A brain infection that destroys memory is being put to the test against a cheap, widely available steroid. Herpes simplex virus encephalitis kills or severely impairs roughly half of those it strikes, with survivors often left unable to form new verbal memories—forgetting conversations minutes after they happen. The swelling in the brain’s temporal lobes drives much of this damage, but doctors have hesitated to give corticosteroids like dexamethasone, fearing they might let the virus run unchecked. This trial will randomise 90 adults with proven HSV encephalitis to receive either intravenous dexamethasone for four days alongside standard antiviral treatment, or antivirals alone. The primary measure is verbal memory score on the Wechsler Memory Scale at six months. Secondary outcomes include temporal lobe volume on MRI, viral clearance from spinal fluid at two weeks, and long-term disability scales up to 18 months. If dexamethasone improves memory without worsening viral replication, it could become routine treatment for this devastating condition. The health economic costs of a single severe case are estimated at £3–5 million; a simple, inexpensive intervention that reduces long-term disability would change outcomes for patients and reduce lifelong care burdens.
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Herpes simplex virus (HSV) encephalitis is a rare but devastating brain infection, with temporal lobe swelling and severe memory impairment in survivors, particularly verbal memory. The swelling appears to respond to corticosteroid treatment, though some clinicians worry about uncontrolled viral replication. PRIMARY HYPOTHESIS: In HSV encephalitis treatment with the corticosteroid dexamethasone is associated with an improvement in verbal memory, assessed at 6 months. DESIGN: A multicentre observer-blind trial of corticosteroids in 90 adults with HSV encephalitis. SETTING: Recruitment through NHS Hospital Trusts in the Brain Infections UK Network: up to 90 sites TARGET POPULATION: Adults with HSV encephalitis, proven by PCR of the cerebrospinal fluid (CSF). INTERVENTION: Patients will be randomised to dexamethasone 40 mg intravenously every 24 hours for 4 days, or no dexamethasone; in addition all will receive standard antiviral treatment: 10 mg/kg aciclovir 8 hourly for 14 days. OUTCOME and ASSESSMENT: Assessments at baseline, 2 weeks, 6 & 18 months. Primary outcome will be the verbal memory score, as determined the Wechsler Memory Scale (WMS-IV), at 6 months. Secondary outcomes: Temporal lobe volume, assessed by MRI The proportion of patients that still have HSV detectable in their CSF at 2 weeks Blood and CSF inflammatory markers at baseline, 2 weeks, and 6 months (blood only) Time to - Recovery of Glasgow Coma Scale - Cessation of ventilatory support - Hospital discharge 6 & 18 months outcome assessed by - Detailed Neuropsychology - MRI - Modified Rankin Scale - Glasgow Outcome Scale - Liverpool Outcome Score - Incidence of epilepsy - EuroQol 5D-5L - Mortality SAMPLE SIZE and STATISTICAL ANALYSIS: Memory is badly affected after HSV encephalitis. In one study, 19 of 22 patients, assessed at least 6 months after the acute illness, had memory impairment at follow up, with verbal memory being most severely affected. In that study the mean (standard deviation, SD) verbal memory score was 88.9 (18.9) [population mean (SD) 100 (15)]. Allowing for the 10% of patient that die, and are allocated the lowest possible score, the mean (SD) verbal memory score for adults with HSV encephalitis in the untreated group is 84.8 (23.1). A final sample size of 36 participants per group (72 total) will allow us to detect a clinically meaningful difference of 15.5 on the verbal memory score, between the untreated and dexamethasone-treated groups, with 80% power, at a significance level of 0.05. Allowing for up to 20% dropout gives a target sample size of 45 participants per group, for a total of 90. Mean verbal memory score will be compared between groups using linear regression. The two week results for detection of HSV in the CSF will be reported with a 95% confidence interval for the difference in proportions between groups. ECONOMIC BENEFIT: The total health economic costs of each patient with HSV encephalitis and severe sequelae are estimated at £3-5M; if dexamethasone improves outcome, it will be used routinely. DURATION & STAGES: 69 months total; 9 months set up, 4¼ years recruitment, 6 months follow up; 3 months final analysis and write-up. RECRUITMENT RATE: Average 21 patients per year, through the 72 centres.
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