Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti‐N‐methyl‐d‐aspartate receptor encephalitis

Abstract

AIM We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti-N-methyl-D-aspartate (anti-NMDA) receptor antibodies.METHOD We reviewed the four cases retrospectively and we also reviewed the literature. RESULTS Anti-NMDA receptor antibodies (without ovarian teratoma detected so far) were found in the two children tested in this study. INTERPRETATIONThe clinical features are similar to those first reported in 1992 by Sebire et al., 1 and rarely recognized since. Sleep disturbance was not emphasized as part of the disorder, but appears to be an important feature, whereas coma is less certain and difficult to evaluate in this setting. The combination of symptoms, evolution (mainly seizures at onset), severity, paucity of abnormal laboratory findings, very slow recovery, and difficult management justify its recognition as a specific entity. The neuropathological substrate may be anatomically close to that involved in encephalitis lethargica, in which the same target functions (sleep and movement) are affected but in reverse, with hypersomnolence and bradykinesia. This syndrome closely resembles anti-NMDA receptor encephalitis, which has been reported in adults and is often paraneoplastic.In 1992, Sebire et al.1 reported a series of six children presenting with a novel combination of intense dyskinesia and severe regression with prolonged cognitive impairment but who made an unexpected excellent recovery.1 Since then, similar cases have been described. The disorder is sometimes called Sebire syndrome and is considered inflammatory or infectious in aetiology.2-5 Hartley et al., 6 in a paper entitled 'Immune-mediated chorea encephalopathy syndrome in childhood', specifically commented on the marked similarity between their cases and those of Sebire et al. Sleep disturbances (hypersomnolence) and dyskinesia (parkinsonism) are hallmarks of encephalitis lethargica, a condition increasingly recognized in children and presumed to be of autoimmune aetiology. In some cases, phases of insomnia and hyperkinesia, as in Sebire syndrome, may occur, suggesting that the localization of the acquired brain dysfunction may be in closely related areas and that common pathogenetic mechanisms are involved. This clinical picture is similar to the recently recognized entity, anti-N-methyl-D-aspartate (anti-NMDA) receptor encephalitis, 7 which may be the underlying cause of the disorder reported by Sebire et al.We describe four new cases of Sebire syndrome, in which sleeplessness was a highly significant clinical feature 'masked' by severe dyskinesia and agitation, persisting long after dyskinesia had resolved. Anti-NMDA receptor antibodies were found in the two individuals who were tested. Their serum was analysed at the Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK (P...

Neuropsychological characterization of three adolescent females with anti-NMDA receptor encephalitis in the acute, post-acute, and chronic phases: an inter-institutional case series

“…Deficits Downloaded by [University of Sussex Library] at 13:55 22 June 2016 in attention, executive functioning, verbal fluency, and rapid naming were seen in two pediatric patients (one patient at 10 months after disease onset and the other at 21 months post-onset); the first patient showed significant improvement 22 months after onset, with many performances returning to the patient's estimated premorbid baseline (iadisernia et al, 2012). Persistent deficits in working memory and/or attention have been similarly reported in other studies (Azizyan, Albrektson, Maya, Pressman, & Moser, 2014;Dalmau et al, 2008;Poloni et al, 2010). in sum, most studies have documented persistent memory and executive deficits for adults in the chronic phase of anti-NMDA receptor encephalitis.…”

A Multidisciplinary Approach to the Treatment of Anti-NMDA-Receptor Antibody Encephalitis: A Case and Review of the Literature

“…16 NMDAR antagonists in animal studies cause insomnia and hyperactivity, prolonged changes in non-REM sleep, and hypoventilation. 17 In humans, NMDAR antagonists at low doses induce psychotic behavior, memory problems, and decreased response to pain. At higher doses, they can cause dissociative anesthesia, catatonic symptoms, and autonomic disruption, causing hypersalivation, cardiac arrhythmias, and hypertension.…”

Anti–N-methyl-D-aspartate (NMDA) Receptor Encephalitis in a Young Lebanese Girl

“…Poloni et al reported the following recovery sequence: gradual resolution of dyskinesias followed by improvement in motor, then comprehension and expressive functions. 6 In most reports, the brain MRI is often normal or shows transient fluid attenuation inversion recovery or contrast-enhancing abnormalities involving the medial temporal lobes, basal ganglia, corpus callosum, and brainstem. The electroencephalogram reveals diffuse slowing without epileptiform discharges or disorganized activity that does not correlate with most abnormal movements.…”

“…Immune modulation through the use of immunoglobulin, corticosteroids, cyclophosphamide, plasmapheresis, and possibly rituximab are the mainstay of treatment in nonparaneoplastic encephalitis. 1,6,12,13 Individuals with ovarian teratoma are treated by tumor excision and with immunotherapy. About 75% of individuals have full or substantial regression of symptoms.…”

“…6,12,13 The reported time to clinical recovery is variable, ranging from 2 weeks to 24 months. 1,4,6 Our patient has no evidence of an ovarian tumor and has made a full recovery after immunotherapy. Periodic surveillance for at least 2 years using MRI of the pelvis has been recommended in females of all ages diagnosed with anti-NMDA receptor encephalitis.…”