Anti-NMDAR encephalitis or schizophrenia?
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1 Anti-NMDAR encephalitis or schizophrenia? Maarten Titulaer
2 Disclosures Received a travel grant for lecturing in India from Sun Pharma Will discuss unlabeled use of different immunotherapeutics
3 Anti-NMDA receptor encephalitis Discovered in 2007 patient serum NR1 monoclonal merged 1) rat brain immunohistochemistry (IHC) 2) live rat hippocampal neurons 3) cell based assay (CBA) Dalmau et al. Ann Neur 2007 Dalmau et al. Lancet Neurol 2008
4 Demographics Median age 19 years < % 45 5 % 81% female % < 12 or % 39% tumour 96% teratoma < 12 F or M 4 % 12 F 54 % 45 F or M 23 % Titulaer et al. Lancet Neurol 2013 Titulaer et al. Neurology 2013
5 First symptom Titulaer et al. Lancet Neurol 2013
6 Anti-NMDA receptor encephalitis Clinical Worsening prodrome agitation, psychosis, catatonia, memory deficit, speech reduction, abnormal movements +/- seizures coma, hypoventilation, +/- dysautonomia Clinical Improvement Dalmau et al. Lancet Neurol 2008 Irani et al. Brain 2010 Dalmau et al. Lancet Neurol 2011 Titulaer et al. Lancet Neurol 2013
7 100% 90% 80% 70% 60% Symptoms within 1 st month ** * *** < 12 years years 18 years 50% 40% 30% 20% 10% *** *** *** 0% behaviour/ speech cognition memory movement autonomic cerebellar disorder symptoms ataxia seizures loss of hypoventilation hemiparesis consciousness Titulaer et al. Lancet Neurol 2013
8 Severity of disease 30% 25% 20% < 12 years years 18 years ICU stay <12 years 75% years 73% 18 years 78% p = NS 15% 10% 5% 0% Number of major symptoms maximum modified Rankin Scale (mrs) of 5 <12 years 90% years 86% 18 years 86% p = NS Titulaer et al. Lancet Neurol 2013
9 NMDAR antibodies in psychiatric patients? (1) 3 of 46 cases (6.5%) with 1 st -episode schizophrenia (CBA serum) 1/3 diagnosis doubtful; 2/3 had (mild) verbal dysfunction Zandi et al, J Neurol of 51 cases (7.8%) met schizophrenia; 2/4 had seizures, 1/4 orofacial dyskinesias (CBA serum) Tsutsui et al, BMC Psych of 207 patients with schizophrenia; 2 others were antibodypositive, but these had extensive anti-nmdar encephalitis Steiner, JAMA Psych 2013; Masdeu, Am J Psych 2012; Rhoads J, Schizophr Res 2011 Seropositive (IgG) CSF Serum Schizophrenia (1081) n.d % Depression (148) n.d % Parkinson (263) n.d % Controls (1272) n.d % Hammer et al. Mol Psych 2013
10 NMDAR antibodies in psychiatric patients (2) 5 of 571 NMDAR patients had purely psychiatric symptoms during 1 st disease episode (retrospectively 2 mild orofacial dyskinesias) Kayser et al, JAMA Neur of 900 NMDAR patients developed schizophrenia Test in patients with new-onset psychosis, be cautious for (subtle) neurological symptoms; chance of NMDAR-antibodies will decrease sharply without additional symptoms < 4 weeks Titulaer & Dalmau, Lancet Neur 2013
11 Sensitivity en specificity Sensitivity CSF Serum p McNemar's test Number of patients Both tests positive % % < % CI ( %) ( %) CBA negative 0 0.0% % Specificity 100% ( %), in serum and CSF (n = 100) Serum positive in 0.4-3% healthy patients CBA, not IHC Confirm positive serum test in CSF and/or by IHC Gresa, Titulaer et al. Lancet Neurol 2014 Viacozz et al. Neurology 2014 Hammer et al. Mol Psych 2013
12 Diagnostics CSF: 79% abnormal Lymphocytic pleocytosis WBC 32 (6-511) 75% Raised total protein 18% Oligoclonal bands 53% EEG: 89% abnormal Extreme Delta Brushes 30% MRI: 33% abnormal Dalmau et al. Lancet Neurol 2008 Irani et al. Brain 2010 Titulaer et al. Lancet Neurol 2013 Schmitt et al. Neurology 2012 Armangue et al. J Ped 2012
13 NMDA-R antibody synthesis and effects in CNS Moscato et al. Eur J Neurosci 2010
14 NMDA receptor hypofunction theory Glutamate levels after intracerebral injections with patients antibodies Gordon Nature Neurosci 2010 Manto et al. Orphanet J Rare Dis 2010
15 Antibodies diminish the number of NMDAR clusters Hughes et al. J Neurosci 2010
16 Passive transfer leads to (reveresible) encephalitis Planaguma, Leypoldt, Mannara et al. Brain in press
17 Long-term outcome Modified Better Rankin outcome Scale (mrs) Follow-up (months) 0 No symptoms. no ICU stay 1 No significant disability. Able to carry out all usual activities. shorter time until treatment 2 Slight disability. Independent in activities of daily living (ADL). 3 Moderate disability. Needs some help, longer follow-up but able to walk unassisted. 4 Moderately severe disability. Requires assistance, and unable to walk unassisted. 5 All Severe significant disability. in Requires multivariate constant nursing care and attention, bedridden. 6 Dead. (until 18 months) analysis Titulaer Van Swieten al. Lancet al. Neurol Stroke
18 Treatment-related outcome NMDARencephalitis (n = 501) immunosuppression tumour removal (n = 472) improvement (n = 251) (50%) no treatment (n = 29 ; 6%) 29% died / poor outcome no improvement / limited response (n = 221 ; 44%) no additional treatment / repetition 1 st -line IS (n = 96 ; 43%) 2 nd -line immunotherapy (n = 125 ; 57%) follow-up (months)
19 Efficacy of 2 nd -line treatment 100% 80% 60% 40% 20% 0% 6 100% % % 40% nd -line treatment 20% OR = 2.69 ( ) 0% p = Follow-up (months) Follow-up (months) no 2 nd -line treatment rituximab / cyclophosphamide Titulaer et al. Lancet Neurol 2013
20 Plasma cells in PA brain of patients CD20 CD3 CD4 CD8 CD138 CD138 Martinez-Hernandez et al. Neurology 2011
21 AMPAR: clinical symptoms (36 patients) Epidemiology: 67% female, median age ~60 (23-87) Symptoms: 60% limbic encephalitis 30% limbic encephalitis plus 10% psychosis or rapid progressive dementia 15% low sodium 60-65% SCLC, breast cancer, thymoma, ovarian teratoma Sensitivity serum 71% (10/14 paired samples) MRI: 80-85% temporal FLAIR hyperintensity Outcome: ~25% complete, ~50% partial recovery; However, outcome depends on additional onconeuronal abs Lai et al. Ann Neur 2009 Graus et al. Neur 2010 Hoftberger et al. submitted
22 Conclusions Psychiatric symptoms are frequent in anti-nmdar encephalitis Psychiatric symptoms are often the first symptoms Isolated psychiatric symptoms (> 4 weeks) are rare Beware of pitfalls in diagnosis, especially in serum; check CSF Outcome depends on treatment delay and severity of disease If 1 st -line immunotherapy (steroids, plasma exchange, IVIG) fails, 2 nd -line IT (rituximab, cyclophosphamide) is usually effective Overall, 80% have a good outcome
23 Erasmus University, Rotterdam Agnes van Sonderen Esther Hulsenboom Peter Sillevis Smitt Marco Schreurs Marienke de Bruijn Institut d investigacions Biomediques August Pi i Sunyer (IDIBAPS) / University of Barcelona Frank Leypoldt Iñigo Gabilondo Thais Armangue Eugenia Martinez-Hernandez Núria Gresa-Arribas Esther Aguilar Romana Höftberger Abiguei Torrents Maria Rodes Myrna R. Rosenfeld Francesc Graus Josep Dalmau (ICREA) University of Pennsylvania, Philadelphia Lindsey McCracken Emilia Moscato Marion Scott Rita Balice-Gordon Eric Lancaster Ankit Jain Josep Dalmau
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