Encephalitis is an inflammation of the brain that remains a global health concern, affecting 1.7 to 7.4 people per 100,000 person-years. It is typically caused by infections and is highly lethal, and may lead to long-term cognitive, motor, and psychological damage to the survivors. The causative pathogen is identified in about 50% of the cases with the advances in diagnostic tools, with viruses accounting for up to 50%. Common viral agents are the herpes simplex virus and varicella-zoster virus, which are frequently implicated. However, recent reports indicate that Epstein-Barr Virus (EBV) is associated with the development of cancers, autoimmune diseases, and central nervous system (CNS) infections.
In a recent retrospective cohort study, which was approved by the West China Hospital, Sichuan University, researchers examined all cases of encephalitis from June 2020 to April 2021. Straight clinical and laboratory criteria were used to achieve diagnostic confirmation. Data were obtained from electronic records, and they consisted of clinical symptoms, CSF features, immune status, MRI findings, and viral loads.
EBV was detected by using metagenomic next-generation sequencing (mNGS), with auxiliary conventional tests used to rule out other pathogens. The patients with incomplete clinical documentation were excluded. Variables like Lymphocyte subsets, glucose levels, and chloride levels in CSF and the MRI findings were used to differentiate the cases associated with EBV from those caused by other herpesviruses. Statistical analysis was done by using SPSS with a p<0.05 significance.
EBV was found in approximately 24% of encephalitis patients in the CSF. The EBV-associated cases of encephalitis had a distinct clinical profile compared to other herpesvirus-related cases. These cases had increased counts of CSF leukocytes, high protein levels, and remarkably low glucose and chloride levels. Imaging studies showed a significantly higher percentage of meningeal involvement – 30% of EBV patients versus 6% for non-EBV herpesvirus infections.
Further analysis identified older patients, immunocompromised patients, and patients with active peripheral EBV infection as patients more prone to develop EBV-related encephalitis. These individuals had lower CD3+ and CD4+ T-cell counts, which shows a more generalized immune dysregulation.
The results support the growing awareness of EBV as a major pathogen in encephalitis, especially in immunocompromised individuals. This unique cerebrospinal fluid pattern, found to have decreased glucose and chloride, may be a sign of impaired blood-brain barrier function or enhanced metabolic action in the CNS. The frequent meningeal involvement confirms the assumption that EBV may enter the CNS through disturbed barriers or lymphatic penetrations.
The high co-occurrence of infections like tuberculosis and cryptococcosis in EBV-positive patients raises questions about the possible synergistic impact or opportunistic activation in a weak host. Notably, EBV can contribute to immune suppression, which could be associated with autoimmune complications like NMDA receptor encephalitis, thus requiring further research on post-infectious autoimmune mechanisms.
This study identifies EBV as an important and likely underrecognized cause of encephalitis with distinct laboratory and imaging findings. Its widespread occurrence among immunocompromised persons with simultaneous infections implies an opportunistic behavior enhanced by systemic and CNS immunocompromise. The EBV should be considered by clinicians as part of the differential diagnosis of encephalitis, specifically in cases of unidentified pathogens and when the CSF has low glucose and chloride levels with meningeal signs confirmed on MRI.
Further prospective studies are required to clarify the pathogenic contribution of EBV in mixed infections and to evaluate the opportunity of antiviral or immunomodulatory therapy. In addition, the autoimmune screening can make the diagnosis more accurate and have better outcomes for EBV-related encephalitis.
References: Liu Z, Peng A, Huang L, et al. Clinical features and risk factors for Epstein-Barr virus-associated encephalitis: a retrospective cohort study. Virol J. 2025;22:141. doi:10.1186/s12985-025-02768-w
