Editorial Commentary: Strokes and Infection With Varicella Zoster Virus (2013)

It was long assumed, before recent developments proved otherwise, that the presence of an infection with varicella zoster virus (VZV) was inevitably associated with a rash. We now know, due to the use of polymerase chain reaction (PCR) and other methods that have improved diagnosis, that patients can harbor infections with VZV even in the absence of cutaneous manifestations Such “occult” VZV infections often affect the nervous and gastrointestinal systems. Central nervous system (CNS) VZV infections without rash were initially identified at autopsy [1] and subsequently in patients with meningitis through the PCR detection of VZV DNA in cerebrospinal fluid (CSF) [2]. Although there appears to be a relationship between VZV infection and arterial ischemic stroke (AIS) [3], these patients also do not display a rash when they develop symptoms involving the CNS. In the current issue of Clinical Infectious Diseases, Thomas et al describe the connection between varicella and subsequent AIS in children. They used 4 large databases and a self-controlled case series, analyzing data from strokes in the varicella cases. Data were analyzed 0–6 months after an episode of varicella and again at a later time. This method avoids confounding factors and is efficient at relating a rare condition, such as stroke in childhood, to a common infection, varicella, although it does not provide information on the absolute risk of postvaricella stroke. Thomas et al’s study revealed that in the 6 months following varicella, the incidence of childhood stroke is increased by a factor of approximately 4. There was no significant increase in strokes in adults after varicella, nor was there any increase in strokes 7– 12 months after varicella in children. The pathogenesis of postvaricella stroke is not known, but VZV can infect cerebral arteries, which provokes inflammatory responses that damage the infected arteries and may lead to aneurysms [4–6]. Because the interval between an episode of varicella and a stroke can be as long as 6 months, reactivation of latent VZV acquired during varicella, rather than a smoldering persistent infection in arteries, seems more likely to cause AIS, although either possibility remains plausible. The VZV that infects arteries could be delivered from sensory neurons in which VZV reactivates or as a result of a viremia. It may well be that most strokes following varicella are, in reality, strokes following zoster without rash. When one such stroke develops, there may be recurrences [7]. Strokes may also follow classic zoster, particularly when the ophthalmic branch of the trigeminal nerve is involved. It is conceivable that AIS after varicella in children is a manifestation of a rare defect in innate immunity described in certain severe alpha herpesvirus infections [8–12]. One mystery is why VZV would be at increased risk for reactivation soon after varicella. This timing may reflect the putative immunologic predisposition. Clearly, additional knowledge of the state of VZV prior to infection of cerebral arteries, as well as the immunologic status of the host who has experienced a VZV-induced stroke, is needed. A relationship between zoster and stroke was appreciated before postvaricella stroke was recognized. At first termed giant cell arteritis, it now appears that this vasculitis syndrome is similar to what is termed VZV vasculopathy [13]. VZV vasculopathy may be a subset of giant cell arteritis. It was recognized historically that in the months following zoster, patients (usually adults) might manifest symptoms of stroke ipsilateral to the side of the body where zoster occurred. Because strokes in children are unusual or rare, this increase in CNS disease from varicella, albeit serious to individuals, is not a major public health problem. The morbidity (which may be long-lasting) Received 16 September 2013; accepted 18 September 2013; electronically published 2 October 2013. Correspondence: Anne A. Gershon, MD, Department of Pediatrics, Columbia University College of Physicians and Surgeons, 622 W 168th St, PH 19-110, New York, NY 10032 (aag1@columbia.edu). Clinical Infectious Diseases 2014;58(1):69–71 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/cit663