Stroke - Harrison's Principles of Internal Medicine, 22nd Edition (2025)

Definition and Epidemiology

• Stroke is the second leading cause of death worldwide - 7.1 million deaths in 2020
• Nearly 7 million Americans age 20+ report having had a stroke
• Prevalence is expected to rise by 3.4 million adults (to 4% of the entire adult population) in the next decade
• Age-standardized death rate has fallen ~15% due to better prevention and treatment
• Overall disease burden continues to climb as populations age

Types of Stroke

1. Ischemic stroke (~87%) - caused by reduction in blood flow
2. Hemorrhagic stroke - bleeding directly into or around the brain

• TIA: all neurologic signs and symptoms resolve within 24 h without evidence of brain infarction on imaging
• Stroke: neurologic signs/symptoms last >24 h or brain infarction is demonstrated on imaging

Pathophysiology of Ischemic Stroke

Figure 438-1: Major steps in the cascade of cerebral ischemia. NOS = inducible nitric oxide synthase; PARP = poly A ribose polymerase.

• Blood flow to zero kills brain tissue (neurons, dendrites, axons, glia) within 4-10 minutes
• CBF <16-18 mL/100 g tissue/min causes infarction
• The ischemic penumbra - surrounding tissue at risk - is the target of acute therapy

1. Ischemic energy failure → glutamate release → glutamate receptor activation
2. Ca²⁺/Na⁺ influx → proteolysis → membrane and cytoskeletal breakdown → cell death
3. Mitochondrial damage → free oxygen species → lipolysis → phospholipase → arachidonic acid production
4. iNOS activation → more free oxygen species
5. PARP activation
6. Reperfusion (after thrombolysis/thrombectomy) → inflammatory response → leukocyte adhesion

Approach to the Patient - FAST

• Facial weakness
• Arm weakness
• Speech abnormality
• Time (treatments are highly time sensitive)

Stroke Syndromes

Anterior Circulation

• Most common cause: embolus (artery-to-artery, cardiac, or cryptogenic)
• M1 segment gives rise to lenticulostriate arteries supplying putamen, globus pallidus, posterior limb of internal capsule, caudate
• Complete MCA occlusion: contralateral hemiplegia, hemianesthesia, homonymous hemianopia, ipsilateral gaze preference
• Dominant hemisphere: global aphasia
• Non-dominant hemisphere: anosognosia, constructional apraxia, neglect
• Superior division: Broca's (non-fluent) aphasia + right arm weakness
• Inferior division: Wernicke's (fluent) aphasia + right homonymous hemianopia

• Supplies medial frontal and parietal lobes
• Occlusion: contralateral leg > arm weakness, frontal lobe signs (abulia, incontinence)

Posterior Circulation

• Supplies midbrain, thalamus, temporal and occipital lobes
• P1 occlusion (proximal): thalamic syndromes, midbrain signs
• P2 occlusion: contralateral homonymous hemianopia (macular sparing), cortical blindness if bilateral

• "Locked-in syndrome" with bilateral ventral pontine infarction
• Occlusion: coma, quadriplegia, cranial nerve palsies

• Lateral medullary (Wallenberg) syndrome: ipsilateral facial numbness, Horner syndrome, ataxia; contralateral limb pain/temperature loss; dysphagia, hoarseness

Small-Vessel (Lacunar) Stroke

• Accounts for ~20% of all strokes
• Caused by atherothombotic or lipohyalinotic occlusion of 30-300 µm penetrating branches of MCA, circle of Willis, basilar artery
• Principal risk factors: hypertension and age
• Infarct size: 3 mm to 2 cm

1. Pure motor hemiparesis - infarct in posterior limb of internal capsule or pons (face + arm + leg all involved)
2. Pure sensory stroke - infarct in ventral thalamus
3. Ataxic hemiparesis - infarct in ventral pons or internal capsule
4. Dysarthria-clumsy hand - infarct in ventral pons or genu of internal capsule

Etiology of Ischemic Stroke

1. Embolism - cardiac sources (AF, mural thrombus, valvular disease) or artery-to-artery (carotid plaque)
2. In-situ thrombosis - typically small penetrating arteries
3. Hypoperfusion - flow-limiting stenosis causing "watershed" ischemia

Acute Treatment of Ischemic Stroke

Step 1: Imaging

• Emergency noncontrast CT head to differentiate ischemic vs. hemorrhagic stroke
• Features favoring hemorrhage: depressed consciousness, very high BP, worsening after onset
• Features favoring ischemia: maximal deficit at onset, or deficit that remits

6 Treatment Categories:

1. Medical support
2. IV thrombolysis
3. Endovascular revascularization (thrombectomy)
4. Antithrombotic treatment
5. Neuroprotection
6. Stroke centers and rehabilitation

Medical Support

• Optimize cerebral perfusion in ischemic penumbra
• Prevent complications: pneumonia, UTI, skin breakdown, DVT/PE
• DVT prophylaxis: subcutaneous heparin or pneumatic compression stockings
• BP management:
  • Reduce if BP >220/120 mmHg
  • Reduce if BP >185/110 mmHg before thrombolysis
  • Avoid routine lowering below these thresholds (risks worsening outcome)
  • β-blockers (e.g., esmolol) useful when managing competing cardiac demands
• Treat fever (detrimental to outcomes)

IV Thrombolysis (tPA)

• Alteplase (rt-PA) 0.9 mg/kg IV (max 90 mg); 10% as bolus, rest over 60 min
• Window: within 3-4.5 hours of symptom onset
• Benefit is strongly time-dependent: "time is brain"
• Contraindications include hemorrhage on CT, recent surgery, coagulopathy, and BP >185/110 (must be controlled before giving)

Endovascular Thrombectomy

• For large-vessel occlusion (MCA, ICA, basilar)
• Extended window up to 24 hours with perfusion imaging selection
• Combined with tPA when eligible

Antithrombotic Therapy (Acute)

• Aspirin 160-325 mg within 48 h of ischemic stroke (reduces recurrence risk by ~1%)
• Not a substitute for thrombolysis

Stroke Prevention

Antiplatelet Agents

• Aspirin: acetylates platelet COX → irreversibly inhibits thromboxane A2 (platelet aggregating) while transiently inhibiting prostacyclin; low-dose preferred
• Clopidogrel: blocks ADP receptor (P2Y12) → inhibits glycoprotein IIb/IIIa activation; CAPRIE trial showed marginal superiority over aspirin
• Aspirin + extended-release dipyridamole: combination option
• Ticagrelor + aspirin: shown to reduce secondary stroke risk; not superior as monotherapy

• Clopidogrel 300 mg load then 75 mg/d + aspirin 75 mg/d for the first 21 days after TIA or minor ischemic stroke → superior to aspirin alone (8.2% vs 11.7% 90-day stroke risk); benefit limited to non-CYP2C19 poor metabolizers
• Long-term DAPT is NOT recommended (increased hemorrhage and mortality in SPS3, MATCH, CHARISMA trials)

Anticoagulation

• Warfarin (or DOAC) for cardioembolic stroke due to atrial fibrillation
• Target INR 2-3 for warfarin
• DOACs (dabigatran, rivaroxaban, apixaban) preferred over warfarin in non-valvular AF
• Not routinely recommended for non-cardioembolic stroke

Risk Factor Modification

• Hypertension control: most important modifiable risk factor
• Statin therapy (LDL reduction)
• Smoking cessation
• Diabetes management
• Carotid endarterectomy or stenting for high-grade symptomatic carotid stenosis (>70%)

Stroke Centers and Rehabilitation

• Stroke units improve outcomes compared to general medical wards
• Multidisciplinary teams (neurology, nursing, PT, OT, speech therapy)
• Early rehabilitation initiated within 24-48 h
• Rehabilitation goals: maximize recovery in the ischemic penumbra that has not yet infarcted, and compensatory strategies for infarcted tissue

Less Common Causes

• Hypercoagulable states: protein C/S deficiency, antiphospholipid syndrome - more commonly cause cortical vein/sinus thrombosis than arterial stroke
• CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy): hereditary small-vessel disease
• Vasculitis (CNS, systemic)
• Arterial dissection (carotid, vertebral): especially in young patients with neck trauma or spontaneous; Horner syndrome + ipsilateral neck pain is a clue
• Fabry disease: X-linked lysosomal storage disorder; stroke in young patients
• Sickle cell disease
• Drug use: cocaine, amphetamines (vasospasm, accelerated atherosclerosis)