Therapeutic Measures to Prevent Ischemic Stroke
Management of risk of cardioembolism Disorders in many parts of the heart can potentially lead to stroke [see Figure 4]. Cardiac valves affected by bacterial endocarditis can give rise to septic emboli. The therapy for this condition is aggressive administration of antibiotics [see 7:XVIIIInfective Endocarditis]. Akinetic ventricular segments can cause mural thrombi that in turn act as cardiac emboli. The treatment for this disorder is anticoag-ulation with warfarin to an international normalized ratio (INR) of 2.0 to 3.0. Similarly, anticoagulation after myocardial infarction is beneficial for patients with concomitant atrial fibrillation, decreased left ventricular function, or left ventricular thrombus.44 Long-term warfarin therapy is necessary for patients with mechanical prosthetic valves. However, bioprosthetic valves require only brief anticoagulation, followed by antiplatelet treatment. Other conditions, such as patent foramen ovale, septal aneurysm, so-called ventricular smoke, and aortic arch athero-ma, are more of a therapeutic dilemma. Although these conditions are known to increase stroke risk, there is still uncertainty as to whether antiplatelet or antithrombotic treatment is superior for stroke prevention. Indications for surgical intervention are also uncertain.
The most rigorously studied cardiac condition in terms of stroke prevention is fortunately the one most commonly related to stroke: atrial fibrillation [see Table 4 and 1:IV Atrial Fibrillation]. Nonvalvular atrial fibrillation is a common and readily preventable cause of stroke in the elderly.68
Lack of treatment of at-risk patients remains a significant public health challenge. The groups at highest risk for stroke include those with hypertension, diabetes mellitus, previous TIA or stroke, or poor left ventricular function and women older than 75 years. These patients should be treated with warfarin if they are appropriate candidates. For patients without risk factors and for those younger than 65 years, the risk of stroke is 1% a year without therapy. Thus, warfarin treatment is not necessary. For those individuals 65 to 75 years of age who are without risk factors, the yearly risk of stroke is 1.1% with warfarin therapy and 1.4% with aspirin therapy. Patients’ INRs must be monitored and maintained in the 2.0 to 3.0 range so as to minimize the risk of ischemic stroke or hemorrhage from undertreatment or overtreatment.69 An oral direct thrombin inhibitor, ximelaga-tran, has been shown to have efficacy and safety similar to those of warfarin in patients with atrial fibrillation and deep vein thromboembolism.70,71 Ximelagatran offers several apparent advantages over warfarin, including minimal if any food or drug interactions, a high therapeutic index, rapid onset, and no need for INR monitoring. However, 6% of patients on this agent develop elevations in the transaminase level, which may limit its use.
Management of carotid artery disease Surgical treatment of symptomatic carotid stenosis (i.e., after a TIA or minor stroke) greatly reduces stroke risk.72 In patients with a stenosis that is greater than 70% of the vessel diameter and who are good surgical candidates, surgery dramatically reduces the risk of stroke occurring within 2 years from 26% to 9%. For patients with 50% to 70% stenosis, the benefit is not as great. In this moderate-stenosis group, surgery reduces the risk of stroke over 5 years from 22% to 16%. This benefit is seen mostly in men, in those with recent stroke symptoms, and in those with hemispheric rather than ocular symptoms. Endarterectomy is most beneficial when it can be performed in the first 2 to 4 weeks after the initial cerebrovascular event.
Asymptomatic patients whose stenosis is less than 60% of the carotid diameter also benefit from surgery, but the risk and the results from surgery are more modest. In the Asymptomatic Carotid Atherosclerosis Study, surgery reduced stroke risk at 5 years from 11% to 5%. A surgical benefit was not seen in subgroup analysis for disabling stroke or death, and no benefit was seen for women.73 Studies of community practice suggest that the risk of carotid endarterectomy may be higher than that seen in randomized clinical trials.74 Many endarterectomies are done for asymptomatic patients in low-volume hospitals where peri-operative morbidity and mortality are high.74 For the beneficial effect of carotid endarterectomy in symptomatic patients to be realized, referring physicians should insist that surgeons provide objective evidence of surgical complication rates of no higher than 6%.74 In asymptomatic carotid stenosis, surgical risk must be less than 3% because the combined risk of angiography and surgery in trials demonstrating surgical benefit was 2.4%.74
Carotid angioplasty and stenting (CAS) is being evaluated as an alternative to carotid endarterectomy. For patients who are at high risk for major complications during carotid endarterecto-my, such as those with severe cardiac disease or prior carotid endarterectomy, CAS has been associated with better outcomes, both in the short term and long term.75 However, for patients who would be candidates for carotid endarterectomy, there are no data from randomized clinical trials to support CAS except as part of a research protocol with appropriate informed consent from the patient.
Antiplatelet and antithrombotic treatment Inhibition of platelet activation can be achieved with several agents, including aspirin, dipyridamole, ticlopidine, and clopidogrel [see Table 5]. The role of aspirin in the primary prevention of stroke is uncertain, although it prevents myocardial infarction in high-risk patients.76 However, aspirin is clearly indicated for secondary prevention of stroke in patients who have already experienced TIA or stroke. Numerous trials of antiplatelet therapy demonstrated that aspirin reduced the risk of nonfatal stroke by about 30%.77 The ideal aspirin dose is controversial, and there is significant variability in patient responses. For the majority of patients, 50 to 325 mg a day (the dose range recommended by the FDA) appears to maximize the prophylactic effect and minimize the bleeding risk.
Other antiplatelet drugs offer modest additional preventive benefit, compared with aspirin, but at a greater cost and with more potential adverse effects. These medications are recommended for patients who are unable to tolerate aspirin or who have recurrent vascular events while on aspirin. Ticlopidine and clopidogrel reduce the risk of stroke by approximately 21%78 and Z.3%,79 respectively, compared with aspirin. Ticlopidine may cause significant neutropenia and thrombocytopenia and therefore requires complete blood count monitoring every 2 weeks for the first 3 months. Although early studies suggested a possible specific benefit for ticlopidine, as compared with aspirin, in African Americans, this was refuted by a large randomized trial.80 Clopidogrel is associated with a lower frequency of neutropenia than ticlopidine, but thrombotic thrombocytopenic purpura has been reported.81 Dipyridamole inhibits platelet phosphodi-esterase activity and increases the availability of adenosine. Although early trials failed to demonstrate any benefit of dipyri-damole, the European Stroke Prevention Study-2 compared regimens consisting of aspirin (50 mg), dipyridamole (extended release, 200 mg), both drugs in combination, and placebo and found a relative risk reduction with the combination of aspirin and dipyridamole of 23% when compared with aspirin alone.82
Oral anticoagulation with warfarin is used to inhibit the coagulation cascade and the formation of red blood cell thrombi, and it is appropriate for prevention in patients with high-risk sources of cardioembolism (see above). Warfarin was sometimes used empirically for patients with recurrent cerebrovascular events while on antiplatelet therapy, but in this setting warfarin may not be warranted. The Warfarin Aspirin Recurrent Stroke Study (WARSS) compared warfarin with aspirin in 2,000 patients with noncardioembolic strokes, most of which were lacunar strokes.
Table 5 Comparison of Antiplatelet Therapies for Prevention of Ischemic Stroke
|
Antiplatelet Drug |
Relative Risk Reduction* |
Major Side Effects |
|
Aspirin |
(Reference drug) |
Gastritis Peptic ulcer disease |
|
Ticlopidine |
21% |
Neutropenia Diarrhea Rash |
|
Clopidogrel |
7.3% |
Rash Diarrhea Thrombotic thrombo-cytopenic purpura |
|
Dipyridamole + aspirin |
23% |
Headache |
*Relative risk reduction for stroke.
The risk of recurrent stroke was the same in the two treatment arms, although the risk of hemorrhage tended to be slightly higher in the warfarin group.83 Consequently, the role of warfarin in noncardioembolic strokes has become somewhat dubious. Further, in the randomized Warfarin versus Aspirin for Symptomatic Intracranial Disease (WASID) trial, both drugs had similar impact on the risk of recurrent stroke or death in patients with large-vessel intracranial stenosis, but the use of warfarin was associated with an increased risk of major bleeding complications.84 Together, WARSS and WASID show that aspirin is at least as effective as warfarin, and in real-world practice, it is likely safer. Some stroke specialists use warfarin for acute internal carotid artery occlusion and arterial dissection, although controlled trials are lacking.
Contraindications to warfarin include pregnancy, poor compliance, alcohol abuse, and risk of falling. Long-term anticoagu-lation therapy is associated with a risk of major hemorrhage, which occurs at a rate of 1% to 3% a year.85
Uncommon causes of ischemic stroke
Mechanisms other than cardioembolism, large-vessel athero-thromboembolism, and small-vessel occlusive disease account for only a minority of all ischemic strokes, but they have specific diagnostic and therapeutic implications. Moreover, these unusual causes are disproportionately represented in young stroke victims, accounting for nearly one third of strokes in patients younger than 45 years.86
Atherosclerosis of the extracranial and intracranial arteries is a common cause of stroke, but several nonatherosclerotic disorders may also cause stroke. These disorders include inflammatory arteriopathies such as collagen vascular diseases, Takayasu disease, and neurovascular syphilis, as well as noninflammatory arteriopathies such as arterial dissection, fibromuscular dyspla-sia, moyamoya disease, CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencepha-lopathy), radiation vasculopathy, and vasospasm after sub-arachnoid hemorrhage (SAH).
Arterial Dissection
Dissection of the internal carotid artery and vertebral artery can occur after head and neck trauma but may also occur spontaneously. Some connective tissue disorders may be risk factors, including fibromuscular dysplasia, Marfan syndrome, and Ehlers-Danlos syndrome. Arterial wall dissection causes vascular stenosis, occlusion, or a dissecting aneurysm. Clinical features include neck pain, headache, Horner syndrome, TIA or ischemic stroke, and tinnitus or audible bruits. Conventional angiography is the diagnostic gold standard and reveals the string sign, tapered stenosis or occlusion, dissecting aneurysm, intimal flap, distal pouch formation, and an underlying arteri-opathy. Dissection may be diagnosed noninvasively with ultra-sonography, CTA, MRI, or MRA, but each modality has potential limitations.
Prevention of stroke secondary to extracranial arterial dissection consists primarily of antithrombotic therapy. Heparin should be considered early because stroke risk is greatest in the first few days after the initial vascular injury. If anticoagulation is contraindicated, aspirin is recommended. Antithrombotic therapy should be continued until serial imaging demonstrates recanalization or stabilization of the dissected vessel.87
Inflammatory Arteriopathy
Inflammatory arteriopathies, or vasculitides, are a heterogeneous group of disorders in which vascular inflammation results in cerebral ischemia.88 Vasculitis may be primary (e.g., isolated angiitis of the central nervous system) or secondary to infections (e.g., syphilis, tuberculosis, or varicella-zoster virus), toxins (e.g., cocaine, amphetamines, or LSD), neoplasms, or systemic inflammatory disorders (e.g., polyarteritis nodosa, Churg-Strauss angiitis, Wegener granulomatosis, giant cell arteritis, systemic lupus erythematosus, or rheumatoid arthritis). Symptoms may include headache, seizures, focal neurologic deficits, and multifocal encephalopathy. Clinical and serologic features of the vasculitides vary, but angiographic findings tend to be similar and nonspecific, showing segmental narrowing and dilatation ("beading"). Brain biopsy may confirm the diagnosis. Treatment should be directed at any underlying systemic disorder. Immunosuppressive regimens with corticosteroids and other agents are often used empirically.
Prothrombotic States
Ischemic stroke may be associated with hereditary and acquired prothrombotic states, including abnormalities of red cell or platelet function, of coagulation factors, or of endogenous fib-rinolysis. Such disorders are uncommon but should be considered when no alternative etiology is identified.
Cerebral Vein Thrombosis
Cerebral vein thrombosis (CVT) is a rare but important cause of stroke that is often missed or discovered late in diagnosis. Infection is the most common cause of CVT in children; in adults, most cases are associated with pregnancy. Infrequent etiologies include severe dehydration, sickle cell anemia, malignancy, and hypercoagulable states. Oral contraceptive agents have also been implicated. Severe headache, nausea, and vomiting are nonspecific but common symptoms. Papilledema, if present, may be the only abnormality on initial examination. Fluctuating focal neurologic deficits, such as unilateral weakness, numbness, or seizures, may appear. Lumbar puncture may demonstrate elevated protein levels, the presence of red blood cells, or xan-thochromia. Noncontrast CT can determine whether acute hemorrhage or mass effect is present. Contrast CT may demonstrate a so-called empty delta sign in the sagittal sinus. MRI and MR venogram (MRV) have better sensitivity for detection of CVT; conventional cerebral angiography remains the diagnostic gold standard. A small randomized trial demonstrated safety and efficacy of intravenous heparin in CVT, even in patients with preexisting hemorrhage.90 Consequently, acute anticoagulation is recommended for most patients with CVT. Thrombolysis may be considered, but its role remains unconfirmed, and it should be reserved for patients whose condition declines despite adequate anticoagulation.91,92 After the acute period, oral anticoagu-lation is typically used for several months until MRI or MRV demonstrates sinus patency. Mortality from CVT is estimated to be 5% to 30%, but survivors have a good prognosis with little residual deficit.91
Idiopathic Stroke
Cryptogenic (idiopathic) stroke is diagnosed when all indicated studies fail to identify the likely stroke mechanism. About half of strokes in young patients are diagnosed as cryptogenic.86 In general, the risk of recurrent stroke in this context is believed to be relatively low.
Hemorrhagic Stroke
Intracerebral hemorrhage
ICH accounts for 11% of stroke deaths. Prevalence among African Americans is notably higher than in the general popula-tion.93 ICH cannot be reliably distinguished from ischemic stroke by clinical criteria alone. Noncontrast CT imaging establishes the diagnosis and is required to detect the presence of blood. The volume of ICH and the level of consciousness are the two most powerful predictors of outcome [see Figure 2]. Specific therapy for ICH remains largely an enigma. Patients with ICH frequently deteriorate as edema worsens over the first 24 to 48 hours. Late hematoma evacuation is ineffective in reducing mortality or improving outcome. Early surgical evacuation remains controversial. Theoretically, early hematoma evacuation may reduce surrounding ischemic injury and prevent edema formation and consequent herniation. Pilot studies of surgery within 12 hours94 and 24 hours95 suggested that early surgery is feasible and may be beneficial. In contrast, a trial comparing surgical evacuation with medical management for patients with ICH who appeared to be clinically stable (i.e., whose condition was not declining or who did not show signs of herniation) up to 48 hours after onset showed no difference in mortality or functional outcomes.
Besides surgery, other strategies may be used to control ICP [see Table 6]. Intraventricular hemorrhage is a particularly bad complication of ICH. Prompt ventricular drainage should be performed if there are any signs of hydrocephalus. Ventricular drainage may reduce ICP without obvious hydrocephalus. Sedation with or without chemical neuromuscular paralysis is often helpful in controlling ICP in intubated patients. Propofol is an especially useful agent because of its short half-life. An ICP monitor should be used in all sedated patients and in patients who are obtunded (i.e., those whose Glasgow Coma Scale score is less than 9) to follow ICP. Osmotic diuretics are often useful in the short term before a definitive procedure such as hematoma evacuation is performed. The benefit of osmotic diuretics dissipates after 12 to 24 hours, but rebound elevations in ICP can occur. The same is true of hyperventilation, which lowers ICP by reducing cerebral blood flow through vasoconstriction. Although use of hyperventilation to reduce carbon dioxide tension (PCO2) to 30 to 35 mm Hg may transiently lower ICP, the effect is short-lived (6 to 12 hours), and rebound elevations in ICP are a serious problem if normocapnia is not slowly restored. Steroids are not recommended.
Table 6 Management Strategies for Elevated Intracranial Pressure
|
Strategy |
Comment |
|
Ventricular drainage |
Most useful in hydrocephalus |
|
Osmotic diuresis |
Mannitol load, 0.5-1.0 g/kg I.V.; maintenance dose, 0.25-1.0 g q. 6 hr; titrate to keep serum osmolality 300 to 310 mOsm/kg H2O |
|
Hyperventilation |
Titrate to keep PCO2 30-35 mm Hg; wean slowly |
|
Sedation |
Consider propofol or other benzodiaze-pine drip |
|
Neuromuscular blockade |
Always combine with sedation |
|
Barbiturate coma |
Rarely indicated |
Blood pressure management in ICH also remains controversial. Observations suggest that about one third of ICHs expand during the first 24 hours.97 Some investigators have therefore concluded that blood pressure should be lowered in patients with acute ICH. No trial has demonstrated that this action is necessary, and the concern about reducing cerebral perfusion pressure in patients with elevated ICP remains. The American Heart Association guidelines recommend only that mean arterial blood pressure be kept lower than 130 mm Hg in patients with a history of hypertension.
A novel approach to preventing ICH expansion involves the use of procoagulants, and activated factor VII is currently under investigation. This approach may increase the risk of throm-boembolic events, which are common complications in patients with ICH, so extreme caution is warranted until further data become available.
Further supportive care should probably be similar to those for patients with ischemic stroke [see Supportive Medical Management, above]. Premature withdrawal of these measures may worsen outcome.
Subarachnoid hemorrhage
Spontaneous SAH most commonly results from aneurysms of the circle of Willis. Aneurysms of the anterior and posterior communicating arteries are most frequently responsible [see Figure 5]. Hypertension and cigarette smoking are clear risk factors for aneurysmal rupture. A family history of SAH associated with ruptured intracranial aneurysms in first-degree relatives of patients with SAH is also a risk factor for aneurysm (unruptured aneurysms are detected in about 4% of such patients), but routine screening is not recommended.100 The risk of rupture depends on aneurysm size. For patients with no history of SAH, the risk of rupture of aneurysms less than 7 mm in diameter is 0.05% a year. For aneurysms greater than 10 mm in diameter, the risk is slightly less than 1% a year. For aneurysms at least 25 mm in diameter, the risk jumps to 6% in the first year.
Diagnosis
Up to 50% of patients with SAH present with a so-called warning leak or sentinel hemorrhage. Establishing the diagnosis early and consequent prompt aneurysm clipping can reduce long-term morbidity and mortality. Modern head CT imaging [see Figure 2] can establish the diagnosis in 97% of patients presenting to the emergency department with "the worst headache of my life." In the remaining small percentage of patients, lumbar puncture and examination of the cerebrospinal fluid for xan-thochromia are necessary.102 In addition to severe headache, the following all suggest SAH and should prompt a thorough evaluation: rapid onset, photophobia, stiff neck, decreased level of consciousness, and focal neurologic signs.
Treatment
The treatment of SAH involves localizing the aneurysm with cerebral angiography and securing it to prevent subsequent bleeding. Traditionally, surgical clipping within 72 hours of onset has been recommended, although in patients with severe symptoms (coma), surgery is often delayed.103 In a randomized trial involving 2,143 patients with ruptured intracranial aneurysms for whom both surgery or endovascular coiling were technically feasible, disability-free survival at 1 year was better with coiling.104 However, these patients were very carefully selected, and there is considerable debate about how widely these results can be generalized. In practice, evaluations by both a neurosurgeon and an endovascular interventionalist are recommended.
Before aneurysm clipping or coiling, patients are kept mildly sedated in a quiet room and given stool softeners to reduce the risk of rebleeding. Anticonvulsants should be given at the first sign of seizure. Blood pressure is gently controlled. Although hypertension is related to rebleeding, some investigators believe that blood pressure works to tamponade the bleeding, and drastic reductions in blood pressure should be avoided.
Hydrocephalus is common after SAH and is very treatable with ventricular drainage. Any change in mental status should prompt the performance of an emergency CT scan to look for signs of hydrocephalus. Because it has been shown to improve outcome, nimodipine, a calcium channel blocker, is begun on the first day and continued for 21 days. After aneurysm clipping, the goal is to prevent vasospasm. Daily transcranial Doppler examinations are warranted. Patients should be well hydrated, and blood pressure should be slightly high. At the first clinical or transcranial Doppler sign of vasospasm, so-called triple H (hypertensive, hypervolemic, and hemodilution) therapy should be initiated to maximize cerebral blood flow, but only in patients with secured (i.e., clipped or coiled) aneurysms. Both colloid and crystalloid therapy are employed, and frequently, pressor support is needed.
