DexEnceph trial finds dexamethasone does not improve outcomes in herpes simplex encephalitis but safe to use 

A UK phase 3 trial has reported that adding the corticosteroid dexamethasone to aciclovir did not improve verbal memory at 26 weeks after herpes simplex virus encephalitis, although earlier steroid use appeared to correlate with better recovery

A major UK clinical trial has shown that adding the corticosteroid dexamethasone to standard antiviral treatment for herpes simplex virus encephalitis (HSVE) did not improve long-term outcomes overall, although earlier administration may support better recovery. The DexEnceph study has provided the most definitive evidence so far on whether clinicians should prescribe corticosteroids alongside aciclovir, the antiviral medicine that forms the foundation of treatment for this severe and potentially life-changing brain infection.

HSVE is a rare but devastating neurological emergency. It occurs when herpes simplex virus infects the brain, which can trigger intense inflammation and swelling. Without rapid treatment, the condition can cause lasting disability or death. Even with effective antiviral therapy, many survivors experience persistent cognitive impairment, particularly memory problems that can affect work, education and independent living. Since the introduction of aciclovir in the 1970s, survival has improved dramatically, but the burden of long-term neurological consequences has remained substantial, which has driven efforts to identify supportive treatments that might reduce brain injury.

Corticosteroids such as dexamethasone can suppress inflammation and reduce swelling, and clinicians already use them in several inflammatory neurological disorders. In autoimmune encephalitis, for example, early immunosuppressive treatment can improve outcomes by limiting immune-mediated damage to the brain. However, HSVE presents an obvious dilemma: steroids might reduce harmful inflammation, but they might also impair antiviral immune responses and worsen infection. This uncertainty has persisted for decades, particularly at the point of first presentation, when a patient may appear critically unwell and clinicians must decide whether to treat for more than one possible cause before test results return.

DexEnceph, led by researchers at the Liverpool-based Pandemic Institute, the University of Liverpool and Walton Centre National Health Service (NHS) Foundation Trust, Fazakerley, Liverpool, addressed this long-standing clinical question through a pragmatic, multicentre, randomised, controlled, observer-blind phase three trial delivered across the NHS.

The trial enrolled 94 patients from 53 NHS hospitals across the UK, reflecting the national challenge of recruiting participants rapidly in an acute, time-critical condition. All participants received intravenous aciclovir. Those in the intervention group also received intravenous dexamethasone at a dose of 10 mg four times daily for four days, a regimen designed to provide early anti-inflammatory effect during the period of greatest risk from brain swelling.

Researchers assessed verbal memory at 26 weeks as the primary outcome, using the Wechsler Memory Scale, a widely used neuropsychological test designed to quantify memory function. The results showed no significant difference overall between patients who received dexamethasone plus aciclovir and those who received aciclovir alone. Of the 94 patients recruited, 81 were included in the modified intention-to-treat analysis, which reflected the realities of acute clinical research where consent, confirmation of diagnosis and availability of follow-up data can vary.

Although the trial found no overall long-term benefit, the investigators reported an important signal in an exploratory analysis. When dexamethasone was given earlier in the course of illness, patients tended to have better outcomes than those who started steroids later. Such analyses do not provide the same level of certainty as a primary endpoint, but they may help to define where, and in whom, an adjunctive approach might still offer value.

Crucially, the trial also demonstrated that dexamethasone was safe in patients with confirmed HSVE, with no evidence that steroids increased harm when prescribed alongside antivirals. Secondary measures included cognitive and functional outcomes, imaging findings, relapse, mortality and safety endpoints, which helped to build a more complete picture of benefits and risks beyond memory performance alone.

“For decades people have wondered whether corticosteroids would improve the outcome of HSVE, or perhaps make things worse because of their immunosuppressive effects,” said Professor Tom Solomon CBE, Chief Investigator of DexEnceph and Director of The Pandemic Institute.

“Increasingly, when patients present with encephalitis, clinicians want to give corticosteroids in case it is an autoimmune encephalitis, but until they have ruled out HSVE they have not felt it was safe to do so.

“This study shows that if you suspect a patient has encephalitis which might be autoimmune or could be herpes simplex virus, it is safe to give steroids. The fact that early corticosteroid use seems to be associated with improved outcomes may well encourage doctors to do this as soon as they see the patient,” he added.

The safety finding may prove particularly relevant to front-line clinicians, because early management often relies on suspicion rather than confirmation. Patients commonly arrive with fever, confusion, seizures or reduced consciousness, and clinicians typically start empirical treatment while they await brain imaging, cerebrospinal fluid analysis and viral polymerase chain reaction testing.

In this early phase, a safe steroid strategy could allow clinicians to treat suspected autoimmune encephalitis promptly without the fear of harming those who ultimately have a viral cause. As Professor Solomon noted, European guidelines for encephalitis are currently under revision, and the DexEnceph results may support earlier corticosteroid use when clinicians suspect encephalitis and cannot yet exclude competing causes.

“People living with the consequences of encephalitis urgently need better treatments,” said Dr Ava Easton, chief executive of Encephalitis International.

“This landmark trial shows what works and what does not. We are proud to have supported this effort and to see a question that has puzzled clinicians for decades finally answered,” she added.

Dr. Mark Ellul, clinical lecturer at the University of Liverpool and consultant neurologist, said the study had addressed an area of day-to-day uncertainty in the early management of HSVE and had provided evidence to guide treatment during the crucial first days of illness. He added that DexEnceph had also demonstrated the feasibility of running high-quality randomised trials in acute, life-threatening neurological disease through national collaboration and represented an important step towards improving outcomes and standardising care based on evidence rather than assumption.

The study was funded by the Efficacy and Mechanism Evaluation Programme, a partnership between the National Institute for Health and Care Research and the UK Research and Innovation Medical Research Council, under reference 12/205/28. The University of Liverpool sponsored the trial, with support from the Liverpool Clinical Trials Centre and wide participation from NHS hospitals across the country, in partnership with Encephalitis International.

For further reading please visit: 10.1016/S1474-4422(25)00454-5