title: Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study.
abstract: BACKGROUND
  Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome.
  
  
  METHODS
  In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution.
  
  
  RESULTS
  We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months, range 4-186): 472 (94%) underwent first-line immunotherapy or tumour removal, resulting in improvement within 4 weeks in 251 (53%). Of 221 patients who did not improve with first-line treatment, 125 (57%) received second-line immunotherapy that resulted in a better outcome (mRS 0-2) than those who did not (odds ratio [OR] 2·69, CI 1·24-5·80; p=0·012). During the first 24 months, 394 of 501 patients achieved a good outcome (mRS 0-2; median 6 months, IQR 2-12) and 30 died. At 24 months' follow-up, 203 (81%) of 252 patients had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (0·62, 0·50-0·76; p<0·0001) and no admission to an intensive care unit (0·12, 0·06-0·22; p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46 (67%) of 69 relapses were less severe than initial episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were similar to those of the entire cohort.
  
  
  CONCLUSIONS
  Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months.
  
  
  BACKGROUND
  The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundació la Marató de TV3.
authors.affiliation: Department of Neurology and Neurosciences, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Titulaer
authors.forename: Lindsey
authors.initials: L
authors.lastname: McCracken
authors.forename: Iñigo
authors.initials: I
authors.lastname: Gabilondo
authors.forename: Thaís
authors.initials: T
authors.lastname: Armangué
authors.forename: Carol
authors.initials: C
authors.lastname: Glaser
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iizuka
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Honig
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Benseler
authors.forename: Izumi
authors.initials: I
authors.lastname: Kawachi
authors.forename: Eugenia
authors.initials: E
authors.lastname: Martinez-Hernandez
authors.forename: Esther
authors.initials: E
authors.lastname: Aguilar
authors.forename: Núria
authors.initials: N
authors.lastname: Gresa-Arribas
authors.forename: Nicole
authors.initials: N
authors.lastname: Ryan-Florance
authors.forename: Abiguei
authors.initials: A
authors.lastname: Torrents
authors.forename: Albert
authors.initials: A
authors.lastname: Saiz
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.forename: Rita
authors.initials: R
authors.lastname: Balice-Gordon
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis / Q000097:blood / Q000134:cerebrospinal fluid / Q000175:diagnosis* / Q000628:therapy*; D001323:Autoantibodies / Q000097:blood* / Q000134:cerebrospinal fluid*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007167:Immunotherapy / Q000379:methods*; D007223:Infant; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D019370:Observation; D016194:Receptors, N-Methyl-D-Aspartate / Q000276:immunology*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D016756:Immunoglobulins, Intravenous; D016194:Receptors, N-Methyl-D-Aspartate