Ischemic Stroke

Mechanism-based causes (TOAST framework)

• Large-artery atherosclerosis: Plaque at the carotid bifurcation, vertebral origin, or intracranial vessels causes artery-to-artery embolism or flow-limiting stenosis. Suspect when a stem gives repeated TIAs in one territory, amaurosis fugax, or a carotid bruit.
• Cardioembolism: Atrial fibrillation is the prototype; also LV thrombus after anterior MI, dilated cardiomyopathy, prosthetic/rheumatic valves, and infective endocarditis (septic emboli, mycotic aneurysm). Emboli favor the MCA and produce abrupt, maximal-at-onset cortical deficits, sometimes in multiple vascular territories.
• Small-vessel (lacunar) disease: Lipohyalinosis and microatheroma of penetrating lenticulostriate, thalamoperforating, and basilar branches, driven chiefly by chronic hypertension and diabetes. Produces pure motor, pure sensory, ataxic-hemiparesis, or dysarthria–clumsy hand syndromes without cortical signs.
• Other determined causes: Cervical artery dissection (young patient, neck trauma or chiropractic manipulation, neck pain plus partial Horner syndrome); hypercoagulable states (antiphospholipid syndrome, malignancy, nephrotic syndrome); paradoxical embolism through a PFO; vasculitis; sickle cell disease; moyamoya; fibromuscular dysplasia; cocaine or amphetamine use; and watershed infarcts from global hypoperfusion after cardiac arrest or hemorrhage.
• Cryptogenic/undetermined: Diagnosis of exclusion; prompts prolonged cardiac rhythm monitoring for occult atrial fibrillation.

Modifiable risk factors

• Hypertension: The single most important modifiable risk factor for both ischemic and hemorrhagic stroke (AHA/ASA 2021 secondary prevention guideline).
• Others: Smoking, diabetes, dyslipidemia, atrial fibrillation, obesity and physical inactivity, obstructive sleep apnea, heavy alcohol use, stimulant drugs, and combined estrogen-containing contraceptives — especially with smoking or migraine with aura.

Non-modifiable risk factors

• Age: Risk roughly doubles with each decade after 55.
• Others: Male sex at any given age (though women carry higher lifetime risk), Black and Hispanic ancestry, family history, prior stroke or TIA, and sickle cell disease — for which transcranial Doppler screening and chronic transfusion are the recognized prevention strategy in children.

• Cerebral perfusion failure: Occlusion of a cerebral artery (most commonly middle cerebral artery/MCA) reduces oxygen delivery below the critical threshold of 10-15 mL/100g/min, causing energy depletion in neurons.

• Core infarction: Within minutes, severely ischemic tissue (blood flow <10 mL/100g/min) undergoes irreversible cytotoxic edema, mitochondrial failure, and neuronal death through necrotic pathways. This core is typically irreversible after 3-6 hours.

• Ischemic penumbra: Surrounding tissue with moderately reduced blood flow (10-20 mL/100g/min) remains viable but dysfunctional. This tissue can be salvaged with reperfusion if accomplished within hours, representing the target of acute therapy.

• Excitotoxicity: Loss of ATP-dependent ion pumps leads to glutamate accumulation in the extracellular space, causing excessive NMDA and AMPA receptor activation with uncontrolled calcium influx and neuronal death.

• Oxidative stress and inflammation: Reperfusion paradoxically generates reactive oxygen species (ROS) through xanthine oxidase and NADPH oxidase, causing additional cellular damage. Microglia activation and inflammatory cascade amplify injury.

• Cellular cascade: Activation of caspases, endonucleases, and apoptotic pathways; mitochondrial cytochrome C release; blood-brain barrier (BBB) breakdown leading to vasogenic edema; secondary hemorrhage risk.

• Thromboembolism: Most commonly from cardioembolic sources (atrial fibrillation, acute MI, valvular disease) or atherosclerotic large vessel disease; smaller strokes result from small vessel occlusive disease (lacunar strokes).

• Sudden focal neurologic deficits with no prodrome—the hallmark of acute stroke. Symptom onset and severity help guide treatment decisions (critical for determining thrombolytic eligibility).

• Motor deficits: Contralateral hemiparesis or hemiplegia; facial droop (central pattern with sparing of forehead due to bilateral innervation); arm drift; gait disturbance. Lower face weakness suggests contralateral stroke.

• Sensory loss: Contralateral hemisensory loss, often correlating with motor involvement in cortical strokes; discriminative touch and proprioception particularly affected.

• Aphasia: Non-fluent (Broca's) aphasia with preserved comprehension (dominant frontal lobe); fluent (Wernicke's) aphasia with impaired comprehension (dominant temporal-parietal lobe); global aphasia in extensive dominant MCA territory.

• Dysarthria: Slurred speech from motor weakness (different from aphasia—language comprehension preserved); associated with brainstem or cerebellar involvement.

• Visual disturbances: Homonymous hemianopia (contralateral visual field loss); monocular vision loss suggests ipsilateral carotid occlusion; cortical blindness (bilateral occipital infarction) is rare; neglect syndrome with non-dominant parietal lobe involvement.

• Ataxia and coordination loss: Cerebellar stroke presents with truncal ataxia, dysmetria, dysdiadochokinesia; vertebrobasilar distribution.

• Vertigo and nystagmus: Central vertigo with vertical or purely rotatory nystagmus; alternating nystagmus suggests brainstem involvement (Wallenberg syndrome classic presentation).

• Acute confusion or altered consciousness: Suggests large infarcts with mass effect, brainstem involvement, or posterior circulation strokes (vertebrobasilar insufficiency).

• NIHSS (National Institutes of Health Stroke Scale): Quick assessment tool scoring 0-42; helps quantify severity and predict outcomes; score ≥25 suggests poor prognosis without intervention.

• Clinical pearl: "Time is brain"—approximately 1.9 million neurons die per minute of untreated ischemic stroke; never delay imaging/treatment to complete the history.

• Non-contrast CT (NCCT) head: First-line imaging to rule out hemorrhagic stroke (absolute contraindication to thrombolytics). Ischemic changes may not be visible in first 12-24 hours; hypodensity indicates established infarction.

• Diffusion-weighted imaging (DWI) MRI: Gold standard for acute ischemia detection; shows restricted diffusion (bright signal) in infarcted tissue within minutes of symptom onset. Apparent diffusion coefficient (ADC) map confirms true restriction. Far more sensitive than CT in first hours.

• CT perfusion or perfusion-weighted imaging (PWI): Identifies mismatch between perfusion deficit and diffusion abnormality (ischemic penumbra); may extend treatment window eligibility in selected patients.

• Vascular imaging: Carotid ultrasonography, CT angiography (CTA), or MR angiography (MRA) to identify large vessel occlusion (LVO) or significant stenosis. CTA is rapid and becoming standard in acute stroke protocols.

• ECG and cardiac workup: Identify arrhythmias (especially atrial fibrillation), acute MI, or cardioembolic sources. Cardiac echo if cardioembolic stroke suspected.

• Laboratory studies: PT/INR (if on warfarin), CBC, comprehensive metabolic panel, troponin, glucose (hypoglycemia mimics stroke), lipid panel. Blood glucose normalization improves outcomes.

• TOAST classification: Categorizes strokes as large artery atherosclerosis, cardioemboli, small vessel occlusion, other determined etiology, or undetermined etiology; guides secondary prevention.

• Timing for diagnosis: Goal of imaging to needle/catheter is 10 minutes; door-to-thrombolytic time goal is 60 minutes ("door-to-needle").

ACUTE PHASE (Hyperacute: 0-4.5 hours)

• IV recombinant tissue plasminogen activator (rtPA/alteplase): Gold standard thrombolytic for acute ischemic stroke. Dosing: 0.9 mg/kg (maximum 90 mg total), with 10% given as bolus over 1 minute, remainder over 60 minutes. Must be within 4.5 hours of symptom onset (FDA approved to 3 hours; extended to 4.5 hours based on clinical trials). Reduces disability by ~30% with number needed to treat (NNT) of 6-7.

• Mechanical thrombectomy: Indicated for large vessel occlusion (LVO) in anterior circulation (MCA, ICA); window extends to 24 hours if patient meets criteria (early ischemic changes, small infarct core, good collateral circulation). Thrombectomy is superior to thrombolytics alone for LVO. Complications include perforation (0.5-1%), dissection, distal embolization.

• Contraindications to rtPA: Active bleeding, recent surgery, ICH history, INR >1.7, platelet count <100,000, recent stroke (within 3 months), recent MI (within 3 months), severe hypertension unresponsive to treatment (SBP >185 or DBP >110), brain tumor, lumbar puncture within 1 week. Relative contraindications include minor stroke symptoms (NIHSS <4), rapidly improving symptoms, glucose <50 mg/dL.

• Blood pressure management: Target varies by treatment type. For thrombolytic candidates: lower SBP to <185 and DBP <110 before treatment. For non-candidates: permissive hypertension often acceptable (autoregulation). Avoid aggressive lowering unless >220/120 or complications present.

Neurologic emergencies

• Hemorrhagic transformation: Reperfusion into infarcted, BBB-disrupted tissue; risk rises with large infarct volume, cardioembolic source, thrombolysis, and early anticoagulation. Signals: sudden headache, vomiting, acute rise in blood pressure, or NIHSS worsening. Emergency — stop alteplase, obtain STAT non-contrast CT, and reverse with cryoprecipitate (fibrinogen repletion) and/or an antifibrinolytic per AHA/ASA 2019 guidance.
• Malignant cerebral edema: Cytotoxic then vasogenic edema after large MCA or hemispheric infarction, peaking at roughly 2–5 days; presents with declining consciousness, pupillary asymmetry, and midline shift. Emergency — osmotic therapy (hypertonic saline or mannitol) and decompressive hemicraniectomy, which improves survival, particularly in younger patients.
• Cerebellar infarct with fourth-ventricle compression: Swelling in the posterior fossa causes obstructive hydrocephalus and brainstem compression. Emergency — suboccipital decompression with or without EVD.
• Seizures: Cortical irritation early, gliotic scar late; late seizures predict epilepsy. Prophylactic antiepileptics are not recommended.

Treatment-related

• Symptomatic intracranial hemorrhage after alteplase: The dominant thrombolytic risk; markedly higher than placebo, yet net disability benefit persists.
• Orolingual angioedema: Bradykinin-mediated, classically in patients on an ACE inhibitor; often unilateral tongue/lip swelling during the infusion. Airway emergency — antihistamines, corticosteroids, and airway assessment.
• Thrombectomy complications: Vessel perforation, dissection, distal embolization to a new territory, and groin hematoma or retroperitoneal bleed.
• Reperfusion injury: ROS generation and inflammation after restored flow can extend edema despite recanalization.

Systemic and late

• Aspiration pneumonia: Dysphagia is the mechanism — a bedside swallow screen before any oral intake, including medications, is standard.
• VTE: Immobility; use intermittent pneumatic compression, with prophylactic anticoagulation once hemorrhage is excluded.
• Others: Pressure ulcers, urinary retention/UTI, spasticity and contractures, shoulder subluxation, post-stroke depression (screen routinely), vascular cognitive impairment, and Dejerine-Roussy central post-stroke pain after thalamic infarction.

• Check a fingerstick glucose first: Hypoglycemia is the classic stroke mimic and the one reversible cause you can fix at the bedside; Todd paralysis after a seizure, complicated migraine, and conversion disorder are the other mimics examiners plant.
• Non-contrast CT before thrombolysis, always: Its job is to exclude hemorrhage, not to confirm infarct. A normal CT does not exclude stroke and does not withhold alteplase — this is the most common distractor. DWI turns bright within minutes; CT hypodensity takes hours.
• Best next step in suspected large-vessel occlusion: CT angiography, then mechanical thrombectomy. Giving alteplase does not cancel thrombectomy eligibility in an eligible LVO patient (AHA/ASA 2019).
• Do not overtreat blood pressure: In a patient who is not a thrombolysis candidate, permissive hypertension preserves penumbral perfusion; abrupt lowering extends the infarct. The treatment threshold differs before alteplase (<185/110) versus without it.
• Antiplatelets, not acute anticoagulation: Aspirin within 24–48 hours, delayed 24 hours after alteplase. For minor stroke or high-risk TIA, short-course dual antiplatelet therapy (aspirin plus clopidogrel) for about 3 weeks then monotherapy reduces early recurrence. Urgent heparin for cardioembolic stroke is a trap — it raises hemorrhagic transformation risk without benefit.
• Atrial fibrillation: Start oral anticoagulation (a DOAC in nonvalvular AF; warfarin for mechanical valves or moderate-to-severe mitral stenosis), timing based on infarct size.
• Symptomatic carotid stenosis: Revascularization for 70–99% stenosis on the side matching the deficit, generally within 2 weeks; benefit is more modest at 50–69%. Note that USPSTF recommends against screening asymptomatic adults for carotid stenosis.
• Every patient leaves on a high-intensity statin, plus hypertension, diabetes, and smoking-cessation management (AHA/ASA 2021).
• Eponyms to recognize: Wallenberg (lateral medullary — crossed sensory loss, Horner, dysphagia), Weber (midbrain — CN III palsy with contralateral hemiparesis), and Dejerine-Roussy thalamic pain syndrome.