Hypertension is the most important risk factor. The degree of risk increases with elevation and becomes particularly strong with levels higher than 160/95 mm Hg. Systolic hypertension and high mean arterial pressure represent parallel risks. In the Framingham study, a sevenfold increased risk of cerebral infarction was observed in patients who were hypertensive (2). Hypertension increases the risk of thrombotic, lacunar, and hemorrhagic stroke and increases the likelihood of SAH. Successful long-term treatment of hypertension greatly reduces the risk of these events, even after a prior stroke (3). The hypothesis that angiotensin receptor blockers might provide specific stroke prevention benefits beyond their blood pressure lowering effects has not been borne out (4).

Because of concerns regarding maintaining flow distal to critical cerebrovascular stenoses, aggressive management of hypertension immediately after stroke should be avoided. Studies have shown that abrupt reductions in blood pressure within the first 24 hours after stroke are associated with poorer outcomes (5). Clinicians typically aim to gradually bring blood pressure into the normotensive range over a period of weeks after a stroke, though little data exist to guide this practice.

Heart disease is an important risk factor for stroke. To some degree, this reflects the shared risk factors and pathophysiology of stroke and heart disease: hypertension and atherosclerosis. The risk of stroke is doubled in individuals who have coronary artery disease (6), and coronary artery disease accounts for the majority of subsequent deaths among stroke survivors. Atrial fibrillation and valvular heart disease increase the risk of cerebral infarction because both may cause cerebral emboli. In patients with chronic, stable atrial fibrillation, the risk of stroke is increased fivefold (7). When atrial fibrillation is a manifestation of rheumatic heart disease, the risk of embolic stroke is increased up to 17 times normal (7). Prevention of embolic stroke in these patients is best achieved by long-term anticoagulation with warfarin. Treatment carries the danger of intracranial hemorrhage, especially in elderly individuals and in those with impaired balance and who are likely to fall. When the risk of hemorrhage appears to be high, aspirin in a dose of 325 mg daily may be used as an alternative to warfarin in patients with nonvalvular atrial fibrillation, although aspirin is much less effective than warfarin in preventing embolism. Younger patients (below age 75) without valvular heart disease and who lack other risk factors (e.g., hypertension, diabetes, left ventricular hypertrophy, history of TIA or stroke) are at low risk for stroke and may be treated with aspirin rather than with warfarin (8).

Diabetes, as an independent risk factor, doubles the risk of stroke. While achieving good glycemic control is advised for all diabetic patients, studies have not shown a clear relationship between glycemic control and stroke risk (9, 10).

Smoking has been shown to increase the risk of both ischemic stroke and SAH, with greater amounts of smoking carrying greater risk. Individuals who discontinue smoking have substantial reductions in stroke risk, approximating that of nonsmokers after several years (11). Counseling regarding smoking cessation is an essential component of programs to reduce the risk of recurrent stroke.

Hyperlipidemia increases the risk for stroke to a small extent. Treatment with cholesterol-lowering medications other than “statins” has not been found beneficial in reducing the risk of stroke. Conversely, treatment with statin medications has been found to reduce the risk of stroke, in individuals with or without hyperlipidemia (12), raising the possibility that the benefits of statins in stroke prevention may not be related solely to their lipid-lowering effects. Thus, treatment with statins is indicated for primary stroke prevention in patients with coronary heart disease or symptomatic atherosclerotic disease with low-density lipoprotein (LDL) cholesterol levels of 100 mg/dL or greater. In individuals at very high risk for stroke with multiple risk factors, the threshold for treatment is an LDL of 70 mg/dL (13).

Homocysteine: Elevated homocysteine have been found to be associated with a higher risk of ischemic stroke. While homocysteine levels can be lowered with supplementary vitamins (folate, vitamins B6 and B12), treatment has not been found to reduce stroke risk (14). Given the low cost and minimal risk of vitamin treatment to reduce homocysteine levels, the current recommendation is that such treatment is “reasonable” despite the lack of evidence of efficacy (15).

C-reactive protein: C-reactive protein (CRP) levels have been shown to correlate with risk of cardiovascular disease, including stroke, as have elevated fibrinogen levels. A recent study found that treating individuals with elevated CRP with statins reduced major cardiovascular events, despite normal lipid levels prior to treatment (16). While the role of testing CRP levels to guide stroke prevention remains a subject of debate, it may prove a useful adjunct to other tools for assessing risk.

The probability of stroke recurrence is highest early after a stroke. For survivors of an initial stroke, the annual risk of a second stroke is approximately 5%, with a 5-year cumulative risk of recurrence around 25% (17, 18), although it may be as high as 42% (17). Risk factors for initial stroke also increase the risk of recurrence, especially hypertension, heart disease, and diabetes mellitus (19, 20). Heavy alcohol consumption is also a risk factor for recurrent stroke.

Mortality after stroke is high, with between 32% and 58% of initial survivors dead within 5 years after a first stroke, with survival varying based on age, sex, and race (1). Leonberg and Elliott (19) were able to achieve 16% reduction in stroke recurrence rate by an energetic and sustained program of control of multiple risk factors. Therefore, efforts should be made to reduce risk of recurrent stroke and mortality by controlling risk factors.

Thrombosis of the large extracranial and intracranial vessels as the result of atherosclerotic cerebrovascular disease accounts for approximately 30% of all cases of stroke (Table 23-2) (20). Atherosclerotic plaques are particularly prominent in the large vessels of the neck and at the base of the brain. Sudden occlusion of one of these large vessels, in the absence of good collateral circulation, usually results in a large brain infarction. Risk factors for atherosclerosis include hypertension, smoking, diabetes, and hyperlipidemia. In some cases, the gradual progressive stenosis of a major blood vessel provides sufficient time for collateral circulation to develop, and complete occlusion may be asymptomatic or produce fewer effects than might otherwise be expected.

Unlike embolic strokes, which tend to have an abrupt onset, atherothrombotic strokes often begin more subtly, and affected individuals may only become aware that they have weakness or other impairment when they attempt to walk or get out of bed. The extent of the clinical deficit usually worsens over some hours or sometimes days, followed by stabilization and then gradual improvement.

Embolism is responsible for about 30% of all cases of stroke. Emboli may arise from thrombi within the heart or on the heart valves, from paradoxical embolism, or from an ulcerated atherosclerotic plaque within an extracranial artery (Table 23-3). Cardiogenic embolism may occur from thrombus formation at the site of a recent myocardial infarction, an area of myocardial hypokinesis, within the left atrium in patients with atrial fibrillation, or on diseased or prosthetic valves. Paradoxical embolism results from a deep venous thrombosis in the pelvis or leg that embolizes into the right side of heart, then passes through a patent foramen ovale into the left atrium, and ultimately to the cerebral circulation.

Cerebral embolism presents with an abrupt onset that is due to sudden loss of arterial perfusion to a focal area of the brain. The blood flow and anatomy of the cerebral circulation favor passage of an embolism into the middle cerebral artery territory, though any vascular territory may be affected. Many emboli are friable and may break into smaller pieces as they travel through the cerebral circulation, resulting in multiple smaller infarcts affecting several distal branches of the main vessel.

The initial clinical deficit may change rapidly. If the embolus undergoes lysis and fragmentation, the neurologic
signs may fade rapidly. While treatment with anticoagulants is appropriate for long-term secondary prevention of recurrent stroke, immediate anticoagulation with heparin has been found to increase the risk of symptomatic hemorrhagic conversion (25). For this reason, anticoagulation therapy is frequently delayed from the acute onset for up to 2 weeks in individuals with large cardioembolic infarctions.

Lacunar lesions constitute approximately 20% of all strokes and are small, circumscribed lesions, at most 1.5 cm in diameter resulting from occlusions in the deep penetrating branches of the large vessels that perfuse the subcortical structures, including internal capsule, basal ganglia, thalamus, and brainstem. Small lacunar infarcts may produce major neurologic deficits if they occur in key regions but generally cause more minor symptoms than large vessel infarcts and may in fact be asymptomatic. Lacunar strokes are highly associated with hypertension and may result from either microatheroma or lipohyalinosis.

Intracerebral hemorrhage accounts for approximately 11% of all cases of stroke. The most common cause of cerebral hemorrhage is hypertension, and intracerebral hypertensive hemorrhage most commonly occurs at the site of small, deep, penetrating arteries. It is thought that hemorrhage occurs through rupture of microaneurysms (Charcot-Bouchard aneurysms) that develop in these vessels in hypertensive patients. The majority of lesions occur in the putamen or thalamus, and in about 10% of patients, the spontaneous hemorrhage occurs in the cerebellum.

Cerebral amyloid angiopathy is another important cause of cerebral hemorrhage, representing 5% to 20% of cases. It is most common after age 65, although may occasionally affect individuals as early as age 45. Hemorrhages tend to be lobar rather than deep, and there is usually evidence of hemosiderin deposition on MRI imaging indicative of prior microhemorrhages at the time of initial clinical presentation. No specific treatments are yet available, aside from avoidance of medications that may predispose to bleeding and appropriate control of hypertension if present.

The clinical onset of the hemorrhage is often dramatic, with severe headache and rapidly progressive neurologic deficits. In patients with larger hemorrhages, consciousness becomes progressively impaired leading to coma. Brain displacement from the hematoma and cerebral edema may give rise to transtentorial herniation and death, generally within the first few days poststroke. While cerebral hemorrhage is associated with a higher mortality rate than infarction, there is some evidence that the neurological deficit from a hemorrhage may recover to a greater degree than a comparable initial deficit from an infarction (26).

Intracerebral hemorrhages have been demonstrated to continue to expand after initial presentation in a substantial portion of patients. A recent trial of recombinant activated factor VII reduced the growth of the hematomas but failed to show any improvement in functional status or reduction in mortality (27).

Intracerebral hemorrhage is a well-recognized complication of anticoagulant therapy and may occur spontaneously or after minor trauma. For patients on warfarin, the risk is related to the degree of elevation of the INR. In one study, the adjusted odds ratio for sustaining an intracranial hemorrhage was 4.6 for INRs in the range of 3.5 to 3.9 (compared with individuals with INRs between 2.0 and 3.0) and increased to 8.8 for INRs above 4.0 (28).

Other causes of intracerebral hemorrhage include trauma, vasculitis, and bleeding into a tumor. Patients with a bleeding diathesis—for example, thrombocytopenia or coagulation disorders—may develop an intracranial hemorrhage.

Patients with acute cerebellar hemorrhages typically develop a sudden headache and inability to stand, along with nausea, vomiting, and vertigo. With large posterior fossa lesions, the hematoma and edema may occlude the fourth ventricle, causing acute hydrocephalus. Urgent decompression with evacuation of the hematoma can be lifesaving. Patients who survive surgical evacuation of a cerebellar hemorrhage, or who have a less severe lesion, usually make a good functional recovery, as do patients with cerebellar infarcts (29).

In about 7% of all stroke patients, the lesion is an SAH, usually resulting from rupture of an arterial aneurysm at the base of the brain with bleeding into the subarachnoid space. Aneurysms develop from small defects in the wall of the arteries and slowly increase in size. The risk of rupture rises as the size of the aneurysm increases, and for this reason, intervention is generally advised for asymptomatic aneurysms greater than 10 mm in diameter (30). Major rupture of an aneurysm may be preceded by headache from a small bleed or by localized cranial nerve lesions caused by direct pressure by the expanding aneurysm. When rupture occurs, the clinical onset is usually dramatically abrupt. There is severe headache followed by vomiting and signs of meningeal irritation. Focal signs are usually not observed initially but may develop as a result of associated intracerebral bleeding or cerebral infarction occurring as a complication of arterial vasospasm. Coma frequently occurs, and as many as one third of patients may die acutely. Rebleeding is very common, and therefore, early surgical/invasive radiological intervention has become routine, with the objective of obliterating the aneurysm to prevent recurrent hemorrhage. Blood in the subarachnoid space may cause arterial vasospasm, leading to localized areas of cerebral infarction with associated focal neurologic deficits. Nimodipine is routinely administered after SAH to reduce the likelihood and/or severity of vasospasm. Hydrocephalus may develop immediately after SAH due to obstruction of the ventricular system from intraventricular hemorrhage, or as a later complication several weeks after the acute event as a result of arachnoiditis from blood in the CSF.

Obliteration of aneurysms may be performed surgically, by clipping the neck of the aneurysm or by the use of detachable coils placed through an angiographic approach to thrombose the aneurysm.

SAH may also result from bleeding from an arteriovenous malformation (AVM), which is a tangle of dilated vessels found on the surface of the brain or within the brain parenchyma. These lesions are congenital abnormalities and tend to bleed in childhood or young adulthood. In about half the cases, the hemorrhage is the first clinical indication of the lesion. In approximately one third of patients, the AVM presents as a seizure disorder or with chronic headaches. In most patients, the lesions eventually bleed. Most patients survive a single hemorrhagic event. The rate of rebleeding is about 6% in the first year and 2% to 3% per year thereafter. Treatment options include surgical excision of the AVM, proton beam therapy, or neurovascular ablation through embolization.

The relatively predictable anatomy of the brain’s vascular supply, localization of particular functions to certain areas of the brain, and the predilection of stroke for certain vascular territories result in a number of commonly occurring ischemic stroke syndromes. These stroke syndromes can be recognized when they occur and assist in localization of the stroke lesion as well as in predicting functional outcome. While a myriad of stroke syndromes have been described, we discuss only a few of the most common ones in this chapter.

The clinical consequences of complete occlusion of an internal carotid artery vary from no observable deficit to catastrophic. In cases where there is good collateral circulation, no neurological consequences may occur with carotid occlusion. By contrast, massive cerebral infarction in the distribution of the anterior and middle cerebral arteries may present with rapid obtundation, with dense contralateral motor and sensory deficits. In some cases (particularly in younger people), severe cerebral edema may lead to transtentorial herniation and death. In such cases, decompression of the swollen brain with craniectomy may be lifesaving.

Less extensive infarctions result in partial or total lesions in the distribution of the middle cerebral artery. The anterior cerebral circulation may be preserved through flow from the opposite side via the anterior communicating artery.

The internal carotid artery divides into the middle and anterior cerebral arteries. The middle cerebral artery supplies the lateral aspect of the frontal, parietal, and temporal lobes and the underlying corona radiata, extending as deep as the putamen and the posterior limb of the internal capsule. As the main stem of the middle cerebral artery passes out through the Sylvian fissure, it gives rise to a series of small branches called lenticulostriate arteries, which penetrate deeply into the subcortical portion of the brain and perfuse the basal ganglia and internal capsule. At the lateral surface of the hemisphere, the middle cerebral artery divides into upper and lower divisions, which perfuse the lateral surface of the hemisphere. When the middle cerebral artery is occluded at its origin, a large cerebral infarction develops involving all the structures mentioned above. Because of the cerebral edema that usually accompanies such a large lesion with brain displacement, the patient frequently shows depressed consciousness, with head and eyes deviated to the side of the lesion, with contralateral hemiplegia, decreased sensation, and homonymous hemianopia. If the dominant hemisphere is involved, aphasia is usually present, which may be severe if the entire territory of the MCA is infarcted. As the patient’s mental status improves, other features become evident, namely dysphagia, contralateral hemianopia, and, in patients with nondominant hemisphere lesions, perceptual deficits and neglect. Patients who survive the acute lesion regain control of head and eye movements, and normal level of consciousness is restored. However, severe deficits involving motor, visuospatial, and language function usually persist.

Occlusion of the middle cerebral artery branches, except for the lenticulostriate, is almost always embolic in origin, and the associated infarctions are smaller and more peripherally located than those seen after occlusion of the MCA trunk. The superior division of the middle cerebral artery supplies the Rolandic and pre-Rolandic areas, and an infarction in this territory will result in a dense sensory-motor deficit on the contralateral face, arm, and leg, with less involvement of the leg. As recovery occurs, the patient is usually able to walk with a spastic, hemiparetic gait. Little recovery occurs in motor function of the arm. If the left hemisphere is involved, there is usually severe aphasia initially with eventual improvement in comprehension, although an expressive aphasia is likely to persist. Small focal infarctions from occlusions of branches of the superior division will produce more limited deficits such as pure motor weakness of the contralateral arm and face, apraxia, or expressive aphasia.

The inferior division of the middle cerebral artery supplies the parietal and temporal lobes, and lesions on the left side result in severe involvement of language comprehension. The optic radiation is usually involved, resulting in partial or complete contralateral homonymous hemianopia. Lesions affecting the right hemisphere often result in neglect of the left side of the body. Initially, the patient may completely ignore the affected side and even assert that his left upper extremity belongs to someone else. Such severe neglect often gradually improves but may be followed by a variety of persisting impairments such as deficits in attention, constructional apraxia, dressing apraxia, perceptual deficits, and aprosodia.

Several characteristic and rather common syndromes have been described when lacunar strokes occur in the distribution of the lenticulostriate branches of the middle cerebral artery. Among the most common is a lesion in the internal capsule causing a pure motor hemiplegia. An anterior lesion in the internal capsule may cause dysarthria with hand clumsiness, and a lesion of the thalamus or adjacent internal capsule causes
a contralateral sensory loss with or without weakness. The neurologic deficits in these lesions often show early and progressive recovery with good ultimate outcome.

Branches of the anterior cerebral arteries supply the median and paramedian regions of the frontal cortex and the strip of the lateral surface of the hemisphere along its superior border. There are deep penetrating branches that supply the head of the caudate nucleus and the anterior limb of the internal capsule. Occlusions of the anterior cerebral artery are not common, but when they occur, there is contralateral hemiparesis with relative sparing of the hand and face and greater weakness of the leg. There is associated sensory loss of the leg and foot. Lesions affecting the left side may produce a transcortical motor aphasia characterized by diminution of spontaneous speech but preserved ability to repeat words. A grasp reflex is often present along with a sucking reflex and paratonic rigidity (also known as gegenhalten—muscle hypertonia presenting as an involuntary variable resistance during passive movement of a limb). Urinary incontinence is common. Large lesions of the frontal cortex often produce behavioral changes, such as lack of spontaneity, distractibility, and tendency to perseverate. Affected individuals may have diminished reasoning ability. Bilateral anterior cerebral artery infarctions may cause severe abulia (lack of initiation).

The two vertebral arteries join at the junction of the medulla and pons to form the basilar artery. Together, the vertebral and basilar arteries supply the brainstem by paramedian and short circumferential branches and supply the cerebellum by long circumferential branches. The basilar artery terminates by bifurcating at the upper midbrain level to form the two posterior cerebral arteries. The posterior communicating arteries connect the middle to the posterior cerebral arteries, completing the circle of Willis.

Some general clinical features of lesions in the vertebrobasilar system should be noted. In contrast to lesions in the hemispheres, which are unilateral, lesions involving the pons and medulla often cross the midline and produce bilateral symptoms. When motor impairments are present, they are often bilateral, with asymmetric corticospinal signs, and they are frequently accompanied by cerebellar signs. Cranial nerve lesions are very frequent and occur ipsilateral to the main lesion. There may be dissociated sensory loss (involvement of the spinothalamic pathway with preservation of the dorsal column pathway or vice versa), dysarthria, dysphagia, disequilibrium and vertigo, and Horner’s syndrome. Of particular note is absence of cortical deficits, such as aphasia and cognitive impairments. Visual field loss and visuospatial deficits may occur if the posterior cerebral artery is involved, but not with brainstem lesions. Identification of a specific cranial nerve deficit allows precise anatomic localization of the lesion.

Lacunar infarcts are common in the vertebrobasilar distribution, arising from occlusion of small penetrating branches of the basilar artery or posterior cerebral artery. In contrast to cerebral lacunes, most brainstem lacunes are symptomatic. There is a variety of characteristic brainstem syndromes associated with lesions at various levels in the brainstem. Pontine lacunar infarcts frequently result in a pure motor hemiparesis. The reader is referred to neurologic texts for a comprehensive discussion of these lesions. Several brainstem syndromes are relatively common among patients referred for rehabilitation, and these are described in some detail.

The lateral medullary syndrome (Wallenberg’s syndrome) is produced by an infarction in the lateral wedge of the medulla. It may occur as an occlusion of the vertebral artery or the posterior inferior cerebellar artery. The clinical features of this syndrome, along with the corresponding anatomic structures involved, are impairment of contralateral pain and temperature (spinothalamic tract); ipsilateral Horner’s syndrome consisting of miosis, ptosis, and decreased facial sweating (descending sympathetic tract); dysphagia, dysarthria, and dysphonia (ipsilateral paralysis of the palate and vocal cords); nystagmus, vertigo, nausea, and vomiting (vestibular nucleus); ipsilateral limb ataxia (spinocerebellar fibers); and ipsilateral impaired sensation of the face (sensory nucleus of the fifth nerve). Patients with this syndrome are frequently quite disabled initially because of vertigo, disequilibrium, and ataxia, but they often make a good functional recovery.

Occlusion of the basilar artery may result in severe deficits with complete motor and sensory loss and cranial nerve signs from which patients do not recover. Patients are often comatose. Locked-in syndrome is an uncommon but devastating stroke syndrome involving the brainstem. The infarction in such cases affects the upper ventral pons, involving the bilateral corticospinal and corticobulbar pathways but sparing the reticular activating system and ascending sensory pathways. Patients have normal sensation and can see and hear but are unable to move or speak. Blinking and upward gaze are preserved, which provides a very limited but usable means for communication. The patient is alert and fully oriented. Some patients do not survive, and those who do are severely disabled and dependent. Slow improvement and partial recovery may occur in this group of patients, justifying appropriate levels of rehabilitation intervention.

Focal infarctions may occur in the midbrain and affect the descending corticospinal pathway, sometimes also involving the third cranial nerve nucleus (Weber’s syndrome), resulting in ipsilateral third nerve palsy and paralysis of the contralateral arm and leg.

Eye movement abnormalities are seen in a variety of brainstem stroke syndromes due to the location of the nuclei for these cranial nerves in the midbrain (third and fourth cranial nerves) and pons (sixth nerve) and their interconnections.

The posterior cerebral artery perfuses the thalamus through perforating arteries, as well as the temporal and occipital lobes with their subcortical structures, including the optic radiation. An occipital lobe infarction will cause a partial or complete contralateral hemianopia, and when these visual deficits involve the dominant hemisphere, there may be associated
difficulty in reading or in naming objects. When the thalamus is involved, there is contralateral hemisensory loss. A lesion involving the thalamus may cause a syndrome characterized by contralateral hemianesthesia and central pain, although only about 25% of cases of central pain in stroke are caused by lesions of the thalamus. Other lesion sites reported to be associated with central pain are the brainstem and parietal lobe projections from the thalamus. In the thalamic syndrome, patients report unremitting, unpleasant, burning pain affecting the opposite side of the body. Examination of the patient reveals contralateral impairment of all sensory modalities, often with dysesthesia. There may be involvement of adjacent structures, such as the internal capsule (hemiparesis, ataxia) or basal ganglia (choreoathetosis).

For many patients, a stroke represents only one facet of systemic atherosclerotic vascular disease. Such patients will often have multiple risk factors for an event, such as increased age, hypertension, diabetes, and smoking. Stroke, however, can occur in the absence of common risk factors or atherosclerosis.

The investigation undertaken to identify the cause of a stroke depends on the patient’s age and presence or absence of risk factors. For example, a 79-year-old man with hypertension and a long history of smoking who sustains a lacunar infarct will not likely require assessment for a hypercoagulable state, whereas this may be an important component of the investigation of the cause of stroke in a 32-year-old woman without identifiable risk factors.

A basic evaluation of stroke cause includes a thorough physical and neurological examination, cerebral imaging (CT or preferably MRI), an electrocardiogram, noninvasive carotid studies, and an echocardiogram. In cases where there is concern regarding a possible cardiogenic embolism, a 24-hour Holter monitor is appropriate. Transesophageal echocardiography provides superior imaging of left atrium, mitral valve, and the aortic arch. In cases where the possibility of a paradoxical embolism has been raised, the echocardiogram should include a “bubble” study to evaluate for right to left shunting, and studies for deep venous thrombosis are frequently performed. CT or MR angiography may be indicated when concerns regarding large vessel occlusion, stenosis, or dissection are present. Occasionally, conventional angiography may be indicated, although this is increasingly reserved for use during intravascular interventions.

In younger patients, evaluation frequently includes tests for a hypercoagulable state and screening for vasculitis or rheumatological disorder (e.g., lupus).

The goals of acute stroke management are (a) to limit or reverse neurologic damage through thrombolysis or neuroprotection and (b) to monitor and prevent secondary stroke complications such as elevated intracranial pressure.

Intravenous thrombolysis with recombinant tissue plasminogen activator has been known to be effective when administered to appropriate individuals within 3 hours of symptom onset since the mid-1990s (31). While a recent study found
thrombolysis useful and acceptably safe as late as 4.5 hours poststroke in a selected population, it is clear that this intervention is most effective when given as early as possible (32). This has prompted major centers to develop stroke teams that can respond rapidly 24 hours a day with immediate clinical evaluation, urgent CT scan, and infusion as soon as possible within the therapeutic window. The ability of MRI to identify areas of mismatch between perfusion and diffusion has been studied as a means of identifying candidates for intravenous or intra-arterial thrombolysis outside of the standard time windows (33). Ultrasound has been used as a therapeutic tool in studies to enhance the thrombolytic effects of infused medications, although it is not yet been incorporated into routine clinical practice (34).

Thrombolytic agents are being administered intra-arterially in clinical trials and may prove an alternative to intravenous thrombolysis in patients who are not candidates for the latter procedure or as a salvage procedure in patients whose affected artery fails to recanalize with intravenous thrombolytic therapy (35). Clot removal devices, such as the Merci device, have been studied but are not yet in routine clinical use (36). A major challenge in the delivery of all of these therapies remains the delay in obtaining medical care among stroke victims (often due to a lack of recognition of the significance of their symptoms or by the severity of the deficits themselves), inability to identifying the time of onset, and the difficulty in providing these complex therapies in the required, time-dependent manner.

The development of an effective neuroprotective agent remains one of the major goals in acute stroke care but has thus far not been successful. Control of blood pressure, fever, and hyperglycemia have, however, been shown to improve outcome in acute stroke. Other approaches, such as brain cooling, remain under investigation.

Excitotoxicity is believed to play a role in the death of ischemic neurons in the penumbra around an infarction. Dying cells release excitatory amino acids, particularly glutamate, which activate cell membrane channels, allowing toxic levels of calcium to accumulate inside cells that are injured but not yet dead. The elevated intracellular calcium initiates an array of neurochemical changes within the neurons that generate free radicals and result in cell death. Clinical trials of glutamate receptor antagonists and free radical scavengers for acute stroke have been disappointing in humans, despite evidence of efficacy in animal models.

Secondary prevention involves a multipronged effort at risk factor reduction, which may involve behavioral change, such as smoking cessation, aerobic exercise, and dietary modifications in addition to optimizing treatment of associated medical risk factors, such as hypertension and diabetes.

The third aspect of secondary prevention is the use of specific medications for stroke prevention.

Antiplatelet medications are appropriate for the majority of patients for secondary prevention of ischemic stroke. Aspirin in doses of 50 to 325 mg provides a reduction in stroke of approximately 25% (13). Gastrointestinal toxicity (bleeding, dyspepsia) is the most common side effect of aspirin, followed by allergies.

Clopidogrel is another antiplatelet agent with a different mechanism of action from aspirin. In clinical trials, its efficacy in preventing stroke is comparable to aspirin, though it is more costly. It is generally well tolerated, though its use has been associated with rare cases of thrombotic thrombocytopenic purpura. Combining clopidogrel and aspirin is generally not recommended, as the combination appears to raise the risk of hemorrhagic complications without further reduction in stroke risk (37). Ticlopidine is a related drug, with similar efficacy. It has largely fallen out of use due to concerns regarding neutropenia (24).

Another agent, dipyridamole, has some efficacy when taken alone but is generally prescribed as part of a fixed dose combination with aspirin (Aggrenox). In a large European trial, there was a 37% reduction in risk of stroke in patients prescribed both aspirin and dipyridamole (38), which compared favorably with treatment with aspirin alone. A recent study comparing dipyridamole with aspirin versus clopidogrel failed to show any difference in efficacy between these two therapies (39), and uncertainty regarding the ideal selection of antiplatelet agent persists (40).

Stroke can occur despite the use of antiplatelet agents. There is no consensus regarding the management of individuals who sustain a stroke despite preventive antiplatelet therapy, although substitution of combined aspirin plus dipyrdiamole therapy for aspirin monotherapy or substitution of clopidogrel for aspirin monotherapy is commonly instituted.

Warfarin use for stroke prevention is generally restricted to patients with atrial fibrillation or other known cardiac or other embolic source. For most indications, a target INR of 2 to 3 is used, although a higher range is needed for patients with certain types of mechanical heart valves.

Carotid endarterectomy reduces the risk of stroke in those patients with single or multiple TIAs and with 70% or greater stenosis of the ipsilateral internal carotid artery (41). Patients with stenosis of 50% to 70% may be considered for surgery if symptomatic, that is, if they are having TIAs or a stroke ipsilateral to the carotid lesion. The evidence for carotid endarterectomy is less compelling for patients with asymptomatic carotid stenosis, with a recommendation that it be considered for asymptomatic patients with stenoses of 60% to 99% (42).

Carotid stenting has been studied as an alternative to carotid endarterectomy, particularly in patients who may be at poor surgical risks. At present, there is no consensus regarding the relative efficacy, although some data suggest that endarterectomy provides better outcomes overall (43).

The care of stroke survivors is organized in a variety of different systems around the world. In many European countries, stroke units provide a combination of acute stroke management and subsequent intensive rehabilitation in a single unit.
Studies of stroke units have consistently found improved outcomes when compared with care on general medical units (44). Interestingly, much of the benefits in mortality appear to relate to prevention and/or earlier recognition of medical complications of stroke and earlier mobilization (45).

In the United States, acute stroke care is often transitioned rapidly to rehabilitative care, often within a matter of days. Despite this, it is important that rehabilitation not be considered a separate phase of care, that only begins after acute medical intervention. Rather, it is an integral part of medical management and continues longitudinally through acute care, postacute care, and community reintegration. Although diagnosis and medical treatment are the principal focus of early treatment, rehabilitation measures should be offered concurrently. Many of these can be considered preventive in nature. For example, patients who are hemiplegic, lethargic, and incontinent are at high risk for developing pressure ulcers. Deliberate strategies should be followed to prevent skin breakdowns, including protection of skin from excessive moisture, the use of heel-protecting splints, maintenance of proper position with frequent turning, and daily inspection and routine skin cleansing (46).

Many patients with acute stroke have dysphagia and are at risk for aspiration and pneumonia. In the able-bodied, aspiration usually results in vigorous coughing, but as many as 40% of patients with acute stroke experience silent aspiration. Protection against aspiration (and resulting pneumonia) includes avoiding oral feeding in patients who are not alert. Even in alert patients, the ability to swallow should be assessed carefully before oral intake of fluids or food is begun. This is done with a bedside screening assessment that can be efficiently completed by physician or nursing staff and generally includes taking a small drink of water and observing for coughing or change in vocal quality (47). If any doubt exists about aspiration, a swallowing videofluoroscopy examination or flexible endoscopic evaluation of swallowing (FEES) is performed. During the acute phase, nasogastric tube feeding or gastrostomy tube placement may prove necessary. Patients who are lying flat in bed are at significant risk for regurgitation and aspiration, and the head of the bed should be kept elevated (48).

Impairment of bladder control is frequent following a stroke, which may initially cause a hypotonic bladder with overflow incontinence. If an indwelling catheter is used, it should be removed as soon as possible, with careful monitoring to insure that appropriate voiding resumes. For the occasional patient with persistent urinary retention after stroke, regular intermittent catheterization is preferable to an indwelling catheter (49).

Patients with hemiplegia are at high risk for development of contractures due to immobility. Spasticity, if present at this early stage, may contribute to the development of contractures through sustained posturing of the limbs. The harmful effects of immobility can be ameliorated by regular passive stretching and moving the joints through a full range of motion, preferably at least twice daily.

The risk of deep venous thrombosis is high, especially in patients with hemiplegia. Every patient should, therefore, have some form of deep vein thrombosis (DVT) prophylaxis, either subcutaneous heparin or external pneumatic compression boots or both.

Early mobilization is beneficial by reducing the risks of DVT, deconditioning, gastroesophageal regurgitation and aspiration pneumonia, contracture formation, skin breakdown, and orthostatic intolerance. Positive psychological benefits are also likely. Mobilization involves a set of physical activities that may be started passively but that quickly progress to active participation by the patient. Specific tasks include turning from side to side in bed and changing position, sitting up in bed, transferring to a wheelchair, standing, and walking. Mobilization also includes self-care activities such as self-feeding, grooming, and dressing. The timing and progression in these activities depend on the patient’s condition. These activities should begin as soon as possible (generally within 24 to 48 hours of admission (49)) unless the stroke survivor is unresponsive or medically/neurologically unstable.

Evaluation of longer-term rehabilitation needs should occur within the first few days after stroke. Many stroke survivors will benefit from admission to an acute rehabilitation hospital or unit (also known as an Inpatient Rehabilitation Facility), and criteria for admission into such a program are listed in Table 23-5. Some individuals may be more appropriate for a subacute rehabilitation program (based in a Skilled Nursing Facility), which provides a less intense rehabilitation program with a lesser degree of medical supervision over a longer period of time. These programs are most appropriate for individuals who are unlikely to return home due to premorbid conditions (such as dementia), who are too frail to undergo an intensive rehabilitation program, or whose neurological impairments are so profound as to prevent participation in a hospital-level program. Some individuals complete a period of intensive “acute” rehabilitation, followed by “subacute” rehabilitation, before returning home. Stroke survivors with isolated disabilities such as a partial aphasia, visual loss, or monoparesis may more appropriately receive rehabilitation on an outpatient basis or through a homecare agency.