Acute ischaemic stroke

Acute ischaemic stroke is the sudden onset of a focal neurological deficit caused by interruption of arterial blood flow to a region of brain, producing an infarcted core of irreversibly dead tissue surrounded by a salvageable ischaemic penumbra — tissue that is dysfunctional but still alive, kept viable by collateral perfusion and the oxygen it carries. The entire emergency rests on one fact and one clock: the penumbra will die unless flow is restored, and it dies in minutes, not hours. The NINDS trial in 1995 showed that intravenous alteplase given within three hours restored that flow and improved outcome,[1] and ECASS III extended the window to four and a half hours.[2] Mechanical thrombectomy, validated by DAWN and DEFUSE 3, now salvages brain up to 24 hours after onset in selected patients with a perfusion mismatch.[3][4] For the Fellowship candidate the task is unambiguous: recognise the deficit at the door, exclude the mimics (above all hypoglycaemia and the postictal state), exclude haemorrhage on CT, hold the blood pressure within the safe envelope, and move the patient through thrombolysis and on to thrombectomy against a clock that does not pause.

Definition and classification

Stroke is defined by the World Health Organization as rapidly developing clinical signs of focal (at times global) disturbance of cerebral function lasting more than 24 hours (or leading to death) with no apparent cause other than a vascular origin. A transient ischaemic attack produces the same deficit resolving within 24 hours (and by modern tissue-based definition, without infarct on imaging); the distinction from stroke is one of duration and infarction, not of mechanism, and a TIA is a warning that demands urgent investigation rather than reassurance. Roughly 85 per cent of strokes are ischaemic and 15 per cent are haemorrhagic, a ratio that holds across ANZ, the United Kingdom and North America, and the first job of the emergency clinician is to separate them, because the treatments are opposite. [1]

Ischaemic stroke is classified two ways. The Oxford Community Stroke Project classification divides by the clinical territory into total anterior circulation infarct (TACI — all of cortex, sensorimotor and higher function), partial anterior circulation infarct (PACI), posterior circulation infarct (POCI — brainstem, cerebellum, occipital) and lacunar infarct (LACI — pure motor, pure sensory or ataxic-hemiparesis from small deep vessel disease), and it predicts the underlying lesion and the prognosis at the bedside. The TOAST classification divides by aetiology into large-artery atherosclerosis, cardioembolism (atrial fibrillation being the dominant cause), small-vessel occlusion, other determined cause, and undetermined — and it directs the secondary-prevention workup. Both appear in vivas; the OCSP at triage, TOAST on the discharge summary. [1]

Epidemiology and risk factors

Stroke is the second commonest cause of death worldwide and a leading cause of adult disability, with incidence rising steeply with age. The non-modifiable risks are age, male sex, family history and prior stroke or TIA. The modifiable risks, in order of population-attributable importance, are hypertension, atrial fibrillation, smoking, diabetes, dyslipidaemia, obesity, physical inactivity and excess alcohol. Two are examined relentlessly because they are treatable and they change the acute plan: hypertension is the single biggest modifiable risk factor, and atrial fibrillation is the source of the cardioembolic clot that produces the most devastating large-vessel occlusions and dictates lifelong anticoagulation. Carotid stenosis, recent myocardial infarction (mural thrombus), patent foramen ovale in the young, sickle cell disease, and the hypercoagulable and vasculitic states complete the differential of cause. Identifying the mechanism is a secondary-prevention task, but it begins in the emergency department with the ECG and the history. [1]

Pathophysiology — the penumbra and why pressure matters

When a cerebral artery occludes, the territory it supplies falls into two zones. The infarct core is the region of blood flow below roughly 10 millilitres per 100 grams per minute, where energy failure is complete, neurons depolarise irreversibly, and cell death follows within minutes regardless of reperfusion. The penumbra surrounds it: blood flow between 10 and 20 millilitres per 100 grams per minute is enough to keep cells electrically silent but alive, and this tissue is the entire target of therapy — it will recover if flow is restored and it will die if it is not. The penumbra is metabolically precarious: it is maintained by collateral perfusion, and that collateral perfusion is pressure-dependent, which is the entire rationale for permissive hypertension. Lowering the blood pressure in acute ischaemic stroke (unless it is extreme, or unless thrombolysis demands it) drops the collateral pressure, shrinks the penumbra, and grows the infarct. [1]

Clinical presentation

Stroke presents as the sudden onset of a focal deficit that maps to a vascular territory. An anterior-circulation middle-cerebral-artery occlusion — the commonest and the prototype — produces contralateral face and arm weakness (the arm worse than the leg, the cortical hand-over-foot gradient), contralateral sensory loss, a homonymous hemianopia, and, for dominant (left) hemisphere lesions, aphasia; for non-dominant lesions, neglect and anosognosia. An anterior-cerebral-artery occlusion produces leg-dominant weakness and abulia. A posterior-cerebral-artery occlusion produces a homonymous hemianopia with macular sparing. Posterior-circulation (brainstem, cerebellar) strokes are the dangerous atypical presentations: vertigo, diplopia, dysarthria, dysphagia, ataxia, crossed sensory or motor signs, a Horner syndrome, and the four Ds of vertebral dissection (sudden pain in the neck or head, then a posterior-circulation deficit). Lacunar strokes produce a pure motor, pure sensory, ataxic-hemiparesis or dysarthria-clumsy-hand syndrome with no cortical sign. A conscious-level drop is rare in a pure hemispheric stroke and should raise haemorrhage, brainstem stroke, seizure, or hypoglycaemia. [1]

Recognition — FAST and the ROSIER score

Pre-hospital recognition uses FAST — Face drooping, Arm weakness, Speech difficulty, Time — the public-facing tool that drives the ambulance bypass to a stroke centre. The extended BE-FAST adds Balance and Eyes (sudden vertigo or visual loss) and captures roughly 14 per cent more posterior-circulation strokes that FAST misses. [1]

In the emergency department the validated recognition tool is the ROSIER score (Recognition of Stroke in the Emergency Room).[5] It begins with a mandatory finger-prick glucose — hypoglycaemia mimics stroke exactly and must be excluded before any further assessment — and then scores seven bedside features. The two negative items weight against stroke; the five positive items weight for it.

The score runs from minus 2 to plus 5. A score greater than zero is probable stroke (sensitivity around 92 per cent, specificity around 86 per cent in the derivation cohort), and these patients are fast-tracked to CT. A score of zero or below is a stroke mimic until proven otherwise, but the tool is a triage aid, not a rule-out — a convincing deficit with a low ROSIER score (for example a pure visual field loss with a posterior-circulation lesion) still warrants imaging. The NIH Stroke Scale (NIHSS, 0 to 42) is the structured severity measure that quantifies the deficit for the thrombolysis and thrombectomy decisions; a score of 6 or more with a large-vessel occlusion is the usual threshold to activate retrieval. [1]

Differential diagnosis

The mimics of stroke are the examiner's favourite trap, and the bedside job is to separate the true vascular deficit from its imitators by the history, the tempo, and the glucose. The single most dangerous mimic to miss is hypoglycaemia, which reproduces a focal deficit with complete fidelity and is reversed by glucose in minutes; the single most common mislabel is the postictal Todd paresis. [1]

The discriminating moves at the bedside are: check the glucose; ask explicitly about a seizure in the preceding minutes to hours (including tongue-biting or incontinence); establish the tempo (stroke is maximal at onset, migraine marches, Todd paresis follows a seizure); and image every patient in whom stroke is a possibility, because the mimics overlap and a posterior-circulation lesion can be subtle. [1]

Investigations — CT, CT angiography, and glucose

The investigations run in parallel with resuscitation and against the clock. The first is the finger-prick glucose, done at the bedside before anything else. A 12-lead ECG screens for atrial fibrillation and an acute coronary syndrome (stroke and STEMI can coexist in the embolic patient). Bloods include a full blood count, coagulation screen (INR, aPTT), urea and electrolytes, and a group-and-save; troponin is sent but does not delay thrombolysis. Pregnancy testing is done in any woman of reproductive age. [1]

The pivotal imaging is non-contrast CT of the brain. Its purpose in the acute window is not to confirm ischaemia — early ischaemia is often invisible — but to exclude haemorrhage, which is the decision that permits or forbids thrombolysis. The early ischaemic signs to seek on plain CT within the first six hours are: the hyperdense MCA sign (the occluded middle cerebral artery seen as a bright dot or hyperdense band), loss of the insular ribbon, obscuration of the lentiform nucleus, loss of grey–white differentiation, and sulcal effacement. The ASPECTS (Alberta Stroke Program Early CT Score) grades these changes across ten territories (M1 to M6, caudate, lentiform, internal capsule, insula) starting at 10 and subtracting one per area of early ischaemia; a score of 7 or less indicates extensive early change, predicts poor outcome, and raises the bleeding risk with thrombolysis. [1]

CT angiography is the next layer and is now obtained in parallel in any patient with a suspected anterior-circulation deficit, to identify a large-vessel occlusion (intracranial internal carotid, M1 or basilar) that is amenable to mechanical thrombectomy. CT perfusion (or MRI diffusion–perfusion) maps the core against the penumbra and is the selection tool for the extended 6 to 24 hour thrombectomy window, defining a mismatch — a small irreversibly infarcted core with a large at-risk penumbra — that justifies retrieval beyond six hours.[3][4] MRI (diffusion-weighted imaging) is exquisitely sensitive to early ischaemia and is used for the wake-up stroke where the DWI–FLAIR mismatch (a lesion bright on diffusion but not yet on FLAIR) estimates onset within four and a half hours.

Immediate management — resuscitation and the time clock

Resuscitation and the specific therapy are inseparable, and both obey the clock established at the door. Establish the last-known-well time with precision — not the time the patient was found collapsed, but the last moment they were seen normal — because this single fact decides every window. Notify the stroke team and retrieval service at the moment of suspicion, in parallel with assessment, not after it. Give oxygen only if oxygen saturation falls below 94 per cent (hyperoxia is harmful), secure intravenous access, keep the patient nil by mouth pending a swallow screen, and treat pain and agitation gently. A low finger-prick glucose is corrected with intravenous glucose (for example 25 to 50 mL of 50 per cent dextrose, or 100 mL of 10 per cent dextrose), never with hypotonic solutions. [1]

Blood pressure control is the resuscitation manoeuvre most often examined. In the patient not receiving thrombolysis, permissive hypertension is the rule: the pressure is allowed to run high to support the penumbra, and is lowered only when it exceeds roughly 220 over 120, or in the setting of aortic dissection, acute myocardial infarction, acute pulmonary oedema, or a planned thrombolytic. In the patient receiving alteplase, the pressure must be brought under 185 over 110 before the bolus and held under 180 over 105 for 24 hours afterwards, because uncontrolled hypertension is the commonest cause of symptomatic intracranial haemorrhage after thrombolysis. Labetalol 10 to 20 mg intravenously every ten minutes to a maximum of 300 mg, or an infusion of 2 to 8 mg per minute, is first-line (it is alpha and beta balanced and does not raise intracranial pressure); nicardipine 5 to 15 mg per hour by infusion is the alternative and gives smooth titratable control. [1]

Definitive management — intravenous thrombolysis

Intravenous alteplase (recombinant tissue plasminogen activator) is the standard reperfusion therapy for ischaemic stroke within four and a half hours of onset. The NINDS trial established benefit within three hours[1] and ECASS III extended it to four and a half hours.[2] The dose is 0.9 mg per kilogram, to a maximum total dose of 90 mg, given as a 10 per cent bolus over one minute with the remainder infused over 60 minutes. No anticoagulant or antiplatelet is given for 24 hours afterwards, and the blood pressure is held under 180 over 105 throughout that day.

Tenecteplase at 0.25 mg per kilogram as a single five-second bolus is a non-inferior alternative validated in EXTEND-IA TNK and now preferred in several contemporary guidelines for anterior-circulation occlusion, because its single-bolus pharmacokinetics are simpler and it may produce better reperfusion before thrombectomy; the conventional agent examined at Fellowship is still alteplase, and the dose is the one to know cold. [1]

The exclusion criteria for alteplase are extensive and are grouped into absolute and relative. The absolute exclusions are: intracranial haemorrhage on CT; subarachnoid haemorrhage or its clinical suspicion (thunderclap headache); serious head trauma or stroke in the previous three months; intracranial or intraspinal surgery in the previous three months; intracranial neoplasm, arteriovenous malformation or aneurysm; active internal bleeding; a known bleeding diathesis — platelets below 100,000, INR above 1.7, or heparin within 48 hours with a raised aPTT; current use of a direct oral anticoagulant within 48 hours (or with an unknown last-dose time); and blood pressure persistently above 185 over 110 despite treatment. The relative exclusions are recent major surgery or serious non-head trauma within 14 days, gastrointestinal or urinary bleeding within 21 days, myocardial infarction within three months, arterial puncture at a noncompressible site within seven days, seizure at onset (where the residual deficit may be postictal), and glucose below 2.7 or above 22 mmol per litre (correct and reassess). Pregnancy is a relative consideration: alteplase may still be given in pregnancy where the benefit outweighs the bleeding risk, in consultation with obstetrics. [1]

Definitive management — endovascular thrombectomy

Mechanical thrombectomy is now first-line for anterior-circulation large-vessel occlusion, and the evidence transformed practice after 2015. The principle is that an intracranial internal-carotid or M1 occlusion is often refractory to intravenous alteplase alone, and that mechanical retrieval restores flow in a majority within minutes of reperfusion. [1]

The windows are: within six hours of onset, a patient with a large-vessel occlusion, NIHSS of 6 or more and ASPECTS of 6 or more benefits from thrombectomy without the need for perfusion imaging, established by MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME and REVASCAT. Beyond six hours, two trials extended the window on the basis of imaging mismatch. DAWN showed benefit from thrombectomy at 6 to 24 hours in patients selected by a clinical–imaging mismatch (a small core on CT perfusion or MRI relative to the severity of the deficit),[3] and DEFUSE 3 confirmed benefit at 6 to 16 hours in patients selected by a perfusion–core mismatch (a small core with a penumbra at least 1.8 times the core).[4] The practical rule: a salvageable-mismatch patient is a retrieval patient up to 24 hours, and the emergency department's job is to obtain CT angiography and CT perfusion early enough to activate the neuroradiology team within that window. Alteplase is given first (the bridge) if the patient is within 4.5 hours, and thrombectomy follows; thrombectomy alone (without alteplase) is used for those outside the lytic window but within the retrieval window.

Blood-pressure management and the exclusion criteria revisited

The blood-pressure targets deserve their own emphasis because they recur in every exam form. Before alteplase: under 185 systolic and 110 diastolic, lowered if necessary with labetalol 10 to 20 mg intravenously every ten minutes (maximum 300 mg) or nicardipine 5 to 15 mg per hour. During and for 24 hours after alteplase: under 180 over 105. In the patient not receiving alteplase: permissive hypertension up to 220 over 120, lowered only for end-organ threats (dissection, infarction, pulmonary oedema) or to permit thrombolysis. After thrombectomy: the target is debated, but most pathways hold a systolic below 180 to protect the reperfused territory from haemorrhagic transformation. A common error is to lower the pressure reflexively on admission in an untreated stroke — this shrinks the penumbra and grows the infarct and must be resisted unless an indication forces it. [1]

Complications

The feared complication of thrombolysis is symptomatic intracranial haemorrhage (symptomatic ICH), occurring in roughly 2 to 6 per cent of treated patients and carrying a mortality around 50 per cent. The risk rises with large infarct volume (low ASPECTS), high NIHSS, uncontrolled blood pressure, hyperglycaemia, and the use of anticoagulants; it presents as sudden neurological deterioration, headache, vomiting, or a rise in blood pressure during or after the infusion, and is confirmed on an immediate repeat CT. Management is to stop the alteplase infusion, send a coagulation screen, give cryoprecipitate (to raise fibrinogen) and tranexamic acid or prothrombin complex, lower the pressure to under 140 systolic, and involve neurosurgery. [1]

Haemorrhagic transformation also occurs spontaneously in infarcted tissue (petechial and usually clinically silent, versus frank parenchymal haematoma). Cerebral oedema peaks at 48 to 72 hours and, in a complete middle-cerebral-arterity infarct, produces the malignant MCA syndrome — a swollen hemisphere that herniates and kills within days. Young patients (under 60) with a dominant or non-dominant malignant MCA infarct benefit from decompressive hemicraniectomy within 48 hours (DECIMAL, DESTINY, HAMLET), a time-critical neurosurgical referral. Aspiration pneumonia (from dysphagia), seizures, deep-vein thrombosis, pressure injury, and recurrence of stroke complete the complication set, and each is anticipated rather than waited for — a swallow screen before any oral intake, subcutaneous heparin once the bleeding risk has settled, and early secondary-prevention therapy (antiplatelet, statin, anticoagulation where atrial fibrillation is the cause). [1]

Prognosis and disposition

Outcome tracks the severity at presentation (NIHSS), the territory (posterior-circulation and complete anterior-circulation strokes do worse), the patient's age and comorbidity, and above all whether reperfusion was achieved. A patient who reperfuses early can recover remarkably; a patient who does not may be left with dense hemiparesis, aphasia or visual loss. Every acute-stroke patient is admitted to a stroke unit with monitored care and early mobilisation by a multidisciplinary team. Secondary prevention — antiplatelet therapy (for example aspirin 300 mg then 75 mg daily, or clopidogrel) for non-cardioembolic stroke, anticoagulation for atrial fibrillation, a high-intensity statin, blood-pressure control, carotid endarterectomy for symptomatic severe stenosis, and smoking cessation — is begun in the acute admission. Early supported discharge and rehabilitation are planned from the first day. [1]

Special populations

The wake-up stroke — a deficit present on waking, with an unknown onset — is routed to CT perfusion or MRI rather than assumed outside the window; a DWI–FLAIR mismatch or a favourable perfusion profile identifies patients within the lytic or retrieval window. The posterior-circulation and basilar occlusion patient may present with reduced consciousness and quadriparesis and is a thrombectomy emergency even though the anterior-circulation trials did not include them; basilar thrombolysis and retrieval carry the same time imperative. Pregnancy is a relative indication rather than a contraindication to alteplase — the maternal benefit usually outweighs the fetal bleeding risk, in consultation with obstetrics and stroke teams. The anticoagulated patient is excluded from alteplase unless reversed, but remains a retrieval candidate. Young patients (under 50) demand a search for a cause — patent foramen ovale, carotid or vertebral dissection, thrombophilia, vasculitis, drug use — because the mechanism changes prevention. Paediatric stroke is rare, is managed by a paediatric stroke protocol, and is outside the adult alteplase pathway. [1]

Evidence and regional guidelines

The evidence base is one of the strongest in acute medicine. NINDS (1995) established intravenous alteplase within three hours[1] and ECASS III (2008) extended it to four and a half hours.[2] The thrombectomy revolution came in 2015 (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT) for the within-six-hour window, and DAWN[3] and DEFUSE 3[4] extended it to 16 to 24 hours with imaging selection in 2018. The ROSIER score for emergency recognition is from Nor and colleagues.[5] Regionally, the AHA/ASA 2019 acute ischaemic stroke guideline sets the global standard; ANZ practice follows the Stroke Foundation of Australia Clinical Guidelines for Stroke Management; the United Kingdom follows the NICE and Royal College of Physicians/SSNAP pathways (where ROSIER originated); Europe follows the ESO guidelines. The agents, the windows, and the blood-pressure targets are global; the local stroke pathway governs the exact retrieval logistics and the tenecteplase-versus-alteplase choice.

The hyperacute ED stroke pathway — the time targets

The whole treatment of acute ischaemic stroke is engineered around a small set of time targets that govern the system. The patient does not flow through the emergency department — they are propelled. The targets exist because of the decay of the penumbra, and because every minute between the door and the needle destroys brain that was salvageable at the door. The American Heart Association and the American Stroke Association Target: Stroke programme, the Stroke Foundation of Australia, and the United Kingdom Sentinel Stroke National Audit Programme all converge on the same milestones, and the Fellowship candidate is expected to recite them. [1]

Thrombolysis in detail — dose, preparation, the bolus and the hour

Intravenous alteplase is the prototype and the Fellowship-examined standard. The dose and its partition are examined as automatically as an adrenaline dose, and they must be recited exactly. Every line of the dose is a line the examiner can quote. [1]

Tenecteplase at 0.25 mg/kg as a single five-second bolus is a non-inferior alternative validated in EXTEND-IA TNK[11] and NOR-TEST,[12] and it is now the first-line lytic for the eligible anterior-circulation occlusion in several contemporary pathways because the single-bolus pharmacokinetics are simpler and may produce better reperfusion before thrombectomy. The conventional agent examined at Fellowship is still alteplase, and the dose is the one to know cold.

Post-thrombolysis monitoring — the first 24 hours

The hour after the bolus is the hour of greatest preventable harm. Two failures cause most of the bad outcomes: an unrecognised blood-pressure creep that bursts the reperfused territory, and a delayed recognition of the symptomatic haemorrhage. The 24-hour bundle is a defined protocol — the blood pressure, the neurochecks, the prohibition on the anticoagulants and the antiplatelets, and the repeat CT. [1]

Thrombectomy in detail — the two windows

Mechanical thrombectomy is now first-line for an anterior-circulation large-vessel occlusion (an intracranial internal carotid, an M1, or a basilar occlusion), and the evidence base is one of the strongest in acute medicine. The 2015 trials — MR CLEAN[6], ESCAPE[7], EXTEND-IA[8], SWIFT PRIME[9] and REVASCAT[10] — established the within-6-hour window, and the two windows are examined separately because their entry criteria differ.

WAKE-UP[13] opened the thrombolysis to the wake-up stroke on the DWI to FLAIR mismatch, and EXTEND[14] extended the alteplase window to 9 hours in the perfusion-selected patient. Both reframed the unknown-onset stroke from outside-the-window to imaging-defined-inside-the-window.

Malignant MCA syndrome — the time-critical neurosurgical referral

A complete middle-cerebral-artery infarct swells to its worst at 48 to 72 hours and can herniate and kill within days — the malignant MCA syndrome. The treatment is a decompressive hemicraniectomy within 48 hours, validated by the pooled analysis of DECIMAL, DESTINY and HAMLET.[15]

Exam pearls

• Time is brain — the last-known-well time is the single fact that decides every window; hunt it down, never guess.
• Glucose first — in every suspected stroke, before anything else; hypoglycaemia mimics stroke and is reversed in minutes.
• Alteplase 0.9 mg/kg, max 90 mg, 10 per cent bolus over one minute, remainder over 60 minutes, within 4.5 hours — know this dose as automatically as an adrenaline dose.
• Thrombectomy: 0 to 6 hours by occlusion and severity, 6 to 24 hours by perfusion mismatch — DAWN and DEFUSE 3.
• BP under 185/110 before and under 180/105 for 24 h after alteplase; permissive up to 220/120 if not thrombolysed.
• Anticoagulant within 48 h (or INR above 1.7) excludes alteplase — reverse and consider retrieval.
• A normal early CT does not exclude ischaemic stroke — it excludes haemorrhage, which is the question that decides the lytic.
• Malignant MCA infarct in a patient under 60 — decompressive hemicraniectomy within 48 h (DECIMAL/DESTINY/HAMLET). [1]

SAQs

Red flags