By Stan Deresinski, MD, FACP, FIDSA
Clinical Professor of Medicine, Stanford University
SYNOPSIS: The authors concluded that their results indicate a need for controlled trials comparing intravenous acyclovir to valacyclovir or to no antivirals in the management of varicella zoster meningitis without neurological complications in immunocompetent patients.
SOURCE: Dulin M, Chevret S, Salmona M, et al. New insights into the therapeutic management of varicella zoster virus meningitis: A series of 123 polymerase chain reaction-confirmed cases. Open Forum Infect Dis 2024;11:ofae340.
Dulin and colleagues retrospectively examined the records of 123 adults with meningitis due to varicella zoster virus (VZV) at three university hospitals in Paris. Their primary aim was to evaluate the results of various therapeutic approaches. VZV deoxyribonucleic acid (DNA) was detected in cerebrospinal fluid (CSF) in each case. VZV meningitis was defined as the presence of ≥ 5 white blood cells (WBC)/µL of CSF together with meningeal symptoms, with or without cranial nerve abnormalities, and the absence encephalopathy and of a focal abnormality on electroencephalography or imaging. Of the 135 patients evaluated, 123 had meningitis and 13 had encephalitis.
The median age of those with meningitis was 36 years, while it was 51 years in those with encephalitis. Human immunodeficiency virus (HIV) infection was present in 3.2% and 58%, respectively (P = 0.0001). In addition to headache, 73% had nausea and/or vomiting, 63% had photophobia and/or phonophobia, 37% had neck stiffness, and 37% had fever. Focal peripheral neurological signs were present in 14 patients (11%) and were due to cranial nerve involvement or plexopathy in 13 and one, respectively. Herpes zoster, with median onset one day after onset of meningeal symptoms, was present in 43%. One patient had hepatitis believed to be due to VZV. In those who underwent lumbar puncture on the day of hospital admission, the median CSF WBC was 272 cells/ µL with lymphocyte predominance, the median CSF protein was 1.1 g/dL, while the CSF glucose concentration was normal in 82%.
Computerized tomography was normal in all 109 patients in whom it was performed. Magnetic resonance imaging (MRI) was performed in 88 patients and was abnormal in eight (18%), demonstrating labyrinthitis or cranial nerve hyperintensity. Peripheral facial nerve palsy was present in each of the eight patients. In contrast, one-half of the patients with encephalitis had evidence of cerebral vasculitis.
Antiviral treatment was given at the discretion of the clinicians. Among the 123 patients with meningitis, 14% received no antiviral therapy, 20% received only oral valacyclovir, valacyclovir was administered after a short course (less than seven days) of intravenous (IV) acyclovir was administered to 41%, and 25% received a prolonged course of IV acyclovir. Multivariate analysis identified age, underlying immunosuppression, and cranial radiculitis to be independently associated with longer courses of IV acyclovir administration (which, in turn, was associated with more prolonged hospitalization).
Overall, an unfavorable outcome (death or > 2 point decrease in the modified Rankin Scale score, a measure of disability or dependence) occurred in only 5/123 (4%) meningitis patients, with no significant difference among the four treatment groups. There were no relapses. There were no unfavorable outcomes in the 24 patients who received only oral valacyclovir or the 17 who received no antiviral therapy. While no cases of acute kidney injury occurred in either of those groups, 15/82 who received IV acyclovir developed acute kidney injury, with no significant difference between those who received it for less than seven days and those who received it for seven days or longer.
COMMENTARY
This study found that VZV meningitis was a relatively benign illness in most patients, and this also was true for the small number of patients with encephalitis, despite the frequent immunocompromise in that group. Shingles, which occurred in 43% of the meningitis patients, may be associated with mild CSF evidence of inflammation in the absence of clinically evident central nervous system illness, but all the patients in the cohort had VZV DNA detected in CSF by polymerase chain reaction (PCR). Of importance is that only 22 patients, including 11 with HIV infection, were considered immunocompromised and 4/11 with HIV infection and 11/11 with other immunocompromise had encephalitis.
The most recent Infectious Diseases Society of America (IDSA) guideline, published in 2008, recommends administration of IV acyclovir for 10-14 days.1 This retrospective study by Dulin and colleagues, in which patients were treated with IV acyclovir for varying durations with or without follow-on valacyclovir, with valacyclovir alone, or with no antiviral therapy does not find strong support for the IDSA recommendation. However, there was a documented selection bias, with older or immunocompromised patients and/or those with associated radiculitis more likely to receive a more prolonged course of IV acyclovir. One clear result was the greater risk of acute kidney injury in IV acyclovir recipients, whether for less than seven days or greater than seven days, occurring in 15/74 (20.3%) compared to 0/41 in those who did not receive this therapy.
Despite the shortcomings of this study, it can be concluded that, at least in patients without significant immunocompromise, VZV meningitis is relatively mild in most patients and that the role of antiviral therapy remains unclear, but it appears that IV acyclovir is unnecessary. Valacyclovir appears to be sufficient in most patients, and some patients require no antiviral therapy at all. The authors concluded that there is a need for controlled trials comparing IV acyclovir to valacyclovir or to no antivirals in the management of VZV meningitis without neurological complications in immunocompetent patients.
REFERENCE
- Tunkel AR, Glaser CA, Bloch KC, et al; Infectious Diseases Society of America. The management of encephalitis: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008;47:303-327.
