Elsevier

The Lancet Neurology

Volume 12, Issue 2, February 2013, Pages 157-165
The Lancet Neurology

Articles
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study

https://doi.org/10.1016/S1474-4422(12)70310-1Get rights and content

Summary

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 Fundació la Marató de TV3.

Introduction

In 2005, a syndrome with prominent psychiatric symptoms, memory loss, decrease of level of consciousness, and central hypoventilation was described in four young women with an ovarian teratoma and antibodies against an antigen highly expressed in the hippocampus.1 Soon thereafter, the target antigen was identified as the NMDA receptor (NMDAR).2 The disorder, named anti-NMDAR encephalitis, has since been seen in patients of all ages, but most often in young adults and children with or without teratomas.3, 4 Findings from epidemiological studies suggest that this disorder is the most common cause of autoimmune encephalitis after acute demyelinating encephalomyelitis.5 In a centre focused on the study of encephalitis of unclear cause (California Encephalitis Project, CA, USA), the frequency of anti-NMDAR encephalitis surpassed that of any specific viral cause in young individuals.6 Patients usually present with acute behavioural change, psychosis, and catatonia that evolve to include seizures, memory deficit, dyskinesias, speech problems, and autonomic and breathing dysregulation.3 The syndrome resembles the phenotypes obtained with genetic and pharmacological decreases in expression and function of NMDAR.7, 8 Findings from experiments in which patients’ antibodies were added to cultures of hippocampal neurons or infused into the hippocampus of rodents showed specific antibody-mediated internalisation of NMDAR and alteration of the mechanisms of synaptic plasticity.9, 10 Despite the severity of the disease, patients often improve after intensive care support, immunotherapy, and lengthy stays in hospital with multidisciplinary care.3, 11 However, the effectiveness of immunotherapy and its long-term effect have not been established. Many patients do not respond to first-line immunotherapy, such as steroids, plasmapheresis, and intravenous immunoglobulins, and for these patients the treatment strategy and outcome are unknown. Moreover, available evidence suggests that the syndrome and response to treatment can differ between children and adults.4 To address these issues, we assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome.

Section snippets

Study design and participants

In this observational cohort study, we tested for the presence of NMDAR antibodies in serum or CSF samples from patients at the hospitals of the University of Pennsylvania (Philadelphia, PA, USA) and the University of Barcelona (Spain), and from patients whose samples were sent to these institutions (from 200 centres in 35 countries; appendix) for study between Jan 1, 2007, and Jan 1, 2012. Samples were recorded as positive if they fulfilled previously reported criteria,3 including a

Results

Overall, we included 577 patients in the demographic analyses (135 of whom seen by study investigators, all others seen by referring clinicians), of whom 501 had been followed-up for at least 4 months (median 24 months, range 4–186; figure 1). Median age at disease onset was 21 years (range 8 months to 85 years). 468 patients (81%) were female (figure 2 and appendix). 211 (37%) of all 577 patients were younger than 18 years, and 28 (5%) were 45 years or older (figure 2). Many patients younger

Discussion

Our findings show that immunotherapy and tumour removal, if applicable, result in substantial neurological improvement in 81% of patients with anti-NMDAR encephalitis after a median follow-up of 24 months Moreover, second-line immunotherapy with rituximab, cyclophosphamide, or both, improved the outcome of patients who did not respond to first-line treatment and decreased the occurrence of relapses.

Symptom presentation varied between children and adults (symptoms were more often neurological in

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