MED IC A L PR OGR ES S
Medical Progress N EUROLOGIC C OMPLICATIONS OF THE R EACTIVATION OF V ARICELLA –Z OSTER V IRUS
DONALD H. GILDEN, M.D., B.K. KLEINSCHMIDT-DEMASTERS, M.D., J. LAGUARDIA, M.D., RAVI MAHALINGAM, PH.D., AND RANDALL J. COHRS, PH.D.
the infected person; however, the biologic mechanisms that underlie the transition from latency to active viral replicationare unknown. Many laboratories have made serious efforts to determine the physical state of the virus during latency, because understanding this state is essential to predicting or preventing the neurologic complications produced by reactivation of the virus.
DNA of Varicella–Zoster Virus in Human Ganglia
ARICELLA–ZOSTER virus is an exclusively human herpesvirus that causeschickenpox (varicella), becomes latent in cranial-nerve and dorsal-root ganglia, and frequently reactivates decades later to produce shingles (zoster) and postherpetic neuralgia. In immunocompetent elderly persons or immunocompromised patients, varicella–zoster virus may produce disease of the central nervous system. Since the last major review of varicella–zoster virus in the Journal,1,2 advances inmolecular biology have provided important new insights into the pathogenesis of infection with varicella–zoster virus. The detection of varicella–zoster virus in blood vessels and other tissues by methods based on the polymerase chain reaction (PCR) has widened the recognized clinical spectrum of acute and chronic disorders associated with varicella–zoster virus, including latent infections. In thisarticle we highlight current progress in understanding the latency of varicella–zoster virus and review the neurologic complications of viral reactivation, with a focus on previously underemphasized patterns of zoster, preherpetic and postherpetic neuralgia, myelitis, large-vessel granulomatous arteritis, and small-vessel encephalitis, all of which may occur without the rash typical of zoster(Fig. 1).
In latency, the condition that follows acute infection (usually manifested as chickenpox), the virus persists in a noninfectious form with intermittent periods of reactivation and shedding. Varicella–zoster virus reactivates with increasing age or immunosuppression of
From the Departments of Neurology (D.H.G., B.K.K.-D., J.J.L., R.M., R.J.C.), Microbiology (D.H.G.), andPathology (B.K.K.-D.), University of Colorado Health Sciences Center, Denver. Address reprint requests to Dr. Gilden at the Department of Neurology, Mailstop B182, University of Colorado Health Sciences Center, 4200 E. 9th Ave., Denver, CO 80262, or at email@example.com. ©2000, Massachusetts Medical Society.
After it has produced chickenpox, varicella–zoster virus becomes latent in gangliaalong the entire neuraxis. Unlike herpes simplex virus, however, varicella– zoster virus cannot be cultured from human ganglia.3 Although clinicians had long suspected that the ganglia were the site of latency, verification came only after latent varicella–zoster virus was detected in human trigeminal and thoracic ganglia by means of Southern blot analysis and in situ hybridization.4-6 A PCRanalysis that revealed varicella–zoster viral DNA in trigeminal ganglia from 13 of 15 subjects and in thoracic ganglia from 9 of 17 subjects7 validated earlier observations that the thoracic and trigeminal dermatomes were the most common sites of reactivation.8 Most, if not all, of the DNA molecule of varicella– zoster virus is present during latency,7 but the viral burden is low. A competitive PCRassay revealed 6 to 31 copies of varicella–zoster viral DNA in 105 ganglionic cells.9 A noncompetitive PCR assay indicated more varicella–zoster viral DNA,10 similar to the 103 to 105 copies of latent DNA of herpes simplex virus type 1 in 105 cells.11 The difference in the number of varicella–zoster viral copies reported9,10 may result from the fact that different techniques were used. Latent...
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