Abstract
Background
Anti-NMDA receptor (NMDAr) encephalitis is caused by antibodies against synaptic or neuronal cell-surface proteins, which alter their function reversibly. IgG antibodies bind to the GluN1 subunit of NMDA receptors and disable the receptors through capping and cross-linking, producing effects similar to those of NMDAr antagonists such as ketamine and phencyclidine. Anti-NMDA receptor encephalitis (anti-NMDArE) is more frequent than viral encephalitis in children and adolescents and has the greatest propensity among autoimmune encephalitides for mimicking psychiatric disorders early in the illness course, often leading to delayed diagnosis and treatment. This study examines the frequency and temporal progression of clinical features associated with anti-NMDArE in children and adolescents who are likely to be referred for psychiatric evaluation, with the aim of identifying salient signs and symptoms that should prompt active consideration of this diagnosis early in the illness course.
Methods
PubMed and EMBASE databases were searched systematically to identify all published reports of anti-NMDAr encephalitis associated with prominent behavioral or psychiatric symptoms. This search strategy was designed to identify reports in which the clinical presentation was likely to have resulted in a psychiatric evaluation, rather than those with more typical neurological presentations such as delirium. The search yielded 354 PubMed citations and 78 EMBASE citations, and additional reports were found by manually searching bibliographies of the computerized search results; 385 distinct citations remained after eliminating duplicates. The frequencies of clinical features from 7 major symptom domains (behavioral/psychiatric abnormalities, cognitive dysfunction, motor dysfunction, seizures, autonomic dysfunction, catatonic features, and fever) were tabulated, and temporal ranks were assigned to these features based on their order of first appearance relative to one another in each patient. Median ranks were used to determine the temporal sequence in which the clinical domains were first observed.
Results
A total of 167 unique cases (121 female) met inclusion criteria, including age 18 years or younger. A prodrome consisting of non-localizing symptoms was reported in 48 (28.7%) of patients. After behavioral/psychiatric symptoms, the most commonly observed features were seizures (72.5%), other dyskinesias (62.9%), orofacial dyskinesias (49.1%), mutism or staring (40.7%), and insomnia (39.5%). Behavioral signs and symptoms occupied the earliest phase of the illness, accompanied by seizures and fever, but seizures and fever were presenting symptoms in only 31 (18.6%) and 16 (9.6%) cases, respectively. Similarly, insomnia had one of the earliest peaks. Dyskinesias peaked with and immediately after insomnia. Motor dysfunction peaked next, but in many cases emerged later in the course, and cognitive dysfunction tended to peak after motor dysfunction. Catatonic features followed cognitive and motor dysfunction, and autonomic dysfunction peaked relatively late in the illness course.
Discussion
Every psychiatrist is likely to encounter these patients in clinical practice. Without effective treatment a protracted course with significant long-term disability or death is likely to ensue. Clinicians should have a high index of suspicion when a patient presents with new psychiatric symptoms in the context of a recent viral prodrome (malaise, headache, loss of appetite), when accompanied by seizures, unexplained fever or insomnia, or when the quality of the psychiatric symptoms is unusual (e.g., non-verbal auditory hallucinations).