The variegate neurological manifestations of varicella zoster virus infection

Abstract

Varicella zoster virus (VZV) is an exclusively human neurotropic alphaherpesvirus. Primary infection causes varicella (chickenpox), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. With advancing age or immunosuppression, cell-mediated immunity to VZV declines, and the virus reactivates to cause zoster (shingles), dermatomal distribution, pain, and rash. Zoster is often followed by chronic pain (postherpetic neuralgia), cranial nerve palsies, zoster paresis, vasculopathy, meningoencephalitis, and multiple ocular disorders. This review covers clinical, laboratory, and pathological features of neurological complications of VZV reactivation, including diagnostic testing to verify active VZV infection in the nervous system. Additional perspectives are provided by discussions of VZV latency, animal models to study varicella pathogenesis and immunity, and of the value of vaccination of elderly individuals to boost cell-mediated immunity to VZV and prevent VZV reactivation.

Fig. 1

Neurological complications of varicella zoster virus VZV reactivation. (With permission from Gilden D, Mahalingam R, Nagel MA, Pugazhenthi S, Cohrs RJ. The neurobiology of varicella zoster virus infection. Neuropathol Appl Neurobiol. 2011;37:441– 63) [52]

Fig. 2

Brain magnetic resonance image (MRI) of a patient with varicella zoster virus multifocal vasculopathy. Proton-density brain MRI scan shows multiple areas of infarction, particularly involving gray–white matter junctions, in both hemispheres.(With permission from Gilden DH, Mahalingam R, Cohrs RJ, Kleinschmidt-DeMasters BK, Forghani B. The protean manifestations of varicella-zoster vasculopathy. J Neurovirol 2002;8(Suppl. 2):75–9) [53]

Fig. 3

The varicella zoster virus (VZV) genome, open reading frames (ORFs), and transcriptome in productively infected cells. The 125-kbp VZV genome is compose of long and short unique regions (U_L and U_S), each containing terminally and internally located invert repeats (TR_L, IR_L and TR_S, IR_S). DNA analysis identifies 71 ORFs numbered consecutively from the left end of the virus genome. Relative location and direction of transcription is indicated by arrows, and ORFs transcribed in latently infected human ganglia are identified in red (A). ORFs 62–64 are located within TR_S and are also present in IRS as ORF_s 69, 70, and 71. The abundance of each ORF (except ORF 14) was determined and compared with the abundance of housekeeping genes actin and GAPdH (B). VZV ORFs transcribed in latently infected human ganglia are identified by red squares

Fig. 4

Herpes simplex virus-1 (HSV-1) and varicella zoster virus (VZV) transcription after death. Mouse trigeminal ganglia latently infected with HSV-1 were explanted and virus transcripts detected by reverse-transcription quantitative polymerase chain reaction (PCR). Before 3 h post-explantation, latency associated transcripts (LAT) are transcribed from the episomal genome. Three h post-explantation, multiple transcripts are detected. Human trigeminal ganglia were removed at various times post-mortem and VZV transcripts detected by reverse transcription multiplex PCR [54••]. Before 9 h after death, transcripts for only VZV ORF 63 were detected from the virus episome. Nine h post-mortem, multiple VZV transcripts were detected