift. There is sparing of the caudate head and at least part of the lentiform nucleus and internal capsule, which receive blood supply from the lateral lenticulostriate branches of the M1 segment of the MCA. Note the lack of involvement of the medial frontal lobe (ACA territory), thalami and paramedian occipital lobe (PCA territory).

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.

Vascular distributions: PCA infarction. The noncontrast CT images demonstrate PCA distribution infarction involving the right occipital and inferomedial temporal lobes. The image on the right demonstrates additional involvement of the thalamus, also part of the PCA territory.

Vascular distributions: anterior choroidal artery infarction. The diffusion-weighted image (left) demonstrates high signal with associated signal dropout on the apparent diffusion coefficient (ADC) map involving the posterior limb of the internal capsule. This is the typical distribution of the anterior choroidal artery, the last branch of the internal carotid artery before bifurcating into the anterior and middle cerebral arteries. The anterior choroidal artery may also arise from the MCA.

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.

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.[9]

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 barrier’s 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.[10, 11]

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.[9] 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 fluid–like 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.[6, 12, 13]

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.[6, 14, 3] Hemorrhagic transformation is also more likely following administration of t-PA, with noncontrast computed tomography (NCCT) scanning demonstrating areas of hypodensity.

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%).[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.

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.

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.

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.

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.

MRA in the same patient as in the above image (left) demonstrates occlusion of the left precavernous supraclinoid internal carotid artery (ICA, red circle), occlusion or high-grade stenosis of the distal MCA trunk and attenuation of multiple M2 branches. The diffusion-weighted image (right) demonstrates high signal confirmed to be true restricted diffusion on the ADC map consistent with acute infarction.

MIP image from a CTA demonstrates a filling defect or high-grade stenosis at the branching point of the right MCA trunk (red circle), suspicious for thrombus or embolus. CTA is highly accurate in detecting large vessel stenosis and occlusions, which account for approximately one third of ischemic strokes.

Lacunar strokes

Lacunar strokes represent 13-20% of all ischemic strokes. They 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.)

Axial noncontrast CT demonstrates a focal area of hypodensity in the left posterior limb of the internal capsule in this 60-year-old male with new onset of right-sided weakness. The lesion demonstrates high signal on the FLAIR sequence (middle image) and diffusion-weighted MRI (right image), with low signal on the ADC maps indicating an acute lacunar infarction. Lacunar infarcts are typically no more than 1.5 cm in size and can occur in the deep gray matter structures, corona radiata, brainstem and cerebellum.

Causes of lacunar infarcts include the following:

Microatheroma Lipohyalinosis

Fibrinoid necrosis secondary to hypertension or vasculitis

Hyaline arteriosclerosis

Amyloid angiopathy

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.[22] 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. [23, 24] (See the image below.)

Cardioembolic stroke: Axial diffusion-weighted images demonstrate scattered foci of high signal in the subcortical and deep white matter bilaterally in a patient with a known cardiac source for embolization. An area of low signal in the left gangliocapsular region may be secondary to prior hemorrhage or subacute to chronic lacunar infarct. Recurrent strokes are most commonly secondary to cardioembolic phenomenon.

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

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.

MRI was obtained to evaluate this 62-year-old hypertensive and diabetic male with a history of transient episodes of right-sided weakness and aphasia. The FLAIR image (left) demonstrates patchy areas of high signal arranged in a linear fashion in the deep white matter, bilaterally. This configuration is typical for deep border-zone or watershed infarction, in this case the anterior and posterior MCA watershed areas. The left sided infarcts have corresponding low signal on the ADC map (right), signifying acuity. An old left posterior parietal infarct is noted as well have experienced stroke develop chronic seizure disorders.

Epidemiology

Stroke is the leading cause of disability and the third leading cause of death in the United States. 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.

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.

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. Risk of stroke increases with age, especially in patients older than 64 years, Prognosis

The prognosis after acute ischemic stroke varies greatly, depending on the stroke severity and on the patient’s premorbid condition, age, and poststroke complications.

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.

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. [34, 35, 36] in whom 75% of all strokes occur.

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) 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).[37]

Table 2. NIH Stroke Scale (Open Table in a new window)

Category Description Score

1a level of consciousness (LOC) Alert

Drowsy

Stuporous

Coma

0

1

2

3

1b LOC questions (month, age) Answers both correctly

Answers 1 correctly

0

1

Incorrect on both 2

1c Answers both correctly Answers 1 correctly Incorrect on both Obeys both correctly

Obeys 1 correctly

Incorrect on both

0

1

2

2 Best gaze (follow finger) Normal

Partial gaze palsy

Forced deviation

0

1

2

3 Best visual (visual fields) No visual loss

Partial hemianopia

Complete hemianopia

Bilateral hemianopia

0

1

2

3

4 Facial palsy (show teeth, raise brows, squeeze eyes shut) Normal Minor

Partial Complete

0

1

2

3

5 Motor arm left* (raise 90°, hold 10 seconds) No drift

Drift

Cannot resist gravity

No effort against gravity

No movement

0

1

2

3

4

6 Motor arm right* (raise 90°, hold 10 seconds) No drift

Drift

Cannot resist gravity

No effort against gravity

0

1

2

3

No movement 4

7 Motor leg left* (raise 30°, hold 5 seconds) No drift

Drift

Cannot resist gravity

No effort against gravity

No movement

0

1

2

3

4

8 Motor leg right* (raise 30°, hold 5 seconds) No drift

Drift

Cannot resist gravity

No effort against gravity

No movement

0

1

2

3

4

9 Limb ataxia (finger-nose, heel-shin) Absent

Present in 1 limb

Present in 2 limbs

0

1

2

10 Sensory (pinprick to face, arm, leg) Normal

Partial loss

Severe loss

0

1

2

11 Extinction/neglect (double simultaneous testing) No neglect

Partial neglect

Complete neglect

0

1

2

12 Dysarthria (speech clarity to "mama, baseball, huckleberry, tip-top, fifty-fifty")

Normal articulation

Mild to moderate dysarthria

Near to unintelligible or worse

0

1

2

13 Best language** (name items, describe pictures) No aphasia

Mild to moderate aphasia

Severe aphasia

Mute

0

1

2

3

Total - 0-42

* For limbs with amputation, joint fusion, etc, score 9 and explain.

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

Middle cerebral artery stroke

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.

Diagnostic Considerations

Stroke mimics commonly confound the clinical diagnosis of stroke. One study reported that 19% of patients diagnosed with acute ischemic stroke by neurologists before cranial CT scanning actually had noncerebrovascular causes for their symptoms.

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%).

A critical masquerading metabolic derangement not to be missed by providers is hypoglycemia.

Diagnosis and management of a rare form of stroke, cerebral venous thrombosis (CVT), was the subject of a 2011 AHA/ASA statement for healthcare professionals. According to the statement, diagnosing CVT requires a high degree of clinical suspicion. Most people diagnosed with CVT present with headache, often of increasing severity, usually but not always accompanied by focal neurological signs.[40]

Differentials Acute Coronary Syndrome Atrial Fibrillation

Bell Palsy

Benign Positional Vertigo

Brain Abscess

Epidural Hematoma

Hemorrhagic Stroke in Emergency Medicine

Inner Ear Labyrinthitis

Myocardial Infarction

Neoplasms, Brain

Subarachnoid Hemorrhage

Syncope

Transient Ischemic Attack

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 rt-PA 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.

Magnetic resonance imaging

Conventional MRI may take hours to produce discernable findings, well after the diffusion-weighted images have become positive. For this reason, many centers always include diffusion-weighted images in their standard brain MRI protocol. Diffusion-weighted MRI can detect ischemia much earlier than can standard CT scanning or MRI and provides useful data in stroke and TIA patients outside of the initial management window.[18, 41, 42] The most commonly used technique for perfusion MRI is dynamic susceptibility, which involves generating maps of brain perfusion by monitoring the first pass of a rapid bolus injection of contrast through the cerebral vasculature. Susceptibility-related T2 effects create signal loss in capillary blood vessels and

parenchyma perfused by contrast that can be measured and is proportional to the CBV. (See the image below.)

Regions of interest are selected for arterial and venous input (image on left) for dynamic susceptibility-weighted perfusion MRI. Signal-time curves (image on right) obtained from these ROI demonstrate transient signal drop following the administration of IV contrast. The information obtained from the dynamic parenchymal signal changes postcontrast is used to generate maps of different perfusion parameters.

An evidence-based guideline from the American Academy of Neurology recommends that diffusion-weighted imaging (DWI) is more useful than noncontrast CT for the diagnosis of acute ischemic stroke within 12 hours of symptom onset and should be performed for the most accurate diagnosis of acute ischemic stroke (level A). No recommendations were made regarding the use of perfusion-weighted imaging (PWI) in diagnosing acute ischemic stroke, as evidence to support or refute its value in this setting is insufficient.

Intra-arterial contrast enhancement may be seen secondary to slow flow during the first or second day after onset of infarction and has been correlated with increased infarct volume size.[44]

The 3 different techniques used to produce MRA images are 3-dimensional time of flight (3D TOF), phase-contrast (PC), and contrast-enhanced MRA (CEMRA). Three-dimensional TOF takes advantage of the higher signal from protons in flowing blood, compared with protons in stationary tissue, which become partially saturated and lose signal when exposed to a radiofrequency (RF) pulse. Areas of signal loss and narrowing correspond to stenosis and occlusions. PC involves tagging the spins of moving protons using bidirectional gradients and marking their changes in position when each gradient is applied. PC is exquisitely sensitive to flow, which the operator can choose the velocity threshold for, and gives excellent background suppression. CEMRA utilizes the intraluminal signal produced by a timed bolus of paramagnetic contrast material to evaluate vessel patency. Images may be single phase (i.e. arterial) or time resolved.

CT scanning

Imaging with computed tomography (CT) scanning has multiple logistic advantages for patients with acute stroke. CT scanning is able to more rapidly acquire images than MRI, allowing for assessment with an examination that includes noncontrast CT scanning, CT angiography, CT perfusion scanning in less than 10 minutes. Expedient acquisition is of the utmost importance in acute stroke imaging because of the narrow window of time available for definitive ischemic stroke treatment with pharmacologic agents and mechanical devices. CT scanning can also be performed in patients who are unable to tolerate an MR examination or who have contraindications to MRI, including pacemakers, aneurysm clips, or other ferromagnetic

materials in their bodies. Additionally, CT scanning is more easily accessible for patients who require special equipment for maintaining and monitoring life support.

The 2011 AHA/ASA CVT statement notes that MRI is more sensitive for the detection of CVT than CT. However, these modalities do not always accurately reveals positive findings of intraluminal thrombus, which is key to the diagnosis of CVT. Therefore, although a plain CT or MRI is useful in the initial evaluation, a negative finding should not rule out CVT.

Other imaging studies in ischemic stroke

Transcranial Doppler ultrasonography is useful for evaluating more proximal vascular anatomy through the infratemporal fossa, including the MCA, intracranial carotid artery, and vertebrobasilar artery.

Echocardiography is obtained in all patients with acute ischemic stroke in whom cardiogenic embolism is suspected.

Chest radiography has potential utility for patients with acute stroke. However, obtaining a chest radiograph should not delay the administration of recombinant tissue-type plasminogen activator (rt-PA); these radiographs have not been shown to alter the clinical course or decision-making in most cases.

The use of SPECT scanning in stroke is still relatively experimental and available only at select institutions; it can theoretically define areas of altered regional blood flow.

Conventional angiography is the gold standard in evaluating for cerebrovascular disease as well as for disease involving the aortic arch and great vessels in the neck; it also provides for less invasive endovascular interventions. Conventional angiography can be performed to clarify equivocal findings or to confirm and treat disease seen on MRA, CTA, transcranial Doppler or ultrasonography of the neck.

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.

Approach Considerations

Multiple factors contribute to delays in seeking care for symptoms of stroke. Many strokes occur while patients are sleeping (also known as "wake-up" stroke) and are not discovered until the patient wakes. Stroke can leave some patients too incapacitated to call for help. Occasionally, a stroke goes unrecognized by the patient or their caregivers.

The median time from symptom onset to ED presentation ranges from 4-24 hours in the United States. Prehospital care providers are essential to timely stroke care. Course curricula for prehospital care providers are beginning to include more information on stroke than ever before.

Through certification and ACLS instruction, as well as continuing medical education classes, prehospital care providers can remain current on stroke and promote stroke awareness in their own communities.

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.

Emergency Response and Transport

Recognition that a stroke may have occurred and rapid transport to the appropriate receiving facility are necessary after addressing the ABCs. Of patients with signs or symptoms of stroke, 29-65% utilize some facet of the emergency medical services (EMS) system. [50, 51] Furthermore, most patients who call EMS are those who present within 3 hours of symptom onset. EMS use is associated with shorter time periods from symptom onset to hospital arrival.[52, 53]

Stroke should be a priority dispatch with prompt EMS response. EMS responders should provide in as timely a manner as possible advance notice to their emergency department destination so as to allow preparation and marshaling of personnel and resources. There is now ongoing

development of stroke center designation that would then become the preferred destination for patients with acute stroke symptoms utilizing EMS.

Data supporting the use of emergency air transport for patients with acute stroke symptoms are limited. Further evaluation of this transportation modality is necessary to minimize the potentially high number of stroke mimics and to maximize the appropriate use of transport resources. Telemedicine is also a technology that has the potential to provide timely expert advice to rural and underserved clinics and hospitals.

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.[18] 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.[54] 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 >100.4°F). 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.[55]

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.[40]

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. 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.[4, 5, 56] 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.[32] 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.[18]

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.

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 low–molecular-weight heparin did not significantly improve outcomes.

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 study’s authors attempted to assess the precise time to initiate dipyridamole following ischemic stroke or TIA.[59] 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. 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.

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.

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. 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.

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%.

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.[68] 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.

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.

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.

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.[18]

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.

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.

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

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.[18]

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.[18]

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.

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.[1

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.[77]

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.

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.[77]

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.[78]

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

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.

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.

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