Diversity of clinical presentations in anti-N-methyl-D-aspartate receptor encephalitis ― a long way to go

Abstract

The clinical presentation of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is complex and diverse in each setting. Prior to the development of neuropsychiatric symptoms, which are significant in the disease, most people experience a prodromal period, with symptoms similar to those of upper respiratory tract infections or flu-like illness. Neuropsychiatric involvement following the prodromal stage can be lethal and requires intensive care. Prolonged neuropsychiatric symptoms including seizures, changes in personality, memory deficits, psychosis, and sleep disorders are relatively common; however, most patients make a nearly complete recovery with early and aggressive treatment.1Titulaer M.J. McCracken L. Gabilondo I. Armangué T. Glaser C. Iizuka T. et al.Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.Lancet Neurol. 2013; 12: 157-165Abstract Full Text Full Text PDF PubMed Scopus (1815) Google Scholar, 2Dalmau J. Gleichman A.J. Hughes E.G. Rossi J.E. Peng X. Lai M. et al.Anti-NMDA receptor encephalitis: case series and analysis of the effects of antibodies.Lancet Neurol. 2008; 7: 1091-1098Abstract Full Text Full Text PDF PubMed Scopus (2179) Google Scholar, 3Kong S.S. Chen Y.J. Su I.C. Lin J.J. Chou I.J. Chou M.L. et al.Immunotherapy for anti-NMDA receptor encephalitis: experience from a single center in Taiwan.Pediatr Neonatol. 2019; 60: 417-422Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The diagnosis and prognosis of anti-NMDA receptor encephalitis have improved in the past decade with anti-neuronal antibody kits and comprehensive acute clinical management. Nevertheless, long-term follow-up and clarification of pathogenic mechanisms are required to better understand this disease. Recently, Wu et al. reported anti-NMDA receptor encephalitis in two pre-pubertal children (2 of 10 enrolled children) who developed central precocious puberty about 3 years after encephalitis, with one requiring gonadotropin-releasing hormone (GnRH) agonist treatment.4Wu P.M. Teng C.K. Chou Y.Y. Tu Y.F. Precocious puberty as a consequence of anti-NMDA receptor encephalitis in children.Pediatr Neonatol. 2021; 62: 361-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar The authors hypothesized that the gradual reappearance of NMDA receptors on the postsynaptic GnRH neurons resulted in a gradual increase in stimulatory signals into the GnRH neurons. Then, the accumulation of stimulatory signals induced GnRH neurons to secrete GnRH, activating the hypothalamic–pituitary–gonadal axis and inducing sexual precocity. Thus, central precocious puberty may result from anti-NMDA receptor encephalitis in pre-pubertal children.4Wu P.M. Teng C.K. Chou Y.Y. Tu Y.F. Precocious puberty as a consequence of anti-NMDA receptor encephalitis in children.Pediatr Neonatol. 2021; 62: 361-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar Several studies support the hypothesis that repetitive NMDA agonist infusions can induce precocious puberty and that NMDA antagonist infusions can delay pubertal onset.4Wu P.M. Teng C.K. Chou Y.Y. Tu Y.F. Precocious puberty as a consequence of anti-NMDA receptor encephalitis in children.Pediatr Neonatol. 2021; 62: 361-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar,5Bourguignon J.P. Ge´rard A. Alvarez Gonzalez M.L. Franchimont P. Neuroendocrine mechanism of onset of puberty. Sequential reduction in activity of inhibitory and facilitatory N-methyl-D-aspartate receptors.J Clin Invest. 1992; 90: 1736-1744Crossref PubMed Scopus (71) Google Scholar Central precocious puberty is a unique finding of the long-term outcomes of anti-NMDA receptor encephalitis. Further observations and long-term prospective follow-up studies are warranted owing to this study's small sample size; nevertheless, the study finding highlights the diversity of clinical presentations and possible pathogenic mechanisms of anti-NMDA receptor encephalitis and may help improve the quality of clinical care. The discovery of anti-NMDA receptor encephalitis made it possible to recognize that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause may have an autoimmune disease wherein autoantibodies serve as a diagnostic marker and alter NMDA receptor-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder, movement disorder, or viral encephalitis-related status epilepticus is challenging. Severe symptoms often require intensive care. The major clinical intensive care unit problems include disturbance of consciousness, autonomic dysfunction, seizures/status epilepticus, movement disorders/hyperkinetic status, and other complications such as septic shock, organ failure, increased intracranial pressure, resuscitation and surgical complications, psychiatric complications, and ethical conflicts.6Lin K.L. Lin J.J. Neurocritical care for Anti-NMDA receptor encephalitis.Biomed J. 2020; 43: 251-258Crossref PubMed Scopus (9) Google Scholar,7Lin J.J. Lin K.L. Hsia S.H. Chou M.L. Hung P.C. Hsieh M.Y. et al.Anti-N-methyl-D-aspartate receptor encephalitis in Taiwan–a comparison between children and adults.Pediatr Neurol. 2014; 50: 574-580Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar Multi-system involvement and clinical diversity are a challenge for clinicians, and further work to improve the quality of team work in acute care with detailed and long-term follow-up for patients with anti-NMDA receptor encephalitis is required. In particular, pediatric neurologists have the responsibility to care for these patients during their growth, development, and maturation. None.