Open research questions in Acute Ischemic Stroke Management

What the literature leaves open

• Abstract Background Minocycline is a promising anti-inflammatory agent for reducing futile recanalization, but whether it improves clinical outcomes in basilar-artery stroke patients treated with endovascular therapy (EVT) remains unclear.

  Minocycline for acute basilar artery occlusion stroke undergoing endovascular treatment: a randomized, evaluator-blinded, open-label, pilot trial · 2026 · DOI

• BACKGROUND AND OBJECTIVES: Endovascular thrombectomy (EVT) improves outcome in acute ischemic stroke (AIS) due to large vessel occlusion, yet the optimal anesthetic strategy remains controversial.

  General Anesthesia Versus Non-GA in Endovascular Therapy for Acute Ischemic Stroke · 2026 · DOI

• Collectively, while imaging advances have expanded our ability to probe downstream perfusion, the lack of standardized, validated, and clinically feasible measures of microcirculatory dysfunction remains a major barrier to both mechanistic understanding and these microcirculatory Importantly, therapeutic readouts should be interpreted within a well-defined baseline tissue-status context, particularly regarding the presence of salvageable tissue.

  Microcirculatory failure after successful recanalization in ischemic stroke: insights into mechanisms, imaging, and therapeutic strategies · 2026 · DOI

• NBTE, a severe manifestation of MAH, is an important but probably under-recognized cause of AIS in patients with cancer. However, epidemiological data on NBTE prevalence in this context is scarce and highly variable.

  Acute ischemic stroke, active malignancy and non-bacterial thrombotic endocarditis: an exploratory prospective observational study · 2026 · DOI

• Further prospective studies are needed to establish the prevalence of NBTE in larger cohorts of patients with AIS and active malignancy, and to address several important open questions regarding diagnostic and therapeutic strategies: • Are there clinically relevant, clearly defined subgroups of patients, such as those in whom cancer is a by- stander versus those with MAH–related stroke, and do these subgroups differ in prognosis and response to treatment? • Which clinical, laboratory, and imaging markers reliably identify MAH and NBTE (e.g., markedly elevated D-dimer levels, a “three-territory sign” infarction pattern, typical echocardiographic patterns such as the “marantic kiss” sign), and how can these markers be incorporated into diagnostic algorithms and risk strat- ification? • In patients with AIS and suspected MAH but no initially detectable NBTE, does systematic and/or serial echocardiography improve NBTE detection, and is systematic screening for VTE warranted in this popula- tion? • Which anticoagulant agent and what duration are most effective and safe for secondary prevention? • What is the prevalence of NBTE across different cancer types, and is broad echocardiographic screening fea- sible to enable early detection and treatment before stroke occurs?

  Acute ischemic stroke, active malignancy and non-bacterial thrombotic endocarditis: an exploratory prospective observational study · 2026 · DOI

• Optimal endovascular management remains controversial, particularly regarding the role of emergent carotid artery stenting (eCAS) during mechanical thrombectomy (MT).

  Tandem Lesion Strokes: To Stent or Not to Stent, Insights From a Decade of Experience at a Comprehensive Stroke Center in Argentina · 2026 · DOI

• prevention, diagnosis, and therapy. Report of the WHO Task Force other Cerebrovascular Disorders. Stroke 1989; 20: 1407-31. 48. Lindley RI, Landau PB. Early management of acute on Stroke and on stroke. Aust Prescr 2004; 27: 120-3. 49. Gupta A, editor. Measurement scales used in elderly care. 1st ed. Abingdon: Radcliffe Publishing; 2008 50. Thorvaldsen P, Davidsen M, Brønnum-Hansen H, Schroll M.

  EVALUATE THE QUALITY OF LIFE (QOL) OF PATIENTS SUFFERING FROM CEREBRO VASCULAR ACCIDENT (CVA) WITH HEMIPARESIS · 2026 · DOI

• ImportanceMachine-learning models for ischemic stroke risk prediction are rarely validated across ancestrally distinct cohorts, and the contributions of polygenic risk scores (PRS) and self-reported race in such models remain unclear.

  Development and External Validation of a Machine Learning Model for 10-Year Ischemic Stroke Risk Prediction in Diverse Populations · 2026 · DOI

• However, favorable outcomes remain elusive for about half of all treated patients, and a substantial number suffer from neurological deterioration or mortality (12, 25).

  Preoperative multimodal CT for selection of acute anterior circulation occlusion stroke patients for mechanical thrombectomy · 2026 · DOI

• These results add to the limited evidence base on statin intensity in the oldest-old stroke patients and support guideline recommendations for HIST use in this population when tolerated.

  High-intensity statin therapy and functional independence after acute ischemic stroke in adults aged 75 years and older: a retrospective, single-center cohort study · 2026 · DOI

• Background and Purpose: Hemorrhagic transformation (HT) is a serious complication of endovascular thrombectomy (EVT), yet dedicated prediction models for young adults are lacking.

  Hemorrhagic Transformation After Endovascular Thrombectomy in Young Adults: A Prediction Model · 2026 · DOI

• Whether pre-transfer computed tomography angiography (CTA) at the primary stroke center (PSC) reduces futile transfers, and at what workflow cost, remains incompletely characterized.

  Imaging Strategies and Futile Transfers in the Drip-and-Ship Model Within a Densely Connected Stroke Network · 2026 · DOI

• Early neurological deterioration (END) is a frequent and serious complication after intravenous thrombolysis in acute ischemic stroke (AIS), yet the clinical relevance of thrombotic molecular markers related to coagulation, fibrinolysis, and endothelial dysfunction remains incompletely understood.

  Thrombotic molecular markers after intravenous thrombolysis are associated with early neurological deterioration in acute ischemic stroke · 2026 · DOI

• Background and Purpose In patients with large vessel occlusion (LVO), intravenous thrombolysis (IVT) frequently alters thrombus location; however, the clinical impact of this phenomenon remains unclear.

  Thrombus Migration After Tenecteplase Versus Alteplase in Acute Large Vessel Occlusion · 2026 · DOI

• Existing observational series of distal MAT-thrombectomy have reported high recanalization rates and low complica- tion frequencies. Our findings fall within this general range, although meaningful comparison is limited by differences in patient selection, occlusion location, and device choice [4, 6, 8, 9]. The present study is, to our knowledge, the first to systematically evaluate MAT in very distal occlusion sites (M3–M4, A3–A4, P3–P4) using a 0.025-inch micro- catheter. Current evidence on MAT for DVOs remains limited, particularly regarding microcatheters with inner diameters < 0.027 inches [1, 4, 9]. While an isolated case report has The small sample size (n = 21) limits the statistical power and generalizability of the findings. The retrospective mul- ticenter design introduces potential selection and report- ing bias, particularly because only patients with disabling deficits and ASPECTS 10 were eligible and all actively consented to interventional treatment after detailed coun- seling. Best medical management was typically reserved for patients with milder symptoms outside our inclusion criteria; therefore, a well-matched non-interventional con- trol group was not available. This limits any inference re- garding the relative benefit of MAT compared with best medical therapy. Furthermore, the absence of baseline core K volume assessment, the exclusive treatment of very distal occlusions, and possible operator-dependent variations in technique may have influenced outcomes. Future prospec- tive, controlled studies with broader inclusion criteria are required to validate these findings and better define the clin- ical role of MAT in DVOs. ASPECTS (MCA) and PC-AS- PECTS (PCA) were applied according to vascular territory. Since no validated ASPECTS equivalent exists for ACA infarctions, ACA-territory imaging was assessed descrip- tively.

  Microcatheter Aspiration Thrombectomy with a 0.025″ Microcatheter for Distal Vessel Occlusions in Acute Ischemic Stroke with Disabling Deficits · 2026 · DOI

• One limitation in this study is skewness of the scores towards zero, limiting the evaluation of the entire novel 0–2 score range, and creating a prevalence effect that could have artificially lowered the kappa values [10].

  A brief novel questionnaire to estimate premorbid functional state in acute stroke patients · 2026 · DOI

• Strengths of this study include its longitudinal design and the use of large, population-representative, register-based data with near-complete coverage of individuals with type 2 diabetes in Sweden. The large sample size enabled subgroup analyses and es- timation of stroke risk across physical activity levels. The matched cohort design, combined with linkage to high-quality national registers, allowed comprehensive adjustment for a broad range of covariates, thereby enhancing internal validity and reducing confounding. In addition, the use of both cause-specific and com- peting risks models strengthened robustness across different modeling assumptions and accounted for the influence of com- peting events. However, several clinical and laboratory covari- ates were obtained from the NDR and were therefore unavail- able for individuals without diabetes. The use of repeated physical activity measurements provided a more stable estimate of habit- ual activity compared with a single baseline assessment. Nev- ertheless, physical activity was self-reported, introducing the possibility of recall and social desirability bias. Moreover, sum- marizing exposure using median values may obscure meaning- ful changes in physical activity over time. Physical activity data were missing for a proportion of individuals, and those with miss- ing data had a higher-risk profile, suggesting that physical ac- tivity may be less frequently assessed or documented in individ- uals with more complex medical conditions. Additionally, because of limited event counts, individuals with type 1 diabetes were excluded from the analysis. It cannot be excluded that the epi- demiologic definition of type 2 diabetes resulted in some mis- classification of diabetes type. Subgroup analysis by HbA1c level was not performed for hemorrhagic stroke because the number of events within strata was insufficient for reliable estimation. Finally, as in all observational studies, residual confounding and unmeasured variables may persist, and causal inference cannot be established. Therefore, these findings should be interpreted cautiously but may be generalizable to other Western countries with publicly funded health care systems comparable to Swe- den, while recognizing potential differences in health care de- livery, population characteristics, and registry infrastructure.

  Mitigating Stroke Risk in Type 2 Diabetes Through Physical Activity: A Nationwide Population-Based Study in Sweden · 2026 · DOI

• The strengths of this study include its randomized design, large sample size, and systematic use of a validated HRQoL instrument, providing robust evidence on patient-centered outcomes after reperfusion therapy. The prespecified subgroup analyses by BI and mRS further enhance the clinical interpretability of our findings. Nevertheless, several limitations should be acknowledged. First, this is a secondary analysis, and causality cannot be definitively inferred. Second, missing HRQoL data and deaths were addressed through imputation and sensitivity analyses, but residual bias cannot be excluded. Third, subgroup analyses based on 90-day BI and mRS are post-randomization and may be subject to post-treatment stratification; therefore, these findings should be exploratory and interpreted as hypothesis-generating. Finally, long-term HRQoL beyond 90 days was not assessed, and further research is needed to examine whether treatment-related differences persist over time.

  Health-related quality of life after direct endovascular thrombectomy and bridging therapy: findings of DIRECT-MT trial · 2026 · DOI

• This longitudinal observational study is based on real-world data from a resource-constrained environment, which enhances the external validity and applicability of its findings to similar settings in Brazil and other LMICs. The large sample size further strengthens the reliability of statistical estimates and supports the consistency of the observed associations. Nevertheless, the retrospective and observational design inherently limits internal validity and introduces susceptibility to selection, confounding, and measurement biases. In addition, the three care models evaluated (BSU, ASU, and CSU) represent sequential phases of care implementation rather than exchangeable limiting direct comparability between groups and cohorts, precluding causal inference. A key limitation is the nonsystematic registry of information, particularly during the BSU period, which restricted data availability. This was mitigated through independent estimation of baseline NIHSS, structured handling of missing data, and additional subanalyses. Interrater agreement for NIHSS estimation was good, supporting the reliability of reconstructed values. The use of discharge mRS for cases lacking 90-day follow-up may have biased results toward smaller differences between care models, thereby reinforcing the robustness of the observed effects. Changes in regional stroke care pathways over time may also have introduced referral bias. As the study center progressively became a regional hub for acute stroke therapies, particularly reperfusion strategies, there may have been preferential referral of patients with suspected ischemic stroke, while some hemorrhagic cases—potentially more severe and associated with higher case fatality—may have been managed in other institutions. This shift could have influenced the observed distribution of stroke subtypes and clinical outcomes across study periods. Furthermore, the evolution of prehospital care and triage systems likely influenced case mix and baseline stroke severity at admission. Improvements in emergency medical services, increased training of healthcare professionals, greater public awareness of stroke symptoms, and the widespread implementation of time- sensitive treatment protocols may have led to earlier hospital arrival and changes in patient selection over time. These factors may have contributed to differences in baseline characteristics and outcomes between care models. The study population largely reflects the demographic profile of the Porto Alegre metropolitan area—predominantly individuals in their sixties and of European ancestry—supporting regional to more diverse populations. In addition, ambulance arrival rates may be overestimated due to interhospital from neighboring municipalities. representativeness but generalizability transfers limiting A higher proportion of hemorrhagic strokes in the BSU period may also have contributed to poorer outcomes in this group. However, baseline NIHSS was slightly lower during this period, a difference of uncertain clinical relevance that may reflect the inclusion of transient ischemic attacks or differences in case ascertainment. Importantly, the observed reduction in case fatality remained significant in subgroup analyses of hemorrhagic stroke, supporting the consistency of the findings. Although secular improvements in overall medical care over time cannot be fully excluded as contributing factors, they are unlikely to account for the magnitude and consistency of the effects observed across multiple outcomes and analyses.

  Improving stroke outcomes through progressive implementation of stroke unit care in Brazil: a longitudinal observational study · 2026 · DOI

• This meta-analysis has limitations. Our analyses were based on aggregated trial-level data, which is considered less informative than patient-level data. However, individual patient data were unavailable, precluding harmonized subgroup analyses and covariate-adjusted analyses. Nevertheless, we assume that patient-level data would not have revealed any significant differences in the findings of the primary endpoint due to the homogeneity and randomized design of included studies [36]. Although we pooled all the available randomized evidence (7 trials; n=2884), several results remained imprecise, which was reflected by wide CIs and limit the precision of our estimates. Moreover, subgroup cut-off values varied between studies. Thrombolytic regimens were not uniform across trials and differences in dosing and administration (infusion versus bolus) may dilute agent-specific effects and limit applicability to any single thrombolysis protocol. Additionally, data were predominantly derived from anterior circulation large-vessel occlusion. Occlusions in the basilar artery ARTICLE IN PRESS ARTICLE IN PRESS ACCEPTED MANUSCRIPT were included in two trials and only in small numbers. Therefore, external validity to posterior circulation is limited. Moreover, hemorrhage outcomes were defined using different criteria (Heidelberg, SITS-MOST and NINDS), which reduced the comparability and precision of the pooled safety estimates. Nonetheless, sensitivity analyses were comparable (Figure 4B). The overall risk of bias was primarily driven by the open-label treatment allocation, whereas randomization procedures, outcome assessment, and follow-up were largely at low risk. However, certainty was limited mainly by imprecision and inconsistency.

  Endovascular thrombectomy with or without intravenous thrombolysis in large-vessel ischemic stroke: an updated meta-analysis · 2026 · DOI

• and visual an overall judgement summarising the worst-credible inspection alone was used. The pre-specified primary domain. Performance bias due to open-label analysis additionally excluded the prematurely administration was distinguished from detection bias, terminated NOR-TEST 2 Part A trial, with the allbecause outcome assessment in all included trials studies model retained as a secondary descriptive used masked adjudication or central blinded reading analysis. Statistical significance for the pooled of imaging.

  Tenecteplase versus Alteplase or Standard Care for Improving Functional Outcomes in Acute Ischaemic Stroke: A Systematic Review and Meta-Analysis · 2026 · DOI

• Some limitations of the study are worth noting. Although we applied careful propensity score matching, there is still the possibility of selection bias and residual confounding, particularly due to variations in antiplatelet dosing and administration protocols across hospitals. The TriNetX platform’s reliance on ICD-10 codes also limited our ability to assess certain clinical details, such as serial NIHSS scores during hospitalization or functional outcomes at 90 days using the modified Rankin Scale. These measures are critical for evaluating clinical progress and functional recovery, potentially omitting early complications or standardized benefits of therapy. Additionally, reliance on ICD-10 codes precluded direct identification of recurrent strokes as a distinct clinical event, as there is no specific code to distinguish stroke recurrence from previous cerebral ischemia, thereby introducing misclassification bias into the 30- to 90-day recurrence risk of ischemic stroke outcome.

  Efficacy and Safety of Dual Antiplatelet Therapy in Acute Ischemic Stroke With Recurrent Symptoms Post-thrombolysis: A Retrospective Cohort Study From the TriNetX US Collaborative Network · 2026 · DOI

• Despite the valuable insights provided by this study, several limita- tions should be acknowledged: (1) The study population was drawn primarily from a single region or institution, which may limit the gen- eralizability of the findings. (2) Some information relied on patient or caregiver recall, particularly regarding symptom perception and time to seek care, which may affect the accuracy of the data. (3) Elements such as healthcare accessibility and transportation barriers were not thor- oughly quantified, potentially underestimating their impact on pre- hospital delay. (4) Fourth, our measurement of the “initial perception of symptom severity” is susceptible to recall bias. Although we specifically asked participants to recall their thoughts before the diagnosis was con- firmed, their current knowledge of having had a stroke may have influ- enced their retrospective reporting. However, we attempted to mitigate this by interviewing patients as early as possible during their hospitaliza- tion and, when necessary, corroborating the account with family mem- bers who were present at onset. (5) We excluded patients with low GCS scores (<8) due to their inability to provide informed consent or com- plete the health literacy assessment. This exclusion may introduce selec- tion bias and limit the generalizability of our findings. Patients with severe neurological impairment may represent a particularly vulnerable subgroup with distinct delay patterns—potentially experiencing longer pre-hospital delays due to inability to self-activate emergency services, greater reliance on bystander recognition and decision-making, and increased family deliberation time. Their exclusion likely means that our results underestimate the true extent of pre-hospital delay in the overall AIS population. Future studies specifically designed to capture delay patterns in severely affected patients, potentially using proxy respon- dents or alternative data sources, are needed to address this important knowledge gap. (6) Our employment status categorization did not dis- tinguish between retired individuals, homemakers, and those who were truly unemployed, which may obscure important differences in socio- economic circumstances and their potential influence on care-seeking behaviors. Future studies should employ more granular employment classifications.

  Pre-hospital delay and its influencing factors in patients with acute ischemic stroke: a cross-sectional study based on the health ecology model · 2026 · DOI

• The study combines ASL qualitative measures with DTI tract integrity assessment but does not investigate whether specific combinations of ASL parameters (rCBF ranges) and DTI-defined tract disruption patterns (rFA ranges) stratify patients into distinct prognosis categories requiring differentiated treatment escalation strategies (rTPA alone vs. endovascular intervention).

  Harnessing ASL (arterial spin labeling) for hyper acute and acute stroke management: a comparative analysis with DTI (diffusion tensor imaging) · 2026 · DOI

• The paper notes that comparisons with established perfusion modalities were incomplete (text cuts off mid-sentence: 'Comparisons with established perfusion'). Systematic head-to-head comparison between ASL-based perfusion assessment and alternative quantitative perfusion methods (perfusion-weighted imaging, computed tomography perfusion) for identifying penumbra in acute stroke is not addressed.

  Harnessing ASL (arterial spin labeling) for hyper acute and acute stroke management: a comparative analysis with DTI (diffusion tensor imaging) · 2026 · DOI

Most-cited papers in Acute Ischemic Stroke Management

• Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke · New England Journal of Medicine · 2008 · 5,814 citations
• A Randomized Trial of Intraarterial Treatment for Acute Ischemic Stroke · New England Journal of Medicine · 2014 · 5,781 citations
• Global, regional, and national burden of stroke and its risk factors, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021 · The Lancet Neurology · 2024 · 1,215 citations
• Short-term Prognosis After Emergency Department Diagnosis of TIA · JAMA · 2000 · 1,005 citations
• Stroke Incidence among White, Black, and Hispanic Residents of an Urban Community: The Northern Manhattan Stroke Study · American Journal of Epidemiology · 1998 · 553 citations
• Neurologic Outcome in Survivors of Childhood Arterial Ischemic Stroke and Sinovenous Thrombosis · Journal of Child Neurology · 2000 · 524 citations
• Global, regional, and national burden of ischemic stroke, 1990–2021: an analysis of data from the global burden of disease study 2021 · EClinicalMedicine · 2024 · 313 citations
• Risk of Recurrent Childhood Arterial Ischemic Stroke in a Population-Based Cohort: The Importance of Cerebrovascular Imaging · PEDIATRICS · 2007 · 308 citations
• What are the components of effective stroke unit care? · Age and Ageing · 2002 · 273 citations
• Depressive Symptoms and Increased Risk of Stroke Mortality Over a 29-Year Period · Archives of Internal Medicine · 1998 · 267 citations

Most recent work

• Endovascular thrombectomy for patients with large-core ischaemic stroke presenting up to 24 h after onset (ATLAS): a systematic review and individual patient data meta-analysis with central imaging adjudication · The Lancet · 2026
• Endovascular Treatment of Medium-Vessel-Occlusion Strokes · New England Journal of Medicine · 2026
• Brain Frailty Rather than Age Alone Mediates the Lack of Benefit for Endovascular Thrombectomy in the Elderly Population of the <scp>RESILIENT</scp> Trial · Annals of Neurology · 2026
• Tenecteplase for Acute Non–Large Vessel Occlusion After Ischemic Stroke—Reply · JAMA · 2026
• Ticagrelor with aspirin dual antiplatelet therapy combined with intravenous thrombolysis in patients with ischaemic stroke in China (TAPIS): a multicentre, double-blind, randomised controlled trial · The Lancet · 2026
• Neuroimaging and behavioural biomarkers of post-stroke cognitive recovery outcomes · medRxiv · 2026
• Correspondence- Educational and Socioeconomic Correlates of Stroke Risk Behaviors: Findings from the SPRINT INDIA Trial · Annals of Indian Academy of Neurology · 2026
• Prevention of Stroke · CONTINUUM Lifelong Learning in Neurology · 2026
• Sex Differences in Stroke Diagnosis, Treatment, and Outcome · CONTINUUM Lifelong Learning in Neurology · 2026
• Effectiveness of Immediate Angioplasty or Stenting on Functional Outcomes in Acute Ischemic Stroke With Severe Intracranial Stenosis · Neurology · 2026

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