Title: DexEnceph- Dexamethasone in Herpes Simplex Virus Encephalitis Randomised Controlled Trial and NonHSV Cohort Study
Funder: Department of Health and Social Care

Abstract: 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.

Lay abstract: 1. THE PROBLEM: Encephalitis means inflammation (swelling) of the brain, often caused by a virus. In the UK Herpes simplex virus (HSV) is the most important cause, affecting 1 per 250,000-500,000 people. Although classed as a “very rare” disease, it has a significant impact because survivors are incapacitated with severe disability, with estimated costs of £3-5 million per severe case. Inflammation and swelling occurs as part of the body’s defence against infection. However in the brain it can cause damage, because the brain is in a fixed space (the skull) with no room for swelling. In herpes encephalitis the temporal lobes of the brain are especially affected. These lobes are very important for memory. Thus verbal memory is especially badly affected in herpes encephalitis. Verbal memory is the ability to remember the names of objects and people, and to listen to and recall spoken information Brain magnetic resonance imaging (MRI) scans can be used to assess brain swelling. Doctors sometimes give anti-inflammatory corticosteroid drugs (e.g. dexamethasone) to reduce the swelling. However, these drugs can also impair the immune defence system, potentially allowing uncontrolled virus replication. Thus we don't know whether or not giving corticosteroids is a good thing. 2. THE QUESTION: Does the corticosteroid drug dexamethasone improve verbal memory in herpes encephalitis by reducing brain temporal lobe swelling (as seen on brain scans)? 3. HOW AND WHERE THE RESEARCH WILL BE CARRIED OUT: The study will be conducted in 90 adults with herpes encephalitis across hospitals which are part of the Brain Infections UK Network. Through this network, and our previous pilot work, we are confident of good recruitment rates. Half the patients with herpes encephalitis will receive corticosteroid, and the other half will not. When patients have blood tests, lumbar punctures, and brain scans we will collect images and samples for our study. 4. STUDY DRUG: Dexamethasone is given intravenously once a day for four days. It is a generally safe drug, given in several brain infections, with few short-term side effects. 5. OUTCOME MEASURES: For the main outcome we will assess verbal memory at 6 months through neuropsychological testing. We will also examine swelling of the brain by MRI scanning. We will see if virus is detectable in the spinal fluid two weeks after admission. We will also examine the drug’s effect on host immune proteins, and will examine neuropsychological and imaging outcomes at 18 months. 6. ETHICAL ISSUES: Informed written consent will be obtained for all participants, from the patients themselves or their representative, for those with altered consciousness who are unable to give informed consent. 7. THE RESEARCH TEAM: The Liverpool Brain Infections Group is a multidisciplinary team that, with its partners, conducts leading international research on encephalitis, including studies of disease mechanism and treatment. It runs the Brain Infections UK Network, a key asset for conducting an acute treatment trial of a rare disease. 8. COSTS: A multicentre study such as this requires a dedicated team running it, and additional NHS support costs in the local centres.

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFECTION;NEUROLOGICAL