Viral triggering of anti-NMDA receptor encephalitis in a child – An important cause for disease relapse

Abstract

Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-d-aspartate receptors (NMDARs) may be part of this mechanism.

We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15–20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis.

We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.

Introduction

Acute encephalitis due to herpes simplex virus infection remains one of the more severe forms of childhood encephalitis in western countries. The clinical course of herpes simplex encephalitis (HSE) is occasionally complicated by a clinical relapse which usually occurs a few weeks after the initial infection and often during antiviral therapy. It has long been suggested that such a relapse may be due to secondary immune mechanisms rather than a true viral relapse¹ and antibodies against N-methyl-d-aspartate receptors (NMDARs) in particular have been implicated.²

In children, a link between HSE and anti-NMDAR encephalitis was observed with the finding of NMDAR antibodies 4 months after an initial HSE in a 2 year old girl.³ Furthermore, in a study of 7 children with a clinical relapse following HSE NMDAR antibodies were found in two cases. In one of these, NMDAR antibodies were negative in serum on initial presentation but positive after clinical relapse.⁴ Although retrospective in nature, these studies strongly suggest a causal relationship between HSE and anti-NMDAR encephalitis. Single case reports have also prospectively found synthesis of NMDAR antibodies following HSE in an adult⁵ and a recent study of 4 infants corroborates the possibility of a viral triggering of anti-NMDAR encephalitis.⁶

We here report an 11 months old with acute HSE and negative NMDAR antibody serology at presentation, and demonstrate a clinical relapse that was due to production of NMDAR antibodies.