Cerebrovascular Disease

GENERAL PRINCIPLES

• Stroke is a medical emergency that requires rapid diagnosis and treatment. Remember that “TIME IS BRAIN.”

• The hallmark of stroke is acute interruption of cerebral blood flow to a specific brain region, resulting in a sudden-onset focal neurologic deficit.

• Fluctuation of functional deficits after stroke onset or a brief deficit known as TIA suggests tissue at risk for infarction that may be rescued by reestablishing and/or maintaining perfusion.

Epidemiology

More than 795,000 strokes occur per year in the US (one stroke every 40 seconds in the US population), and it is the fourth leading cause of death in the US (one death every 4 minutes).

Etiology

• Ischemic stroke can be subclassified into large artery atherothrombotic, small vessel, embolic, hypoperfusion, or hypercoagulable state (the latter being relatively rare).

î Atherothrombosis results from reduced flow within an artery or embolism of thrombus into the distal segment of an artery.

#9632; Atherosclerosis is the most common etiology of thrombus formation in large vessels.

#9632; Less common etiologies include dissection, fibromuscular dysplasia, moyamoya, and vasculitis.

° Small-vessel disease is due to lipohyalinosis, usually caused by hypertension.

î Cardioembolic strokes account for about 20% of all ischemic strokes. High-risk cardiac sources include atrial fibrillation/flutter, rheumatic valve disease, cardiac thrombus, cardiomyopathy, prosthetic valves, bacterial endocarditis, nonbacterial endocarditis (antiphospholipid antibody syndrome, marantic endocarditis, Libman-Sachs endocarditis), sick sinus syndrome, and coronary artery bypass graft surgery.

î Hypoperfusion occurs due to general circulatory problems and often results in bilateral symptoms. Infarction commonly occurs in border zones between large vessels resulting in watershed infarcts.

î Hypercoagulable states may predispose to arterial thrombosis. These include sickle cell disease, polycythemia vera, essential thrombocythemia, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, hyperhomocysteinemia, and others. Factor V Leiden, protein C and S deficiency, and antithrombin III deficiency typically result in venous, not arterial, infarcts.

• Hemorrhagic stroke occurs in about 20% of all cases.

î The location of an intrapare nchymal hemorrhage (IPH) may suggest its etiology.

#9632; Deep hemorrhage in the basal ganglia, thalamus, or pons is often due to chronic systemic hypertension.

#9632; Amyloid angiopathy typically causes peripheral lobar hemorrhages and is a common etiology in the elderly.

#9632; Head trauma, anticoagulants, drugs (cocaine or amphetamines), arteriovenous malformation (AVM), tumor, blood dyscrasia, hemorrhagic conversion of an ischemic stroke, and vasculitis are other possible hemorrhagic stroke etiologies.

î Aneurysmal subarachnoid hemorrhage (for this section, SAH will refer to aneurysmal subarachnoid hemorrhage unless designated otherwise) is caused by the rupture of an arterial aneurysm resulting in bleeding into the subarachnoid space (which contains CSF). Hypertension, cigarette smoking, genetic factors, and septic emboli (resulting in mycotic aneurysms) can all contribute to aneurysm formation.

• Cerebral venous sinus thrombosis (CVST) is the occlusion of a venous sinus by a thrombus. It occurs in hypercoagulable states such as late pregnancy or postpartum, cancer, and thrombophilias, as well as with trauma and adjacent inflammation/infection. It may manifest with ischemic infarcts and/or hemorrhage.

Risk Factors

Major significant risk factors for ischemic stroke include hypertension, prior TIA/stroke, carotid stenosis, diabetes mellitus, dyslipidemia, heart failure, cigarette smoking, alcohol consumption, oral contraceptive use, obesity, genetics, and age.

DIAGNOSIS

Clinical Presentation

HISTORY

• Time of last known well is critical if thrombolytic therapy is to be administered.

• Onset of symptoms is typically sudden. Ask about progression or fluctuation of symptoms.

• Inquire about cardiac arrhythmias and atherosclerotic risk factors.

• A history of neck trauma or recent chiropractic maneuvers warrants evaluation for arterial dissection.

• SAH commonly presents with sudden onset of a severe thunderclap headache (i.e., the “worst headache of my life”). Lethargy or coma, fever, vomiting, seizures, and low back pain may also be present.

• IPH presents with neurologic deficits accompanied by headache, vomiting, and possibly lethargy.

• CVST often presents with signs and symptoms of elevated intracranial pressure, such as a positional headache with diurnal variability (waking from sleep, worse in the morning), bilateral sixth nerve palsies, blurred vision (typically peripheral with sparing of central vision initially), and papilledema.

PHYSICAL EXAMINATION

• A careful neurologic examination can reliably establish the anatomic location of a stroke in most cases.

• In general, carotid artery distribution (anterior circulation) strokes produce combinations of functional deficits (hemiparesis, hemianopia, cortical sensory loss, often with aphasias or agnosias) contralateral to the affected hemisphere.

• Vertebrobasilar strokes (posterior circulation) produce unilateral or bilateral motor/sensory deficits, usually accompanied by cranial nerve and brainstem signs (vertigo, diplopia, ataxia).

• General physical examination should be focused on possible etiologic factors. Examine for abnormal pulses, arrhythmias, murmurs, carotid bruits, and embolic phenomena.

Differential Diagnosis

Mimics of stroke include postseizure paralysis (Todd paralysis), migraine with aura, and hypo- or hyperglycemia.

Diagnostic Testing

LABORATORY STUDIES

• In the acute setting (e.g., acute evaluation for thrombolytic therapy), these should include blood glucose and may include CBC and coagulation studies (e.g., international normalized ratio [INR], partial thromboplastin time [PTT], antifactor Xa level, thrombin time).

• The following are indicated but not emergent: basic metabolic panel, troponin, lipid profile, and hemoglobin A1C. Tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and blood cultures (if endocarditis is suspected), rapid plasma reagin, antinuclear antibody, antiphospholipid antibodies, drug toxicology screen, and HIV are not part of a “standard screen” but may be indicated in certain clinical contexts.

ELECTROCARDIOGRAPHY

ECG should be done to look for atrial fibrillation or ischemic changes.

IMAGING

• Noncontrast head CT scan should be obtained acutely to rapidly differentiate hemorrhagic from ischemic strokes. It can identify acute hemorrhages in most cases. It is insensitive for acute ischemic strokes. It is often the rate-limiting step in making decisions on thrombolytic therapy. Head CT scan is diagnostic of SAH in 90% of SAH patients in the first 24 hours.

• Emergent vascular imaging (typically CT angiography [CTA] with or without CT perfusion scanning) is now performed in all patients presenting with suspected large vessel occlusion (carotid, proximal middle cerebral artery, or basilar artery) in order to screen for lesions amenable to endovascular thrombectomy.

î CTA is also obtained in patients with IPH to evaluate for the presence of an AVM or aneurysm warranting intervention.

• MRI scan is the most sensitive imaging study for stroke diagnosis. Diffusion-weighted images detect stroke the earliest. If a diagnosis of stroke is clear from clinical examination, MRI is not always necessary because it is unlikely to affect management in a great majority of cases.

• Magnetic resonance angiography (MRA) and venogram are useful noninvasive tests to evaluate large arteries and veins, respectively. MRA of the neck with contrast can serve as a screen for carotid stenosis.

• Carotid Doppler studies enable noninvasive estimation of carotid stenosis and should be done for anterior circulation strokes unless some form of angiography has already been performed for another indication.

• Two-dimensional transthoracic echocardiography is helpful to demonstrate intracardiac thrombi, valve vegetations, valvular stenosis or insufficiency, and right-to-left shunt (bubble study). In some patients, transesophageal echocardiography may be necessary to evaluate the left atrium for thrombi.

DIAGNOSTIC PROCEDURES

• Cerebral catheter angiography is the definitive study for vascular malformations but may miss small aneurysms. Some surgeons prefer having this procedure performed before proceeding with carotid endarterectomy (CEA).

• If suspicion for SAH is high and head CT is negative, an LP should be performed.

î Tubes 1 and 4 should be sent for cell count. If the number of red blood cells (RBCs) decreases dramatically from tube 1 to tube 4, a traumatic LP is more likely than SAH.

î Bloody CSF should be centrifuged and examined for xanthochromia (yellow color). Xanthochromia results from RBC lysis and takes several hours to develop, indicating SAH rather than a traumatic LP.

TREATMENT

• Vital signs, including oximetry and continuous telemetry, should be monitored.

• Hypertension management after ischemic stroke:

° Patients with acute stroke often present hypertensive. Blood pressure (BP) tends to fall on its own over several days following a stroke.

î Aggressive lowering of BP has been associated with neurologic deterioration.¹⁸

î Although management of hypertension in the setting of acute stroke remains controversial, BP should not be lowered acutely unless necessary for treatment of acute coronary syndrome, CHF, hypertensive crisis with end-organ involvement, or systolic BP gt;220 mm Hg or diastolic BP gt;120 mm Hg.¹⁹ BP lowering should proceed cautiously, with 15% during the first 24 hours being a reasonable goal.

• Treatment of intracranial hemorrhage consists of supportive care, gradual reduction in BP, and elevation of head of bed by 15 degrees.

• Treatment of SAH depends on aneurysm anatomy and available resources (surgical clipping vs.

î Supportive measures include bed rest, sedation, analgesia, and laxatives to prevent sudden increases in intracranial pressure.

î Patients with SAH tend toward volume contraction, and although there is insufficient evidence to support a benefit for volume expansion, guidelines do emphasize the importance of maintaining euvolemia to avoid delayed cerebral ischemia (DCI).

î Induced hypertension (unless contraindicated by cardiac comorbidities or in patients with baseline elevated BP) is still recommended in patients with vasospasm/DCI because it has been shown to improve cerebral blood flow in these patients.

î Endovascular angioplasty is recommended in patients with symptomatic vasospasm of proximal cerebral arteries that fail to respond to induced hypertension. In many instances, endovascular therapies are combined with intra-arterial vasodilator therapies (e.g., calcium channel blockers).

î Other nonpharmacologic (i.e., hemodilution) and pharmacologic (i.e., statins, endothelin receptor antagonists, magnesium) therapies have failed to demonstrate a definitive benefit in patients with SAH.

î Future therapies for preventing and treating cerebral vasospasm hinge on gaining a better understanding of the mechanisms underlying cerebral vasospasm and DCI.

Medications

• Recombinant tissue plasminogen activator (t-PA) remains the only FDA-approved pharmacologic therapy for acute ischemic stroke.

î Generally, administration of t-PA must commence within 4.5 hours of stroke onset but should be started as close to onset as possible (i.e., do not delay to see if the patient “gets better” if they present early in the window).²⁰ Some centers are now using perfusion imaging to administer t-PA up to 9 hours from stroke onset.

î Hyperacute MRI may be used to estimate the time of onset for patients with strokes of unknown onset time in order to make decisions regarding thrombolysis.²¹

î t-PA treatment increases the risk for symptomatic brain hemorrhage, compared to placebo, but without any significant impact on 3- and 12-month mortality rates.

î Exclusion criteria differ by stroke center protocol (Table 27-6). The acute stroke team should be contacted emergently to evaluate all acute strokes because some patients ineligible for IV t-PA may be candidates for other interventions, such as thrombectomy.

TABLE 27-6

INCLUSION AND EXCLUSION CRITERIA FOR T-PA FOR ACUTE ISCHEMIC STROKE (WASHINGTON UNIVERSITY STROKE CENTER PROTOCOL)

t-PA Inclusion Criteria

1. Age #8805;18 y

2. Clinical diagnosis of ischemic stroke causing disabling neurologic deficit

3. Onset of stroke symptoms well established to be lt;4.5 h before treatment would begin

t-PA Exclusion Criteria

1. Intracranial hemorrhage on noncontrast head CT

2. Serious head trauma within 3 mo

3. Active bleeding, or suspected underlying coagulopathy including thrombocytopenia (lt;100), INR gt;1.7, therapeutic anticoagulation (verify with coagulation testing)^a

4. Sustained SBP gt;185 or DBP gt;110 at the time of treatment

5. Nondisabling or rapidly improving symptoms

6. Symptoms suggest subarachnoid hemorrhage despite negative CT scan

7. Infective endocarditis suspected as cause of stroke

8. For 3-4.5 h window, severe stroke (NIHSS gt;25)

Relative Exclusion Criteria

Balance potential benefit of t-PA in reducing long-term disability with risk of hemorrhagic

complications. Consultation with a stroke team and other subspecialists is advised.

1. Major surgery or serious trauma within 30 d

2. Intracranial or spinal surgery within 3 mo

3. Serum glucose lt;50 mg/dL or gt;400 mg/dL (reassess after treatment for blood sugar)

4. Stroke within past 3 mo

5. History of intracranial hemorrhage

6. GI/GU hemorrhage within 21 d, or known structural GI malignancy at risk of bleeding

7. Primary or metastatic intracranial, intra-axial neoplasm

8. Seizure at onset (with deficits thought related to postictal paresis)

9. Recent arterial puncture at a noncompressible site

10. Large (gt;10 mm) unsecured intracranial aneurysm

11. Intracranial arteriovenous malformation

12. Extensive regions of clear hypoattenuation on CT (large subacute stroke)

DBP, diastolic blood pressure; GI, gastrointestinal; GU, genitourinary; INR, international normalized ratio; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; t-PA, tissue plasminogen activator.

^aBecause time is critical, thrombolytic therapy should not be delayed while waiting for the results of the PT, PTT, or platelet count unless a bleeding abnormality or thrombocytopenia is suspected; the patient has been taking warfarin, heparin, dabigatran, rivaroxaban, or apixaban; or anticoagulation use is uncertain.

The current American Heart Association/American Stroke Association Guidelines can be found at: Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018;49(3):e46-e110.²²

î Advanced radiology can assist with selection of patients with large vessel occlusions who would benefit from endovascular thrombectomy (Table 27-7).

TABLE 27-7

INCLUSION AND EXCLUSION CRITERIA FOR ENDOVASCULAR THROMBECTOMY (WASHINGTON UNIVERSITY STROKE CENTER PROTOCOL)

Endovascular Thrombectomy Inclusion Criteria

1. Age #8805;18 y

2. Clinical diagnosis of ischemic stroke causing disabling neurologic deficit

a. NIHSS #8805;6 if lt;16 h from time last seen well

b. NIHSS #8805;10 if 16-24 h from time last seen well

3. Ability to initiate thrombectomy in appropriate time window (24 h based on current trials)

4. For posterior circulation strokes (e.g., basilar thrombus), time window is at the discretion of the stroke and neurointerventional attending physicians

Imaging Inclusion Criteria

1. Noncontrast head CT: absence of intracranial hemorrhage/mass/mass effect

2. Noncontrast head CT/MRI: absence of evidence of large, completed infarct

3. CT/MR angiography: large vessel occlusion, e.g., ICA, MCA (M1/M2), vertebral or

basilar artery

4. CT perfusion within 6-16 h^a: core infarct volume #8804;70 mL, core-penumbra mismatch volume #8805;15 mL, core-penumbra mismatch ratio #8805;1.8

5. CT perfusion within 16-24 h^b: core infarct volume #8804;30ml (if age lt;80 y), core infarct volume #8804;20 mL (if age #8805;80 y)

Endovascular Thrombectomy Exclusion Criteria

1. Premorbid disability (mRS #8805;2) or comorbidities that affect recovery potential

2. Intracranial hemorrhage, mass, or mass effect as cause of stroke symptoms

3. Current severe uncontrolled hypertension, SBP gt;185 or DBP gt;110, despite reasonable treatment

4. Active bleeding, or suspected underlying coagulopathy including thrombocytopenia (lt;30), INR gt;3, therapeutic anticoagulation (verify with coagulation testing)

DBP, diastolic blood pressure; INR, international normalized ratio; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure.

^aBased on the results of the DEFUSE 3 trial.²³

^bBased on the result of the DAWN trial.²⁴

î Aspirin and anticoagulants should be held for the first 24 hours after t-PA.

• Aspirin reduces atherosclerotic stroke morbidity and mortality and is typically given at an initial dose of 325 mg within 24-48 hours of stroke onset. The dose may be reduced to 81 mg in the post-acute stroke period.

• Other antiplatelet-aggregating drugs (clopidogrel, aspirin/dipyridamole) are available and may be of benefit for certain patients. Both of these drugs have a significant advantage over aspirin in secondary stroke prevention. Dual antiplatelet therapy for secondary prevention may benefit select patients, though is also associated with increased risk of hemorrhage.

• Heparin, low-molecular-weight heparin (LMWH), and warfarin anticoagulation are not recommended routinely for acute ischemic stroke.

• Anticoagulation with a DOAC or warfarin is indicated to prevent recurrent embolic strokes due to atrial fibrillation. This is typically started after 4-14 days.

• Nimodipine, a calcium channel blocker, improves outcome in SAH patients and may reduce the incidence of associated cerebral infarction with few side effects. However, the mechanism by which nimodipine offers neuroprotection remains unclear (i.e., no evidence that it prevents vasospasm).

• Anticoagulation with heparin/LMWH followed by warfarin is indicated for venous sinus thrombosis both with and without hemorrhagic infarcts. Trials of DOACs for this indication are ongoing. Boluses of heparin to correct the activated PTT (aPTT) should be avoided in the setting of hemorrhage. aPTTs should be closely monitored and maintained between 60 and 80 seconds.

Nonpharmacologic Therapies

• Published trials have demonstrated a clear benefit to endovascular thrombectomy in select patients with acute ischemic stroke. This may be combined with IV t-PA.

• CTA and CT perfusion scans may be used to select patients who will benefit from thrombectomy up to 24 hours after the time they were last known well.²⁴

• These studies represent the first major breakthrough in acute ischemic stroke therapy since the introduction of IV t-PA in 1996.

• Physical, occupational, and speech therapy are extremely important in stroke rehabilitation and have a clear beneficial impact on poststroke outcomes.

• Stroke patients with obvious dysphagia, dysarthria, or a facial droop should be kept nothing by mouth until an experienced individual can assess their swallowing abilities.

Surgical Management

• CEA decreases the risk of stroke and death in patients with recent TIAs or nondisabling strokes and ipsilateral high-grade (70%-99%) carotid stenosis.²⁵

î The CREST (Carotid Revascularization Endarterectomy vs. Stenting) trial provides evidence to suggest that carotid stenting is of equal efficacy to CEA but carries a higher periprocedural stroke risk.²⁶

î Neurology and surgery recommendations should be sought before deciding between the two approaches.

• CEA for asymptomatic high-grade carotid stenosis (#8805;60%) reduces the 5-year risk of ipsilateral stroke in men, provided that the operator’s surgical/angiography complication rate is lt;3%.^27,28

• See the earlier section on Other Nonpharmacologic Therapies for information on endovascular therapies in acute ischemic stroke.

• Hemicraniectomy increases survival and can improve functional outcomes in select patients with large hemispheric infarcts and severe edema (e.g., “malignant” middle cerebral artery infarcts). Neurosurgical consultation should be obtained early in these cases.

• Cerebellar infarction or hematomas may result in brainstem compression or obstructive hydrocephalus and may also warrant urgent neurosurgical intervention.

Lifestyle/Risk Modification

Modifiable risk factors (Table 27-8) include the following:

TABLE 27-8

SECONDARY STROKE PREVENTION (“BLASTED”)

• Blood pressure

• LDL

• ASA (antiplatelet), A1C

• Stroke management and rehabilitation team (varies from facility to facility)

î PT, OT, ST, stroke educator, smoking cessation counseling

• Telemetry: cardiac rhythm monitoring

• Echocardiography

• Doppler for carotid stenosis, diabetes (A1C, diabetes educator, etc.)

ASA, acetylsalicylic acid; LDL, low-density lipoprotein; OT, occupational therapy; PT, physical therapy; ST, speech therapy.

• BP reduction even in normotensive stroke patients is beneficial.²⁹

• Diabetes control is important with care taken to avoid hypoglycemia and hyperglycemia.

• Smoking cessation.

• Patients younger than 75 years with no concerns for safety of statin therapy should be placed on “high- intensity” statin therapy (e.g., atorvastatin 40-80 mg or rosuvastatin 20-40 mg), whereas patients older than 75 years or patients for whom there is concern for safety of statin therapy should be placed on “moderate-intensity” statin therapy (e.g., atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20­40 mg, pravastatin 40-80 mg).³⁰

• Identify and treat obstructive sleep apnea.

• Oral contraceptives or hormonal therapies may need to be discontinued in women with stroke.

Complications

• Cerebral edema following ischemic stroke peaks at 48-96 hours after stroke, and patients need to be watched closely during this time.

• Hemorrhagic conversion of an ischemic stroke is more likely in patients who are receiving anticoagulation or in patients with large strokes, particularly those with embolic ischemic infarcts.