Journal of The Association of Physicians of India ■ Vol. 64 ■ July 201674

Cerebral Sinus Venous Thrombosis as a Rare Complication of Primary Varicella Zoster Virus InfectionK Gayathri1, PK Ramalingam1, RPSP Santhakumar1, BV Manjunath1, N Karuppuswamy2, B Vetriveran2, S Selvamani2, P Vishnuram2, Kumar Natarajan3

Abstract We present the case of a 23 year old with acute onset left hemiparesis and meningeal irritation, associated with recent history of chickenpox 15 days prior. Varicella-IgG and IgM was positive in the CSF and blood along with reduced serum/CSF ratios of VZV immunoglobulins. MRV showed thrombosis (CVT) of superior sagittal, transverse, right sigmoid sinuses with haemorrhagic infarct in right frontoparietal region. Patient responded well to intravenous heparin, Acyclovir and oral anticoagulant therapy.

1Postgraduate, 2Assistant Professor, 3Professor and Head of Medicine, Department of General Medicine, Coimbatore Medical College Hospital, Coimbatore, Tamil NaduReceived: 12.12.2014; Revised: 09.04.2015; Accepted: 28.07.2015

Introduction

Va r i c e l l a z o s t e r v i r u s ( V Z V ) causes chicken pox after which it

establishes latency and can subsequently get reactivated to cause Herpes zoster in later life. Central nervous system complications can follow both primary infection and reactivation of VZV. VZV infection can cause unifocal or multifocal vasculopathy and arterial strokes. Primary Varicella infection causing venous infarct is very rare1 and hence this case is being reported. There are only a few published reports of cerebral venous sinus thrombosis (CVST) associated with primary VZV infection.

Case Report

23 yr old male was brought to our emergency department with severe headache and a l tered sensor ium . His illness started two weeks back wi th profound rash and ves ic les

predominantly on the trunk and limbs and to a less degree on the face. The lesions were centripetal and hence he was diagnosed to have chicken pox at local hospital. Patient did not receive any form of treatment in the interval of diagnosis of chicken pox and development of neurological complications. When patient reached our hospital, these lesions were in crusting stage. His present symptoms started with sudden onset of continuous holocranial non-throbbing headache which was associated with vomiting

and fever for 2 days. Patient gradually developed altered sensorium associated with weakness of left upper limb and left lower limb. There was no history of se izures . Past his tory was not significant.

When patient came to emergency ward, he was drowsy and restless but responded to verbal commands. General examination revealed scabbing chicken pox lesions in trunk and limbs (Figure 1). On neurological examination he had nuchal rigidity, Kernig sign was positive. Pupils were equal and reacting to light, left eye abducent nerve palsy was present. Fundus showed bilateral papi l l edema. Motor examinat ion revealed left hemiparesis with muscle power of 3/5, loss of superficial reflexes, exaggerated deep tendon reflexes and extensor plantar reflex on left side. Right side examination was normal.

His routine investigations including complete blood count, blood sugar, renal parameters, liver function tests, electrolytes, coagulation profile and blood culture were normal. Serology for Human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), Anti-HCV were negative. A N A p r o f i l e , A n t i p h o s p h o l i p i d ant ibodies , Prote in C, prote in S , antithrombin III, homocysteine levels were normal. Serum IgG for varicella zoster was positive. Cerebrospinal fluid examination (Table 1) showed pleocytosis with 20 cells/mm3, mildly raised protein 60 mg%, and normal glucose (40 mg%). Varicella-specific IgG was positive in the cerebrospinal fluid (CSF) and the blood with reduced CSF/serum ratios of VZV IgG. CSF VZV DNA by PCR was positive.

Chest X-ray and 2D-Echo were

Fig. 1: Showing healed varicella lesions with scars

Table 1: Cerebrospinal fluid analysis

Observed value Reference range

Cell count 20 cells/micL 0 – 5 cells/micLCSF protein 60 mg/dl 40 – 80 mg/dlCSF glucose 40 mg/dl 15 – 60 mg/dlSerum IgG varicella zoster

190.31 Neg < 80; Borderline

80-110; Positive >110

CSF IgG varicella zoster

74.64 -

Serum total IgG 1850.0 700 – 1600 mg/dl

CSF total IgG 12.90 0 – 3.4 mg/dl CSF / Serum quotient reference

0.27 Normal < 1.3Equivocal 1.3

to 1.5Positive > 1.5

CSF VZV DNA Positive

C a s e R e p o R t s

Journal of The Association of Physicians of India ■ Vol. 64 ■ July 2016 75

Figs. 2 and 3: CT plain showing hyperdensity of straight sinus, superior sagittal sinus and right transverse sinus

Figs. 4 and 5: MR Venogram showing dural sinus thrombosis in superior sagittal sinus, straight sinus and sigmoid sinuses

Figs. 6 and 7: MR Venogram showing superior sagittal sinus thrombosis and bilateral transverse sinus with no flow in internal cerebral veins

normal. A plain Computed Tomography of brain showed diffuse cerebral edema and hyperdense superior sagittal , straight sinus and right transverse sinuses (Figures 2, 3). A possibility of venous sinus thrombosis was considered and a Magnetic Resonance Venography with gadolinium enhancement was done. MRI brain with MRV showed

(Figures 4, 5, 6 and 7) thrombosis in superior sagittal, bilateral transverse and r ight s igmoid s inuses which extends into the straight sinus. There was no flow in the internal cerebral veins. Venous haemorrhagic infarcts were seen in r ight f rontoparieta l cerebral parenchyma (largest 4 cm in length) and in r ight thalamus.

Multiple lacunar infarcts in bilateral frontoparietal white matter (Figures 8, 9) were also seen.

Patient was treated with cerebral decongestants, intravenous Acyclovir 500 mg three times daily and low molecular weight heparin for one week . Pa t ient s tar ted improving gradually over the next few days with improvement in sensorium and limbs weakness. At the time of discharge, physiotherapy and oral anticoagulant was advised. Tab. Acitrom 2 mg orally once daily was continued for next 12 weeks to maintain INR between 1.5 to 2.5. There was no history of worsening of symptoms or any bleeding manifestations. Tab. Aspirin 150 mg once daily was started and continued for next 12 weeks. After 6 months of treatment, patient improved well and he is on regular follow up.

Discussion

Va r i c e l l a - r e l a t e d n e u r o l o g i c a l complications are seen in less than 1% cases of chickenpox. Neurological complications frequently encountered are cerebel l i t i s and encephal i t i s . It can cause unifocal or multifocal vasculopathy. However several rare complications related to central nervous system involvement have been reported like aseptic meningitis, Guillain-Barre syndrome and transverse myelitis. Our patient had post-varicella CVST.

Primary VZV infection can cause vascular thrombosis approximately 6 weeks after primary infection. In elderly immunocompetent patients it occurs as a large-vessel vasculopathy i.e. a granulomatous arteritis involving single vessel (unifocal), whereas in immunocompromised hosts, it presents as multivessel involvement (multifocal vasculopathy).1 Unifocal large-vessel infarcts may occur in either anterior or posterior circulation. These infarcts are believed to result from transaxonal transport of varicella zoster virus from cervical or trigeminal afferent fibers to the cerebral blood vessels and their smaller branches.2,3 The occurrence of venous thrombosis following primary Varicella Zoster infection is very rare, though i t can occur secondary to reactivation and due to herpes zoster infection.4 Our case developed CVST in the stage of primary infection itself (that is, in 2 weeks of primary varicella infection).

Journal of The Association of Physicians of India ■ Vol. 64 ■ July 201676

Figs. 8 and 9: Venous haemorrhagic infarcts in right frontoparietal cerebral parenchyma (largest 4 cm in length) and infarcts in right thalamus and right frontal region

The causa l assoc ia t ion in th i s part icular case was evidenced by positive varicella antibodies in serum and CSF. VZV vasculopathy patients do not always have VZV DNA in CSF, but the diagnosis can be confirmed by anti-VZV antibody in CSF, along with reduced serum/CSF ratios of VZV IgG.5 Serum and CSF IgG was positive in our patient with reduced CSF/serum ratios of VZV IgG and VZV DNA was positive.

The exact pathogenesis of varicella venous thrombosis i s not known but similar to VZV arterial strokes,

activated varicella virus may migrate transaxonally to infect the meninges and venous s inuses of brain. The mechanisms under ly ing cerebra l vascular events after VZV infection could be vasculitis, thrombosis due to direct endothelial damage, and acquired protein S deficiency.6,7 Our patient developed thrombosis during primary varicella infection and not as a delayed complication. He had no other r isk factors for cerebral venous thrombosis. Probably, the same pathogenic mechanisms underlying arteriopathy may have played a role

in the development of CVST in our patient. These patients require antiviral treatment and symptomatic treatment with heparin and oral anticoagulants. Our patient improved with above treatments.Conclusion

O u r c a s e d e m o n s t r a t e s t h a t CVST is one of the rare neurological complications of primary varicella zoster infection and early diagnosis of this is essential for the proper management of the patient.

References1. Gilden DH. Varicella zoster virus vasculopathy and

disseminated encephalomyelitis. J Neurol Sci 2002; 195:99-101.

2. Mayberg M, Langer RS, Zervas NT, Moskowitz MA. Perivascular meningeal projections from the cat trigeminal ganglia: Possible pathway for vascular headaches in man. Science 1981; 213:228-30.

3. Saito K, Moskowitz MA. Contributions from the upper cervical dorsal roots and trigeminal ganglia to the feline circle of Willis. Stroke 1989; 20:524-6.

4. Siddiqi SA, Nishat S, Kanwar D, Ali F, Azeemuddin M, Wasay M. Cerebral venous sinus thrombosis: association with primary varicella zoster virus infection. J Stroke Cerebrovasc Dis 2012; 21:917.

5. Reiber H, Lange P. Quantification of virus-specific antibodies in cerebrospinal fluid and serum: Sensitive and specific detection of antibody synthesis in brain. Clin Chem 1991; 37:1153-60.

6. Nagel MA, Traktinskiy I, Azarkh Y, Kleinschmidt-DeMasters B, Hedley-Whyte T, Russman A, et al. Varicella zoster virus vasculopathy: Analysis of virus-infected arteries. Neurology 2011; 77:364-70.

7. Nguyên P, Reynaud J, Pouzol P, Munzer M, Richard O, François P. Varicella and thrombotic complications associated with transient protein C and protein S deficiencies in children. Eur J Pediatr 1994; 153:646-9.