Varicella-Associated Stroke

Abstract

A previously healthy, unimmunized 11-month-old boy presented with acute right-sided weakness. On the day of presentation, his mother noted that his right arm and leg seemed to be weak when she woke him from his usual afternoon nap. Evaluation at an urgent care center confirmed right-sided facial weakness, decreased strength and movement of his right upper and lower extremities, and a lack of right-sided support in a sitting position. Computed tomography of the head without contrast was normal. He was transferred to a regional care center where head magnetic resonance imaging and magnetic resonance angiography demonstrated a left middle cerebral artery stroke and irregularities in the middle cerebral artery concerning for thrombus and vasculopathy (Figure, A and B). History revealed that the patient, as well as his older siblings, had primary chickenpox infection 2-3 months previously. The patient had a mild case of varicella, with a few scattered vesicular lesions which resolved without obvious sequelae. Owing to concern about varicella zoster virus (VZV) vasculopathy, he was started on high-dose intravenous acyclovir. A lumbar puncture performed 2 days after admission revealed a cerebrospinal fluid VZV DNA level of 880 copies/mL. Serum was positive for VZV IgG and negative for IgM. He received 10 days of intravenous acyclovir and was discharged home on oral valacyclovir 20 mg/kg 3 times daily. His weakness improved; however, follow-up imaging demonstrated progressive arteriopathy involving the distal left internal carotid and proximal left middle and anterior cerebral arteries. VZV is a neurotropic herpesvirus that becomes latent after primary infection. Neurologic complications include meningoencephalitis, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Ramsay-Hunt syndrome, cerebellar ataxia, myelitis, and vasculopathy. Rash is often not present at the time of these presentations. A review of children admitted to the Hospital for Sick Children between 1999 and 2012 identified 84 children with central nervous system complications of VZV, 10 of whom had a stroke.1Science M. MacGregor D. Richardson S.E. Mahant S. Tran D. Bitnun A. Central nervous system complications of varicella-zoster virus.J Pediatr. 2014; 165: 779-785Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar The median time between rash onset of clinical varicella and stroke was 16 weeks. Using electronic health records in the United Kingdom, Thomas et al found a 4-fold increased risk of stroke in children in the first 6 months after chickenpox.2Thomas S.L. Minassian C. Ganesan V. Langan S.M. Smeeth L. Chickenpox and risk of stroke: a self-controlled case series analysis.Clin Infect Dis. 2014; 58: 61-68Crossref PubMed Scopus (46) Google Scholar In contrast, no increase in childhood stroke was reported after varicella vaccination.3Donahue J.G. Kieke B.A. Yih W.K. Berger N.R. McCauley J.S. Baggs J. et al.Varicella vaccination and ischemic stroke in children: is there an association?.Pediatrics. 2009; 123: e228-e234Crossref PubMed Scopus (36) Google Scholar DeVeber et al noted a decrease in post-varicella arteriopathy after the widespread availability of vaccination in Canada.4deVeber G.A. Kirton A. Booth F.A. Yager J.Y. Wirrell E.C. Wood E. et al.Epidemiology and outcomes of arterial ischemic stroke in children: the Canadian Pediatric Ischemic Stroke Registry.Pediatr Neurol. 2017; 69: 58-70Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar VZV vasculopathy results from active viral infection of arteries, with viral particles in the media of affected vessels with a lymphocytic infiltrate and granulomatous angiitis on histopathology.5Berger T.M. Caduff J.H. Gebbers J.O. Fatal varicella-zoster virus antigen-positive giant cell arteritis of the central nervous system.Pediatr Infect Dis J. 2000; 19: 653-656Crossref PubMed Scopus (73) Google Scholar Involvement of the large vessels of the anterior circulation is most frequently reported in VZV vasculopathy in children.6Amlie-Lefond C. Gilden D. Varicella zoster virus: a common cause of stroke in children and adults.J Stroke Cerebrovasc Dis. 2016; 25: 1561-1569Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Stroke can occur after primary or reactivated varicella.7Gilden D. Cohrs R.J. Mahalingam R. Nagel M.A. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment.Lancet Neurol. 2009; 8: 731-740Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar The diagnosis can be confirmed by finding virus in the cerebrospinal fluid via polymerase chain reaction or by elevated cerebrospinal fluid VZV antibody, the latter being more sensitive.7Gilden D. Cohrs R.J. Mahalingam R. Nagel M.A. Varicella zoster virus vasculopathies: diverse clinical manifestations, laboratory features, pathogenesis, and treatment.Lancet Neurol. 2009; 8: 731-740Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar Varicella vasculopathy is usually monophasic, although progressive disease can occur. The possibility of varicella vasculopathy should be considered in children with cerebral arteriopathy and stroke, because antiviral treatment may improve outcome.