Cerebral Venous Sinus Thrombosis as Delayed Complication of Dengue Infection: A Case Report and Mini Review

INTRODUCTION Dengue and its complications have been a major public health problem, especially in tropical countries. In 2012, the World Health Organization coined the term 'expanded dengue' to describe cases not falling into either dengue shock syndrome or dengue haemorrhagic fever. Neurological involvement in dengue is heterogeneous including meningitis, encephalitis, acute disseminated encephalomyelitis, encephalopathy, parkinsonism, neuro-ophthalmic events, cranial neuropathies, plexopathy, transverse myelitis, Guillain–Barre syndrome and vascular events such as intracranial haemorrhage or thrombosis.[1] Cortical venous sinus thrombosis has been rarely reported as a complication of dengue. CASE REPORT A 22-year-old male presented with 6 days history of acute onset, severe, holocranial, throbbing headache, aggravated on lying down and partially relieved by non-steroidal anti-inflammatory drugs. The patient had recently recovered from dengue fever 2-week back. On examination, the patient was conscious and alert, with no fever or skin rash. Neurological examination revealed bilateral Grade 3 papilloedema. The remainder of the neurological examination was unremarkable. Laboratory workup revealed haemoglobin of 15.6 mg/dL, raised haematocrit of 50.11%, total leucocyte counts 11,280/mm3, platelet counts 3.04 lacs/mm3, mildly raised serum glutamic-oxaloacetic transaminase/serum glutamic-pyruvic transaminase – 78/71 IU/L, total bilrubin 0.4 mg/dL, direct bilirubin 0.2 mg/dL, alkaline phosphatase 231 U/L, gamma-glutamyl transferase 31.5 U/L, serum protein 7.3 g/dL, serum albumin 4.6 g/dL, serum globulin 2.7 gm/dL, serum sodium 139 meq/L, serum potassium 4.1 meq/L, blood urea 34.1 mg/dL, serum creatinine 1.07 mg/dL, serum uric acid 7.3 mg/dL, C reactive protein 2 mg/L, serum homocysteine levels 17.03 μmol/L and low Vitamin B12 of 172 pg/mL, INR of 0.87. Viral markers for HIV/hepatitis B virus/hepatitis C virus were negative. Two-week-old dengue NS1 antigen was positive in the outside report and a repeat test at our centre turned negative. Magnetic resonance imaging of the brain with venography revealed absent flow in the left transverse and sigmoid sinus with partial flow in the right transverse and sigmoid sinus suggestive of cerebral venous sinus thrombosis (CVST) [Figure 1]. Thrombophilia profile, including common genetic causes, came negative. Treatment included intravenous fluids, subcutaneous enoxaparin (1 mg/kg/day in two divided doses) followed by oral warfarin to maintain INR of 2-3. Over the subsequent 1 week, the patient improved significantly with relief in headache. During follow-up, the patient was asymptomatic and anti-coagulation was stopped after 6-month duration.Figure 1: Magnetic resonance venography images showing absent flow in the left transverse and sigmoid sinus (red arrow), whereas partial flow in the right transverse and sigmoid sinus (black arrow), suggestive of cerebral venous sinus thrombosisDISCUSSION Dengue fever is an acute febrile illness characterised by fever, headache, myalgia and arthralgia with thrombocytopenia. Neurological manifestations resulting from dengue fever are relatively uncommon but well-known.[2] It can involve any neurological axis from the meninges, brain, spinal cord and peripheral nerves to cerebral vessels with meningoencephalitis being the more common of all.[2] Although haemorrhagic complications are more common than thrombotic in view of dengue-associated thrombocytopenia, the cases of large vessel thrombosis have also been documented.[1,2] Five cases of non-neurological thrombotic events due to dengue viral infection were delineated by da Costa et al.[3] CVST and ischaemic stroke without known vascular risk factors have been rarely reported in dengue fever.[4,5] To the best of our knowledge, only four cases of dengue-associated CVST have been documented to date in the literature [Table 1]. Three cases had pure thrombotic complications with good response to medical management, whereas one case developed a haemorrhagic complication requiring surgical intervention.[2,6-8]Table 1: A review of dengue fever-associated cerebral venous sinus thrombosis cases reported so farSeveral factors have been suggested to increase the risk of thrombosis in patients suffering from dengue fever,[9,10] which include haemoconcentration, low levels of platelets and anti-coagulant factors along with immune-mediated endothelial damage. Dehydration, by increasing haematocrit, may additionally predispose to venous thrombosis. Downregulation of thrombomodulin-thrombin-protein C complex formation by dengue virus leading to reduced levels of activated protein C, S and anti-thrombin III has been reported in severe dengue infection without clinical thrombosis.[11] Increased plasma levels of plasminogen activator inhibitor-1 have also been observed in such cases.[10] Both of these mechanisms predispose the patient to a high risk of thrombosis. Cross-reactivity of host anti-bodies directed against dengue non-structural protein 1 with human endothelial cells and platelets may lead to endothelial inflammation and disruption, further increasing the likelihood of thrombosis in the affected vessel.[12] Anti-bodies directed against phospholipids, cardiolipin, and increased lupus anti-coagulant have also been associated with thrombotic events.[4,9] In addition, as a component of disseminated intravascular coagulation, microthrombi may also contribute to large vessel thrombosis. Headache, visual disturbance, diplopia, focal neurological deficit and altered sensorium have been symptoms in previously reported cases. Tilara et al. have reported CVST as early as on the 4th day of fever which suggests the development of thrombosis even during the acute phase.[6] Usually, dengue patients are evaluated for the above symptoms with brain imaging but high suspicion of CVST and inclusion of magnetic resonance (MR) venography will prevent missing these cases. In post-acute illness, dengue cases red flags in headache such as new onset, continuous headache (not only with febrile episode), severe headache, associated with visual disturbance or other neurological deficits and headache disturbing sleep should be asked. On examination, papilloedema or other features of raised intracranial pressure can be helpful, as was in our case in the case reported by Hameed et al.[2] Sometimes computed tomography (CT) scan can show bleeding only and due to low sensitivity, venous thrombosis can be missed. Details of bleeding pattern, associated infarct and other imaging features suggestive of venous aetiology can help in further evaluation with CT/MR venography in such cases. Surgical intervention in cases with impending herniation due to bleed or large infarct has a good outcome compared to that of arterial, as shown in the case by Sharma et al.[8] Apart from common haemorrhagic manifestations in dengue, rare thrombotic manifestations may be seen in dengue. New onset acute severe headache, papilloedema and raised haematocrit with a history of recent dengue infection lead to the possibility of CVST in our case. Possibly procoagulant milieu created after dengue infection (persisting even after resolution of active viral infection) was further enhanced by dehydration, borderline homocysteine and low serum Vitamin B12, leading to thrombosis in our patient. Anti-coagulation with fluid replacement is the main treatment regimen for patients with CVST with good clinical recovery.[2] In all cases of dengue virus-associated CVST, including our case, the patients attained complete neurological recovery.[2,6-8] CONCLUSION CVST in the dengue and post-dengue phase is rare but has a favourable prognosis if diagnosed and treated timely. Learning point A patient of a new-onset acute headache after febrile illness specially dengue should undergo a thorough neurological examination including a fundus examination and possibility of CVST should be kept in mind. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. 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