Autoimmune Encephalitis After Herpes Simplex Virus Encephalitis

By Ulrike W. Kaunzner, MD

Assistant Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: A recent study showed that about 25% of patients with herpes simplex encephalitis develop neurological symptoms three to six weeks after the infection, pointing toward an autoimmune process with different neurological and psychiatric symptoms. Anti-neuronal antibodies, such as anti-N-methyl-D-aspartate receptor antibodies, have been found in this post-viral autoimmune encephalitis presentation.

SOURCE: Armangué T, Olivé-Cirera G, Martínez-Hernandez E, et al. Neurologic complications in herpes simplex encephalitis: Clinical, immunological and genetic studies. Brain 2023;146:4306-4319.

Herpes simplex encephalitis (HSE) has an incidence of two to four per million people and is the most frequent sporadic infectious encephalitis in high-income countries, affecting both the pediatric and adult populations. Mortality in untreated cases can be up to 70%. Patients can have residual symptoms from the actual infection; however, approximately 25% of patients develop novel neurological symptoms in the months following the encephalitis. These different neurological manifestations occur one to two months after the infection and have been described as autoimmune encephalitis (AE) post-HSE. Anti-neuronal antibodies have been found, including N-methyl-D-aspartate receptor (NMDAR) antibodies.

These findings first were described in 2013, and several case reports and studies have been published on this subject. The scientific commentary discussed in this article describes the fascinating journey leading to the discovery of neuronal antibodies and AE post-HSE in the last decade. The risks for development of AE post-HSE are unknown, but a possible molecular mimicry process has been suggested between NMDAR and the herpes simplex virus. However, other neuronal antibodies have been found and other types of viral encephalitis also have been associated with post-infectious AE.

It can be difficult for the clinician to differentiate between ongoing encephalitis or sequelae from the actual infection vs. a secondary neurological presentation. This study by Armangue et al evaluated clinical, genetic, and immunological markers to elucidate which risk factors might contribute to the development of AE post-HSE. In this prospective, international study, pediatric and adult patients were included in two cohorts: one with HSE at onset and one with new neurological symptoms. A total of 190 patients was recruited, and the majority (52%) were male. Out of the cohort with HSE at onset, 42% of patients (39 in total), developed neuronal antibodies. Out of these 39 antibody-positive patients, 21 patients developed AE.

The cohorts then were investigated for different neurological presentations, and three distinct syndromes were described: choreoathetotic, anti-NMDAR-like encephalitis, and behavioral/psychiatric. Possible predictive markers were assessed, and serum interferon-1 (IFN) levels were measured. A continuously elevated IFN level (median Z > 4) pointed to a continued viral infection and uncontrolled viral load. On the other hand, increasing IFN levels at week three (median Z > 1.5 but < 4), yet not to the extreme of the levels associated with uncontrolled viral load, was more indicative of AE post-HSE. The team also investigated possible genetic markers and showed that the presence of a common human leukocyte antigen (HLA) class I gene (HLA-A*02) protected patients from developing AE.

COMMENTARY

This is an important study that sheds light on the development of and raises awareness for the risk factors of AE following HSE. In addition, it offers possible markers that can be followed in the future to evaluate the risk for development AE post-HSE, including genetic markers and immunological markers.

It will be interesting to see what other neuronal antibodies are associated with these AEs post-HSE, and if there are any other classic neurological presentations. In
addition, it will be important to know if other viral infections carry the risk of this AE development.

In summary, every clinician treating HSV encephalitis should know about this possible development and should be mindful about careful follow-up of patients recovering from HSE, check for autoimmune encephalitis antibodies, and consider repeat lumbar punctures. In addition, markers that predict AE development can guide the clinician in post-encephalitis management. The clinical use of immunological markers needs further investigation.