Stroke — Ischemic and Hemorrhagic

Ischemic Stroke Mechanisms

• Cerebral ischemia-reperfusion cascade: Arterial occlusion reduces cerebral blood flow below the critical threshold of 10–15 mL/100g/min, initiating a complex pathophysiologic cascade. Within minutes, ATP depletion leads to failure of Na+/K+-ATPase, causing cellular depolarization, uncontrolled calcium influx, mitochondrial dysfunction, and activation of proteases and phospholipases. Excitotoxic release of glutamate perpetuates neuronal injury through NMDA and AMPA receptor activation. The ischemic penumbra—tissue with reduced perfusion but preserved membrane potential—represents salvageable tissue before irreversible infarction. Reperfusion injury, paradoxically worsening outcomes through reactive oxygen species generation, inflammatory cell infiltration, and blood-brain barrier disruption, occurs upon restoration of flow.

• Thromboembolic mechanisms: Large vessel occlusion (LVO) typically results from atherosclerotic plaque rupture at bifurcation points (carotid bifurcation, middle cerebral artery [MCA] stem) with superimposed thrombosis. Cardioembolic events originate from atrial fibrillation, acute myocardial infarction with wall motion abnormality, valvular disease, or left ventricular thrombus, accounting for 15–20% of ischemic strokes. Small vessel disease (lacunar infarcts <15 mm) results from lipohyalinosis of penetrating arteries secondary to chronic hypertension or diabetes, producing subcortical white matter and brainstem infarcts. Arterial dissection (carotid or vertebral) causes thrombosis or hemodynamic stroke through disruption of arterial intima with subsequent thrombus formation.

• Metabolic and hemodynamic mechanisms: Hypoperfusion strokes occur in watershed zones between major arterial territories during severe hypotension, cardiac arrest, or severe anemia. Thrombotic occlusion develops in situ from atherosclerotic disease at the site of vascular lesion. Paradoxical embolism occurs when venous thrombi traverse patent foramen ovale (PFO) or other right-to-left shunts to enter systemic circulation.

Hemorrhagic Stroke Mechanisms

• Intracerebral hemorrhage (ICH): Hypertensive hemorrhage results from rupture of lipohyalinotic small penetrating arteries damaged by chronic hypertension, classically affecting the basal ganglia, thalamus, pons, and cerebellum. Amyloid angiopathy causes microinfarcts and microhemorrhages through amyloid-β deposition in cortical vessels, predominantly in elderly patients without hypertension history. Expansion of hematomas occurs in the hyperacute phase (first 24–48 hours) through continued bleeding from damaged vessels, driven by coagulopathy, hypertension, or anticoagulant use. Mass effect from expanding hematoma causes increased intracranial pressure, midline shift, herniation, and compression of vital brainstem structures. Secondary brain injury results from perihematomal edema (maximal at 24–72 hours), inflammatory response, and release of hemoglobin-derived iron causing oxidative stress.

• Subarachnoid hemorrhage (SAH): Rupture of aneurysms—commonly at arterial bifurcations (anterior communicating artery 30%, posterior communicating artery 35%, MCA bifurcation 20%)—causes acute blood accumulation in the subarachnoid space. Vasospasm, occurring 4–14 days after SAH, results from endothelial dysfunction and vascular smooth muscle contraction triggered by subarachnoid blood products, causing secondary ischemic injury. Rebleeding, hydrocephalus from blood clot obstruction of cerebrospinal fluid drainage, and seizures represent major complications.

Ischemic Stroke Causes

• Atherosclerotic disease (50% of ischemic strokes): Intracranial atherosclerosis, extracranial carotid stenosis (>50%), and aortic atherosclerosis cause artery-to-artery thromboembolism or hemodynamic stroke
• Cardiac embolism (15–20%): Atrial fibrillation, acute myocardial infarction with reduced ejection fraction, dilated cardiomyopathy, mechanical prosthetic valves, endocarditis, cardiac myxoma, and hypercoagulable states
• Small vessel disease (25% of ischemic strokes, lacunar): Chronic hypertension and diabetes causing lipohyalinosis of penetrating arteries (lenticulostriate arteries, pontine perforators)
• Arterial dissection (1–2%, younger patients): Spontaneous or post-traumatic carotid/vertebral dissection with flow-limiting stenosis or thromboembolism
• Hypercoagulable states: Antiphospholipid syndrome, malignancy, factor V Leiden, prothrombin gene mutation, protein C/S deficiency, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura (TTP)
• Paradoxical embolism: PFO with deep venous thrombosis, particularly in young patients with cryptogenic stroke
• Other causes: Vasculitis (infectious, autoimmune), fibromuscular dysplasia, reversible cerebral vasoconstriction syndrome (RCVS), Moyamoya disease, hypercoagulable malignancy

Hemorrhagic Stroke Causes

• Intracerebral hemorrhage (80% of hemorrhagic strokes)
• Hypertensive hemorrhage (50–60%): Chronic hypertension with acute elevation causing rupture of lipohyalinotic vessels
• Cerebral amyloid angiopathy (10–20%): Amyloid-β deposition in cortical vessels, lobar hemorrhages in elderly
• Anticoagulation and antiplatelet therapy: Warfarin (elevated INR), DOACs, aspirin/clopidogrel combinations
• Coagulopathy: Thrombocytopenia, hemophilia, liver disease with coagulation factor deficiency, disseminated intravascular coagulation (DIC)
• Structural lesions: Arteriovenous malformation (AVM), cavernous malformation, tumor, aneurysm

• Subarachnoid hemorrhage (20% of hemorrhagic strokes)
• Ruptured aneurysm (80%): Anterior communicating artery, posterior communicating artery, MCA bifurcation, basilar artery bifurcation
• Non-aneurysmal SAH: Perimesencephalic hemorrhage (10%), reversible cerebral vasoconstriction syndrome, venous sinus thrombosis

Major Stroke Risk Factors (Modifiable and Non-modifiable)

• Hypertension (most significant modifiable risk): Present in 50–70% of stroke patients; each 10 mmHg reduction decreases stroke risk by ~17%
• Atrial fibrillation: Increases ischemic stroke risk 5-fold; drives cardioembolic events
• Diabetes mellitus: Increases stroke risk 1.5–3 fold through accelerated atherosclerosis and endothelial dysfunction
• Dyslipidemia: LDL cholesterol elevation and low HDL cholesterol are independent risk factors
• Smoking: Increases ischemic stroke risk 2–4 fold through atherosclerotic progression and hypercoagulability
• Obesity and sedentary lifestyle: Associated with metabolic syndrome and increased cardiovascular risk
• Non-modifiable factors: Age (exponential increase >65 years), male sex (slightly higher incidence), race/ethnicity (higher incidence in Black and Hispanic populations), family history, prior stroke/TIA

Cardinal Symptoms (Acute Onset)

• Sudden focal neurological deficit: Hallmark of stroke; symptoms develop within minutes of vascular event, distinguishing stroke from gradual-onset conditions (tumors, subdural hematoma)
• Motor weakness: Contralateral hemiparesis, often most prominent in upper extremity and face (MCA distribution most common). Facial droop, arm drift, and speech difficulty comprise the FAST mnemonic (Face, Arms, Speech, Time)
• Speech disturbance: Expressive aphasia (Broca's area, non-fluent) with preserved comprehension; receptive aphasia (Wernicke's area, fluent) with impaired comprehension; dysarthria from brainstem/cerebellar involvement
• Sensory loss: Contralateral hemianesthesia or dissociative sensory loss pattern depending on lesion location
• Vision changes: Homonymous hemianopia (contralateral visual field loss from optic radiations or occipital cortex), monocular vision loss (amaurosis fugax in carotid distribution), diplopia or nystagmus (brainstem/cerebellar stroke)
• Headache: Present in 30–50% of acute ischemic strokes, more common in hemorrhagic strokes; thunderclap headache suggests SAH or hypertensive emergency
• Vertigo and ataxia: Indicates posterior circulation (vertebrobasilar) involvement; risk of basilar artery occlusion causing locked-in syndrome
• Altered mental status: Inattention, confusion, or diminished consciousness suggests large territory stroke with mass effect, increased intracranial pressure, or metabolic derangement

Physical Examination Findings by Stroke Location

• MCA (most common, 80% of hemispheric strokes): Contralateral hemiparesis (arm > leg), hemisensory loss, contralateral homonymous hemianopia, aphasia (dominant hemisphere), neglect (non-dominant hemisphere), gaze deviation toward lesion
• Anterior cerebral artery (ACA): Contralateral leg weakness > arm, urinary incontinence, abulia (with medial frontal involvement), contralateral sensory loss in leg
• Posterior cerebral artery (PCA): Contralateral homonymous hemianopia (macular-sparing if territory), contralateral sensory loss (thalamic), visual agnosia, alexia without agraphia (angular gyrus)
• Vertebrobasilar/brainstem strokes: Crossed syndromes with ipsilateral cranial nerve findings and contralateral body weakness/sensory loss; Weber syndrome (CN III palsy + contralateral hemiparesis), Wallenberg syndrome (lateral medullary infarction: ipsilateral facial pain/temperature loss, Horner syndrome, palatal weakness; contralateral body pain/temperature loss)
• Cerebellar stroke: Ipsilateral ataxia, dysmetria, dysdiadochokinesia, nystagmus, headache; life-threatening complications include tonsillar herniation and obstructive hydrocephalus
• Lacunar infarcts: Pure motor stroke (internal capsule), pure sensory stroke (thalamus), ataxic hemiparesis (pons/internal capsule), dysarthria-clumsy hand (pons)

Hemorrhagic Stroke Presentation

• Intracerebral hemorrhage: Acute focal neurological deficit identical to ischemic stroke, but with severe headache in 50%, nausea/vomiting, progressive worsening over hours (continuous bleeding/edema expansion) distinguishing from stable ischemic stroke. Focal seizures occur in 5–10%. Vital sign changes (hypertension, bradycardia, irregular respirations) suggest increased intracranial pressure.
• Subarachnoid hemorrhage: Thunderclap headache ("worst headache of life") in 80%, often followed by loss of consciousness, neck stiffness (meningeal irritation from subarachnoid blood), photophobia, focal neurological deficits variable depending on aneurysm location. Sentinel headache (sentinel leak) precedes major hemorrhage in 10–20% of cases.

Clinical Assessment and Risk Stratification

• NIHSS (National Institutes of Health Stroke Scale): Standardized 15-item assessment (score 0–42) evaluating consciousness, language, neglect, motor/sensory function, cerebellar signs, and visual fields; used to quantify stroke severity, prognosticate outcome, and guide treatment eligibility. Scores <5 indicate mild stroke, 5–15 moderate, 15–20 moderately severe, >20 severe. Each point increase correlates with worse prognosis.
• ABCD2 score (for TIA/minor stroke): Age ≥60 (1 point), Blood pressure ≥140/90 (1 point), Clinical features (speech disturbance 1 point, unilateral weakness 2 points), Duration ≥60 minutes (2 points), Diabetes (1 point). Scores 0–3 indicate 1.6% 2-day stroke risk (low), 4–5 indicate 4.1% risk (intermediate), 6–7 indicate 8.1% risk (high); guides admission and investigation intensity.

Neuroimaging

• Non-contrast CT head: Performed emergently to differentiate ischemic (hypodense or normal in hyperacute phase) from hemorrhagic stroke (hyperdense blood), which is critical as thrombolysis is contraindicated in hemorrhage. Detects subarachnoid blood (hyperdense in basal cisterns), mass effect, and herniation. Sensitivity 100% for acute blood but may miss hyperacute ICH. CT hypodensity becomes evident 6–8 hours after ischemic stroke onset; early hypodensity (within 6 hours) indicates extensive infarction and poor thrombolysis candidate.
• MRI brain with DWI/PWI: Diffusion-weighted imaging (DWI) detects ischemic stroke within minutes (appears hyperintense) with corresponding hypointensity on apparent diffusion coefficient (ADC), indicating restricted water diffusion from cytotoxic edema; more sensitive than CT for acute ischemia and establishes infarct age. Perfusion-weighted imaging (PWI) identifies hypoperfused tissue (penumbra). DWI/PWI mismatch represents salvageable tissue; absence of mismatch indicates completed infarction. T2-weighted and FLAIR sequences identify subacute/chronic infarction and white matter disease. MR angiography assesses intracranial/extracranial vessels for occlusion or stenosis. MRI contraindications (pacemakers, claustrophobia) may preclude use in emergency setting.
• CT angiography (CTA) head and neck: Rapidly identifies large vessel occlusion (MCA stem, basilar artery, ICA terminus) and cervical carotid/vertebral artery stenosis or dissection, essential for mechanical thrombectomy candidacy. Demonstrates collateral circulation, predicting tissue viability. Hyperdense artery sign indicates thrombus. CTA preferred over MRA in acute setting due to speed and superior visualization of large vessels.
• CT perfusion (CTP): Maps cerebral blood flow (CBF), mean transit time (MTT), and cerebral blood volume (CBV); identifies ischemic core (reduced CBF and CBV) and penumbra (prolonged MTT). Helps identify candidates for extended window thrombolysis beyond 4.5 hours. Core volume <70 mL and mismatch ratio >1.8 predict better outcomes with thrombectomy.
• Transcranial Doppler ultrasound: Non-invasive assessment of cerebral vessel velocities; elevated velocities indicate vasospasm in SAH; useful bedside tool for

Immediate stabilisation (all suspected stroke)

• Airway, glucose, and imaging first: check fingerstick glucose (hypoglycemia is the great mimic), obtain non-contrast CT before any therapy, and perform a dysphagia screen before oral intake or medication. The AHA/ASA acute ischemic stroke guideline prioritises door-to-needle time over completing the full workup.

Ischemic stroke — first-line reperfusion

• IV thrombolysis: alteplase 0.9 mg/kg (maximum 90 mg), 10% as bolus and the remainder over 60 minutes, within 4.5 hours of last known well per AHA/ASA. Tenecteplase as a single weight-based bolus is an accepted alternative, particularly in patients being transferred for thrombectomy. Blood pressure must be brought below 185/110 mmHg before the bolus (IV nicardipine, clevidipine, or labetalol) and kept below 180/105 mmHg for 24 hours.
• Mechanical thrombectomy: for anterior-circulation large vessel occlusion within 6 hours, and out to 24 hours in patients selected by perfusion or clinical–core mismatch (the DAWN and DEFUSE 3 selection paradigm endorsed by AHA/ASA). Thrombectomy is not withheld because the patient received thrombolysis.

Antithrombotics and escalation

• Aspirin within 24–48 hours; delay 24 hours and repeat imaging if thrombolysis was given.
• Short-course dual antiplatelet therapy (aspirin plus clopidogrel) for 21 days then single agent, for minor non-cardioembolic stroke or high-risk TIA (CHANCE/POINT data, AHA/ASA secondary prevention guideline).
• High-intensity statin (atorvastatin), blood pressure control after the acute phase, glycemic control targeting roughly 140–180 mg/dL, normothermia, and VTE prophylaxis.
• Anticoagulation (DOAC, or warfarin for mechanical valves/moderate–severe mitral stenosis) for atrial fibrillation, typically started days after the event to avoid hemorrhagic transformation.
• Carotid endarterectomy or stenting for symptomatic 70–99% stenosis, generally within two weeks.

Hemorrhagic stroke

• Reverse the coagulopathy: vitamin K plus 4-factor PCC for warfarin, idarucizumab for dabigatran, andexanet alfa for factor Xa inhibitors (AHA/ASA ICH guideline). Lower systolic pressure smoothly toward ~140 mmHg; avoid abrupt drops.
• Surgery: suboccipital decompression for cerebellar hemorrhage with brainstem compression or hydrocephalus; external ventricular drain for hydrocephalus.
• Aneurysmal SAH: secure the aneurysm early by coiling or clipping, plus oral nimodipine for 21 days.

Neurologic emergencies

• Hemorrhagic transformation: reperfusion into infarcted tissue with a disrupted blood–brain barrier; signalled by abrupt neurologic decline, headache, vomiting, or hypertension in the 24 hours after thrombolysis. Emergency — stop the infusion, obtain stat non-contrast CT, and give cryoprecipitate or fibrinogen concentrate plus platelets as indicated.
• Malignant MCA syndrome: cytotoxic edema peaking at 48–96 hours after a large hemispheric infarct causes midline shift and uncal herniation; heralded by declining level of consciousness, new pupillary asymmetry, and Cushing reflex. Emergency — decompressive hemicraniectomy improves survival, with the strongest benefit in younger patients treated early (AHA/ASA).
• Cerebellar infarct or hemorrhage with fourth-ventricle compression: obstructive hydrocephalus and brainstem compression; new somnolence in a patient with ataxia is the tell. Emergency — suboccipital decompression and/or ventricular drainage.
• Delayed cerebral ischemia from vasospasm (SAH, days 4–14): new focal deficit or confusion with rising transcranial Doppler velocities. Emergency — nimodipine prophylaxis, euvolemia, induced hypertension, and endovascular rescue.
• Aneurysm rebleeding and acute hydrocephalus in SAH: sudden headache recurrence or coma before the aneurysm is secured. Emergency.

Treatment-related

• Orolingual angioedema from alteplase: bradykinin accumulation, markedly more frequent in patients on ACE inhibitors; tongue and lip swelling minutes into the infusion. Airway emergency.
• Systemic bleeding from thrombolysis or antithrombotics; groin hematoma, dissection, or distal embolisation from thrombectomy.

Subacute and chronic

• Aspiration pneumonia: impaired swallow and cough; fever and hypoxia in the first days — the reason for a formal dysphagia screen before anything by mouth.
• VTE/pulmonary embolism: immobilised paretic limb; asymmetric leg swelling or unexplained hypoxia.
• Post-stroke seizures and epilepsy: cortical scar irritability; higher after hemorrhagic and cortical infarcts. Prophylactic anticonvulsants are not recommended.
• Cardiac injury: catecholamine surge producing neurogenic stunned myocardium / takotsubo pattern with deep T-wave inversions and QT prolongation, classically after SAH.
• Hyponatremia: SIADH versus cerebral salt wasting — distinguished by volume status, which dictates fluid restriction versus saline repletion.
• Spasticity, shoulder subluxation, pressure ulcers, post-stroke depression, and Dejerine–Roussy central post-stroke pain after thalamic infarction.

• Non-contrast CT is always the single best next step in suspected acute stroke — not MRI, not CTA, not aspirin. Its only job is to exclude hemorrhage before thrombolysis; a normal CT does not exclude ischemic stroke.
• Check a fingerstick glucose in every stroke code. Hypoglycemia and hyperglycemic hyperosmolar state reproduce focal deficits perfectly and are the classic reversible mimic in a stem where the patient is diabetic.
• Timing drives therapy: alteplase within 4.5 hours, thrombectomy for large vessel occlusion within 6 hours and up to 24 hours with favourable perfusion mismatch. "Last known well," not symptom discovery, starts the clock — the wake-up stroke stem is testing exactly this.
• Blood pressure paradox: lower BP below 185/110 mmHg before giving alteplase, but otherwise permit hypertension in ischemic stroke unless it exceeds ~220/120 mmHg, because the penumbra is pressure-dependent. In intracerebral hemorrhage the logic reverses — lower it to limit hematoma expansion (AHA/ASA).
• Dual antiplatelet therapy is a 21-day course, not lifelong. The common distractor is continuing aspirin plus clopidogrel indefinitely, which raises bleeding without added benefit (AHA/ASA secondary prevention guideline).
• Do not start anticoagulation acutely in a large cardioembolic infarct; heparin bridging adds hemorrhagic transformation risk without preventing early recurrence. Start a DOAC after the acute window.
• Buzzword bank: hyperdense MCA sign (thrombus on CT), thunderclap headache with a negative CT beyond 6 hours → lumbar puncture for xanthochromia, amaurosis fugax → carotid duplex, lateral medullary (Wallenberg) syndrome → PICA/vertebral territory with crossed sensory loss and Horner syndrome, lobar hemorrhage in a normotensive elderly patient → cerebral amyloid angiopathy.
• The association examiners love: orolingual angioedema during alteplase in a patient taking an ACE inhibitor — bradykinin-mediated, an airway emergency, and not an allergy to the lytic itself.
• Young patient with cryptogenic stroke → transthoracic/transesophageal echo with bubble study for PFO and cervical vessel imaging for dissection, especially after neck trauma or chiropractic manipulation.