Clinical Characteristics and Pharmacological Management of COVID-19 Vaccine-Induced Immune Thrombotic Thrombocytopenia With Cerebral Venous Sinus Thrombosis: A Review.

Importance: The COVID-19 pandemic saw one of the fastest developments of vaccines in an effort to combat an out-of-control pandemic. The 2 most common COVID-19 vaccine platforms currently in use, messenger RNA (mRNA) and adenovirus vector, were developed on the basis of previous research in use of this technology. Postauthorization surveillance of COVID-19 vaccines has identified safety signals, including unusual cases of thrombocytopenia with thrombosis reported in recipients of adenoviral vector vaccines. One of the devastating manifestations of this syndrome, termed vaccine-induced immune thrombotic thrombocytopenia (VITT), is cerebral venous sinus thrombosis (CVST). This review summarizes the current evidence and indications regarding biology, clinical characteristics, and pharmacological management of VITT with CVST. Observations: VITT appears to be similar to heparin-induced thrombocytopenia (HIT), with both disorders associated with thrombocytopenia, thrombosis, and presence of autoantibodies to platelet factor 4 (PF4). Unlike VITT, HIT is triggered by recent exposure to heparin. Owing to similarities between these 2 conditions and lack of high-quality evidence, interim recommendations suggest avoiding heparin and heparin analogues in patients with VITT. Based on initial reports, female sex and age younger than 60 years were identified as possible risk factors for VITT. Treatment consists of therapeutic anticoagulation with nonheparin anticoagulants and prevention of formation of autoantibody-PF4 complexes, the latter being achieved by administration of high-dose intravenous immunoglobin (IVIG). Steroids, which can theoretically inhibit the production of new antibodies, have been used in combination with IVIG. In severe cases, plasma exchange should be used for clearing autoantibodies. Monoclonal antibodies, such as rituximab and eculizumab, can be considered when other therapies fail. Routine platelet transfusions, aspirin, and warfarin should be avoided because of the possibility of worsening thrombosis and magnifying bleeding risk. Conclusions and Relevance: Adverse events like VITT, while uncommon, have been described despite vaccination remaining the most essential component in the fight against the COVID-19 pandemic. While it seems logical to consider the use of types of vaccines (eg, mRNA-based administration) in individuals at high risk, treatment should consist of therapeutic anticoagulation mostly with nonheparin products and IVIG.

The Venous Occlusion Image Score: A Novel Quantitative Scoring Instrument for Cerebral Venous Sinus Thrombosis.

PURPOSE: This study aims to test the validity of a new quantitative scoring instrument-the Venous Occlusion Image Score (VOIS), and assess the diagnostic and prognostic value of VOIS for cerebral venous sinus thrombosis (CVST). METHODS: The VOIS divided the major cerebral venous sinuses and internal jugular veins into nine parts of interest. CT venography and DSA source images and reconstruction were extracted from the database, then interpreted and scored independently according to VOIS by a panel of three reviewers. Inter-observer and intra-observer reliability were determined using the intraclass correlation coefficient (ICC) and the kappa coefficient (κ). The primary outcome was the 3-month functional outcome and evaluated by modified Rankin Scale (mRS). The sensitivity and specificity of VOIS for the primary outcomes were computed. Logistic regression was applied to evaluate the association between the score on VOIS and the primary outcomes. RESULTS: Fifty-six patients with CVST were included in the study. For 16 patients underwent cerebral CTV and DSA, excellent interobserver agreement was observed for DSA (ICC=0.90, 95%CI = 0.87 - 0.92, P < 0.001), and CTV (ICC = 0.92, 95%CI = 0.84 - 0.93, P < 0.001). The κ coefficient of agreement for the two radiology measures was 0.88 (95%CI = 0.79-0.92), indicating good inter-method agreement. For 56 patients followed up by CTV, baseline VOIS value correlated inversely with the severity of stroke on the National Institutes of Health Stroke Scale (r = -0·53, P < 0·001), and modified Rankin Scale (r = -0·59, P < 0·001). Baseline CTV-VOIS value predicted functional outcome (P < 0·05). CONCLUSION: VOIS may serve as a convenient and reliable method in the treatment guidance and outcome prediction of patients with CVST.

Glasgow Coma Scale ≤ 12 at Admission is a Predictor of Poor Functional Outcome (mRS 2-6) at One Year in Patients with Cerebral Venous Thrombosis.

OBJECTIVE: To determine factors at hospitalization of cerebral venous thrombosis (CVT) which determine outcome at one year. METHODS: This was an ambispective study with outcome at one year follow up. Patients angiographically proven as CVT were included in study and functional modified Rankin Scale (mRS) determined at one year. They were dichotomized into "good" outcome (mRS 0-1) and "poor" outcome (mRS 2-6). Variables at admission were compared on univariate and then by cox proportional hazard regression for significance. Complications during follow up period were also compared. RESULTS: One hundred and seventy five patients were included, data of 71 was collected prospectively. One hundred and seventeen (66.9%) had "good" outcome while 58 (33.1%) had "poor" outcome. Univariate analysis showed poor outcome associated with age < 30 years, female sex, focal deficit, GCS ≤ 12, ≥3 sinuses involved and intracerebral haemorrhage. On Cox proportional hazard regression only GCS ≤ 12 was significant. Around 96% had complete/ partial recanalization at 6 months. Over one year, the complications included dural AV fistula in 10 (5.7%), intracranial hypertension in 4 (2.3%), venous thromboembolism in 6 (3.4%) and arterial infarct in 4 (2.3%). Proportions with complications in each group were similar. At one year 41 patients (25.2%) were continued on anticoagulation and 97 (55.2%) on antiepileptic drugs. Proportion in each group were similar. CONCLUSION: In patients with CVT, GCS ≤ 12 at admission was a predictor of poor functional outcome (mRS 2-6) at one year. During this period, complications were few and similar in the both the groups.

Neurological Manifestations in COVID-19 Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Growing evidence showed that coronavirus disease 2019 (COVID-19) infection may present with neurological manifestations. This review aimed to determine the neurological manifestations and complications in COVID-19. METHODS: We conducted a systematic review and meta-analysis that included cohort and case series/reports involving a population of patients confirmed with COVID-19 infection and their neurologic manifestations. We searched the following electronic databases until April 18, 2020: PubMed, Embase, Scopus, and World Health Organization database (PROSPERO registration number: CRD42020180658). RESULTS: From 403 articles identified, 49 studies involving a total of 6,335 confirmed COVID-19 cases were included. The random-effects modeling analysis for each neurological symptom showed the following proportional point estimates with 95% confidence intervals: "headache" (0.12; 0.10-0.14; I2 = 77%), "dizziness" (0.08; 0.05-0.12; I2 = 82%), "headache and dizziness" (0.09; 0.06-0.13; I2 = 0%), "nausea" (0.07; 0.04-0.11; I2 = 79%), "vomiting" (0.05; 0.03-0.08; I2 = 74%), "nausea and vomiting" (0.06; 0.03-0.11; I2 = 83%), "confusion" (0.05; 0.02-0.14; I2 = 86%), and "myalgia" (0.21; 0.18-0.25; I2 = 85%). The most common neurological complication associated with COVID-19 infection was vascular disorders (n = 23); other associated conditions were encephalopathy (n = 3), encephalitis (n = 1), oculomotor nerve palsy (n = 1), isolated sudden-onset anosmia (n = 1), Guillain-Barré syndrome (n = 1), and Miller-Fisher syndrome (n = 2). Most patients with neurological complications survived (n = 14); a considerable number of patients died (n = 7); and the rest had unclear outcomes (n = 12). CONCLUSION: This review revealed that neurologic involvement may manifest in COVID-19 infection. What has initially been thought of as a primarily respiratory illness has evolved into a wide-ranging multi-organ disease.

The clinical characteristic, diagnosis, treatment, and prognosis of cerebral cortical vein thrombosis: a systematic review of 325 cases.

Cerebral cortical vein thrombosis (CCVT) is a rare type of cerebral venous thrombosis, which is frequently combined with cerebral venous sinus thrombosis (CVST). We aimed to compare the difference of clinical features between the isolated and the combined subtypes of CCVT. A literature search was conducted utilizing the PubMed Central and EMBASE databases to identify studies up to Dec 2019. Clinical manifestations, presumable risk factors, imaging modalities, radiological findings, treatment, and prognosis in patients with CCVT were recorded. 335 publications were identified (n = 325, 141 males and 184 females, mean age 40.24 ± 16.26 years). Headaches (46.8%), motor/sensory disorders (43.3%), and seizures (42.5%) were commonly seen. Pregnancy/postpartum (n = 29), oral contraception use (n = 15), fertility drug use (n = 4) ranked the top three comorbidities of CCVT in female patients, while for general populations, thrombophilia, invasive interventions in the cerebrospinal system, as well as malignancy, would be the common risk factors. MRV and DSA were more likely to confirm diagnosis. More than 30% of CCVT presented brain lesions, including infarction (6.5%) and hemorrhage (24.0%). Isolated CCVT was prone to develop hemorrhagic infarction while combined CCVT was more likely to have ischemic lesions. More than 90% of the patients acquired good outcomes at discharge or short-term follow-up (within one year). There is a difference between Isolated CCVT and CCVT combined CVST on the sites and types of brain lesions. MRV and DSA may contribute to the final diagnosis. Most patients acquired complete or partial recovery of clinical symptoms or imaging presentations after long-term anticoagulation (3-6 months).

Deep cerebral venous blood flow monitoring by transcranial doppler ultrasonography in the treatment of cerebral venous sinus thrombosis: A case report.

We report the case of a patient in whom we used deep cerebral venous blood flow monitoring by transcranial Doppler ultrasonography to monitor the effect of anticoagulation therapy on cerebral venous sinus thrombosis. The blood flow velocity of deep cerebral veins increased in the early stage of cerebral venous sinus thrombosis, then gradually decreased to the normal level as the disease improved. Moreover, the recovery of the blood flow velocity of deep cerebral veins occurred earlier than the morphological recovery demonstrated by magnetic resonance venography.

Cerebral venous sinus thrombosis in pregnancy and puerperium.

Cerebral venous sinus thrombosis (CVST) is more common in women than in men, possibly due to gender-specific risk factors in young adults. The purpose of this study was to investigate whether the clinical and radiological findings, other risk factors, and clinical course of CVST associated with pregnancy and puerperium differ from those of other CVST cases. We retrospectively reviewed patients diagnosed with CVST in our hospital between September 2007 and December 2019. The risk factors, clinical and radiological characteristics, and follow-up data for female patients with CVST were compared between cases associated with pregnancy and puerperium with those of other cases. A total of 50 female patients with CVST were included in the study. Twenty-four (48%) cases occurred during pregnancy and puerperium. The mean age of the pregnant or puerperal patients was lower than that of the other patients (p = 0.007). There was no significant difference between the groups in terms of clinical and neuroradiological findings or presence of any additional risk factors including hereditary thrombophilia. There was also no difference in terms of in-hospital mortality rates and modified Rankin Scale (mRS) scores at 6 months between the groups. The clinical presentation of CVST and the frequencies of the presence of other risk factors including genetic thrombophilia in pregnant and puerperal patients were similar to those of non-pregnant female patients. Screening for additional risk factors, especially genetic thrombophilia, should therefore not be neglected in CVST occurring during pregnancy and puerperium.

Fetal dural sinus thrombosis: A systematic review.

INTRODUCTION: Fetal dural sinus thrombosis (DST) is a rare condition. Although numerous case reports exist, the findings appear heterogenous and providing accurate patient counselling remains challenging. METHODS: A systematic literature review was conducted in accordance with PRISMA guidance. RESULTS: Thirty-one studies including 78 patients were included in this review. No association with maternal or neonatal coagulopathy, infection or trauma was found. The average gestational age at diagnosis was 25 weeks (range 17-34 weeks). Approximately half of foetuses affected were female (48.7%); one quarter were male (25.6%) and one quarter had no sex stated (25.6%). Termination of pregnancy was chosen in 25.6% of cases (20/78). In continuing pregnancies,10.3% (6/58) experienced a perinatal death. Antenatally, the majority of lesions either decreased in size (38.5%) or completely resolved (32.7%). The neonatal or childhood outcome was normal in 88.0% of survivors (44/50). The average age at follow up was 16.4 months, ranging from birth to 6 years. CONCLUSION: This review found that 10% of DST cases experience in-utero or neonatal death. In survivors, the majority of cases reduce in size or completely resolve in pregnancy and 85% are reported to have a good outcome. However, further evidence is needed regarding long-term neurocognitive sequelae.

The case of a 69-year-old man with COVID-19 and encephalopathy.

A 69-year-old man with uncontrolled type 2 diabetes presented to an outside hospital with altered mental status. He progressed from being argumentative to encephalopathic and agitated by the evening with urinary frequency, urinary urgency, nausea, and vomiting. His vital signs were normal, and he had no focal neurological deficits on presentation. He was generally encephalopathic, only groaning with no ability to follow commands. He was found to have diabetic ketoacidosis on initial labs. A left parietal hypodensity on CT Head was found, and he was positive for Sars-COV-2.

Cerebral Venous Sinus Thrombosis in the COVID-19 Pandemic.

BACKGROUND: Recent studies have noted concern for increased thromboembolic events in the setting of Coronavirus Disease 2019 (COVID-19). Cerebral venous sinus thrombosis (CVST) is a form of thromboembolism that has been observed as a neuro-ophthalmologic complication of COVID-19. METHODS: Review of the scientific literature. RESULTS: In this article, we report an overview of CVST epidemiology, clinical presentation, diagnostics, disease pathophysiology, and management in the setting of COVID-19. CONCLUSION: CVST is an uncommon thromboembolic event with variable phenotypes and multiple etiologies. Neurologic complications can be severe, including significant visual deficits and death. Current observations suggest that the risk of CVST may be profoundly impacted by this novel COVID-19 pandemic, thus prompting increased attention to disease presentation, pathogenesis, and management.

Acute Seizures in Cerebral Venous Sinus Thrombosis: Risk Factors and Prognosis.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) often presents with acute seizures, and recurrent seizures may also be seen in the long term in some patients. The purpose of this retrospective study was to investigate the frequency and type of acute seizures and to define the risk factors. METHODS: Sixty-two patients diagnosed with CVST between September 2007 and October 2018 were retrospectively evaluated for the occurrence of acute seizures. Seizures which developed as a presenting symptom or occurred within 2 weeks of diagnosis were defined as acute seizures. Demographic, clinical, and radiologic characteristics were compared between patients with or without acute seizures. RESULTS: Twenty (32.3%) of the 62 CVST patients had acute seizures. Univariate analysis revealed a significant association between acute seizures and aphasia (P=0.03), motor deficit (P<0.001), sensory deficit (P=0.018), severe (≥3) modified Rankin Scale scores on admission (P=0.017), sagittal sinus thrombosis (P=0.037), cortical vein thrombosis (P<0.001), supratentorial lesions (P<0.001), and hemorrhagic lesions (P<0.001). Multivariate regression analysis identified supratentorial lesions (P=0.015, odds ratio: 9.131, 95% confidence interval: 1.525-54.687) and cortical vein thrombosis (P=0.034, odds ratio: 5.802, 95% confidence interval: 1.146-29.371) as independent factors for acute seizures. Although 25% of patients with acute seizures had recurrent seizures during hospitalization, only 2.6% of the 38 patients with long-term follow-up had recurrent seizures. CONCLUSIONS: Approximately one third of patients with CVST had acute seizures. Cortical vein thrombosis, supratentorial, and especially hemorrhagic lesions were the most significant risk factors associated with acute seizures. Although seizure recurrence may occur early in the course, long-term recurrence is rare in CVST.

IgM nephropathy complicated by cerebral venous sinus thrombosis: a case study.

BACKGROUND: IgM nephropathy is a rare disease with variable clinical presentations and is an unusual cause of nephrotic syndrome. Histopathological findings typically include mesangial hypercellularity with IgM and complement deposition, though the spectrum may range from normal glomeruli through to focal and segmental glomerulosclerosis. Thromboembolism is a well recognised complication of nephrotic syndrome, but cerebral venous sinus thrombosis is rarely described. CASE PRESENTATION: This is the case of a 23-year-old male presenting with the nephrotic syndrome, whose initial renal biopsy was consistent with minimal change disease. Complete remission was achieved with prednisone, however multiple relapses and steroid dependence prompted re-biopsy, the results of which were more consistent with IgM nephropathy. His last relapse was complicated by cerebral venous sinus thrombosis. He then received rituximab and a weaning course of prednisone to again enter remission. CONCLUSIONS: This case highlights the need to consider IgM nephropathy in the differential diagnosis of nephrotic syndrome. Additionally, it emphasises the risk of thrombosis in patients with severe nephrosis.

COVID-19: A Global Threat to the Nervous System.

In less than 6 months, the severe acute respiratory syndrome-coronavirus type 2 (SARS-CoV-2) has spread worldwide infecting nearly 6 million people and killing over 350,000. Initially thought to be restricted to the respiratory system, we now understand that coronavirus disease 2019 (COVID-19) also involves multiple other organs, including the central and peripheral nervous system. The number of recognized neurologic manifestations of SARS-CoV-2 infection is rapidly accumulating. These may result from a variety of mechanisms, including virus-induced hyperinflammatory and hypercoagulable states, direct virus infection of the central nervous system (CNS), and postinfectious immune mediated processes. Example of COVID-19 CNS disease include encephalopathy, encephalitis, acute disseminated encephalomyelitis, meningitis, ischemic and hemorrhagic stroke, venous sinus thrombosis, and endothelialitis. In the peripheral nervous system, COVID-19 is associated with dysfunction of smell and taste, muscle injury, the Guillain-Barre syndrome, and its variants. Due to its worldwide distribution and multifactorial pathogenic mechanisms, COVID-19 poses a global threat to the entire nervous system. Although our understanding of SARS-CoV-2 neuropathogenesis is still incomplete and our knowledge is evolving rapidly, we hope that this review will provide a useful framework and help neurologists in understanding the many neurologic facets of COVID-19. ANN NEUROL 2020;88:1-11 ANN NEUROL 2020;88:1-11.

Chemotherapy associated dural sinus thrombosis presenting as a cerebrospinal fluid leak.

Despite the well documented increased risk of thrombosis in patients with cancer and during chemotherapy, cerebral venous sinus thrombosis (CVT) remains a rare entity. We present a rare case of cerebrospinal fluid (CSF) rhinorrhoea secondary to a left transverse sinus thrombus which occurred 2 years previously during chemotherapy for breast cancer. The patient underwent a three-layer repair using Neuro-Patch, septal cartilage and middle turbinate pedicle flap and was started on acetazolamide. There was no recurrence at 1-year follow-up. Raised intracranial pressure secondary to cerebral venous occlusion can erode the base of skull and predispose to CSF leaks. Despite the theoretical risk, there have been no cases reported where CSF leaks have occurred following chemotherapy induced CVT. We describe the first case and discuss pathophysiology and management.

Epileptic seizures in cerebral venous sinus thrombosis: Subgroup analysis of VENOST study.

PURPOSE: The aim of this study is to evaluate the presence and prognostic impact of early seizures in cerebral venous sinus thrombosis patients (CVST). METHOD: VENOST is a retrospective and prospective national multicenter observational study. CVST patients with or without epileptic seizures (ES) were analyzed and compared in terms of demographic and imaging data, causative factors, clinical variables, and prognosis in a total of 1126 patients. RESULTS: The mean age of the patients in the ES group was 39.73 ± 12.64 and 40.17 ± 14.02 years in the non-ES group (p > 0.05). Epileptic seizures were more common (76.6 %) in females (p < 0.001). Early ES occurred in 269 of 1126 patients (23.9 %). Epileptic seizures mainly presented in the acute phase (71.4 %) of the disease (p < 0.001). Majority of these (60.5 %) were in the first 24 h of the CVST. The most common neurological signs were focal neurologic deficits (29.9 %) and altered consciousness (31.4 %) in the ES group. Superior sagittal sinus (SSS) and cortical veins (CV) involvement were the most common sites of thrombosis and the mostly related etiology were found puerperium in seizure group (30.3 % vs 13.9 %). Patients with seizures had worse outcome in the first month of the disease (p < 0.001) but these did not have any influence thereafter. CONCLUSIONS: In this largest CVST cohort (VENOST) reported female sex, presence of focal neurological deficits and altered consciousness, thrombosis of the SSS and CVs, hemorrhagic infarction were risk factors for ES occurrence in patients with CVST.

Computed Tomography Perfusion Showing Cerebral Hypoperfusion in a Patient with Acute Cerebral Venous Sinus Thrombosis-A Case Report.

Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke. We report the case of a patient with acute CVST, showing perfusion abnormalities on computed tomography perfusion with perfusion defect in the relevant hemisphere. The defect was found in a region adjacent to the occluded sinus and was not corresponding to an arterial territory. To the best of our knowledge this is the first ever report on CT perfusion abnormalities few hours after acute symptom onset in CVST.

Recurrent intracranial hemorrhage and cerebral venous sinus thrombosis: an atypical case of Neuro-Behçet's Syndrome.

We report the case of a 22-year-old man with an history of headaches, seizures, cognitive impairment associated with recurrent intracranial hemorrhage (ICH), acute ischemic stroke (AIS), worsened over the last eighteen months for a new onset of uveitis and cerebral venous sinus thrombosis (CVST). After excluding common causes of lobar ICH, and some rare ones according to the diagnostic protocol proposed by Beuker et al, in the suspicion of Primary Angiitis of the Central Nervous System (PACNS), the gradual development of a low-grade fever, a cutaneous rash, and a papulopustular manifestation on lower back after rachicentesis (pathergy phenomenon), allowed us to make a diagnosis of Neuro-Behçet's Syndrome (NBS) without oral/genital aphthous ulcerations, according to the International Study Group for Behçet's Disease classification criteria for BD (ICBD).

Presentation and Progression of Papilledema in Cerebral Venous Sinus Thrombosis.

PURPOSE: To determine the natural history and visual outcomes of papilledema in cerebral venous sinus thrombosis (CVST). DESIGN: Retrospective observational case series. METHODS: This multicenter study included 7 tertiary care neuro-ophthalmology clinics. Sixty-five patients with CVST were identified who received serial eye examinations with documented papilledema from 2008-2016. Outcome measures included time from diagnosis to papilledema documentation, papilledema progression, time to papilledema resolution, treatment interventions and final visual outcomes. RESULTS: Papilledema was present on initial presentation in 54% of patients or detected later during the course of the disease in 46% of patients. The average time from CVST diagnosis to papilledema documentation was 29 days with a mean (SD) initial Frisén grade of 2.7 (1.3). In 21.5% of cases, papilledema progressed over an average of 55.6 (56.6) days. Time to papilledema resolution was approximately 6 months. Final visual acuity ranged from 20/20 to light perception, with 40% of patients having residual visual field defects on standard automated perimetry. Frisén grade ≥3 (odds ratio [OR] 10.21, P < .0053) and cases with worsening papilledema (3.5, P < .043) were associated with permanent visual field deficits. CONCLUSIONS: Our study indicates the importance of serial ophthalmic evaluation in all cases of CVST. Follow-up fundoscopy is critical given that a subset of cases can show delayed onset and/or worsening of papilledema with time. Specifically, we recommend an ophthalmic examination at the time of initial diagnosis, with repeat examination within a few weeks and further follow-up depending on the level of papilledema or vision changes.