Open questions — stroke¶
Last curated: 2026-08-28
Stable IDs are retained when questions are refined. Tier 1 questions could change practice and are designable now; Tier 2 questions require enabling measurement, mechanistic, or implementation work. “Open” means the retrieved evidence leaves a decision unresolved, not that no study exists.
Tier 1 — practice-changing and designable now¶
OQ-1 — Which distal or medium-vessel occlusions benefit from thrombectomy?¶
Why open: HERMES established a large disability benefit for predominantly proximal anterior-circulation occlusion (common OR 2.49, 95% CI 1.76–3.53), but smaller vessels combine lower untreated tissue burden with greater procedural perforation risk. Active trials test different anatomical and deficit thresholds (Goyal 2016, PMID 26898852; NCT06146790; NCT07185022).
Design: Pragmatic randomized comparison stratified by vessel, eloquent territory, NIHSS domain, core, collaterals, and rescue crossover; ordinal mRS plus cognition, language, vision, and safety.
OQ-2 — What is the net benefit of thrombectomy across the full large-core spectrum?¶
Why open: DAWN and DEFUSE 3 selected small-core mismatch phenotypes, leaving uncertainty at very large core volumes and across ASPECTS, age, edema risk, and desired outcome states (Nogueira 2018, PMID 29129157; Albers 2018, PMID 29364767).
Design: Individual-patient prospective meta-analysis with common imaging reprocessing, ordinal/utility outcomes, hemorrhage, decompression, and survival with severe disability.
OQ-3 — Does adjunct intra-arterial lysis improve outcome after successful thrombectomy?¶
Why open: Angiographic reperfusion does not guarantee microvascular tissue flow. Active phase 3 work tests intra-arterial alteplase after successful reperfusion, but hemorrhage may offset distal-thrombus benefit (NCT07727395; Jiang 2018, PMID 28987927).
Design: Double-blind randomized adjunct trial with eTICI-stratification, perfusion normalization, symptomatic ICH, ordinal mRS, and prespecified no-reflow phenotype.
OQ-4 — Which tenecteplase dose and population should replace alteplase?¶
Why open: AcT demonstrated pragmatic non-inferiority, but optimal dose and effects before thrombectomy, in non-LVO stroke, and in extended or unknown windows require consistent evidence (Menon 2022, PMID 35779553; Thomalla 2020, PMID 33176180).
Design: Harmonized individual-patient network comparison with dose, occlusion, imaging, time, reperfusion, symptomatic ICH, and ordinal function.
OQ-5 — Can a prehospital intervention safely preserve penumbra during transfer?¶
Why open: Collaterals determine infarct tempo and treatment delay erodes benefit, but collateral augmentation, conditioning, or neuroprotection has not shown a replicated patient-centered effect (Leng 2016, PMID 26579719; Paul 2021, PMID 33144066).
Design: Ambulance or spoke-hospital platform trial requiring confirmed occlusion, rapid target-engagement marker, and interaction with transfer/reperfusion delay.
OQ-6 — Which acute ICH care-bundle components add independent functional benefit?¶
Why open: INTERACT2's dichotomous primary outcome was neutral while ordinal outcome favored intensive BP lowering; hemostasis, temperature, glucose, airway, and surgery may produce additive effects (Anderson 2013, PMID 23713578; Greenberg 2022, PMID 35579034; NCT06429332).
Design: Factorial or response-adaptive platform initiated ultra-early, measuring achieved physiological separation, hematoma expansion, renal/ischemic harms, and ordinal mRS.
OQ-7 — Who benefits from minimally invasive ICH evacuation, and when?¶
Why open: Location, volume, intraventricular extension, neurological trajectory, timing, and surgical technique define biologically different groups; active studies test catheter and stereotactic approaches (Greenberg 2022, PMID 35579034; NCT07187687; NCT07471256).
Design: Technique-specific randomized trials with time-to-evacuation, residual volume, mortality, ordinal disability, and cognitive/communication outcomes.
OQ-8 — When and how should anticoagulation resume after anticoagulant-associated ICH?¶
Why open: Avoiding anticoagulation reduces recurrent bleeding exposure but leaves AF-related embolic risk; hemorrhage location, cerebral amyloid angiopathy markers, and competing risk vary (Greenberg 2022, PMID 35579034; NCT03243175).
Design: Randomized restart strategies stratified by lobar/deep site, microbleeds/siderosis, AF embolic risk, and left-atrial-appendage alternatives.
OQ-9 — Which aneurysmal-SAH strategy prevents delayed cerebral ischemia without causing harm?¶
Why open: Aneurysm securing prevents rebleeding, but delayed ischemia reflects vasospasm, microvascular dysfunction, spreading depolarization, and systemic complications; no single monitor or rescue pathway captures all (Claassen 2022, PMID 35985353; van Gijn 2007, PMID 17258671).
Design: Phenotype-triggered platform comparing monitoring/treatment bundles with infarction, cognition, quality of life, and treatment complication endpoints.
OQ-10 — Can mechanism-guided monitoring outperform fixed rhythm-monitoring duration after cryptogenic stroke?¶
Why open: Longer monitoring detects more AF, but detected short episodes may be incidental and do not uniformly establish embolic causality. TOAST also conflates incomplete and genuinely negative workups (Adams 1993, PMID 7678184; Amarenco 2013, PMID 23899749).
Design: Randomize monitoring intensity by atrial, imaging, age, and competing-source phenotype; primary endpoint should be recurrent stroke, not AF detection alone.
OQ-11 — Which PFO patients gain a causal—not merely associative—benefit from closure?¶
Why open: Closure trials enrich younger patients and high-risk anatomy after excluding competing mechanisms; extrapolation to older patients or low-risk anatomy is uncertain (Lee 2018, PMID 29544871).
Design: Prospective causal-risk model validated against closure interaction and recurrent embolic phenotype.
OQ-12 — What antithrombotic duration best balances early recurrence and bleeding after minor stroke/TIA?¶
Why open: CHANCE and POINT show early dual-antiplatelet benefit but accumulated bleeding with longer exposure; mechanism, infarct burden, genotype, and adherence may change the optimum (Wang 2013, PMID 23803136; Johnston 2018, PMID 29766750; Pan 2019, PMID 31424481).
Design: Patient-level adaptive-duration trial with ischemic and major-bleeding utility weights.
OQ-13 — Can rehabilitation dose be assigned by response phenotype?¶
Why open: Motor, language, cognitive, and participation recovery differ by tract integrity, impairment, time, fatigue, and learning capacity; recovery biomarkers lack cross-validated treatment-response rules (Kim 2017, PMID 27503908; Bernhardt 2017, PMID 28697708).
Design: Sequential multiple-assignment trial using early within-person response to adapt task, intensity, and rest, with meaningful-change thresholds.
OQ-14 — Which caregiver intervention has a replicable effect on caregiver health and burden?¶
Why open: Nineteen RCTs had no pooled burden/strain effect, while seven individual educationally intensive studies were positive; remote interventions were also neutral with low certainty (Jammal 2024, PMID 39194341; Yu 2023, PMID 37696638).
Design: Multisite trial stratified by survivor dependency/cognition and caregiver baseline risk; specify intervention dose, respite access, mental health, work loss, and survivor outcomes.
OQ-15 — Does scheduled long-term needs review improve participation and quality of life?¶
Why open: An average 73.8% of survivors reported at least one unmet need, but descriptive prevalence has not established the effective review-and-response service (Chen 2019, PMID 31110106; Guo 2021, PMID 33671734).
Design: Cluster-randomized primary-care/community pathway with repeated accessible assessment, funded response options, participation, caregiver, and cost outcomes.
OQ-16 — Which system redesign closes reperfusion and stroke-unit inequities?¶
Why open: Low-income settings have 3.6-fold higher age-standardized mortality, while implementation evidence for affordable stroke services remains limited (GBD 2019 Stroke Collaborators 2021, PMID 34487721; Pandian 2017, PMID 28848165).
Design: Stepped-wedge regional trial comparing transport, telemedicine, essential imaging, drug access, transfer, and stroke-unit bundles; analyze treatment and disability equity.
Tier 2 — enabling science and measurement¶
OQ-17 — What is irreversibly injured “core” at the individual level?¶
Perfusion and diffusion thresholds are model-dependent; DWI can be negative or reversible, and CTP misses small lesions (Edlow 2017, PMID 28615423; Biesbroek 2013, PMID 23736122; Guadagno 2004, PMID 15090879).
OQ-18 — What causes microvascular no-reflow after macrovascular reperfusion?¶
Pericytes, distal emboli, endothelial swelling, leukocytes, and microthrombi are plausible mechanisms (Jiang 2018, PMID 28987927; Candelario-Jalil 2022, PMID 35387495). A PubMed update through 2026-08-30 found emerging retrospective human prediction work—DSA-NRP reported AUROC 0.933 for an angiographic machine-learning model but explicitly requires larger independent validation—without a prospectively validated treatment-selection phenotype or proven phenotype-linked intervention (Athreya 2026, PMID 42184179).
OQ-19 — When does post-stroke inflammation switch from injury to repair?¶
Microglial and peripheral immune responses are time- and context-dependent; indiscriminate suppression may block recovery (Jayaraj 2019, PMID 31291966; Zhao 2017, PMID 28260801).
OQ-20 — Can a blood biomarker add a safe, actionable diagnostic decision?¶
Across 141 studies and 136 candidates, few markers had meaningful clinical value; large associations for MMP-9 and other candidates remain heterogeneous and threshold-dependent (Hasan 2012, PMID 22320313; Krishnamoorthy 2022, PMID 34569521).
OQ-21 — How should cerebral small-vessel-disease progression be measured?¶
Lacunes, white-matter hyperintensities, microbleeds, perivascular spaces, and atrophy reflect overlapping mechanisms; a single burden score may hide causal heterogeneity (Wardlaw 2019, PMID 31097385).
OQ-22 — What biology drives post-stroke fatigue?¶
Forty-six imaging studies found no consistent association with common lesion measures, while fatigue remains functionally important (Jolly 2023, PMID 37485902).
OQ-23 — Which outcomes represent recovery rather than compensation?¶
The mRS and impairment scales cannot distinguish restitution, strategy change, environmental support, or participation; standard definitions exist but require adoption (Bernhardt 2017, PMID 28697708).
OQ-24 — How can aphasia and cognitive disability be included without biased consent or outcomes?¶
Communication difficulty persists for years and affects service access, social networks, and research participation (Wray 2017, PMID 28988185).
Dots not yet connected¶
These are testable junctions between evidence bodies already represented in this condition. “Missing junction” is a scoped synthesis gap, not a claim that no study exists.
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D1 | Collateral grade predicts infarct tempo | Ambulance transfer delay varies by geography | Use transfer-time distribution to select/test collateral-support interventions | OQ-5, OQ-16 |
| D2 | BBB permeability predicts hemorrhage | Adjunct lysis may improve distal reperfusion | A joint marker deciding who gains net benefit from post-thrombectomy lysis | OQ-3, OQ-20 |
| D3 | Large-core reperfusion can preserve tissue | Survivor utility differs across severe mRS states | Preference-weighted large-core treatment effects, not binary independence alone | OQ-2, OQ-23 |
| D4 | ICH care components have modest effects | Stroke units improve outcomes through coordination | An ICH-specific coordinated bundle tested as a system intervention | OQ-6, OQ-16 |
| D5 | CAA imaging predicts recurrent lobar hemorrhage | AF burden predicts embolic risk imperfectly | Integrated competing-risk rule for anticoagulation restart | OQ-8, OQ-10 |
| D6 | Post-stroke cognition affects caregiver outcomes | Caregiver interventions are pooled neutral | Target caregiver treatment using survivor cognitive phenotype | OQ-14 |
| D7 | Fatigue limits activity and work | Rehabilitation dose is usually prescribed by impairment | Fatigue-responsive dose scheduling with vocational outcome | OQ-13, OQ-22 |
| D8 | Aphasia causes long-term participation barriers | Most digital follow-up assumes fluent language | Communication-accessible remote prevention and needs review | OQ-15, OQ-24 |
| D9 | Small-vessel imaging burden predicts cognitive decline | BP lowering prevents recurrent stroke | Treatment targets based on SVD progression plus cognition, not stroke alone | OQ-21 |
| D10 | Indigenous incidence disparities are documented | Stroke-system trials rarely use Indigenous governance | Community-governed system trials with locally defined benefit | OQ-16 |
| D11 | No-reflow separates recanalization from reperfusion | Neuroprotection trials fail without target engagement | Enroll only a validated no-reflow phenotype and prove engagement | OQ-3, OQ-18 |
| D12 | Return to work continues rising for years | Trials center 90-day mRS | Add sustainable work/role participation to young-stroke trials | OQ-15, OQ-23 |
Maintenance rules¶
- Retire a question only when evidence resolves the decision, not when one trial reports.
- Record neutral and harmful results as answers.
- Preserve the stable ID and add a resolution note when closing.
- Re-query ClinicalTrials.gov before describing any NCT status.
- Re-run absence searches before converting a “missing junction” into a claimed literature gap.