The German trial on Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE): a multicenter, randomized, double-blind, placebo-controlled trial

Abstract

Introduction Comprehensive treatment of Herpes-simplex-virus-encephalitis (HSVE) remains a major clinical challenge. The current therapy gold standard is aciclovir, a drug that inhibits viral replication. Despite antiviral treatment, mortality remains around 20% and a majority of survivors suffer from severe disability. Experimental research and recent retrospective clinical observations suggest a favourable therapy response to adjuvant dexamethasone. Currently there is no randomized clinical trial evidence, however, to support the routine use of adjuvant corticosteroid treatment in HSVE. Methods The German trial of Aciclovir and Corticosteroids in Herpes-simplex-virus-Encephalitis (GACHE) studied the effect of adjuvant dexamethasone versus placebo on top of standard aciclovir treatment in adult patients aged 18 up to 85 years with proven HSVE in German academic centers of Neurology in a randomized and double blind fashion. The trial was open from November 2007 to December 2012. The initially planned sample size was 372 patients with the option to increase to up to 450 patients after the second interim analysis. The primary endpoint was a binary functional outcome after 6 months assessed using the modified Rankin scale (mRS 0–2 vs. 3–6). Secondary endpoints included mortality after 6 and 12 months, functional outcome after 6 months measured with the Glasgow outcome scale (GOS), functional outcome after 12 months measured with mRS and GOS, quality of life as measured with the EuroQol 5D instrument after 6 and 12 months, neuropsychological testing after 6 months, cranial magnetic resonance imaging findings after 6 months, seizures up to day of discharge or at the latest at day 30, and after 6 and 12 months. Results The trial was stopped prematurely for slow recruitment after 41 patients had been randomized, 21 of them treated with dexamethasone and 20 with placebo. No difference was observed in the primary endpoint. In the full analysis set (n = 19 in each group), 12 patients in each treatment arm achieved a mRS of 0–2. Similarly, we did not observe significant differences in the secondary endpoints (GOS, mRS, quality of life, neuropsychological testing). Conclusion GACHE being prematurely terminated demonstrated challenges encountered performing randomized, placebo-controlled trials in rare life threatening neurological diseases. Based upon our trial results the use of adjuvant steroids in addition to antiviral treatment remains experimental and is at the decision of the individual treating physician. Unfortunately, the small number of study participants does not allow firm conclusions. Trial registration EudraCT-Nr. 2005–003201-81.

Post-Infectious Autoimmunity in the Central (CNS) and Peripheral (PNS) Nervous Systems: An African Perspective

“…It is unclear if early steroid treatment during HSV could decrease the risk of secondary autoimmunity, but a clinical trial is under way ( 187 ). Therefore, to date, early steroid and acyclovir combination therapy remains experimental ( 188 ).…”

Case Report: HSV-2 Encephalitis Presenting With Chorea; Effects of Infection Alone or Combination of Infection and Autoimmunity?

“…Although, both early and delayed glucocorticoid administration has been shown to equally improve outcomes, it is typically withheld early in the course of active infections in order to presumably limit viral replication (9). In addition, randomized trials examining concurrent administration of glucocorticoid and acyclovir are also inconclusive (19). In this case, early initiation of plasmapheresis clearly yielded full and rapid resolution of chorea.…”

“…Finally, a diagnostic challenge lies in that there have been rapidly emerging cases of encephalitis with preceding virallike illness of suspected immune origin but with undetectable neuronal autoantibodies in serum and CSF and normal neuroimaging as in this case (15)(16)(17)(18). This is confounded with an overdependence on antibody status to diagnose encephalitis of suspected immune origin, which may delay diagnosis and treatment (19). Therefore, a high index of clinical suspicion is pivotal to timely diagnose and treat such patients.…”

Recovery of intracranial stenoses in varicella zoster virus vasculitis after long-term treatment with valacyclovir and prednisolone

“…This multicenter, randomized, double-blind, placebo-controlled trial was intended to analyse adjuvant dexamethason additionally to acyclovir in Herpes-simplex virus encephalitis. It was stopped prematurely for slow recruitment after 41 patients and failed to show significant differences in this small patient group [ 18 ].…”

“…Another limitation is that this report does not represent a randomized controlled study. However, in rare diseases, recruitment is difficult as demonstrated in the GACHE study [ 18 ]. This multicenter, randomized, double-blind, placebo-controlled trial was intended to analyse adjuvant dexamethason additionally to acyclovir in Herpes-simplex virus encephalitis.…”