Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study

Department of Neurology and Neurosciences, Hospital of the University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
The Lancet Neurology (Impact Factor: 21.9). 02/2013; 12(2). DOI: 10.1016/S1474-4422(12)70310-1


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. INTERPRETATION: 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. FUNDING: The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundacio la Marato de TV3.

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Available from: Iñigo Gabilondo, Nov 14, 2014
    • "Although numerous imaging descriptions exist, large cohort studies reported MRI abnormalities only in 23– 50% of the patients (Irani et al., 2010b; Dalmau et al., 2011; Titulaer et al., 2013). This clinico-radiological paradox constitutes one of the main challenges in NMDAR encephalitis neuroimaging. "
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    ABSTRACT: The field of autoimmune encephalitides associated with antibodies targeting cell-surface antigens is rapidly expanding and new antibodies are discovered frequently. Typical clinical presentations include cognitive deficits, psychiatric symptoms, movement disorders and seizures and the majority of patients responds well to immunotherapy. Pathophysiological mechanisms and clinical features are increasingly recognized and indicate hippocampal dysfunction in most of these syndromes. Here, we review the neuroimaging characteristics of autoimmune encephalitides, including N-methyl-D-aspartate (NMDA) receptor, leucine-rich glioma inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2) encephalitis as well as more recently discovered and less frequent forms such as dipeptidyl-peptidase-like protein 6 (DPPX) or glycine receptor encephalitis. We summarize findings of routine MRI investigations as well as FDG-PET and SPECT imaging and relate these observations to clinical features and disease outcome. We furthermore review results of advanced imaging analyses such as diffusion tensor imaging, volumetric analyses and resting state functional MRI. Finally, we discuss contributions of these neuroimaging observations to the understanding of the pathophysiology of autoimmune encephalitides. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 05/2015; 309. DOI:10.1016/j.neuroscience.2015.05.037 · 3.36 Impact Factor
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    • "Combination therapy with corticosteroid, plasma exchange, and intravenous administration of immunoglobulin is recommended as the first-line treatment (Dalmau et al. 2011). Recently, rituximab, an anti-CD20 monoclonal antibody, and/or cyclophosphamide, has been increasingly used for intractable patients requiring second-line immunotherapy (Titulaer et al. 2013). Patients without ovarian tumor seem to be more resistant to these therapeutic approaches (Lancaster et al. 2011). "
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    ABSTRACT: Autoimmune synaptic encephalitis is characterized by the presence of autoantibodies against synaptic constituent receptors and manifests as neurological and psychiatric disorders. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is such an autoimmune disorder that predominantly affects young women. It is associated with antibodies against the extracellular region of the NR1 subunit of postsynaptic NMDAR. Each NMDAR functions as a heterotetrameric complex that is composed of four subunits, including NR1 and NR2A, NR2B, or NR2C. Importantly, ovarian teratoma is a typical complication of anti-NMDAR encephalitis in female patients and may contain antigenic neural tissue; however, antigenic sites remain unknown in female patients without ovarian teratoma. The purpose of this study was to investigate the expression of NMDARs in the ovum. We detected NR1 and NR2B immunoreactivity in protein fractions extracted from the bovine ovary and ova by SDS-polyacrylamide gel electrophoresis and immunoblotting analysis. Immunoprecipitates digested with trypsin were analyzed by reverse phase liquid chromatography coupled to tandem mass spectrometry. We obtained the following five peptides: SPFGRFK and KNLQDR, which are consistent with partial sequences of human NR1, and GVEDALVSLK, QPTVAGAPK, and NEVMSSK, which correspond to those of NR2A, NR2B and NR2C, respectively. Immunocytochemical analysis revealed that the bovine ovum was stained with the immunoglobulin G purified from the serum of a patient with anti-NMDAR encephalitis. Taken together, we propose that the normal ovum expresses NMDARs that have strong affinity for the disease-specific IgG. The presence of NMDARs in ova may help explain why young females without ovarian teratomas are also affected by anti-NMDAR encephalitis.
    The Tohoku Journal of Experimental Medicine 03/2015; 235(3):223-31. DOI:10.1620/tjem.235.223 · 1.35 Impact Factor
    • "Identification of the disorder is fairly new thus the extant literature on treatments and outcomes remains fairly limited. Titulaer et al. (2013) found that 81% of a cohort of 577 patients had a good outcome (i.e. improvement from severe to slight disability and no need for admission to an intensive care unit) in the first 24 months following diagnosis, and 45 patients (12%) had a relapse requiring continued immunotherapy and supportive care in intensive care. "
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    ABSTRACT: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an auto immune-disorder. It is a life threatening condition that typically presents with viral illness, headaches, severe psychiatric symptoms, seizures, behavioural changes, decreasing levels of unconsciousness and progressive unresponsiveness, cognitive impairment, abnormal movements (e.g., dyskinesia), ataxia and hypoventilation.
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