Acute Ischemic Stroke

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 magnetic resonance imaging (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 Transient Ischemic Attack (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 hypertension 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.

Specialized Classifications and Variants

Beyond the standard TOAST criteria, clinicians use specialized systems to guide management 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:

1. Proximal Segment: Involving the vertebral arteries up to the posterior inferior cerebellar artery (PICA).
2. Middle Segment: Involving the basilar artery up to the superior cerebellar artery (SCA).
3. 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].

Epidemiologic context

The supplied evidence does not provide a single contemporary population-wide incidence or prevalence estimate for acute ischemic stroke (AIS); instead, it characterizes risk across distinct clinical populations, including older adults with diabetes, patients with atrial fibrillation (AF), individuals with left ventricular (LV) systolic dysfunction, patients with transient ischemic attack (TIA), and people with established ischemic stroke. ^{[187] [193]} Ischemic stroke risk is also heterogeneous according to vascular, metabolic, inflammatory, hematologic, cardiac, socioeconomic, and geriatric factors. ^{[120] [127] [190] [193] [200]C}

Established vascular and metabolic risk factors

Hypertension and abnormalities of glucose metabolism remain clinically important risk markers. In a population-based study of patients with TIA or minor ischemic stroke, cerebral arterial pulsatility and small-vessel disease were evaluated in relation to current and premorbid blood pressure, with particular attention to confounding by heart rate, pulse pressure, and prior blood pressure exposure. ^[120] This supports the relevance of cumulative hemodynamic burden when considering small-vessel ischemic disease, although the study was not designed to establish a new population incidence estimate. ^[120]

Diabetes is an important high-risk context: a retrospective cohort specifically examined first-ever ischemic stroke among adults with diabetes aged ≥60 years who were free of previous stroke. ^[197] Glycemic dysregulation is also relevant after stroke; stress hyperglycemia, quantified using the glucose-to-glycated hemoglobin ratio within 24 hours, was investigated in patients with minor ischemic stroke, and hemorrhagic transformation was assessed as a potential mediator of worse functional outcome. ^[122] In patients with first-ever ischemic stroke, the LDL-cholesterol/HDL-cholesterol ratio was studied in relation to carotid artery plaque across different glucose-metabolic conditions, with HbA1c and fasting plasma glucose examined as potentially relevant factors. ^[190]

Inflammatory and lipid-related phenotypes may identify additional risk heterogeneity. A large retrospective AIS cohort of 20,538 middle-aged and older adults used age, NIH Stroke Scale score, triglycerides, LDL cholesterol, HDL cholesterol, HbA1c, and C-reactive protein to derive immune-metabolic subtypes associated with post-stroke epilepsy susceptibility. ^[200]C These findings concern complications and biological heterogeneity after AIS rather than proof that any single cluster causes incident stroke. ^[200]C Among patients who already had ischemic stroke, higher lipoprotein-associated phospholipase A2 levels were evaluated as a marker of recurrent cerebrovascular events, mainly recurrent ischemic stroke or cerebral infarction. ^[186]

Cardiac and embolic risk factors

AF is a major embolic-risk phenotype represented in several studies. The AVANT-GARDE prospective multicenter trial evaluated adhesive single-lead ECG against 24-hour Holter monitoring in embolic stroke of undetermined source (ESUS); the primary ESUS cohort underwent baseline monitoring and repeat patch monitoring at 6 months, reflecting the importance of detecting intermittent AF after apparently cryptogenic stroke. ^[121] AF-associated stroke also appears concentrated in older populations: a prospective cohort enrolled patients aged ≥65 years with ECG-confirmed AF and imaging-confirmed AIS to assess vitamin D status and subsequent functional, depressive, and fall outcomes. ^[188]

LV systolic dysfunction, defined in the cited American Heart Association statement as LV ejection fraction ≤40% or a left-wall-motion abnormality, is commonly found in patients with ischemic stroke. ^[187] Even without a detected intracardiac thrombus, LV dysfunction is associated with increased concern for incident and recurrent embolic stroke, although evidence supporting routine anticoagulation in this setting is limited. ^[187] In AF patients with previous intracranial hemorrhage, the balance between preventing ischemic stroke and avoiding recurrent intracranial hemorrhage is particularly difficult; a systematic review compared direct oral anticoagulants with vitamin K antagonists for ischemic stroke, recurrent intracranial hemorrhage, and mortality. ^[185]

TIA, recurrence, and social determinants

TIA is a clinically important warning state because subsequent ischemic stroke risk is greatest during the first days to weeks after the event. ^[193] A national All of Us cohort followed adults with TIA for 30 days to evaluate subsequent ischemic stroke in relation to race, sex, age, income, insurance status, smoking, hypertension, diabetes, and AF, highlighting the combined contribution of clinical and socioeconomic factors to very early stroke progression. ^[193]

Age, frailty, and functional vulnerability

Advanced age increases the clinical complexity of AIS risk and recovery. Studies specifically examined older adults with diabetes, older adults with AF-associated stroke, and frailty among patients with ischemic stroke. ^{[197] [188] [189]} Frailty was categorized as robust, prefrail, or frail using a deficit-accumulation frailty index in a multicenter China National Stroke Registry III cohort assessing 1-year functional outcome and recurrence. ^[189] Frailty therefore represents an important vulnerability marker for long-term prognosis, although it should not be interpreted as an independent cause of stroke without adjustment for coexisting disease. ^[189]

Other potentially relevant factors

A bidirectional Mendelian-randomization analysis and meta-analysis found evidence for an association between genetically higher protein C levels and lower ischemic stroke risk, with an odds ratio of 0.918 per standard-deviation increase; comparable causal evidence was not established for protein S or antithrombin in the cited abstract. ^[127] Seasonal influenza vaccination was examined in a population-based cohort of 131,045 adults with diabetes aged ≥60 years who were free of prior ischemic stroke; vaccination exposure was receipt of the 2021/2022 inactivated influenza vaccine, and first-ever ischemic stroke was the primary outcome. ^[197] This is an observational association and does not establish that vaccination independently prevents stroke.

Post-stroke hemorrhagic transformation and subdural hematoma are important competing complications when assessing risk. ^{[122] [192]} In a nationwide Korean cohort of adults with incident ischemic stroke followed from 2010–2023, traumatic and non-traumatic subdural hematoma were modeled with competing-risk methods, reflecting the influence of aging, multimorbidity, and long-term antithrombotic exposure. ^[192] Intravenous thrombolysis and endovascular treatment populations represent selected, high-acuity subgroups; contemporary studies evaluated extended-window thrombolysis selected with perfusion imaging, adjunctive tirofiban during thrombectomy for large-vessel occlusion, and radiologic intracranial-hemorrhage subtypes after anterior-circulation treatment. ^{[182] [183] [184] [114]} These treatment-focused cohorts should not be generalized to the epidemiology of all AIS.

Practical synthesis

Risk assessment should integrate age, prior TIA or stroke, hypertension, diabetes and glycemic control, atherogenic lipid patterns, smoking and socioeconomic context, AF or other cardiac dysfunction, frailty, and potentially inflammatory or hematologic markers. ^{[120] [127] [186] [188] [189] [190] [193] [197] [200]C} The available evidence also emphasizes that incident stroke risk, early post-TIA stroke risk, recurrent stroke risk, treatment-related hemorrhage, and long-term disability are distinct outcomes and should not be conflated. ^{[122] [182] [185] [186] [187] [192] [193]}

Overview

Acute ischemic stroke (AIS) results from abrupt arterial occlusion that deprives brain tissue of oxygen and glucose. The supplied evidence supports several clinically important etiologic pathways: cardioembolism, large-artery atherosclerosis, small-vessel disease, paradoxical embolism, thrombophilia, systemic or cancer-associated hypercoagulability, and stroke occurring despite antithrombotic therapy. Etiologic classification should remain mechanism-based because more than one vascular or cardiac risk factor may coexist in the same patient. ^{[120][127][191]}

Cardioembolism and atrial fibrillation

Atrial fibrillation (AF) is a major embolic mechanism, and clinically relevant AF may be newly detected after an apparently cryptogenic or embolic stroke. In the AVANT-GARDE prospective multicenter study, AF was identified at baseline in 13.3% of acute ischemic stroke patients monitored with a 72-hour adhesive single-lead patch and 24-hour Holter monitoring; detection was associated with larger left atrial size. ^[121] In a separate cohort of cryptogenic-stroke patients undergoing insertable cardiac monitoring, AF detection was specifically investigated over as long as 36 months, demonstrating the importance of prolonged rhythm surveillance when an embolic source is not initially established. ^[194] Patients with patent foramen ovale (PFO) had lower AF detection in that study, suggesting that PFO-associated paradoxical embolism and occult AF may represent competing explanations rather than interchangeable findings. ^[194]

AF-related embolism can occur despite oral anticoagulation (OAC). The ASPERA-R study defined ongoing treatment as a direct OAC dose within 48 hours or a therapeutic vitamin K antagonist INR and examined breakthrough stroke mechanisms, including interacting medications, active cancer, and competing stroke etiologies. ^[191] Thus, a stroke during OAC should not automatically be attributed to anticoagulant failure; nonadherence, pharmacologic interactions, malignancy, or a separate arterial mechanism may be involved. ^[191] AF burden also varies substantially during early hospitalization: continuous telemetry in patients with AF-related stroke categorized peak 24-hour burden as low (≤1 hour), medium (>1–6 hours), or high (>6 hours), supporting AF burden as a potentially relevant marker of embolic exposure. ^[195]

Left ventricular systolic dysfunction is another potential cardioembolic substrate. The American Heart Association defines clinically relevant dysfunction in this context as left ventricular ejection fraction ≤40% or a left-ventricular wall-motion abnormality. Embolic risk is increased even when no intracardiac thrombus is detected, although evidence supporting routine anticoagulation in the absence of thrombus remains limited. ^[187]

Atherosclerotic and small-vessel mechanisms

Atherosclerotic disease can generate stroke through plaque rupture, in situ thrombosis, artery-to-artery embolism, or progressive arterial stenosis. In a retrospective cohort of 12,166 patients with first-ever ischemic stroke, the LDL-C/HDL-C ratio was evaluated in relation to carotid plaque across different glucose-metabolic states, supporting the interaction between lipid imbalance, dysglycemia, and carotid atherosclerotic burden. ^[190] Elevated lipoprotein-associated phospholipase A2 was also investigated as a marker associated with recurrent cerebrovascular events after ischemic stroke, although this evidence concerns recurrence risk rather than proof of a direct initiating mechanism. ^[186]

Small-vessel disease (SVD) is associated with chronic vascular injury rather than a single acute trigger. A population-based study of patients with TIA or minor ischemic stroke examined cerebral arterial pulsatility, premorbid blood pressure, and imaging-defined SVD; the study specifically addressed whether pulsatility remained independently associated after accounting for blood pressure and other vascular confounders. ^[120] These findings support considering long-standing hemodynamic stress and hypertension-related vascular remodeling when evaluating lacunar or small-vessel stroke, while avoiding attribution to pulsatility alone. ^[120]

Thrombosis, hypercoagulability, and paradoxical embolism

Inherited or acquired abnormalities of coagulation may promote arterial thrombosis. Bidirectional Mendelian-randomization and meta-analytic evidence found an association between genetically higher protein C and lower ischemic-stroke risk, whereas comparable causal evidence was not established for protein S or antithrombin. The reported odds ratio for ischemic stroke per standard-deviation increase in protein C was 0.918 (95% CI, 0.884–0.954). ^[127] This supports protein-C biology as a plausible thrombotic pathway but does not justify diagnosing a coagulation disorder from stroke alone. ^[127]

Active cancer was identified as a potential explanation for breakthrough ischemic stroke during OAC, indicating that cancer-associated hypercoagulability may compete with AF as the dominant mechanism. ^[191] PFO is another potential pathway: venous thrombus can cross an intracardiac shunt and cause paradoxical embolism, particularly when no other cause is found; however, the supplied PFO study primarily demonstrated differences in subsequent AF detection rather than proving causality for individual infarcts. ^[194]

Preceding ischemia and acute physiological triggers

A TIA may precede completed ischemic stroke, with risk concentrated in the first days to weeks. A national cohort study evaluated 30-day progression from TIA to ischemic stroke and included age, sex, socioeconomic variables, smoking, hypertension, diabetes, and AF as candidate risk factors. ^[193] A recent ischemic event therefore represents both a warning syndrome and a period of heightened short-term vulnerability. ^[193]

Acute metabolic stress may worsen tissue injury after vessel occlusion. In minor stroke without large-vessel occlusion, stress hyperglycemia measured within 24 hours using the glucose-to-glycated-hemoglobin ratio was studied as a determinant of hemorrhagic transformation and functional outcome; the analysis evaluated hemorrhagic transformation within 7 days as a mediating pathway. ^[122] This evidence concerns early complication and outcome rather than the primary cause of arterial occlusion, but it identifies hyperglycemia as an important acute aggravating factor. ^[122]

Treatment-related and procedure-associated considerations

The indication for reperfusion treatment does not define stroke etiology. Evidence from randomized trials and meta-analysis supports intravenous thrombolysis in selected patients presenting in an extended time window using perfusion imaging, predominantly CT perfusion, but this addresses treatment eligibility rather than the initiating cause. ^[182] Similarly, tirofiban studies concern adjunctive therapy during endovascular thrombectomy for large-vessel occlusion and the risk or classification of post-treatment intracranial hemorrhage, not the cause of the original ischemic event. ^[114][184]

Long-term antithrombotic exposure may introduce additional hemorrhagic complications after stroke. A nationwide competing-risk model examined traumatic and non-traumatic subdural hematoma among ischemic-stroke survivors and considered aging, multimorbidity, and antithrombotic exposure as contributors. ^[192] These factors are consequences or modifiers of stroke management rather than primary ischemic etiologies. Finally, low vitamin D status, frailty, and their associations with depression, falls, disability, or one-year prognosis should be treated as prognostic or recovery-related factors, not established causes of the index ischemic stroke. ^{[188][189][196]}

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 head 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.

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].

Core diagnostic principle

Acute focal neurological symptoms should be treated as possible acute ischemic stroke (AIS) until intracranial hemorrhage and important mimics have been assessed. Clinical presentation alone cannot reliably distinguish ischemic from hemorrhagic stroke; definitive discrimination depends on brain neuroimaging. ^[66] Sudden unilateral weakness, facial asymmetry, speech disturbance, visual loss, neglect, ataxia, or cortical sensory deficits increase suspicion for stroke but do not establish infarction or exclude hemorrhage. ^[66] Headache, vomiting, altered consciousness, seizure, and severe neurological deficit may occur more often in hemorrhage, but their individual diagnostic performance is insufficient to replace imaging. ^[66]

Immediate mimics and metabolic confounders

The initial differential includes hypoglycemia or marked hyperglycemia, seizure with postictal deficit, migraine with aura, functional neurological disorder, toxic or metabolic encephalopathy, syncope, vestibular disorders, infection, tumor, demyelination, and peripheral disorders. A bedside glucose measurement is essential because glucose abnormalities can produce focal or global neurological dysfunction and may coexist with true AIS; admission hyperglycemia is common in AIS and has been associated with worse discharge outcomes, although it is not itself diagnostic of stroke. ^[204] Prehospital consensus guidance specifically identifies evaluation for stroke mimics as part of acute AIS assessment. ^[201]

Functional stroke mimics are particularly important when examination findings are inconsistent, fluctuate, or are incompatible with a vascular territory. In a comparative cohort, patients with functional stroke-like episodes were substantially younger than AIS patients and had higher rates of psychiatric disorders; these features may raise suspicion but cannot independently exclude ischemia. ^[205] A Brazilian telestroke study evaluated the Telestroke Mimic Score for distinguishing ischemic cerebrovascular disease from mimics, but its retrospective regional validation means that clinical scores should complement, rather than replace, imaging and expert assessment. ^[210]

Seizure-related deficits may resemble AIS, especially when witnessed convulsions are absent or when aphasia or weakness persists after the event. Acute aphasia also occurs in stroke mimics; a retrospective study evaluated CT perfusion (CTP) for differentiating stroke-related from mimic-related aphasia, supporting CTP as an adjunct whose interpretation must remain integrated with clinical examination and structural imaging. ^[208] MRI-negative ischemia is another source of diagnostic uncertainty: among patients treated with intravenous thrombolysis for suspected AIS, subsequent classification may include diffusion-positive infarction, MRI-negative ischemia, or a stroke mimic. ^[160]

Hemorrhage and vascular emergencies

Noncontrast CT (NCCT) is central to excluding intracerebral hemorrhage (ICH) before reperfusion treatment. ^[66] A prehospital point-of-care glial fibrillary acidic protein (GFAP) study investigated rapid differentiation of ICH from ischemic stroke and mimics within 6 hours of symptom onset; GFAP may support triage, but it is an investigational adjunct rather than a substitute for brain imaging. ^[203]C Blood-based biomarkers remain complementary: a systematic review of early fluid biomarkers evaluated AIS against controls and mimics, while a separate meta-analysis assessed blood MMP-9 within 24 hours of onset for this purpose. ^[64][65]

CTA is used to identify large-vessel occlusion (LVO), dissection, aneurysmal disease, and other vascular causes of acute deficit. Several clinical severity scales are available for prehospital LVO detection; the DAFNES scale was newly developed with preliminary internal hospital validation, so it should not be regarded as a definitive diagnostic test. ^[148]C Extended CTA imaging below the carina was evaluated against standard head-and-neck CTA for detection of cardioaortic thrombi in ischemic stroke or transient ischemic attack, addressing etiology rather than the initial distinction between stroke and mimic. ^[68] Cardiac CT similarly has an emerging role in detecting thrombi during acute AIS evaluation, but studies excluded stroke mimics and therefore do not establish cardiac CT as a mimic-exclusion test. ^[202]

Imaging strategy and treatment uncertainty

For patients otherwise eligible for thrombolysis within 4.5 hours, the PRACTISE randomized trial compared NCCT alone with NCCT plus CTA and CTP. Additional multimodal imaging was studied because it may identify occlusion, salvageable tissue, or mimics, but it can delay treatment; therefore, imaging should be selected according to onset time, clinical severity, treatment eligibility, and local workflow. ^[40] A normal early CT does not exclude AIS, and persistent diagnostic uncertainty may require MRI with diffusion-weighted imaging or repeat imaging. ^[66][160]

Stroke mimics may occasionally receive thrombolytic therapy before the final diagnosis is known. A retrospective cohort specifically compared tenecteplase safety in stroke mimics and confirmed AIS, reflecting the reality that emergency treatment decisions are often made before definitive confirmation. ^[69] This evidence supports rapid assessment and careful risk-benefit reasoning rather than withholding time-sensitive therapy solely because a mimic is possible. ^[69][201]

Special populations and post-treatment findings

In young adults, arterial dissection, inflammatory arteriopathy, vasculitis, moyamoya disease, and other vessel-wall disorders should be considered; high-resolution vessel-wall MRI has been studied in young patients with stroke, TIA, and mimics. ^[209] In children, focal cerebral arteriopathy-inflammatory type and unilateral moyamoya disease may appear similar, and a focal cerebral arteriopathy severity score with temporal imaging patterns has been evaluated to aid distinction. ^[206]

After thrombectomy, new CT hyperdensities may represent hemorrhagic transformation, contrast extravasation, or both. These entities cannot be reliably assumed from a single postprocedural NCCT; follow-up CT at 24–72 hours was used in a validation study as the reference classification, while machine-learning models were investigated as an adjunct. ^[207] Glibenclamide studies addressed cerebral edema and functional outcomes in ischemic and hemorrhagic stroke, not primary diagnostic discrimination, and therefore do not justify using the drug as a diagnostic test. ^[63][67]

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].

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].

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].

Secondary prevention is the cornerstone of long-term management 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 atrial fibrillation ), and small-vessel disease.

Antiplatelet Strategies for Non- Cardioembolic Stroke

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

1. Step 1: Risk Assessment. Identify high-risk TIA (ABCD2 ≥4) or minor stroke (NIHSS ≤3). Confirm absence of contraindications (e.g., active hemorrhage).
2. 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].
3. 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 cryptogenic stroke 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].

Older adults, frailty, and prestroke disability

Older adults with acute ischemic stroke frequently have dysphagia, aspiration risk, feeding intolerance, disability, depression, and falls, making treatment goals and outcome interpretation particularly important ^{[216][188][189][220]}. In a single-center randomized trial of older patients with dysphagia requiring post-pyloric nasoenteric feeding, a staged enteral-nutrition nursing pathway based on dynamic assessment of feeding tolerance and aspiration risk was compared with usual care; the primary outcome was 7-day feeding intolerance, with nutritional delivery also assessed ^[216]. The study directly addresses practical nutritional management rather than reperfusion efficacy ^[216].

Frailty should be incorporated into prognostic discussions rather than used alone to deny acute treatment. A multicenter cohort from the China National Stroke Registry III classified patients as robust, prefrail, or frail using a deficit-accumulation frailty index and evaluated 1-year excellent functional outcome, favorable functional outcome, and stroke recurrence ^[189]. Because prestroke disability can similarly influence apparent treatment benefit, the EVA-TRISP cohort compared patients with prestroke modified Rankin Scale (mRS) 3–4 with those with mRS 0–2 who underwent endovascular therapy (EVT); outcomes included disability relative to prestroke status, 3-month mortality, symptomatic intracranial hemorrhage, and unsuccessful recanalization ^[220]. These observational data support individualized selection and outcome assessment, but they do not replace randomized evidence ^[189][220].

Atrial fibrillation, anticoagulation, and nutritional risk

In older adults aged ≥65 years with atrial-fibrillation-associated ischemic stroke, low serum 25-hydroxyvitamin D measured within 48 hours was evaluated in relation to 3-month mRS shift, Barthel Index, clinically significant depressive symptoms, and falls through 12 months, with death treated as a competing event for time-to-fall analyses ^[188]. The cohort modeled vitamin D both per 10-ng/mL decrement and as <20 versus ≥20 ng/mL; these associations are prognostic and should not be interpreted as evidence that vitamin D replacement improves stroke recovery ^[188].

Breakthrough ischemic stroke may occur despite apparently ongoing oral anticoagulation for atrial fibrillation. The ASPERA-R retrospective study defined ongoing treatment as a direct oral anticoagulant taken within 48 hours or a therapeutic vitamin-K-antagonist INR, and investigated interacting drugs, active cancer, and competing stroke etiologies, together with 90-day outcomes ^[191]. These findings emphasize verification of adherence, dosing, interactions, renal or hepatic considerations, and alternative mechanisms before changing antithrombotic therapy ^[191].

Large-core infarction, hemorrhagic risk, and adjunctive agents

Patients with large ischemic cores undergoing EVT have substantial risk of parenchymal hematoma. In a retrospective cohort of 133 patients with large-core anterior-circulation infarction treated with EVT, parenchymal hematoma occurred in 26 patients (19.5%); predictors were selected using LASSO and multivariable logistic regression, and a nomogram was internally validated with 1,000-bootstrap resampling, including stratification by age, baseline ASPECTS, and prior intravenous thrombolysis ^[222]. This model requires external validation before routine clinical adoption ^[222].

In thrombolyzed patients, propensity-score-matched data from 1,541 participants compared alteplase plus dl-3-N-butylphthalide with alteplase alone for hemorrhagic transformation, reflecting the proposed effects of dl-3-N-butylphthalide on microcirculation, oxidative stress, and blood-brain barrier integrity ^[198]. As a nonrandomized analysis, the association should not be treated as proof of a preventive indication ^[198]. In the RESCUE BT randomized trial, intravenous tirofiban administered before EVT was compared with placebo in anterior-circulation large-vessel occlusion, with hemorrhage classified as HI-1, HI-2, PH-1, PH-2, or extra-parenchymal hemorrhage using the Heidelberg classification ^[184].

Blood pressure and anesthesia-related individualization

The DETERMINE randomized clinical trial enrolled adults with anterior large-vessel occlusion undergoing MT at 8 French comprehensive stroke centers between March 10, 2021, and September 18, 2023, comparing individualized BP control with standard BP control and assessing 90-day functional outcome ^[212]. The trial addresses whether a one-size-fits-all strategy aimed at preventing hypertension should be replaced by patient-specific intra-procedural targets; its results should inform, rather than eliminate, individualized hemodynamic management ^[212].

Posterior circulation and less common vascular mechanisms

Posterior-circulation stroke remains underrepresented in many reperfusion studies. The EXPAND subgroup included patients with vertebrobasilar occlusion or stenosis of ≥50% and compared edaravone dexborneol, 37.5 mg twice daily for 14 days, with no edaravone dexborneol treatment; the study evaluated clinical effectiveness in this subgroup ^[214]. Edaravone dexborneol has antioxidant and anti-inflammatory properties, but the available evidence is subgroup-specific and should not be generalized automatically to all posterior-circulation stroke ^[214].

Carotid web is an uncommon potential embolic source. A retrospective DSA-based series of 48 patients described clinical characteristics, imaging findings, association with ischemic stroke, treatment strategies, and follow-up outcomes, including stroke, transient ischemic attack, and recurrent ipsilateral ischemic events ^[215]. Management should therefore be individualized according to recurrent-event risk, anatomy, and competing etiologies ^[215].

Prehospital, imaging, and systems considerations

A secondary analysis of the FAST-MAG randomized trial examined 401 patients who received post-arrival thrombolysis: 214 had received prehospital magnesium sulfate and 187 placebo. Participants had presented within 2 hours of last-known-well time, and 90-day disability was assessed by mRS ^[213]. This evidence evaluates a bridging neuroprotective strategy, not replacement of timely reperfusion therapy ^[213].

AI-assisted NCCT and CTA interpretation was prospectively evaluated in two tele-stroke centers referring patients to one comprehensive center. In the CATalyze-AI quasi-experimental cohort, remote vascular neurologists retained clinical oversight while the software supported LVO detection and transfer decisions ^[219]. The DAFNES scale was developed for telephone-based LVO recognition in a prospective cohort of 593 suspected-stroke presentations; after excluding mimics and intracerebral hemorrhage, 408 patients were analyzed for preliminary internal validation ^[148]C. These tools may support triage, but local validation and specialist confirmation remain necessary ^[148]C[219].

Additional emerging markers may help personalize care but are not yet routine standards. Plasma brain-derived tau was measured daily during the first week and again at 3 months, with MRI infarct volume assessed at 48–72 hours, to define its temporal profile and relationship to brain injury ^[217]C. Post-thrombectomy HARM on post-contrast FLAIR and ocular gadolinium leakage were retrospectively studied as markers of blood-brain barrier disruption, reperfusion injury, infarct progression, and poor outcome ^[218]. Diffusion reversal after successful reperfusion was investigated using baseline DSC-MRI-derived oxygen extraction fraction in anterior-circulation LVO treated to mTICI ≥2c with follow-up MRI within 48 hours ^[221].

Prevention and long-term complications

Among adults with diabetes aged ≥60 years without prior ischemic stroke, a population-based cohort evaluated whether receipt of the 2021/22 seasonal inactivated influenza vaccine was associated with first-ever ischemic stroke ^[197]. This preventive association should not be extrapolated to secondary prevention without appropriate evidence ^[197]. Lp-PLA2 was examined in a systematic review and meta-analysis of observational studies for recurrent cerebrovascular events, with searches through May 20, 2026 ^[186]. Finally, a Korean nationwide cohort followed incident ischemic-stroke survivors from 2010–2023 for traumatic and nontraumatic subdural hematoma, using competing-risk models to account for mortality; the work addresses individualized long-term antithrombotic stewardship, particularly in older, multimorbid patients ^[192].

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]