DexEnceph
Safety and efficacy of adjunct dexamethasone in adults with herpes simplex virus encephalitis in the UK (DexEnceph): a multicentre, observer-blind, randomised, phase 3, controlled trial
Bottom Line
In adults with HSV encephalitis, adding IV dexamethasone (10 mg QID x 4 days) to aciclovir did not improve verbal memory at 26 weeks compared with aciclovir alone, but was safe with no increase in CSF HSV PCR positivity at 2 weeks; routine adjunct dexamethasone is not supported, although the safety profile makes empirical use in suspected encephalitis before HSV exclusion reasonable.
Major Points
- First completed phase 3 RCT of corticosteroids in HSV encephalitis: 94 adults from 53 UK NHS hospitals (Sep 2016–Feb 2022).
- Primary outcome (Wechsler Memory Scale-IV Auditory Memory Index at 26 weeks) showed no benefit: 71 vs 69; adjusted difference 1.77 (95% CI –9.57 to 13.12; p=0.76).
- No significant difference in any secondary neuropsychological, functional, imaging, or quality-of-life endpoint, nor in all-cause mortality (13% vs 13% at 78 weeks).
- Dexamethasone did not increase detectable HSV in CSF at 2 weeks (11% vs 21%; adj OR 0.47, 95% CI 0.13–1.70; p=0.25), addressing the long-standing concern of unrestricted viral replication.
- All 5 clinical relapses occurred in the dexamethasone group; 2 were NMDAR antibody-positive but events were generally later than typical post-HSV autoimmune encephalitis.
- Exploratory post-hoc analysis: each day of delay in dexamethasone initiation was associated with a 4.89-point lower verbal memory score (95% CI 2.70–7.08; p<0.0001), suggesting timing may matter.
- Findings do not support routine corticosteroid use in HSV encephalitis but support empirical early steroid use in suspected encephalitis before HSV PCR results return.
Design
Study Type: Randomized Controlled Trial
Randomization: 1
Blinding: Observer-blind (open-label to patients/site clinicians; neuropsychologists, radiologists, statisticians, and lead investigators masked)
Enrollment Period: Sept 22, 2016 – Feb 2, 2022
Follow-up Duration: 78 weeks (primary outcome at 26 weeks)
Centers: 53
Countries: United Kingdom
Sample Size: 94
Analysis: Modified intention-to-treat (n=81: 39 dex, 42 control); safety: as-treated (received ≥1 dose)
Inclusion Criteria
- Adults aged ≥16 years
- Suspected encephalitis: febrile illness with new-onset seizure, new focal neurological signs, or alteration in consciousness, cognition, personality, or behaviour
- Positive PCR for HSV type 1 or type 2 DNA in CSF
- Result reported no longer than 7 days before randomisation
- Receiving intravenous aciclovir 10 mg/kg three times daily (or reduced dose if clinically indicated)
- Written informed consent from patient or legal representative
Exclusion Criteria
- Oral or injectable corticosteroid therapy within the 30 days before entry (topical/inhaled allowed)
- Known hypersensitivity to corticosteroids
- Immunosuppression: HIV with CD4 <200/mm3, current biological or other immunosuppressive therapy, solid organ transplant with ongoing immunosuppression, prior bone marrow transplant, current chemotherapy or radiotherapy, primary immunodeficiency, current haematological malignancy
- Pre-existing indwelling ventricular device
- Peptic ulcer disease within the past 6 months (endoscopy-proven or upper GI bleed)
- Current antiretroviral regimen containing rilpivirine (unless switched)
Arms
| Field | Dexamethasone + aciclovir | Control |
|---|---|---|
| Intervention | Intravenous dexamethasone 10 mg four times daily for 4 days (starting within 24 h of randomisation) + intravenous aciclovir 10 mg/kg three times daily for ≥14 days | Intravenous aciclovir 10 mg/kg three times daily for ≥14 days (standard care) |
| Duration | 4 days dexamethasone; aciclovir ≥14 days | ≥14 days |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Verbal memory score at 26 weeks measured by Wechsler Memory Scale-IV Auditory Memory Index | Primary | 69 (SD 25); n=42 | 71 (SD 26); n=39 | 0.76 | |
| Visual memory (WMS-IV) at 26 weeks | Secondary | 71 (SD 26) | 69 (SD 25) | 0.86 | |
| Immediate memory (WMS-IV) at 26 weeks | Secondary | 67 (SD 24) | 71 (SD 25) | 0.85 | |
| Delayed memory (WMS-IV) at 26 weeks | Secondary | 65 (SD 24) | 68 (SD 24) | 1.00 | |
| Working memory (WAIS-IV) at 26 weeks | Secondary | 82 (SD 27) | 85 (SD 25) | 0.47 | |
| Processing speed (WAIS-IV) at 26 weeks | Secondary | 77 (SD 26) | 80 (SD 23) | 0.50 | |
| Trail Making Test A (seconds) at 26 weeks | Secondary | 134 (SD 119) | 96 (SD 99) | 0.14 | |
| Trail Making Test B (seconds) at 26 weeks | Secondary | 202 (SD 106) | 165 (SD 96) | 0.15 | |
| Addenbrookes Cognitive Examination-III at 26 weeks | Secondary | 63 (SD 29) | 69 (SD 28) | 0.50 | |
| All-cause mortality at 78 weeks | Secondary | 6/47 (13%) | 6/47 (13%) | NS | |
| Seizure frequency at 78 weeks | Secondary | 10/38 (26%) | 7/36 (19%) | 0.55 | |
| Time to hospital discharge (weeks; median, IQR) | Secondary | 4 (2–6) | 3 (2–8) | 0.75 | |
| HSV detectable in CSF by PCR at 2 weeks (safety) | Secondary | 9/43 (21%) | 4/36 (11%) | 0.25 | |
| EQ-5D-5L at 26 weeks | Secondary | 75 (SD 18) | 64 (SD 25) | 0.11 | |
| Any notable adverse event | Adverse | 40% (18/47) dex vs 38% (18/47) control | |||
| Serious adverse events (≥1) | Adverse | 15% (7/47) dex vs 9% (4/47) control | |||
| Seizure requiring readmission | Adverse | 2% (1/47) dex vs 2% (1/47) control | |||
| Autoimmune encephalitis or meningoencephalitis | Adverse | 6% (3/47) dex vs 0 control | |||
| Headache (serious) | Adverse | 4% (2/47) dex vs 0 control | |||
| Peroneal nerve palsy | Adverse | 2% (1/47) dex vs 0 control | |||
| Deep vein thrombosis | Adverse | 2% (1/47) dex vs 0 control | |||
| Pulmonary embolism | Adverse | 2% (1/47) dex vs 0 control | |||
| Lower respiratory tract infection | Adverse | 2% (1/47) dex vs 0 control | |||
| Acute kidney injury | Adverse | 2% (1/47) dex vs 0 control | |||
| Cognitive disorder (serious) | Adverse | 0 dex vs 4% (2/47) control | |||
| Hepatic encephalopathy | Adverse | 0 dex vs 2% (1/47) control | |||
| Suicidal ideation | Adverse | 0 dex vs 2% (1/47) control | |||
| Falls | Adverse | 0 dex vs 4% (2/47) control | |||
| Dehydration | Adverse | 0 dex vs 2% (1/47) control | |||
| Treatment-related deaths | Adverse | 0 in both groups | |||
| Clinical relapses | Adverse | 5 in dex group (all) vs 0 in control; 2 of these were NMDAR antibody positive | |||
Subgroup Analysis
No beneficial effect of dexamethasone on the primary outcome in any prespecified subgroup (age, baseline GCS, time to aciclovir, prior steroid use). Sensitivity analyses excluding control patients who received steroids and dex patients who did not complete full course did not alter the result. Post-hoc analysis: each additional day of delay to dexamethasone was associated with a 4.89-point lower verbal memory score (95% CI 2.70–7.08; p<0.0001).
Criticisms
- Underpowered for clinically meaningful effects: the 95% CI for primary outcome (–9.6 to 13.1) does not exclude a relevant benefit or harm.
- Open-label, observer-blind design — patients and treating clinicians were not masked, which could bias self-reported and subjective endpoints.
- Long permitted window from admission to randomisation (up to ~3 weeks); median 7 days delay may have placed dexamethasone after the peak inflammatory phase, potentially diluting any benefit.
- Substantial protocol deviations: 17% of control patients received dexamethasone before randomisation as empirical meningitis treatment, and 9% of control patients received dexamethasone after randomisation; one dex-group patient received no dexamethasone.
- Recruited only 94 patients over 5.5 years, far below initial epidemiologic expectations, limiting power for subgroup and imaging analyses.
- Predominantly White UK population (>90%); limited generalisability across racial/ethnic groups and outside high-resource settings.
- Recruitment paused for the COVID-19 pandemic and some follow-up assessments shifted to remote modalities, introducing measurement heterogeneity.
- All 5 clinical relapses occurred in the dexamethasone group — a potential safety signal warranting longer follow-up despite no clear mechanistic explanation.
Funding
UK National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (12/205/28). Trial registration: ISRCTN11774734; EudraCT 2016-004835-19.
Based on: DexEnceph (Lancet Neurology, 2026)
Authors: Solomon T, Hooper C, Easton A, et al.
Citation: Lancet Neurol 2026;25(2):136-146
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