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

Abstract

Background Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. Methods In this multi-institutional observational study (2007-2012), all patients with GluN1 antibodies were assessed at symptom onset and 4, 8, 12, 18, and 24 months using the modified Rankin Scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumor removal. Predictors of outcome were determined at the Universities of Pennsylvania and Barcelona using generalized linear mixed models with binary distribution. Results 577 patients (1-85 years, median 21) were studied, 212 were children (<18 years). Treatment effects and outcome were assessable in 501 (median follow-up 24 months): 472 (94%) underwent first-line immunotherapy or tumor removal, resulting in improvement within four weeks in 251 (53%). Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy resulting in better outcome than those who did not (OR 2·69, CI 1·24-5·80, p=0·012). During the first 24 months, 394/501 reached good outcome (mRS 0-2; median 6 months), and 30 died. At 24 month follow-up 204/252 (81%) had good outcome. Outcomes continued to improve for up to 18 months after symptom onset. Predictors of good outcome were early treatment (OR 0·62, CI 0·50-0·76, p<0·0001) and lack of ICU admission (OR 0.12, CI 0·06-0·22,p<0·0001). 45 patients had one or multiple relapses (representing a 12% risk within 2 years); 46/69 (67%) relapses were milder than previous episodes (p<0·0001). In 177 children, predictors of good outcome and the magnitude of effect of second-line immunotherapy were comparable to those of the entire cohort. Conclusions Patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line therapies fail. Recovery can take more than 18 months.

Bortezomib treatment for severe refractory anti‐NMDA receptor encephalitis

“…Therapeutic intervention targeting B cells and plasmablasts by two different agents, rituximab and tocilizumab,4 theoretically allows the evaluation of bortezomib efficacy by targeting long‐lived plasma cells. Follow‐up was continued for long enough (13–20 months post‐onset) to evaluate the mRS score improvement considering the disease course of anti‐NMDAR encephalitis 1. However, several limitations of this study should be considered when interpreting the results.…”

“…Although most patients with autoimmune encephalitis respond to immunotherapy,1, 2, 3 a small, but significant, number of patients show an insufficient response even after aggressive immunotherapy; therefore, several treatment options are being explored 4, 5, 6. Long‐lived plasma cells that can survive without cell division and continuously secrete autoantibodies are considered to contribute to the poor clinical course in the patients, given their known resistance to B‐cell depleting agents, conventional immunosuppressants, and antiproliferative agents 7…”

Botulinum toxin treatment for hypersalivation in anti‐NMDA receptor encephalitis

“…Within the first 4 weeks of symptom onset, more than 40% of the patients with anti‐NMDAR encephalitis experience autonomic symptoms including hyperthermia, tachycardia, hypersalivation, bradycardia, hypertension, and hypotension 1, 3, 5. Although hypersalivation is one of the main autonomic dysfunctions in anti‐NMDAR encephalitis, there has been no clear consensus regarding which treatment is better for controlling hypersalivation.…”

“…By the first‐line immunotherapy (steroids, immunoglobulins, or plasma exchange) and second‐line immunotherapy (rituximab or cyclophosphamide), about 80% of patients with anti‐NMDAR encephalitis recovers favorably to be able to look after own affairs without assistance 5. However, 7% of the patients still die due to complications such as autonomic dysfunction, pneumonia, hypoventilation, rhabdomyolysis, or status epilepticus 5, 6, 7…”

A case report: anti-NMDA receptor encephalitis

“…Reported relapse rates range between 12% and 24%, more often in those without teratoma [4]. The largest cohort study to date of 577 patients reported 53% recovery based on the modified Rankin Scale, and 97% of those who improved had good outcome at 24 months [8]. …”