Dexamethasone in HSV Encephalitis: Current Evidence Does Not Support Routine Use
Based on the most recent and highest quality evidence, dexamethasone should NOT be used routinely in adults with HSV encephalitis, as the 2026 DexEnceph trial definitively showed no improvement in verbal memory outcomes compared to aciclovir alone. 1
Key Evidence from the Definitive Trial
The DexEnceph trial (2026) was a multicentre, randomized, phase 3 trial in the UK that directly addressed this question in 94 adults with HSV encephalitis 1:
- Primary outcome (verbal memory at 26 weeks): No significant difference between dexamethasone plus aciclovir versus aciclovir alone (71 vs 69 points; adjusted difference 1.77,95% CI -9.57 to 13.12; p=0.76) 1
- Safety profile: Dexamethasone was safe with no treatment-related deaths, though thrombotic events (DVT, PE) occurred in the dexamethasone group 1
- Timing consideration: Dexamethasone was initiated a median of 7 days after hospital admission, which may have been too late to impact outcomes 1
Current Guideline Recommendations
The most relevant guidelines predate the DexEnceph trial but anticipated its results:
- British Neurologists/British Infection Association (2012): Corticosteroids should NOT be used routinely in HSV encephalitis while awaiting results of randomized controlled trials (Grade B, III) 2
- Pediatric guidelines (2012): Same recommendation—corticosteroids should not be used routinely in children with HSV encephalitis (Grade B, III) 2
- These guidelines acknowledged that corticosteroids may have a role under specialist supervision, but emphasized that data were needed 2
The Biological Rationale and Why It Failed
The theoretical concern has always been bidirectional 2:
- Potential benefit: Corticosteroids reduce cerebral edema, brain shift, and raised intracranial pressure—all major contributors to morbidity in HSV encephalitis 2
- Potential harm: Strong immunomodulatory effects could theoretically facilitate viral replication 2
- Retrospective data suggested benefit: A 45-patient retrospective analysis showed lack of corticosteroid administration was an independent predictor of poor outcome 2
- However, the prospective trial failed to confirm this benefit 1
Specific Clinical Scenarios Where Dexamethasone Might Still Be Considered
While routine use is not supported, there may be exceptional circumstances under specialist supervision 2:
- Severe cerebral edema with brain shift or herniation risk: In patients with life-threatening mass effect, dexamethasone may be used as part of intensive care management, though this remains expert opinion rather than evidence-based 2
- Raised intracranial pressure requiring intervention: When ICP monitoring demonstrates dangerously elevated pressures unresponsive to other measures 2
Critical Pitfalls to Avoid
- Do not delay or withhold aciclovir (10 mg/kg IV three times daily for at least 14 days) while considering corticosteroids—aciclovir is the only proven therapy 1
- Do not confuse HSV encephalitis with VZV encephalitis: VZV encephalitis has a stronger case for corticosteroid use due to its vasculitic and immune-mediated pathophysiology (Grade B, II) 2
- Do not assume early administration would have changed the DexEnceph results: While dexamethasone was started at a median of 7 days in the trial, the lack of benefit suggests the underlying hypothesis may be flawed 1
Contrast with Bacterial Meningitis
It is important to distinguish HSV encephalitis from bacterial meningitis, where dexamethasone has proven benefit 3, 4:
- Bacterial meningitis: Dexamethasone 10 mg IV every 6 hours for 4 days reduces mortality and hearing loss in pneumococcal and H. influenzae meningitis (Grade A) 3, 4
- HSV encephalitis: No such benefit has been demonstrated despite similar inflammatory pathophysiology 1
Future Directions
The DexEnceph trial authors suggest that more targeted immunomodulatory approaches (rather than broad corticosteroid suppression) should be investigated in future studies 1. A systematic review noted that CSF inflammatory markers might guide appropriate timing in future clinical practice, but this remains theoretical 5.