Guidelines urge prompt aciclovir for suspected encephalitis

The first joint guidelines from the EAN and ESCMID highlight pitfalls and major gaps in the evidence-base for managing this potentially devastating condition

New European guidelines on infectious encephalitis in adults recommend starting intravenous aciclovir as soon as the condition is suspected, ideally within six hours, and caution against replacing pathogen-specific cerebrospinal fluid (CSF) polymerase chain reaction (PCR) testing with multiplex PCR panels.

Jointly produced by the European Academy of Neurology (EAN) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the guidelines are the first co-authored by the two organisations and update European guidance last published in 2010. They address a condition that can cause severe neurological injury and long-term disability, but for which the evidence supporting many diagnostic and treatment decisions remains limited.

Issues addressed in the new guidelines include how to recognise encephalitis early, which tests give the most reliable answers, and when treatments like antiviral medicines, steroids, or seizure prevention are helpful. The guidelines also look at who benefits from ICU care, repeated testing, or rehabilitation to improve recovery and reduce lasting effects.

Developed by a taskforce of 19 experts from eight European countries, the guidelines were informed by systematic literature searches, assessment of evidence quality, and the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach.

Sixteen clinical questions were considered, resulting in two formal recommendations, and 13 good practice statements covering clinical recognition, microbiological investigations, additional diagnostic procedures, treatment, ongoing care, and rehabilitation.

Diagnostic testing: Retain pathogen-specific PCR

A central recommendation in the new guidelines concerns the use of multiplex PCR panels in the investigation of suspected infectious encephalitis.

While multiplex testing can detect several pathogens simultaneously, the guideline taskforce recommends against using these panels as a replacement for pathogen-specific CSF PCR in adults with suspected infectious encephalitis.

The evidence review found that multiplex PCR had a pooled sensitivity of approximately 76 per cent for herpes simplex virus (HSV)-1, lower than that reported for pathogen-specific PCR. Although sensitivity for some other pathogens and overall specificity were high, the certainty of the evidence was low, and false-positive results have also been reported.

“As a group, we felt that multiplex panels have a role, but they should not replace pathogen-specific CSF PCR in suspected infectious encephalitis. It is worth noting that newer multiplex PCRs are in development which may address these shortcomings,” said Dr Julia Granerod Whitehouse, EAN-ESCMID Guideline Taskforce.

The findings have practical implications for clinicians seeking to establish a diagnosis quickly and reliably, particularly when HSV encephalitis is suspected and delays in appropriate treatment may adversely affect outcomes.

The guidelines also emphasise the importance of further investigation when initial results do not resolve the diagnostic uncertainty. If the first lumbar puncture is non-diagnostic, but clinical suspicion remains, it should be repeated after two to three days.

Microbial antibody testing may be required in selected cases, with specialist advice recommended to guide its use. The taskforce also advises testing for neuronal autoantibodies, including anti-NMDA receptor antibodies, in patients who relapse after HSV encephalitis.

This reflects the need to consider additional or alternative diagnoses when the clinical course is not as expected, rather than assuming that an initial diagnosis accounts for all subsequent symptoms.

Prompt antiviral treatment is a priority

The guidelines strongly emphasise the need to initiate intravenous aciclovir as soon as possible when encephalitis is suspected, ideally within six hours.

HSV is an important treatable cause of encephalitis, and the potential consequences of delayed treatment make timely recognition and management critical. Clinicians should therefore avoid unnecessary delays while awaiting diagnostic confirmation when the clinical presentation raises suspicion of encephalitis.

The guidance also addresses when empirical aciclovir can be discontinued. Treatment should be stopped only when HSV PCR is negative and the clinical presentation, CSF findings and neuroimaging do not support HSV encephalitis.

A negative PCR result should not, in isolation, prompt cessation of treatment if the overall clinical picture continues to suggest HSV infection. In such circumstances, treatment should continue while the diagnosis is reassessed and further investigations are considered.

For patients with proven HSV encephalitis, the recommended treatment duration is at least 14 days. This should be extended to 21-to-28 days in patients with severe disease, those who are not improving, or those who are immunocompromised.

These recommendations underline the importance of integrating laboratory results with clinical assessment and the patient’s subsequent progress. They also reinforce the need to maintain appropriate antiviral cover when uncertainty persists.

Corticosteroids: Insufficient evidence to recommend for or against treatment

The guidelines also conclude that there is insufficient evidence to recommend either for or against corticosteroid treatment in patients with confirmed HSV encephalitis.

The role of corticosteroids in proven HSV encephalitis has been debated for many years. Their anti-inflammatory effects could potentially reduce cerebral inflammation and associated tissue injury, but their immunomodulatory properties have also raised concerns that they might facilitate viral replication.

After reviewing the available evidence, the guideline taskforce was unable to recommend either for or against corticosteroid treatment in adults with proven HSV encephalitis. The studies examined did not demonstrate improved outcomes with corticosteroid treatment. However, they also did not show evidence of harm, with moderate certainty in the available data.

The distinction has implications for patients initially treated for other suspected neurological infections or inflammatory conditions. Corticosteroids may be given empirically in the management of conditions such as bacterial meningitis and central nervous system tuberculosis, or when autoimmune encephalitis is suspected.

In clinical practice, treatment may be withheld while clinicians investigate whether HSV is responsible for the presentation. The guideline authors suggest that the available evidence indicates corticosteroid treatment given for these other suspected conditions is unlikely to be harmful in patients subsequently diagnosed with HSV encephalitis.

This may help clinicians avoid unnecessary delays when corticosteroids are indicated for a competing or alternative diagnosis. However, it should not be interpreted as evidence that corticosteroids improve outcomes in HSV encephalitis or as a recommendation to administer them routinely to these patients.

The uncertainty surrounding corticosteroids illustrates a broader limitation identified by the guideline authors: Several important clinical decisions remain insufficiently supported by robust evidence, despite the potentially serious consequences of the disease.

Early investigation and ongoing assessment

The guidelines include good practice statements intended to support timely diagnosis and appropriate escalation of care.

Lumbar puncture should be performed as soon as possible unless contraindicated. Neuroimaging should not routinely delay the procedure, except where clinical signs suggest raised intracranial pressure with brain shift.

This approach seeks to avoid unnecessary delays in obtaining CSF for diagnostic testing while recognising circumstances in which lumbar puncture may be unsafe.

Electroencephalography is not recommended routinely for every patient with suspected infectious encephalitis. It should, however, be used when seizures are suspected or when it is difficult to distinguish psychiatric symptoms from an organic cause.

Brain biopsy is not part of the initial diagnostic assessment. It may be considered in patients who deteriorate despite extensive investigation when a diagnosis remains elusive.

Together, these statements highlight the need for a structured diagnostic approach that can be adapted to the patient’s presentation and clinical trajectory. Initial investigations may not always establish the cause, making reassessment and selective use of additional tests important when symptoms persist or worsen.

A continuing evidence gap

These guidelines address a condition that can cause severe neurological injury and long-term disability, but for which the evidence supporting many diagnostic and treatment decisions remains limited.

Infectious encephalitis can cause confusion, drowsiness, fever, seizures, and changes in behaviour. Early symptoms may resemble those of more common illnesses, complicating recognition, and potentially delaying treatment.

The consequences can be severe. Even when patients survive, they may experience persistent cognitive difficulties, including problems with memory and concentration, as well as other long-term neurological effects.

Conclusion

The updated guidelines aim to improve clinical decision-making in infectious encephalitis, from early recognition and diagnostic testing to treatment and recovery. They also reflect changes since the previous European guidance in 2010, including the emergence of new causes and developments in diagnostic practice.

However, the authors stress that the evidence supporting many aspects of diagnosis and management remains limited. The difficulty of conducting large studies in a relatively uncommon and clinically heterogeneous condition may contribute to this gap, but the consequences of uncertainty for patients make further research a priority.

The taskforce calls for large-scale, transnational research to establish a stronger evidence-base for clinical recommendations and improve outcomes for adults with infectious encephalitis.

The guidelines, Diagnosis and Management of Infectious Encephalitis in Adults: Guidelines from the EAN and the ESCMID, are available in the European Journal of Neurology.

Reference

Granerod J, et al. Diagnosis and management of infectious encephalitis in adults: Guidelines from the European Academy of Neurology and European Society of Clinical Microbiology and Infectious Diseases. Eur J Neurol. 2026 Oct;33(10):e70647