E D I T O R I A L C O M M E N T A R Y

Strokes and Infection With Varicella Zoster Virus

Anne A. Gershon

Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, New York

(See the Major Article by Thomas et al on pages 61–8.)

Keywords. varicella; zoster; stroke; varicella-zoster virus; varicella vaccine.

It was long assumed, before recent devel-opments proved otherwise, that the pres-ence of an infection with varicella zostervirus (VZV) was inevitably associatedwith a rash. We now know, due to theuse of polymerase chain reaction (PCR)and other methods that have improveddiagnosis, that patients can harbor infec-tions with VZV even in the absence ofcutaneous manifestations Such “occult”VZV infections often affect the nervousand gastrointestinal systems. Centralnervous system (CNS) VZV infectionswithout rash were initially identified atautopsy [1] and subsequently in patientswith meningitis through the PCR detec-tion of VZV DNA in cerebrospinal fluid(CSF) [2]. Although there appears to be arelationship between VZV infection andarterial ischemic stroke (AIS) [3], these pa-tients also do not display a rash when theydevelop symptoms involving the CNS.

In the current issue of Clinical Infec-tious Diseases, Thomas et al describe theconnection between varicella and subse-quent AIS in children. They used 4 large

databases and a self-controlled caseseries, analyzing data from strokes in thevaricella cases. Data were analyzed 0–6months after an episode of varicella andagain at a later time. This method avoidsconfounding factors and is efficient at re-lating a rare condition, such as stroke inchildhood, to a common infection, vari-cella, although it does not provideinformation on the absolute risk of post-varicella stroke. Thomas et al’s study re-vealed that in the 6 months followingvaricella, the incidence of childhoodstroke is increased by a factor of approxi-mately 4. There was no significant in-crease in strokes in adults after varicella,nor was there any increase in strokes 7–12 months after varicella in children. Thepathogenesis of postvaricella stroke is notknown, but VZV can infect cerebral ar-teries, which provokes inflammatory re-sponses that damage the infected arteriesand may lead to aneurysms [4–6].Because the interval between an episodeof varicella and a stroke can be as long as6 months, reactivation of latent VZV ac-quired during varicella, rather than asmoldering persistent infection in arter-ies, seems more likely to cause AIS,although either possibility remains plau-sible. The VZV that infects arteries couldbe delivered from sensory neurons inwhich VZV reactivates or as a result of aviremia. It may well be that most strokesfollowing varicella are, in reality, strokesfollowing zoster without rash. When

one such stroke develops, there maybe recurrences [7]. Strokes may alsofollow classic zoster, particularly whenthe ophthalmic branch of the trigeminalnerve is involved. It is conceivable thatAIS after varicella in children is a mani-festation of a rare defect in innate immu-nity described in certain severe alphaherpesvirus infections [8–12]. One mys-tery is why VZV would be at increasedrisk for reactivation soon after varicella.This timing may reflect the putative im-munologic predisposition. Clearly, addi-tional knowledge of the state of VZVprior to infection of cerebral arteries, aswell as the immunologic status of the hostwho has experienced a VZV-inducedstroke, is needed.

A relationship between zoster andstroke was appreciated before postvaricel-la stroke was recognized. At first termedgiant cell arteritis, it now appears thatthis vasculitis syndrome is similar towhat is termed VZV vasculopathy [13].VZV vasculopathy may be a subset ofgiant cell arteritis. It was recognized his-torically that in the months followingzoster, patients (usually adults) mightmanifest symptoms of stroke ipsilateralto the side of the body where zoster oc-curred.

Because strokes in children are unusualor rare, this increase in CNS disease fromvaricella, albeit serious to individuals, isnot a major public health problem. Themorbidity (which may be long-lasting)

Received 16 September 2013; accepted 18 September2013; electronically published 2 October 2013.

Correspondence: Anne A. Gershon, MD, Department of Pe-diatrics, Columbia University College of Physicians and Sur-geons, 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 Presson behalf of the Infectious Diseases Society of America. Allrights reserved. For Permissions, please e-mail: journals.permissions@oup.com.DOI: 10.1093/cid/cit663

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associated with strokes in childhood, how-ever, makes childhood stroke a particularlyimportant phenomenon to understand.The data of Thomas et al are similar tothose reported in an earlier much smallercase-control study [14]; because of itsmagnitude, the study of Thomas et al pro-vides significant confirmatory evidence fora causal relationship between varicella andstroke. An important next step would beto analyze possible effects of varicellavaccine on the incidence of childhoodstrokes. One published study of >3 millionvaccinated children in the United Statesfound no association with AIS within 1month of vaccination [15].

Routine vaccination of children againstvaricella does not occur in the UnitedKingdom, where the current study wasperformed. Whether vaccination againstvaricella would lessen the risk of strokecan only be speculated upon, but if reacti-vation of VZV plays a role in productionof strokes as has been postulated, vaccina-tionmight reduce thisproblem. Inboth im-munocompromised and healthy children,reactivation of VZV is less common aftervaccination than after varicella [16–18].

Vaccine policy in the UK may havebeen influenced against licensure of vari-cella vaccine because it is thought thatchildren have to experience varicella tomaintain circulating wild-type VZV toboost adult immunity and thus preventwaning immunity and consequent epi-demics of zoster [19]. The incidence ofzoster has been increasing in the UnitedStates, where varicella vaccine was li-censed in 1995; however, zoster began itsincrease in the 1950s and has been in-creasing linearly since then [20]. The USincrease in zoster thus is probably multi-factorial and relates to an aging population,increased numbers of immunocompro-mised patients, and improved diagnosticmethods, rather than simply universalvaricella vaccination. Subclinical reacti-vation of VZV clearly occurs [21–25] andmay boost immunity to the virus [26, 27].Fears of epidemic zoster from routinevaccination against varicella may thus be

unfounded. Universal immunization hasdriven the incidence of varicella and itscomplications to vanishingly low levels inthe United States, and the disease is nowuncommon or rare [28]. The predictedepidemic of zoster since vaccine licensurehas not materialized. It would be interest-ing to determine whether the incidenceof childhood strokes has changed in theUnited States in the past 10–12 years.It is now possible to determine

whether AIS in a given patient may bedue to VZV. Molecular methods areavailable for diagnosis, including PCR toidentify VZV in CSF, immunofluores-cence of VZV antigens in arterial biop-sies, and the ratio between VZVantibodies in CSF and serum [4]. Thesediagnostic tests should be employed inpatients who suffer AIS, not only for in-dividual diagnosis, but also to under-stand better the nature and severity ofpostvaricella VZV-induced stroke as aproblem. In countries where the varicellavaccine is used routinely, it is potentiallypossible to identify the vaccine strain(Oka) in CSF using PCR, as has been donein the very rare cases of VZV meningitisattributed to the vaccine type virus [2].Although there have been at least 2reports of stroke in children followingvaccination [3], the vaccine strain wasnot identified in CSF in these children.There is currently intensive interest in

the United States in cases of VZV reacti-vation that occur without an accompany-ing rash. In addition to strokes, meningitishas been reported to be due to reactivationof VZV without rash [2]. The phenome-non of visceral zoster, affecting the gastro-intestinal tract in the absence of rash,furthermore, may lead to achalasia, gastriculcers, and intestinal pseudo-obstruction[29]. VZV achieves latency in the humangut, and therefore local reactivationmight account for some of these condi-tions [30]. Whether universal varicellavaccination has lowered the frequency ofthese problems deserves further study.In conclusion, VZV causes a wide

variety of medical problems, including

AIS, in children, as shown in the Thomaset al study, and in adults. Varicellavaccine prevents severe or fatal varicellain healthy and immunocompromised in-dividuals, and reduces of the incidence ofzoster. If strokes are due to reactivationof latent VZV, varicella vaccine might de-crease the incidence of strokes because ofits decreased propensity to cause reacti-vation disease. AIS might thus be yet onemore reason to prefer vaccination to vari-cella in children.

Notes

Financial support. National Institutes ofHealth (grant R0 1 DK 093094).Potential conflicts of interest. The author

has served as a consultant for Merck and GlaxoSmithKline on VZV vaccines when invited, andhas had a service contract (diagnostic) for safetyof VZV vaccines from Merck, with results sub-mitted to Merck and the Food and Drug Admin-istration.The author has submitted the ICMJE Form for

Disclosure of Potential Conflicts of Interest. Con-flicts that the editors consider relevant to thecontent of the manuscript have been disclosed.

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