Cerebrovascular Disease Pathology

ISCHEMIC STROKE MECHANISMS

• Thrombotic occlusion: Atherosclerotic plaque rupture with superimposed thrombosis at the site of luminal stenosis (>50% diameter reduction). Rupture-prone plaques contain lipid-rich cores, thin fibrous caps, and abundant inflammatory infiltrate (macrophages, T lymphocytes). Platelet aggregation and fibrin deposition on exposed collagen and tissue factor initiate the coagulation cascade via TF-FVIIa complex.
• Embolic occlusion: Cardioembolism (most common source), artery-to-artery embolism from proximal atherosclerotic disease, and paradoxical embolism via patent foramen ovale (PFO). Emboli lodge at vascular bifurcations (middle cerebral artery [MCA] stem, basilar artery bifurcation) where caliber reduces abruptly.
• Hypoperfusion/watershed infarction: Global cerebral hypoperfusion in the setting of systemic hypotension or severe proximal arterial stenosis causes infarction in "watershed" zones—border territories between major arterial distributions (ACA-MCA, MCA-PCA boundaries). These regions have the lowest collateral flow and represent the distal zones of arterial trees.

ISCHEMIC CASCADE AND NEURONAL INJURY

• Acute phase (minutes to hours): Vascular occlusion → cessation of oxidative metabolism → ATP depletion within 4-5 minutes. Loss of ATP-dependent Na+/K+-ATPase causes intracellular sodium accumulation, osmotic water influx, and cytotoxic edema. Membrane depolarization causes uncontrolled calcium influx via NMDA and AMPA glutamate receptors and L-type voltage-gated calcium channels.
• Excitotoxicity and oxidative stress (hours): Intracellular calcium overload activates calpains (proteases), phospholipases, endonucleases, and mitochondrial permeability transition. Mitochondrial dysfunction generates excessive reactive oxygen species (ROS) via uncoupling of the electron transport chain. ROS damage lipids (peroxidation), proteins (oxidative modification), and DNA. Free radical-mediated lipid peroxidation creates malondialdehyde and 4-hydroxynonenal, amplifying cellular injury.
• Inflammatory response (hours to days): Ischemic tissue releases damage-associated molecular patterns (DAMPs: HMGB1, ATP, uric acid). Microglial activation via TLR2/4 and NLRP3 inflammasome signaling produces TNF-α, IL-1β, and IL-6, perpetuating BBB disruption and neutrophil infiltration. Leukocyte rolling, adhesion, and transmigration are mediated by selectins and integrins; matrix metalloproteinases (MMP-2, MMP-9) degrade collagen IV and laminin of the basal lamina, worsening BBB disruption.

PENUMBRA vs. CORE DISTINCTION

• Ischemic core: Severely hypoperfused tissue (CBF <10-20 mL/100g/min) with irreversible injury within minutes; characterized by failure of evoked electrical activity and cytotoxic edema on ADC-MRI.
• Ischemic penumbra: Moderately hypoperfused tissue (CBF 20-40 mL/100g/min) with preserved neuronal membrane function but impaired electrical activity; potentially salvageable with reperfusion within therapeutic window (typically <4.5 hours for IV tPA, <24 hours for mechanical thrombectomy in selected patients with imaging evidence of mismatch).

HEMORRHAGIC STROKE MECHANISMS

• Hypertensive intracerebral hemorrhage (ICH): Chronic hypertension causes lipohyalinosis of penetrating arteries (lipid deposition in vessel walls with hyaline material, medial hypertrophy, and fibrinoid necrosis). Microaneurysm formation (Charcot-Bouchard aneurysms) in the basal ganglia, thalamus, pons, and cerebellum predisposes to rupture. Acute hemorrhage creates mass effect with increased intracranial pressure, midline shift, and herniation.
• Amyloid angiopathy (cerebral amyloid angiopathy, CAA): Amyloid-beta (Aβ) deposition in media and adventitia of cortical and leptomeningeal vessels causes vessel fragility and microhemorrhages (particularly lobar locations). Associated with Alzheimer disease pathology.
• Subarachnoid hemorrhage (SAH): Rupture of intracranial aneurysms (berry aneurysms at arterial bifurcations in Circle of Willis: anterior communicating artery [AComm] > posterior communicating artery [PComm] > MCA bifurcation) causes acute elevation of intracranial pressure, meningeal irritation, and vasospasm.
• Bleeding cascade and hematoma expansion: Acute hemostasis fails; continued bleeding in the first 24-48 hours is driven by residual anticoagulation, platelet dysfunction, and coagulopathy. Hematoma expansion correlates with poor outcome and is most active in the first 3 hours.

ISCHEMIC STROKE ETIOLOGY (TOAST CLASSIFICATION)

Thrombotic (Large-Vessel Atherosclerosis)

• Atherosclerotic plaque with luminal narrowing ≥50% in major intracranial or extracranial arteries (carotid, vertebral, MCA, basilar)
• Pathology: Intimal plaque with lipid core, smooth muscle proliferation, fibrous cap disruption

Cardioembolic

• Atrial fibrillation (most common source, ~45% of cardioembolic strokes)
• Acute myocardial infarction with apical/anterior wall thrombus (dilated akinetic segment)
• Valvular disease: Rheumatic mitral stenosis, prosthetic valves, endocarditis
• Dilated cardiomyopathy with intracardiac thrombus
• Left ventricular thrombus formation following MI
• Paradoxical embolism via PFO with venous thromboembolism

Small-Vessel Occlusion (Lacunar Infarcts)

• Lipohyalinosis of penetrating arterioles from chronic hypertension
• Microatheroma of small vessels
• Classic lacunar syndromes (pure motor stroke, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis)

Uncommon Causes

• Arterial dissection: Carotid or vertebral artery intimal tear → thrombosis and/or hemodynamic compromise; often post-traumatic (whiplash) or associated with connective tissue disorders (fibromuscular dysplasia, Ehlers-Danlos syndrome, Marfan syndrome)
• Vasculitis: Infectious (TB meningitis, neurosyphilis), autoimmune (granulomatosis with polyangiitis [GPA], polyarteritis nodosa [PAN], systemic lupus erythematosus [SLE])
• Hypercoagulable states: Antiphospholipid syndrome (lupus anticoagulant, anticardiolipin antibodies), malignancy, thrombophilia (Factor V Leiden, prothrombin G20210A)
• Drug-related: Oral contraceptives (especially with smoking), sympathomimetics (cocaine, amphetamines)

HEMORRHAGIC STROKE ETIOLOGY

• Chronic hypertension (BP >160/100) with lipohyalinosis of penetrating vessels
• Deep locations: basal ganglia (35-50%), thalamus (15-20%), pons (5-10%), cerebellum (5-10%)

Cerebral Amyloid Angiopathy (CAA)

• Aβ deposition in cortical and leptomeningeal vessel walls
• Lobar microhemorrhages and macroscopic lobar ICH
• Increased risk with age and Alzheimer disease pathology

Ruptured Aneurysm (SAH)

• Berry aneurysms at Circle of Willis bifurcations (~85% of non-traumatic SAH)
• Risk factors: hypertension, smoking, alcohol, polycystic kidney disease, connective tissue disorders, family history

Arteriovenous Malformation (AVM)

• Abnormal direct connections between arteries and veins without intervening capillary bed
• Hemorrhage risk: 2-4% per year

Coagulopathy-Related Hemorrhage

• Anticoagulation (warfarin, DOACs, heparin); elevated INR >3 increases risk
• Thrombolytic therapy (tPA)
• Thrombocytopenia, disseminated intravascular coagulation (DIC)

MAJOR RISK FACTORS (ALL TYPES)

• Hypertension (most significant modifiable risk factor for both ischemic and hemorrhagic stroke)
• Diabetes mellitus (2-4x increased risk; accelerates atherosclerosis; impairs collateral vessel development)
• Atrial fibrillation (5-fold increased stroke risk)
• Smoking (dose-dependent; increases thrombosis and atherosclerosis)
• Dyslipidemia (elevated LDL-C promotes atherosclerosis)
• Advanced age (exponential increase after age 55)
• Male sex (higher incidence in men; women catch up post-menopause)
• Previous transient ischemic attack (TIA) or stroke (~10% of TIA patients have stroke within 90 days; 50% within 5 years)
• Obesity and sedentary lifestyle

ACUTE ISCHEMIC STROKE PRESENTATION

• Focal neurological deficits reflecting specific vascular territory involved
• MCA territory infarction (most common, ~45% of ischemic strokes): Contralateral hemiparesis (arm > leg), hemisensory loss, homonymous hemianopia, aphasia (dominant hemisphere), neglect (non-dominant hemisphere)
• ACA territory infarction (~5-10%): Contralateral leg weakness > arm (bilateral leg weakness if bilateral ACA syndrome), abulia, personality changes
• PCA territory infarction (~10-20%): Contralateral homonymous hemianopia ± cortical blindness, alexia without agraphia (if dominant hemisphere), memory impairment
• Vertebrobasilar territory infarction (~10%): Crossed syndromes (ipsilateral CN deficits + contralateral motor/sensory loss), ataxia, nystagmus, dysarthria, dysphagia, locked-in syndrome (bilateral pontine infarction with preserved consciousness)
• Lacunar syndrome (small-vessel disease): Pure motor stroke, pure sensory stroke, clumsy hand syndrome, ataxic hemiparesis
• "Wake-up stroke": Patient awakens with stroke symptoms; time of onset unknown

Physical Examination Findings

• NIHSS score (National Institutes of Health Stroke Scale; correlates with infarct volume and outcome)
• Focal motor deficits: Pronator drift, hemiplegia
• Sensory deficits: Cortical sensory loss (extinction, graphesthesia, stereognosis) vs. subcortical/brainstem (spinothalamic or dorsal column pattern)
• Speech abnormalities: Broca aphasia (non-fluent, agrammatic, preserved comprehension) vs. Wernicke aphasia (fluent, poor comprehension) vs. dysarthria (motor speech)
• Visual field defects: Homonymous hemianopia (cortical) vs. monocular vision loss (amaurosis fugax from retinal artery occlusion)
• Cerebellar signs: Ataxia, nystagmus, dysmetria (posterior circulation involvement)
• Eye abnormalities: Oculocephalic reflex intact but eyes fail to deviate toward side of weakness (pontine stroke with disrupted lateral gaze center); eyes deviate toward side of hemiplegia (frontal lobe lesion affecting gaze fields)

Imaging-Pathology Correlates

• Diffusion-weighted imaging (DWI) hyperintensity = cytotoxic edema (restricted water diffusion); appears within minutes of ischemia
• Apparent diffusion coefficient (ADC) hypointensity = cytotoxic edema (reduced ADC values)
• Perfusion-weighted imaging (PWI) defect = hypoperfusion; mismatch between PWI and DWI = penumbra
• CT perfusion: Low cerebral blood volume (CBV) and prolonged mean transit time (MTT) in ischemic tissue
• Conventional MRI T2/FLAIR: T2 hyperintensity and vasogenic edema appear after 6-12 hours

ACUTE HEMORRHAGIC STROKE PRESENTATION

Intracerebral Hemorrhage (ICH) Symptoms

• Sudden onset severe headache (often worst headache of life in SAH; mild or absent in hypertensive ICH)
• Rapid progression of focal deficits (worsening over minutes to hours due to mass effect and edema)
• Alterations in consciousness: Obtundation, coma (from increased ICP, midline shift, or brainstem involvement)
• Vomiting (from raised ICP or posterior circulation involvement)
• Hypertension (often >180/110 mmHg; reactive or causative)
• Seizures (more common with lobar ICH than deep ICH)

ICH Location-Dependent Presentation

• Basal ganglia/internal capsule (putaminal): Contralateral hemiparesis, hemisensory loss, homonymous hemianopia; may have aphasia (left) or neglect (right)
• Thalamic: Sensory loss > motor loss; vertical gaze palsy (dorsal midbrain compression); memory impairment
• Pontine: Rapid coma, pinpoint pupils, loss of horizontal gaze, quadriplegia
• Cerebellar: Ataxia, headache, vomiting, rapidly progressing coma; obstructive hydrocephalus from fourth ventricle compression
• Lobar (subcortical white matter): Variable deficits depending on location; higher hemorrhage recurrence (CAA)

Subarachnoid Hemorrhage (SAH) Classic Presentation

• Thunderclap headache (instantaneous, maximal intensity at onset, "worst headache of life")
• Meningeal signs: Neck stiffness (meningeal irritation), photophobia, kernig sign, brudzinski sign
• Focal deficits (depends on aneurysm location and vasospasm)
• Vasospasm (occurs 4-14 days post-hemorrhage): Delayed cerebral ischemia, progressive neurological decline
• Rebleeding (most common within 24 hours if untreated)

LABORATORY AND IMAGING CORRELATES

Acute Phase

• Elevated troponin, BNP (cardiac biomarkers from stress cardiomyopathy or demand ischemia)
• Elevated D-dimer, fibrin degradation products (from thrombin generation and fibrinolysis)
• Glucose elevation (stress hyperglycemia; associated with worse outcome)
• CT head without contrast: Hyperdensity in SAH/ICH; hypodensity in

Step 1 — exclude mimics and hemorrhage

• Fingerstick glucose: hypoglycemia is the classic stroke mimic; the AHA/ASA acute ischemic stroke guideline places it before all imaging.
• Noncontrast head CT: the first imaging study in every suspected stroke. Its purpose is to exclude blood, not to "see" the infarct — cytotoxic edema takes hours to become hypodense. Early ischemic signs: loss of gray–white differentiation, insular ribbon sign, sulcal effacement, and the hyperdense MCA sign (intraluminal thrombus). The ASPECTS score grades early MCA-territory ischemic change; a low score implies a large established core.

Step 2 — define vessel, core, and penumbra

• CTA of head and neck: identifies large-vessel occlusion and dissection; CT perfusion or MR perfusion defines core/penumbra mismatch used for late-window thrombectomy selection.
• MRI-DWI: most sensitive and specific test for acute ischemia — DWI hyperintense with low ADC within minutes, the imaging correlate of cytotoxic edema.

Step 3 — subarachnoid hemorrhage pathway

• Noncontrast CT is highly sensitive when obtained within the first several hours; if negative and suspicion persists, lumbar puncture for xanthochromia (bilirubin from RBC breakdown — distinguishes true SAH from traumatic tap, along with non-clearing RBCs across tubes). CTA followed by digital subtraction angiography is definitive for aneurysm.

Acute ischemic stroke — first line

• IV thrombolysis: alteplase within 4.5 hours of last known well; tenecteplase (single bolus) is an accepted alternative in AHA/ASA guidance. BP must be brought below 185/110 mmHg before lysis (short-acting IV agents — labetalol, nicardipine) and kept below 180/105 mmHg for 24 hours after.
• Permissive hypertension if no thrombolysis: do not treat BP unless markedly elevated (roughly above 220/120 mmHg) — lowering pressure collapses collateral perfusion to the penumbra.

Escalation

• Mechanical thrombectomy for anterior-circulation large-vessel occlusion within 6 hours, and up to 24 hours in patients selected by perfusion/clinical mismatch (DAWN and DEFUSE 3 selection criteria, endorsed by AHA/ASA).
• Antiplatelet therapy: aspirin within 24–48 hours (delayed 24 hours after lytic). Short-course dual antiplatelet therapy (aspirin plus clopidogrel) for ~21 days is recommended after minor stroke or high-risk TIA, then monotherapy.
• High-intensity statin (atorvastatin) and risk-factor control per AHA/ASA secondary prevention.

Of the infarct itself

• Malignant cerebral edema: cytotoxic edema is joined by vasogenic edema as the blood–brain barrier fails, peaking around days 3–5. Signal: declining consciousness with midline shift on repeat CT. Emergency — decompressive hemicraniectomy is life-saving in large MCA infarcts (AHA/ASA).
• Herniation: uncal herniation produces an ipsilateral blown pupil (CN III compression) and contralateral hemiparesis; brainstem descent causes Duret hemorrhages. Emergency.
• Hemorrhagic transformation: reperfusion into vessels already necrotic from ischemia; classically an embolic, cortical infarct that becomes petechial or confluently hemorrhagic. Signal: sudden headache, deterioration, new hyperdensity. Emergency.
• Seizures and post-stroke epilepsy: cortical gliotic scar acts as an epileptogenic focus; prophylactic antiseizure drugs are not recommended.
• Aspiration pneumonia from dysphagia; DVT/PE from immobility.
• Central post-stroke pain (Dejerine–Roussy) after thalamic infarction; vascular cognitive impairment and pseudobulbar affect after multiple infarcts.

Of hemorrhage

• Hematoma expansion in the first hours — deterioration with an enlarging clot; emergency.
• Vasospasm and delayed cerebral ischemia after SAH, days 4–14: blood breakdown products and reduced nitric oxide bioavailability constrict vessels. Signal: new focal deficit or drop in mental status in a previously stable SAH patient. Emergency.
• Hydrocephalus: acute obstructive from intraventricular blood, or communicating from arachnoid granulation scarring; also rebleeding of an unsecured aneurysm.
• Hyponatremia from SIADH versus cerebral salt wasting (distinguished by volume status); neurogenic stunned myocardium with troponin rise and QT prolongation.

Of treatment

• Symptomatic ICH after alteplase — stop the infusion, image, give cryoprecipitate/fibrinogen. Emergency.
• Orolingual angioedema with alteplase, disproportionately in patients on ACE inhibitors (bradykinin accumulation).
• Reperfusion/hyperperfusion injury and vessel dissection after thrombectomy or carotid endarterectomy; cranial nerve injury after endarterectomy.

• The single best next step in any acute focal deficit is noncontrast head CT — to exclude hemorrhage, not to see the infarct. Check glucose first at the bedside. Ordering MRI first is the classic distractor.
• Red neurons (shrunken eosinophilic cytoplasm, pyknotic nucleus, loss of Nissl substance) are the earliest light-microscopic sign of irreversible neuronal injury, appearing at roughly 12–24 hours. Neutrophils follow, then macrophages producing liquefactive necrosis, then a cystic cavity walled by gliosis — the brain has no fibroblast-driven scar; astrocytes do the job.
• The CNS is the one organ where ischemia yields liquefactive rather than coagulative necrosis — high lipid content, scant fibrous stroma, and abundant lysosomal enzymes from microglia.
• Hemorrhagic (red) infarcts are embolic and cortical — reperfusion after the embolus fragments floods vessels already damaged by ischemia. Bland (pale) infarcts follow persistent thrombotic occlusion. This is the association examiners test most.
• Selective vulnerability to global hypoxia: hippocampal CA1 (Sommer sector) pyramidal neurons, cerebellar Purkinje cells, and cortical layers 3/5/6 (pseudolaminar necrosis) — plus watershed infarcts in ACA–MCA and MCA–PCA border zones ("man in a barrel" proximal arm weakness).
• Lacunar infarcts arise from lipohyalinosis of penetrating arterioles in a chronic hypertensive; posterior limb of the internal capsule gives pure motor hemiparesis with no cortical signs (no aphasia, no neglect).
• Berry aneurysms lack an internal elastic lamina and media at the bifurcation apex; a PComm aneurysm compresses CN III from the outside, producing a pupil-involving third nerve palsy — unlike the pupil-sparing ischemic palsy of diabetes.
• Do not aggressively lower blood pressure in an untreated ischemic stroke; permissive hypertension preserves collateral flow to the penumbra (AHA/ASA).