Subarachnoid hemorrhage (SAH) carries high mortality and disability rates, which are substantially driven by complications. Early brain injury and vasospasm can happen after SAH and are crucial events to prevent and treat to improve prognosis. In recent decades, immunological mechanisms have been implicated in SAH complications, with both innate and adaptive immunity involved in mechanisms of damage after SAH. The purpose of this review is to summarize the immunological profile of vasospasm, highlighting the potential implementation of biomarkers for its prediction and management. Overall, the kinetics of central nervous system (CNS) immune invasion and soluble factors’ production critically differs between patients developing vasospasm compared to those not experiencing this complication. In particular, in people developing vasospasm, a neutrophil increase develops in the first minutes to days and pairs with a mild depletion of CD45+ lymphocytes. Cytokine production is boosted early on after SAH, and a steep increase in interleukin-6, metalloproteinase-9 and vascular endothelial growth factor (VEGF) anticipates the development of vasospasm after SAH. We also highlight the role of microglia and the potential influence of genetic polymorphism in the development of vasospasm and SAH-related complications.

Background: Symptomatic intracerebral hemorrhage (sICH) and major bleeding can be fatal complications of intravenous thrombolysis (IVT) for acute ischemic stroke. We investigated the impact of early fibrinogen depletion after IVT on major bleeding events. Methods: This multicenter observational prospective cohort study enrolled 1678 consecutive patients receiving IVT for acute ischemic stroke at 6 Italian centers, undergoing fibrinogen concentration assessment at baseline, 2 hours and 6 hours after IVT. Fibrinogen depletion was defined as a reduction below 200 mg/dL after 2 hours from IVT, or as a reduction below 50% of baseline fibrinogen levels after 2 hours from IVT. Main outcomes were (1) sICH (National Institute of Neurological Disorders and Stroke criteria) and (2) major bleeding defined as fatal bleeding, decrease in the hemoglobin level>2 g/dL/>1 unit transfusion, or bleeding at critical site. Additional outcomes were (1) any ICH, (2) any bleeding, (3) fatal ICH, and (4) sICH according to ECASSII definition. Good functional recovery was defined as modified Rankin Scale score 0 to 2 at 3 months. Results: Overall, 1678 patients were included (mean age 72 years, 46% female). sICH (n=116) and major bleeding (n=297) were associated with lower rate of good functional recovery ( P <0.001). Despite similar fibrinogen levels at admission, fibrinogen depletion after 2 hours from IVT was more common in people with sICH, major bleeding and all additional bleeding outcomes. In the backward stepwise multivariable logistic regression model, fibrinogen depletion remained a significant predictor of sICH (OR, 1.55 [95% CI, 1.04–2.32]) and major bleeding (OR, 1.36 [95% CI, 1.03–1.8]). Thirty-one percent of sICH could be attributable to fibrinogen depletion. The association between fibrinogen depletion and worse clinical outcome at 3 months after stroke ( P =0.012) was attributable to the higher risk of major bleeding/sICH. Conclusions: Fibrinogen depletion significantly increases the risk of sICH and major bleeding after IVT for acute ischemic stroke. Fibrinogen depletion represents an independent risk factor for bleeding, and routine assessment could be considered to stratify the risk of ICH. Trials on early fibrinogen repletion are needed to investigate mitigation of bleeding risk.

Objective: Cerebral venous thrombosis (CVT) caused by vaccine‐induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus‐based severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non‐heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality.Methods: We used data from an international prospective registry of patients with CVT after the adenovirus‐based SARS‐CoV‐2 vaccination. We analyzed possible, probable, or definite VITT‐CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis.Results: Ninety‐nine patients with VITT‐CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in‐line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16–1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06–0.58). Treatment with non‐heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24–2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74–6.54).Conclusions: In patients with VITT‐CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT‐CVT. ANN NEUROL 2022;92:562–573

Background: The effect of the COVID pandemic on stroke network performance is unclear, particularly with consideration of drip&ship vs. mothership models. Aims: We systematically reviewed and meta-analyzed variations in stroke admissions, rate and timing of reperfusion treatments during the first wave COVID pandemic vs. the pre-pandemic timeframe depending on stroke network model adopted. Summary of findings: The systematic review followed registered protocol (PROSPERO-CRD42020211535), PRISMA and MOOSE guidelines. We searched MEDLINE, EMBASE, and CENTRAL until 9 October 2020 for studies reporting variations in ischemic stroke admissions, treatment rates, and timing in COVID (first wave) vs. control-period. Primary outcome was the weekly admission incidence rate ratio (IRR = admissions during COVID-period/admissions during control-period). Secondary outcomes were (i) changes in rate of reperfusion treatments and (ii) time metrics for pre- and in-hospital phase. Data were pooled using random-effects models, comparing mothership vs. drip&ship model. Overall, 29 studies were included in quantitative synthesis (n = 212,960). COVID-period was associated with a significant reduction in stroke admission rates (IRR = 0.69, 95%CI = 0.61–0.79), with higher relative presentation of large vessel occlusion (risk ratio (RR) = 1.62, 95% confidence interval (CI) = 1.24–2.12). Proportions of patients treated with endovascular treatment increased (RR = 1.14, 95%CI = 1.02–1.28). Intravenous thrombolysis decreased overall (IRR = 0.72, 95%CI = 0.54–0.96) but not in the mothership model (IRR = 0.81, 95%CI = 0.43–1.52). Onset-to-door time was longer for the drip&ship in COVID-period compared to the control-period (+32 min, 95%CI = 0–64). Door-to-scan was longer in COVID-period (+5 min, 95%CI = 2–7). Door-to-needle and door-to-groin were similar in COVID-period and control-period. Conclusions: Despite a 35% drop in stroke admissions during the first pandemic wave, proportions of patients receiving reperfusion and time-metrics were not inferior to control-period. Mothership preserved the weekly rate of intravenous thrombolysis and the onset-to-door timing to pre-pandemic standards.

The management of anticoagulation after ischemic stroke while on direct oral anticoagulants (DOACs) is controversial. We performed an aggregate-data meta-analysis to compare anticoagulation strategies against each other to define the effect of switch to warfarin, switch to another DOAC, change in dosage, and add-on antiplatelet for the prevention of recurrent stroke, intracranial hemorrhage (ICH), any stroke, and mortality. The study protocol was deposited with PROSPERO (CRD42025639057). We systematically searched MEDLINE, Scopus, and the Cochrane Library-all studies reporting on anticoagulation strategies after a stroke while on DOAC up to January 31, 2025. We included randomized controlled clinical studies and cohort studies with sample size ≥50 that (1) enrolled adult patients who experienced ischemic stroke while on DOACs, (2) assessed modifications to anticoagulation therapy, and (3) reported on at least one of the outcomes. Main outcome was recurrent ischemic stroke; secondary outcomes were ICH, all-cause mortality, and any stroke. We pooled estimates by random-effects modelling, reporting risk ratio (RR) with 95% CIs comparing anticoagulation strategies against each other. We retrieved 2,171 results, with 8 observational studies reaching quantitative synthesis (n = 14,307 patients, mean age = 75 years, 48% female). Switching to warfarin was associated with a higher risk of ischemic stroke compared with keeping the same DOAC (RR 1.80, 95% CI 1.42-2.29, I² = 0%, n_studies = 5) or changing DOAC dosage (RR 1.72, 95% CI 1.20-2.45, I² = 0%, n_studies = 4). Switching to warfarin was also associated with higher ICH rates compared with keeping the same DOAC (RR 2.90, 95% CI 2.01-4.18, I² = 0%, n_studies = 5) and DOAC-to-DOAC switch (RR 3.25, 95% CI 2.13-4.96, I² = 0%; n_studies = 5). Keeping the same DOAC and switching to another DOAC, independently from mechanism, had similar rates of primary and secondary outcomes. Our meta-analysis indicates that switching to warfarin after a stroke while on DOAC seems less effective and safe in stroke recurrence prevention, ICH, and mortality compared with DOAC-based strategies.

The risk of recurrent ischemic stroke, intracranial hemorrhage, and mortality in people with atrial fibrillation detected after stroke (AFDAS) is still unclear compared with people with known atrial fibrillation (KAF). We systematically reviewed the literature to provide updated estimates for the risk of recurrent stroke, intracerebral hemorrhage, and mortality in AFDAS compared with KAF. Our protocol was registered in PROSPERO (CRD42024583064). Presentation followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. We searched MEDLINE, EMBASE, Cochrane CENTRAL, and MedRxiv up to August 28, 2024, for studies comparing AFDAS and KAF for the following outcomes of interest: recurrent ischemic stroke (primary), intracerebral hemorrhage, mortality, and any stroke recurrence. We included cohort, observational studies (either prospective or retrospective) and randomized controlled trials and excluded studies with less than 15 patients per group. Eligible studies were assessed for bias using the Risk of Bias in Non-Randomized Studies tool. We pooled study-level results through random-effect meta-analysis of risk ratios (RRs). We also performed prespecified sensitivity analysis for study quality, timing of search for AF, propensity score matching, and study data source (administrative vs local data), and we planned meta-regression analysis to test for the interaction of sex, comorbid cardiovascular risk factors, and anticoagulation status on the difference between AFDAS and KAF. Seventeen studies were retrieved (n = 113,365; n_KAF = 80,339; n_AFDAS = 33,026; female in KAF, 49.0%; female in AFDAS, 45.1%), eight of which had low risk of bias. Ischemic stroke recurrence was significantly lower in AFDAS compared with the KAF group (RR = 0.79, 95% CI = 0.66-0.95, I² = 70%; n_studies = 10). Meta-regression analysis revealed no interaction of anticoagulation, CHA₂DS₂-VASc score, or sex on the difference in risk of recurrent ischemic stroke between groups. Mortality was lower in the AFDAS group compared with KAF (RR = 0.84, 95% CI = 0.74-0.95, I² = 74%; n_studies = 14). The rates of any intracerebral bleeding (RR = 0.97, 95% CI = 0.68-1.39, I² = 58%; n_studies = 5) and any stroke recurrence (RR = 0.99, 95% CI = 0.75-1.30; I² = 60; n_studies = 3) were similar in AFDAS and KAF. AFDAS may carry a lower risk of ischemic stroke recurrence and mortality compared with KAF, with similar risk of intracerebral hemorrhage. Stratification through implementation of AF burden measures may support more personalized management for people with AFDAS.