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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

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Year of Publication: 2026

Authors: Solomon T, Hooper C, Easton A, ..., Ellul MA

Journal: Lancet Neurology

Citation: Lancet Neurol. 2026;25:136-146

Link: https://doi.org/10.1136/pn-2026-005337

Clinical Question

Does adjunct dexamethasone improve verbal memory outcomes in adults with herpes simplex virus encephalitis treated with aciclovir?

Bottom Line

Adding dexamethasone to standard aciclovir treatment did not improve verbal memory at 26 weeks in adults with HSV encephalitis. The trial was safe with no evidence of harm from dexamethasone and no increase in viral persistence. Routine use of adjunct dexamethasone in HSV encephalitis is not supported; however, a post-hoc signal suggesting earlier treatment may be more effective warrants further study.

        Major Points
        Adjunct dexamethasone (10 mg IV four times daily for 4 days) did not significantly improve verbal memory at 26 weeks compared to aciclovir alone (adjusted difference 1.77 points, 95% CI -9.57 to 13.12, p=0.76).
No significant benefit was found in any secondary neuropsychological domain (visual memory, working memory, processing speed, executive function) or clinical outcomes (mortality, seizure rate, time to discharge) at 26 or 78 weeks.
Dexamethasone was safe: adverse event rates were similar between groups, there were no treatment-related deaths, and there was no significant increase in HSV PCR positivity in CSF at 2 weeks (11% vs 21%, p=0.25).
5 clinical relapses occurred, all in the dexamethasone group -- potentially explained by early corticosteroid suppression of the immune response to HSV before sufficient viral clearance, with subsequent autoimmune activation.
Important post-hoc finding: each day of delay to dexamethasone initiation was associated with a 4.89-point reduction in verbal memory score (95% CI 2.70-7.08, p<0.0001), suggesting that if corticosteroids are beneficial, timing may be critical.
The 95% CI for the primary outcome (-9.57 to 13.12) includes the possibility of a clinically meaningful benefit (15.5-point threshold), meaning the trial may have been underpowered to exclude a real benefit.
Findings are consistent with the hypothesis that early corticosteroid treatment in all suspected encephalitis (before HSV is excluded by CSF PCR) is unlikely to cause harm, and may support empiric use in appropriate patients.

      

Design

Study Type: Multicentre, observer-blind, randomised, phase 3, controlled trial

Randomization: 1

Blinding: Observer-blind (neuropsychologist assessing primary outcome and statisticians masked; patients, site teams not masked)

Allocation: 1:1 (minimisation algorithm incorporating age, hospital GCS score, steroid use since admission, delay in aciclovir)

Enrollment Period: September 9, 2016 – February 21, 2022

Follow-up Duration: 78 weeks (primary outcome at 26 weeks)

Centers: 53

Countries: UK

Sample Size: 94

Analyzed: 81

Analysis: Modified intention-to-treat; linear regression for primary outcome adjusted for minimisation factors

Power Calculation: Sample of 45 per group (90 total) to detect 15.5-point difference in WMS-IV verbal memory with 80% power at alpha=0.05, assuming 10% mortality before 26-week assessment

Registration: ISRCTN11774734; EudraCT2016-004835-19

Inclusion Criteria

Age 16 years or older
Suspected diagnosis of encephalitis (new-onset seizure or new focal neurological signs or altered consciousness, cognition, personality, or behaviour)
HSV type 1 or 2 DNA positive in CSF by PCR, reported within 7 days before randomisation
Receiving intravenous aciclovir 10 mg/kg three times daily

Exclusion Criteria

Oral or injectable corticosteroid therapy within the 30 days before study entry (except topical or inhaled)
History of hypersensitivity to corticosteroids
Immunosuppression (HIV with CD4 <200/mm3, biological therapy, immunosuppressive agents, solid organ transplant with ongoing immunosuppression, bone marrow transplant, current chemotherapy/radiotherapy, primary immunodeficiency, haematological malignancy)
Pre-existing indwelling ventricular devices
Active peptic ulcer disease within past 6 months
Current antiretroviral regimen containing rilpivirine without feasible switch

Arms

Field	Dexamethasone + Aciclovir	Control
N	47	47
Intervention	IV dexamethasone 10 mg four times daily for 4 days (starting within 24 hours of randomisation) plus IV aciclovir 10 mg/kg three times daily for at least 14 days	IV aciclovir 10 mg/kg three times daily for at least 14 days (standard care)
Duration	4 days dexamethasone; aciclovir continued until HSV PCR negative in CSF	At least 14 days (continued until HSV PCR negative)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Verbal memory score at 26 weeks, measured by the Wechsler Memory Scale (WMS-IV) Auditory Memory Index	Primary	69 (SD 25) [n=42]	71 (SD 26) [n=39]	Adjusted difference in mean 1.77 (95% CI -9.57 to 13.12)	0.76
Visual memory (WMS-IV) at 26 weeks	Secondary	71 (25) [n=31]	69 (25) [n=33]		0.86
Immediate memory (WMS-IV) at 26 weeks	Secondary	67 (24) [n=31]	71 (25) [n=33]		0.85
Delayed memory (WMS-IV) at 26 weeks	Secondary	65 (24) [n=31]	68 (24) [n=33]		1.0
Working memory (WAIS-IV) at 26 weeks	Secondary	82 (27) [n=36]	85 (25) [n=36]		0.47
Processing speed (WAIS-IV) at 26 weeks	Secondary	77 (26) [n=32]	80 (23) [n=33]		0.50
All-cause mortality at 78 weeks	Secondary	6/47 (13%)	6/47 (13%)
Seizure frequency at 78 weeks	Secondary	10/38 (26%)	7/36 (19%)		0.55
Time to hospital discharge (weeks)	Secondary	Median 4 (IQR 2-6) [n=45]	Median 3 (IQR 2-8) [n=47]		0.75
HSV DNA detectable in CSF at 2 weeks (secondary safety)	Secondary	9/43 (21%)	4/36 (11%)		0.25
Clinical relapse	Secondary	0	5 (all in dexamethasone group)
Notable adverse events	Safety	18/47 (40%)	18/47 (38%)
Serious adverse events	Safety	5/47 (11%)	7/47 (15%)
Treatment-related deaths	Safety	0	0
Neuropsychiatric disorders	Adverse	5 (11%)	7 (15%)
Seizure (SAE)	Adverse	1 (2%)	1 (2%)
Autoimmune encephalitis or meningoencephalitis	Adverse	0	3 (6%)
Deep vein thrombosis	Adverse	0	1 (2%)
Pulmonary embolism	Adverse	0	1 (2%)
Acute kidney injury	Adverse	0	1 (2%)

Subgroup Analysis

No prespecified subgroup analysis demonstrated a benefit of dexamethasone. A post-hoc analysis found that earlier initiation of dexamethasone was associated with better verbal memory outcomes: each additional day of delay was associated with a 4.89-point reduction in WMS-IV score (95% CI 2.70-7.08, p<0.0001). This association was significant in the dexamethasone group but not in the control group, suggesting a time-sensitive treatment window. This is exploratory and hypothesis-generating.

Criticisms

Small sample size (n=81 in modified ITT) -- underpowered for secondary outcomes; primary outcome 95% CI includes potential clinically meaningful benefit
Recruitment took 5.5 years across 53 hospitals, reflecting the rarity of HSV encephalitis and enrollment challenges
Observer-blind rather than double-blind -- patients and site teams were aware of allocation, introducing potential performance and detection bias
Delayed enrollment: median 7-8 days from hospital admission to randomisation -- corticosteroids may be most effective in early inflammation; this could have masked benefit
5 clinical relapses all occurred in the dexamethasone group, raising concern about post-viral autoimmune phenomena potentially triggered by early immune suppression
COVID-19 pandemic required remote assessments for some participants, reducing neuropsychological data quality
All participants were recruited in the UK -- predominantly White population (>90%), limiting generalisability to diverse populations

Funding

National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation Programme (reference 12/205/28); NIHR Global Health Research Group on Brain Infections (17/63/110)

Based on: DexEnceph (Lancet Neurology, 2026)