Varicella zoster disease of the central nervous system: epidemiological, clinical, and laboratory features 10 years after the introduction of the varicella vaccine

Abstract

Background: Since the introduction of live attenuated varicella zoster virus (VZV) vaccine in 1995 there has been a significant reduction in varicella incidence and its associated complications, but the impact on VZV-associated central nervous system (CNS) disease has not been assessed.

Methods: In this descriptive study we evaluated patients referred to the California Encephalitis Project from 1998 to 2009 with VZV PCR-positive cerebrospinal fluid (CSF). Epidemiological, clinical, and laboratory data were collected using a standardized case form. Specimens were genotyped using multi-single nucleotide polymorphism (SNP) analysis.

Results: Twenty-six specimens were genotyped from patients 12-85 years of age (median, 46 years). Clinical presentations included meningitis (50%), encephalitis (42%), and acute disseminated encephalomyelitis (ADEM) (8%). Only 11 patients (42%) had a concomitant herpes zoster rash. Genotype analysis identified 20 European Group (Clade1, Clade 3) strains; 4 Asian (Clade 2) strains, and 2 Mosaic Group (Clade 4, Clade VI) strains. One specimen was recognized as vaccine strain by identifying vaccine-associated SNPs.

Conclusions: VZV continues to be associated with CNS disease, with meningitis being the most frequent clinical presentation. CNS VZV disease often presented without accompanying zoster rash. Sequencing data revealed multiple genotypes, including 1 vaccine strain detected in the CSF of a young patient with meningitis.

Figure 1.

Single nucleotide polymorphism (SNP) profiles for the VZV genotypes identified in this study. The base positions for the SNP are based on the published sequence for the Dumas strain (GenBank accession no. XO4370). The principle reference strain for each clade is indicated in parentheses. Clade VI is provisional; no complete genome sequences are currently available.

Figure 2.

Distribution of VZV genotypes identified in this study. The vaccine strain was differentiated from other clade 2 viruses by evaluating vaccine specific SNP at positions 106262 and 107252 (ORF62), and genotyping SNP at ORF38 (PstI site), ORF54 (BglI site) and sequence analysis of targeted regions in ORF21, ORF22, and ORF50. Clade 1/Clade 3 indicates European group isolates that could not be further characterized due to failure to amplify the regions in ORF21 and ORF50.