Fulminant Extra- And Intracranial Arteriovenous Thrombosis And Non-aneurysmal Subarachnoid Hemorrhage Following COVID-19 Infection.

PURPOSE: Coronavirus disease of 2019 (COVID-19) is associated with increased risk of stroke and intracranial hemorrhage. This first report of fulminant panvascular arteriovenous thrombosis with subarachnoid hemorrhage (SAH) in a post-COVID-19 infection is attributed to extensive arteriovenous inflammation leading to arterial rupture following vasculitis. CASE REPORT: We report a rare case of extensive extra- and intra-cranial cerebral arteriovenous thrombosis following COVID-19 infection, presenting as fatal non-aneurysmal subarachnoid hemorrhage. The clinical course, biochemical and radiological evaluation is discussed. The other possible etiological differentials which were analysed and ruled out during case management are also detailed. CONCLUSION: A high degree of suspicion for COVID-19 induced coagulopathy leading to extensive non- aneurysmal, non-hemispheric SAH and malignant intracranial hypertension should be entertained. Our experience and previous reports on non-aneurysmal SAH in such patients show a poor prognosis.

Thrombotic events following the BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) in Aotearoa New Zealand: A self-controlled case series study.

BACKGROUND: An association between thrombotic events and SARS-CoV-2 infection and the adenovirus-based COVID-19 vaccines has been established, leading to concern over the risk of thrombosis after BNT162b2 COVID-19 vaccination. OBJECTIVES: To evaluate the risk of arterial thrombosis, cerebral venous thrombosis (CVT), splanchnic thrombosis, and venous thromboembolism (VTE) following BNT162b2 vaccination in New Zealand. METHODS: This was a self-controlled case series using national hospitalisation and immunisation records to calculate incidence rate ratios (IRR). The study population included individuals aged ≥12 years, unvaccinated, or vaccinated with BNT162b2, who were hospitalised with one of the thrombotic events of interest from 19 February 2021 through 19 February 2022. The risk period was 0-21 days after receiving a primary or booster dose of BNT162b2. RESULTS: 6039 individuals were hospitalised with one of the thrombotic events examined, including 5127 with VTE, 605 with arterial thrombosis, 272 with splanchnic thrombosis, and 35 with CVT. The proportion of individuals vaccinated with at least one dose of BNT162b2 ranged from 82.7 % to 91.4 %. Compared with the control unexposed period, the IRR (95 % CI) of VTE, arterial thrombosis, splanchnic thrombosis, and CVT were 0.87 (0.76-1.00), 0.73 (0.56-0.95), 0.71 (0.43-1.16), and 0.87 (0.31-2.50) in the 21 days after BNT162b2 vaccination, respectively. There was no statistically significant increased risk of thrombosis following BNT162b2 in different ethnic groups in New Zealand. CONCLUSION: The BNT162b2 vaccine was not found to be associated with thrombosis in the general population or different ethnic groups in New Zealand, providing reassurance for the safety of the BNT162b2 vaccine.

Diagnosis and Treatment of Cerebral Venous Thrombosis.

OBJECTIVE: Cerebral venous thrombosis (CVT), thrombosis of the dural sinus, cerebral veins, or both, is a rare cerebrovascular disease. Although mortality rates after CVT have declined over time, this condition can result in devastating neurologic outcomes. This article reviews the latest literature regarding CVT epidemiology, details new factors associated with the development of CVT, and describes advances in CVT treatment. It also contains a discussion of future directions in the field, including novel diagnostic imaging modalities, and potential strategies to reduce the risks associated with CVT. LATEST DEVELOPMENTS: The incidence of CVT may be as high as 2 per 100,000 adults per year. It remains a difficult condition to diagnose given its variable clinical manifestations and the necessity of neuroimaging for confirmation. The COVID-19 pandemic has revealed a novel CVT trigger, vaccine-induced immune thrombotic thrombocytopenia (VITT), as well as an association between COVID-19 infection and CVT. Although VITT is a very rare event, timely diagnosis and treatment of CVT due to VITT likely improves patient outcomes. Direct oral anticoagulants are currently being used to treat CVT and emerging data suggest that these agents are as safe and effective as vitamin K antagonists. The role of endovascular therapy to treat CVT, despite a recent clinical trial, remains unproven. ESSENTIAL POINTS: The incidence of CVT has increased, outcomes have improved, and the use of direct oral anticoagulants to treat CVT represents an important advance in the clinical care of these patients. Rates of CVT as a complication of COVID-19 vaccines using adenoviral vectors are very low (<5 per million vaccine doses administered), with the benefits of COVID-19 vaccination far outweighing the risks.

SARS-CoV-2 Possible Etiology of Cerebral Venous Thrombosis in a Teenager: Case Report and Review of Literature.

Cerebral venous thrombosis in pediatric patient has a varied etiology. The authors present the case of a teenager who, since the debut of SARS-CoV-2 infection, has accused intermittent right side hemicrania, which has become persistent in association with nausea and vomiting since the 5th day of quarantine. She was hospitalized in the 9th day since the debut. Neuroimaging revealed extended venous cerebral thrombosis affecting the right sigmoid sinus, the transverse sinus bilaterally, the confluence of the transverse sinuses and the right internal jugular vein. The evolution was favorable under anticoagulant and symptomatic treatment. Laboratory tests excluded other etiological causes for the cerebral venous thrombosis, thus the authors consider that cerebral thrombosis is a possible complication of SARS-CoV-2 infection in teenagers.

Cerebral venous thrombosis after ChAdOx1 nCoV-19 vaccination: a systematic review.

OBJECTIVE: To perform a systematic review of case reports or case series regarding thrombosis with thrombocytopenia syndrome (TTS) and cerebral venous thrombosis (CVT) related to ChAdOx1 nCoV-19 vaccination to address the clinical features, laboratory findings, treatment modalities, and prognosis related with CVT. SUBJECTS AND METHODS: We included 64 TTS patients from 19 articles, 6 case series and 13 case reports, in which thrombosis occurred after the first dose of ChAdOx1 nCoV-19 vaccination published up to 30 June 2021 in Embase, ePubs, Medline/PubMed, Scopus, and Web of Science databases. RESULTS: Of the 64 TTS patients, 38 (59.3%) had CVT. Patients with CVT were younger (median 36.5 vs. 52.5 years, p<0.001), had lower fibrinogen levels (130 vs. 245 mg/dL, p=0.008), had more frequent history of intracerebral hemorrhage (ICH), and had higher mortality rate (48.6% vs. 19.2%, p=0.020) than that of patients without CVT. In multivariable analysis, the possibility of presence of CVT was higher in younger age groups [odd ratio (OR): 0.91, 95% confidence interval (CI): (0.86-0.97, p<0.001)] and those with accompanying intracerebral hemorrhage (ICH) (OR: 13.60, 95% CI (1.28-144.12, p=0.045). CONCLUSIONS: Our study demonstrated that CVT related to ChAdOx1 nCoV-19 vaccination was associated with younger age, low levels of fibrinogen, presence of ICH and more frequent mortality compared to those of non-CVT. If TTS occurs after ChAdOx1 nCoV-19 vaccination, the presence of CVT in patients with young age or ICH should be considered.

Encephalopathy as the Only Manifestation in Simultaneous Arterial Infarct and Cerebral Venous Sinus Thrombosis in Recent COVID-19 Infection.

BACKGROUND Emerging cases of SARS-CoV-2 infection associated with cerebral thromboembolism episodes manifesting as arterial strokes or cerebral venous thrombosis have been reported. However, the co-occurrence of arterial strokes and cerebral venous thrombosis is rare. CASE REPORT We report the case of a previously healthy young patient with recent SARS-CoV-2 infection, who presented with encephalopathy. His computed tomography venography and magnetic resonance imaging of the brain showed thrombosis of the vein of Galen and straight sinus, and arterial infarcts in both hemispheres. His inflammatory markers, D-dimer levels, and coagulation profile were normal. He was started on anticoagulation and recovered well. CONCLUSIONS Concurrent arterial and venous thrombosis can happen rarely in patients with SARS-CoV-2 infection, including patients who have recently recovered from COVID-19. Cerebral thromboembolism associated with SARS-CoV-2 can present with a variety of subtle clinical manifestations, including encephalopathy without focal neurological deficits. Inflammatory markers, D-dimer levels, and coagulation profiles can be normal, especially in patients with mild infection or who have recovered from the infection. Therefore, it is important to be vigilant and recognize this clinical entity so that the diagnosis can be made and treatment can be started promptly. However, larger and prospective studies are needed to determine the clinical outcomes, therapeutic benefits, and complications of concurrent arterial stroke and cerebral venous thrombosis associated with SARS-CoV-2 infection.

Cerebral Venous Thrombosis in COVID-19.

Background: COVID-19 causes a hypercoagulable state leading to thrombosis. Many of these thrombotic complications occur in those with severe disease and late in the disease course. COVID-19 has recently been associated with cerebral venous thrombosis (CVT). Objective: To study the onset of CVT in relation to COVID-19 and compare their characteristics and outcomes with non-COVID CVT patients admitted during the same period. Materials and Methods: This multicentric, retrospective study conducted between April 4 and October 15, 2020, included adult patients with CVT who were positive for the SARS-CoV-2 virus and compared them with CVT patients who were negative for the SARS-CoV-2 virus hospitalized during the same period. We studied their clinical profile, risk factors for CVT, and markers of COVID coagulopathy, imaging characteristics, and factors influencing their outcomes. Results: We included 18 COVID-19-infected patients and compared them with 43 non-COVID-19 CVT patients. Fourteen patients in the COVID-19 group presented with CVT without the other typical features of COVID-19. Thirteen patients had non-severe COVID-19 disease. Twelve patients had a good outcome (mRS ≤2). Mortality and disability outcomes were not significantly different between the two groups. Conclusion: Our study suggests a possible association between COVID-19 and CVT. CVT can be the presenting manifestation of an underlying COVID-19, occurring early in the course of COVID-19 and even in those with mild disease. Patients with worse GCS on admission, abnormal HRCT chest, severe COVID-19, and need for invasive ventilation had a poor outcome.

MRI-negative myelitis associated with cerebral venous thrombosis after COVID-19 infection.

Transverse myelitis and cerebral venous thrombosis represent some of the described neurological complications of coronavirus disease. A woman in her early 30s presented with headache, left-sided sensory symptoms and voiding difficulty. The patient also reported dry cough, fever, nasal congestion, anosmia and ageusia 2 weeks before presentation. The clinical examination showed sensory disturbances on the left side of the body, starting from the lower abdomen and extending to the left leg, which was consistent with transverse myelitis. The laboratory assessment confirmed a previous infection with coronavirus disease and excluded autoimmune entities. Radiological investigations revealed left transverse sinus thrombosis with no spinal cord abnormalities. The treatment was started with therapeutic anticoagulation and intravenous high-dose steroids. The patient showed significant improvement, and the neurological deficits resolved after 3 months. This is the first documented case of imaging-negative myelitis associated with cerebral venous thrombosis after coronavirus disease.

[Cerebral venous thrombosis associated with COVID-19]. / Tserebral'nye venoznye trombozy, assotsiirovannye s COVID-19.

The literature reports that cerebral venous thrombosis (CVT) develops in 1-1.5% of patients with COVID-19. Recently, a new syndrome named vaccine-induced immune thrombotic thrombocytopenia (VITT) has been described. VITT is a rare side-effect of COVID-19 vaccination that also causes CVT. The article presents an overview of the above problem and a clinical case of a patient with CVT that developed within a month after the first component of the Sputnik V vaccination and COVID-19.

Concomitant Guillain-Barré syndrome and cerebral venous thrombosis complicating a SARS-CoV-2 infection: a case report.

Cerebral venous thrombosis associated to acute inflammatory axonal polyneuropathy during infection with SARS-CoV-2 (coronavirus-2) is unusual. We describe the case of a 66-year-old patient with typical clinical and electrophysiological criteria of acute axonal motor neuropathy, who was positive for SARS-CoV-2. The symptoms started with fever associated with respiratory symptoms, and complicated one week later by headaches, and general weakness. The examination showed bilateral peripheral facial palsy, predominantly proximal tetraparesis, and areflexia with tingling of limbs were found. The whole was concomitant with the diagnosis of an acute polyradiculoneuropathy. Electrophysiologic evaluation confirmed the diagnosis. Cerebrospinal fluid examination showed albuminocytologic dissociation, and brain imaging revealed sigmoid sinus thrombophlebitis. Neurological manifestations improved during treatment with plasma exchange and anticoagulants. Our case draws attention to the occurrence of cerebral venous thrombosis and Guillain-Barré syndrome (GBS) in patients with COVID-19. The neuro-inflammation induced by the systemic immune response to infection, can lead to neurological manifestations. Further studies should be conducted on the full clinical spectrum of patients with COVID-19 with neurological symptoms.

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.

Cerebral venous thrombosis.

Cerebral venous sinus thrombosis (CVT) consists of partial or complete occlusion of a sinus or a cerebral vein. CVT represents 0.5-1% of all strokes and is more frequent in young women. This review discusses particular aspects of CVT diagnosis and management: decompressive craniectomy (DC), anticoagulation with direct oral anticoagulants (DOACs), CVT after coronavirus-disease 19 (COVID-19) and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT).

Retrospective review COVID-19 vaccine induced thrombotic thrombocytopenia and cerebral venous thrombosis-what can we learn from the immune response.

INTRODUCTION: Cerebral Venous Thrombosis (CVT), prior to the COVID pandemic, was rare representing 0.5 of all strokes, with the diagnosis made by MRI or CT venography.1-,3 COVID-19 patients compared to general populations have a 30-60 times greater risk of CVT compared to non-affected populations, and up to a third of severe COVID patients may have thrombotic complications.4-8 Currently, vaccines are the best way to prevent severe COVID-19. In February 2021, reports of CVT and Vaccine-induced immune thrombotic thrombocytopenia (VITT) related to adenovirus viral vector vaccines including the Oxford-AstraZeneca vaccine (AZD1222 (ChAdOx1)) and Johnson & Johnson COVID-19 vaccine (JNJ-78436735 (Ad26.COV2·S)), were noted, with a 1/583,000 incidence from Johnson and Johnson vaccine in the United States.11, 12 This study retrospectively analyzed CVT and cross-sectional venography at an Eastern Medical Center from 2018 to 2021, and presents radiographic examples of CVT and what is learned from the immune response. METHODS: After IRB approval, a retrospective review of cross-sectional CTV and MRVs from January 1st 2018 to April 30th 2021, at a single health system was performed. Indications, vaccine status, patient age, sex, and positive finding incidence were specifically assessed during March and April for each year. A multivariable-adjusted trends analysis using Poisson regression estimated venogram frequencies and multivariable logistic regression compared sex, age, indications and vaccination status. RESULTS AND DISCUSSION: From January 1, 2018 to April 30, 2021, (Fig. 1), a total of n = 2206 in patient and emergency room cross-sectional venograms were obtained, with 322 CTVs and 1884 MRVs. In 2018, 2019, 2020, respective totals of cross-sectional venograms were 568, 657, 660, compared to 321 cross-sectional venograms in the first four months of 2021. CTV in 2018, 2019, 2020, respective totals were 51, 86, 97, MRV totals were 517, 571, 563, compared to the 2021 first four month totals of 88 CTVs and 233 MRVs. March, April 2018, 2019, 2020, CTVs respectively were 6, 17, 11, compared to the 2021 first four months of 59 CTVs, comprising 63% of the total 93 CTVs, respective MRVs were 79, 97, 52, compared to 143 MRVs in the first four months of 2021 for 39% of the total 371 MRVs. In March, April 2020 during the pandemic onset, cross-sectional imaging at the East Coast Medical Center decreased, as priorities were on maintaining patient ventilation, high level of care and limiting spread of disease. In March/April 2021, reports of VITT and CVT likely contributed to increased CTVs and MRVs, of 39.65% [1.20-1.63] increase (P < 0.001) from prior. In March, April 2021 of 202 venograms obtained, 158 (78.2.%) were unvaccinated patients, 16 positive for CVT (10.1%), 44 were on vaccinated patients (21.7%), 8 specifically ordered with vaccination as a clinical indication, 2 positive for CVT (4.5%), (odds ratio = 0.52 [0.12-2.38], p = 0.200). CONCLUSION: CTV prior to the COVID pandemic, was rare, responsible for 0.5 of all strokes, at the onset of the pandemic in the East Coast, overall cross-sectional imaging volumes declined due to maintaining ventilation, high levels of care and limiting disease spread, although COVID-19 patients have a 30-60 times greater risk of CVT compared to the general population, and vaccination is currently the best option to mitigate severe disease. In early 2021, reports of adenoviral vector COVID vaccines causing CTV and VITT, led to at 39.65% increase in cross-sectional venography, however, in this study unvaccinated patients in 2021 had higher incidence of CVT (10.1%), compared to the vaccinated patients (4.5%). Clinicians should be aware that VITT CVT may present with a headache 5-30 days post-vaccination with thrombosis best diagnosed on CTV or MRV. If thrombosis is present with thrombocytopenia, platelets <150 × 109, elevated D-Dimer >4000 FEU, and positive anti-PF4 ELISA assay, the diagnosis is definitive.13 VITT CVT resembles spontaneous autoimmune heparin induced thrombocytopenia (HIT), and is postulated to occur from platelet factor 4 (PF4) binding to vaccine adenoviral vectors forming a novel antigen, anti-PF4 memory B-cells and anti-PF4 (VITT) antibodies.14-17.

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.

Inflammation in Cerebral Venous Thrombosis.

Cerebral venous thrombosis (CVT) is a rare form of cerebrovascular disease that impairs people's wellbeing and quality of life. Inflammation is considered to play an important role in CVT initiation and progression. Several studies have reported the important role of leukocytes, proinflammatory cytokines, and adherence molecules in the CVT-related inflammatory process. Moreover, inflammatory factors exacerbate CVT-induced brain tissue injury leading to poor prognosis. Based on clinical observations, emerging evidence shows that peripheral blood inflammatory biomarkers-especially neutrophil-to-lymphocyte ratio (NLR) and lymphocyte count-are correlated with CVT [mean difference (MD) (95%CI), 0.74 (0.11, 1.38), p = 0.02 and -0.29 (-0.51, -0.06), p = 0.01, respectively]. Moreover, increased NLR and systemic immune-inflammation index (SII) portend poor patient outcomes. Evidence accumulated since the outbreak of coronavirus disease-19 (COVID-19) indicates that COVID-19 infection and COVID-19 vaccine can induce CVT through inflammatory reactions. Given the poor understanding of the association between inflammation and CVT, many conundrums remain unsolved. Further investigations are needed to elucidate the exact relationship between inflammation and CVT in the future.