The Case for Immunomodulatory Approaches in Treating HSV Encephalitis

Abstract

HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis. Although safe and effective antiviral therapies and greatly improved noninvasive diagnostic procedures have significantly improved outcomes, mortality (~20%) and debilitating neurological sequelae in survivors remain unacceptably high. An encouraging new development is that the focus is now shifting away from the virus exclusively, to include consideration of the host immune response to infection in the pathology underlying development of HSE. In this article, the authors discuss results from recent studies in experimental mouse models, as well as clinical reports that demonstrate a role for exaggerated host inflammatory responses in the brain in the development of HSE that is motivating researchers and clinicians to consider new therapeutic approaches for treating HSE. The authors also discuss results from a few studies that have shown that immunomodulatory drugs can be highly protective against HSE, which supports a role for deleterious host inflammatory responses in HSE. The impressive outcomes of some immunomodulatory approaches in mouse models of HSE emphasize the urgent need for clinical trials to rigorously evaluate combination antiviral and immunomodulatory therapy in comparison with standard antiviral therapy for treatment of HSE, and support for such an initiative is gaining momentum.

Cerebrospinal fluid cyto‐/chemokine profile during acute herpes simplex virus induced anti‐N‐methyl‐d‐aspartate receptor encephalitis and in chronic neurological sequelae

“…22,24 Previous studies reported that patients with HSE treated with steroids had a better outcome and a rapid decline of cyto-/chemokines. 8,25,26 Similarly, in our acute post-HSE NMDAR case who had longitudinal CSF cytokine analysis, aggressive immunomodulatory treatment with induction and ongoing rituximab, IVIG, and steroids resulted in clinical improvements, and the patient remained well without relapses 18 months after HSE except for mild speech delay. By contrast, the chronic post-HSE cases 2 and 3 were treated latently (many years later) with courses of methylprednisolone, IVIG, and valacyclovir, which resulted in some subjective but marginal improvements.…”

“…Previous studies reported that patients with HSE treated with steroids had a better outcome and a rapid decline of cyto‐/chemokines . Similarly, in our acute post‐HSE NMDAR case who had longitudinal CSF cytokine analysis, aggressive immunomodulatory treatment with induction and ongoing rituximab, IVIG, and steroids resulted in clinical improvements, and the patient remained well without relapses 18 months after HSE except for mild speech delay.…”

A Population-Based Acute Meningitis and Encephalitis Syndromes Surveillance in Guangxi, China, May 2007- June 2012

“…More than 100 organisms can cause viral encephalitis [ 5 ]. HSV was the most common causative virus reported in the United States [ 13 ]. A hospital based study in Taiwan showed that HSV was the predominant pathogen (36%), followed by VZV (13%) [ 14 ].…”

“…These viral investigations were confined to 2007 and 2008 making trend analysis of viral AME rather limited. The positive rate of bacteria culture was low, which may be due to the prior antibiotic use or inadequate culture technique [ 13 ].…”

Effects of Acyclovir and IVIG on Behavioral Outcomes after HSV1 CNS Infection

“…We previously reported that ACV protection of susceptible 129S6 (129) mice was reduced when treatment was initiated after day 2 pi because ACV failed to curtail the escalating CNS inflammatory responses [ 28 ]. In contrast, IVIG administered at 24 h pi protected all mice as did ACV [ 17 ].…”