Ischemic Stroke¶
Chapter 438 | Part 13: Neurologic Disorders · Part 13 – Neurologic Disorders · Chapter 438
Key Clinical Points¶
- The ischemic penumbra is defined as the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction; saving this tissue is the primary goal of revascularization.
- IV thrombolysis (rtPA or tenecteplase) is indicated within 4.5 hours of onset if no hemorrhage is seen on CT; tenecteplase is an alternative bolus option.
- Endovascular thrombectomy improves outcomes for large-vessel occlusions (LVO) (ICA, MCA, basilar) up to 24 hours from onset if imaging shows a mismatch.
- Blood pressure management: Target <185/110 mmHg if thrombolysis is anticipated; otherwise, reduce only if >220/120 mmHg.
- Aspirin is the only antiplatelet agent proven effective for acute treatment; dual antiplatelet therapy (DAPT) is used for 21-30 days after minor stroke or TIA.
- Nonvalvular atrial fibrillation is the most common cause of cardioembolic stroke globally.
- Cerebellar infarction can mimic labyrinthitis; even small amounts of edema can cause brainstem compression requiring emergency suboccipital decompression.
- Hemicraniectomy reduces mortality by 50% in patients with significant cerebral edema.
- Paradoxical embolization often occurs via a patent foramen ovale (PFO) or atrial septal defect (ASD).
- Carotid artery stenosis >50% requires endarterectomy regardless of infarct size.
DEFINITION & OVERVIEW¶
• Ischemic Penumbra:
Definition (Harrison's 22e): the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction. ◦ Goal: Save the penumbra via revascularization to prevent progression to infarction. ◦ Mechanism: Restoration of blood flow provides oxygen and glucose, reverses tissue acidosis, clears glutamate and toxic oxygen species, and halts waves of cortical spreading depression. • Transient Ischemic Attack (TIA): Definition (Harrison's 22e): a clinical syndrome characterized by transient symptoms resulting from ischemia without infarction unless prolonged.
EPIDEMIOLOGY¶
• Cardioembolic Stroke: Responsible for ~20% of all ischemic strokes. ◦ Primary cause: Nonvalvular atrial fibrillation (risk of stroke ≈ 5% annually). • Carotid Atherosclerosis: Accounts for approximately 10% of ischemic strokes.
ETIOLOGY & PATHOPHYYSICOLOGY¶
• Mechanism of Injury: ◦ Reduced blood flow leads to death of brain tissue (neurons, glia) within 4–10 min if flow reaches zero. ◦ Factors influencing survival: Collateral blood flow, anatomical location, and systemic blood pressure. ◦ Management: It is reasonable to suppress fever and prevent hyperglycemia during/after ischemia. Mild hypothermia efficacy is not clearly demonstrated.
Pathophysiology Cascade¶
• Cascade Steps: Arterial occlusion → energy failure, spreading depression, mitochondrial damage, PARP activation, glutamate release, Ca2+/Na+ influx, inflammatory response, iNOS, free oxygen species, proteolysis, leukocyte adhesion, lipolysis, membrane/cytoskeletal breakdown, arachidonic acid production, phospholipase activation, and acid production. ◦ Reperfusion Injury: Can trigger leukocyte adhesion, lipolysis, and production of free oxygen species.
Mechanisms of Ischemic Stroke¶
• Embolism: ◦ Cardioembolic (e.g., atrial fibrillation, myocardial infarction, valvular lesions). ◦ Artery-to-artery (from carotid atherosclerotic plaque). • In situ Thrombosis: ◦ Typically affects small penetrating arteries (e.g., lacunar strokes). • Hypoperfusion: ◦ Caused by flow-limiting stenosis of major extracranial or intracranial vessels; often results in 'watershed' ischemia.
CLINICAL FEATURES¶
• General Presentation: ◦ Embolic strokes typically occur suddenly with maximum deficit at onset. ◦ Reperfusion may cause petechial hemorrhages (usually not clinically significant unless causing mass effect). • Site-Specific Risks: ◦ Cerebellar Infarction: May mimic labyrinthitis (vertigo/vomiting). → Warning: Head or neck pain suggests vertebral artery dissection. → Risk: Even small amounts of edema can cause brainstem compression → coma/respiratory arrest → requires emergency suboccipital decompression. • Imaging Findings: ◦ Hyperdensity in the MCA on CT is highly specific for occlusion but only seen in 20% of cases.
DIFFERENTIAL DIAGNOSIS¶
• Hemorrhagic Stroke: Identified via noncontrast head CT. ◦ No reliable clinical findings can conclusively separate ischemic from hemorrhagic stroke. • Infectious/Inflammatory: Meningitis (syphilis, TB, fungal, bacterial, zoster). • Vascular/Other: ◦ Subarachnoid hemorrhage vasospasm. ◦ Moyamoya disease. ◦ Eclampsia. ◦ Labyrinthitis (mimicked by cerebellar stroke).
DIAGNOSTIC APPROACH¶
- Initial Screening: ◦ Perform emergency noncontrast head CT to rule out hemorrhage. ◦ Obtain finger stick blood glucose (required before thrombolysis).
- Advanced Imaging: ◦ CTA: Identify large-vessel occlusion (LVO) in ICA, MCA, or basilar artery. ◦ CTP: Measure ischemic penumbra; identify 'mismatch' (tissue at risk vs. core). ◦ MRI: Used to confirm infarct size and rule out other pathologies.
- Laboratory/Supportive Workup: ◦ ECG and cardiac telemetry (detect arrhythmias/MI). ◦ Standard labs (CBC, electrolytes, BUN, Cr, lipid profile, PT, PTT) should be performed but must not delay thrombolysis.
MANAGEMENT & TREATMENT¶
- Initial Stabilization: ◦ ABCs; correct hyperglycemia/hypoglycemia.
- Blood Pressure Management: ◦ If thrombolysis anticipated: Target <185/110 mmHg. ◦ Otherwise: Reduce only if >220/120 mmHg.
- Thrombolysis (rtPA or Tenecteplase): ◦ Criteria: Clinical stroke, onset ≤4.5h, no hemorrhage on CT, age ≥18. ◦ rt1-rtPA Dose: 0.9 mg/kg IV (max 90 mg) as 10% bolus + remainder over 1 hr. ◦ Tenecteplase Dose: 0.25 mg/kg IV (max 25 mg) push over 5 sec. ◦ Monitoring: Frequent cuff BP; stop infusion if status declines or BP is uncontrolled → give cryoprecipitate and re-image. ◦ Safety: Avoid urethral catheterization for ≥2 h; no other antithrombotic for 24 h.
- Endovascular Revascularization: ◦ Indicated for LVO (ICA, MCA, basilar) up to 24 hours from onset if imaging shows mismatch.
- Antithrombotic Therapy: ◦ Aspirin: Standard initial treatment. ◦ DAPT (Aspirin + Clopidogrel/Ticagrelor): Used for 21-30 days after minor stroke or TIA. ◦ Clopidogrel Dose: 600 mg load, then 75 mg daily. ◦ Ticagrelor Dose: 180 mg load, then 90 mg twice daily (preferred in patients with CYP2C19 polymorphisms).
- Special Interventions: ◦ Hemicraniectomy: Reduces mortality by 50% in cases of significant cerebral edema. ◦ Suboccipital Decompression: For cerebellar infarcts showing signs of brainstem compression.
Decision Pathway (Flowchart 1)¶
- Pre-hospital: Suspected stroke → Call ahead → Code stroke activation.
- Initial Assessment (Onset <6h): ◦ CT shows no hemorrhage & patient is thrombolysis eligible → Give IVPA (rtPA or Tenecteplase). ◦ Followed by CTP: If 'ICM-1 or BA occlusion' → Thrombectomy; else → Inpatient management.
- Initial Assessment (Onset ≥6h): ◦ CT shows no hemorrhage & CTP shows favorable perfusion → Proceed to CTP analysis. ◦ If 'ICM-1 or BA occlusion' → Thrombectomy; else → Inpatient management.
- Post-Acute Management: ◦ If Atrial Fibrillation (AF) identified: Apixaban 5 mg BID (or 2.5 mg if low GFR). ◦ If no AF detected: Ambulatory monitor + antiplatelets; switch to OAC if intermittent AF is found. ◦ If significant carotid stenosis: Refer for endarterectomy during same stay regardless of infarct size. ◦ Standard Care: DAPT (Aspirin 81 mg + Clopidogrel 600/75 or Ticagrelor 180/90) for 21-30 days, then Aspirin 81 mg.
PROGNOSIS & COMPLICATIONS¶
• Cerebral Edema: ◦ Peaks on day 2-3; can cause mass effect for up to 10 days. ◦ Risk: Large infarcts are more likely to develop significant edema. • Complications of Revascularization: ◦ Hemorrhage or petechial hemorrhage (usually not clinically significant unless causing mass effect). ◦ Thrombolysis risks: Bleeding, hypertension, and deterioration of status.
SPECIAL CONSIDERATIONS¶
• Pregnancy: ◦ Eclampsia may present with stroke-like symptoms. • Elderly: ◦ Benefit from hemicraniectomy is less than in younger patients but still significant. • Cardiac Conditions (Antithrombotic Selection): ◦ Nonvalvular AF: → CHADS-VASc 0: Aspirin or none. → CHADS-VASc 1: Aspirin or OAC. → CHADS-VASc ≥2: OAC. ◦ Mitral Annular Calcification: → No AF + systemic embolism/cryptogenic: Aspirin. → Recurrent embolism: OAC. → With AF: OAC. ◦ Aortic Arch Mobile Atheroma: → Cryptogenic/TIA: Aspirin or OAC. ◦ Mechanical Heart Valve: → Aortic, bileaflet, Medtronic Hall + normal LA & sinus rhythm: VKA INR 2.5 (range 2-3). → Mitral position tilting/bileaflet: VKA INR 3.0 (range 2.5-3.5). → Mitral/Aortic + MI or LA enlargement: VKA INR 3.0 (range 2.5-3.5). → Mitral/Aortic + AF, hypercoagulable, low EF, or atherosclerotic disease: Aspirin + VKA INR 3.0 (range 2.5-3.5). → Systemic embolism despite target INR: Add aspirin and/or increase INR (2.5 to 3.0; 3.0 to 3.5). ◦ Infective Endocarditis: Avoid antithrombotic agents. ◦ Nonbacterial Thrombotic Endocarditis: → Systemic embolism: Full-dose heparin or LMWH, or Xa inhibitor.
KEY PEARLS & CLINICAL TRAPS¶
• Time is Brain: Rapid reversal of ischemia is paramount; do not delay thrombolysis for non-essential labs. ◦ Thrombolytic Window: 4.5 hours for rtPA/tenecteplase; up to 24 hours for mechanical thrombectomy in select cases. • Symptom Mimics: Cerebellar stroke → Labyrinthitis; Vasculopathy → Beading on angiogram. • Risk Factors (Table 4): → Hypertension: RR 2-5, Reduction 38% (Primary), 68% (Secondary). → Diabetes: RR 1.8-6; No proven effect (Primary); 50% at 1 year (Secondary). → Hyperlipidemia: RR 1.8-2.6, Reduction 16-30% (Primary), 53% (Secondary). → Symptomatic carotid stenosis (70-99%): 65% at 2 years, 29% at 5 years. • ABCD2 Score for TIA: → Score 1: 2% 3-month stroke rate. → Score 3: 3% 3-month stroke rate. → Score 5: 12% 3-month stroke rate. → Score 7: 22% 3-month stroke rate.
Reference Tables¶
TABLE 438-1 Administration of Intravenous Recombinant Tissue Plasminogen Activator (rtPA) or Tenecteplase for Acute…¶
Harrison's 22e, p.3441
| INDICATION | CONTRAINDICATION |
|---|---|
| Clinical diagnosis of stroke Onset of symptoms to time of drug administration ≤4.5 hb CT scan showing no hemorrhage, and no edema > 1/3 of the MCA territory Age ≥18 years |
Sustained BP >185/110 mmHg despite treatment Bleeding diathesis Recent head injury or intracerebral hemorrhage Major surgery in preceding 14 days Gastrointestinal bleeding in preceding 21 days Recent myocardial infarction |
| Administration of stroke thrombolysis | |
| IV access with two peripheral IV lines (avoid arterial or central line placement) | |
| Review eligibility for stroke thrombolysis | |
| Administer 0.9 mg/kg IV (maximum 90 mg) rtPA IV as 10% of total dose by bolus, followed by remainder of total dose over 1 hc |
|
| Or Administer 0.25 mg/kg IV (maximum 25 mg) tenecteplase IV push over 5 sd Frequent cuff BP monitoring |
|
| No other antithrombotic treatment for 24 h | |
| For decline in neurologic status or uncontrolled BP, stop infusion, give cryoprecipitate, and reimage brain emergently |
|
| Avoid urethral catheterization for ≥2 h |
TABLE 438-2 Causes of Ischemic Stroke¶
Harrison's 22e, p.3444
| COMMON CAUSES | UNCOMMON CAUSES |
|---|---|
| Thrombosis Lacunar stroke (small vessel) Large-vessel thrombosis Dehydration Embolic occlusion Artery-to-artery Carotid bifurcation Aortic arch Arterial dissection Cardioembolic Atrial fibrillation Mural thrombus Myocardial infarction Dilated cardiomyopathy Valvular lesions Mitral stenosis Mechanical valve Bacterial endocarditis Paradoxical embolus Atrial septal defect Patent foramen ovale Atrial septal aneurysm Spontaneous echo contrast Stimulant drugs: cocaine, amphetamine |
Hypercoagulable disorders Protein C deficiencya Protein S deficiencya Antithrombin III deficiencya Antiphospholipid syndrome Factor V Leiden mutationa Prothrombin G20210A mutationa Systemic malignancy Sickle cell anemia β Thalassemia Polycythemia vera Systemic lupus erythematosus Homocysteinemia Thrombotic thrombocytopenic purpura Disseminated intravascular coagulation Dysproteinemiasa Nephrotic syndromea Inflammatory bowel diseasea Oral contraceptives COVID-19 infection Venous sinus thrombosisb Fibromuscular dysplasia Vasculitis Systemic vasculitis (PAN, granulomatosis with polyangiitis, Takayasu’s, giant cell arteritis) Primary CNS vasculitis Meningitis (syphilis, tuberculosis, fungal, bacterial, zoster) Noninflammatory vasculopathy Reversible vasoconstriction syndrome Fabry’s disease Angiocentric lymphoma Cardiogenic Mitral valve calcification Atrial myxoma Intracardiac tumor Marantic endocarditis Libman-Sacks endocarditis Subarachnoid hemorrhage vasospasm Moyamoya disease Eclampsia |
TABLE 438-3 Recommendations on Chronic Use of Antithrombotics for Various Cardiac Conditions CONDITION Nonvalvular…¶
Harrison's 22e, p.3445
| CONDITION | RECOMMENDATION |
|---|---|
| Nonvalvular atrial fibrillation | Calculate CHADS-VASc scorea 2 2 |
| • CHADS-VASc score of 0 2 2 |
Aspirin or no antithrombotic |
| • CHADS-VASc score of 1 2 2 |
Aspirin or OAC |
| • CHADS-VASc score of ≥2 2 2 |
OAC |
| Mitral annular calcification | |
| • Without atrial fibrillation but systemic embolization, or otherwise cryptogenic stroke or TIA |
Aspirin |
| • Recurrent embolization despite aspirin | OAC |
| • With atrial fibrillation | OAC |
| Aortic arch mobile atheroma | |
| • Otherwise cryptogenic stroke or TIA | Aspirin or OAC |
| Mechanical heart value | |
| • Aortic position, bileaflet or Medtronic Hall tilting disk with normal left atrial size and sinus rhythm |
VKA INR 2.5, range 2–3 |
| • Mitral position tilting disk or bileaflet valve | VKA INR 3.0, range 2.5–3.5 |
| • Mitral or aortic position, anterior-apical myocardial infarct or left atrial enlargement |
VKA INR 3.0, range 2.5–3.5 |
| • Mitral or aortic position, with atrial fibrillation, or hypercoagulable state, or low ejection fraction, or atherosclerotic vascular disease |
Aspirin plus VKA INR 3.0, range 2.5–3.5 |
| • Systemic embolization despite target INR | Add aspirin and/or increase INR: prior target was 2.5, increase to 3.0, range 2.5–3.5; prior target was 3.0, increase to 3.5, range 3–4 |
| Infective endocarditis | Avoid antithrombotic agents |
| Nonbacterial thrombotic endocarditis | |
| • With systemic embolization | Full-dose, unfractionated heparin or SC LMWH, or Xa inhibitor |
TABLE 438-4 Risk Factors for Stroke¶
Harrison's 22e, p.3446
| RISK FACTOR | RELATIVE RISK | RELATIVE RISK REDUCTION WITH TREATMENT |
NUMBER NEEDED TO TREATa | |
|---|---|---|---|---|
| PRIMARY PREVENTION | SECONDARY PREVENTION | |||
| Hypertension | 2–5 | 38% | 100–300 | 50–100 |
| 1.8–2.9 | 68% warfarin, 21% aspirin | 20–83 | ||
| Diabetes | 1.8–6 | No proven effect | ||
| 1.8 | 50% at 1 year, baseline risk at 5 years postcessation |
|||
| Hyperlipidemia | 1.8–2.6 | 16–30% | 560 | 230 |
| 2.0 | 53% | 85 | ||
| Symptomatic carotid stenosis (70–99%) | 65% at 2 years | N/A | 12 | |
| 29% at 5 years | N/A |
TABLE 438-5 Risk of Stroke Following Transient Ischemic Attack: The ABCD 2 Score¶
Harrison's 22e, p.3448
| CLINICAL FACTOR | SCORE |
|---|---|
| A: Age ≥60 years | 1 |
| C: Clinical symptoms | |
| Unilateral weakness | 2 |
| Speech disturbance without weakness | 1 |
| D: Diabetes (oral medications or insulin) | 1 |
| TOTAL SCORE | SUM EACH CATEGORY |
| ABCD2 Score Total | 3-Month Rate of Stroke (%)a |
| 1 | 2 |
| 3 | 3 |
| 5 | 12 |
| 7 | 22 |