key: cord-0837056-od9532aj
authors: Abdalkader, Mohamad; Shaikh, Shamsh P.; Siegler, James E.; Cervantes-Arslanian, Anna M.; Tiu, Cristina; Radu, Razvan Alexandru; Tiu, Vlad Eugen; Jillella, Dinesh V.; Mansour, Ossama Yassin; Vera, Víctor; Chamorro, Ángel; Blasco, Jordi; López, Antonio; Farooqui, Mudassir; Thau, Lauren; Smith, Ainsley; Gutierrez, Santiago Ortega; Nguyen, Thanh N.; Jovin, Tudor G.
title: Cerebral Venous Sinus Thrombosis in COVID-19 Patients: A Multicenter Study and Review of Literature
date: 2021-03-04
journal: J Stroke Cerebrovasc Dis
DOI: 10.1016/j.jstrokecerebrovasdis.2021.105733
sha: d2f1a9edd009a749c0bec02475bbf8a49cdb326d
doc_id: 837056
cord_uid: od9532aj

BACKGROUND: COVID-19 infection has been known to predispose patients to both arterial and venous thromboembolic events such as deep venous thrombosis, pulmonary embolism, myocardial infarction, and stroke. A few reports from the literature suggest that Cerebral Venous Sinus Thrombosis (CVSTs) may be a direct complication of COVID-19. OBJECTIVE: To review the clinical and radiological presentation of COVID-19 positive patients diagnosed with CVST. METHODS: This was a multicenter, cross-sectional, retrospective study of patients diagnosed with CVST and COVID-19 reviewed from March 1, 2020 to November 8, 2020. We evaluated their clinical presentations, risk factors, clinical management, and outcome. We reviewed all published cases of CVST in patients with COVID-19 infection from January 1, 2020 to November 13, 2020. RESULTS: There were 8 patients diagnosed with CVST and COVID-19 during the study period at 7 out of 31 participating centers. Patients in our case series were mostly female (7/8, 87.5%). Most patients presented with non-specific symptoms such as headache (50%), fever (50%), and gastrointestinal symptoms (75%). Several patients presented with focal neurologic deficits (2/8, 25%) or decreased consciousness (2/8, 25%). D-dimer and inflammatory biomarkers were significantly elevated relative to reference ranges in patients with available laboratory data. The superior sagittal and transverse sinuses were the most common sites for acute CVST formation (6/8, 75%). Median time to onset of focal neurologic deficit from initial COVID-19 diagnosis was 3 days (interquartile range 0.75–3 days). Median time from onset of COVID-19 symptoms to CVST radiologic diagnosis was 11 days (interquartile range 6–16.75 days). Mortality was low in this cohort (1/8 or 12.5%). CONCLUSIONS: Clinicians should consider the risk of acute CVST in patients positive for COVID-19, especially if neurological symptoms develop.

The COVID-19 pandemic originated in December 2019 in Wuhan, China and quickly spread across the world with over 110 million reported global cases and 2.4 million global deaths as of February 20 th , 2021 [1] . Though COVID-19 was initially feared due to its respiratory sequelae, a spectrum of thromboembolic and neurologic complications have been reported [2] [3] [4] [5] [6] .

Several reports suggest that COVID-19 may be associated with an increased risk of stroke in young patients or patients with cryptogenic stroke [7] [8] [9] . Proposed mechanisms for ischemic events include systemic inflammation (as evidenced by biomarkers), hypercoagulable state (due to renin-angiotensin-aldosterone disruption and cytokine storm), and endothelial injury leading to alterations in the normal coagulation cascade [10] .

Both cerebral venous thrombosis and COVID-19 infection are known to occur independently in young populations, the former often with concomitant risk factors such as oral contraceptives, malignancy, dehydration, hypercoagulable state, or trauma [11] . The clinical presentation may be compounded by recent reports suggesting that CVST may be a direct consequence of COVID-19 [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] . Age, abnormal level of consciousness, and focal motor deficits on admission may be harbingers of poorer outcome in CVST patients [31] .

Here, we present a case series of 8 patients and review the literature to characterize the presentation, management, and outcomes related to CVST events in COVID-19 patients.

A retrospective observational registry (The SVIN COVID-19 Multinational Registry involving prospectively gathered data from 17 healthcare networks (31 unique hospitals) across four countries (USA, Spain, Egypt, and Romania) was queried [32] . Of the 31 participating centers, 7 hospitals reported patients diagnosed with CVST and COVID-19 between March 1, 2020 to November 8, 2020. The clinical presentations, risk factors, management, and outcomes of these patients were subsequently reviewed. Patient demographic information, pertinent medical history, National Institutes of Health Stroke Scale (NIHSS) score, neuroimaging, treatment, laboratory testing (inflammatory and hematologic parameters, D-dimer), discharge modified Rankin Scale (mRS), and discharge disposition were recorded. De-identified data elements (including age, which was binned by decade for de-identification purposes) were documented by local investigators on a HIPAA-compliant, previously described online platform.

Cooper University Hospital served as the central coordinating site of data.

We reviewed the literature and extracted published cases of CVST in patients with COVID-19 infection from January 1, 2020 to November 13, 2020 using the keywords "cerebral venous sinus thrombosis AND COVID-19," "cerebral venous sinus thrombosis AND SARS-CoV-2," or "cerebral venous sinus thrombosis AND coronavirus," "Stroke AND COVID-19," or "venous thromboembolism AND COVID-19" searched on PubMed and Google Scholar.

Abstracts and published articles were reviewed for the following parameters: patient demographics, clinical presentation, comorbidities, relevant laboratory studies, imaging data, hospitalization events, and outcomes. Studies that did not utilize PCR testing for COVID-19 diagnosis or studies without a confirmed radiologic diagnosis of CVST were excluded. One study was excluded in its entirety, whereas several individual patients from other studies were also excluded if they did not have confirmed RT-PCR nasopharyngeal swab results (two patients were excluded).

This study was approved under a waiver of informed consent by the local institutional review board at each participating center. Anonymized data are available upon reasonable request to the corresponding author.

There were 8 patients with COVID-19 infection confirmed by RT-PCR testing who developed CVST ( Table 1) . Patients were mostly female (N = 7, 87.5%), with an average age of 63.3 ± 20 years old. Essential hypertension (N = 4, 50%) and diabetes mellitus (N = 3, 37.5%) were the most common medical comorbidities. Two patients (25%) had identifiable risk factors for CVST including an underlying hypercoagulable state likely due to antiphospholipid syndrome as well as morbid obesity. Most patients presented with non-specific symptoms such as headache (50%), fever (50%), and gastrointestinal symptoms (75%). Other neurological symptoms such as decreased consciousness (12.5%) and focal neurologic deficit (25%) were also seen. The median time to onset of focal neurologic deficit from initial COVID-19 diagnosis (as defined by numbness, hemiparesis, weakness, facial palsy, vision changes, or aphasia) was 3 days (interquartile range 0.75 -3 days). The median time from onset of COVID-19 symptoms to CVST radiologic diagnosis was 11 days (interquartile range 6-16.75 days).

The radiologic diagnosis of acute CVST was confirmed via observing cord-like hyperintensities or cord-like filling defects on Computerized Tomography Venogram (CTV) studies in five (62.5%) patients. CVST in the remaining three patients was confirmed by the absence of flow-related signal loss on Magnetic Resonance Imaging (MRI) or by visualizing cord-like filling defects on Magnetic Resonance Venogram (MRV) studies. The superior sagittal and transverse sinuses were the most common sites for CVST formation (N = 6 or 75% for both). However, CVST was also observed in the torcular herophili in 1 patient and in smaller caliber "deep" venous structures such as the vein of Galen and internal cerebral veins (N = 2 or 25% for both). Half of our patients (N = 4, 50%) had CVST spanning multiple cerebral venous sinuses. If bilateral CVST was presentas seen in two patients (25%)the transverse sinuses were most likely to be affected (Figure 1) . Lastly, serum glucose levels were found to be elevated (342 ± 279.6 mg/dL).

The severity of COVID-19 infection at the time of hospital admission was classified according to the World Health Organization (WHO) guidelines into the following categories: asymptomatic, mild, moderate, severe, and critical [33] . Three patients presented with severe disease as characterized by their need for supplemental oxygen upon arrival, elevated systolic blood pressure >160mmHg, and CT chest imaging data. The remaining five patients had mild to moderate disease as evidenced by oxygen saturation ≥ 90% on room air, normotensive blood pressure, or absence of pulmonary findings on chest radiographs. Coagulation studies such as D-dimer (9,571 ± 14,439 ng/mL) were significantly elevated.

Our literature series of patients also experienced a similar spectrum of in-hospital events, such as intubation (6/ 

Our series of 8 cases, as well as the published data of patients with CVST and COVID-19, suggest that acute CVST is a rare event associated with COVID-19 infection. Most patients in our series (75%) as well as 74% of the published cases of CVST and COVID-19 did not have identifiable risk factors for CVST.

In our current series, the majority of patients with CSVT and COVID-19 were women (87.5%), similar to incidence rates reported in non-COVID-19 patient populations [34] .

Although CVST is usually more commonly reported in young individuals [35] , the mean age of patients with CVST and COVID-19 in our series was older (~63 years old). Our findings indicate that age may not play as significant of a role in assessing risk for CVST in COVID-19 patients as previously suggested. In-hospital mortality was also relatively low in our current series (1/8 patients or 12.5%). This is in contrast to data aggregated from our literature review, Notably, ESR, CRP, ferritin, and LDH were elevated in the majority of our patients with available laboratory data when compared to reference ranges. Moreover, our case series revealed extreme elevations in standard coagulation studies such as D-dimer, which was noted to exceed 3,000 ng/mL and approach 10,000 ng/mL in five out of six of our patients with laboratory data.

These findings support the notion that COVID-19 infection may be associated with widespread, systemic prothrombotic consequences [41] [42] .

Although the presentation of CVST is subtle, the most common initial symptoms seen in our series included headache, low-grade fever, and gastrointestinal symptoms. However, clinicians should be prepared for a wide variety of symptoms as COVID-19 patients with acute CVST can present with seizures, signs of intracranial hypertension, decreased consciousness, altered sensorium, and classic stroke symptoms such as numbness/weakness of the extremities. Laboratory data such as abnormal coagulation studies as well as elevated inflammatory biomarkers in COVID-19 patients suggest that systemic inflammation and underlying hypercoagulable state may be responsible for acute arterial and/or venous thromboembolic events. However, these findings alone do not sufficiently explain the discrepancy seen between the aforementioned rates of arterial ischemic stroke versus purely venous infarcts (i.e. CVSTs).

We speculate that additional confounding factors such as endothelial dysfunction may be responsible for the overrepresentation of arterial consequences. In fact, while the endothelial dysfunction is pathognomonic for arterial ischemic strokethat is, an atherosclerotic plaque matures, ruptures, then subsequently undergoes thrombosisits role in venous thrombogenesis is less clear [52] . Autopsy studies of patients who succumbed to COVID-19 revealed severe endothelial injury, endotheliitis, and widespread microvascular trauma that likely preceded organ Limitations of this review stem from the small number of patients analyzed with CVST, a reflection of its rare association with COVID-19. Furthermore, there were missing laboratory data values as consensus on laboratory data was not unified among centers. Nevertheless, we believe that our case series provides valuable information, adding to the literature on a diverse, multinational cohort of patients with COVID-19 infection who also developed CVST.

In summary, clinicians should consider the risk of developing acute CVST in patients with co-existing COVID-19 infection, especially if neurological symptoms develop that are not otherwise explained by other conditions.

This manuscript is exempt from ethical committee approval due to its retrospective nature and use of de-identified data.

The authors have no conflicts of interest to declare. All additional co-authors were consulted regarding their final approval of the version to be published.

All authors: Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. 

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Death -N (%) 1 (12.5%) 8 (24.2%) 9 (21.9%)Readmission -N (%) 6 2 (25%) 3 (9.1%) 5 (12.2%) GCS at time of CVST diagnosismedian (IQR) 15 (14.75-15) 15 (14) (15) 15 (12) (13) (14) (15) NIHSS at time of CVST diagnosismedian (IQR) 1 (0.75-1.25) 15 (7-15.5) 4 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) Days to neurological symptomsmedian (IQR) 3 (0.75-3) 1 (0-13) 1 (0-12.5) modified Rankin Scale (mRS) ≤ 2 5 (62.5%) 15 (45.5%) 20 (48.8%) SD = standard deviation; GCS = Glasgow Coma Scale; NIHSS = National Institutes of Health Stroke Scale; IQR = interquartile range medical history of bleeding disorders such as Immune Thrombocytopenic Purpura, von Willebrand disease, and Evans syndrome. 4 One patient suffered from Disseminated Intravascular Coagulation while another was found to have a pulmonary embolism 5 Including but not limited to hydroxychloroquine and azithromycin 6 Defined as subsequent hospitalization for COVID-19 related symptoms less than 1 month after CVST