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].

Global and Demographic Trends

Acute ischemic stroke (AIS) remains a leading cause of morbidity and mortality worldwide. Recent epidemiological data highlights significant disparities in outcomes based on socioeconomic status (SES) and sex. Analysis of the National Inpatient Sample (2016-2021) indicates that lower SES, measured by ZIP code income quartile, is independently associated with higher stroke mortality, with significant first-order sex-income interactions observed across all stroke subtypes ^[129]. While mechanical thrombectomy (MT) has become the standard of care for large vessel occlusion (LVO), social vulnerability indices have not shown a direct association with 3-month functional outcomes post-procedure, suggesting that clinical factors may outweigh sociodemographic variables in the recovery phase following advanced intervention ^[124]. In very elderly populations (≥80 years), prospective multicenter data from low- and middle-income countries confirm that endovascular thrombectomy (EVT) is safe and effective, though functional independence rates may differ from younger cohorts ^[123].

Vascular and Hemodynamic Risk Factors

Traditional vascular risk factors are being refined by new evidence regarding cerebral hemodynamics and covert disease. Cerebral artery pulsatility is independently associated with small vessel disease (SVD) on brain imaging, even after adjusting for heart rate, pulse pressure, and premorbid blood pressure ^[120]. Furthermore, arterial input function (AIF) dispersal, as measured by computed tomography perfusion (CTP), reflects contrast passage through the cerebral circulation and is significantly associated with a higher burden of SVD, including white matter hyperintensities ^[133].

Covert macrovascular disease (CMVD)—defined as non-culprit macrovascular pathology such as non-stenotic carotid or vertebral plaques (<50%)—is a prevalent but often overlooked form of vascular vulnerability that may influence early outcomes after ischemic events ^[125]. Additionally, stress hyperglycemia (SHG), assessed via the glucose-to-glycated hemoglobin ratio, is associated with worse functional outcomes in minor ischemic stroke (NIHSS ≤5), a relationship mediated by the occurrence of hemorrhagic transformation (HT) within 7 days ^[122].

Cardiac and Genetic Predispositions

Atrial fibrillation (AF) is a critical, often subclinical, driver of embolic stroke of undetermined source (ESUS). Detection rates for AF are significantly higher when using adhesive single-lead patch ECG monitoring compared to standard 24-hour Holter monitoring; in the AVANT-GARDE trial, AF was identified in 13.3% of the cohort at baseline, frequently associated with left atrial enlargement ^[121]. Multiple scoring systems, such as the HAVOC and CHA2DS2-VASc scores, have been externally validated to predict incident AF after cryptogenic stroke, though their predictive accuracy varies ^[131].

Genetic and biochemical markers also provide insight into stroke risk. Bidirectional Mendelian randomization (MR) and meta-analysis have established a causal association between decreased levels of Protein C and increased risk of ischemic stroke, whereas Protein S and antithrombin levels did not show a similar causal link ^[127]. Serum uric acid (SUA) has emerged as a sex-dependent risk marker; while observational studies suggest a U-shaped relationship with post-stroke epilepsy, MR analyses are ongoing to determine if this relationship is truly causal ^[126].

Large Vessel Occlusion (LVO) and Imaging Predictors

LVO strokes represent a particularly severe subset of AIS. Prehospital screening scales are essential for triage, though their diagnostic accuracy for identifying CTA-confirmed LVO varies significantly across different scale-threshold combinations ^[115][132]. Imaging markers such as the fluid-attenuated inversion recovery vascular hyperintensity/diffusion-weighted imaging (FVH/DWI) mismatch have been identified as predictors of successful recanalization (mTICI 2b-3) following mechanical thrombectomy ^[130].

In patients with established large infarcts (large core), secondary analysis of the TENSION trial suggests that EVT remains safe and effective regardless of whether the patient received prior antithrombotic or thrombolytic treatment ^[116]. However, the efficacy of thrombolysis itself may be time-dependent; while tenecteplase and alteplase show similar safety profiles regarding serious adverse events (SAEs), the probability of successful reperfusion in LVO patients treated with thrombolysis may decrease as the time from onset to treatment increases within the 4.5-hour window ^[117][118].

Predictors of Functional Recovery

Beyond the acute vascular event, baseline cognitive status is a powerful predictor of long-term recovery. Admission cognitive function, measured by the Mini-Mental State Examination (MMSE), independently predicts both discharge walking function and overall functional independence following inpatient rehabilitation ^[128]. In patients prone to hemorrhage (those with prior ICH or microbleeds), the cumulative burden of small-vessel disease (cSVD) scores serves as a critical predictor for the specific type of stroke recurrence, distinguishing between future ischemic versus hemorrhagic events ^[119].

Acute ischemic stroke (AIS) is a heterogeneous clinical syndrome resulting from the sudden occlusion of a cerebral artery, leading to focal brain ischemia and subsequent infarction ^[37]D. The etiology of AIS is multifactorial, involving a complex interplay between fixed genetic predispositions, chronic metabolic derangements, and acute triggering events. Identifying the specific mechanism is critical, as secondary prevention strategies must be tailored to the underlying cause to effectively reduce the risk of recurrence ^[37]D.

Cardioembolic Sources

Cardioembolism is a primary driver of AIS, characterized by the formation of a thrombus within the heart that subsequently embolizes to the cerebral circulation.

• Atrial Fibrillation (AF): AF, including non-valvular atrial fibrillation (NVAF), is a major cause of thromboembolic events ^[19]. The mechanism involves blood stasis in the left atrial appendage, leading to thrombus formation. The risk is significantly elevated in patients with concomitant atherosclerotic cardiovascular disease (ASCVD) ^[31]. In patients with AF-associated large vessel occlusion, the thromboembolic burden is particularly high, often requiring mechanical thrombectomy ^[34].
• Mechanical Heart Valves: These devices represent a high-risk source for thromboembolism. The clinical dilemma involves balancing the risk of recurrent ischemic events against the risk of hemorrhagic expansion when resuming anticoagulation like warfarin after an intracranial bleed ^[12].
• Malignancy-Associated Embolism: Cancer patients with AF face a significantly higher thromboembolic burden due to a prothrombotic state and complex interactions between malignancy and cardiac rhythm disturbances ^[36].

Large Artery Atherosclerosis and Stenosis

Atherosclerosis of the extracranial and intracranial arteries leads to stroke via plaque rupture, in situ thrombosis, or artery-to-artery embolism.

• Cerebrovascular Stenosis: Significant narrowing of the internal carotid or intracranial arteries is a major risk factor ^[22]. Extracranial internal carotid artery stenosis often requires revascularization (e.g., carotid artery stenting) to prevent subsequent AIS or TIA ^[35].
• Atherosclerotic Cardiovascular Disease (ASCVD): The presence of systemic atherosclerosis increases the likelihood of cerebral large-vessel disease ^[31].

Metabolic and Lifestyle Triggers

Chronic metabolic conditions and lifestyle choices significantly modify the risk profile for AIS by promoting vascular inflammation and endothelial dysfunction.

• Metabolic Syndrome (MetS): Characterized by obesity, diabetes, hypertension , and dyslipidemia, MetS is strongly associated with an increased risk of ischemic stroke ^[20]. It serves as a potent driver of perioperative ischemic stroke (PIS) in patients undergoing non-cardiac surgery ^[20].
• Cardiovascular Health (Life's Essential 8): Cardiovascular health (CVH) is quantified by the Life's Essential 8 (LE8) score. Low CVH (score < 50) is associated with a significantly higher hazard ratio for incident IS compared to high CVH (score ≥ 80) ^[21].
• Dietary Patterns: Low adherence to healthy dietary patterns, such as the Mediterranean or DASH diets, is prospectively linked to a higher incidence of total and ischemic stroke ^[15].
• Nutritional Status: Malnutrition, assessed via the Controlling Nutritional Status (CONUT) score (incorporating serum albumin, lymphocyte count, and total cholesterol), is a predictor of cerebrovascular stenosis and poor stroke prognosis ^[22].

Genetic Susceptibility and Frailty

• Polygenic Risk Score (PRS): Genetic susceptibility, measured by a GWAS-derived PRS, modifies the risk of IS. High genetic risk (Q5) significantly increases stroke hazard, though high cardiovascular health can partially offset this risk ^[21].
• Frailty: Pre-stroke frailty is common and exerts a disease-modifying effect. It influences survival and disability outcomes and may modify the efficacy of reperfusion therapies like thrombolysis and thrombectomy ^[11].

Acute Triggering Events

• Transient Ischemic Attack (TIA): A TIA is a critical warning sign. High-risk TIAs (e.g., ABCD2 score 6-7 or presence of infarct on imaging) carry a substantial residual risk of ischemic stroke even when treated with dual antiplatelet therapy (DAPT) ^[17].
• Perioperative State: Non-cardiac surgery can trigger AIS, particularly in patients with underlying metabolic syndrome, due to systemic inflammation and hemodynamic fluctuations ^[20].

Protocol for Etiological Workup

To determine the specific etiology and guide secondary prevention, clinicians should follow this diagnostic sequence:

1. Step 1: Vascular Imaging: Perform CTA or MRA to identify extracranial or intracranial stenosis ^[22][35].
2. Step 2: Cardiac Evaluation: Utilize ECG and prolonged monitoring to detect Atrial Fibrillation ^[19][33].
3. Step 3: Metabolic Screening: Assess for Metabolic Syndrome components (HbA1c, lipid profile, BMI) and calculate the LE8 score ^[20][21].
4. Step 4: Nutritional/Systemic Assessment: Calculate the CONUT score and evaluate for underlying malignancy or frailty ^[11][22][36].

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].

The differential diagnosis of acute ischemic stroke (AIS) is broad, encompassing a variety of neurological and systemic conditions known as "stroke mimics." These mimics account for a significant proportion of emergency department presentations, particularly in pediatric populations where nonspecific symptoms and distinct etiologies complicate the clinical picture ^[69][71]D. Rapid and accurate differentiation is critical because the therapeutic window for interventions like thrombolysis is narrow, yet the administration of tenecteplase (0.25 mg/kg, max 25 mg) in stroke mimics has been shown to have a low incidence of intracranial hemorrhage, suggesting a favorable safety profile when the diagnosis is uncertain ^[69].

Differentiating Ischemic from Hemorrhagic Stroke

Clinical assessment alone is insufficient to reliably distinguish between ischemic and hemorrhagic stroke ^[66]. While certain signs like severe headache, vomiting, and a rapid decrease in consciousness are traditionally associated with intracerebral hemorrhage (ICH), a systematic meta-analysis confirms that neuroimaging remains the only valid method for discrimination ^[66][70]D. Non-contrast CT (NCCT) is the initial modality of choice due to its high sensitivity for acute blood, though it may appear normal in the early stages of AIS ^[70]D.

Common Stroke Mimics

Metabolic and Systemic Derangements

Hypoglycemia is the most critical mimic to exclude, as it can present with focal neurological deficits that perfectly replicate an arterial territory syndrome. Blood glucose must be checked in all patients presenting with stroke-like symptoms. Conversely, the use of glibenclamide (a SUR1-TRPM4 inhibitor) in the context of stroke management requires careful monitoring to avoid secondary hypoglycemia, although its primary role is the reduction of cerebral edema ^[63][67].

Seizures and Post-ictal States

Todd's paralysis, a focal neurological deficit following a seizure, is a frequent mimic. The diagnosis is suggested by a witnessed seizure, a post-ictal state, or a known history of epilepsy . However, because a stroke can itself trigger a seizure, imaging is often required to differentiate the two.

Migraine and Functional Disorders

Complicated or hemiplegic migraines can present with focal deficits and aphasia. These are typically distinguished by a prior history of similar episodes and a gradual "march" of symptoms rather than the sudden onset characteristic of AIS. Functional Neurological Disorder (FND) often presents with non-anatomical weakness or sensory loss, but clinicians must remain cautious as FND can coexist with organic pathology.

The Role of Fluid Biomarkers

Emerging evidence suggests that fluid biomarkers may eventually assist in the early differentiation of AIS from mimics ^[64]. Matrix metalloproteinase-9 (MMP-9) has been identified as a promising candidate; meta-analyses show that serum MMP-9 levels are significantly higher in AIS patients within the first 24 hours of symptom onset compared to stroke mimics or healthy controls ^[65]. While not yet standard of care, these biomarkers offer a potential adjunct to clinical and neuroimaging assessments ^[64].

Advanced Neuroimaging for Differentiation

When NCCT is inconclusive, multimodal imaging including CT Angiography (CTA) and CT Perfusion (CTP) can improve diagnostic specificity ^[40][70]D. CTP is particularly useful for identifying the "penumbra" and can help exclude mimics by demonstrating a lack of perfusion deficit in patients with functional or metabolic symptoms ^[40]. Furthermore, extended CTA (extending at least 6 cm below the carina) can identify cardioaortic thrombi, providing evidence for an embolic ischemic source that might otherwise be missed ^[68].

Diagnostic Algorithm for Stroke Mimics

Step 1: Immediate Clinical Stabilization and Glucose Check → Rule out hypoglycemia (Glucose < 60 mg/dL). Step 2: Non-Contrast CT (NCCT) → Rule out intracerebral hemorrhage or large space-occupying lesions (e.g., tumors) ^[70]D. Step 3: CTA and CTP → Identify large vessel occlusion (LVO) and assess tissue perfusion to confirm ischemia and exclude mimics ^[40][68]. Step 4: MRI (DWI/ADC) → The gold standard for confirming small or early infarcts that are invisible on CT ^[70]D. Step 5: Secondary Workup → If imaging is negative, consider EEG for seizures or lumbar puncture if demyelinating disease or infection is suspected.

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].

Large Infarct and Extended Time Windows

Recent evidence from the TENSION trial indicates that endovascular thrombectomy (EVT) is safe and effective for patients with large vessel occlusion (LVO) and established large infarcts, regardless of prior antithrombotic or thrombolytic treatment ^[116]. Hierarchical win ratio (WR) analysis of the TENSION trial, which prioritized time to death and 12-month mRS, confirmed the superiority of EVT plus best medical therapy (BMT) over BMT alone in this population ^[145]. Infarct growth rate (IGR) remains a critical prognostic factor; patients are categorized into progressor phenotypes based on ASPECTS decay (slow: <0.25 pts/h; intermediate: 0.25-0.50 pts/h; fast: >0.50 pts/h) or CTP-estimated core growth (slow: <5 mL/h; intermediate: 5-10 mL/h; fast: >10 mL/h) ^[168].

Very Elderly Patients (≥80 Years)

In patients aged ≥80 years with anterior circulation LVO, EVT remains a viable intervention. A prospective multicenter study in Vietnam demonstrated that while functional independence is achievable, clinicians must monitor for secondary outcomes including malignant cerebral edema and intracranial hemorrhage (ICH) ^[123].

Minor Stroke and TIA

In patients with minor ischemic stroke (NIHSS ≤5) without LVO, stress hyperglycemia (SHG)—defined by the glucose-to-glycated hemoglobin ratio—is a significant predictor of poor functional outcomes, a relationship mediated by hemorrhagic transformation (HT) within 7 days ^[122]. For mild ischemic stroke or high-risk TIA, dual antiplatelet therapy (DAPT) with clopidogrel and aspirin initiated within 72 hours shows consistent efficacy in reducing new stroke risk within 90 days across both sexes, with no significant sex-by-treatment interaction for moderate-to-severe bleeding ^[146].

Embolic Stroke of Undetermined Source (ESUS)

Detecting atrial fibrillation (AF) is paramount in ESUS management. The AVANT-GARDE trial found that a 72-hour adhesive patch ECG identified AF in 13.3% of patients at baseline, outperforming standard 24-hour Holter monitoring ^[121]. Additionally, atrial natriuretic peptide (ANP) has emerged as a potential biomarker to identify latent paroxysmal AF in ESUS patients admitted within 24 hours of symptom onset, showing diagnostic utility alongside brain natriuretic peptide (BNP) and left atrial diameter (LAD) ^[180].

Sociodemographic and Cognitive Factors

Socioeconomic status (SES) significantly influences stroke mortality, with intersectional effects observed between sex and income quartiles ^[129]. However, recent data suggests that social vulnerability indices may not independently associate with 3-month functional outcomes (ΔmRS) specifically following mechanical thrombectomy ^[124]. Cognitively, admission Mini-Mental State Examination (MMSE) scores independently predict discharge walking function and overall functional independence; patients with scores <18 (moderate-to-severe impairment) face significantly worse recovery trajectories ^[128].

Emerging Biomarkers and Diagnostics

• EASIX Score: The Endothelial Activation and Stress Index (creatinine × LDH / platelets) serves as a prognostic biomarker for both short- and long-term mortality in acute ischemic stroke ^[149]C.
• sGFAP: Serum glial fibrillary acidic protein levels are elevated within 24 hours of onset and correlate with clinical severity, offering potential as an astroglial injury marker ^[159].
• DAFNES Scale: A new telephone-compatible scale has been developed for early LVO identification, facilitating rapid triage when bedside assessment is unavailable ^[148]C.
• BBB Disruption: Blood-brain barrier disruption assessed via MR perfusion before interhospital transfer for EVT is associated with 24-hour hemorrhagic transformation and 3-month outcomes ^[162].

Technical and Adjunctive Considerations

Adjunctive tirofiban during EVT for LVO has been evaluated in a meta-analysis of 30 studies; while it may influence recanalization, its safety profile regarding ICH must be balanced against efficacy ^[114]. Regarding access, transradial access (TRA) for mechanical thrombectomy has shown successful implementation in primary stroke centers with comparable outcomes to transfemoral access (TFA) ^[181]. Furthermore, while combined stent retriever (SR) and contact aspiration (CA) improves first-line recanalization rates compared to either alone, pooled analysis of ASTER and VECTOR trials suggests this does not necessarily translate to superior 90-day clinical outcomes ^[139]. Workflow metrics also differ by agent; tenecteplase is associated with simplified administration compared to alteplase, though its impact on door-in-door-out times in registry data continues to be characterized ^[150]. Finally, the presence of covert macrovascular disease (CMVD)—non-culprit plaques <50%—represents a form of vascular vulnerability that may influence early outcomes after TIA or stroke ^[125].

Clinical practice guidelines for acute ischemic stroke have evolved to emphasize precision in subtype management , particularly regarding cryptogenic mechanisms and small vessel pathology. The latest recommendations from the European Stroke Organisation (ESO) in 2024 provide rigorous, evidence-based frameworks for managing patent foramen ovale (PFO) and lacunar ischemic strokes, utilizing the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology to ensure clinical decisions are rooted in high-quality randomized controlled trial (RCT) data ^[112][113].

ESO 2024: Patent Foramen Ovale (PFO) Management

The 2024 ESO guidelines address the complex relationship between PFO and ischemic stroke, a common finding in younger patients with otherwise cryptogenic events. The guideline identifies three primary mechanisms for PFO-mediated stroke: paradoxical embolism (where a venous thrombus traverses the PFO into systemic circulation), in situ thrombus formation within the PFO tunnel, and atrial arrhythmias triggered by electrical signaling disruptions at the atrial septum ^[112].

The TIA Controversy

A significant distinction in the 2024 update is the exclusion of Transient Ischemic Attack (TIA) as a primary index event for PFO closure recommendations. While subgroup analyses from RCTs suggest no significant difference in outcomes between TIA and stroke patients following PFO closure, the ESO working group noted that only one major RCT included TIA patients. Consequently, the guideline focuses on confirmed ischemic stroke to maintain the highest level of evidence-based certainty ^[112].

Protocol: Management of PFO-Associated Stroke

1. Step 1: Diagnostic Confirmation – Confirm the index event as an ischemic stroke (not TIA) and identify the presence of a PFO via transesophageal echocardiography (TEE) or agitated saline contrast study ^[112].
2. Step 2: Etiological Screening – Rule out other competing causes of stroke, such as atrial fibrillation or large-artery atherosclerosis, to ensure the PFO is the likely culprit.
3. Step 3: Risk Stratification – Assess the PFO characteristics (e.g., presence of atrial septal aneurysm or large shunt size) which may increase the risk of recurrence ^[112].
4. Step 4: Intervention Selection – Determine eligibility for percutaneous PFO closure versus long-term medical management based on the patient's age and the strength of the causal link between the PFO and the stroke ^[112].

ESO 2024: Lacunar Ischemic Stroke

Lacunar strokes account for approximately 25% of all ischemic strokes and are characterized by their origin in the intrinsic pathology of the cerebral small vessels ^[113]. These events are often neurologically mild but carry distinct risk factor profiles and long-term outcomes compared to large-vessel or cardioembolic strokes. The 2024 ESO guideline on cerebral small vessel disease (SVD) emphasizes that management must be tailored to this specific subtype rather than applying generalized stroke protocols ^[113].

Acute Treatment and Secondary Prevention

Thrombolysis remains a priority for acute lacunar stroke . The guideline supports the use of intravenous thrombolysis within the standard window, even in cases that appear mild, because the underlying small vessel pathology can still lead to significant functional impairment ^[113]. For secondary prevention, the focus shifts to aggressive management of small vessel disease markers and the use of antiplatelet agents. The ESO emphasizes that the risk-benefit ratio for antiplatelets in lacunar stroke differs from other subtypes due to the higher baseline risk of small vessel-related intracranial hemorrhage ^[113].

Clinical Prediction and Tools

Clinicians are encouraged to use standardized tools to implement these guidelines effectively. For PFO, this involves assessing the probability that the PFO is stroke-related rather than an incidental finding. For lacunar stroke, the focus is on identifying markers of systemic small vessel disease, such as white matter hyperintensities or microbleeds on MRI, which guide the intensity of secondary prevention ^[113].