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Overview and Recommendations
Background
- •Define Acute Ischemic Stroke (AIS) as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction confirmed by clinical symptoms or neuroimaging evidence of tissue death.
- •Recognize the TOAST classification system to guide secondary prevention: Large-Artery Atherosclerosis (LAA), Cardioembolism (CE), Small-Vessel Occlusion (SVO/lacunar), Other Determined Etiology (ODE), and Undetermined Etiology (UDE).
- •Identify the ischemic penumbra as the primary therapeutic target; this is the zone of functionally impaired tissue maintained by that will progress to irreversible infarction (the core) without rapid reperfusion.
- •Screen for major modifiable risk factors including , diabetes mellitus, and , which significantly increase the hazard ratio for incident stroke.
- •Distinguish specialized variants such as Embolic Stroke of Undetermined Source (ESUS), which accounts for 17% of cases and often requires intensive cardiac monitoring to detect occult sources like a patent foramen ovale (PFO).
Evaluation
- •Suspect AIS in any patient presenting with sudden-onset focal deficits; use the FAST-ED or NIHSS (National Institutes of Health Stroke Scale) to quantify severity and localize the vascular territory.
- •Obtain a fingerstick glucose immediately to rule out hypoglycemia, the most common metabolic stroke mimic, which can perfectly replicate focal neurological deficits.
- •Order a non-contrast computed tomography (NCCT) of the head as the first-line imaging modality to exclude and identify early ischemic changes.
- •Look for the Hyperdense Middle Cerebral Artery Sign (HMCAS) on NCCT, which indicates an erythrocyte-rich thrombus and suggests a high likelihood of large vessel occlusion (LVO).
- •Perform CT Angiography (CTA) from the aortic arch to the vertex to identify the site of arterial occlusion and evaluate the robustness of collateral vessels.
- •Utilize CT Perfusion (CTP) or MRI Diffusion-Weighted Imaging (DWI) in patients presenting in the 6–24 hour window or with an unknown time of onset to identify a mismatch between the small infarct core and the larger salvageable penumbra.
- •Apply the DWI-FLAIR mismatch principle for 'wake-up' strokes: a positive DWI lesion without a corresponding FLAIR signal suggests the stroke occurred within the last 4.5 hours, potentially allowing for thrombolysis.
- •Calculate the ABCD2 score (Age, Blood pressure, Clinical features, Duration, Diabetes) for patients with (TIA) to risk-stratify for imminent stroke.
- •Order baseline laboratory tests including coagulation studies, lipid profiles, and the CONUT score (Controlling Nutritional Status) to assess physiological reserve and vascular risk.
- •Monitor for Early Neurological Deterioration (END), defined as an NIHSS increase of ≥2 points within the first 7 days, which may indicate re-occlusion or hemorrhagic transformation.
Management
- •Administer Tenecteplase 0.25 mg/kg (maximum 25 mg) as a single IV bolus for eligible patients within 4.5 hours of symptom onset; it is preferred over alteplase for its higher fibrin specificity and ease of administration.
- •Initiate Mechanical Thrombectomy (MT) for patients with LVO (ICA or M1/M2 segments of the MCA) within 6 hours of onset, or up to 24 hours if perfusion imaging shows salvageable tissue.
- •Maintain blood pressure <185/110 mmHg prior to thrombolysis and <180/105 mmHg for at least 24 hours following treatment to minimize the risk of .
- •Optimize post-recanalization blood pressure: for patients with successful reperfusion (mTICI 2c/3), target a systolic blood pressure (SBP) of 90–120 mmHg using Clevidipine 1–2 mg/hr IV titration.
- •Start Dual Antiplatelet Therapy (DAPT) with Aspirin 100 mg and Clopidogrel 75 mg daily for 21–90 days in patients with minor stroke (NIHSS ≤3) or high-risk TIA who did not receive thrombolysis.
- •Initiate anticoagulation for -related strokes; early initiation (within 4 days) is generally safe for minor-to-moderate strokes, while larger infarcts may require a 7–14 day delay.
- •Administer high-intensity statins (e.g., Atorvastatin 80 mg daily) for all patients with evidence of atherosclerosis, regardless of baseline LDL levels.
- •Manage hyperglycemia by maintaining blood glucose between 140–180 mg/dL; avoid aggressive correction to <110 mg/dL due to the risk of secondary brain injury from hypoglycemia.
- •Refer for urgent decompressive hemicraniectomy in patients <60 years old with malignant MCA syndrome (large-volume infarct with midline shift) within 48 hours of onset.
- •Avoid the use of prophylactic anticonvulsants; however, treat clinical seizures promptly with agents like Levetiracetam 500–1000 mg BID.
- •Delay non-cardiac surgery for at least 3 months post-stroke whenever possible to reduce the risk of perioperative recurrent events.
- •Screen for and treat stroke-associated pneumonia (SAP) and dysphagia; maintain NPO status until a formal swallow evaluation is completed.
Board Review — High Yield
- •Hyperdense MCA sign — A high-attenuation signal on NCCT representing an acute thrombus in the M1 segment.
- •DWI-FLAIR Mismatch — Presence of a DWI lesion without FLAIR signal, indicating a stroke duration <4.5 hours.
- •Penumbra — Ischemic tissue that is functionally silent but structurally intact, salvageable by reperfusion.
- •ABCD2 Score — Used to predict the 2-day risk of stroke after a TIA; a score of 6-7 indicates high risk.
- •Malignant MCA Syndrome — Rapidly progressive cerebral edema following large MCA territory infarcts; requires hemicraniectomy.
- •Tenecteplase vs. Alteplase — Tenecteplase is more fibrin-specific and has a longer half-life, allowing for bolus dosing.
- •Todd's Paralysis — A focal neurological deficit following a seizure; a key stroke mimic.
- •mTICI Score — The standard for grading reperfusion after thrombectomy; mTICI 2b, 2c, and 3 are considered successful.
Deep Dive — Evidence Details
Definition, Synonyms, and Classification of Acute Ischemic Stroke
- ▸Acute Ischemic Stroke is now defined by tissue-based evidence of infarction (MRI DWI-FLAIR mismatch) rather than just the 24-hour clinical symptom threshold.
- ▸The TOAST classification is the gold standard for etiology, but approximately 17% of strokes are classified as ESUS, which may involve hidden sources like the Left Atrial Septal Pouch (LASP).
- ▸Early Neurological Deterioration (END) is a critical clinical milestone defined as a ≥ 2-point NIHSS increase within 7 days of onset.
Acute Ischemic Stroke (AIS) is defined as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction resulting from the interruption of blood supply to the central nervous system [2][10]D. While historically defined by clinical symptoms lasting more than 24 hours, the modern definition has evolved toward a tissue-based approach, where evidence of acute infarction on neuroimaging—specifically (MRI) showing diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) mismatch—confirms the diagnosis regardless of symptom duration [3].
Synonyms and Alternate Names
AIS is frequently referred to by several terms in clinical and research literature, including:
- Cerebral Infarction: The pathological term for brain tissue death due to ischemia.
- Brain Attack: A public health term used to emphasize the urgency of treatment, analogous to a heart attack.
- Non-hemorrhagic Stroke: A broad category distinguishing ischemic events from intracranial hemorrhages.
- Ischemic Cerebrovascular Accident (CVA): An older clinical term for sudden neurological deficit of vascular origin.
Key Definitions of Phases and Clinical Stages
Understanding the temporal progression of AIS is critical for determining eligibility for interventions such as intravenous thrombolysis (IVT) or mechanical thrombectomy (MT) [6].
- Prodromal Phase: Often manifests as a (TIA), characterized by focal neurological deficits that resolve completely. High-risk TIAs are often defined by an ABCD2 score of 6 or 7 [2].
- Acute Phase: The period immediately following symptom onset, typically defined as the first 72 hours [2]. This is the window where most therapeutic interventions occur.
- Nadir: The point at which neurological deficits reach their maximum severity, often measured by the National Institutes of Health Stroke Scale (NIHSS).
- Early Neurological Deterioration (END): A clinical phenomenon defined as an increase in the NIHSS score by ≥ 2 points within the first 7 days of admission [4][8]. END is a significant predictor of poor long-term outcomes and may be influenced by factors such as large artery atherosclerosis [4].
- Progressive Ischemic Stroke (PIS): A subset of AIS where neurological deficits continue to worsen after the initial presentation, often seen in patients with concurrent and diabetes [9].
- Plateau Phase: A period of clinical stability following the acute phase where no further worsening or significant improvement is noted.
- Recovery Phase: The long-term period where neuroplasticity and rehabilitation lead to functional improvements, typically assessed at 90 days using the modified Rankin Scale (mRS) [3].
The TOAST Classification System
The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification remains the most widely utilized system for categorizing AIS etiology [4][7]D. It divides strokes into five distinct subtypes based on clinical features and diagnostic data [7]D.
| Subtype | Abbreviation | Key Distinguishing Features | Associated Markers/Findings |
|---|---|---|---|
| Large-Artery Atherosclerosis | LAA / LAAS | Significant (>50%) stenosis or occlusion of a major brain artery or branch [4][7]D. | Plaque on carotid ultrasound or CTA; associated with END [4]. |
| Cardioembolism | CE / CEI | Arterial occlusion likely from a cardiac source (e.g., ) [3][7]D. | DWI-FLAIR mismatch on MRI; high risk of recurrence [3]. |
| Small-Vessel Occlusion | SVO / SVD | Also called " "; involves deep small perforating arteries [4][7]D. | Small subcortical lesions (<1.5 cm); often associated with hypertension [7]D. |
| Other Determined Etiology | ODE | Rare causes such as vasculitis, arterial dissection, or hypercoagulable states [7]D. | Specific to the underlying pathology (e.g., vessel wall imaging). |
| Undetermined Etiology | UDE | Stroke where no cause is found despite thorough evaluation, or multiple causes exist [7]D. | Includes and ESUS [1][10]D. |
Specialized Classifications and Variants
Beyond the standard TOAST criteria, clinicians use specialized systems to guide in specific populations.
Embolic Stroke of Undetermined Source (ESUS)
ESUS is a clinical construct proposed to describe non-lacunar cryptogenic strokes that appear embolic on imaging but lack an identifiable source after standard diagnostic workup [10]D. ESUS accounts for approximately 17% of all ischemic strokes and often affects younger patients with fewer traditional risk factors [10]D. Recent research highlights the role of the Left Atrial Septal Pouch (LASP)—a blind-ended pouch in the heart—as a potential unrecognized embolic source in these patients, often requiring transesophageal echocardiography (TEE) for detection [1].
Posterior Circulation Stroke (PCS)
The New England Medical Center Posterior Circulation Registry (NEMC-PCR) classification is used specifically for strokes involving the vertebrobasilar system [5]. This system classifies PCS based on topography:
- Proximal Segment: Involving the vertebral arteries up to the posterior inferior cerebellar artery (PICA).
- Middle Segment: Involving the basilar artery up to the superior cerebellar artery (SCA).
- Distal Segment: Involving the rostral basilar artery and posterior cerebral arteries (PCA) [5].
Large Vessel Occlusion (LVO)
LVO-AIS refers to the occlusion of major intracranial arteries (e.g., internal carotid, M1 or M2 segments of the middle cerebral artery). In young adults (aged 18-50), LVO etiologies often differ from older populations, requiring distinct diagnostic considerations [6].
| Subtype | Mechanism | Clinical Significance |
|---|---|---|
| Large-Artery Atherosclerosis (LAA) | Thrombosis or embolism from large vessel plaque | High risk of early neurological deterioration (END) [4] |
| Cardioembolism (CE) | Emboli from heart (e.g., Atrial Fibrillation) | Often presents with maximal deficit at onset; MRI-guided thrombolysis is effective [3] |
| Small-Vessel Occlusion (SVO) | Lipohyalinosis of small perforating arteries | Typically presents as a lacunar syndrome; better short-term prognosis [4] |
| Other Determined Etiology (ODE) | Non-atherosclerotic vasculopathy | Includes dissection, vasculitis, and genetic disorders [7]D |
| Undetermined Etiology (UDE) | Cryptogenic or multiple potential causes | Includes ESUS; requires extensive workup including TEE for LASP [1][10]D |
Epidemiology and Risk Factors
- ▸AIS has heterogeneous mechanisms, and risk assessment should include cardioembolism, atherosclerosis, dissection, cancer-associated thrombosis, autoimmune disease, environmental exposure, and unexplained embolic mechanisms.[230][234][235][236][237]
- ▸ICAS is a major high-risk substrate; in the cited study, it was defined as **≥50% intracranial stenosis or occlusion**.[236]
- ▸CCAD is a major cause of stroke in young adults and warrants consideration when evaluating younger patients with AIS or TIA.[234]
- ▸SLE and invasive cancer are associated with increased stroke risk in large cohort-based evidence syntheses.[227][237]
- ▸Occult AF remains an important diagnostic consideration after apparently noncardioembolic stroke; the cited cohort evaluated ECG-derived PRD within **5 days** of AIS.[233]
- ▸The modifiable risk landscape extends beyond traditional factors to early-life, lifestyle, environmental, psychosocial, physical, medical, and sociodemographic domains.[230]
Epidemiology
Acute ischemic stroke (AIS) is a heterogeneous clinical syndrome arising from multiple mechanisms, including cardioembolism, large-artery atherosclerosis, intracranial atherosclerotic disease, small-vessel disease, arterial dissection, cancer-associated thrombosis, and strokes that remain unexplained after evaluation.[235][236][237] The available updated evidence does not provide a single global incidence estimate, but it demonstrates clinically important variation by age, vascular substrate, systemic disease, and exposure profile.[230][234][237]
Stroke in younger adults requires particular attention to nontraditional mechanisms. Craniocervical artery dissection (CCAD) is described as a major cause of stroke in young adults; in a nationwide South Korean registry, patients with acute ischemic stroke or transient ischemic attack and CCAD were diagnosed within 7 days of symptom onset, with a median arrival time of 7.7 hours.[234] The study evaluated recurrent ischemic stroke according to dissection location and vascular morphology, emphasizing that arterial anatomy may influence subsequent risk.[234] Young stroke survivors also have clinically relevant treatment-related bleeding risk: in the prospective, multicenter Dutch ODYSSEY cohort, antithrombotic exposure and bleeding outcomes were assessed over short- and long-term follow-up, although the supplied evidence does not provide the numerical estimates.[228]
Major vascular and systemic risk factors
The strongest contemporary evidence supports a broad, multidomain model of modifiable risk. A UK Biobank exposome-wide analysis combined with bidirectional two-sample Mendelian randomization evaluated 323 modifiable factors across seven domains: early life, health and medical history, lifestyle, local environment, physical measures, psychosocial factors, and sociodemographic characteristics.[230] This framework indicates that AIS risk is not attributable only to conventional vascular factors and supports integrated prevention across medical, behavioral, environmental, and social domains.[230]
Intracranial atherosclerotic stenosis (ICAS) is an important mechanism and high-risk vascular substrate. In a prospective cohort of 942 patients with ischemic stroke, ICAS was defined as ≥50% stenosis or occlusion; the study examined inflammatory markers as predictors of major adverse cardiovascular events, including recurrent nonfatal stroke, acute coronary syndrome, and vascular death.[236] Elevated interleukin-6, defined as ≥4.2 pg/mL, and elevated high-sensitivity C-reactive protein, defined as ≥2.0 mg/L, were investigated as markers of residual vascular risk in ICAS-related stroke.[236] These biomarkers are prognostic correlates rather than established independent causes of first-ever AIS.[236]
Systemic autoimmune disease may increase stroke susceptibility. A 2026 systematic review and meta-analysis included 25 cohort studies involving 5,220,837 individuals and evaluated the association between systemic lupus erythematosus (SLE) and composite, ischemic, and hemorrhagic stroke.[227] The pooled analysis specifically addressed ischemic stroke risk, supporting SLE as an important comorbidity to consider when assessing vascular risk, although the supplied abstract does not report the pooled effect estimate.[227]
Cancer is another clinically important prothrombotic context. A nationwide Israeli registry study followed 182,221 adults aged ≥40 years with a first invasive cancer diagnosis during 2014–2021 and assessed first-ever ischemic stroke within 1 year, examining cancer site, stage, time from diagnosis, and demographic subgroup.[237] The study found an elevated risk of ischemic stroke after invasive cancer diagnosis, highlighting malignancy-associated thrombosis as a relevant risk context; the supplied abstract does not include the site-specific standardized incidence ratios or cumulative-incidence values.[237]
Cardioembolic and cryptogenic mechanisms
Atrial fibrillation (AF) is a major cardioembolic mechanism and may be newly detected after stroke. In the prospective STROKE-CARD cohort, 263 patients with AIS were enrolled while in sinus rhythm and without prior or current AF; a standardized high-resolution ECG performed within 5 days of stroke assessed periodic repolarization dynamics (PRD), heart-rate variability, and supraventricular premature complexes as potential predictors of AF detected after stroke or transient ischemic attack.[233] These findings support prolonged or intensified rhythm assessment when occult AF is suspected, although the supplied abstract does not provide the PRD effect size.[233]
Embolic stroke of undetermined source (ESUS) should not be considered a uniform epidemiologic entity. A multicenter cohort categorized ESUS into strokes in which a mechanism was subsequently established, cases with comprehensive testing but no identified cause (“ESUS 2.0”), and cases without advanced workup.[235] The study compared recurrent ischemic stroke across these groups, supporting the principle that recurrence risk depends partly on the completeness of diagnostic evaluation and the underlying mechanism that remains concealed.[235]
Environmental and demographic considerations
Environmental exposure may contribute to cerebrovascular risk and poststroke outcomes. In the population-based Brain Attack Surveillance in Corpus Christi Project, transportation-noise exposure was derived from US Department of Transportation data and measured as the maximum area-weighted noise level within a 100-m residential buffer among patients with incident AIS.[231] The study assessed associations with initial NIH Stroke Scale severity, recurrence, and all-cause mortality, expanding the risk framework beyond individual medical characteristics.[231]
Age, AF, and baseline vascular disease also shape poststroke vulnerability. Among 802 adults aged ≥65 years with AF-associated AIS, serum 25-hydroxyvitamin D was measured within 48 hours and modeled using a 20 ng/mL deficiency threshold; the study examined disability, depressive symptoms, and falls after stroke.[188] These findings concern prognosis and complications rather than established causes of first AIS, but they identify older age, AF, and vitamin D deficiency as clinically relevant risk-stratification factors after presentation.[188]
Interpretation of the updated evidence
The updated literature supports evaluating AIS risk through a structured assessment of age, conventional vascular disease, AF and other cardioembolic sources, ICAS, arterial dissection, autoimmune disease, malignancy, environmental exposures, and the wider modifiable exposome.[230][233][234][236][237] Several cited studies are prognostic or treatment-focused rather than incidence studies: perfusion-selected extended-window thrombolysis, dual-antiplatelet strategies, ticagrelor-based therapy, edaravone dexborneol, and endovascular techniques address acute management rather than population risk factors.[182][183][224][225][226] Similarly, studies of poststroke cognitive impairment, S100B, CD147, seizure patterns, Lp-PLA2, and antithrombotic bleeding primarily describe outcomes or recurrence rather than causes of incident AIS.[186][223][228][229][232] These distinctions should be maintained when applying the evidence clinically.
| Risk domain | Evidence and clinical relevance |
|---|---|
| Atherosclerotic disease | ICAS defined as ≥50% stenosis or occlusion; inflammatory markers were evaluated for residual vascular risk.[236] |
| Cardioembolism | Occult AF may be detected after stroke; PRD and other ECG measures were studied within 5 days of AIS.[233] |
| Arterial dissection | CCAD is a major cause of stroke in young adults and may influence recurrence according to vascular morphology.[234] |
| Autoimmune disease | A meta-analysis of 25 cohorts and 5,220,837 individuals evaluated stroke risk in SLE.[227] |
| Malignancy | In 182,221 adults with invasive cancer, ischemic stroke risk was assessed during the first 1 year after diagnosis.[237] |
| Environmental and social exposures | The exposome framework included 323 modifiable factors; transportation noise was assessed within a 100-m residential buffer.[230][231] |
Etiology and Triggering Factors
- ▸Evaluate AIS by mechanism, particularly cardioembolism, large-artery atherosclerosis, intracranial stenosis, dissection, systemic inflammation or autoimmunity, and malignancy-associated thrombosis.[233][238][227][234][237]
- ▸Occult paroxysmal AF may be detected only after stroke; prolonged or advanced cardiac assessment can therefore be relevant in apparently cryptogenic cases.[233][235]
- ▸ICAS in the cited study was defined as **at least 50% stenosis or occlusion**.[236]
- ▸Cancer-associated stroke risk was assessed during the **first year** after invasive cancer diagnosis and varied by cancer site, stage, and timing.[237]
- ▸Biomarkers, seizures, frailty, vitamin D status, and treatment-related bleeding are mainly prognostic or consequential findings and should not automatically be labeled as stroke triggers.[188][189][223][228][229][232][239]
Overview
Acute ischemic stroke (AIS) results from arterial occlusion causing focal cerebral ischemia. The supplied evidence supports a mechanism-based approach: cardioembolism, large-artery atherosclerosis, small- or intracranial-artery disease, arterial dissection, systemic inflammatory or autoimmune disease, malignancy-associated thrombosis, and modifiable environmental or lifestyle exposures may contribute to stroke risk. Several cited studies concern prognosis, treatment, or recurrence rather than the initial cause; their findings should therefore not be interpreted as proof that the measured biomarker or clinical feature directly triggered the index infarct.
Cardioembolism and competing vascular mechanisms
Atrial fibrillation (AF) is a major cardioembolic mechanism and may be newly detected after an apparently cryptogenic stroke. In a prospective cohort of patients without known AF, periodic repolarization dynamics—an ECG measure associated with sympathetic activity—was evaluated as a predictor of AF detected after stroke or TIA, supporting the possibility that occult paroxysmal AF can remain undiagnosed at initial presentation.[233] In patients with both nonvalvular AF and large-artery atherosclerosis (LAA), the coexistence of cardioembolic and atherosclerotic mechanisms creates uncertainty about whether oral anticoagulation alone or anticoagulation plus antiplatelet therapy is preferable; this treatment question does not establish that either mechanism caused an individual stroke.[238]
Prior intracranial hemorrhage complicates anticoagulation decisions in AF, but the comparative evidence on direct oral anticoagulants and vitamin K antagonists addresses prevention and safety rather than stroke etiology.[185] Similarly, studies of dual antiplatelet strategies after minor stroke or high-risk TIA evaluate secondary prevention and do not identify the cause of the presenting ischemic event.[183] Extended-window intravenous thrombolysis selected using perfusion imaging demonstrates the importance of tissue viability and time-to-treatment, but perfusion selection is a treatment criterion, not an etiologic trigger.[182]
Atherosclerosis and arterial disease
Large-artery atherosclerosis and intracranial atherosclerotic stenosis (ICAS) are important noncardioembolic mechanisms. In the cited ICAS cohort, ICAS was defined as at least 50% stenosis or occlusion; elevated interleukin-6 and high-sensitivity C-reactive protein were investigated as markers of residual vascular risk after the stroke, rather than as proven initiating causes.[236] Lipoprotein-associated phospholipase A2 was likewise studied in relation to recurrent cerebrovascular events after ischemic stroke, supporting its role as a possible marker of vascular inflammatory risk rather than a confirmed immediate trigger.[186]
When AF and LAA coexist, the observed uncertainty regarding combined antithrombotic therapy reflects overlapping mechanisms and competing hemorrhagic risks.[238] A comprehensive diagnostic evaluation is particularly important for embolic stroke of undetermined source (ESUS), because further testing may reveal an established mechanism; patients categorized as ESUS with a subsequently identified cause, comprehensively investigated ESUS, and incompletely investigated ESUS represent clinically heterogeneous groups.[235]
Dissection and systemic disease
Craniocervical artery dissection is a major cause of ischemic stroke in young adults. Vascular imaging features and the timing of recurrence were evaluated in a national registry of patients diagnosed within 7 days of symptom onset, emphasizing that the arterial wall lesion itself can provide a distinct cause of ischemia and embolization.[234]
Systemic lupus erythematosus (SLE) is associated with stroke risk in a meta-analysis of 25 cohort studies involving 5,220,837 individuals; both inflammatory vascular injury and conventional vascular risk factors may contribute, although the cited evidence estimates association rather than a single causal pathway.[227] Invasive cancer is another systemic prothrombotic context. A nationwide registry study of 182,221 adults aged 40 years or older evaluated ischemic stroke within 1 year after cancer diagnosis and found that risk varied according to cancer site, stage, time from diagnosis, and demographic characteristics.[237]
Modifiable and environmental exposures
A UK Biobank exposome-wide analysis evaluated 323 modifiable factors across seven domains: early life, health and medical history, lifestyle, local environment, physical measures, psychosocial factors, and sociodemographic characteristics. The accompanying Mendelian-randomization analyses were designed to examine associations and potential causality across multiple exposures, supporting a multifactorial model of stroke susceptibility rather than a single universal trigger.[230] Transportation-noise exposure was separately examined in a population-based cohort of incident ischemic stroke; the study assessed relationships with initial severity, recurrence, and mortality, so it informs environmental risk and outcomes but does not prove that noise directly caused an individual infarct.[231]
Biomarkers and post-stroke phenomena that should not be misclassified as causes
Several studies identify biological responses or prognostic markers after AIS. Plasma CD147 was associated with assessment of post-stroke cognitive impairment at 3 months in CATIS participants, while soluble CD163, S100B, high-sensitivity C-reactive protein, platelet count, and vitamin D status were evaluated for associations with functional, cognitive, depressive, fall, or vascular outcomes.[223][239][232][188] These findings describe consequences, susceptibility markers, or prognostic correlates—not established initiating etiologies. Frailty similarly predicted 1-year prognosis but is a reserve state rather than a specific vascular mechanism.[189]
Acute symptomatic seizures, including status epilepticus and multiple seizures, were studied after pediatric ischemic stroke and should generally be regarded as clinical manifestations or complications of cerebral injury rather than primary causes of the infarct.[229] Finally, post-stroke bleeding risk in young adults receiving antithrombotic therapy reflects treatment-related harm and does not define the original stroke mechanism.[228]
| Category | Evidence-supported examples | Interpretation |
|---|---|---|
| Cardioembolic | AF, including potentially occult AF detected after stroke | Important mechanism; post-stroke AF detection does not prove timing of onset.[233] |
| Atherosclerotic | LAA and ICAS | ICAS threshold: ≥50% stenosis or occlusion; inflammatory markers indicate residual risk rather than definitive causation.[236][238] |
| Arteriopathic | Craniocervical artery dissection | Recognized cause of stroke in young adults; diagnosis depends on vascular imaging.[234] |
| Systemic | SLE and invasive cancer | Associated with increased stroke risk through heterogeneous inflammatory, thrombotic, and vascular pathways.[227][237] |
| Environmental or modifiable | Lifestyle, psychosocial, physical, early-life, sociodemographic, and transportation-noise exposures | Multifactorial associations; individual causality may remain uncertain.[230][231] |
| Post-stroke or prognostic | Seizures, frailty, CD147, sCD163, S100B, hsCRP, platelet count, vitamin D | Should not be misclassified as established initiating causes.[188][189][223][229][232][239] |
Pathophysiology of Acute Ischemic Stroke
- ▸The ischemic penumbra is a metabolically stressed but salvageable zone of tissue maintained by collateral flow, surrounding an irreversibly damaged infarct core [40][41].
- ▸Calcium overload is the central executioner of the ischemic cascade, activating calpains and phospholipases that lead to rapid cellular degradation [43].
- ▸NETosis (neutrophil extracellular traps) links innate immunity to thrombosis by stabilizing clots and promoting microvascular obstruction [45].
The pathophysiology of acute ischemic stroke (AIS) is a dynamic, time-dependent process initiated by the cessation of cerebral blood flow, which triggers a complex sequence of biochemical events known as the ischemic cascade. This cascade progresses from immediate metabolic failure to delayed inflammatory and programmed cell death pathways [38][47]D. Understanding these mechanisms is critical for identifying salvageable tissue and developing neuroprotective strategies.
The Ischemic Penumbra and Infarct Core
Cerebral ischemia is spatially heterogeneous. The infarct core represents tissue with blood flow below the critical threshold (typically <10-12 mL/100g/min), where rapid energy failure leads to irreversible terminal depolarization and necrosis within minutes [40][49]D. Surrounding this core is the ischemic penumbra, a zone of functionally impaired but structurally intact tissue maintained by collateral circulation [40][41].
In the penumbra, blood flow is sufficient to maintain cellular integrity but insufficient for electrical activity. This region is the primary target for hyperacute interventions, such as cathodal transcranial direct current stimulation (C-tDCS) or convective cooling, which aim to stabilize the metabolic state of these cells until recanalization occurs [39][41]. Without intervention, the penumbra is progressively consumed by the core through waves of spreading depolarization and secondary injury cascades [40].
The Ischemic Cascade: Step-by-Step Mechanism
Step 1: Energy Failure and Ionic Dyshomeostasis Upon arterial occlusion, the depletion of oxygen and glucose halts oxidative phosphorylation, leading to a rapid decline in adenosine triphosphate (ATP). The failure of ATP-dependent ion pumps, specifically the Na+/K+-ATPase, results in intracellular sodium accumulation and potassium efflux [43]D. This causes water to shift into the intracellular space (cytotoxic edema) and leads to membrane depolarization [49]D.
Step 2: Excitotoxicity and Calcium Overload Depolarization triggers the massive release of the excitatory neurotransmitter glutamate into the synaptic cleft. The impairment of glutamate transporters (e.g., GLT-1) prevents reuptake, leading to overactivation of N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors [38][43]D. This results in a catastrophic influx of calcium (Ca2+) into the cytoplasm.
Step 3: Activation of Degradative Enzymes and ROS Intracellular calcium overload activates a variety of calcium-dependent enzymes, including calpains, phospholipases (PLA2), and protein kinases [43]D. These enzymes degrade the cytoskeleton and membrane lipids. Simultaneously, mitochondrial dysfunction and the activation of NADPH oxidase generate reactive oxygen species (ROS), which cause oxidative damage to proteins, lipids, and DNA [38][44]D.
Step 4: Neuroinflammation and NETosis Ischemic injury releases Damage-Associated Molecular Patterns (DAMPs) that activate resident microglia and recruit peripheral immune cells [45]D. A key feature of this stage is NETosis, where neutrophils release neutrophil extracellular traps (NETs). These DNA-based structures interact with platelets and the endothelium to promote microvascular thrombosis and enhance thrombus stability, further impairing microcirculatory flow [45]D.
Molecular Mediators and Signaling Pathways
The Role of TNF-α and ERK
Tumor Necrosis Factor-alpha (TNF-α) exhibits a dual, phase-dependent role. In the acute phase, TNF-α primarily binds to the TNFR1 receptor, promoting apoptosis, necroptosis, and blood-brain barrier (BBB) disruption [47]D. Conversely, in later stages, it may signal through TNFR2 to promote neuroprotection and tissue repair [47]D. Similarly, the extracellular signal-regulated kinase (ERK) pathway acts as a critical regulator, modulating cellular growth and survival responses to ischemic stress [48]D.
The Nitrate-Nitrite-Nitric Oxide Pathway
Under normal conditions, nitric oxide (NO) is produced via the L-arginine-NOS pathway. However, during ischemia, this pathway is impaired by hypoxia and acidosis [42]D. The nitrate-nitrite-NO pathway serves as an essential 'backup system,' where inorganic nitrate and nitrite are reduced to NO in hypoxic environments to maintain vasodilation and limit neuroinflammation [42]D.
Neurovascular Unit (NVU) and BBB Disruption
The integrity of the neurovascular unit (NVU)—comprising neurons, astrocytes, microglia, and endothelial cells—is vital for brain homeostasis [46]D. Ischemia disrupts the tight-junction (TJ) proteins (e.g., occludin, claudin-5) and the basement membrane, leading to BBB breakdown [46]D[47]D. This disruption is regulated by various microRNAs (miRNAs), which facilitate bidirectional communication between NVU components [46]D. BBB failure allows the extravasation of plasma proteins and fluid, resulting in vasogenic edema, which increases intracranial pressure and risks secondary herniation.
Circadian and Immunogenetic Factors
Susceptibility to ischemic injury is influenced by the circadian clock. Biological rhythms modulate blood pressure, glucose metabolism, and the inflammatory response, often leading to a peak in stroke onset during the morning hours [49]D. These rhythms also influence the metabolic rate of the penumbra and the efficiency of glial scar formation during the subacute phase [49]D.
| Cell Death Type | Key Mediators | Pathophysiological Role |
|---|---|---|
| Apoptosis | Caspases, Bax/Bcl-2, TNF-α (TNFR1) | Programmed cell shrinkage and fragmentation in the penumbra [38][47]D. |
| Necroptosis | RIPK1, RIPK3, MLKL | Regulated necrosis triggered by TNF-α; involves membrane rupture [47]D. |
| Pyroptosis | Inflammasomes (NLRP3), Gasdermin D | Pro-inflammatory cell death involving IL-1β and IL-18 release [38]. |
| Ferroptosis | Iron accumulation, Lipid peroxidation | Iron-dependent oxidative death linked to glutathione depletion [38]. |
| Pathway | Mechanism | Clinical Significance |
|---|---|---|
| Excitotoxicity | Glutamate → NMDA/AMPA activation | Primary driver of intracellular calcium overload [43]D. |
| Oxidative Stress | ROS generation (Nrf2/HO-1 modulation) | Causes direct damage to NVU structural components [38][44]D. |
| Nitrate-Nitrite-NO | Hypoxic reduction of Nitrite to NO | Backup system for vasodilation when L-arginine pathway fails [42]D. |
| ERK Signaling | MAPK/ERK phosphorylation | Regulates survival, differentiation, and neuroprotection [48]D. |
Diagnosis and Workup
- ▸The DAFNES scale is a new tool for early identification of large vessel occlusion (LVO) in the emergency department.
- ▸Brain frailty markers (atrophy, Fazekas score) on baseline CT/MRI predict worse outcomes after thrombectomy regardless of sex.
- ▸72-hour patch ECG monitoring is superior to 24-hour Holter for detecting atrial fibrillation in ESUS patients.
- ▸The EASIX score (Creatinine x LDH / Platelets) serves as a validated prognostic marker for mortality in AIS.
- ▸General anesthesia (GA) shows a high posterior probability of better functional outcomes in EVT compared to non-GA.
- ▸IV thrombolysis in minor stroke may not improve functional recovery and carries increased risks of sICH.
- ▸DAPT (clopidogrel + aspirin) should be initiated within 72 hours for mild ischemic stroke or high-risk TIA.
Initial Assessment and Clinical Scales
Rapid identification of acute ischemic stroke (AIS) is paramount, particularly for large vessel occlusion (LVO), where the benefit of reperfusion therapies diminishes rapidly over time [148]C. The DAFNES scale has been developed as a prospective tool for LVO identification in suspected stroke patients, showing promise for internal hospital-based validation [148]C. While prehospital scales often require bedside assessment, the DAFNES scale aims to streamline recognition in the emergency department setting [148]C. In pediatric populations, LVO is a rare but critical subtype; recent meta-analyses suggest that mechanical thrombectomy (MT) may be effective and safe in children, though evidence remains largely observational [147].
Neuroimaging and Brain Frailty
Baseline imaging is essential not only for diagnosis but for prognosticating outcomes. Non-contrast CT (NCCT) and follow-up MRI are used to assess 'brain frailty,' characterized by global cortical atrophy (GCA), subcortical atrophy, Fazekas scores, lacunes, and old infarctions [140]. Post-hoc analysis of the ESCAPE-NA1 trial indicates that these markers of brain frailty are associated with worse outcomes following endovascular thrombectomy (EVT), though the impact of these markers does not appear to differ significantly by sex [140]. Additionally, increased cerebral artery pulsatility on imaging has been independently associated with small vessel disease (SVD), even after adjusting for premorbid blood pressure and heart rate [120].
Cardiac and Biomarker Workup
For patients with embolic stroke of undetermined source (ESUS), detecting atrial fibrillation (AF) is a diagnostic priority to prevent recurrence [121]. The AVANT-GARDE trial demonstrated that a 72-hour adhesive single-lead patch ECG identified AF in 13.3% of the cohort at baseline, proving effective for monitoring compared to standard 24-hour Holter monitoring [121].
Emerging biomarkers are also being utilized for risk stratification. The Endothelial Activation and Stress Index (EASIX)—calculated as (creatinine [mg/dL] × LDH [U/L]) / platelet count [10⁹/L]—has been validated as a prognostic marker for both short- and long-term mortality in AIS patients [149]C. Furthermore, the Systemic Immune-Inflammation Index (SII) at baseline and day 14 can enhance the prediction of neuroprotective effects, such as those seen with butylphthalide, by reflecting the patient's inflammatory status [144].
Evaluation for Reperfusion and Adjunctive Therapy
The workup must determine eligibility for intravenous thrombolysis (IVT) and EVT. Tenecteplase is increasingly utilized as an alternative to alteplase due to simplified administration, which may improve workflow metrics like door-to-needle and door-in-door-out times [150]. However, for minor AIS (typically defined by low NIHSS), a meta-analysis of 13 RCTs suggests that IVT may not be significantly associated with excellent functional recovery and could increase the risk of symptomatic intracranial hemorrhage (sICH) compared to non-thrombolytic standard of care [136].
For patients undergoing EVT, the choice of anesthesia and device is critical. Bayesian meta-analysis indicates a high posterior probability of functional benefit with general anesthesia (GA) compared to non-GA techniques [134]. The use of super large-bore aspiration catheters, such as the Route 92 Reperfusion System, aims to maximize the first-pass effect (FPE) and reperfusion rates [135]. While combining stent retrievers (SR) with contact aspiration (CA) improves first-line recanalization rates, it has not consistently translated to improved 90-day clinical outcomes in pooled analyses [139].
Pharmacological Considerations in Workup
During the acute workup, the role of adjunctive antiplatelet and statin therapy is often evaluated. The INSPIRES trial found that dual antiplatelet therapy (DAPT) with clopidogrel and aspirin initiated within 72 hours of mild stroke or high-risk TIA is effective across both sexes [146]. Combining DAPT with immediate intensive statin therapy is also under investigation for synergistic effects in atherosclerotic stroke [141]. The use of tirofiban as an adjunct to EVT has shown safety and potential efficacy in LVO [114], particularly in patients who achieve successful reperfusion [142]. However, the efficacy of early tirofiban post-IVT may be influenced by the patient's history of diabetes mellitus [138].
| Index/Scale | Components/Definition | Clinical Utility |
|---|---|---|
| EASIX | (Creatinine × LDH) / Platelets | Predicts short- and long-term mortality risk [149]C |
| SII | Systemic Immune-Inflammation Index | Predicts response to neuroprotective therapy [144] |
| DAFNES | Clinical LVO Scale | Early identification of large vessel occlusion [148]C |
| Fazekas | White matter hyperintensity scale | Marker of brain frailty and post-EVT prognosis [140] |
Differential Diagnosis
- ▸Clinical symptoms and signs cannot reliably distinguish ischemic from hemorrhagic stroke; neuroimaging is required [66].
- ▸A negative early MRI may occur in patients with clinically suspected ischemia, and patients treated before definitive imaging may ultimately be classified as MRI-positive ischemia, MRI-negative ischemia, or a stroke mimic [160].
- ▸Functional neurological episodes, seizure, migraine, metabolic or toxic disorders, and psychiatric or systemic conditions are important stroke mimics; younger age and psychiatric comorbidity support but do not establish a functional diagnosis [205].
- ▸GFAP, MMP-9, and other fluid biomarkers are investigational adjuncts and must not replace urgent brain imaging [203][64][65].
- ▸Post-thrombectomy hyperdensity may represent hemorrhagic transformation, contrast extravasation, or both, requiring appropriate follow-up imaging [240][207].
- ▸CTA, CTP, cardiac CT, and vessel-wall MRI refine vascular or etiologic diagnosis but do not replace initial imaging to exclude hemorrhage [40][68][202][209].
Diagnostic principle
Acute focal neurological dysfunction should be treated as suspected stroke until ischemia, hemorrhage, or a mimic is established. Clinical findings alone do not reliably distinguish ischemic from hemorrhagic stroke; validated discrimination requires neuroimaging. The 2025 systematic review and meta-analysis specifically evaluated presenting symptoms and signs in adults with neuroimaging-confirmed stroke and concluded that clinical assessment cannot replace imaging for determining primary stroke type [66].
Noncontrast head CT (NCCT) is therefore the immediate discriminator for intracranial hemorrhage, while MRI—particularly diffusion-weighted imaging—can confirm or refute acute ischemia when the diagnosis remains uncertain. Patients treated empirically with intravenous thrombolysis may subsequently be classified as having MRI-confirmed infarction, MRI-negative ischemia, or a stroke mimic, illustrating that diagnostic uncertainty persists even after initial emergency treatment [160]. A negative early MRI does not automatically exclude ischemia when the clinical syndrome and vascular evaluation remain suggestive [160].
Ischemic stroke versus intracerebral hemorrhage
Symptoms such as headache, vomiting, reduced consciousness, seizure, severe deficit, or very high blood pressure may increase clinical concern for hemorrhage, but none is sufficiently reliable to determine stroke type without imaging [66]. Conversely, the absence of these findings does not establish ischemia [66]. Prehospital GFAP testing is being investigated as a rapid adjunct: the DETECT study evaluated point-of-care plasma GFAP collected before hospital arrival to distinguish intracerebral hemorrhage from ischemic stroke and stroke mimics in patients presenting within 6 hours of symptom onset [203]C. GFAP should be regarded as an adjunct under evaluation rather than a replacement for brain imaging [203]C.
Stroke mimics
Important mimics include functional neurological episodes, seizure-related deficits, migraine or other headache syndromes, metabolic disturbances, toxic or medication-related states, syncope, and systemic or psychiatric disorders. The available evidence emphasizes that no single clinical feature reliably excludes a mimic or confirms ischemia [66]. Functional stroke-like episodes were associated with younger age, psychiatric comorbidity, and a history of prior functional symptoms in a comparative cohort; however, these characteristics are supportive rather than diagnostic [205].
Acute aphasia is a frequent diagnostic challenge because it may reflect ischemia or a mimic. In a retrospective study, CT perfusion (CTP) was assessed for differentiating stroke-related from mimic-related aphasia, but its role remained under investigation rather than established as a standalone diagnostic test [208]. Additional CTA and CTP may improve characterization by identifying vascular occlusion or tissue at risk, but they can add time; the randomized PRACTISE trial was designed to compare NCCT alone with NCCT plus CTA and CTP in thrombolysis-eligible patients treated within 4.5 hours [40].
Stroke mimics may occasionally receive reperfusion therapy because treatment decisions precede definitive diagnostic confirmation. A retrospective cohort specifically evaluated intracranial hemorrhage after tenecteplase in patients later classified as having a mimic versus acute ischemic stroke, supporting the need to balance diagnostic uncertainty against time-sensitive treatment [69]. Prehospital consensus recommendations likewise identify recognition of mimics, patient destination, positioning, and hemodynamic management as important unresolved or variable components of acute stroke transport [201].
Additional vascular and structural differentials
When ischemia is confirmed, the mechanism may still be uncertain. Cardioaortic thrombus can be missed by standard vascular imaging; the DAYLIGHT randomized trial evaluated extending CTA from the head and neck to at least 6 cm below the carina to increase thrombus detection in ischemic stroke or transient ischemic attack [68]. Cardiac CT is also an emerging acute-protocol modality for detecting cardiac thrombi; the AIS of HEARTS individual-patient meta-analysis included four prospective cohorts and compared CT findings with echocardiographic assessment [202]. These tests help identify embolic sources but do not replace acute brain imaging for distinguishing ischemia from hemorrhage.
In young patients, arterial dissection, inflammatory arteriopathy, moyamoya disease, and other vessel-wall disorders should be considered. High-resolution vessel-wall MRI has been used to identify vessel-wall lesions in patients aged 18–50 years with ischemic stroke or transient ischemic attack, with stroke mimics included as controls [209]. In children, focal cerebral arteriopathy-inflammatory type must be distinguished from unilateral moyamoya disease; a Korean study evaluated severity scoring and temporal imaging patterns for this purpose [206].
Post-treatment imaging pitfalls
After endovascular therapy, new hyperdensities on NCCT may represent hemorrhagic transformation, contrast extravasation, or both. These entities have different implications for subsequent antithrombotic management and generally require follow-up imaging; recent studies evaluated noncontrast-CT habitat analysis and machine-learning models for this distinction [240][207]. This is a post-reperfusion differential and should not be confused with the initial diagnosis of spontaneous intracerebral hemorrhage.
Biomarkers and non-diagnostic treatment studies
Fluid biomarkers may eventually supplement clinical assessment and imaging, but current evidence remains heterogeneous. A 2026 umbrella review evaluated early-phase biomarkers for acute ischemic stroke versus controls or mimics and highlighted uncertainty in temporal dynamics and diagnostic performance [64]. Blood MMP-9 has been meta-analyzed for differentiation of ischemic stroke from mimics or controls within 24 hours of symptom onset, but it remains an investigational adjunct rather than a definitive test [65].
Glibenclamide studies address cerebral edema and neurological outcomes across ischemic and hemorrhagic stroke, not the initial differential diagnosis; their findings should therefore not be used to classify stroke type [63][67]. Similarly, studies of extended CTA and cardiac CT concern etiologic work-up after ischemia is suspected or confirmed rather than primary discrimination between ischemia and hemorrhage [68][202].
| Diagnostic possibility | Features or context prompting consideration | Best-supported diagnostic approach |
|---|---|---|
| Ischemic stroke | Sudden focal deficit; may be MRI-negative early or after empiric treatment [160] | NCCT to exclude hemorrhage, followed by MRI, CTA, or CTP when indicated [40][160] |
| Intracerebral hemorrhage | Headache, vomiting, impaired consciousness, seizure, or severe deficit may raise suspicion, but clinical findings are insufficient [66] | Immediate brain imaging; GFAP is an investigational adjunct [66][203]C |
| Functional neurological episode | Younger age, psychiatric comorbidity, or prior functional symptoms [205] | Neurological examination plus appropriate imaging and diagnostic adjudication [205] |
| Seizure, migraine, metabolic, toxic, or systemic mimic | Stroke-like symptoms without definitive infarction; clinical overlap is substantial [66][208] | Targeted history, examination, laboratory assessment, and brain/vascular imaging [66][208] |
| Post-EVT hemorrhagic transformation or contrast extravasation | New hyperdensity after thrombectomy [240][207] | Follow-up CT and, where available, validated imaging analysis [240][207] |
Supportive Care and Complication Management
- ▸Basal ganglia infarction (BGI) increases the risk of parenchymal hemorrhage when bridging therapy is used over mechanical thrombectomy alone.
- ▸Net water uptake (NWU) on CT is a more accurate predictor of futile recanalization than ASPECTS or rCBF <30%.
- ▸Stress hyperglycemia in minor stroke patients mediates poor outcomes specifically through the mechanism of hemorrhagic transformation.
- ▸Serum GFAP levels peak between days 5-7 post-stroke and serve as a marker for infarct volume.
- ▸Quantitative pupillometry combined with CSF volumetrics can predict neurologic deterioration in large hemispheric strokes.
- ▸The TCAB score is a validated tool for predicting ischemic stroke risk following CABG surgery.
Management of Hemorrhagic Transformation (HT)
Hemorrhagic transformation remains a critical complication of reperfusion therapy, potentially offsetting the benefits of mechanical thrombectomy (MT) [156]. In patients with basal ganglia infarction (BGI), bridging therapy (intravenous thrombolysis followed by MT) is associated with a significantly higher risk of parenchymal hematoma (PH) compared to MT alone [156]. For minor ischemic strokes (NIHSS ≤5), HT is a key mediator between stress hyperglycemia (glucose-to-glycated hemoglobin ratio) and poor 90-day functional outcomes [122]. Furthermore, novel lipid-derived biomarkers, specifically Remnant Cholesterol (RC) and the Cholesterol, High-Density Lipoprotein, and Glucose (CHG) index, have been identified as independent predictors of HT and poor prognosis following intravenous thrombolysis [60]. In minor strokes with visible vessel occlusion, any pattern of intracranial hemorrhage (ICH) negatively impacts functional recovery [154].
Cerebral Edema and Intracranial Pressure
Cerebral edema is a life-threatening complication, particularly in large hemispheric infarctions (LHI) [155][165]. Endovascular thrombectomy (EVT) has been shown to reduce the development of edema in patients with a large ischemic core, and lower edema levels are associated with improved short-term and long-term outcomes [155]. Monitoring edema progression can be achieved by integrating brain imaging volumetrics (cerebrospinal fluid volume loss) with quantitative pupillometry, which provides real-time bedside assessment of neurologic decline [165]. Ischemic lesion net water uptake (NWU) on CT is a superior biomarker for predicting "futile recanalization" (poor outcome despite successful EVT) compared to traditional measures like ASPECTS or CT perfusion-derived rCBF <30% [163].
Glycemic and Coagulation Monitoring
Baseline plasma fibrinogen levels influence the efficacy and safety of thrombolytic agents. In the RAISE trial subgroup analysis, reteplase and alteplase showed varying safety profiles based on fibrinogen: patients with low baseline fibrinogen may face different risks of symptomatic ICH within 36 hours [153]. For patients with LHI requiring anticoagulation, the optimal timing remains debated; however, early initiation (≤7 days) must be balanced against the risk of HT, though some data suggest no significant difference in composite recurrence or systemic embolism compared to late initiation (>7 days) in matched cohorts [164].
Specialized Populations and Procedural Complications
- Pediatric ECMO: Pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) face significant neurological morbidity post-decannulation, particularly when involving carotid artery ligation (CAL) vs. repair (CAR) [151].
- Very Elderly (≥80 years): EVT is considered safe and effective in patients aged ≥80 years, though they remain at high risk for malignant cerebral edema and mortality [123].
- Post-CABG Stroke: The Total Cerebral Atherosclerosis Burden (TCAB) score, which sums stenosis severity across intracranial and extracranial segments, is a novel predictor for postoperative AIS after coronary artery bypass grafting [161].
- EC-IC Bypass: In patients with symptomatic atherosclerotic internal carotid or middle cerebral artery occlusion, a mismatch between perfusion-directed targeting and the recipient vessel (frontal vs. temporal) may increase perioperative stroke risk [157].
Emerging Diagnostics and Neuroprotection
Serum glial fibrillary acidic protein (sGFAP), an astroglial biomarker, shows a distinct temporal pattern, increasing within the first 24 hours and peaking between days 5-7, correlating with infarct volume and clinical severity [159]. Remote Ischemic Conditioning (RIC), involving cycles of limb cuff inflation/deflation, is being investigated for neuroprotection; while safe, its efficacy may depend on baseline stroke severity (NIHSS 5-20) [158]. Additionally, blood-brain barrier (BBB) disruption identified on MR perfusion prior to interhospital transfer for EVT is a potent predictor of subsequent HT and poor 3-month functional outcomes [162].
| Biomarker/Tool | Clinical Significance | Evidence Level |
|---|---|---|
| Net Water Uptake (NWU) | Predicts futile recanalization in LVO | 3b [163] |
| sGFAP (Serum) | Correlates with infarct volume and D5-7 peak | 2b [159] |
| TCAB Score | Predicts post-CABG ischemic stroke | 2b [161] |
| CHG Index | Predicts HT after thrombolysis | 3b [60] |
| BBB Disruption | Predicts HT before interhospital transfer | 3b [162] |
Prognosis and Long-term Outcomes
- ▸General anesthesia during EVT may provide better functional outcomes than non-GA techniques based on Bayesian evidence.
- ▸IV thrombolysis in minor stroke (NIHSS ≤5) is associated with higher 90-day mortality and sICH without improving functional recovery.
- ▸Paired Vagus Nerve Stimulation (VNS) shows sustained upper extremity functional benefits up to 2 years post-stroke.
- ▸Brain frailty markers (atrophy, Fazekas score) and the EASIX biomarker are critical predictors of long-term mortality.
- ▸Tirofiban as an adjunct to EVT does not consistently improve functional independence despite improving recanalization in some cohorts.
Functional Recovery and Mortality
Long-term outcomes in acute ischemic stroke (AIS) are heavily influenced by the efficacy of initial revascularization and the management of post-stroke complications. In patients with large vessel occlusion (LVO), endovascular thrombectomy (EVT) remains the cornerstone of treatment. Recent Bayesian meta-analyses indicate that general anesthesia (GA) during EVT may offer a high posterior probability of functional benefit compared to non-GA techniques, despite historical controversy [134]. The use of super large-bore aspiration catheters, such as the Route 92 Reperfusion System, has demonstrated high rates of first-pass effect (FPE) and functional independence (mRS 0-2) [135]. Conversely, combined approaches using both stent retrievers and contact aspiration improve first-line recanalization rates but have not shown superior clinical outcomes compared to either technique alone [139].
For patients with minor AIS (NIHSS ≤5), the prognosis following intravenous thrombolysis (IVT) is less favorable than previously assumed. Meta-analyses of randomized controlled trials (RCTs) show that IVT is not significantly associated with excellent functional recovery in minor stroke and may increase the odds of symptomatic intracranial hemorrhage (sICH) and 90-day mortality [136]. In the extended time window (>4.5 hours), tenecteplase (TNK) is being evaluated as an alternative to best medical treatment, showing potential for improved safety and efficacy in selected populations [167].
Adjunctive Therapies and Neuroprotection
The addition of tirofiban, a glycoprotein IIb/IIIa receptor antagonist, to EVT has shown mixed results. While some systematic reviews suggest it is a safe and effective adjunct for LVO [114], the ATTRACTION trial found that tirofiban administered after successful reperfusion did not consistently improve functional independence [142]. In non-cardioembolic stroke, the efficacy of early tirofiban post-IVT may be influenced by baseline diabetes mellitus (DM) status [138].
Neuroprotective agents continue to be investigated for long-term benefit. Nerinetide, despite failing its primary 90-day endpoint in the ESCAPE-NEXT trial, showed available 1-year follow-up data for a subset of participants, suggesting the need for extended observation windows in neuroprotection research [143]. Butylphthalide has demonstrated enhanced neuroprotective effects in patients with a favorable systemic immune-inflammation status, particularly those showing a transition from unfavorable to favorable inflammatory profiles by Day 14 [144].
Secondary Prevention and Brain Frailty
Secondary prevention strategies significantly impact long-term prognosis. The combination of clopidogrel-aspirin and immediate intensive statin therapy in mild AIS or TIA of atherosclerotic origin is under investigation for synergistic effects [141]. Prespecified subgroup analyses of the INSPIRES trial indicate that the treatment effect of dual antiplatelet therapy (DAPT) initiated within 72 hours does not significantly differ by sex regarding new stroke risk at 90 days [146].
Brain frailty markers, including global cortical atrophy (GCA), Fazekas score, and lacunes, are strong predictors of worse outcomes after EVT [140]. The Endothelial Activation and Stress Index (EASIX)—calculated using creatinine, LDH, and platelet count—has emerged as a validated biomarker for predicting both short- and long-term mortality in AIS registries [149]C. Furthermore, the infarct growth rate (IGR) defines progressor phenotypes; fast progressors (>0.50 ASPECTS points/h or >10 mL/h core growth) face significantly worse prognoses than slow progressors [168].
Specialized Populations and Rehabilitation
In pediatric LVO, mechanical thrombectomy appears to be a viable intervention, though evidence is primarily derived from observational data and Bayesian inferences [147]. For chronic stroke recovery, paired Vagus Nerve Stimulation (VNS) with rehabilitation has shown 2-year retention of benefits in upper extremity function, activity, and quality of life [137].
Outcome assessment is also evolving; hierarchical composite measures like the win ratio (WR) are being applied to trials like TENSION to better capture the spectrum of patient outcomes, including time to death, mRS at 12 months, and serious adverse events [145].
| Phenotype | NCCT Definition (ASPECTS decay) | CTP Definition (Core growth) | Prognostic Outlook |
|---|---|---|---|
| Slow Progressor | < 0.25 pts/h | < 5 mL/h | Favorable; higher salvage potential |
| Intermediate | 0.25 - 0.50 pts/h | 5 - 10 mL/h | Moderate risk |
| Fast Progressor | > 0.50 pts/h | > 10 mL/h | Poor; rapid infarct expansion |
Landmark Trials and Key Evidence
- ▸Tenecteplase (0.25 mg/kg) is effective in the 4.5 to 24-hour window when guided by advanced imaging.
- ▸EVT is now supported for large-core infarcts (ASPECTS ≤5) up to 24 hours post-onset.
- ▸General Anesthesia (GA) may offer superior functional outcomes during EVT compared to conscious sedation.
- ▸Intensive BP lowering (<120 mmHg) post-EVT is not currently supported over standard targets.
- ▸IV Thrombolysis in minor stroke (low NIHSS) may not improve outcomes and increases hemorrhage risk.
- ▸Early anticoagulation in AF-related stroke is generally safe and may prevent early recurrence.
Reperfusion Strategies and Thrombolysis
Recent meta-analyses have refined the therapeutic window and agent selection for intravenous thrombolysis (IVT). Tenecteplase (TNK) has emerged as a potent alternative to alteplase, particularly in the extended window. Evidence from randomized controlled trials (RCTs) indicates that TNK (0.25 mg/kg) administered between 4.5 and 24 hours after the last known well (LKW) status significantly improves functional outcomes compared to best medical treatment (BMT) [167][87]. Bayesian meta-analyses confirm a high probability of clinically meaningful benefit when using advanced neuroimaging to guide extended thrombolysis [100]. However, the benefit of IVT in minor stroke remains controversial; a 2026 meta-analysis of 13 RCTs found that IVT was not significantly associated with excellent functional recovery in minor stroke and may increase the risk of symptomatic intracranial hemorrhage (sICH) and mortality [136].
Endovascular Thrombectomy (EVT) and Large Core Infarcts
The scope of EVT has expanded to include patients with large-core ischemic strokes, previously often excluded. Individual patient data meta-analysis (ATLAS) of trials involving patients with an ASPECTS ≤5 or core volume ≥50 mL demonstrated that EVT significantly improves functional independence even in these extensive infarcts when presenting within 24 hours [170]. Long-term data beyond the standard 90-day endpoint show that EVT benefits persist, improving health-related quality of life (HRQoL) and functional trajectories for over a year [179].
Adjunctive Therapies and Procedural Management
- Anesthesia Strategy: While previously debated, updated Bayesian meta-analyses suggest a high posterior probability of functional benefit with General Anesthesia (GA) over non-GA techniques during EVT [134].
- Bridging Therapy: The necessity of IVT before EVT (bridging) in patients presenting directly to thrombectomy-capable centers is under scrutiny. Current evidence suggests that while bridging with TNK or alteplase is standard, the benefit may not vary significantly by stroke etiology (large-artery atherosclerosis vs. cardioembolism) [171][102].
- Adjunctive Pharmacotherapy: Intra-arterial tenecteplase (IA-TNK) administered after successful EVT (eTICI 2b-3) is being investigated to enhance distal reperfusion [85]. The use of glycoprotein IIb/IIIa inhibitors like tirofiban or eptifibatide as adjuncts to IVT has shown potential in increasing functional independence, though with a higher risk of ICH [101][176]. Conversely, the neuroprotective agent nerinetide did not show significant efficacy in patients undergoing EVT without prior thrombolysis [86].
Secondary Prevention and Post-Stroke Care
- Blood Pressure Management: Following successful EVT, intensive blood pressure control (typically targeting systolic <120 mmHg) has not consistently shown superiority over standard control and may even be less effective in achieving excellent functional outcomes [173].
- Anticoagulation Timing: In patients with atrial fibrillation, early initiation of anticoagulation (within days) appears as safe as late initiation regarding the risk of ICH, while potentially reducing early recurrent embolic events [84].
- PFO Closure: The PASCAL classification system is now recommended to identify patients with patent foramen ovale (PFO) who are most likely to benefit from device closure, specifically those where the PFO is the highly probable cause of the index stroke [174].
- Antiplatelet Failure: For patients who experience a stroke while already on aspirin, switching to dual antiplatelet therapy (DAPT) or direct oral anticoagulants (DOACs) is often considered, though the optimal alternative remains a subject of ongoing network meta-analyses [175].
Rehabilitation and Neuroplasticity
Emerging evidence supports the combination of acupuncture and repetitive transcranial magnetic stimulation (rTMS) to enhance cortical excitability and motor recovery in the lesional hemisphere post-stroke [177].
| Intervention | Population | Key Finding | Evidence Level |
|---|---|---|---|
| Tenecteplase | 4.5–24h window | Improved functional outcome vs BMT | 1a [167][87] |
| EVT | Large Core (ASPECTS ≤5) | Benefit maintained up to 24h | 1a [170] |
| IVT | Minor Stroke | No significant benefit; higher sICH risk | 1a [136] |
| Intensive BP | Post-EVT | No benefit over standard control | 1a [173] |
| GA vs Non-GA | During EVT | GA likely provides better functional benefit | 1a [134] |
Secondary Prevention of Acute Ischemic Stroke
- ▸Early initiation of DOACs (within 4 days) is safe and potentially more effective than delayed initiation for AF-related stroke.
- ▸DAPT (Aspirin + Clopidogrel/Ticagrelor) is the standard for high-risk TIA and minor stroke, with the highest benefit seen in the first 21-90 days.
- ▸PFO closure should be considered even in patients aged 55 and older to reduce recurrence risk.
Secondary prevention is the cornerstone of long-term following an acute ischemic stroke (AIS) or high-risk transient ischemic attack (TIA). The primary objective is to mitigate the high risk of recurrence, which is most pronounced in the first 90 days post-event [17]. Management strategies are tailored based on the underlying etiology, including large-artery atherosclerosis, cardioembolism (primarily ), and small-vessel disease.
Antiplatelet Strategies for Non-
For patients with non-cardioembolic AIS or high-risk TIA, antiplatelet therapy is the standard of care. Dual antiplatelet therapy (DAPT), typically combining aspirin and a P2Y12 inhibitor, is superior to monotherapy for early secondary prevention [14].
Risk Stratification and DAPT Selection
The ABCD2 score (Age, Blood pressure, Clinical features, Duration, Diabetes) remains a vital tool for triaging TIA patients. Patients with an ABCD2 score ≥4 or those with a confirmed infarct on index imaging are at the highest risk for residual ischemic events despite treatment [17]. In the POINT trial analysis, the risk of recurrent stroke at 90 days remained significant even under DAPT, emphasizing the need for strict adherence and risk factor modification [17].
Recent evidence from the CHANCE-2 trial suggests that the choice of P2Y12 inhibitor may be influenced by inflammatory biomarkers. Patients with elevated vascular cellular adhesion molecule-1 (VCAM-1) levels may derive greater benefit from Ticagrelor (180 mg loading, then 90 mg BID) compared to Clopidogrel (300 mg loading, then 75 mg daily) [106]. Furthermore, the presence of diabetes mellitus (DM) does not appear to diminish the relative efficacy of DAPT over aspirin monotherapy, although DM patients carry a higher absolute risk of early neurological deterioration (END) [14].
Protocol: Acute Antiplatelet Initiation
- Step 1: Risk Assessment. Identify high-risk TIA (ABCD2 ≥4) or minor stroke (NIHSS ≤3). Confirm absence of contraindications (e.g., active hemorrhage).
- Step 2: Loading Dose. Administer Aspirin (150–300 mg) plus Clopidogrel (300–600 mg) or Ticagrelor (180 mg) within 24 hours of symptom onset [106].
- Step 3: Maintenance. Continue DAPT for 21 to 90 days depending on the specific trial protocol followed (e.g., CHANCE or POINT), followed by long-term antiplatelet monotherapy [17].
Anticoagulation in Atrial Fibrillation
Atrial fibrillation (AF) necessitates oral anticoagulation (OAC) to prevent recurrent cardioembolic events. Direct oral anticoagulants (DOACs) are now preferred over Warfarin due to a superior safety profile and comparable or better efficacy [109].
Timing of Initiation
The optimal timing for starting OAC after AIS has historically been delayed to avoid hemorrhagic transformation. However, recent data from the TIMING and ELAN trials support earlier initiation. Starting a DOAC within 4 days of an acute event is associated with a trend toward fewer recurrent ischemic events without a significant increase in intracranial hemorrhage (ICH) compared to delayed initiation (5–10 days) [32], [110]. For patients with concomitant atherosclerotic cardiovascular disease (ASCVD) and AF, OAC monotherapy is generally preferred over combining OAC with antiplatelets, as the combination significantly increases bleeding risk without a proportional decrease in ischemic events [31].
Metabolic and Lipid Management
High-intensity statin therapy is mandatory for all patients with atherosclerotic stroke. Beyond LDL-C reduction, metabolic markers such as Free Fatty Acids (FFA) and the Stress Hyperglycemia Ratio (SHR) have emerged as prognostic indicators. High serum FFA concentrations are independently associated with poor 3-month outcomes [103]. Similarly, an elevated SHR—calculated as admission glucose divided by estimated average glucose—is a potent predictor of recurrent stroke and composite vascular events, particularly in patients with mild stroke or TIA [107].
Structural Interventions: PFO Closure
In patients with and a patent foramen ovale (PFO), transcatheter closure is an established secondary prevention strategy. While early trials focused on younger populations, recent meta-analyses indicate that PFO closure is also effective in elderly patients (≥55 years), significantly reducing recurrent stroke and TIA compared to antithrombotic therapy alone [111]. However, clinicians must weigh this against a higher risk of new-onset atrial fibrillation post-procedure [111].
Emerging Therapies: Factor XIa Inhibition
Inhibition of Factor XIa represents a novel approach to uncouple hemostasis from thrombosis. The OCEANIC-STROKE trial is investigating Asundexian (50 mg daily), a direct FXIa inhibitor, as an add-on to standard antiplatelet therapy [2]. Early data suggest that FXIa inhibition may provide additional protection against non-cardioembolic stroke with a lower bleeding risk than traditional anticoagulants, though phase 3 results are pending to confirm superiority over antiplatelets alone [13].
| Strategy | Indication | Key Evidence | Clinical Consideration |
|---|---|---|---|
| DAPT (Asp + Clop) | Minor stroke/High-risk TIA | POINT/CHANCE [17] | Limit to 21-90 days to minimize bleeding |
| Ticagrelor + Asp | Minor stroke/High-risk TIA | CHANCE-2 [106] | Preferred if high VCAM-1 or Clopidogrel resistance |
| DOAC Monotherapy | Atrial Fibrillation | ELAN/TIMING [32], [104] | Superior to Warfarin; early start (≤4d) is safe |
| PFO Closure | Cryptogenic Stroke | Meta-analysis [111] | Effective in patients ≥55 years old |
| Asundexian (50mg) | Non-cardioembolic stroke | OCEANIC-STROKE [2], [13] | Emerging FXIa inhibitor; low bleeding risk |
Special Populations
- ▸Consider EVT in dementia or prestroke dependency using individualized goals, baseline function, and relative-to-baseline outcomes rather than age or mRS alone. [252][220]
- ▸Very-late EVT beyond 24 hours may be feasible in carefully selected anterior-circulation LVO, but evidence remains observational. [242]
- ▸Sedation and intra-procedural blood-pressure management should be individualized rather than protocolized identically for every patient. [241][212]
- ▸Cancer, carotid web, ICAS, and atrial fibrillation require mechanism-specific evaluation and secondary prevention. [237][215][236][253]
- ▸Bone health, inflammation, EEG abnormalities, blood–brain barrier injury, and post-EVT imaging findings are clinically relevant complications or prognostic domains, but most cited evidence remains observational or investigational. [243][245][246][217][218][244][248]
- ▸Immigration status was associated with differences in intensity of acute stroke care in an Ontario population study assessing thrombolysis, thrombectomy, ventilatory support, feeding tubes, ICU admission, and ICU length of stay; such disparities should be interpreted as system-level determinants rather than biological treatment criteria. [247]
- ▸A four-center Belgian–Turkish retrospective study evaluated emergency pathways and door-to-needle time, including prehospital transport, CT location, NIHSS, and treatment characteristics, emphasizing that acute-care organization can influence timely thrombolysis. [249]
- ▸A multicenter machine-learning study using 5,014 patients evaluated granular first-24-hour bedside and nursing data for in-hospital mortality prediction; such models may support risk stratification but require external validation and should not replace clinical judgment. [250]
Older adults, dementia, and prestroke disability
Pre-existing dementia is associated with poorer outcomes after endovascular thrombectomy (EVT), but comparative evidence has been limited. A propensity-matched analysis of the US Nationwide Readmissions Database (2016–2022) compared EVT with best medical management in adults with dementia and large-vessel occlusion (LVO), evaluating discharge home, in-hospital mortality, length of stay, and complications. The study specifically examined whether EVT retained benefit in this population, although the available evidence summary does not provide the outcome estimates; therefore, dementia alone should not be treated as an automatic contraindication, and decisions should incorporate premorbid function, stroke severity, goals of care, and expected quality of life. [252]
Patients with prestroke dependence require individualized assessment because they have frequently been excluded or underrepresented in randomized EVT trials. The EVA-TRISP multicenter registry compared prestroke-dependent patients (prestroke modified Rankin Scale [mRS] 3–4) with prestroke-independent patients (mRS 0–2) undergoing EVT. Outcomes included poor functional status relative to prestroke mRS, 3-month mortality, symptomatic intracranial hemorrhage, and unsuccessful recanalization. Relative-to-baseline outcome assessment is particularly important: failure to return to mRS 0–2 may not represent treatment failure in a patient whose baseline mRS was 3–4. [220]
Very late presentation and advanced imaging selection
Evidence is emerging for EVT beyond the conventional 24-hour window. A propensity-score-matched cohort of patients with anterior-circulation LVO compared EVT performed >24 hours after onset with EVT performed during 6–24 hours, adjusting for age, sex, NIHSS score, ASPECTS, occlusion location, perfusion parameters, and vascular risk factors. The primary endpoint was 3-month functional independence (mRS ≤2). These observational data support evaluation of carefully selected very-late presenters, but do not establish equivalence with randomized-trial evidence or justify treatment without favorable clinical and imaging profiles. [242]
Procedural sedation and blood-pressure management
Sedation requirements may vary substantially among patients undergoing EVT. A post-hoc analysis of the randomized INDIVIDUATE trial included anterior-circulation stroke patients treated under procedural sedation and quantified propofol, remifentanil, and esketamine exposure from protocolized 5-minute medication records. Multivariable analyses assessed patient and procedural determinants of drug requirements and their relationship with outcomes. Sedation should therefore be titrated to procedural tolerance, airway and ventilation safety, hemodynamic stability, and preservation of neurologic assessment rather than applied uniformly. [241]
The DETERMINE randomized clinical trial evaluated individualized versus standard blood-pressure control during thrombectomy in adults with anterior LVO at eight French comprehensive stroke centers. The trial addressed whether patient-specific intra-procedural BP targets improve 90-day functional outcome compared with a one-size-fits-all strategy. Until trial results are incorporated into guidelines, BP management should avoid both severe hypertension and hypotension while accounting for collateral circulation, reperfusion status, anesthesia or sedation, and comorbid cardiovascular disease. [212]
Cancer, atrial fibrillation, and unusual stroke mechanisms
Cancer-associated stroke risk is heterogeneous. A nationwide Israeli registry study followed 182,221 adults aged ≥40 years with newly diagnosed invasive cancer from 2014–2021 and estimated ischemic-stroke risk during the first year using standardized incidence ratios, cancer site, stage, time since diagnosis, demographic subgroup, and competing mortality. Recent cancer diagnosis should prompt consideration of malignancy-associated hypercoagulability, competing bleeding risk, prognosis, and treatment interactions during reperfusion and secondary-prevention decisions. [237]
Carotid web is an important, often underrecognized cause of recurrent ipsilateral ischemia. A retrospective series evaluated 48 patients diagnosed by digital-subtraction angiography, describing clinical characteristics, imaging findings, treatment strategies, and follow-up ischemic events. In younger or otherwise cryptogenic patients, careful review of the carotid bulb and consideration of recurrent-event risk may be warranted; management remains individualized because the cited study is observational and does not establish a preferred intervention. [215]
For patients with newly diagnosed atrial fibrillation, a nationwide Taiwanese cohort examined regular sodium-glucose cotransporter-2 inhibitor use versus nonuse after propensity matching, with a composite outcome of ischemic stroke, hemorrhagic stroke, or TIA and secondary outcomes of mortality and major adverse cardiovascular events. These findings are relevant to longitudinal cardiovascular risk management but do not replace anticoagulation when indicated and do not establish SGLT2 inhibitors as acute stroke therapy. [253]
Intracranial atherosclerosis and inflammatory or endothelial phenotypes
In stroke associated with intracranial atherosclerotic stenosis (ICAS), a prospective study of 942 patients defined ICAS as ≥50% stenosis or occlusion and examined 1-year major adverse cardiovascular events in relation to IL-6 and high-sensitivity CRP, using cutoffs of IL-6 ≥4.2 pg/mL and hsCRP ≥2.0 mg/L. These biomarkers may help characterize residual vascular risk, but they are prognostic measures rather than validated substitutes for vascular imaging or guideline-based secondary prevention. [236]
Peripheral endothelial dysfunction, measured by EndoPAT reactive hyperemia index, was studied in 357 patients with valid measurements; low endothelial function was defined as RHI ≤1.67 and analyzed against early neurologic deterioration, 3-month events, and functional outcomes. This remains a risk-stratification research tool rather than a routine treatment-selection test. [251]
Post-stroke bone, immune, and neurologic complications
Stroke and TIA are associated with unfavorable bone structural and biochemical changes, and post-stroke fractures increase mortality and reduce quality of life. The Post-stroke Osteopathy study used high-resolution peripheral quantitative CT and bone biomarkers to characterize this phenotype, supporting early attention to falls, mobility, nutrition, osteoporosis risk, and fracture prevention during rehabilitation. [243]
Early post-EVT immune profiles may have prognostic value. In successfully reperfused anterior-circulation LVO, lymphocyte-subset associations with 90-day outcome were stratified by WBC count, with normal WBC defined as 4.0–10.0 ×10⁹/L and elevated WBC as >10.0 ×10⁹/L. These retrospective findings should not be used alone to guide immunomodulatory treatment. [245]C Systemic inflammatory markers were also examined in relation to early EEG slow-wave activity and epileptiform discharges in 307 patients monitored within 72 hours, supporting integrated surveillance when reduced consciousness, fluctuating deficits, or suspected seizures occur. [246]
Blood-based brain-derived tau was measured daily during the first week and at 3 months, with infarct volume assessed by MRI at 48–72 hours, to define temporal biomarker behavior and its relationship to tissue injury. [217]C Post-EVT blood–brain barrier disruption, assessed by HARM or ocular gadolinium leakage, was studied as a potential marker of reperfusion injury and poor radiologic or clinical outcome. [218] Immediate post-EVT CT-based Co-ASPECTS, integrating hyperdensity and hypodensity, was developed and externally validated for lesion assessment and outcome prediction, while flat-panel CT distal-occlusion-tracker signs were evaluated against final infarct volume. These tools may refine prognostication but do not replace standard clinical, angiographic, and follow-up imaging assessment. [244][248]C
| Population or issue | Evidence-based consideration |
|---|---|
| Dementia | Compare EVT with medical management using patient-centered outcomes and goals of care. [252] |
| Prestroke mRS 3–4 | Judge outcome relative to baseline disability; assess mortality, sICH, and recanalization. [220] |
| EVT >24 h | Consider only with favorable clinical and imaging selection; evidence is observational. [242] |
| Cancer | Account for hypercoagulability, bleeding risk, prognosis, and treatment interactions. [237] |
| Carotid web | Consider as a mechanism in recurrent or cryptogenic ipsilateral ischemia. [215] |
| ICAS | Use vascular imaging and guideline-based prevention; IL-6 and hsCRP are prognostic, not definitive treatment tests. [236] |
| Post-stroke bone loss | Incorporate fall, fracture, mobility, nutrition, and osteoporosis prevention. [243] |
Guidelines and Resources
- ▸The ESO PFO guideline addresses diagnosis, treatment, and long-term management after ischaemic stroke; proposed mechanisms include paradoxical embolism, thrombus formation within the PFO, and atrial arrhythmias. [112]
- ▸TIA was not the primary index event in the PFO guideline because only one randomised controlled trial included TIA patients, although the available subgroup analysis found no significant outcome difference between TIA and stroke. [112]
- ▸The updated ESO BP guideline advises against routine pre-hospital BP lowering in suspected stroke on the basis of moderate-certainty evidence. [211]
- ▸Lacunar stroke represents approximately one quarter of ischaemic strokes and requires consideration of acute treatment, progressive lacunar stroke, thrombolysis, antiplatelet therapy, and secondary prevention. [113]
Scope and use
The following resources update selected aspects of acute ischaemic stroke (AIS) diagnosis, acute management, blood-pressure management, and secondary prevention. They address three clinically distinct populations: patients with AIS and a patent foramen ovale (PFO), patients with AIS requiring blood-pressure decisions—including those considered for reperfusion therapy—and patients with lacunar ischaemic stroke related to cerebral small-vessel disease. [112][211][113]
These documents were developed under European Stroke Organisation (ESO) procedures and use evidence-based methods. The PFO guideline identified clinical questions and outcomes, graded the evidence, and formulated recommendations for diagnosis, treatment, and long-term management. [112] The lacunar-stroke guideline used ESO standard operating procedures and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. [113] The 2025 update on blood pressure used literature searches, systematic reviews, meta-analyses of relevant randomised controlled trials, evidence-quality assessment, and GRADE-based recommendation development across 8 key clinical questions. [211]
Patent foramen ovale after ischaemic stroke
PFO is frequently identified in younger patients with cryptogenic ischaemic stroke. [112] The guideline recognises several possible mechanisms by which PFO may be associated with stroke: paradoxical embolism, in which a venous thrombus crosses the PFO; thrombus formation within the PFO itself; and atrial arrhythmias potentially resulting from disruption of electrical signalling. [112]
The ESO PFO guideline is intended to support diagnosis, treatment, and long-term management after ischaemic stroke when PFO is identified. [112] Its index-event scope is important: transient ischaemic attack (TIA) was not considered an index event because only one randomised controlled trial included patients with TIA. [112] In the available subgroup analysis, outcomes did not differ significantly between participants with TIA and those with stroke. [112] Accordingly, evidence and recommendations from this guideline should be interpreted primarily in the context of ischaemic stroke rather than extrapolated automatically to TIA. [112]
Blood pressure in acute stroke
The updated ESO blood-pressure guideline addresses both AIS and acute intracerebral haemorrhage (ICH), reflecting continuing uncertainty about optimal acute BP management. [211] For suspected stroke in the pre-hospital setting, it advises against routine BP lowering, supported by moderate-certainty evidence. [211] This recommendation is relevant before stroke subtype and treatment eligibility have been established. [211]
For patients with AIS undergoing reperfusion therapy, the update provides a specific recommendation concerning BP management. [211] The supplied evidence summary does not state the numerical BP target or the complete wording of that recommendation; therefore, a treatment threshold should not be inferred from this summary alone. [211] The full guideline should be consulted when a precise BP target, timing, or treatment pathway is required. [211]
Lacunar ischaemic stroke and cerebral small-vessel disease
Lacunar stroke accounts for approximately one quarter of ischaemic strokes and is typically neurologically mild at presentation. [113] It usually results from intrinsic cerebral small-vessel pathology, and its risk-factor profile and outcome rates differ from those of other ischaemic-stroke subtypes. [113]
The ESO guideline on lacunar ischaemic stroke provides evidence-based recommendations for clinical decisions intended to prevent adverse outcomes. [113] Its scope includes acute treatment and secondary prevention, with specific consideration of thrombolysis, antiplatelet drugs, and progressive lacunar stroke. [113] The guideline therefore supports integrating stroke mechanism and clinical evolution into management rather than treating all AIS phenotypes as clinically interchangeable. [113]
Practical integration
When a patient with AIS has a PFO, clinicians should evaluate the finding within the guideline’s post-stroke framework and consider the proposed mechanisms rather than assuming that the PFO is necessarily causal. [112] When managing BP in suspected stroke, routine pre-hospital lowering is not advised by the updated ESO guidance; subsequent decisions should account for stroke type and whether reperfusion therapy is being pursued. [211] When the presentation is compatible with lacunar stroke, acute treatment—including thrombolysis where applicable—and secondary prevention should be considered using the lacunar-stroke evidence base, with attention to progressive neurological worsening. [113]
These guidelines address complementary questions rather than providing a single universal AIS algorithm. [112][211][113] The PFO document focuses on diagnosis and longitudinal management after stroke, the BP update focuses on acute haemodynamic management in AIS and ICH, and the lacunar guideline focuses on aetiology-specific acute care and prevention. [112][211][113] Numerical treatment thresholds or recommendations not stated in the cited summaries should be verified in the full publications before implementation. [211]
References
[112] Caso V, Turc G, Abdul-Rahim AH et al. European Stroke Organisation (ESO) Guidelines on the diagnosis and management of patent foramen ovale (PFO) after stroke. European Stroke Journal. 2024. PMID: 38752755. [112]
[211] Sandset EC, Palaiodimou L, Jahr SH et al. 2025 update to European Stroke Organisation (ESO) guideline on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage. European Stroke Journal. 2026. PMID: 42095756. [211]
[113] Wardlaw JM, Chabriat H, de Leeuw FE et al. European Stroke Organisation (ESO) guideline on cerebral small vessel disease, part 2: lacunar ischaemic stroke. European Stroke Journal. 2024. PMID: 38380638. [113]
| Resource | Main population or question | Key evidence-based scope |
|---|---|---|
| PFO guideline [112] | Ischaemic stroke with PFO | Diagnosis, treatment, and long-term management; mechanisms include paradoxical embolism, PFO thrombus, and atrial arrhythmias. [112] |
| BP update [211] | AIS and acute ICH | BP management across 8 clinical questions; routine pre-hospital BP lowering in suspected stroke is advised against. [211] |
| Lacunar-stroke guideline [113] | Lacunar ischaemic stroke | Acute treatment, progressive lacunar stroke, thrombolysis, antiplatelet drugs, and secondary prevention. [113] |
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