by Julia Granerod Whitehouse, EAN-ESCMID Guideline Task Force
Two findings stand out in the new guidelines on the diagnosis and management of infectious encephalitis in adults published jointly by the European Academy of Neurology (EAN) and the European Society for Clinical Microbiology and Infectious Diseases (ESCMID). Firstly, we advise against replacing pathogen-specific cerebrospinal fluid (CSF) PCR testing with multiplex panels in routine diagnosis; secondly, we are unable to recommend corticosteroid treatment in proven HSV encephalitis. The current evidence does not show clear benefits, but, importantly, there was no evidence of harm.
On PCR diagnostics, we recommend against replacing pathogen-specific PCR testing of CSF with multiplex panels for diagnosis of adults with suspected infectious encephalitis. A meta-analysis showed that multiplex PCR has lower pooled sensitivity for HSV-1, at around 76 percent, compared with pathogen-specific PCR. Although sensitivity for some other pathogens and overall specificity were high, the certainty of the evidence was low, and false positives have 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.
We also examined the role of corticosteroids in proven HSV encephalitis, an area that has generated debate for many years. Corticosteroids may reduce cerebral inflammation, but their immunomodulatory effects could in theory facilitate viral replication. The studies we reviewed did not demonstrate improved outcomes with corticosteroid treatment, but they also did not show evidence of harm, with moderate certainty in the available data. In patients with suspected encephalitis, corticosteroids are often withheld until HSV is excluded; the evidence now suggests that corticosteroid therapy given as part of empirical treatment for other suspected brain infections such as bacterial meningitis and CNS tuberculosis, or for suspected autoimmune encephalitis, is unlikely to be harmful in patients ultimately diagnosed with HSV encephalitis, and so it is likely to be used more promptly in such patients.
The new guidelines, developed by a Task Force of 19 experts from eight European countries, were unique in that they represented the first joint guidelines between the EAN and ESCMID. They comprise 16 PICO (population, intervention, comparison, and outcomes) recommendations or good practice statements. Given the clinical severity and public health importance of this encephalitis, the paucity of high-quality evidence identified was striking.
The recommendations/good practice statements include the need to perform lumbar puncture as soon as possible unless contraindicated; it should not be delayed for imaging unless there are clinical signs of raised intracranial pressure with brain shift. If the initial lumbar puncture is non-diagnostic but clinical suspicion remains, it should be repeated after 2–3 days. Specialist advice should be sought for microbial antibody testing, and neuronal autoantibodies (including anti-NMDA receptor antibodies) should be tested in patients who relapse after HSV encephalitis. Brain biopsy is not part of the initial assessment but may be considered in patients who deteriorate without a diagnosis despite extensive investigation. EEG is not required routinely but should be used when seizures are suspected or when it is difficult to distinguish psychiatric from organic causes. Intravenous aciclovir should be started as soon as encephalitis is suspected, ideally within 6 hours. It should be stopped only if HSV PCR is negative and the clinical, CSF, and imaging features do not support HSV; if suspicion remains, treatment should continue. Proven HSV encephalitis should be treated for at least 14 days, extending to 21–28 days in severe, non-improving, or immunocompromised cases.
For the patient and caregiver
Encephalitis, a serious condition caused by inflammation of the brain, can make people feel confused, drowsy, or unwell with a fever, and can lead to seizures or changes in behaviour. Even when people survive, many are left with long-term problems such as memory difficulties or trouble concentrating. Encephalitis can be hard to recognise because its early symptoms are similar to many common illnesses. This can delay treatment, which may worsen recovery. Doctors use tests on fluid taken from around the brain and scans of the head to look for the cause, but these do not always give clear answers. Some types of encephalitis can be treated effectively if diagnosed early, while others have no proven treatment. In the present guidelines, issues addressed 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.
