Detection of human herpesviruses in the cerebrospinal fluid from patients diagnosed with or suspected of having progressive multifocal leukoencephalopathy

Abstract

Background: Progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease caused by JC virus (JCV), occurs mainly in immunocompromised patients. While JCV DNA is detected in the cerebrospinal fluid (CSF) from a certain proportion of patients suspected of having PML, JCV-negative patients may also develop brain lesions due to other infectious agents. This study assessed the prevalence of six herpesviruses in the CSF from patients diagnosed with or suspected of PML.

Methods: Two hundred and ninety-nine CSF specimens and clinical data were collected from 255 patients, including 31 confirmed PML cases. Quantitative PCR assays were carried out to detect the genomic DNA of JCV, herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6).

Results: Herpesvirus DNAs were detected in the CSF specimens from 29 of 255 patients (11.4%). HSV-1 and CMV were detected in JCV-negative patients, whereas VZV and EBV were detected in both CSF JCV-positive and -negative individuals. The herpesvirus-positive patients had underlying disorders that caused immunosuppression, such as HIV infection, congenital immunodeficiencies, and hematologic malignancies, and presented with neurologic symptoms and MRI lesions, mainly in the cerebral white matter. The median values of CSF cell counts and protein levels in the herpesvirus-positive patients were slightly higher than those in the PML patients.

Conclusions: The results demonstrate that herpesviruses are occasionally detected in the CSF from PML patients and immunocompromised individuals suspected of having PML. Thus, this study provides a significant basis for the diagnosis and treatment of neurological disorders in immunocompromised patients.

Figure 1

Viral loads of herpesvirus DNAs in the CSF specimens from patients. The CSF viral loads of HSV-1, VZV, CMV, and EBV are shown (left to right). Each open circle indicates the copy number of viral DNA in each sample, and the horizontal lines represent the medians.

Figure 2

CSF cell counts (A) and total protein contents (B) in PML and herpesvirus-positive patients. Since the CSF cell counts and/or total protein contents were not defined in the questionnaires in some cases, the numbers of patients are not identical in panels A and B. The data of patients positive for both CSF JCV and herpesvirus DNAs are not included in each panel. In box-and-whisker plots, the thick horizontal line within each box is the median; the lower and upper boundaries are the 25th and 75th percentiles, respectively; vertical whiskers extend over the range; and dots and arrows show outliers.