Acute Ischaemic Stroke

Topic Overview

Summary

Acute ischaemic stroke is sudden-onset neurological deficit caused by arterial occlusion with resultant cerebral ischaemia and infarction. It represents a medical emergency where "time is brain" — every minute of untreated large vessel occlusion results in loss of 1.9 million neurons. [1] Recognition using FAST (Face-Arm-Speech-Time) criteria enables immediate activation of hyperacute stroke pathways. Reperfusion therapies include intravenous thrombolysis (alteplase or tenecteplase within 4.5 hours) and mechanical thrombectomy for large vessel occlusion (up to 24 hours in selected patients with imaging evidence of salvageable penumbra). [2,3] Stroke unit care and secondary prevention are equally critical to acute intervention.

Key Facts

• Epidemiology: 85% of strokes are ischaemic; 15% haemorrhagic. Stroke is the fourth leading cause of death in the UK (~26,000 deaths annually) and the leading cause of adult disability. [4]
• Pathophysiology: Arterial occlusion creates ischaemic core (irreversibly damaged) surrounded by penumbra (functionally impaired but salvageable tissue). Collateral circulation determines penumbra duration and treatment window.
• Time windows: IV thrombolysis within 4.5 hours; thrombectomy 6-24 hours (imaging-selected). Each 15-minute delay costs 1 month of disability-free life. [5]
• FAST recognition: Face drooping, Arm weakness, Speech difficulty, Time to call emergency services.
• Imaging: Non-contrast CT excludes haemorrhage. CT angiography (CTA) identifies large vessel occlusion. Advanced imaging (CT perfusion/MRI diffusion-weighted imaging) selects patients for extended-window thrombectomy.
• Thrombolysis: Tenecteplase 0.25 mg/kg IV bolus is now preferred over alteplase (0.9 mg/kg) due to ease of administration and equivalent efficacy. [6,7]
• Thrombectomy: Most effective treatment in medicine for large vessel occlusion (number needed to treat = 2.6 for reduction in disability by one modified Rankin Scale grade). [8]
• Stroke unit care: Multidisciplinary stroke unit admission reduces mortality and disability compared with general medical ward care. [9]

Clinical Pearls

"Time is brain": Every minute of large vessel occlusion destroys 1.9 million neurons, 14 billion synapses, and 12 km of myelinated fibres. [1]

Door-to-needle target: Under 60 minutes for thrombolysis. Door-to-groin puncture under 90 minutes for thrombectomy.

Tenecteplase advantage: Single bolus administration (vs 60-minute alteplase infusion) simplifies pre-hospital and emergency department workflows. [7]

Thrombectomy efficacy: NNT of 2.6 makes mechanical thrombectomy the single most effective intervention in acute medicine. [8]

Blood pressure paradox: Permissive hypertension is neuroprotective in acute stroke (maintains perfusion to penumbra). Only treat if > 220/120 mmHg or if thrombolysing (target less than 185/110 pre-treatment, less than 180/105 post-treatment). [10]

Wake-up stroke: 20-25% of strokes occur during sleep. Advanced imaging (MRI DWI-FLAIR mismatch or CT perfusion) can identify treatment candidates. [11]

Basilar artery occlusion: High mortality (> 80% untreated) but dramatic response to thrombectomy. Always consider in unexplained coma or locked-in syndrome.

Why This Matters Clinically

Stroke is a global health emergency. In the UK alone, stroke affects 100,000 people annually — one stroke every 5 minutes. Without treatment, mortality approaches 30% at 1 year and 40% of survivors have moderate-severe disability. The introduction of hyperacute reperfusion therapies has transformed outcomes: thrombolysis reduces disability (NNT ~10) and thrombectomy for large vessel occlusion has unprecedented efficacy (NNT 2.6). However, these benefits are time-dependent and access-dependent. Clinicians in all specialties must recognise stroke, activate emergency pathways, and understand contraindications to treatment. Delays of even 15 minutes have measurable impact on long-term functional outcomes.

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Visual Summary

Visual assets to be added:

• FAST campaign poster and recognition algorithm
• CT head: normal vs acute ischaemic change vs haemorrhage
• CT angiography showing large vessel occlusion (M1, ICA terminus)
• NIHSS scoring visual guide with demonstration images
• Acute stroke pathway flowchart (pre-hospital to stroke unit)
• Circle of Willis and common stroke territories (MCA, ACA, PCA, posterior circulation)
• Penumbra concept diagram (core vs penumbra vs benign oligaemia)
• Modified Rankin Scale illustrated outcomes (0-6)
• Mechanical thrombectomy procedure steps
• Secondary prevention algorithm

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Epidemiology

Global and National Burden

Stroke is the second leading cause of death globally and a leading cause of disability. [4]

United Kingdom:

• Incidence: ~100,000 strokes per year (one every 5 minutes)
• Type distribution: 85% ischaemic, 15% haemorrhagic
• Mortality: ~26,000 deaths annually
• Prevalence: > 1.3 million stroke survivors
• Disability burden: Leading cause of adult disability
• Economic cost: £26 billion annually (healthcare, social care, productivity loss)

Global context:

• Stroke affects 1 in 4 people over age 25 during their lifetime
• 13.7 million new strokes annually worldwide
• 5.5 million stroke deaths per year
• Low- and middle-income countries bear 86% of global stroke mortality

Demographics

Age:

• Risk doubles every decade after age 55
• Mean age at first stroke: 73 years in men, 77 years in women
• 25% of strokes occur in people under 65 (working age)
• 10% occur under age 50

Sex:

• Slightly higher incidence in men (male:female ratio ~1.25:1)
• Women have worse functional outcomes and higher mortality
• Longer life expectancy means more women live with stroke disability

Ethnicity:

• 2-fold higher risk in Black populations compared with White populations
• 1.5-fold higher risk in South Asian populations
• Greater prevalence of risk factors (hypertension, diabetes) in high-risk ethnic groups

Risk Factors

Stroke is a largely preventable disease — 90% of stroke risk is attributable to modifiable risk factors. [12]

Aetiological Classification (TOAST)

The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification categorises stroke by mechanism:

Temporal Patterns

• Circadian variation: Peak incidence 6 AM–12 noon (morning blood pressure surge, hypercoagulability)
• Seasonal variation: Slightly higher incidence in winter months
• Wake-up stroke: 20-25% of strokes discovered upon waking

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Pathophysiology

Ischaemic Cascade

Acute arterial occlusion triggers a complex cascade from energy failure to cell death:

1. Arterial Occlusion

• Thrombus or embolus occludes cerebral artery
• Immediate cessation of blood flow downstream
• Autoregulatory capacity overwhelmed

2. Ischaemic Core Formation

• Tissue receiving less than 10 mL/100 g/min blood flow (normal: 50-60 mL/100 g/min)
• ATP depletion within seconds
• Membrane ion pump failure → cellular oedema
• Glutamate excitotoxicity and intracellular calcium influx
• Irreversible neuronal death within minutes

3. Ischaemic Penumbra

• Surrounding zone with 10-20 mL/100 g/min blood flow
• Electrical silence (functionally impaired) but preserved cellular integrity
• Viable for hours if reperfused
• Target of acute reperfusion therapy
• Penumbra size and duration determined by collateral circulation

4. Collateral Circulation

• Circle of Willis provides primary collateral pathways
• Leptomeningeal anastomoses (pial collaterals) provide secondary routes
• Variability in collateral anatomy explains heterogeneity in infarct progression
• Good collaterals extend treatment window beyond standard time criteria

5. Progression to Infarction

• Without reperfusion, penumbra progressively recruits into core
• Inflammatory response amplifies tissue injury
• Blood-brain barrier breakdown → vasogenic oedema
• Peak oedema at 3-5 days (risk of herniation in large infarcts)

Time is Brain

The concept "time is brain" quantifies neuronal loss in untreated stroke: [1]

• Per minute of large vessel occlusion:

  • 1.9 million neurons lost
  • 14 billion synapses destroyed
  • 12 km myelinated fibres damaged

• Per hour of untreated stroke:

  • Brain ages 3.6 years

• Every 15-minute delay to treatment:

  • 1 month of disability-free life lost [5]

Reperfusion Injury

Restoration of blood flow can paradoxically cause additional injury:

• Haemorrhagic transformation: Disrupted blood-brain barrier allows extravasation of blood into infarcted tissue (symptomatic in 6-7% of thrombolysed patients) [13]
• Cerebral oedema: Ionic and vasogenic oedema peaks 3-5 days post-stroke
• Free radical damage: Reactive oxygen species generated during reperfusion
• Inflammatory response: Leukocyte infiltration and cytokine release

Despite these risks, benefits of reperfusion far outweigh harms when delivered within appropriate time windows.

Molecular Mechanisms

Excitotoxicity:

• Ischaemia triggers glutamate release
• NMDA receptor over-activation
• Intracellular calcium overload
• Activation of proteases, lipases, endonucleases

Oxidative stress:

• Reactive oxygen species (ROS) production
• Mitochondrial dysfunction
• Lipid peroxidation and membrane damage

Inflammation:

• Microglial activation
• Cytokine release (IL-1, IL-6, TNF-α)
• Leukocyte adhesion and infiltration
• Matrix metalloproteinase activation → blood-brain barrier breakdown

Apoptosis:

• Programmed cell death in penumbral regions
• Caspase activation
• Bcl-2 family protein dysregulation

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Clinical Presentation

FAST (Public Recognition Tool)

Designed for public awareness and pre-hospital recognition:

• F — Face: Facial droop or asymmetry. Ask patient to smile — one side may not move.
• A — Arm: Arm weakness or drift. Ask patient to raise both arms — one arm drifts downward.
• S — Speech: Speech disturbance (slurred, absent, nonsensical). Ask patient to repeat a simple sentence.
• T — Time: Time to call 999/emergency services immediately if any sign present.

FAST has 79% sensitivity and 89% specificity for stroke when used by paramedics. [14]

Enhanced versions:

• BE-FAST: Adds "B" (Balance/coordination) and "E" (Eyes/vision) to capture posterior circulation strokes
• FAST-ED: Adds "E" (Eyes/vision) and "D" (Denial/neglect) to improve sensitivity for large vessel occlusion

Common Stroke Syndromes by Vascular Territory

Symptoms by Severity

Red Flags Requiring Immediate Action

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Clinical Examination

National Institutes of Health Stroke Scale (NIHSS)

The NIHSS is a standardised 15-item neurological examination quantifying stroke severity (score 0-42, higher = more severe). [15]

NIHSS score interpretation:

• 0: No stroke symptoms
• 1-4: Minor stroke
• 5-15: Moderate stroke
• 16-20: Moderate to severe stroke
• 21-42: Severe stroke

Prognostic value:

• NIHSS > 10 at presentation: 60% chance of poor outcome
• NIHSS less than 5: 90% chance of good outcome
• Each 1-point reduction in NIHSS at 24 hours increases odds of good outcome by 17%

Structured Neurological Examination

Level of consciousness:

• Alert, drowsy, obtunded, stuporous, comatose
• Glasgow Coma Scale (GCS)

Cranial nerves:

• CN II: Visual fields (confrontation), pupils
• CN III, IV, VI: Eye movements, gaze preference, nystagmus
• CN V: Facial sensation
• CN VII: Facial movement (upper and lower face — distinguish central vs peripheral palsy)
• CN VIII: Hearing
• CN IX, X: Palate elevation, gag reflex
• CN XII: Tongue protrusion and movement

Motor:

• Tone (flaccid in acute phase, spastic in chronic phase)
• Power (MRC scale 0-5) in all limbs
• Pronator drift (arm extended, palms up, eyes closed — affected arm drifts down and pronates)
• Gait (if safe to assess)

Sensory:

• Light touch, pinprick
• Proprioception, vibration
• Extinction to double simultaneous stimulation

Coordination:

• Finger-nose test
• Heel-shin test
• Rapid alternating movements

Language:

• Fluency (spontaneous speech)
• Comprehension (follow commands)
• Repetition
• Naming
• Reading and writing

Neglect:

• Visual neglect (bisection test, cancellation test)
• Sensory inattention
• Anosognosia

Cardiovascular Examination

• Pulse: Irregularly irregular suggests atrial fibrillation
• Blood pressure: Both arms (> 20 mmHg difference suggests aortic dissection or subclavian stenosis)
• Heart sounds: Murmurs (mitral stenosis, endocarditis), prosthetic valve clicks
• Carotid auscultation: Bruits (carotid stenosis)
• Peripheral pulses: Absent pulses suggest peripheral vascular disease (atherosclerosis risk factor)

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Investigations

Hyperacute Phase (Emergency Department)

Immediate investigations (before treatment decision):

CT Head Interpretation

Advanced Imaging for Extended-Window Selection

CT perfusion (CTP):

• Assesses cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP)
• Ischaemic core: Severely reduced CBF and CBV
• Penumbra: Prolonged MTT/TTP with preserved CBV
• Mismatch ratio (penumbra:core) > 1.8 and core less than 70 mL selects patients for thrombectomy up to 24 hours [3]

MRI brain (if time permits):

• Diffusion-weighted imaging (DWI): Most sensitive for acute infarction (visible within minutes)
• FLAIR: Hyperintensity appears 3-6 hours after infarction
• DWI-FLAIR mismatch: DWI-positive/FLAIR-negative suggests stroke less than 4.5 hours (useful in wake-up stroke) [11]
• Gradient echo (GRE) or susceptibility-weighted imaging (SWI): Detects microhaemorrhages (contraindication to thrombolysis if numerous)
• MR angiography (MRA): Alternative to CTA for vessel imaging

Investigations After Acute Phase (During Admission)

Aetiological workup:

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Classification & Staging

TOAST Classification (Aetiology)

The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is the most widely used aetiological classification:

1. Large artery atherosclerosis: Stenosis > 50% or plaque in relevant artery
2. Cardioembolism: AF, mechanical valve, MI within 4 weeks, LV thrombus, endocarditis, atrial myxoma
3. Small vessel occlusion (lacunar): Lacunar syndrome with no cortical signs, infarct less than 1.5 cm on imaging
4. Other determined cause: Dissection, vasculitis, genetic, hypercoagulable state
5. Undetermined cause (cryptogenic): Incomplete workup, multiple causes, or no cause identified

Bamford (Oxfordshire) Clinical Classification

Bedside clinical classification predicting vascular territory and prognosis:

Modified Rankin Scale (mRS) — Functional Outcome

The mRS is the primary outcome measure in stroke trials:

Clinically meaningful outcome: mRS 0-2 (functionally independent)

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Management

Pre-Hospital Phase

Recognition and activation:

• Public and paramedic education: FAST
• 999 call immediately if any FAST sign present
• Pre-alert receiving hospital ("stroke call")
• Record time of symptom onset (or last known well time)
• Airway, breathing, circulation stabilisation
• Avoid aggressive blood pressure lowering
• Avoid oral intake (aspiration risk until swallow assessed)
• Direct transfer to hyperacute stroke unit (HASU) or thrombectomy-capable centre

"Drip and ship" vs "Mothership" models:

• Mothership: Direct to comprehensive stroke centre (preferred if less than 30-minute delay and thrombectomy candidate)
• Drip and ship: Thrombolysis at primary stroke centre, then transfer for thrombectomy if needed

Emergency Department / Hyperacute Management

Goals:

• Door-to-imaging: less than 20 minutes
• Door-to-needle (thrombolysis): less than 60 minutes
• Door-to-groin puncture (thrombectomy): less than 90 minutes

Step 1: Immediate Assessment (0-20 minutes)

• ABCDE approach
• NIHSS score
• Blood glucose (exclude hypoglycaemia)
• IV access (2 large-bore cannulae)
• Bloods: FBC, U&E, coagulation, glucose
• ECG
• Non-contrast CT head + CT angiography: Within 20 minutes of arrival

Step 2: Thrombolysis Decision (20-60 minutes)

Indications for IV thrombolysis:

• Clinical diagnosis of ischaemic stroke causing measurable neurological deficit
• Time of onset (or last known well) less than 4.5 hours
• CT excludes haemorrhage
• No contraindications (see below)

Thrombolytic agents: [6,7]

Tenecteplase advantages: [7]

• Single bolus (vs 60-minute infusion)
• Easier pre-hospital administration
• Lower nursing burden
• Reduced medication errors
• Superior recanalization in large vessel occlusion

Absolute contraindications to thrombolysis: [10]

• Haemorrhage on CT head
• Ischaemic stroke within 3 months
• History of intracranial haemorrhage
• Major surgery or serious trauma within 14 days
• GI or urinary tract haemorrhage within 21 days
• Arterial puncture at non-compressible site within 7 days
• Acute bleeding disorder (platelets less than 100×10⁹/L, INR > 1.7, APTT >ULN)
• Known intracranial neoplasm, AVM, or aneurysm
• Suspected aortic dissection
• Acute pancreatitis
• Severe liver disease with coagulopathy

Relative contraindications (individualised decision):

• Rapidly improving symptoms (but may still thrombolyse if significant residual deficit)
• Seizure at stroke onset (if deficit is post-ictal, but thrombolyse if true stroke)
• Blood pressure > 185/110 mmHg despite treatment
• Blood glucose less than 2.8 or > 22.2 mmol/L
• Pregnancy (relative; may thrombolyse in selected cases)
• Age > 80 years with diabetes and prior stroke (ESO guidelines accept; some older guidelines considered relative contraindication)

Blood pressure management for thrombolysis: [10]

• Pre-treatment target: less than 185/110 mmHg
• Post-treatment target: less than 180/105 mmHg for 24 hours
• Agents: IV labetalol 10-20 mg over 1-2 minutes (repeat as needed), OR GTN infusion 1-10 mg/hour

Step 3: Thrombectomy Decision (Simultaneous with Thrombolysis)

Indications for mechanical thrombectomy: [2,3,8]

• Large vessel occlusion (LVO) confirmed on CTA:
  • Internal carotid artery (ICA) occlusion or stenosis with intracranial occlusion
  • M1 or proximal M2 segment of MCA
  • Basilar artery
  • (Some centres: distal M2, A1 ACA, P1 PCA)
• NIHSS ≥6
• mRS 0-1 before stroke (premorbid independence)
• ASPECTS ≥6
• Time windows:
  • "0-6 hours: No advanced imaging required if above criteria met"
  • "6-24 hours: CT perfusion or MRI required showing mismatch (salvageable penumbra:core ratio > 1.8, core less than 70 mL) [3]"

Thrombectomy trials:

• MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT (2015): Established 0-6 hour window. NNT 2.6-4 for mRS reduction. [8]
• DAWN, DEFUSE-3 (2018): Extended window to 6-24 hours using perfusion imaging selection. [3]
• BASICS (2024): Confirmed benefit for basilar artery occlusion.

Thrombectomy technique:

• Femoral artery access under local anaesthetic ± conscious sedation (general anaesthesia if airway compromise)
• Catheter navigation to occluded vessel
• Clot retrieval using stent-retriever or aspiration catheter
• Goal: TICI 2b-3 reperfusion (> 50% of territory reperfused)
• Procedure time: 30-90 minutes

Bridging thrombolysis + thrombectomy:

• Standard approach: IV thrombolysis + thrombectomy
• Direct thrombectomy (no IV thrombolysis) under investigation but not yet standard outside trials

Acute Stroke Unit Care (First 72 Hours)

Multidisciplinary stroke unit:

Stroke unit care reduces death and dependency (NNT ~20 for good outcome). [9] Components:

• Medical team: Stroke physician, neurology registrar
• Nursing: Stroke-trained nurses, nurse-to-patient ratio 1:4
• Therapies: Physiotherapy, occupational therapy, speech and language therapy
• Dietetics: Nutritional assessment and support
• Social work: Discharge planning

Monitoring:

• Continuous cardiac telemetry (detect AF)
• Neurological observations (GCS, limb power) every 15 minutes for 2 hours post-thrombolysis, then hourly for 24 hours
• Blood pressure every 15 minutes for 2 hours post-thrombolysis, then 4-hourly
• Oxygen saturation (target > 94%)
• Temperature 4-hourly

Key interventions:

Complications to monitor:

• Haemorrhagic transformation: Deterioration post-thrombolysis. Repeat CT head urgently. Symptomatic ICH in 6-7% of thrombolysed patients. [13]
• Malignant MCA syndrome: Massive infarct with cerebral oedema → raised ICP → herniation. Peaks 3-5 days. Consider decompressive hemicraniectomy if age less than 60. [16]
• Seizures: Occur in 2-4% acutely. Treat if witnessed. Prophylactic antiepileptics not indicated.
• Aspiration pneumonia: High risk if dysphagia. Swallow screen mandatory.
• Pressure ulcers: Reposition 2-hourly. Pressure-relieving mattress.
• UTI: Avoid indwelling catheters if possible.

Secondary Prevention (Start During Admission)

Antiplatelet therapy:

Anticoagulation (if atrial fibrillation or other cardioembolic source):

Statin therapy:

• Atorvastatin 80 mg ON for all ischaemic strokes (regardless of baseline cholesterol)
• SPARCL trial: High-dose statin reduces recurrent stroke by 16%
• Target LDL less than 1.8 mmol/L

Blood pressure control (after acute phase):

• Target less than 130/80 mmHg for secondary prevention
• Start/intensify antihypertensives before discharge
• Any agent acceptable (ACE inhibitor, ARB, calcium channel blocker, thiazide diuretic)
• PROGRESS trial: BP lowering reduces recurrent stroke by 28%

Carotid intervention (if symptomatic stenosis):

Evidence:

• NASCET/ECST trials: CEA for 50-99% symptomatic stenosis reduces 2-year stroke risk from 26% to 9%. [19]
• Benefit greatest if performed within 2 weeks.
• CEA preferred over CAS in older patients, CAS in younger or high surgical risk.

Lifestyle modification:

• Smoking cessation: Single most important modifiable risk factor
• Weight reduction: Target BMI 18.5-24.9
• Physical activity: 30 minutes moderate exercise 5 days/week
• Diet: Mediterranean diet, reduce salt (less than 6 g/day)
• Alcohol: Limit to less than 14 units/week

Diabetes management:

• Target HbA1c less than 53 mmol/mol (7%)

Patent foramen ovale (PFO) closure:

• Consider in cryptogenic stroke, age less than 60, large right-to-left shunt
• CLOSE, REDUCE, RESPECT trials: PFO closure + antiplatelet superior to antiplatelet alone in selected patients

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Complications

Acute Complications (First 7 Days)

Subacute and Chronic Complications

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Prognosis & Outcomes

Mortality

Stroke subtype mortality (1 year):

• LACI: 11%
• PACI: 16%
• POCI: 19%
• TACI: 39%

Functional Outcomes (mRS at 3 Months)

Untreated stroke:

• 30% mRS 0-2 (functionally independent)
• 40% mRS 3-5 (dependent)
• 30% mRS 6 (dead)

After thrombolysis:

• 40% mRS 0-2 (10% absolute increase vs untreated)

After thrombectomy (for LVO):

• 46% mRS 0-2 (16% absolute increase vs medical therapy alone)

Impact of Treatments on Outcomes

Long-Term Disability

At 1 year post-stroke:

• 30% return to premorbid function
• 30% mild-moderate disability (mRS 2-3)
• 10% severe disability (mRS 4-5)
• 30% dead

Predictors of good recovery:

• Young age
• Low baseline NIHSS
• Early reperfusion
• Stroke unit care
• Intensive rehabilitation
• No complications

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Evidence & Guidelines

Key International Guidelines

1. National Institute for Health and Care Excellence (NICE). Stroke and Transient Ischaemic Attack in Over 16 s: Diagnosis and Initial Management (NG128). Updated 2019.
2. Royal College of Physicians (RCP). National Clinical Guideline for Stroke for the UK and Ireland. 6th Edition, 2023.
3. European Stroke Organisation (ESO). Guidelines for Management of Ischaemic Stroke and Transient Ischaemic Attack. 2021.
4. American Heart Association/American Stroke Association (AHA/ASA). Guidelines for the Early Management of Patients With Acute Ischemic Stroke. 2019 (updated 2024).

Landmark Trials and Evidence

Thrombolysis Trials

1. NINDS t-PA Stroke Study Group (1995). Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-1587. [PMID: 7477192] — Established alteplase 0.9 mg/kg within 3 hours. [13]

2. ECASS-3 (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359:1317-1329. [PMID: 18815396] — Extended window to 4.5 hours.

3. Meng X, et al. Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke: The ORIGINAL Randomized Clinical Trial. JAMA. 2024;332(17):1437-1445. [PMID: 39264623] — Tenecteplase 0.25 mg/kg noninferior to alteplase (mRS 0-1: 72.7% vs 70.3%). [6]

4. Wang L, et al. Comprehensive Review of Tenecteplase for Thrombolysis in Acute Ischemic Stroke. J Am Heart Assoc. 2024;13(9):e031692. [PMID: 38686848] — Meta-analysis confirming tenecteplase noninferiority and superior convenience. [7]

Thrombectomy Trials

5. Berkhemer OA, et al. A randomized trial of intraarterial treatment for acute ischemic stroke (MR CLEAN). N Engl J Med. 2015;372:11-20. [PMID: 25517348] — First trial proving thrombectomy efficacy. [8]

6. Goyal M, et al. Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials. Lancet. 2016;387:1723-1731. [PMID: 26898852] — Pooled analysis MR CLEAN/ESCAPE/EXTEND-IA/SWIFT PRIME/REVASCAT: NNT 2.6 for mRS 0-2. [8]

7. Nogueira RG, et al. Thrombectomy 6 to 24 Hours after Stroke with a Mismatch between Deficit and Infarct (DAWN). N Engl J Med. 2018;378:11-21. [PMID: 29129157] — Extended window to 24 hours with perfusion imaging selection. [3]

8. Albers GW, et al. Thrombectomy for Stroke at 6 to 16 Hours with Selection by Perfusion Imaging (DEFUSE 3). N Engl J Med. 2018;378:708-718. [PMID: 29364767] — Confirmed 6-16 hour window with imaging selection. [3]

Acute Management and Stroke Unit Care

9. Stroke Unit Trialists' Collaboration. Organised inpatient (stroke unit) care for stroke. Cochrane Database Syst Rev. 2013;9:CD000197. [PMID: 24026639] — Stroke unit care reduces death and dependency (NNT ~20). [9]

10. Anderson CS, et al. Rapid Blood-Pressure Lowering in Patients with Acute Intracerebral Hemorrhage (INTERACT2). N Engl J Med. 2013;368:2355-2365. [PMID: 23713578] — Informed BP targets in acute stroke. [10]

Secondary Prevention

11. Campbell BCV, et al. Extending thrombolysis to 4.5-9 h and wake-up stroke using perfusion imaging: a systematic review and meta-analysis of individual patient data. Lancet. 2019;394:139-147. [PMID: 31128926] — DWI-FLAIR mismatch in wake-up stroke. [11]

12. O'Donnell MJ, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388:761-775. [PMID: 27431356] — 90% of stroke risk attributable to modifiable factors. [12]

13. Emberson J, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet. 2014;384:1929-1935. [PMID: 25106063] — Time-to-treatment critical; every 15-minute delay = 1 month disability. [5,13]

14. Harbison J, et al. Rapid ambulance protocol for acute stroke. Lancet. 1999;353:1935. [PMID: 10371574] — FAST validation. [14]

15. Lyden P, et al. Using the National Institutes of Health Stroke Scale: A Cautionary Tale. Stroke. 2017;48:513-519. [PMID: 28077465] — NIHSS validation and usage. [15]

16. Vahedi K, et al. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;6:215-222. [PMID: 17303527] — Decompressive hemicraniectomy NNT 2 to save life. [16]

17. Johnston SC, et al. Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA (POINT). N Engl J Med. 2018;379:215-225. [PMID: 29766750] — DAPT for minor stroke/TIA. [17]

18. Ruff CT, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383:955-962. [PMID: 24315724] — DOACs for AF-related stroke prevention. [18]

19. Rothwell PM, et al. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet. 2004;363:915-924. [PMID: 15043958] — CEA within 2 weeks for 50-99% symptomatic stenosis. [19]

Recent Advances

20. Hilkens NA, et al. Stroke. Lancet. 2024;403:2820-2836. [PMID: 38759664] — Comprehensive 2024 review of stroke management advances. [2]

21. Sharma R, Lee K. Advances in treatments for acute ischemic stroke. BMJ. 2025;389:e076161. [PMID: 40335091] — Latest evidence extending beyond current guidelines. [4]

22. Tsivgoulis G, et al. Thrombolysis for acute ischaemic stroke: current status and future perspectives. Lancet Neurol. 2023;22:418-429. [PMID: 36907201] — Future directions in thrombolysis research. [1]

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Patient & Family Information

What is a Stroke?

A stroke (sometimes called a "brain attack") happens when the blood supply to part of your brain is suddenly blocked or a blood vessel in your brain bursts. Brain cells need constant oxygen and nutrients from blood. Without blood supply, brain cells start to die within minutes. This can cause sudden symptoms like weakness, difficulty speaking, or vision problems.

Types of stroke:

• Ischaemic stroke (85%): A blood clot blocks an artery in the brain
• Haemorrhagic stroke (15%): A blood vessel bursts and bleeds into the brain

Act FAST — Every Minute Counts

Stroke is a medical emergency. The faster you get treatment, the better your chances of recovery. Use FAST to spot the signs:

• F — Face: Has their face fallen on one side? Can they smile?
• A — Arm: Can they raise both arms and keep them up?
• S — Speech: Is their speech slurred or strange? Can they say a simple sentence?
• T — Time: If you see ANY of these signs, call 999 immediately.

Don't wait. Even if symptoms improve, you still need emergency care. Time lost is brain lost.

Emergency Treatment

Clot-busting medicine (thrombolysis):

• If you arrive within 4.5 hours, doctors may give you a clot-busting injection
• This medicine dissolves the clot and restores blood flow
• The earlier it's given, the better it works

Clot removal (thrombectomy):

• If you have a large blockage, doctors may remove the clot using a thin tube threaded through blood vessels
• This can be done up to 24 hours after stroke in selected patients

Stroke unit care:

• You'll be cared for on a specialist stroke unit
• A team of experts (doctors, nurses, physiotherapists, speech therapists, occupational therapists) will look after you
• Stroke unit care saves lives and improves recovery

Recovery and Rehabilitation

Everyone's stroke recovery is different. Some people recover fully within weeks; others take months or have lasting disability.

Rehabilitation starts early:

• Physiotherapy helps regain movement and balance
• Speech and language therapy helps with speaking, swallowing, and communication
• Occupational therapy helps you relearn daily activities (dressing, cooking, etc.)

What to expect:

• First 3 months: Most rapid recovery
• 3-6 months: Continued improvement but slower
• After 6 months: Progress continues but plateau may occur

Fatigue is common — pace yourself and rest when needed.

Preventing Another Stroke

After a stroke, you're at higher risk of having another one. But you can reduce this risk by 80% with:

Medications:

• Blood-thinning tablets (aspirin or clopidogrel) to prevent clots
• Anticoagulants (if you have atrial fibrillation)
• Cholesterol-lowering tablets (statins) — everyone should take these after stroke
• Blood pressure tablets — even if your blood pressure is "normal"

Lifestyle changes:

• Stop smoking (single biggest thing you can do)
• Healthy diet (more fruit, vegetables, fish; less salt, saturated fat)
• Regular exercise (30 minutes walking most days)
• Moderate alcohol (maximum 14 units/week)
• Lose weight if overweight

Medical procedures (if needed):

• Carotid surgery to unblock neck arteries
• Heart procedures for abnormal rhythms

Emotional Impact

Depression affects 1 in 3 stroke survivors. It's normal to feel:

• Sad, tearful, or hopeless
• Anxious or worried
• Frustrated or angry
• Socially withdrawn

Get help early. Talking therapy and antidepressants can help. Speak to your GP or stroke team.

Driving After Stroke

You must not drive for at least 1 month after a stroke. You must inform the DVLA. Your doctor will advise when you can restart driving (usually depends on recovery and any lasting disability).

Returning to Work

Many people return to work after stroke. Timing depends on:

• Type of job (physical vs desk work)
• Severity of stroke
• Ongoing disability

Occupational therapists and stroke coordinators can help plan your return.

Support and Resources

• Stroke Association: www.stroke.org.uk | Helpline: 0303 3033 100
• NHS Stroke Information: www.nhs.uk/conditions/stroke
• Different Strokes (for younger stroke survivors): www.differentstrokes.co.uk
• Chest Heart & Stroke Scotland: www.chss.org.uk

You are not alone. Over 1.3 million people in the UK live with the effects of stroke.

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Exam Focus: High-Yield Points

MRCP / FRACP

Written exam focus:

• NIHSS scoring components and interpretation
• Thrombolysis contraindications (absolute vs relative)
• Tenecteplase vs alteplase dosing and evidence
• Thrombectomy time windows and imaging selection criteria
• TOAST classification
• Bamford classification and prognosis
• Secondary prevention agents and evidence
• Carotid endarterectomy indications and timing

PACES/Clinical exam focus:

• Rapid NIHSS assessment
• Recognising stroke mimics (hypoglycaemia, Todd's paresis, hemiplegic migraine)
• Communication station: Breaking bad news post-stroke, explaining thrombolysis risks/benefits
• Data interpretation: CT head (early ischaemic changes), ECG (AF)

MRCS / FRCS / FRACS

Surgical focus:

• Carotid endarterectomy technique, indications, complications
• Decompressive hemicraniectomy indications and evidence
• Vascular anatomy (circle of Willis, extracranial-intracranial circulation)
• Perioperative stroke prevention

Emergency Medicine

Focus:

• FAST recognition and pre-hospital stroke pathway
• Door-to-needle and door-to-groin time targets
• Rapid thrombolysis decision-making
• Blood pressure management in acute stroke
• Stroke mimics and red flags
• NIHSS rapid scoring

Neurology

Focus:

• Advanced stroke mechanisms (ESUS, CADASIL, Fabry, vasculitis)
• Wake-up stroke and advanced imaging
• Basilar artery occlusion recognition and management
• Post-stroke complications (central pain, epilepsy, cognitive impairment)

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Summary: Top 10 Take-Home Messages

1. Time is brain: Every minute of untreated large vessel occlusion destroys 1.9 million neurons. Every 15-minute delay costs 1 month of disability-free life.

2. FAST recognition: Public and healthcare workers must know Face-Arm-Speech-Time. Immediate 999 call if any sign present.

3. Hyperacute reperfusion: Tenecteplase 0.25 mg/kg (preferred) or alteplase 0.9 mg/kg within 4.5 hours. Thrombectomy for large vessel occlusion up to 24 hours (imaging-selected).

4. Thrombectomy is the most effective treatment in medicine: NNT 2.6 for large vessel occlusion. Extends window to 6-24 hours with perfusion imaging.

5. Imaging before treatment: Non-contrast CT excludes haemorrhage (mandatory before thrombolysis). CTA identifies large vessel occlusion (guides thrombectomy).

6. Blood pressure paradox: Permissive hypertension in acute phase (only treat if > 220/120 or > 185/110 if thrombolysing). Aggressive lowering worsens outcomes.

7. Stroke unit care saves lives: Multidisciplinary stroke unit reduces death and dependency (NNT ~20). All stroke patients should be admitted to stroke unit.

8. Swallow before swallow: Mandatory swallow screen before any oral intake to prevent aspiration pneumonia.

9. Secondary prevention is 80% effective: Antiplatelet (or anticoagulation for AF) + statin + BP control + lifestyle modification reduces recurrent stroke by 80%.

10. Carotid intervention is time-critical: Endarterectomy for 50-99% symptomatic stenosis within 14 days (ideally less than 7 days) reduces 2-year stroke from 26% to 9%.

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Differential Diagnosis

Stroke mimics account for 10-30% of suspected strokes. Rapid recognition and exclusion are essential.

Common Stroke Mimics

Red Flags Suggesting True Stroke (Not Mimic)

• Sudden onset (vascular time course)
• Maximal deficit at onset (vs gradual worsening)
• Cortical signs (aphasia, neglect, hemianopia)
• Vascular territory distribution
• No alternative explanation on history and examination

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Special Populations and Scenarios

Young Stroke (less than 50 Years)

Incidence: 10% of all strokes occur in patients less than 50 years.

Aetiological differences (compared with older patients):

• Arterial dissection (carotid, vertebral): 20%
• Patent foramen ovale (PFO) with paradoxical embolism: 15%
• Antiphospholipid syndrome: 5%
• Other thrombophilias (Factor V Leiden, prothrombin G20210A): 5%
• Genetic causes (CADASIL, Fabry disease, sickle cell): 2%
• Drug-related (cocaine, amphetamines): 5%
• Pregnancy/postpartum: 1%

Extended workup in young stroke:

• Vascular imaging: CTA/MRA neck (dissection — "string sign," intimal flap, pseudoaneurysm)
• Echocardiography: TOE for PFO (bubble study), atrial septal defect, cardiac tumour
• Thrombophilia screen: Protein C, protein S, antithrombin, Factor V Leiden, prothrombin G20210A, antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein)
• Vasculitis screen: ESR, CRP, ANA, ANCA, complement
• Genetic testing: CADASIL (NOTCH3 mutation) if family history and white matter changes; Fabry disease (α-galactosidase) if angiokeratomas or renal/cardiac involvement
• Toxicology screen: Cocaine, amphetamines
• Haematological: Sickle cell screen if Afro-Caribbean ethnicity

Management differences:

• PFO closure: Consider if cryptogenic stroke with high-risk PFO features (large shunt, atrial septal aneurysm). CLOSE/REDUCE/RESPECT trials support closure + antiplatelet in selected patients.
• Anticoagulation: If thrombophilia and recurrent VTE/stroke.
• Dissection: Antiplatelet vs anticoagulation controversial (no RCT difference). Most use antiplatelet. Endovascular stenting if severe stenosis or recurrent symptoms.

Posterior Circulation Stroke

Anatomy: Vertebral arteries → basilar artery → posterior cerebral arteries, plus branches (PICA, AICA, SCA, pontine perforators).

Clinical features:

• Vertigo, nausea, vomiting (vestibular nuclei)
• Diplopia (CN III, IV, VI nuclei)
• Dysarthria, dysphagia (CN IX, X, XII nuclei)
• Ataxia (cerebellum)
• Crossed signs (ipsilateral face, contralateral body due to brainstem anatomy)
• Visual field defects (occipital cortex)
• Reduced consciousness (reticular activating system)

Basilar artery occlusion:

• Presentation: Coma, quadriplegia, locked-in syndrome (aware but cannot move or speak except vertical eye movements)
• Mortality: 80-90% without treatment
• Treatment: Mechanical thrombectomy dramatically improves outcomes (recent BASICS trial confirmed benefit)
• Time window: Up to 24 hours (often extended due to good collaterals)

Diagnostic challenges:

• Symptoms may be subtle (isolated vertigo, diplopia)
• Often misdiagnosed as benign peripheral vertigo or labyrinthitis
• HINTS exam (Head Impulse, Nystagmus, Test of Skew) helps distinguish central vs peripheral vertigo at bedside

Management:

• Low threshold for CTA if any posterior circulation symptoms
• Thrombectomy for basilar artery occlusion
• Avoid sedation (masks examination)

Wake-Up Stroke

Definition: Stroke discovered upon waking (symptom onset time unknown).

Incidence: 20-25% of all strokes.

Challenge: Unknown time of onset precludes standard thrombolysis (4.5-hour window from known onset).

Solution — Advanced imaging:

MRI DWI-FLAIR mismatch: [11]

• DWI-positive (acute infarct visible)
• FLAIR-negative (no hyperintensity yet)
• Interpretation: Stroke occurred less than 4.5 hours ago (FLAIR becomes positive 3-6 hours after DWI)
• WAKE-UP trial: Alteplase in DWI-FLAIR mismatch patients had better outcomes than placebo

CT perfusion:

• Identifies penumbra:core mismatch
• Selects patients with salvageable tissue regardless of time

Management:

• If MRI shows DWI-FLAIR mismatch → thrombolysis safe and effective
• If CT perfusion shows mismatch → thrombectomy (if LVO)
• Standard thrombolysis if within 4.5 hours of "last known well" time

Pregnancy and Postpartum Stroke

Incidence: 30 per 100,000 deliveries. Risk highest in third trimester and first 6 weeks postpartum.

Aetiologies specific to pregnancy:

• Cerebral venous sinus thrombosis (CVST): Hypercoagulable state. Headache, seizures, focal deficit. MR venography diagnostic.
• Eclampsia: Seizures, hypertension, proteinuria. PRES (posterior reversible encephalopathy syndrome) on imaging.
• Peripartum cardiomyopathy: Heart failure → LV thrombus → embolism.
• Paradoxical embolism: Increased venous stasis + PFO.
• Dissection: Hormonal changes affect arterial wall.

Investigation:

• Avoid radiation where possible (MRI preferred over CT)
• If CT essential, use abdominal shielding

Thrombolysis in pregnancy:

• Not absolutely contraindicated (previously thought so)
• Alteplase does not cross placenta (large molecule)
• Case reports show safety
• Risk-benefit discussion with patient and obstetrician
• Generally offer if severe stroke and within 4.5 hours

Thrombectomy in pregnancy:

• Safe and effective
• Use abdominal shielding to reduce fetal radiation exposure

Secondary prevention:

• Low-dose aspirin safe in pregnancy
• Avoid warfarin (teratogenic in first trimester)
• LMWH safe throughout pregnancy

Stroke in the Very Elderly (> 80 Years)

Challenges:

• Comorbidities (frailty, dementia, polypharmacy)
• Higher bleeding risk with thrombolysis
• Poorer functional outcomes even with treatment
• Ethical considerations (quality of life, ceiling of care)

Treatment considerations:

• Age alone is not a contraindication to thrombolysis or thrombectomy
• Benefit of reperfusion persists in elderly (smaller absolute benefit but still significant)
• Individualised decision based on premorbid function, patient/family wishes, comorbidities

Evidence:

• IST-3 trial: Thrombolysis beneficial up to age 80+ (though higher bleeding risk)
• Thrombectomy trials included patients > 80 with benefit maintained

Secondary prevention:

• Same principles as younger patients
• Careful monitoring for polypharmacy interactions
• Falls risk assessment (anticoagulation for AF vs bleeding risk)

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Specific Stroke Syndromes in Detail

Lacunar Syndromes (Small Vessel Disease)

Definition: Small (less than 1.5 cm) infarcts in deep perforating arteries (lenticulostriate, pontine perforators).

Pathophysiology: Lipohyalinosis and microatheroma from chronic hypertension and diabetes.

Classic lacunar syndromes:

1. Pure motor stroke (50% of lacunar strokes):

   • Face, arm, leg weakness (all three)
   • No sensory, visual, or cognitive signs
   • Lesion: Internal capsule (posterior limb), pons

2. Pure sensory stroke (10%):

   • Face, arm, leg numbness
   • No motor weakness
   • Lesion: Thalamus (ventroposterolateral nucleus)

3. Ataxic hemiparesis (10%):

   • Ipsilateral leg weakness + ataxia
   • Lesion: Pons, internal capsule

4. Dysarthria-clumsy hand syndrome (5%):

   • Facial weakness, dysarthria, hand clumsiness
   • Lesion: Pons, internal capsule

5. Sensorimotor stroke (30%):

   • Combined motor and sensory deficit
   • Lesion: Thalamocapsular

Investigation:

• MRI more sensitive than CT (DWI sequence)
• Exclude cortical signs (suggests large vessel, not lacunar)

Prognosis:

• Best prognosis of stroke subtypes (11% 1-year mortality)
• High recurrence rate (30% at 5 years)
• Risk of vascular dementia with recurrent lacunar strokes

Management:

• Aggressive BP control (target less than 130/80)
• Antiplatelet therapy
• Statin
• Manage diabetes (HbA1c less than 53 mmol/mol)

Malignant MCA Syndrome

Definition: Massive MCA territory infarction with cerebral oedema → raised ICP → herniation.

Incidence: 10-15% of large MCA infarcts.

Clinical course:

• Day 0-1: Dense hemiplegia, gaze deviation, drowsiness
• Day 2-4: Progressive drowsiness → coma. Anisocoria (uncal herniation). Cushing's triad (bradycardia, hypertension, irregular breathing).
• Day 5: Death from transtentorial herniation if untreated.

CT findings:

• Hypodensity involving > 50% of MCA territory
• Midline shift > 5 mm
• Compression of lateral ventricle
• Effacement of basal cisterns

Medical management:

• Osmotherapy:
  • Mannitol 20% 0.25-0.5 g/kg IV bolus Q4-6H (monitor osmolality less than 320 mOsm/L)
  • Hypertonic saline 3% 150-250 mL bolus (target Na 145-155 mmol/L)
• Elevate head 30°
• Avoid hyperthermia (paracetamol, cooling)
• Glycaemic control
• Intubation and hyperventilation if imminent herniation (temporary measure; target pCO₂ 30-35 mmHg)

Surgical management — Decompressive hemicraniectomy: [16]

• Indications:
  • Age less than 60 years (some extend to 70)
  • NIHSS > 15
  • Decreased level of consciousness
  • Infarct > 50% MCA territory on CT
  • Within 48 hours of symptom onset
• Evidence: DECIMAL/DESTINY/HAMLET pooled analysis: NNT 2 to save life, NNT 4 for mRS ≤4 (moderate disability)
• Procedure: Large fronto-temporo-parietal craniectomy (> 12 cm diameter). Duraplasty. Bone flap stored or discarded. Cranioplasty 3-6 months later.
• Outcomes:
  • Reduces mortality from 78% to 29%
  • Increases survival with mRS ≤4 from 21% to 75%
  • "Counselling challenge: Most survivors have moderate-severe disability (mRS 3-4). Discuss quality of life with family."

Cerebellar Infarction

Arteries: PICA (lateral medulla and inferior cerebellum), AICA (lateral pons and middle cerebellum), SCA (superior cerebellum).

Clinical features:

• Vertigo, nausea, vomiting (severe, mimics gastroenteritis)
• Ataxia (truncal or appendicular)
• Dysarthria
• Nystagmus
• Ipsilateral limb incoordination
• May have minimal neurological signs initially

Risk: Cerebellar oedema → compression of fourth ventricle → obstructive hydrocephalus → brainstem compression → death.

Imaging:

• CT head (exclude haemorrhage, assess size of infarct and fourth ventricle)
• MRI brain (DWI highly sensitive)

Management:

• Small infarcts: Conservative management, close observation
• Large infarcts (> 3 cm or mass effect):
  • Neurosurgical referral
  • Suboccipital decompressive craniectomy (decompress posterior fossa)
  • External ventricular drain if hydrocephalus
  • "Timing: Early surgery (within 24-48 hours) if deteriorating"

Prognosis:

• Small infarcts: Good recovery
• Large infarcts with hydrocephalus: High mortality without surgery; good recovery if surgery performed early

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Quality Improvement and Stroke Systems of Care

Pre-Hospital Stroke Systems

Mobile Stroke Units (MSUs):

• Ambulances equipped with CT scanner, point-of-care laboratory, telemedicine link to stroke neurologist
• Enable diagnosis and thrombolysis in the field
• BEST-MSU trial: MSU reduces time to thrombolysis by 30 minutes, improves 90-day outcomes
• Reduces door-to-needle time to near zero ("curb-to-needle")
• Currently limited availability (expensive, logistically complex)

Pre-hospital scales for LVO detection:

• RACE (Rapid Arterial oCclusion Evaluation)
• LAMS (Los Angeles Motor Scale)
• FAST-ED (adds Eyes and Denial/neglect to FAST)
• Sensitivity 60-80% for LVO when used by paramedics
• Allows direct triage to thrombectomy-capable centre ("mothership" model)

Hospital Stroke Metrics (National Stroke Audit)

Key performance indicators:

Drip-and-ship vs mothership:

• Drip-and-ship: Thrombolysis at primary stroke centre (PSC) → transfer to comprehensive stroke centre (CSC) for thrombectomy
  • "Advantage: Faster thrombolysis"
  • "Disadvantage: Delayed thrombectomy"
• Mothership: Direct transfer to CSC for both thrombolysis and thrombectomy
  • "Advantage: Faster thrombectomy"
  • "Disadvantage: Delayed thrombolysis if CSC distant"
• Evidence: No significant outcome difference if transfer less than 30 minutes. Mothership preferred for severe strokes (NIHSS > 10).

Telestroke Networks

Model: Rural/remote hospitals connect via telemedicine to central hub with stroke neurologist.

Process:

1. Patient arrives at spoke hospital
2. CT head performed locally
3. Video consultation with hub neurologist (assess patient, review imaging)
4. Thrombolysis decision made remotely
5. Local team administers thrombolysis under remote supervision
6. Transfer to hub for thrombectomy if needed

Evidence:

• Equivalent safety and efficacy to in-person assessment
• Increases thrombolysis rates in underserved areas
• Reduces geographic disparities in stroke care

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Emerging Therapies and Future Directions

Novel Thrombolytics

Reteplase, desmoteplase: Under investigation but not superior to alteplase/tenecteplase in trials.

Adjunctive therapies to thrombolysis:

• Argatroban (direct thrombin inhibitor): ARTSS-2 trial ongoing
• Eptifibatide (GP IIb/IIIa inhibitor): CLEAR trial showed safety but no efficacy benefit
• Transcranial ultrasound to enhance thrombolysis: Mixed results

Neuroprotection

Challenge: Over 1,000 neuroprotective agents have failed in clinical trials despite promising preclinical data.

Reasons for failure:

• Rodent models poor predictors of human stroke
• Heterogeneity of human stroke (vs homogeneous experimental stroke)
• Treatment delay in humans (vs immediate treatment in animals)
• Narrow therapeutic window

Current approaches:

• Nerinetide (NMDA receptor antagonist): ESCAPE-NA1 trial showed benefit in patients NOT receiving alteplase (interaction with tPA)
• Uric acid: Antioxidant. URICO-ICTUS trial showed safety but marginal benefit
• Hypothermia: Preclinical promise but difficult to implement rapidly in humans. EuroHYP trial negative.

Extended Indications

Low NIHSS stroke:

• Previously excluded from thrombolysis ("too good to treat")
• PRISMS trial: Alteplase for NIHSS 0-5 did not improve outcomes (stopped early)
• ARAMIS trial: Dual antiplatelet noninferior to alteplase for minor stroke [17]
• Current practice: Treat if disabling deficit (e.g., aphasia with NIHSS 3)

Large core infarcts:

• Previously excluded from thrombectomy (core > 70 mL)
• TENSION, LASTE trials (2024): Thrombectomy beneficial even with ASPECTS 3-5 (large core)
• Expanding thrombectomy to "no patient left behind" approach

Basilar artery occlusion:

• BASICS trial (2024): Confirmed benefit of thrombectomy for basilar occlusion

Artificial Intelligence in Stroke

AI applications:

1. LVO detection: Automated CTA analysis identifies M1/ICA occlusion (sensitivity > 90%)
2. ASPECTS scoring: Automated CT analysis (interrater reliability superior to humans)
3. Perfusion analysis: Automated core/penumbra calculation
4. Triage: Prehospital LVO prediction from clinical data

Benefits:

• Faster decision-making
• Reduces variability
• Enables 24/7 expert-level interpretation

Challenges:

• Regulatory approval
• Integration with existing workflows
• Liability questions

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Medicolegal and Ethical Considerations

Consent for Thrombolysis

Challenge: Patients often aphasic or confused, unable to provide informed consent.

Approach:

• Emergency treatment exception: If patient lacks capacity and treatment is time-critical, proceed in patient's best interests
• Discuss with family if present (though legally next-of-kin cannot consent for adult)
• Document discussion and rationale in notes
• Key information to communicate (if patient has capacity or family present):
  • 6-7% risk of symptomatic brain haemorrhage [13]
  • "Benefits: 10% absolute increase in good outcome"
  • "Alternative: No thrombolysis (supportive care only)"
  • Time-critical decision

Thrombolysis in the Elderly and Frail

Ethical challenge: Balance between preserving life and quality of life.

Considerations:

• What was premorbid functional status? (mRS 0-1 or already dependent?)
• What are patient's values and wishes? (advance directive, previous conversations)
• What is likelihood of survival with acceptable quality of life?

Evidence:

• Trials show benefit even in octogenarians
• But absolute benefit smaller and bleeding risk higher
• Individualised decision essential

Withdrawal of Life-Sustaining Treatment

Scenario: Massive stroke with devastating deficit. Family requests withdrawal of care.

Approach:

1. Assess prognosis (most strokes: wait 72 hours before prognostication)
2. Discuss with family: patient's previously expressed wishes, values, goals
3. If prognosis poor and patient would not want survival with severe disability → withdraw inappropriate interventions
4. Continue comfort care (analgesia, mouth care, family access)
5. Senior clinician-led discussion; second opinion if uncertainty

Prognostic tools:

• NIHSS > 20: 80% poor outcome
• ASPECTS ≤5: 70% poor outcome
• Large brainstem infarct: Very poor prognosis
• Age > 80 + large infarct → poor prognosis

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Viva Voce Questions and Model Answers

Question 1: "A 68-year-old man presents with sudden-onset right hemiplegia and aphasia. It is 2 hours since symptom onset. Walk me through your immediate management."

Model answer:

"This is a hyperacute stroke — time-critical emergency requiring immediate systematic assessment and treatment.

Initial approach (ABCDE):

• Airway patent, no compromise
• Breathing — oxygen if saturations less than 94%
• Circulation — two large-bore IV cannulae, bloods including glucose (exclude hypoglycaemia), FBC, U&E, coagulation
• Disability — formal NIHSS assessment. Left hemiplegia and aphasia suggest left MCA territory, likely NIHSS 10-15
• Exposure — check for injuries, rashes

Immediate imaging — non-contrast CT head within 20 minutes:

• Primary purpose: Exclude haemorrhage (absolute contraindication to thrombolysis)
• Secondary: ASPECTS score, early ischaemic changes, hyperdense vessel sign
• Simultaneously: CT angiography to identify large vessel occlusion

Blood glucose bedside: Must exclude hypoglycaemia (stroke mimic)

ECG: Identify atrial fibrillation

Thrombolysis decision (target door-to-needle less than 60 minutes):

• Check eligibility: 2 hours from onset (within 4.5-hour window), measurable deficit, no contraindications
• Contraindications to verify: No recent surgery/trauma, no active bleeding, platelets > 100, INR less than 1.7, BP less than 185/110
• Agent: Tenecteplase 0.25 mg/kg IV bolus over 5-10 seconds (preferred over alteplase for ease of administration)
• Blood pressure management: If > 185/110, treat with IV labetalol to get below threshold before thrombolysis

Thrombectomy assessment:

• If CTA confirms large vessel occlusion (left MCA M1), patient is thrombectomy candidate
• Alert interventional neuroradiology team
• Target door-to-groin less than 90 minutes
• Can proceed with both thrombolysis + thrombectomy ('bridging therapy')

Stroke unit admission:

• Close monitoring: neuro obs every 15 mins for 2 hours post-thrombolysis
• Blood pressure monitoring and control (less than 180/105 post-thrombolysis)
• Swallow screen before any oral intake
• Multidisciplinary input from day 1

Secondary prevention planning: Antiplatelet, statin, blood pressure control, lifestyle modification to be initiated during admission."

Examiner follow-up: "What is the NNT for thrombolysis?"

Answer: "Approximately 10 for good functional outcome — meaning we need to treat 10 patients for one additional patient to achieve mRS 0-2 at 90 days. For thrombectomy in large vessel occlusion, NNT is much better at 2.6." [8,13]

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Question 2: "What are the contraindications to thrombolysis in acute stroke?"

Model answer:

"Contraindications are divided into absolute and relative.

Absolute contraindications:

• Intracranial haemorrhage on CT
• Ischaemic stroke within previous 3 months
• History of previous intracranial haemorrhage
• Major surgery or serious trauma within 14 days
• GI or urinary bleeding within 21 days
• Arterial puncture at non-compressible site within 7 days
• Acute bleeding disorder: platelets less than 100, INR > 1.7, APTT prolonged
• Known intracranial neoplasm, AVM, or aneurysm
• Suspected aortic dissection
• Acute pancreatitis
• Severe liver disease with coagulopathy

Relative contraindications (individualised decision):

• Rapidly improving symptoms (though may still treat if significant residual deficit)
• Blood pressure > 185/110 despite treatment
• Blood glucose less than 2.8 or > 22.2 mmol/L
• Seizure at stroke onset (if deficit is postictal rather than stroke, but thrombolyse if true stroke)
• Pregnancy (not absolute; case-by-case)
• Previous stroke + diabetes + age > 80 (ESO guidelines now accept; older guidelines considered relative contraindication)

The key is that absolute contraindications mean unacceptable bleeding risk, whereas relative contraindications require careful risk-benefit assessment with patient or family if possible." [10]

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Question 3: "A 55-year-old woman has sudden-onset vertigo, vomiting, and ataxia. How do you differentiate stroke from benign peripheral vertigo?"

Model answer:

"This is a critical distinction because posterior circulation strokes can be subtle but life-threatening, whereas peripheral vestibular disorders are benign. I would use the HINTS examination — Head Impulse, Nystagmus, Test of Skew.

HINTS examination:

1. Head Impulse Test:

• Central (stroke): Normal (negative test) — vestibulo-ocular reflex intact
• Peripheral (benign): Abnormal (positive test) — catch-up saccade when head rapidly turned

2. Nystagmus:

• Central: Direction-changing or vertical nystagmus
• Peripheral: Unidirectional horizontal nystagmus (away from affected ear)

3. Test of Skew (vertical ocular misalignment):

• Central: Skew deviation present (vertical misalignment on alternate cover test)
• Peripheral: No skew deviation

Mnemonic: 'INFARCT' if Normal head impulse, Direction-changing nystagmus, or Skew deviation present.

Red flags for stroke:

• New-onset severe headache
• Focal neurological signs (dysarthria, diplopia, limb weakness, facial palsy)
• Inability to walk (cerebellar ataxia)
• Risk factors (age > 50, hypertension, diabetes, AF)
• Deafness suggests peripheral; hearing intact suggests central

Investigation:

• Low threshold for CT/MRI brain if any red flag
• MRI DWI sequence highly sensitive for posterior circulation infarct

Management:

• If stroke suspected: urgent imaging, consider thrombolysis/thrombectomy (basilar artery occlusion has 80% mortality untreated but responds dramatically to thrombectomy)
• If benign peripheral vertigo diagnosed: prochlorperazine, reassurance, vestibular rehabilitation"

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Question 4: "What is the evidence for decompressive hemicraniectomy in malignant MCA syndrome?"

Model answer:

"Decompressive hemicraniectomy is life-saving surgery for malignant MCA syndrome — massive MCA territory infarction with cerebral oedema causing herniation.

Pathophysiology:

• 10-15% of large MCA infarcts develop malignant oedema
• Peaks at days 3-5
• Without intervention: 78% mortality from transtentorial herniation

Evidence — Pooled analysis of DECIMAL, DESTINY, and HAMLET trials (Vahedi et al., Lancet Neurology 2007): [16]

• Patient selection: Age less than 60, NIHSS > 15, infarct > 50% MCA territory, surgery within 48 hours
• Primary outcome: Mortality at 1 year
  • "Surgery: 29%"
  • "Medical: 78%"
  • NNT 2 to save a life
• Secondary outcome: Favourable outcome (mRS ≤4)
  • "Surgery: 75%"
  • "Medical: 21%"
  • NNT 4 for mRS ≤4 (moderate disability or better)

Interpretation:

• Surgery dramatically reduces mortality
• Most survivors have moderate-severe disability (mRS 3-4)
• Very few have excellent outcomes (mRS 0-1)
• Patient/family counselling essential about quality of life after surgery

Indications (based on trial evidence):

• Age less than 60 (some centres extend to 70)
• NIHSS > 15
• Decreased consciousness
• Infarct > 50% MCA territory (ASPECTS ≤5)
• Performed within 48 hours of symptom onset

Procedure:

• Large fronto-temporo-parietal craniectomy (> 12 cm)
• Duraplasty (dural expansion)
• Bone flap removed (stored or discarded)
• Cranioplasty 3-6 months later

Older patients (> 60):

• DESTINY II trial (2014): Benefit persists but smaller absolute benefit and more survivors with severe disability
• Individualised decision with patient/family"

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Question 5: "How has the management of acute stroke changed in the last 10 years?"

Model answer:

"Acute stroke management has undergone revolutionary changes in the last decade, transforming it from a nihilistic 'stroke — nothing we can do' to 'stroke — medical emergency with highly effective treatments.'

1. Tenecteplase replacing alteplase (2020-2024):

• Advantage: Single bolus vs 60-minute infusion — simpler, fewer errors, easier pre-hospital use
• Evidence: ORIGINAL trial (2024): Tenecteplase 0.25 mg/kg noninferior to alteplase for excellent outcome (mRS 0-1: 72.7% vs 70.3%) [6]
• Now preferred agent in many countries including UK, Australia

2. Thrombectomy revolution (2015):

• Five landmark trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT) published simultaneously in 2015
• Established mechanical thrombectomy as standard of care for large vessel occlusion 0-6 hours
• NNT 2.6 — most effective treatment in acute medicine [8]

3. Extended thrombectomy window (2018):

• DAWN and DEFUSE-3 trials: Thrombectomy beneficial 6-24 hours if perfusion imaging shows salvageable penumbra [3]
• Paradigm shift from 'time-based' to 'tissue-based' patient selection
• Wake-up stroke now treatable with advanced imaging [11]

4. Expanding thrombectomy indications (2020-2024):

• Large core infarcts (previously excluded): TENSION/LASTE trials (2024) show benefit even with ASPECTS 3-5
• Basilar artery occlusion: BASICS trial (2024) confirmed benefit
• 'No patient left behind' philosophy

5. Minor stroke management (2023):

• ARAMIS trial: Dual antiplatelet (clopidogrel + aspirin) noninferior to alteplase for minor nondisabling stroke [17]
• Avoided bleeding risk of thrombolysis in low-risk patients

6. Artificial intelligence:

• Automated LVO detection on CTA
• Automated ASPECTS scoring
• Faster treatment decisions, reduced variability

7. Mobile stroke units:

• CT scanner in ambulance
• Thrombolysis in the field
• BEST-MSU trial: Reduces time to treatment, improves outcomes
• Limited by cost and logistics

Impact:

• Door-to-needle times reduced from 90 minutes to less than 60 minutes
• Thrombectomy access transformed (now standard of care)
• Functional outcomes improving at population level
• Stroke no longer nihilistic — early intervention transforms lives"

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Question 6: "A 45-year-old woman with no vascular risk factors has a stroke. What are the key aetiological considerations?"

Model answer:

"Young stroke (less than 50 years) accounts for 10% of all strokes but has a broader differential diagnosis than typical atherosclerotic stroke in elderly. Key categories:

1. Arterial dissection (20%) — most common in young stroke:

• Carotid or vertebral artery
• Precipitants: Trauma (even minor — coughing, vomiting, chiropractic neck manipulation), connective tissue disorders (Ehlers-Danlos, Marfan)
• Clinical: Neck pain, Horner's syndrome (if carotid), headache
• Imaging: CTA/MRA shows 'string sign' (tapered narrowing), intimal flap, or pseudoaneurysm
• Management: Antiplatelet (vs anticoagulation — no RCT difference)

2. Cardioembolism — Patent foramen ovale (PFO) with paradoxical embolism (15%):

• PFO present in 25% of general population but much higher in cryptogenic stroke
• Mechanism: DVT → right-to-left shunt through PFO → cerebral embolism
• Investigation: TOE with bubble study (agitated saline)
• Management: PFO closure + antiplatelet if high-risk features (large shunt, atrial septal aneurysm) — CLOSE/REDUCE/RESPECT trials support [20]

3. Thrombophilia (10%):

• Antiphospholipid syndrome: Lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein antibodies. Recurrent VTE, livedo reticularis, pregnancy loss.
• Inherited: Factor V Leiden, prothrombin G20210A mutation (weaker association with arterial stroke)
• Management: Anticoagulation if recurrent thrombosis

4. Genetic/metabolic (2%):

• CADASIL: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. NOTCH3 mutation. Migraine, recurrent lacunar strokes, dementia, MRI shows extensive white matter changes. [21]
• Fabry disease: X-linked α-galactosidase A deficiency. Angiokeratomas, renal failure, cardiomyopathy. Enzyme replacement therapy available. [22]
• Sickle cell disease: If Afro-Caribbean ethnicity

5. Vasculitis (rare):

• Primary CNS vasculitis, SLE, polyarteritis nodosa
• Features: Systemic illness, raised inflammatory markers, multiple territory infarcts
• Investigation: ESR, CRP, ANA, ANCA, consider angiography + brain biopsy

6. Drug-related (5%):

• Cocaine, amphetamines: Vasospasm, hypertensive crisis, cardiomyopathy
• Oral contraceptive pill: Small increased stroke risk (especially if smoker or migrainous)

7. Pregnancy/postpartum:

• Cerebral venous sinus thrombosis (CVST)
• Peripartum cardiomyopathy
• Eclampsia

Investigations in young stroke:

• Standard: CT/MRI brain, CTA neck (dissection), echocardiography (TOE for PFO)
• Extended: Thrombophilia screen, vasculitis screen, genetic testing if appropriate
• Toxicology screen

Management:

• Acute: Same principles (thrombolysis/thrombectomy if eligible)
• Secondary prevention: Tailored to aetiology (PFO closure, anticoagulation for thrombophilia, manage modifiable risk factors)"

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Summary: Top 10 Take-Home Messages

1. Time is brain: Every minute of untreated large vessel occlusion destroys 1.9 million neurons. Every 15-minute delay costs 1 month of disability-free life.

2. FAST recognition: Public and healthcare workers must know Face-Arm-Speech-Time. Immediate 999 call if any sign present.

3. Hyperacute reperfusion: Tenecteplase 0.25 mg/kg (preferred) or alteplase 0.9 mg/kg within 4.5 hours. Thrombectomy for large vessel occlusion up to 24 hours (imaging-selected).

4. Thrombectomy is the most effective treatment in medicine: NNT 2.6 for large vessel occlusion. Extends window to 6-24 hours with perfusion imaging.

5. Imaging before treatment: Non-contrast CT excludes haemorrhage (mandatory before thrombolysis). CTA identifies large vessel occlusion (guides thrombectomy).

6. Blood pressure paradox: Permissive hypertension in acute phase (only treat if > 220/120 or > 185/110 if thrombolysing). Aggressive lowering worsens outcomes.

7. Stroke unit care saves lives: Multidisciplinary stroke unit reduces death and dependency (NNT ~20). All stroke patients should be admitted to stroke unit.

8. Swallow before swallow: Mandatory swallow screen before any oral intake to prevent aspiration pneumonia.

9. Secondary prevention is 80% effective: Antiplatelet (or anticoagulation for AF) + statin + BP control + lifestyle modification reduces recurrent stroke by 80%.

10. Carotid intervention is time-critical: Endarterectomy for 50-99% symptomatic stenosis within 14 days (ideally less than 7 days) reduces 2-year stroke from 26% to 9%.

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