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Importance: One of 10 patients develop epilepsy in the late phase after cerebral venous thrombosis (CVT) diagnosis but predicting the individual risk is difficult., Objective: To develop and externally validate a prognostic score to estimate the individual risk of post-CVT epilepsy., Design, Setting, and Participants: This observational cohort study included both retrospective and prospective patients enrolled from 1994 through 2022. For development of the DIAS3 score, data from the International CVT Consortium (n = 1128), a large international hospital-based multicenter CVT cohort, were used. For validation, data from 2 independent multicenter cohorts, the ACTION-CVT (n = 543) and the Israel CVT study (n = 556), were used. Of 2937 eligible, consecutively enrolled adult patients with radiologically verified CVT, 710 patients with a history of epilepsy prior to CVT, follow-up less than 8 days, and missing late seizure status were excluded., Exposure: The prediction score (DIAS3) was developed based on available literature and clinical plausibility and consisted of 6 readily available clinical variables collected during the acute phase: decompressive hemicraniectomy, intracerebral hemorrhage at presentation, age, seizure(s) in the acute phase (excluding status epilepticus), status epilepticus in the acute phase, and subdural hematoma at presentation., Main Outcome and Measure: Time to a first late seizure, defined as occurring more than 7 days after diagnosis of CVT., Results: Of 1128 patients included in the derivation cohort (median age, 41 [IQR, 30-53] years; 805 women [71%]), 128 (11%) developed post-CVT epilepsy during a median follow-up of 12 (IQR, 3-26) months. According to the DIAS3 score, the predicted 1-year and 3-year risk of epilepsy in individual patients ranged from 7% to 68% and 10% to 83%, respectively. Internal and external validation showed adequate discrimination in the derivation cohort (1 year and 3 years: C statistic, 0.74; 95% CI, 0.70-0.79) and the 2 independent validation cohorts, (ACTION-CVT) 1 year: C statistic, 0.76; 95% CI, 0.67-0.84; 3 years: C statistic, 0.77; 95% CI, 0.66-0.84; and Israel CVT study 1 year: C statistic, 0.80; 95% CI, 0.75-0.86. Calibration plots indicated adequate agreement between predicted and observed risks., Conclusions and Relevance: The DIAS3 score (freely available online) is a simple tool that can help predict the risk of post-CVT epilepsy in individual patients. The model can improve opportunities for personalized medicine and may aid in decision-making regarding antiseizure medication, patient counseling, and facilitation of research on epileptogenesis in CVT.

Introduction: Previous reports and meta-analyses derived from small case series reported a mortality rate of up to 40% in patients with coronavirus disease 2019 associated cerebral venous thrombosis (COVID-CVT). We assessed the clinical characteristics and outcomes in an international cohort of patients with COVID-CVT., Patients and Methods: This was a registry study of consecutive COVID-CVT patients diagnosed between March 2020 and March 2023. Data collected by the International Cerebral Venous Thrombosis Consortium from patients with CVT diagnosed between 2017 and 2018 served as a comparison. Outcome analyses were adjusted for age and sex., Results: We included 70 patients with COVID-CVT from 23 hospitals in 15 countries and 206 controls from 14 hospitals in 13 countries. The proportion of women was smaller in the COVID-CVT group (50% vs 68%, p  < 0.01). A higher proportion of COVID-CVT patients presented with altered mental state (44% vs 25%, p  < 0.01), the median thrombus load was higher in COVID-CVT patients (3 [IQR 2-4] vs 2 [1-3], p  < 0.01) and the length of hospital stay was longer compared to controls (11 days [IQR 7-20] vs 8 [4-15], p  = 0.02). In-hospital mortality did not differ (5/67 [7%, 95% CI 3-16] vs 7/206 [3%, 2-7], aOR 2.6 [95% CI 0.7-9]), nor did the frequency of functional independence after 6 months (modified Rankin Scale 0-2; 45/58 [78%, 95% CI 65-86] vs 161/185 [87%, 81-91], aOR 0.5 [95% CI 0.2-1.02])., Conclusion: In contrast to previous studies, the in-hospital mortality rate and functional outcomes during follow-up did not differ between COVID-CVT patients and the pre-COVID-19 controls., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AS reports a grant from the Swiss Heart Foundation. MRH reports grants from SITEM Research Support Funds and Swiss National Science Foundation, Swiss Heart Foundation, not directly related to this manuscript. MA reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Amgen. JMC has received grants paid to his institution from Boehringer Ingelheim and Bayer, and payments paid to his institution for data safety monitoring board participation by Bayer. JMF has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer. DAS reports travel support from Boehringer Ingelheim, speaker fees from Bayer, and Advisory Board participation for AstraZeneca. TT has received personal fees from Argenx, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma. NR received consultant fees from Novartis. KJ has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 965417) for research on CVT. SP received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research, Helena Laboratories and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside the submitted work). TNN reports advisory board Idorsia, Brainomix. KA reports a grant from Swiss National Science Foundation and Medtronic advisory board participation in 2022, not related to this manuscript. EL has received academic grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG 942851), Swedish Neurologic Society, Elsa and Gustav Lindh’s Foundation, Wennerströms’ Foundation, P-O Ahl’s Foundation and Rune and Ulla Amlöv’s Foundation for research on CVT. All other co-authors report no disclosures.

Background: Due to the rarity of cerebral venous thrombosis (CVT), performing high-quality scientific research in this field is challenging. Providing answers to unresolved research questions will improve prevention, diagnosis, and treatment, and ultimately translate to a better outcome of patients with CVT. We present an international research agenda, in which the most important research questions in the field of CVT are prioritized., Aims: This research agenda has three distinct goals: (1) to provide inspiration and focus to research on CVT for the coming years, (2) to reinforce international collaboration, and (3) to facilitate the acquisition of research funding., Summary of Review: This international research agenda is the result of a research summit organized by the International Cerebral Venous Thrombosis Consortium in Amsterdam, the Netherlands, in June 2023. The summit brought together 45 participants from 15 countries including clinical researchers from various disciplines, patients who previously suffered from CVT, and delegates from industry and non-profit funding organizations. The research agenda is categorized into six pre-specified themes: (1) epidemiology and clinical features, (2) life after CVT, (3) neuroimaging and diagnosis, (4) pathophysiology, (5) medical treatment, and (6) endovascular treatment. For each theme, we present two to four research questions, followed by a brief substantiation per question. The research questions were prioritized by the participants of the summit through consensus discussion., Conclusions: This international research agenda provides an overview of the most burning research questions on CVT. Answering these questions will advance our understanding and management of CVT, which will ultimately lead to improved outcomes for CVT patients worldwide., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: J.M.C. has received research support paid to his institution from Boehringer Ingelheim, Bayer, and Astra Zeneca. J.M.C. is co-founder and shareholder of TrianecT; D.A.d.S. reported personal fees for Astra Zeneca, Organon, Daiichi Sankyo and Johnson & Johnson advisory board participation, DSMB participation for the SECRET trial (University of British Columbia), and speaking fees from Bayer and Bial; S.P. has received research support from BMS/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education and Research, Helena Laboratories, and Werfen as well as speakers’ honoraria/consulting fees from Alexion, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen; A.A. has received research support paid to his Institution from Astra Zeneca; M.S.v.K. has received research support from the Amstol foundation; R.v.d.B. has received research support paid to his institution from CERENOVUS; T.S.F. has received in-kind study medication from Bayer Canada and has received personal fees from Bayer Canada and Roche for advosiry board participation; M.R.H. has received grants from the Swiss National Science Foundation, the SITEM Research Funds, and the Swiss Heart Foundation, all outside the submitted work; M.H.-P. has received compensation for scientific research by AptaTargets; F.A.K. has received research support from Bayer, BMS, BSCI, Astra Zeneca, MSD, Leo Pharma, Actelion, Farm-X, The Netherlands Organization for Health Research and Development, The Dutch Thrombosis Foundation, The Dutch Heart Foundation, and the Horizon Europe Program; R.R.L. has received speaker honoraria from IscemaView, Boehringer Ingelheim, Pfizer, Jansen, Biogen, Medtronic, and Abott and advisory board honoraria from Jansen, Bayer, and Filterlex; T.N.N. has disclosed advisory board for Idorsia and Brainomix; G.S. has received a stipend as the Editor-in-Chief of the World Stroke Academy for the World Stroke Organization; V.T. has received speaker honoraria from Boehringer Ingelheim and Bayer & Astra Zeneca and is on the steering committee of the Librexia Stroke trial, sponsored by Johnson & Johnson; D.J.W. has received grant funding from the Stroke Association and British Heart Foundation, speaking honoraria from Bayer, speaking and chairing honoraria from Alexion and NovoNordisk, and consultancy fees from Alnylam, Bayer, and NovoNordisk; T.T. has served/serves on scientific advisory boards for Astra Zeneca, Argenx, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharm and has received academic funding from University of Gothenburg, Sahlgrenska University Hospital, European Union, Sigrid Juselius Foundation, and Wennerström’s Foundation. The other authors have nothing to disclose.

Introduction: Current guidelines recommend that patients with cerebral venous thrombosis (CVT) should be treated with vitamin K antagonists (VKAs) for 3-12 months. Direct oral anticoagulants (DOACs), however, are increasingly used in clinical practice. An exploratory randomized controlled trial including 120 patients with CVT suggested that the efficacy and safety profile of dabigatran (a DOAC) is similar to VKAs for the treatment of CVT, but large-scale prospective studies from a real-world setting are lacking., Methods: DOAC-CVT is an international, prospective, observational cohort study comparing DOACs to VKAs for the prevention of recurrent venous thrombotic events after acute CVT. Patients are eligible if they are 18 years or older, have a radiologically confirmed CVT, and have started oral anticoagulant treatment (DOAC or VKA) within 30 days of CVT diagnosis. Patients with an absolute contra-indication for DOACs, such as pregnancy or severe renal insufficiency, are excluded from the study. We aim to recruit at least 500 patients within a three-year recruitment period. The primary endpoint is a composite of recurrent venous thrombosis and major bleeding at 6 months of follow-up. We will calculate an adjusted odds ratio for the primary endpoint using propensity score inverse probability treatment weighting., Discussion: DOAC-CVT will provide real-world data on the comparative efficacy and safety of DOACs versus VKAs for the treatment of CVT., Clinical Trial Registration: ClinicalTrials.gov, NCT04660747., Competing Interests: DA reports travel support from Boehringer Ingelheim, speaker fees from Bayer, and Advisory Board participation for AstraZeneca; MH reports grants from Swiss National Science Foundation, SITEM Support Funds and Swiss Heart Foundation, all outside the submitted work; TK has received educational meeting cost assistance from Boehringer Ingelheim; RL reports fees paid to his institution for consultancy by Boehringer Ingelheim, Genentech, Ischemaview, Medtronic and Medpass; SP has received research support from BMS/Pfizer, Boehringer-Ingelheim, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, German Federal Ministry of Education and Research, Helena Laboratories, and Werfen as well as speakers’ honoraria/consulting fees from Alexion, AstraZeneca, Bayer, Boehringer-Ingelheim, BMS/Pfizer, Daiichi Sankyo, Portola, and Werfen (all outside of the submitted work); MA reports personal fees from AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Novartis, Pfizer, and Amgen; TT has received personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Inventiva, and Portola Pharma; JF has received personal fees from Boehringer Ingelheim, Bayer, and Daiichi Sankyo as well as grants from Bayer; JC has received grants paid to his institution from Boehringer Ingelheim and Bayer, and payments paid to his institution for data safety monitoring board participation by Bayer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 van de Munckhof, Sánchez van Kammen, Krzywicka, Aaron, Aguiar de Sousa, Antochi, Arauz, Barboza, Conforto, Dentali, Galdames Contreras, Ji, Jood, Heldner, Hernández-Pérez, Kam, Kleinig, Kristoffersen, Leker, Lemmens, Poli, Yeşilot, Wasay, Wu, Arnold, Lucas-Neto, Middeldorp, Putaala, Tatlisumak, Ferro and Coutinho.)

Background and Purpose: A prognostic score was developed to predict dependency and death after cerebral venous thrombosis (CVT) to identify patients for targeted therapy in future clinical trials., Methods: Data from the International CVT Consortium were used. Patients with pre-existent functional dependency were excluded. Logistic regression was used to predict poor outcome (modified Rankin Scale score 3-6) at 6 months and Cox regression to predict 30-day and 1-year all-cause mortality. Potential predictors derived from previous studies were selected with backward stepwise selection. Coefficients were shrunk using ridge regression to adjust for optimism in internal validation., Results: Of 1454 patients with CVT, the cumulative number of deaths was 44 (3%) and 70 (5%) for 30 days and 1 year, respectively. Of 1126 patients evaluated regarding functional outcome, 137 (12%) were dependent or dead at 6 months. From the retained predictors for both models, the SI 2 NCAL 2 C score was derived utilizing the following components: absence of female-sex-specific risk factor, intracerebral hemorrhage, infection of the central nervous system, neurological focal deficits, coma, age, lower level of hemoglobin (g/l), higher level of glucose (mmol/l) at admission, and cancer. C-statistics were 0.80 (95% confidence interval [CI] 0.75-0.84), 0.84 (95% CI 0.80-0.88) and 0.84 (95% CI 0.80-0.88) for the poor outcome, 30-day and 1-year mortality model, respectively. Calibration plots indicated a good model fit between predicted and observed values. The SI 2 NCAL 2 C score calculator is freely available at www.cerebralvenousthrombosis.com., Conclusions: The SI 2 NCAL 2 C score shows adequate performance for estimating individual risk of mortality and dependency after CVT but external validation of the score is warranted., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is an adverse drug reaction occurring after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. CVST-VITT patients often present with large intracerebral haemorrhages and a high proportion undergoes decompressive surgery. Clinical characteristics, therapeutic management and outcomes of CVST-VITT patients who underwent decompressive surgery are described and predictors of in-hospital mortality in these patients are explored., Methods: Data from an ongoing international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 10 May 2022, were used. Definite, probable and possible VITT cases, as defined by Pavord et al. (N Engl J Med 2021; 385: 1680-1689), were included., Results: Decompressive surgery was performed in 34/128 (27%) patients with CVST-VITT. In-hospital mortality was 22/34 (65%) in the surgical and 27/94 (29%) in the non-surgical group (p < 0.001). In all surgical cases, the cause of death was brain herniation. The highest mortality rates were found amongst patients with preoperative coma (17/18, 94% vs. 4/14, 29% in the non-comatose; p < 0.001) and bilaterally absent pupillary reflexes (7/7, 100% vs. 6/9, 67% with unilaterally reactive pupil, and 4/11, 36% with bilaterally reactive pupils; p = 0.023). Postoperative imaging revealed worsening of index haemorrhagic lesion in 19 (70%) patients and new haemorrhagic lesions in 16 (59%) patients. At a median follow-up of 6 months, 8/10 of surgical CVST-VITT who survived admission were functionally independent., Conclusions: Almost two-thirds of surgical CVST-VITT patients died during hospital admission. Preoperative coma and bilateral absence of pupillary responses were associated with higher mortality rates. Survivors often achieved functional independence., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Recent reports suggest an association between dural AVFs and cerebral venous thrombosis. We aimed to investigate the specific temporal and anatomic association between the 2 conditions., Materials and Methods: A consecutive cohort of adult patients with dural AVFs was seen at Amsterdam University Medical Centers (2007-2020). An experienced neuroradiologist re-evaluated the presence and imaging characteristics of dural AVFs and cerebral venous thrombosis on all available imaging. The temporal (previous/concurrent/subsequent) and anatomic (same/adjacent/unrelated venous sinus or vein) association between dural AVFs and cerebral venous thrombosis was determined., Results: Among 178 patients with dural AVFs, the mean age was 58.3 (SD, 13.2) years and 85 (48%) were women. Of 55 patients (31%) with cerebral venous thrombosis, 34 (62%) were women. Four patients (7%) had cerebral venous thrombosis before the development of a dural AVF, 33 (60%) had cerebral venous thrombosis at the time of dural AVF diagnosis (concurrent), and 18 (33%) developed cerebral venous thrombosis during follow-up after conservative treatment. The incidence rate of cerebral venous thrombosis after a dural AVF was 79 per 1000 person-years (95% CI, 50-124). In 45 (82%) patients with dural AVFs and cerebral venous thrombosis, the thrombosis was located in the same venous sinus as the dural AVF, whereas in 8 (15%) patients, thrombosis occurred in a venous sinus adjacent to the dural AVF., Conclusions: One-third of patients with a dural AVF in this study were diagnosed with cerebral venous thrombosis. In almost two-thirds of patients, cerebral venous thrombosis was diagnosed prior to or concurrent with the dural AVF. In 97% of patients, there was an anatomic association between the dural AVF and cerebral venous thrombosis. These data support the hypothesis of a bidirectional association between the 2 diseases., (© 2022 by American Journal of Neuroradiology.)

Background: Cerebral venous thrombosis (CVT) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe condition, with high in-hospital mortality rates. Here, we report clinical outcomes of patients with CVT-VITT after SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccination who survived initial hospitalization., Methods: We used data from an international registry of patients who developed CVT within 28 days of SARS-CoV-2 vaccination, collected until February 10, 2022. VITT diagnosis was classified based on the Pavord criteria. Outcomes were mortality, functional independence (modified Rankin Scale score 0-2), VITT relapse, new thrombosis, and bleeding events (all after discharge from initial hospitalization)., Results: Of 107 CVT-VITT cases, 43 (40%) died during initial hospitalization. Of the remaining 64 patients, follow-up data were available for 60 (94%) patients (37 definite VITT, 9 probable VITT, and 14 possible VITT). Median age was 40 years and 45/60 (75%) patients were women. Median follow-up time was 150 days (interquartile range, 94-194). Two patients died during follow-up (3% [95% CI, 1%-11%). Functional independence was achieved by 53/60 (88% [95% CI, 78%-94%]) patients. No new venous or arterial thrombotic events were reported. One patient developed a major bleeding during follow-up (fatal intracerebral bleed)., Conclusions: In contrast to the high mortality of CVT-VITT in the acute phase, mortality among patients who survived the initial hospitalization was low, new thrombotic events did not occur, and bleeding events were rare. Approximately 9 out of 10 CVT-VITT patients who survived the acute phase were functionally independent at follow-up.

Background: Cerebral venous thrombosis (CVT) has recently been reported as a common thrombotic manifestation in association with vaccine-induced thrombotic thrombocytopenia, a syndrome that mimics heparin-induced thrombocytopenia (HIT) and occurs after vaccination with adenovirus-based SARS-CoV-2 vaccines. We aimed to systematically review the incidence, clinical features, and prognosis of CVT occurring in patients with HIT., Methods: The study protocol was registered with PROSPERO (CRD42021249652). MEDLINE, EMBASE and Cochrane CENTRAL were searched up to June 1, 2021 for HIT case series including >20 patients, or any report of HIT-related CVT. Demographic, neuroradiological, clinical, and mortality data were retrieved. Meta-analysis of proportions with random-effect modeling was used to derive rate of CVT in HIT and in-hospital mortality. Pooled estimates were compared with those for CVT without HIT and HIT without CVT, to determine differences in mortality., Results: From 19073 results, we selected 23 case series of HIT (n=1220) and 27 cases of HIT-related CVT (n=27, 71% female). CVT developed in 1.6% of 1220 patients with HIT (95% CI,1.0%-2.5%, I 2 =0%). Hemorrhagic brain lesions occurred in 81.8% of cases of HIT-related CVT and other concomitant thrombosis affecting other vascular territory was reported in 47.8% of cases. In-hospital mortality was 33.3%. HIT-related CVT carried a 29% absolute increase in mortality rate compared with historical CVT controls (33.3% versus 4.3%, P <0.001) and a 17.4% excess mortality compared with HIT without CVT (33.3% versus 15.9%, P =0.046)., Conclusions: CVT is a rare thrombotic manifestation in patients with HIT. HIT-related CVT has higher rates of intracerebral hemorrhage and a higher mortality risk, when compared with CVT in historical controls. The recently reported high frequency of CVT in patients with vaccine-induced thrombotic thrombocytopenia was not observed in HIT, suggesting that additional pathophysiological mechanisms besides anti-platelet factor-4 antibodies might be involved in vaccine-induced thrombotic thrombocytopenia-related CVT.

Background and Purpose: To explore the prevalence, risk factors, time correlation, characteristics and clinical outcome of dural arteriovenous fistulas (dAVFs) in a cerebral venous thrombosis (CVT) population., Methods: We included patients from the International CVT Consortium registries. Diagnosis of dAVF was confirmed centrally. We assessed the prevalence and risk factors for dAVF among consecutive CVT patients and investigated its impact on clinical outcome using logistic regression analysis. We defined poor outcome as modified Rankin Scale score 3-6 at last follow-up., Results: dAVF was confirmed in 29/1218 (2.4%) consecutive CVT patients. The median (interquartile range [IQR]) follow-up time was 8 (5-23) months. Patients with dAVF were older (median [IQR] 53 [44-61] vs. 41 [29-53] years; p < 0.001), more frequently male (69% vs. 33%; p < 0.001), more often had chronic clinical CVT onset (>30 days: 39% vs. 7%; p < 0.001) and sigmoid sinus thrombosis (86% vs. 51%; p < 0.001), and less frequently had parenchymal lesions (31% vs. 55%; p = 0.013) at baseline imaging. Clinical outcome at last follow-up did not differ between patients with and without dAVF. Additionally, five patients were confirmed with dAVF from non-consecutive CVT cohorts. Among all patients with CVT and dAVF, 17/34 (50%) had multiple fistulas and 23/34 (68%) had cortical venous drainage. Of 34 patients with dAVF with 36 separate CVT events, 3/36 fistulas (8%) were diagnosed prior to, 20/36 (56%) simultaneously and 13/36 after (36%, median 115 [IQR 38-337] days) diagnosis of CVT., Conclusions: Dural arteriovenous fistulas occur in at least 2% of CVT patients and are associated with chronic CVT onset, older age and male sex. Most CVT-related dAVFs are detected simultaneously or subsequently to diagnosis of CVT., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: We aimed to describe the clinical presentation, risk of bleeding and recurrent thrombosis, and perioperative anticoagulant management of children with cerebral venous thrombosis (CVT) and an associated head or neck infection., Methods: In this subgroup analysis of the EINSTEIN-Jr study, we included children with CVT and an associated head or neck infection who received therapeutic anticoagulants with either low-molecular-weight heparin (with or without subsequent vitamin K antagonists) or rivaroxaban for a period of 3 months. Analyses are descriptive., Results: Of 74 included children, 59 (80%) had otomastoiditis, 21 (28%) a central nervous system infection, 18 (24%) sinusitis, and 9 (12%) another upper respiratory tract infection; 29 (39%) had infection of multiple regions of the head or neck. All 74 children received antibiotics and therapeutic anticoagulants; 41 (55%) underwent surgery, of whom 34 were diagnosed with CVT preoperatively. Anticoagulation was started before surgery in 12 children and interrupted 0-1 days prior to surgery. Anticoagulation was (re)started in all 34 children at a median of 1 day (interquartile range: 0-1) postoperatively, in therapeutic doses in 94%. Overall, one child (1%, 95% confidence interval: 0-7) had recurrent thrombosis, and one (1%, 95% confidence interval: 0-7) had major bleeding; neither was associated with surgery. At 3 months, no children had died, 3 (4%) had persistent focal neurologic deficits, and 2 (3%) had impaired vision., Conclusions: Children with CVT and an associated head or neck infection administered therapeutic anticoagulants generally had low risks of bleeding and thrombotic complications, including those who had surgical interventions with delay or interruption of anticoagulation., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Cerebral venous sinus thrombosis (CVST) as a part of the thrombosis and thrombocytopenia syndrome is a rare adverse drug reaction of severe acute respiratory syndrome coronavirus disease 2 (SARS-CoV-2) vaccination. Estimated background rate of CVST with thrombocytopenia is 0.1 per million per month. We assessed the age-stratified risk of CVST with and without thrombocytopenia after SARS-CoV-2 vaccination., Methods: We estimated the absolute risk of CVST with and without thrombocytopenia within 28 days of a first dose of 4 SARS-CoV-2 vaccinations using data from the European Medicines Agency's EudraVigilance database (until June 13, 2021). As a denominator, we used data on vaccine delivery from 31 European countries. For 22.8 million adults from 25 countries, we estimated the absolute risk of CVST after the first dose of ChAdOx1 nCov-19 per age category., Results: The absolute risk of CVST within 28 days of first-dose vaccination was 7.5 (95% confidence interval [CI] 6.9-8.3), 0.7 (95% CI 0.2-2.4), 0.6 (95% CI 0.5-0.7), and 0.6 (95% CI 0.3-1.1) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. The absolute risk of CVST with thrombocytopenia within 28 days of first dose vaccination was 4.4 (95% CI 3.9-4.9), 0.7 (95% CI 0.2-2.4), 0.0 (95% CI 0.0-0.1), and 0.0 (95% CI 0.0-0.2) per million of first doses of ChAdOx1 nCov-19, Ad26.COV2.S, BNT162b2, and mRNA-1273, respectively. In recipients of ChAdOx1 nCov-19, the absolute risk of CVST, both with and without thrombocytopenia, was the highest in the 18- to 24-year-old group (7.3 per million, 95% CI 2.8-18.8 and 3.7 per million, 95% CI 1.0-13.3, respectively). The risk of CVST with thrombocytopenia in ChAdOx1 nCov-19 recipients was the lowest in the age group ≥70 years (0.2, 95% CI 0.0-1.3). Age <60 years compared to ≥60 years was a predictor for CVST with thrombocytopenia (incidence rate ratio 5.79, 95% CI 2.98-11.24, p < 0.001)., Discussion: The risk of CVST with thrombocytopenia within 28 days of first-dose vaccination with ChAdOx1 nCov-19 was higher in younger age groups. The risk of CVST with thrombocytopenia was slightly increased in patients receiving Ad26.COV2.S compared with the estimated background risk. The risk of CVST with thrombocytopenia was not increased in recipients of SARS-CoV-2 mRNA vaccines., (© 2021 American Academy of Neurology.)

Background and Purpose: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time., Methods: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published., Results: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died., Conclusion: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported., Methods: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium., Results: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%)., Conclusions: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson)., Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS., Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination., Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria., Main Outcomes and Measures: Clinical characteristics and mortality rate., Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later., Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism., Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic., Design, Setting, and Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies., Exposures: Diagnosis of cerebral venous sinus thrombosis., Main Outcomes and Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/μL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples)., Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/μL) in 52 (6.0%), moderate (50-99 ×103/μL) in 17 (2.0%), and severe (<50 ×103/μL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies., Conclusions and Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.

Anticoagulant treatment of pediatric cerebral venous thrombosis has not been evaluated in randomized trials. We evaluated the safety and efficacy of rivaroxaban and standard anticoagulants in the predefined subgroup of children with cerebral venous thrombosis (CVT) who participated in the EINSTEIN-Jr trial. Children with CVT were randomized (2:1), after initial heparinization, to treatment with rivaroxaban or standard anticoagulants (continued on heparin or switched to vitamin K antagonist). The main treatment period was 3 months. The primary efficacy outcome, symptomatic recurrent venous thromboembolism (VTE), and principal safety outcome, major or clinically relevant nonmajor bleeding,were centrally evaluated by blinded investigators. Sinus recanalization on repeat brain imaging was a secondary outcome. Statistical analyses were exploratory. In total, 114 children with confirmed CVT were randomized. All children completed the follow-up. None of the 73 rivaroxaban recipients and 1 (2.4%; CVT) of the 41 standard anticoagulant recipients had symptomatic, recurrent VTE after 3 months (absolute difference, 2.4%; 95% confidence interval [CI], -2.6% to 13.5%). Clinically relevant bleeding occurred in 5 (6.8%; all nonmajor and noncerebral) rivaroxaban recipients and in 1 (2.5%; major [subdural] bleeding) standard anticoagulant recipient (absolute difference, 4.4%; 95% CI, -6.7% to 13.4%). Complete or partial sinus recanalization occurred in 18 (25%) and 39 (53%) rivaroxaban recipients and in 6 (15%) and 24 (59%) standard anticoagulant recipients, respectively. In summary, in this substudy of a randomized trial with a limited sample size, children with CVT treated with rivaroxaban or standard anticoagulation had a low risk of recurrent VTE and clinically relevant bleeding. This trial was registered at clinicaltrials.gov as #NCT02234843., (© 2020 by The American Society of Hematology.)

Objective: To identify characteristics, predictors, and outcomes of acute symptomatic seizures (ASS) in cerebral venous thrombosis (CVT), we investigated 1,281 consecutive adult patients with CVT included from 12 hospitals within the International CVT Consortium., Methods: We defined ASS as any seizure between symptom onset and 7 days after diagnosis of CVT. We stratified ASS into prediagnosis and solely postdiagnosis ASS. Status epilepticus (SE) was also analyzed separately. We analyzed predictors for ASS and the association between ASS and clinical outcome (modified Rankin Scale) with multivariable logistic regression., Results: Of 1,281 eligible patients, 441 (34%) had ASS. Baseline predictors for ASS were intracerebral hemorrhage (ICH; adjusted odds ratio [aOR] 4.1, 95% confidence interval [CI] 3.0-5.5), cerebral edema/infarction without ICH (aOR 2.8, 95% CI 2.0-4.0), cortical vein thrombosis (aOR 2.1, 95% CI 1.5-2.9), superior sagittal sinus thrombosis (aOR 2.0, 95% CI 1.5-2.6), focal neurologic deficit (aOR 1.9, 95% CI 1.4-2.6), sulcal subarachnoid hemorrhage (aOR 1.6, 95% CI 1.1-2.5), and female-specific risk factors (aOR 1.5, 95% CI 1.1-2.1). Ninety-three (7%) patients had solely postdiagnosis ASS, best predicted by cortical vein thrombosis (positive/negative predictive value 22%/92%). Eighty (6%) patients had SE, independently predicted by ICH, focal neurologic deficits, and cerebral edema/infarction. Neither ASS nor SE was independently associated with outcome., Conclusion: ASS occurred in one-third of patients with CVT and was associated with brain parenchymal lesions and thrombosis of the superficial system. In the absence of prediagnosis ASS, no subgroup was identified with sufficient risk of postdiagnosis ASS to justify prophylactic antiepileptic drug treatment. We found no association between ASS and outcome., (© 2020 American Academy of Neurology.)

Objective: To examine the incidence, characteristics, treatment, and predictors of late seizures (LS) after cerebral venous thrombosis (CVT), we described these features in a registry of 1,127 patients with CVT., Methods: We included consecutive adult patients from an international consortium of 12 hospital-based CVT registries. We excluded patients with a history of epilepsy or with <8 days of follow-up. We defined LS as seizures occurring >7 days after diagnosis of CVT. We used multivariable Cox regression to identify predictors of LS., Results: We included 1,127 patients with CVT. During a median follow-up of 2.0 years (interquartile range [IQR] 1.0-6.3), 123 patients (11%) experienced ≥1 LS (incidence rate for first LS 30 per 1,000 person-years, 95% confidence interval [CI] 25-35). Median time to first LS was 5 months (IQR 1-16 months). Baseline predictors of LS included status epilepticus in the acute phase (hazard ratio [HR] 7.0, 95% CI 3.9-12.6), decompressive hemicraniectomy (HR 4.2, 95% CI 2.4-7.3), acute seizure(s) without status epilepticus (HR 4.1, 95% CI 2.5-6.5), subdural hematoma (HR 2.3, 95% CI 1.1-4.9), and intracerebral hemorrhage (HR 1.9, 95% CI 1.1-3.1). Eighty-five patients (70% of patients with LS) experienced a recurrent seizure during follow-up, despite the fact that 94% received antiepileptic drug treatment after the first LS., Conclusion: During a median follow-up of 2 years, ≈1 in 10 patients with CVT had LS. Patients with baseline intracranial bleeding, patients with acute symptomatic seizures, and those who underwent decompressive hemicraniectomy were at increased risk of developing LS. The high recurrence risk of LS justifies epilepsy diagnosis after a first LS., (© 2020 American Academy of Neurology.)

Background and Purpose: Prediction of intracranial aneurysm growth risk can assist physicians in planning of follow-up imaging of conservatively managed unruptured intracranial aneurysms. We therefore aimed to externally validate the ELAPSS (Earlier subarachnoid hemorrhage, aneurysm Location, Age, Population, aneurysm Size and Shape) score for prediction of the risk of unruptured intracranial aneurysm growth., Methods: From 11 international cohorts of patients ≥18 years with ≥1 unruptured intracranial aneurysm and ≥6 months of radiological follow-up, we collected data on the predictors of the ELAPSS score, and calculated 3- and 5-year absolute growth risks according to the score. Model performance was assessed in terms of calibration (predicted versus observed risk) and discrimination (c-statistic)., Results: We included 1,072 patients with a total of 1,452 aneurysms. During 4,268 aneurysm-years of follow-up, 199 (14%) aneurysms enlarged. Calibration was comparable to that of the development cohort with the overall observed risks within the range of the expected risks. The c-statistic was 0.69 (95% confidence interval [CI], 0.64 to 0.73) at 3 years, compared to 0.72 (95% CI, 0.68 to 0.76) in the development cohort. At 5 years, the c-statistic was 0.68 (95% CI, 0.64 to 0.72), compared to 0.72 (95% CI, 0.68 to 0.75) in the development cohort., Conclusion: s The ELAPSS score showed accurate calibration for 3- and 5-year risks of aneurysm growth and modest discrimination in our external validation cohort. This indicates that the score is externally valid and could assist patients and physicians in predicting growth of unruptured intracranial aneurysms and plan follow-up imaging accordingly.

Background: Intracranial aneurysms more often occur in the same arterial territory within families. Several aneurysm locations are associated with specific circle of Willis variations. We investigated whether the same circle of Willis variations are more likely to occur in first-degree relatives than in unrelated individuals., Methods: We assessed four circle of Willis variations (classical, A1-asymmetry, incomplete posterior communicating artery and fetal circulation) in two independent groups of families with familial aneurysms and ≥2 first-degree relatives with circle of Willis imaging on MRA/CTA. In each (index) family we determined the proportion of first-degree relatives with the same circle of Willis variation as the proband and compared it to the proportion of first-degree relatives of a randomly selected unrelated (comparison) family who had the same circle of Willis variation as the index family's proband. Concordance in index families and comparison families was compared with a conditional logistic events/trials model. The analysis was simulated 1001 times; we report the median concordances, odds ratios (ORs), and 95% confidence intervals (95%CI). The groups were analysed separately and together by meta-analysis., Results: We found a higher overall concordance in circle of Willis configuration in index families than in comparison families (meta-analysis, 244 families: OR 2.2, 95%CI 1.6-3.0) mostly attributable to a higher concordance in incomplete posterior communicating artery (meta-analysis: OR 2.8, 95%CI 1.8-4.3). No association was found for the other three circle of Willis variations., Conclusions: In two independent groups of families with familial aneurysms, the incomplete PcomA variation occurred more often within than between families suggesting heritability of this circle of Willis variation. Further studies should investigate genetic variants associated with circle of Willis formation.