Cerebrovascular Disease

Chapter 6

Cerebrovascular Disease

Recent Developments

  • Intravenous recombinant tissue plasminogen activator (rtPA) is strongly recommended for carefully selected patients who meet additional exclusion criteria and who can be treated within 4½ hours of onset of ischemic stroke.
  • Carotid endarterectomy (CEA) is beneficial for symptomatic patients with recent nondisabling carotid artery ischemic events and ipsilateral carotid artery stenosis of 70%–99%. CEA is not beneficial for symptomatic patients with 0%–29% or 100% stenosis.
  • Newer oral anticoagulants, which include direct thrombin inhibitors and factor Xa inhibitors, should be considered for carefully selected patients with nonvalvular atrial fibrillation.
  • Patients with acute ischemic stroke presenting within 48 hours of symptom onset should be given aspirin (160–325 mg/day) to prevent recurrent stroke, reduce stroke mortality, and decrease morbidity, provided contraindications such as allergy and gastrointestinal bleeding are absent and rtPA was not or will not be used as treatment. Patients who are not tPA candidates may be considered for intra-arterial (IA) therapies.
  • Statin use reduces the risk of stroke and coronary events in patients with coronary artery disease and in those who have had an ischemic stroke of atherosclerotic origin.


Stroke is the third leading cause of death in developed countries, ranking behind heart disease and cancer. From 2000 to 2010, the relative rate of stroke death decreased by 35.8% in the United States, and the actual number of US stroke deaths declined by 22.8%; yet the number of strokes occurring annually in the United States remains approximately 795,000, of which 610,000 are first attacks. Better control of hypertension, cholesterol levels, and diabetes mellitus, as well as increases in smoking cessation, have contributed to this drop in stroke mortality. The annual incidence of ischemic stroke has increased in Eastern Europe, China, and other nations where the widespread adoption of unhealthful lifestyles has accompanied improved economic status. Stroke is the leading cause of long-term disability in the United States today.

There are 2 primary types of stroke: ischemic stroke and hemorrhagic stroke. For extensive discussion of the ophthalmic manifestations of cerebrovascular disease, see BCSC Section 5, Neuro-Ophthalmology.

Cerebral Ischemia

Cerebral ischemia results from interference with circulation to the brain. Usually, cerebral circulation is maintained by a very efficient collateral arterial system that includes the 2 carotid and the 2 vertebral arteries, anastomoses in the circle of Willis, and collateral circulation in the cerebral hemispheres. However, atheromas and congenital arteriovenous malformations can lead to a reduction in cerebral blood flow. This reduction may be generalized or localized. Interruptions in cerebral blood flow can result in permanent neurologic deficits, depending on the extent and duration of the cerebral ischemia.

There are varying degrees of ischemia, which may be classified by severity and duration. A transient ischemic attack (TIA) is a focal loss of neurologic function of sudden onset, persisting for less than 24 hours and clearing without residual signs. Most TIAs last only a few minutes, and the symptoms are primarily associated with insufficiency of the internal carotid, middle cerebral, or vertebrobasilar arterial territories. A completed stroke is an ischemic event that produces a stable, permanent neurologic disability. Most ischemic strokes consist of small regions of complete ischemia in conjunction with a larger area of incomplete ischemia. This ischemic but not infarcted area has been termed the penumbra. The penumbra is dynamic, resulting in changes to the once passive approach to treating patients with acute cerebral ischemia. Clinical manifestations of cerebral ischemia reflect the functions associated with the area of ischemia and include paresis, paresthesia, vision loss, language disturbances, vertigo, diplopia, ataxia, dysarthria, headache, nausea, and vomiting.

Emboli or thrombi caused by atherosclerosis, hypertension, or diabetes mellitus and located in large, medium, and small arteries account for most strokes. Strokes caused by emboli of cardiac origin account for 20% of the total ischemic stroke incidence. Atrial fibrillation is the most common cause of cardioembolic strokes, occurring in up to 20% of such patients. Mural thrombi forming on the endocardium in conjunction with myocardial infarction (MI) account for 8%–10% of the total stroke incidence worldwide. Mitral stenosis and atrial myxoma are other cardiac conditions associated with intracranial embolism. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a rare genetic small-vessel vasculopathy, can mimic multiple sclerosis and cause ischemic stroke.

Nonarteriosclerotic causes of thrombotic occlusion leading to TIA and stroke include internal carotid dissection (causing the classic triad of Horner sign, neck pain/headache, and neurologic signs and symptoms) and inflammatory arteritis (eg, collagen vascular disease, giant cell arteritis, meningovascular syphilis, acute and chronic meningitis, and moyamoya disease).

Another cause of cerebral ischemia is increased viscosity of the blood due to pregnancy and the postpartum period, use of oral contraceptives, postoperative and posttraumatic states, hyperviscosity syndromes, polycythemia, and sickle cell disease. Also, stroke may occur as a result of hypoxemia caused by conditions such as carbon monoxide poisoning, chronic obstructive pulmonary disease, profound anemia, and pulmonary emboli, in which there is decreased oxygenation and oxygen-carrying capacity of the blood.

Diagnosis and Management

The diagnosis of ischemic stroke and TIAs should be differentiated from the diagnosis of diabetic and convulsive seizures, migraine, vertigo, and neoplasms. Although the presentation of stroke is usually characteristic, the diagnosis should be differentiated from that of other conditions that may mimic strokes, such as multiple sclerosis, subdural hematoma, cranial nerve palsy, encephalitis, hypoglycemia, seizures, brain tumor, hypertensive encephalopathy, syncope, migraine, and functional disorder.

A detailed history, including the time and duration of onset, is important. Also, an assessment of risk factors is critical for treating a patient with suspected stroke. Nonmodifiable risk factors include age older than 60 years, male sex, and family history or prior history of stroke or TIAs. Modifiable risk factors include diabetes mellitus, hypertension, hyperlipidemia, cardiac arrhythmias, smoking, alcohol use, illicit drug use, migraine, and hypercoagulable states.

The clinical severity of a stroke can be determined using the US National Institutes of Health Stroke Scale, which assesses level of consciousness, gaze, visual fields, facial strength, motor function of the arms and legs, ataxia, sensation, language, dysarthria, and inattention, giving a specified number of points to each impairment uncovered. A scale of 0–42 is used for the assessment, with 0 being normal function and 42 being the most severe functional impairment. More information on this scale, as well as training in its use and certification, is available at www.strokeassociation.org.

Diagnostic studies

For practical purposes, diagnostic studies may be separated into those done in an acute care setting, such as in the emergency department, and those done in a more subacute setting, such as in a stable inpatient or stable outpatient setting. Emergent testing assesses the patient’s clinical stability and the possibility of stroke mimics or conditions that could contribute to stroke; the tests should include blood glucose, complete blood count, blood chemistry, coagulation studies such as PT/aPTT (prothrombin time/activated partial thromboplastin time), international normalized ratio, troponins, and electrocardiogram. Ideally, all suspected cases of stroke and TIA should receive urgent computed tomography (CT) of the brain. The scan should be completed without contrast because contrast and blood appear similar on CT, and this similarity can result in misinterpretation of the image. CT is very sensitive for the presence of intracranial hemorrhage.

Once the urgent investigations are complete, imaging studies such as magnetic resonance imaging (MRI), magnetic resonance cerebral angiography, CT angiography, and conventional catheter angiography can be considered. MRI is often more sensitive than CT in detecting an evolving stroke within hours of its onset, whereas CT results may be negative for up to several days after an acute cerebral infarct. These techniques can distinguish between acute and chronic infarction and help date hemorrhagic infarction; they can also evaluate for unsuspected space-occupying lesions. MRI, CT, or catheter angiography may be necessary to examine the intracranial and extracranial vessels for stenoses or to identify an aneurysm. Carotid duplex ultrasonography may be used to evaluate the patency of the extracranial carotid arteries; transcranial Doppler ultrasonography can evaluate the intracranial arteries. Diffusion-weighted MRI, apparent diffusion coefficient (ADC) mapping, and CT perfusion imaging are useful in the evaluation of early cerebral ischemia and regional blood flow. Early detection of these conditions by such techniques may allow for early treatment, which may be beneficial in salvaging tissue at risk. Cerebral arteriography is usually required only if the cause is unclear or if intra-arterial thrombolysis or surgical intervention is being strongly considered.

Investigation of the systemic arteries and the heart is essential in determining the cause of cerebral ischemia. Differences between upper limb pulse rates and blood pressure (BP) may indicate serious subclavian disease. Multiple bruits may suggest widespread arterial disease but may be present without significant occlusion. Evidence of a cardioembolic source should be pursued aggressively, especially in younger normotensive persons with cerebral ischemia and in older patients, for whom atrial fibrillation is included in the differential diagnosis. Electrocardiography and telemetry or Holter monitoring should be routine to exclude cardiac dysrhythmia and occult MI. Echocardiography is often helpful in excluding intracardiac emboli; transesophageal Doppler echocardiography is most sensitive in this regard. Lumbar puncture is rarely required in the evaluation of stroke or TIA, unless meningovascular syphilis, meningitis, or subarachnoid hemorrhage is a serious consideration.


The goals of treating ischemic stroke are to restore blood flow to the brain and to salvage ischemic brain tissue that has not already infarcted. Achieving these goals involves ensuring the patient’s medical stability and determining whether the patient is eligible for thrombolytic therapy. There is a narrow window in which to accomplish these objectives, typically within 4½ hours of the onset of symptoms.

Thrombolytic and antithrombotic agents are the primary drugs used in the treatment of ischemic stroke. One such drug is recombinant tissue plasminogen activator (rtPA), a fibrinolytic agent that converts plasminogen into plasmin in the presence of fibrin. This initiates fibrinolysis at the thrombus site, thereby improving blood flow to ischemic areas not yet infarcted (ischemic penumbra). In the US National Institute of Neurological Diseases and Stroke (NINDS) rtPA Stroke Study, the administration of rtPA within 3 hours of acute ischemic stroke was associated with improved function at 3 months but not with earlier neurologic improvement or lower mortality. The European Cooperative Acute Stroke Study III (ECASS III) showed a benefit of rtPA initiated up to 4½ hours after the onset of stroke. However, the exclusion criteria for patients treated 3–4½ hours from symptom onset (age >80 years, severe stroke, diabetes mellitus with a previous infarct, and any anticoagulant use) were more restrictive than for those treated at 3 hours or less. Most studies indicate that the sooner rtPA is initiated, the more likely it is to be beneficial. The most serious complication of administering rtPA is symptomatic intracranial hemorrhage, which occurs in 6.4% of treated patients and has a mortality rate of 50%. Recently, stroke centers have used intra-arterial catheter-directed treatment for delivering thrombolytic agents directly to the site of the vascular occlusion. This has been shown to improve recanalization rates and clinical outcomes and is recommended for middle cerebral artery infarctions up to 6 hours after stroke onset.

Patients with a large cerebral artery occlusion are less likely to benefit from rtPA; endovascular clot removal is often performed in these patients after treatment with rtPA. Clot removal or thrombectomy can be performed within 8 hours of stroke onset and is a reasonable alternative for those patients who cannot receive rtPA. In the Solitaire With the Intention for Thrombectomy (SWIFT) trial, which compared the Solitaire Flow Restoration device (Covidien, Dublin, Ireland) and the Merci Retriever (University of California, Los Angeles) in the treatment of patients with acute ischemic stroke, the Solitaire device achieved better safety, angiographic, and clinical outcomes than did the Merci Retriever.

In addition to thrombolytic drugs, 2 major classes of antithrombotic agents can be used to treat ischemic stroke: antiplatelets and anticoagulants. Although aspirin, clopidogrel, and aspirin/extended-release dipyridamole combination are acceptable drug choices for secondary stroke prevention, aspirin is the only antiplatelet agent that is effective in the early treatment of ischemic stroke. Two large clinical trials showed a benefit of treatment with aspirin over placebo in short-term mortality and recurrent stroke risk when aspirin is initiated within 48 hours of ischemic stroke onset. Early use of combination antiplatelet agents such as aspirin with clopidogrel for acute ischemic stroke may be beneficial, but the available evidence is not consistent and is limited to the specific populations studied. Heparin and related agents are not effective in reduction of mortality or recurrent stroke in patients with cardioembolic or noncardioembolic stroke. In fact, these agents are associated with higher mortality and a worse outcome. Use of heparin may be considered in the acute care setting for stroke due to postoperative atrial fibrillation in patients with mechanical heart valves or in those with cervicocephalic arterial dissections.

A cornerstone of stroke management is to prevent future events, especially because most stroke patients do not receive the acute care treatment previously discussed. Hypertension is the most important risk factor for stroke; thus, patients with hypertension after a stroke should be treated even in the absence of a history of high blood pressure. Hyperlipidemia is also an important and modifiable risk factor for stroke recurrence. There is evidence that the use of high-dose statins in patients with a low-density lipoprotein (LDL) cholesterol level greater than 100 mg/dL (2.59 mmol/L) may be beneficial in preventing future ischemic strokes.

Adams H, Adams R, Del Zoppo G, Goldstein LB; Stroke Council of the American Heart Association; American Stroke Association. Guidelines for the early management of patients with ischemic stroke: 2005 guidelines update a scientific statement from the Stroke Council of the American Heart Association/American Stroke Association. Stroke. 2005;36(4):916–923.

Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med. 2000;343(10):710–722.

Carotid Occlusive Disease

Carotid atherosclerosis occurs most frequently in the proximal internal carotid artery (origin) and at the carotid bifurcation. The progression of luminal narrowing and ulceration leads to ischemic stroke or TIA from embolization, thrombosis, or hemodynamic compromise. Carotid atherosclerosis can be asymptomatic or symptomatic. This is an important distinction, as the management recommendations for these 2 conditions differ.

Asymptomatic carotid bruits occur in 4% of the population older than 40 years, and the annual stroke rate in these individuals is 1.5%. This same population has an annual mortality rate of 4%, primarily from complications of heart disease. The presence of a carotid bruit is a better predictor of arteriosclerotic disease than of stroke. Patients with asymptomatic carotid artery stenosis should be screened for modifiable risk factors for stroke, with lifestyle changes suggested and medical therapy such as antihypertensive and cholesterol-lowering medications prescribed as necessary. The physician should assess life expectancy and comorbid conditions before considering the patient for carotid revascularization, and the patient should be aware of the risks and benefits of the procedure. The use of aspirin in conjunction with CEA is recommended unless contraindicated. In carefully selected patients at high risk for stroke with asymptomatic carotid stenosis (minimum of 60% stenosis confirmed by angiography and 70% by Doppler ultrasonography), prophylactic CEA, performed in a medical center with less than 3% morbidity and mortality, is beneficial. Prophylactic carotid artery stenting (CAS) may be considered in carefully selected patients (stenosis ≥60% on angiography, ≥70% on Doppler ultrasonography, or ≥80% on CT angiography/MR angiography) if the stenosis was 50%–69% on ultrasonography. However, the advantage of CEA over medical therapy is currently not well established. The usefulness of CAS compared to CEA in this asymptomatic population, which is at high risk for surgery, is uncertain.

Patients with TIA or previous stroke in the territory of carotid stenosis are considered symptomatic. The risk of stroke within a year of onset of symptoms is 8% in patients with TIA; the risk thereafter is approximately 6% per year, with a 5-year risk of 35%–50%.

For patients with recent (within the past 6 months) TIA or ischemic stroke and severe (70%–99%) ipsilateral carotid artery stenosis, CEA is recommended if the perioperative morbidity and mortality risk is less than 6%. For patients with recent events and moderate ipsilateral stenosis (50%–69%), CEA is recommended depending on patient-specific factors such as age, sex, and comorbidities and depending on whether the perioperative risk is less than 6%. There is no benefit of CEA or CAS for stenosis of less than 50%. As there is no contraindication to early revascularization with CEA, surgery can be performed within 2 weeks of a TIA or stroke. CAS is considered as an alternative to CEA in symptomatic patients when the patient is at low risk for endovascular intervention and the residual lumen diameter indicates internal carotid artery stenosis of greater than 70% by noninvasive imaging or greater than 50% by catheter angiography. CAS may also be considered in patients with severe stenosis that is difficult to assess surgically; in those with medical comorbidities that greatly increase surgical risk; or in other specific conditions, such as radiation-induced stenosis or restenosis after CEA. It is important to note that CAS is a treatment option for symptomatic patients only when the interventionist’s morbidity and mortality rates are 4%–6%.

The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) randomly assigned patients with asymptomatic or symptomatic carotid disease to CEA or CAS. The primary endpoint of the trial—a composite of any stroke, MI, or death within 30 days of the procedure and ipsilateral stroke during long-term follow-up—was similar in both groups, including the rate of ipsilateral stroke at 31 days to 4 years after the procedure. Interestingly, the study showed that endarterectomy had a greater benefit in older patients (≥70 years), whereas stenting was more beneficial in younger age groups. There was a greater incidence of stroke at 30 days in the stenting group versus the endarterectomy group, but the incidence of MI was significantly lower in the CAS group. A CREST substudy found that at 1 year, despite the higher rate of stroke with stenting, there were no significant differences in any quality of life measure between the CEA and CAS groups.

In addition to cerebral conditions, ocular conditions such as transient monocular visual loss (TMVL) and retinal TIAs can be associated with carotid stenosis. The ophthalmologist is often the first physician to see a patient with TMVL, which is usually embolic, having either a carotid or a cardiac source. The annual stroke rate among patients with isolated TMVL, retinal infarcts, or TIAs is approximately 2%, 3%, and 8%, respectively. Untreated patients with TMVL, retinal infarcts, or TIAs have a 30% risk of MI and an 18% risk of death over a 5-year period. A cardiac source of embolization should be excluded for all patients presenting with isolated TMVL. Transthoracic echocardiography can identify multiple potential cardiac causes for embolism and, as expected, the yield is highest if the clinical history and physical examination suggest a cardiac source such as atrial fibrillation, rheumatic mitral stenosis, diffuse atherosclerosis, left ventricular aneurysm, or clinical endocarditis. Transesophageal echocardiography is superior to transthoracic echocardiography in diagnosing a cardiac source, but despite this improved diagnostic yield, the efficacy of transesophageal echocardiography in cryptogenic stroke or TIA is controversial. Other modalities that are being used in the diagnosis of cardioembolic sources of stroke include inpatient telemetry, ambulatory Holter monitoring, loop recorders, and surgically implantable cardiac monitors.

If evidence suggests that a carotid lesion is the cause of the TMVL, or if venous stasis retinopathy is present, duplex ultrasonography should be performed to determine the presence of vessel wall disease or carotid stenosis.

The following approach should be considered for a patient presenting with a cerebral or retinal TIA:

  • emergency department or urgent outpatient evaluation or hospital admission if the event occurred within the previous 48 hours
  • patient evaluation for the presence of risk factors associated with atherogenesis: hypertension, diabetes mellitus, obesity, hyperlipidemia, and smoking
  • institution of appropriate medical therapy
  • evaluation by appropriate testing for the presence of a cardiac source of emboli
  • determination using duplex ultrasonography of the possibility of carotid stenosis

If ipsilateral carotid stenosis exceeds 70%, if bilateral carotid stenosis greater than 50% is present, or if long-term evidence indicates progressive disease, CEA should be considered—but only if the surgeon’s perioperative stroke and death rate is less than 6%. Otherwise, antiplatelet therapy with aspirin (325 mg/day), aspirin/extended-release dipyridamole combination, or clopidogrel should be initiated. A patient presenting with TIA symptoms who has previously undergone CEA should be evaluated and treated similarly. Special attention should be paid to evaluating early restenosis and thrombosis.

Intracranial Hemorrhage

Intracranial hemorrhage constitutes approximately 15% of acute cerebrovascular disorders. Bleeding from aneurysms of the arteries composing the circle of Willis, bleeding from arterioles damaged by hypertension or arteriosclerosis, and trauma are the most common causes of intracranial hemorrhage. Although there are many causes of intracranial hemorrhage, the anatomical location of the bleeding greatly influences the clinical picture. By location, hemorrhages can be broadly categorized as follows:

  • subarachnoid hemorrhage
  • intracerebral hemorrhage
  • intraventricular hemorrhage

A variety of vascular malformations within and on the surface of the brain parenchyma may present with seizures and headaches. Arteriovenous malformations (AVMs) produce symptoms more commonly than do other types of cerebrovascular malformations.

Approximately 85% of congenital saccular, or “berry,” aneurysms develop in the anterior part of the circle of Willis derived from the internal carotid artery in its major branches. The most common site is at the origin of the posterior communicating artery from the internal carotid artery. Such an aneurysm typically presents with headache and third nerve palsy involving the pupil. Vascular malformations within and on the surface of the brain parenchyma constitute approximately 7% of cases with subarachnoid hemorrhage. Four varieties are recognized:

  1. capillary telangiectasia
  2. cavernous angioma
  3. venous angioma
  4. AVM

Capillary telangiectasias and both types of angiomas typically have a low bleeding risk (<0.5%/year).

Findings that suggest an AVM as the cause of subarachnoid hemorrhage include a history of previous focal seizures, slow stepwise progression of focal neurologic signs, and, occasionally, recurrent unilateral throbbing headache resembling migraine. In addition to meningeal irritation and focal neurologic signs reflecting bleeding, a bruit may be present over the orbit or skull in approximately 40% of patients.

Hypertensive intracerebral hemorrhages can be catastrophic events. Headache is the predominant feature at the onset in 40%–50% of hemorrhages. Generalized seizures are common with intracerebral hemorrhage and are less frequent with subarachnoid hemorrhage or cerebral infarction. The most important clues in the diagnosis of intracranial hemorrhage are explosive onset of headache, history of high BP, and early decline of the level of consciousness with evidence of a focal neurologic deficit.

Immediate CT examination shows blood in the subarachnoid space in approximately 95% of the cases of ruptured aneurysm within 24 hours of headache onset. CT scans identify the size and location of intracerebral hemorrhages, as well as the degree of surrounding edema and the amount and location of any distortion of the brain. If subarachnoid hemorrhage is suspected and CT results are negative, lumbar puncture is indicated. CT should always be carried out first to rule out a mass lesion. Cerebral arteriography remains the definitive procedure for identifying an aneurysm or AVM.

Control and maintenance of BP are mandatory in the treatment of ruptured aneurysms. Surgical intervention is best accomplished by placing a small clip or ligature across the neck of the sac. Coil embolization of the aneurysm is an alternative procedure that may be used. If the aneurysm cannot be directly obliterated, surgical ligation of a proximal vessel may be necessary. Symptomatic AVMs sometimes can be dissected and removed, depending on their location. Proton-beam irradiation remains controversial. Ligation of the feeding vessels, coupled with balloon catheter embolization, may be carried out. Results of surgical drainage or clot removal of parenchymal intracerebral hemorrhages are mostly unsatisfactory.

Furie KL, Kasner SE, Adams RJ, et al; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(1):227–276.

Goldstein LB, Bushnell CD, Adams RJ, et al; American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Epidemiology and Prevention, Council for High Blood Pressure Research, Council on Peripheral Vascular Disease, Interdisciplinary Council on Quality of Care and Outcomes Research. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517–584.

The authors would like to thank Renee B. Van Stavern, MD, for her contributions to this chapter.

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Jan 21, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Cerebrovascular Disease

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