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Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

ABSTRACT: To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection.We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time of symptom onset (4 to 7 years ago) and the present.All patients sequentially developed prodromal symptoms, psychosis, hypoventilation, severe orofacial dyskinesias, and bizarre immunotherapy-resistant involuntary movements that lasted 1 to 12 months. Two patients required mechanical ventilation for 6 and 9 months. Initial tests were normal or unrevealing, including the presence of nonspecific CSF pleocytosis, and normal or mild changes in brain MRI. Eventually, all patients had dramatic recovery of cognitive functions, although one had bilateral leg amputation due to systemic complications. Antibodies to NR1/NR2 heteromers were found in archived serum or CSF but not in long-term follow-up samples. An ovarian teratoma was subsequently demonstrated in three patients (all confirmed pathologically).1) These findings indicate that "juvenile acute nonherpetic encephalitis" or a subset of this disorder is mediated by an antibody-associated immune response against NR1/NR2 heteromers of the NMDA receptor (NMDAR). 2) Our patients' clinical features emphasize that anti-NMDAR encephalitis is severe but potentially reversible and may precede by years the detection of an ovarian teratoma. 3) Although recovery may occur without tumor removal, the severity and extended duration of symptoms support tumor removal.

SUBMITTER: Iizuka T

PROVIDER: S-EPMC2586938 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

Iizuka T T Sakai F F Ide T T Monzen T T Yoshii S S Iigaya M M Suzuki K K Lynch D R DR Suzuki N N Hata T T Dalmau J J

Neurology 20070926 7

<h4>Objective</h4>To report the definitive diagnosis of anti-NMDA receptor (NMDAR) encephalitis in four Japanese women previously diagnosed with "juvenile acute nonherpetic encephalitis" of unclear etiology, and to describe their long-term follow-up in the absence of tumor resection.<h4>Methods</h4>We extensively reviewed the case histories with current clinical and laboratory evaluations that include testing for antibodies to NR1/NR2 heteromers of the NMDAR in serum/CSF available from the time ...[more]

PMID: 17898324

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Project description: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.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.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.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.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.

Project description:Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is an immune-mediated disorder that occurs with IgG antibodies against the GluN1 subunit of NMDAR. Some patients develop reversible diffuse cerebral atrophy (DCA), but the long-term clinical significance of progressive brain and cerebellar atrophy is unknown.To report the long-term clinical implications of DCA and cerebellar atrophy in anti-NMDAR encephalitis.A retrospective observational study and long-term imaging investigation was conducted in the Department of Neurology at Kitasato University. Fifteen patients with anti-NMDAR encephalitis admitted to Kitasato University Hospital between January 1, 1999, and December 31, 2014, were included; data analysis was conducted between July 15, 2015, and January 18, 2016.Neurologic examination, immunotherapy, and magnetic resonance imaging (MRI) studies were performed.Long-term MRI changes in association with disease severity, serious complications (eg, pulmonary embolism, septic shock, and rhabdomyolysis), treatment, and outcome.The clinical outcome of 15 patients (median age, 21 years, [range, 14-46 years]; 10 [67%] female) was evaluated after a median follow-up of 68 months (range, 10-179 months). Thirteen patients (87%) received first-line immunotherapy (intravenous high-dose methylprednisolone, intravenous immunoglobulin, and plasma exchange alone or combined), and 4 individuals (27%) also received cyclophosphamide; 2 patients (13%) did not receive immunotherapy. In 5 patients (33%), ovarian teratoma was found and removed. Serious complications developed in 4 patients (27%). Follow-up MRI revealed DCA in 5 patients (33%) that, in 2 individuals (13%), was associated with progressive cerebellar atrophy. Long-term outcome was good in 13 patients (87%) and poor in the other 2 individuals (13%). Although cerebellar atrophy was associated with poor long-term outcome (2 of 2 vs 0 of 13 patients; P?=?.01), other features, such as DCA without cerebellar atrophy, serious complications, ventilatory support, or prolonged hospitalization, were not associated with a poor outcome. Five patients with DCA had longer hospitalizations (11.1 vs 2.4 months; P?=?.002), required ventilatory support more frequently (5 of 5 vs 4 of 10 patients; P?=?.04), and developed more serious complications (4 of 5 vs 0 of 10 patients; P?=?.004) compared with those without DCA. Although DCA was reversible, cerebellar atrophy was irreversible.In anti-NMDAR encephalitis, DCA can be reversible and does not imply a poor clinical outcome. In contrast, cerebellar atrophy was irreversible and associated with a poor outcome. This observation deserves further study to confirm progressive cerebellar atrophy as a prognostic marker of poor outcome.

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Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

Publications

Anti-NMDA receptor encephalitis in Japan: long-term outcome without tumor removal.

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