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Corticosteroids in herpes simplex virus encephalitis
  1. H Openshaw,
  2. E M Cantin
  1. Departments of Neurology and Virology, City of Hope National Medical Center and Beckman Research Institute, Duarte, CA, USA
  1. Correspondence to:
 Dr Harry Openshaw
 City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA; hopenshawcoh.org

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The effectiveness of corticosteroids in herpes simplex virus encephalitis is not proven

Despite receiving standard antiviral therapy, an appreciable number of patients with herpes simplex virus encephalitis (HSVE) experience poor acute outcome or delayed neurological progression. It is uncertain whether all poor outcomes are due to viral cytopathology or whether an immune mediated pathogenesis also occurs. In support of an immunopathological cause, Kamei et al (see pages XX–XX of this issue) report that corticosteroid administration was a significant predictor of favourable outcome at 3 months after HSVE infection.

Immune cells persist and elaborate cytokines in the nervous system long after the virus has entered latency.1 It is likely that there is ongoing antigenic stimulation, probably from low level HSV reactivation. To determine the effect of long term silencing of HSV, a clinical trial sponsored by the National Institutes of Allergy and Infectious Diseases has been designed and compares 3 months of oral valaciclovir to placebo in HSVE subjects who have completed their intravenous acyclovir course (http://clinicaltrials.gov). This long term treatment may significantly influence the CNS inflammatory cell infiltrate. Evidence suggesting that CNS inflammation has a detrimental effect comes from an experimental study in knockout mice lacking the Toll-like receptor 2, one of the receptors that mediate the inflammatory cytokine response to HSV.2 Despite similar CNS viral titres, lethal encephalitis occurred in a lower percentage of the knockout mice. A similar beneficial effect from corticosteroids, presumably through an anti-inflammatory mechanism, was reported in a brain magnetic resonance imaging (MRI) study of limbic HSVE in mice. Significantly less brain T2 hyperintensity was seen in animals receiving acyclovir and methylprednisolone compared to acyclovir alone at 2 and 6 months after HSV inoculation.3 Unlike the report of Kamei et al, where patients received corticosteroids concurrently with acyclovir, initiation of methylprednisolone was delayed until after completion of a 2 week course of acyclocivir, and methylprednisolone was given only for 1 week. In the same animal model, acyclovir started 1 day after HSV inoculation reduced levels of brain chemokine mRNA expression, particularly CCL5, and concurrently administered methylprednisolone resulted in an additional decrease.4 If a similar reduction in chemokines occurs in patients, the extent of chronic inflammation and neuronal damage caused by HSVE would be expected to be less.

There are, of course, problems applying results from animal models to HSVE in patients. Furthermore, concerns that early corticosteroid administration may increase viral CNS spread have led many practitioners to restrict corticosteroids to patients with significant brain oedema. The retrospective study of Kamei et al should not be taken as evidence of the effectiveness of early corticosteroid treatment in HSVE. After all, the decision to use corticosteroids (as well as the preparation and schedule) was at the discretion of the treating physician. Perhaps the real predictor of outcome is not corticosteroids per se but rather some (undefined) characteristic of the infection that leads to corticosteroid use. The effectiveness of corticosteroids in HSVE can only be determined by prospective, randomised studies. Before such studies are designed, it would be helpful to have additional animal model results describing the optimum timing of corticosteroid administration as regards the effect on the CNS inflammatory cell infiltrate.

The effectiveness of corticosteroids in herpes simplex virus encephalitis is not proven

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