Cerebral Venous Sinus Thrombosis in the COVID-19 Pandemic

Recent studies have noted concern for increased thromboembolic events in the setting of Corona- virus 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.

Disease of the Year 2020: Cerebrovascular Disorders Section Editors: Valerie Biousse, MD Koto Ishida, MD Cerebral Venous Sinus Thrombosis in the COVID-19 Pandemic Chaitanya B. Medicherla, MD, Rachel A. Pauley, MD, Adam de Havenon, MD, Shadi Yaghi, MD, Koto Ishida, MD, Jose L. Torres, MD 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 COVID19. 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. Journal of Neuro-Ophthalmology 2020;40:457–462 doi: 10.1097/WNO.0000000000001122 © 2020 by North American Neuro-Ophthalmology Society S troke is the fifth leading cause of mortality in the United States, affecting 795,000 Americans yearly (1). Cerebral venous sinus thrombosis (CVST) is a complex venous thromboembolic (VTE) phenomenon with variable clinical presentation, many etiologies, and multiple potential complications including stroke and visual loss. Although overall incidence and mortality is low, patients with CVST can have significant neuro-ophthalmic disability (2–4). This study provides an overview of CVST with a focus on Department of Neurology (CM, RAP, SY, KI, JT), New York University Langone Medical Center, New York, New York; and Department of Neurology (AdH), University of Utah School of Medicine, Salt Lake City, Utah. The authors report no conflicts of interest. Address correspondence to Jose Torres, MD, Department of Neurology, New York University Langone Medical Center, 530 First Avenue, HCC-5A, New York, NY 10016; E-mail: jose.torres2@ nyulangone.org Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 neuro-ophthalmic complications and highlights the impact of the Coronavirus Disease 2019 (COVID-19) pandemic on CVST given the significant concern for associated increase in thromboembolic events. EPIDEMIOLOGY CVST is a rare form of VTE with annual incidence historically noted to be approximately 3–4 per million in adults and approximately 7 per million in children (5). More recently, with the advent of advanced imaging techniques combined with overall increased awareness, CVST has been recognized with increasing frequency, with newer studies reporting incidence of up to 15 per million (2,6). Interestingly, these studies have noted up to a 3-fold increased incidence in women compared with men, an imbalance likely because of CVST risk factors such as pregnancy, postpartum state, and oral contraceptive use (5,7,8). The median age of patients ranges from 37 to 49 years, with a lower median age in women. This number fluctuates depending on the population studied, but despite this variability, the median age is significantly lower than for arterial strokes (7,8). CVST is an uncommon mechanism for ischemic stroke with a prevalence of 0.5% and mortality of 4% in preCOVID-19 pandemic studies (2,3,9). The effect of COVID-19 on both mortality and incidences of isolated CVST, and CVST-related stroke has yet to be determined. However, preliminary review of cases within our system indicates a decrease in absolute number of admissions for CVST but an increase in mortality among stroke patients with CVST. CLINICAL PRESENTATION The clinical presentation of CVST is variable, which can create a diagnostic challenge. The median time from symptom onset to diagnosis is approximately 7 days, with women seeking care sooner than men (7,10). Symptoms 457 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders depend on location and extent of occlusion, sufficiency of collateral venous drainage, mode of onset, patient age, and underlying risk factors (11,12). Clinical features of intracranial hypertension arise when drainage of collateral vessels is sufficient, whereas symptoms related to infarction tend to occur in the setting of venous congestion (12–14). Headache is the most common symptom, present in nearly 90% of patients, and is an isolated finding in 25% of patients, many of whom have associated papilledema on funduscopic examination. Patients older than 50 are more likely to have infarction (10). Other symptoms include altered consciousness, nausea and vomiting, seizures, cranial nerve abnormalities, aphasia, paresis, and paresthesias (7,10). Visual deficits may be a result of papilledema secondary to raised intracranial pressure (ICP), direct ischemic injury of intracranial visual pathways, and/or direct injury to cranial nerves responsible for ocular motility and pupillary function (15,16). According to the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT), visual findings included papilledema (28%), vision loss (13%), and diplopia (13%), often from sixth cranial nerve palsy (7). Papilledema was noted in 85% of patients with acute (less than 48 hours) and subacute onset (48 hours–1 month), and in all patients with chronic onset (greater than 1 month). Among those with chronic onset, 65% had visual disturbances secondary to papilledema and postpapilledema optic atrophy (7,10–12). DIAGNOSTICS As clinical presentation is variable, urgent neuroimaging is encouraged if there is suspicion of CVST. Computed tomography (CT) of the head without and with contrast is recommended for initial assessment because it can detect some abnormalities related to CVST as described below (3,12). However, 10%–30% of head CTs are normal in the workup for CVST (17,18). MRI in combination with magnetic resonance venography (MRV) of the head has the highest sensitivity and specificity in the diagnosis of CVST (10). Although digital subtraction angiography (DSA) has historically been the gold standard, it has now been replaced by MRI in combination with MRV (19). DSA remains beneficial because it offers a better understanding of the dynamics of the venous system and is reserved for patients with inconclusive neuroimaging studies or if an interventional therapy is being considered (19). Computed tomography venography (CTV) is another diagnostic modality, with evidence suggesting it may be superior to MRV in evaluation of the inferior sagittal sinus, nondominant transverse sinus, and small cortical veins (19). There are direct and indirect signs of CVST on imaging. Direct signs, present in only a third of the cases, include visualization of the thrombus (dense triangle sign, dense vessel sign, or cord sign), a contrast filling defect (empty delta sign), or lack of flow signal (18,19). Indirect signs 458 include venous edema, infarction, parenchymal hemorrhage, or subarachnoid hemorrhage (Fig. 1 depicts some of these classic direct and indirect findings) (19). The most common site of occlusion is the superior sagittal sinus (62%), followed by the left lateral (45%) and right lateral sinuses (41%) (7). More than 50% of patients have multiple sinuses involved (10). Infarct is present on imaging in approximately 47% of patients, with hemorrhagic infarct occurring in 20%–30% (7,10). Infarcts occur more often in the left hemisphere and rarely involve the posterior fossa (7). ETIOLOGY Large scale studies have identified several key conditions frequently associated with CVST (2,6–8,10). All of these are classically linked to Virchow’s triad of thrombogenesis: hypercoagulability, hemostasis, and vessel wall injury (20). As such, the most commonly identified risk factors are acquired and congenital thrombophilia (3). The aforementioned increased incidence among women is due to acquired thrombophilic risk factors including pregnancy, postpartum state, oral contraceptive use, and hormone replacement therapy (8,10). In the ISCVT, 65% of women had these gender-specific risk factors, with 50% of female patients having more than one thrombotic risk factor. Prognosis was better among this cohort, possibly because of younger age and regular check-ups during pregnancy or while on contraceptives (7,8). Acquired risk factors such as antiphospholipid antibodies, malignancy, arteriovenous malformations, and mechanical head injury are also frequently associated. The most common risk factor in developed countries is congenital thrombophilia, including inherited diseases such as factor V Leiden, prothrombin G20210A mutation, and deficiency in protein C, protein S, and antithrombin III (3,7,21). All these conditions have been identified in varying proportions in patients with CVST (10,22,23). Active or recent infection is another common acquired risk factor. Interestingly, the first report of thrombosis from the 19th century led to a long-standing belief of a direct relationship between CVST and infections (9,24). Current studies reveal that infections account for approximately 10% of adult cases with CVST, especially in developing countries (7,10). These include central nervous system infections, notably, abscess, empyema, and meningitis, as well as local parameningeal infections such as mastoiditis, sinusitis, otitis, facial cellulitis, tonsillitis, and osteomyelitis (3,5,12). Endocarditis, tuberculosis, measles, herpes, HIV, cytomegalovirus, malaria, aspergillus, and cryptococcus are systemic infections that have been described as well (12). In addition to infections, there is also increased thrombotic risk related to comorbid inflammatory disorders such as Behçet disease, granulomatosis with polyangiitis, sarcoidosis, and systemic lupus erythematosus (4,5,10). Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders FIG. 1. Common findings of CVST on CT imaging. CT head without contrast revealing cortical vein thrombosis with (A) dense vessel sign and (B) cord sign, as well as (C) dense triangle sign and (D) venous hemorrhage with surrounding edema. CT, computed tomography; CVST, cerebral venous sinus thrombosis.The arrow for (A) is pointing at a dense vessel, arrow in (B) is pointing at a cord sign, the triangle in (C) is highlighting a triangle sign. THERAPEUTICS Clinical stabilization is a key in this population as patients may present with intracerebral hemorrhage, cerebral edema, elevated ICP with increased risk of herniation, alteration in level of consciousness, and respiratory compromise. In some cases, intensive care unit admission with administration of hyperosmolar therapies and hyperventilation may be warranted. Additional emergent surgical interventions such as thrombolysis/thrombectomy and decompressive craniectomy (DC) may be necessary if medical management were to fail (3,12,25). Studies assessing safety and efficacy of endovascular treatment have been limited by small number of patients, publication bias, and lack of blinding (26–29). A recent randomized controlled trial revealed that endovascular treatment did not show improvement over standard care. This study was stopped short for futility and was limited in number of patients enrolled (29). Additional studies implementing advanced venous techniques as they are developed may offer better results. Currently, there are no formal guidelines on endovascular treatment for CVST. Although the quality of evidence for DC has also been poor, DC is recommended Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 for patients with acute CVST complicated by parenchymal lesions and impending herniation (25). In nonemergent cases, early initiation of anticoagulation is a mainstay of treatment of CVST. The use of anticoagulation in CVST has been controversial, largely because of the presence of venous infarcts with hemorrhagic complications in up to 40% of cases. Studies addressing this question have been few and limited by the low prevalence of CVST. A meta-analysis of 2 studies noted better prognosis, although not statistically significant, without worsening of hemorrhagic lesions when treated with either unfractionated heparin (UFH) or low molecular weight heparin (LMWH) anticoagulation (30–32). UFH may be favored in cases where surgical intervention may require quick anticoagulant reversal. Small studies have shown that LMWH is comparable with UFH, but statistical significance was not achieved because studies were underpowered (33–35). Cumulatively, these studies are meaningful in reinforcing use of early anticoagulation for treatment of CSVT (14). Recommendations regarding safety and efficacy of direct oral anticoagulant regimens to prevent recurrent CVSTs are currently limited to small observational studies on 459 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders rivaroxaban and dabigatran (25,36–39). Although one larger randomized trial has demonstrated similar safety and efficacy of dabigatran to warfarin, more high-quality studies are necessary (40,41). Given similarities between extracerebral VTEs and CVSTs, it may be reasonable to adopt VTE guidelines with attention to each patient’s thrombotic and bleeding risk profile when considering time-limited anticoagulation for secondary prevention (3). Additional treatments should be considered for patients with visual compromise secondary to papilledema from elevated ICP. A lumbar puncture (LP) is warranted before initiation of anticoagulation in patients with isolated raised ICP, absence of cerebral infarction or hemorrhage, and no other risk factors for herniation. The goal of the LP is to acutely decrease ICP and prevent further visual loss while allowing anticoagulation to have a therapeutic effect. Acetazolamide may also be used, although this has a more limited role in the acute management of severe cases of papilledema. Corticosteroids are associated with a worse prognosis in CVST and should be avoided. Surgical management, with either cerebrospinal fluid shunt or optic nerve fenestration, may be needed in severe or refractory cases of elevated ICP and vision loss. A discussion of the benefits and risks of these interventions is needed, particularly in the acute phase, as temporary discontinuation of anticoagulation for any surgical intervention can lead to further thrombus formation. Although ICP normalizes in most cases after treatment of CVST, patients rarely may have chronically elevated ICP and papilledema, requiring long-term management (25,42). IMPACT OF COVID-19 ON CEREBRAL VENOUS SINUS THROMBOSIS Multiple neurologic complications, including encephalopathy, anosmia, ageusia, seizures, strokes, encephalitis, meningitis, and neuropathy have been identified in the setting of COVID-19. Several case-reports have also observed CVST among patients with COVID-19 (9,43–48). However, reported CVST numbers have been low (first half of the year 2020) because COVID-19 has had a significant impact on the number of overall neurologic admissions. Several studies globally have reported a decreased rate of neurologic hospitalizations and admissions. This decrease is believed to be due to increased social distancing, fear of contracting the virus, stay-at-home guidelines, and increased telehealth triaging of clinical problems (49,50). Therefore, although only a handful of CVST cases have been reported, to date, it is possible that patients simply have not presented to the hospital because of the aforementioned reasons, particularly if symptoms have been mild. It is also possible that many CVST cases have been underdiagnosed in the pandemic setting. Many patients with COVID-19 presented critically ill with cardiopulmonary instability often necessitating emergent sedation and mechanical ventilation. This has caused deferral of radiographic studies 460 until clinical stability is maintained, making diagnosis of neurologic disease more difficult (49,51). Although the numbers of reported CVST during the COVID-19 pandemic have been low, the pandemic has helped to further our understanding of CVST pathophysiology and treatments. The role of infections and their association with thrombophilia in CVST is of key interest. Numerous viral infections are associated with coagulopathy, including HIV, cytomegalovirus, varicella zoster virus, and Ebola–Marburg virus (52). Regarding respiratory viruses, H1N1 influenza A virus, Middle East respiratory syndrome coronavirus, and severe acute respiratory syndrome coronavirus have also been shown to have abnormal coagulopathic presentations including disseminated intravascular coagulopathy (DIC), deep vein thromboses, and pulmonary thromboemboli (52,53). Although pathophysiology still remains to be elucidated, there is growing consensus that viral infections may lead to profound dysregulation between inherent procoagulant and anticoagulant mechanisms. Suggested mechanisms include endothelial dysfunction, excess inhibition of fibrinolysis, increased blood viscosity, and septic-associated coagulopathy (20,52). COVID-19, similarly, has been associated with a significant coagulopathy leading to a newly recognized syndrome known as COVID-19-associated coagulopathy, involving venous, arterial, and microcirculatory systems (20,54,55). It is known to cause dysregulation of natural anticoagulants resulting in elevated D-dimer levels and platelet dysfunction with potential hyperactivation through inflammatory cascades (20,48), with whole blood thromboelastograms revealing heightened coagulation parameters (56). Although similar to DIC and microangiopathy, factors such as elevated fibrinogen, profoundly elevated D-dimer, and lack of thrombocytopenia have served as key distinguishing markers (20). These findings suggest a potentially strong link between CVST and COVID-19-associated coagulopathy, but supporting evidence is limited and extensive studies are required. As previously mentioned, the strength of recommendation for anticoagulation in CVST has been challenged given the frequency of concurrent parenchymal hemorrhage on presenting imaging and the paucity of well-powered studies. The nature of COVID-19-associated coagulopathy bolsters the need for larger randomized trials in this setting. Presently, many experts have recommended therapeutic doses of anticoagulation in COVID-19 when not contraindicated based on anecdotal experience and theoretical physiologic risk; objective scoring criteria and case-based recommendations have been proposed to guide clinical decision-making (20,57,58). Clinical trials are underway to determine optimal antithrombotic regimen. CONCLUSION CVST is an uncommon thromboembolic event with variable phenotypes and multiple etiologies. Neurologic complications can be severe, including significant visual deficits, Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders stroke, 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. REFERENCES 1. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW, Wong SS, Heard DG. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation. 2020;141:e139– e596. 2. Devasagayam S, Wyatt B, Leyden J, Kleinig T. Cerebral venous sinus thrombosis incidence is higher than previously thought: a retrospective population-based study. Stroke. 2016;47:2180– 2182. 3. Saposnik G, Barinagarrementeria F, Brown RD, Bushnell CD, Cucchiara B, Cushman M, Deveber G, Ferro JM, Tsai FY. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:1158–1192. 4. Purvin VA, Trobe JD, Kosmorsky G. Neuro-ophthalmic features of cerebral venous obstruction. Arch Neurol. 1995;52:880– 885. 5. Stam J. Current concepts: thrombosis of the cerebral veins and sinuses. N Engl J Med. 2005;352:1791–1797. 6. Coutinho JM, Zuurbier SM, Aramideh M, Stam J. The incidence of cerebral venous thrombosis: a cross-sectional study. Stroke. 2012;43:3375–3377. 7. Ferro JM, Canhão P, Stam J, Bousser MG, Barinagarrementeria F. Prognosis of cerebral vein and dural sinus thrombosis: results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT). Stroke. 2004;35:664–670. 8. Coutinho JM, Ferro JM, Canhão P, Barinagarrementeria F, Cantú C, Bousser MG, Stam J. Cerebral venous and sinus thrombosis in women. Stroke. 2009;40:2356–2361. 9. Cavalcanti DD, Raz E, Shapiro M, Dehkharghani S, Yaghi S, Lillemoe K, Nossek E, Torres J, Jain R, Riina HA, Radmanesh A, Nelson PK. Cerebral venous thrombosis associated with COVID-19. AJNR Am J Neuroradiol. 2020;41:1370–1376. 10. Colakoglu S, Duman T, Tüfekci A, Bakar M, Nazliel B, Caglayan HZ, Tascilar N, Acıkgoz M, Goksan B, Ince B, Zeydan B, Uluduz D, Kozak HH, Demir S, Senol MG, Ozdag F, Tekeli H, Misirli CH, Kucukoglu H, Baybas S, Cinar N, Domac FM, Ozturk S, Ekmekci H, Yayla V, Cabalar M, Karahan AY, Afsar N, Ozaydin Goksu E, Ucan Tokuc FE, Mengulluoglu N, Aytac E, Yesilot N, Yalin ÖO, Oruc S, Yaman M, Demirci S, Yurekli VA, Yilmaz A, Genc H, Gokce M, Utku U, Kuspeci ÖY, Uzuner G, Uzuner N, Midi I, Bektas H, Kablan Y, Goksel BK, Milanlioglu A, Necioglu Orken D, Aluclu U. A multicenter study of 1144 patients with cerebral venous thrombosis: the VENOST study. J Stroke Cerebrovasc Dis. 2017;26:1848–1857. 11. Eliseeva N, Serova N, Yakovlev S, Mikeladze K, Arkhangelskaya Y, Gasparyan S. Neuro-ophthalmological features of cerebral venous sinus thrombosis. Neuroophthalmology. 2015;39:69–76. 12. Guenther G, Arauz A. Cerebral venous thrombosis: a diagnostic and treatment update. Neurologia. 2011;26:488–489. 13. Biousse V, Ameri A, Bousser MG. Isolated intracranial hypertension as the only sign of cerebral venous thrombosis. Neurology. 1999;53:1532–1537. 14. Biousse V, Tong F, Newman N. Cerebral venous thrombosis. Curr Treat Options Neurol. 2003;5:409–420. Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 15. Aaron S, Arthur A, Prabakhar A, Mannam P, Shyamkumar N, Mani S, Mathew V, Peter J, Sivadasan A, Alexander A, Karthik M, Benjamin R, Alexander M. Spectrum of visual impairment in cerebral venous thrombosis: importance of tailoring therapies based on pathophysiology. Ann Indian Acad Neurol. 2017;20:294–301. 16. Kuehnen J, Schwartz A, Neff W, Hennerici M. Cranial nerve syndrome in thrombosis of the transverse/sigmoid sinuses. Brain. 1998;121:381–388. 17. Saudagar M, Konin B. Study of clinical features, CT findings in correlation with MR venogram studies in acute cerebral venous thrombosis. ISOR J Dent Med Sci. 2016;15:14–22. 18. Poon CS, Chang JK, Swarnkar A, Johnson MH, Wasenko J. Radiologic diagnosis of cerebral venous thrombosis: pictorial review. Am J Roentgenol. 2007;189:S64–S75. 19. Linn J, Brückmann H. Cerebral venous and dural sinus thrombosis: state-of-the-art imaging. Clin Neuroradiol. 2010;20:25–37. 20. Becker RC. COVID-19 update: covid-19-associated coagulopathy. J Thromb Thrombolysis. 2020;50:54–67. 21. Garrido-Barbero M, Arnaez J, Loureiro B, Arca G, Agut T, GarciaAlix A. The role of factor V Leiden, prothrombin G20210A, and MTHFR C677T mutations in neonatal cerebral sinovenous thrombosis. Clin Appl Thromb. 2019;25:1–6. 22. Wang B, Peng C, Zhou MK, Guo J, He L. Clinical characteristics and prognosis of patients with cerebral venous sinus thrombosis in Southwest China [in Chinese]. J Sichuan Univ. 2014;45:515–518. 23. Terni E, Giannini N, Chiti A, Gialdini G, Orlandi G, Montano V, Orsucci D, Brondi M, Bonuccelli U, Mancuso M. Cerebral sinus venous thrombosis: clinical and pathogenetic perspectives from Tuscany. Blood Coagul Fibrinolysis. 2015;26:505–508. 24. Krayenbühl HA. Cerebral venous and sinus thrombosis. Neurol Med Chir. 1968;10:1–24. 25. Ferro JM, Bousser MG, Canhão P, Coutinho JM, Crassard I, Dentali F, di Minno M, Maino A, Martinelli I, Masuhr F, Aguiar de Sousa D, Stam J. European stroke organization guideline for the diagnosis and treatment of cerebral venous thrombosis— endorsed by the European Academy of Neurology. Eur J Neurol. 2017;24:1203–1213. 26. Coutinho JM, Ferro JM, Zuurbier SM, Mink MS, Canhão P, Crassard I, Majoie CB, Reekers JA, Houdart E, de Haan RJ, Bousser MG, Stam J. Thrombolysis or anticoagulation for cerebral venous thrombosis: rationale and design of the TOACT trial. Int J Stroke. 2013;8:135–140. 27. Siddiqui FM, Dandapat S, Banerjee C, Zuurbier SM, Johnson M, Stam J, Coutinho JM. Mechanical thrombectomy in cerebral venous thrombosis. Stroke. 2015;46:1263–1268. 28. Dentali F, Squizzato A, Gianni M, De Lodovici ML, Venco A, Paciaroni M, Crowther M, Ageno W. Safety of thrombolysis in cerebral venous thrombosis: a systematic review of the literature. Thromb Haemost. 2010;104:1055–1062. 29. Coutinho JM, Zuurbier SM, Bousser MG, Ji X, Canhão P, Roos YB, Crassard I, Nunes AP, Uyttenboogaart M, Chen J, Emmer BJ, Roosendaal SD, Houdart E, Reekers JA, Van Den Berg R, De Haan RJ, Majoie CB, Ferro JM, Stam J. Effect of endovascular treatment with medical management vs standard care on severe cerebral venous thrombosis: the TO-ACT randomized clinical trial. JAMA Neurol. 2020;77:966–973. 30. Coutinho JM, De Bruijn SF, Deveber G, Stam J. Anticoagulation for cerebral venous sinus thrombosis. Cochrane Database Syst Rev. 2011;2011:1–30. 31. De Bruijn SF, Stam J. Randomized, placebo-controlled trial of anticoagulant treatment with low-molecular-weight heparin for cerebral sinus thrombosis. Stroke. 1999;30:484–488. 32. Einhäupl KM, Villringer A, Mehraein S, Garner C, Pellkofer M, Haberl RL, Pfister HW, Schmiedek P, Meister W. Heparin treatment in sinus venous thrombosis. Lancet. 1991;338:597–600. 33. Misra UK, Kalita J, Chandra S, Kumar B, Bansal V. Low molecular weight heparin versus unfractionated heparin in cerebral venous sinus thrombosis: a randomized controlled trial. Eur J Neurol. 2012;19:1030–1036. 461 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Disease of the Year 2020: Cerebrovascular Disorders 34. Afshari D, Moradian N, Nasiri F, Razazian N, Bostani A, Sariaslani P. The efficacy and safety of low-molecular-weight heparin and unfractionated heparin in the treatment of cerebral venous sinus thrombosis. Neurosciences. 2015;20:357–361. 35. Coutinho JM, Ferro JM, Canhão P, Barinagarrementeria F, Bousser MG, Stam J. Unfractionated or low-molecular weight heparin for the treatment of cerebral venous thrombosis. Stroke. 2010;41:2575–2580. 36. Geisbüsch C, Richter D, Herweh C, Ringleb PA, Nagel S. Novel factor Xa inhibitor for the treatment of cerebral venous and sinus thrombosis: first experience in 7 patients. Stroke. 2014;45:2469–2471. 37. Mendonça MD, Barbosa R, Cruz-e-Silva V, Calado S, VianaBaptista M. Oral direct thrombin inhibitor as an alternative in the management of cerebral venous thrombosis: a series of 15 patients. Int J Stroke. 2015;10:1115–1118. 38. Gosk-Bierska I, Wysokinski W, Brown RD, Karnicki K, Grill D, Wiste H, Wysokinska E, McBane RD. Cerebral venous sinus thrombosis: incidence of venous thrombosis recurrence and survival. Neurology. 2006;67:814–819. 39. Lurkin A, Derex L, Fambrini A, Bertoletti L, Epinat M, Mismetti P, Dargaud Y. Direct oral anticoagulants for the treatment of cerebral venous thrombosis. Cerebrovasc Dis. 2019;48:32–37. 40. Bose G, Graveline J, Yogendrakumar V, Fergusson D, Dowlatshahi D. Direct oral anticoagulants in treatment of cerebral venous thrombosis: a systematic review protocol. Syst Rev. 2019;8:99. 41. Ferro JM, Coutinho JM, Dentali F, Kobayashi A, Alasheev A, Canhão P, Karpov D, Nagel S, Posthuma L, Roriz JM, Caria J, Frässdorf M, Huisman H, Reilly P, Diener HC. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: a randomized clinical trial. JAMA Neurol. 2019;76:1457–1465. 42. Brodsky MC, Biousse V. A bloody mess! Surv Ophthalmol. 2018;63:268–274. 43. Klein DE, Libman R, Kirsch C, Arora R. Cerebral venous thrombosis: a typical presentation of COVID-19 in the young. J Stroke Cerebrovasc Dis. 2020;29:1–5. 44. Hemasian H, Ansari B. First case of Covid-19 presented with cerebral venous thrombosis: a rare and dreaded case. Rev Neurol (Paris). 2020;176:521–522. 45. Bastidas HI, Márquez-pérez T, García-salido A. Cerebral venous sinus thrombosis in a pediatric patient with COVID-19. eNeurologicalSci. 2020;20:100256. 46. Hughes C, Nichols T, Pike M, Subbe C, Elghenzai S. Cerebral venous sinus thrombosis as a presentation of COVID-19. Eur J Case Rep Intern Med. 2020;7:001691. 47. Roy-Gash F, Marine DM, Jean-Michel D, Herve V, Raphael B, Nicolas E. COVID-19-associated acute cerebral venous thrombosis: clinical, CT, MRI and EEG features. Crit Care. 2020;24:419. 462 48. Poillon G, Obadia M, Perrin M, Savatovsky J, Lecler A. Cerebral venous thrombosis associated with COVID-19 infection: causality or coincidence? J Neuroradiol. 2020 May 11 (epub ahead of print). 49. Yaghi S, Ishida K, Torres J, Mac Grory B, Raz E, Humbert K, Henninger N, Trivedi T, Lillemoe K, Alam S, Sanger M, Kim S, Scher E, Dehkharghani S, Wachs M, Tanweer O, Volpicelli F, Bosworth B, Lord A, Frontera J. SARS-CoV-2 and stroke in a New York healthcare system. Stroke. 2020;51:2002– 2011. 50. Garcia S, Albaghdadi MS, Meraj PM, Schmidt C, Garberich R, Jaffer FA, Dixon S, Rade JJ, Tannenbaum M, Chambers J, Huang PP, Henry TD. Reduction in ST-segment elevation cardiac catheterization laboratory activations in the United States during COVID-19 pandemic. J Am Coll Cardiol. 2020;75:2871–2878. 51. Agarwal S, Scher E, Rossan-Raghunath N, Marolia D, Butnar M, Torres J, Zhang C, Kim S, Sanger M, Humbert K, Tanweer O, Shapiro M, Raz E, Nossek E, Nelson PK, Riina HA, de Havenon A, Wachs M, Farkas J, Tiwari A, Arcot K, Parella DT, Liff J, Wu T, Wittman I, Caldwell R, Frontera J, Lord A, Ishida K, Yaghi S. Acute stroke care in a New York City comprehensive stroke center during the COVID-19 pandemic. J Stroke Cerebrovasc Dis. 2020;29:105068. 52. Goeijenbier M, van Wissen M, van de Weg C, Jong E, Gerdes VE, Meijers JC, Brandjes DP, van Gorp EC. Review: viral infections and mechanisms of thrombosis and bleeding. J Med Virol. 2012;84:1680–1696. 53. Li K, Wohlford-Lenane C, Perlman S, Zhao J, Jewell AK, Reznikov LR, Gibson-Corley KN, Meyerholz DK, McCray PB. Middle east respiratory syndrome coronavirus causes multiple organ damage and lethal disease in mice transgenic for human dipeptidyl peptidase 4. J Infect Dis. 2015;212:712–722. 54. Khan IH, Savarimuthu S, Leung MS, Harky A. The need to manage the risk of thromboembolism in COVID-19 patients. J Vasc Surg. 2020;72:799–804. 55. Iba T, Levy JH, Levi M, Connors JM, Thachil J. Coagulopathy of coronavirus disease 2019. Crit Care Med. 2020;20:1–7. 56. Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, Pesenti A, Peyvandi F, Tripodi A. Hypercoagulability of COVID-19 patients in intensive care unit. A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020;18:1738–1742. 57. Kutny MA, Rajpurkar M, Alonzo TA, Gerbing RB, Gamis AS, Feusner JH, Gregory J. Evaluation of ISTH DIC score to predict significant bleeding and thrombosis events in pediatric acute promyelocytic leukemia; A report from the children’s oncology group AAML0631 trial. Blood. 2014;124:3669. 58. Dumitrascu OM, Volod O, Bose S, Wang Y, Biousse V, Lyden PD. Acute ophthalmic artery occlusion in a COVID-19 patient on apixaban. J Stroke Cerebrovasc Dis. 2020;29:1–3. Medicherla et al: J Neuro-Ophthalmol 2020; 40: 457-462 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.