External validation of the SI2NCAL2C score for outcomes following cerebral venous thrombosis.

OBJECTIVES: Prognostication for cerebral venous thrombosis (CVT) remains difficult. We sought to validate the SI2NCAL2C score in an international cohort. MATERIALS AND METHODS: The SI2NCAL2C score was originally developed to predict poor outcome (modified Rankin Scale (mRS) 3-6) at 6 months, and mortality at 30 days and 1 year using data from the International CVT Consortium. The SI2NCAL2C score uses 9 variables: the absence of any female-sex-specific risk factors, intracerebral hemorrhage, central nervous system infection, focal neurological deficits, coma, age, lower level of hemoglobin, higher level of glucose, and cancer. The ACTION-CVT study was an international retrospective study that enrolled consecutive patients across 27 centers. The poor outcome score was validated using 90-day mRS due to lack of follow-up at the 6-month time-point in the ACTION-CVT cohort. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plots. Missing data were imputed using the additive regression and predictive mean matching methods. Bootstrapping was performed with 1000 iterations. RESULTS: Mortality data were available for 950 patients and poor outcome data were available for 587 of 1,025 patients enrolled in ACTION-CVT. Compared to the International CVT Consortium, the ACTION-CVT cohort was older, less often female, and with milder clinical presentation. Mortality was 2.5% by 30 days and 6.0% by one year. At 90-days, 16.7% had a poor outcome. The SI2NCAL2C score had an AUC of 0.74 [95% CI 0.69-0.79] for 90-day poor outcome, 0.72 [0.60-0.82] for mortality by 30 days, and 0.82 [0.76-0.88] for mortality by one year. CONCLUSIONS: The SI2NCAL2C score had acceptable to good performance in an international external validation cohort. The SI2NCAL2C score warrants additional validation studies in diverse populations and clinical implementation studies.

Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.

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.

A scoring tool to predict mortality and dependency after cerebral venous thrombosis.

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 SI2 NCAL2 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 SI2 NCAL2 C score calculator is freely available at www.cerebralvenousthrombosis.com. CONCLUSIONS: The SI2 NCAL2 C score shows adequate performance for estimating individual risk of mortality and dependency after CVT but external validation of the score is warranted.

Decompressive surgery in cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

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.

Outcomes of Cerebral Venous Thrombosis due to Vaccine-Induced Immune Thrombotic Thrombocytopenia After the Acute Phase.

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.

Declining mortality of cerebral venous sinus thrombosis with thrombocytopenia after SARS-CoV-2 vaccination.

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.

Color Naming and Categorization Depend on Distinct Functional Brain Networks.

Naming a color can be understood as an act of categorization, that is, identifying it as a member of a category of colors that are referred to by the same name. But are naming and categorization equivalent cognitive processes and consequently rely on same neural substrates? Here, we used task and resting-state functional magnetic resonance imaging as well as behavioral measures to identify functional brain networks that modulated naming and categorization of colors. We first identified three bilateral color-sensitive regions in the ventro-occipital cortex. We then showed that, across participants, color naming and categorization response times (RTs) were correlated with different resting state connectivity networks seeded from the color-sensitive regions. Color naming RTs correlated with the connectivity between the left posterior color region, the left middle temporal gyrus, and the left angular gyrus. In contrast, color categorization RTs correlated with the connectivity between the bilateral posterior color regions, and left frontal, right temporal and bilateral parietal areas. The networks supporting naming and categorization had a minimal overlap, indicating that the 2 processes rely on different neural mechanisms.

Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency.

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.

When colours split from objects: The disconnection of colour perception from colour language and colour knowledge.

We investigated object-colour knowledge in RDS, a patient with impaired colour naming after a left occipito-temporal stroke. RDS's colour perception, object naming and verbal colour-knowledge (the ability to verbally say the typical colour of an object) were relatively spared. RDS was also able to state if an object was appropriately coloured or not. However, he could neither match colour names to coloured objects, nor match colour patches to grey-scale objects. Thus, RDS's colour-naming deficit was associated with an impaired ability to conceptually relate visually presented object shapes and colours. These results suggest that objects in their typical colour are processed holistically in the visual modality, and that abilities important for colour naming may also be involved in abstracting colours from visual objects. We discuss these findings in the context of developmental psychology and linguistic anthropology, and propose a model of neuro-functional organization of object-colour knowledge.

Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation.

The entorhinal cortex is one of the first regions to exhibit neurodegeneration in Alzheimer's disease, and as such identification of entorhinal cortex dysfunction may aid detection of the disease in its earliest stages. Extensive evidence demonstrates that the entorhinal cortex is critically implicated in navigation underpinned by the firing of spatially modulated neurons. This study tested the hypothesis that entorhinal-based navigation is impaired in pre-dementia Alzheimer's disease. Forty-five patients with mild cognitive impairment (26 with CSF Alzheimer's disease biomarker data: 12 biomarker-positive and 14 biomarker-negative) and 41 healthy control participants undertook an immersive virtual reality path integration test, as a measure of entorhinal-based navigation. Behavioural performance was correlated with MRI measures of entorhinal cortex volume, and the classification accuracy of the path integration task was compared with a battery of cognitive tests considered sensitive and specific for early Alzheimer's disease. Biomarker-positive patients exhibited larger errors in the navigation task than biomarker-negative patients, whose performance did not significantly differ from controls participants. Path-integration performance correlated with Alzheimer's disease molecular pathology, with levels of CSF amyloid-ß and total tau contributing independently to distance error. Path integration errors were negatively correlated with the volumes of the total entorhinal cortex and of its posteromedial subdivision. The path integration task demonstrated higher diagnostic sensitivity and specificity for differentiating biomarker positive versus negative patients (area under the curve = 0.90) than was achieved by the best of the cognitive tests (area under the curve = 0.57). This study demonstrates that an entorhinal cortex-based virtual reality navigation task can differentiate patients with mild cognitive impairment at low and high risk of developing dementia, with classification accuracy superior to reference cognitive tests considered to be highly sensitive to early Alzheimer's disease. This study provides evidence that navigation tasks may aid early diagnosis of Alzheimer's disease, and the basis of this in animal cellular and behavioural studies provides the opportunity to answer the unmet need for translatable outcome measures for comparing treatment effect across preclinical and clinical trial phases of future anti-Alzheimer's drugs.

Endovascular treatment of cerebral sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia.

INTRODUCTION: There is little data on the role of endovascular treatment (EVT) of cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT). Here, we describe clinical characteristics and outcomes of CVST-VITT patients who were treated with EVT. PATIENTS AND METHODS: We report data from an international registry of patients who developed CVST within 28 days of SARS-CoV-2 vaccination, reported between 29 March 2021 and 6 March 2023. VITT was defined according to the Pavord criteria. RESULTS: EVT was performed in 18/136 (13%) patients with CVST-VITT (92% aspiration and/or stent retrieval, 8% local thrombolysis). Most common indications were extensive thrombosis and clinical or radiological deterioration. Compared to non-EVT patients, those receiving EVT had a higher median thrombus load (4.5 vs 3). Following EVT, local blood flow was improved in 83% (10/12, 95% confidence interval [CI] 54-96). One (6%) asymptomatic sinus perforation occurred. Eight (44%) patients treated with EVT also underwent decompressive surgery. Mortality was 50% (9/18, 95% CI 29-71) and 88% (8/9, 95% CI 25-66) of surviving EVT patients achieved functional independence with a modified Rankin Scale score of 0-2 at follow-up. In multivariable analysis, EVT was not associated with increased mortality (adjusted odds ratio, 0.66, 95% CI 0.16-2.58). DISCUSSION AND CONCLUSION: We describe the largest cohort of CVST-VITT patients receiving EVT. Half of the patients receiving EVT died during hospital admission, but most survivors achieved functional independence.

Reducing the global burden of cerebral venous thrombosis: An international research agenda.

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.

Characteristics and outcomes of cerebral venous thrombosis associated with COVID-19.

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.

When practice does not make a perfect - paradoxical learning curve in schizophrenia and bipolar disorder revealed by different serial reaction time task variants.

Introduction: Our previous studies identified a paradoxical implicit motor learning curve in schizophrenia (SZ) and bipolar disorder (BD) patients. This study aimed to verify whether those previously observed deficits may be captured by a new version of the ambidextrous serial reaction time task (SRTT), prepared for use in the MRI. Methods: This study involved 186 participants. A total of 97 participants (33 BD, 33 SZ, and 31 healthy controls, HCs) completed the original, unlimited time response variant of SRTT. A total of 90 individuals (30 BD, 30 SZ, and 30 HCs) underwent a newer, limited response time version of this procedure. Results: There was no significant difference in terms of implicit motor learning indices between both limited and unlimited response time SRTT. Compared to HCs, SZ, and BD patients presented decreased indices of implicit motor learning. Both clinical groups showed a paradoxical learning pattern that differed significantly from the HCs. Moreover, in the SZ group, the pattern depended on the hand performing SRTT. Discussion: The limited response time SRTT variant allowed us to replicate the findings of disrupted implicit motor learning in SZ and BD. The use of this paradigm in further neuroimaging studies may help to determine the neuronal underpinnings of this cognitive dysfunction in the abovementioned clinical groups.

Sex differences in cerebral venous sinus thrombosis after adenoviral vaccination against COVID-19.

INTRODUCTION: Cerebral venous sinus thrombosis associated with vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) is a severe disease with high mortality. There are few data on sex differences in CVST-VITT. The aim of our study was to investigate the differences in presentation, treatment, clinical course, complications, and outcome of CVST-VITT between women and men. PATIENTS AND METHODS: We used data from an ongoing international registry on CVST-VITT. VITT was diagnosed according to the Pavord criteria. We compared the characteristics of CVST-VITT in women and men. RESULTS: Of 133 patients with possible, probable, or definite CVST-VITT, 102 (77%) were women. Women were slightly younger [median age 42 (IQR 28-54) vs 45 (28-56)], presented more often with coma (26% vs 10%) and had a lower platelet count at presentation [median (IQR) 50x109/L (28-79) vs 68 (30-125)] than men. The nadir platelet count was lower in women [median (IQR) 34 (19-62) vs 53 (20-92)]. More women received endovascular treatment than men (15% vs 6%). Rates of treatment with intravenous immunoglobulins were similar (63% vs 66%), as were new venous thromboembolic events (14% vs 14%) and major bleeding complications (30% vs 20%). Rates of good functional outcome (modified Rankin Scale 0-2, 42% vs 45%) and in-hospital death (39% vs 41%) did not differ. DISCUSSION AND CONCLUSIONS: Three quarters of CVST-VITT patients in this study were women. Women were more severely affected at presentation, but clinical course and outcome did not differ between women and men. VITT-specific treatments were overall similar, but more women received endovascular treatment.

Cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia in middle-income countries.

BACKGROUND: Adenovirus-based COVID-19 vaccines are extensively used in low- and middle-income countries (LMICs). Remarkably, cases of cerebral venous sinus thrombosis due to vaccine-induced immune thrombotic thrombocytopenia (CVST-VITT) have rarely been reported from LMICs. AIMS: We studied the frequency, manifestations, treatment, and outcomes of CVST-VITT in LMICs. METHODS: We report data from an international registry on CVST after COVID-19 vaccination. VITT was classified according to the Pavord criteria. We compared CVST-VITT cases from LMICs to cases from high-income countries (HICs). RESULTS: Until August 2022, 228 CVST cases were reported, of which 63 were from LMICs (all middle-income countries [MICs]: Brazil, China, India, Iran, Mexico, Pakistan, Turkey). Of these 63, 32 (51%) met the VITT criteria, compared to 103 of 165 (62%) from HICs. Only 5 of the 32 (16%) CVST-VITT cases from MICs had definite VITT, mostly because anti-platelet factor 4 antibodies were often not tested. The median age was 26 (interquartile range [IQR] 20-37) versus 47 (IQR 32-58) years, and the proportion of women was 25 of 32 (78%) versus 77 of 103 (75%) in MICs versus HICs, respectively. Patients from MICs were diagnosed later than patients from HICs (1/32 [3%] vs. 65/103 [63%] diagnosed before May 2021). Clinical manifestations, including intracranial hemorrhage, were largely similar as was intravenous immunoglobulin use. In-hospital mortality was lower in MICs (7/31 [23%, 95% confidence interval (CI) 11-40]) than in HICs (44/102 [43%, 95% CI 34-53], p = 0.039). CONCLUSIONS: The number of CVST-VITT cases reported from LMICs was small despite the widespread use of adenoviral vaccines. Clinical manifestations and treatment of CVST-VITT cases were largely similar in MICs and HICs, while mortality was lower in patients from MICs.

Direct oral anticoagulants for the treatment of cerebral venous thrombosis - a protocol of an international phase IV study.

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.

The connectional anatomy of visual mental imagery: evidence from a patient with left occipito-temporal damage.

Most of us can use our "mind's eye" to mentally visualize things that are not in our direct line of sight, an ability known as visual mental imagery. Extensive left temporal damage can impair patients' visual mental imagery experience, but the critical locus of lesion is unknown. Our recent meta-analysis of 27 fMRI studies of visual mental imagery highlighted a well-delimited region in the left lateral midfusiform gyrus, which was consistently activated during visual mental imagery, and which we called the Fusiform Imagery Node (FIN). Here, we describe the connectional anatomy of FIN in neurotypical participants and in RDS, a right-handed patient with an extensive occipito-temporal stroke in the left hemisphere. The stroke provoked right homonymous hemianopia, alexia without agraphia, and color anomia. Despite these deficits, RDS had normal subjective experience of visual mental imagery and reasonably preserved behavioral performance on tests of visual mental imagery of object shape, object color, letters, faces, and spatial relationships. We found that the FIN was spared by the lesion. We then assessed the connectional anatomy of the FIN in the MNI space and in the patient's native space, by visualizing the fibers of the inferior longitudinal fasciculus (ILF) and of the arcuate fasciculus (AF) passing through the FIN. In both spaces, the ILF connected the FIN with the anterior temporal lobe, and the AF linked it with frontal regions. Our evidence is consistent with the hypothesis that the FIN is a node of a brain network dedicated to voluntary visual mental imagery. The FIN could act as a bridge between visual information and semantic knowledge processed in the anterior temporal lobe and in the language circuits.

Age-Stratified Risk of Cerebral Venous Sinus Thrombosis After SARS-CoV-2 Vaccination.

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.