Large vessel infarctions, areas tissue death due to lack of blood flow, are commonly caused by emboli (a foreign body traveling through the bloodstream) to the brain from the heart, the aortic arch, the carotid arteries in the neck, or from the cerebral vessels themselves (Figure 1). Emboli from the heart (e.g., a blood clot) can result from abnormal cardiac rhythms such as atrial fibrillation, from structural disease of the heart valves including endocarditis, or from areas of the heart that have decreased mobility following damage from myocardial infarction (MI). The aortic arch is a common source of atherosclerotic deposits that may dislodge and occlude downstream cerebral vessels. It has been known for decades that the carotid arteries are a common source of emboli that cause stroke; in addition, progressive narrowing of the carotid arteries due to atherosclerosis may lead to decreased blood flow to the ipsilateral cerebral hemisphere and subsequent ischemia. Finally, the intracerebral vessels themselves may become diseased with atherosclerotic plaque leading to either progressive occlusion (thrombosis) or a source of more distal emboli.
Small vessel-related strokes, termed "lacunar" infarctions due to their lake-like appearance in the brain on imaging, are usually caused by thrombosis of small penetrating arteries that arise from the larger vessels (Figure 2). These small arteries are particularly susceptible to injury from smoking, hypertension, and diabetes and can eventually thrombose due to platelet-rich clots. Although the area of the brain injured is much smaller than in most large vessel strokes, many of the key motor and sensory pathways run through small-vessel territory, often resulting in significant symptoms despite the smaller size of injury.
The best proven treatment for ischemic stroke is administration of intravenous tissue plasminogen activator (IV t-PA), a drug designed to dissolve clots and restore blood flow. The initial randomized trial proving its efficacy was published in 1995 and multiple studies, including a large observational experience in the European Union published in 2007, have verified these results1, 2. IV t-PA is most commonly used within 3 hours of onset of stroke symptoms; studies of IV t-PA between 3-4.5 hours have recently been published and have led many to expand this treatment window22. IV t-PA has no significant effect on mortality, but 3 months after an ischemic stroke, patients treated with IV t-PA are approximately 30 percent more likely to have minimal or no functional deficits compared with those given placebo. The risk of any drug used to lyse (dissolve) blood clots is bleeding, and IV t-PA use is associated with an increased risk of intracerebral hemorrhage of about 6 percent in the first 36 hours (compared with 0.6 percent of patients given placebo)1. In order to reduce this risk of bleeding, strict criteria are used to select patients for IV t-PA therapy, including assuring a normal platelet count, normal coagulation studies, and no signs of intracranial hemorrhage on the initial imaging study (CT or MRI).
In patients with large vessel occlusions, 2 other less-proven strategies are often used to open blood vessels in patients who are ineligible to receive IV t-PA, most commonly because they present too late to fall within the 3-hour time window for IV t-PA. These techniques involve first a catheter-based angiogram of the cerebral vessels. Physicians achieve access to the cerebral vessels through a long catheter inserted into the femoral artery in the groin. Contrast injection allows for visualization of the cerebral circulation and proximal blood clots which may either be removed with a mechanical embolectomy device or dissolved using local intra-arterial delivery of lytic medications.
The PROACT studies as well the recent MELT trial demonstrated the efficacy of intra-arterial lysis within 6 hours of symptom onset using pro-urokinase3, 4. These trials have not resulted in United States Food and Drug Administration (FDA) approval of this medication, although intra-arterial lysis with t-PA and other agents is commonly performed. The MERCI retriever was the first of the FDA-approved devices which has been demonstrated to successfully open occluded blood vessels after stroke within 8 hours of symptom onset5. A randomized trial is needed in order to compare intra-arterial lysis and mechanical embolectomy in a head-to-head fashion. Trails of a combination of intravenous thrombolysis (IV t-PA) followed by endovascular therapies are ongoing.
Video cartoon of L5 MERCI retriever mechanical embolectomy device from Concentric Medical. From: http://www.concentric-medical.com/resources.html
One disadvantage of these endovascular techniques is that they can only be performed by specialists (neurointerventional radiologists and others) who are generally available mainly at tertiary care centers. Recent Joint Commission accreditation of primary Stroke Centers has established hospitals of excellence where IV t-PA, and in some cases endovascular techniques, are commonly used. This designation of specific hospitals that specialize in stroke care allows emergency medical personnel to quickly triage patients having a stroke to centers that can provide rapid, effective, state-of-the-art stroke care.
Another approach to the treatment of acute stroke involves administration of so-called neuroprotective compounds, designed to delay or block the cascade of events in ischemic neurons that is triggered by lack of blood flow and eventually results in cell death. Although animal studies of multiple neuroprotective agents have been successful over the past 2 decades, human trials have largely been disappointing. Currently, none of these drugs is commercially available or approved to treat ischemic stroke although trials continue.
High blood pressure remains the major risk factor for ischemic stroke, but in the acute setting, a rise in blood pressure may actually be protective, allowing increased collateral blood flow to reach areas of the brain that are ischemic but have not yet suffered irreversible injury (ischemic penumbra). As a result, current guidelines suggest allowing "permissive hypertension" in the acute setting, followed by aggressive lowering beginning days to weeks after an ischemic stroke. Blood pressure should be allowed to rise without treatment to at least 220 mmHg systolic acutely6; randomized trials are currently underway to test this approach. An important exception involves the use of IV t-PA where control of the blood pressure below 185 mmHg systolic is required to at least theoretically reduce the chances of intracerebral hemorrhage following drug delivery. Tight control of glucose and temperature is also recommended in the treatment of acute stroke as hyperglycemia and fever likely increase neuronal damage and have a deleterious effect on eventual outcome.
Prevention of Complications in the Acute Setting
Patients with ischemic stroke are at risk for multiple hospital-acquired complications, and much of the care of these patients in the first days to weeks focuses on prevention of these complications. Hospitals are increasingly relying on multidisciplinary "stroke teams" to manage these sometimes critically ill patients during their inpatient course.
Patients who have lost mobility of their limbs are at risk for deep venous thrombosis and pulmonary embolus. Prophylaxis involves administration of either subcutaneous heparinoid compounds or sequential compression devices placed on the legs. Recent data has called into question the effectiveness of the latter approach while studies have demonstrated the superiority of a low molecular weight heparin (enoxaparin) over unfractionated heparin in this patient population7.
Patients who have difficulty swallowing after a stroke are at risk for development of aspiration pneumonia, and all stroke patients should be screened for dysphagia prior to eating or drinking by mouth. If the patient does not have the ability to safely take food by mouth, a feeding tube should be placed via a nasogastric or percutaneous route in order to provide adequate nutrition which is essential for recovery in the early peri-stroke period.
In some patients with very large strokes involving the middle cerebral artery or the cerebellum, malignant cerebral edema may develop over the first 2-5 days which can result in brain herniation and death. Medical treatment with osmotic agents such as mannitol and hypertonic saline can modestly reduce swelling. A surgical approach is sometimes necessary for refractory cases; hemicraniectomy, where part of the skull overlying the area of the stroke is removed in order to allow the brain to swell outward, therefore relieving pressure, has been shown in 3 randomized trials and a meta-analysis to reduce morbidity and mortality in young patients (less than 60 years old) with large middle cerebral artery ischemic stroke8.
Evaluation of Stroke Etiology
Much of the initial evaluation of ischemic stroke patients in the first hours and days is directed toward determining the cause of the stroke and then choosing effective therapy, based on the etiology identified, to prevent subsequent strokes (secondary prevention). A careful evaluation of modifiable stroke risk factors is a key component of early stroke evaluation and treatment; screening for smoking, hypertension, diabetes, and hypercholesterolemia drive individualized secondary prevention strategies.
Evaluation of the carotid arteries is required in most cases of anterior circulation, large vessel ischemic stroke. The carotid arteries can be imaged with carotid ultrasound, CT angiography, MR angiography, or catheter-based conventional angiography (Figure 5). Patients in whom the carotid artery is narrowed between 70 and 99 percent ipsilateral to (on the same side as) the stroke benefit from a surgical procedure, endarterectomy, in order to reduce their chances of subsequent stroke, as proven in large multicenter trials in North America and Europe9, 10. During the procedure, a vascular surgeon or neurosurgeon makes an incision in the neck, opens the carotid artery, and removes the atherosclerotic plaque. Recently, carotid stenting, a less-invasive endovascular technique, has been performed for this same indication, and results of large trials of this technique compared with endarterectomy have shown mixed results11, 12, 23.
Figure 5: CT Angiography (A.) and catheter-based conventional angiography (B.) images in a patient with a right hemispheric embolic stroke demonstrating critical stenosis of the right internal carotid artery in the neck (arrows).
Atrial fibrillation remains an important etiology of embolus, accounting for an estimated 15 to 20 percent of ischemic strokes yearly. Patients who continuously or intermittently experience this cardiac rhythm are at risk for stroke when blood clots form in the less mobile portions of their left atrium and travel to the brain. Patients with stroke and atrial fibrillation are generally treated with anticoagulant medications such as warfarin to prevent further events. Detection of atrial fibrillation in patients with stroke involves an electrocardiogram on admission, followed by monitoring of the heart rhythm for a variable period of time either in the hospital or in the outpatient setting. In some patients with paroxysmal atrial fibrillation, extended monitoring may be needed in order to detect this rhythm.
Most patients with suspected embolic stroke will also undergo imaging of the heart via transthoracic (TTE) or transesophageal (TEE) echocardiography. These ultrasound-based techniques allow for detection of structural heart disease including endocarditis, prior myocardial infarction with regional wall-motion abnormalities, and thrombus in the heart chambers. Most echocardiogram studies performed on patients following stroke will also include a shunt or "bubble" study, looking for defects in the intraventricular septum that could allow clots from the legs and other parts of the body to travel directly to the brain. Controversy exists as to how best to treat patients with this septal defect, termed patent foramen ovale (PFO); current trials are comparing the use of medical therapy to surgical or endovascular cardiac procedures designed to permanently close these intracardiac shunts.
Secondary Prevention of Stroke
Following the initiation of acute therapy (if eligible), stroke management focus shifts toward prevention of a second event (secondary prevention). All patients should be discharged with either an antithrombotic (such as aspirin) or anticoagulant (Coumadin or Heparin) medication that will usually be used for life6. Before the late 1990s, most patients with stroke were treated with anticoagulants. However, the results of multiple large randomized trials have demonstrated the equal efficacy of antithrombotic medications in most types of stroke, with lower rates of bleeding13, 14. As a result, few stroke patients are now treated with anticoagulant medications.
However, some patients will benefit from anticoagulation after stroke, most prominently patients with proven atrial fibrillation. Other indications for anticoagulation which are less evidenced-based but widely practiced include stroke associated with cervical artery dissection, stroke in the setting of severely depressed cardiac ejection fraction (less than 35 percent), and stroke resulting from venous sinus thrombosis.
Antithrombotic medications are the current mainstay of secondary stroke prevention. Current widely-used medications for this purpose include aspirin, clopidogrel (Plavix), and a combination of extended-release dipyridamole and aspirin (Aggrenox). Significant variability in practice has dictated which of these medicines is prescribed for an individual patient following a stroke. Aspirin at a dose of at least 160 mg per day is effective in the acute period (within 48 hours), and thereafter most physicians in the United States prescribe either 81 mg or 325 mg. Studies have demonstrated the superiority of extended-release dipyridamole and aspirin over aspirin alone15. Subgroup analysis of mainly cardiac trials comparing clopidogrel with aspirin suggests that clopidogrel may be superior16. Despite the results of these trials, aspirin is still widely used as it is probably more well-tolerated, inexpensive, and widely-available than either of the other compounds. The results of a large randomized trial (PRoFESS) comparing extended-release dipyridamole and aspirin with clopidogrel for secondary stroke prophylaxis indicate that the two compounds have essentially equal efficacy21.
Modification of stroke risk factors is an important part of stroke management and secondary prevention. Patients who are smoking tobacco should be encouraged to quit using all available techniques and medications. After the acute period of permissive hypertension, blood pressure should be lowered to a normal range. Angiotensin converting-enzyme inhibitor and thiazide diuretic classes of medications have been shown to be particularly effective in preventing subsequent stroke. Diabetes, if present, should be tightly controlled with diet and exercise or medications. Hypercholesterolemia in the form of elevated LDL or low HDL is usually treated with the HMG-CoA reductase class of medications known as "statins." A large study demonstrated a modest reduction in secondary vascular events over a 5-year period when stroke patients were placed on a high dose of atorvastatin17.
Primary prevention
Prevention of acute ischemic stroke in patients without a previous history of stroke or TIA (primary prevention) mainly involves modification of vascular risk factors including smoking, hypertension, diabetes, and hypercholesterolemia18. Exercise and maintaining a healthy weight also likely reduce the risk of stroke. Daily aspirin and/or folic acid supplementation may help reduce stroke risk, although study results have been mixed. Many patients with atrial fibrillation and no previous history of stroke will benefit from anticoagulation with warfarin or other compounds although the benefit of this treatment must be weighed carefully against the increased risk of bleeding complications. In those patients who cannot tolerate warfarin, either aspirin or the combination of aspirin and clopidogrel should be used. Patients who have asymptomatic carotid stenosis greater than 60 percent often benefit from revascularization with endarterectomy provided that the surgeon performing the procedure has a low complication rate19; there is no clear consensus as to which patients without symptoms of stroke should undergo screening for carotid stenosis.
Special Etiologies of Ischemic Stroke in Young Persons
Stroke in patients younger than age 55 is fairly uncommon and may be associated with specific etiologies other than those that are typically identified in older individuals. Young patients, including children, do indeed suffer strokes, and therefore the sudden onset of a neurologic deficit in any patient, regardless of age, should prompt rapid investigation into the possibility of stroke.
Cervical artery dissection occurs when there is a tear in the wall of either the carotid artery or vertebral artery in the neck. This tear exposes thrombogenic portions of the endothelium leading to local clot formation; stroke occurs either through embolic events or via progressive stenosis and eventual occlusion of the involved vessel (Figure 6). Cervical artery dissections often present with neck pain and associated neurologic signs, although pain may be absent in some cases. A proportion of patients with dissection have underlying connective tissue disorders, but other risk factors for dissection are often identified, including neck trauma, a recent history of severe vomiting or coughing, motor vehicle accidents, and high-velocity chiropractic neck manipulation. Cervical artery dissection is usually diagnosed through imaging of the neck vessels via ultrasound, CT angiography, MR angiography, or catheter-based conventional angiography. Treatment using short-term anticoagulation is common, although there is no good randomized evidence supporting this approach.
Figure 6: Cartoon of mechanisms of stroke in cervical artery dissection. In (A.) embolic material from the thrombus that forms at the site of the dissection may travel downstream to the cerebral vessels causing a stroke. The vascular wall may dilate causing a pseudoaneurysm that may cause pressure on adjoining structures in the neck. In (B.) progressive narrowing of the vessel due to thrombus at the site of the dissection may lead to stroke via decreased blood flow to the cerebral hemisphere. Image courtesy of Wade S. Smith, MD PhD.
Ischemic strokes resulting from occlusion of the cerebral veins, rather than arteries, usually occur in the setting of hypercoagulable states, often in young patients. Hypercoagulability can result rarely from medications such as oral contraceptives and chemotherapeutic agents. Additional causes of hypercoagulability include genetic mutations in the clotting pathway as well as systemic malignancy and infection. Patients with venous infarction are usually treated with anticoagulation, especially when the stroke involves the large venous sinuses that drain blood from the brain parenchyma. Venous stroke patients who are refractory to treatment with anticoagulation may be candidates for endovascular therapies.
Rehabilitation
A key element of stroke care involves the prompt initiation of rehabilitation services, ideally within the first 24-48 hours. Physical therapy, occupational therapy, and speech therapy all play key roles for recovery of function. Many patients are discharged from the hospital directly into aggressive inpatient or outpatient rehabilitation programs. Newly-developed physical therapy techniques such as constraint-induced therapy have shown promise in recent clinical trials20. Rigorous studies of novel rehabilitation methods that aim to improve stroke patients' strength, language, memory, and sensory processing will be an important focus of research in the coming decade.
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6. Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline. Stroke. 2006;37(2):577-617.
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23. Brott TG, Hobson RW 2nd, Howard G, et al: Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis. N Engl J Med 2010; 363:11-21.
USEFUL WEBSITES
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