Antibodies to N‐methyl‐D‐aspartate and other synaptic receptors in choreoathetosis and relapsing symptoms post–herpes virus encephalitis

Abstract

Herpes simplex-virus encephalitis (HSVE) is the most frequent fatal viral encephalitis in Western countries. The clinical course is usually monophasic, but 14% to 26% of patients develop relapsing symptoms a few weeks after the onset of the infection when they have improved and are no longer on acyclovir. This neurological deterioration has been attributed to (1) inadequate antiviral therapy or viral relapse characterized by the demonstration of HSV by polymerase chain reaction (HSV-PCR) in cerebrospinal fluid (CSF), new necrotic lesions on brain MRI, and response to acyclovir or (2) a disorder of unclear etiology with negative HSV-PCR, no new necrotic lesions on MRI, and no response to acyclovir. This disorder occurs more frequently in children than adults and associates with a clinical picture that is often different from that related to the initial episode of viral encephalitis. Indeed, most children develop several types of abnormal movements, including chorea, dystonia, or ballismus, usually accompanied by irritability, sleep disorder, agitation, aggression, seizures, or decrease of level of consciousness. For this reason, the term “choreoathetosis post-HSVE” is frequently used to describe this complication. In adults, symptoms are similar except for abnormal movements that are uncommon. Because the presentation is usually associated with fever, virtually all patients are restarted on acyclovir. However, when the CSF PCR for HSV comes back negative, alternative etiologies are considered, including, among others, side effects of antiepileptics, other viral infections, or postinfectious demyelination. In general, MRI studies show extensive FLAIR/T2 abnormalities with variable areas of encephalomalacia resulting from the recent viral infection, sometimes with interval progression of white matter changes, but no new necrotic lesions. Despite the prominence of abnormal movements, which are usually refractory to dopamine receptor antagonists or antiepileptics, the basal ganglia are almost always spared on MRI. Overall, most ancillary tests are unrevealing, leading to empirical treatments that are largely unsuccessful. For example, a review by Hargrave and Webb showed that only 5 of 18 patients with this disorder had good outcome or mild deficits; 9 were nonambulatory with major cognitive residual deficits and 4 died. The presence of choreoathetosis appeared to be associated with a poorer outcome. The above-mentioned findings coupled with the frequent detection of CSF inflammatory abnormalities and several observations discussed below, have suggested an immune-mediated pathogenesis as the cause of neurological complications post-HSVE, including the nonviral relapses. For example, the course of HSVE is more severe in immunocompetent patients than in immunocompromised patients, and the use of steroids combined with acyclovir has a beneficial effect. On the other hand, when markers of neuronal destruction and CSF cytokine profile were compared during the episode of viral infection and the clinical relapse, a lack of neuronal destruction and a proinflammatory response were typically associated with the clinical relapse, suggesting an immune-mediated pathogenesis. In 2012, awareness of the encephalitis associated with antibodies (Abs) against the N-methyl-D-aspartate (NMDA) receptor (anti-NMDAR encephalitis) led to suggesting a link between this immune response and complications post-HSVE. During evaluation of -----------------------------------------------------------*Correspondence to: Dr. Josep Dalmau, ICREA-IDIBAPS, Hospital Clinic, Universitat de Barcelona, Department of Neurology, c/Villarroel 170, Barcelona 08036, Spain; Josep.Dalmau@uphs.upem.edu