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

Abstract

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.

Figure 1. Demographic information, distribution by age of initial symptom, and cumulative symptoms during the first month of the disease

Panel A: Patient’s age at disease onset Panel B: Symptom presentation according to patients’ age (age <12 = 111 patients; 12-17 years = 99; ≥ 18 years = 364; 3 unknown). The frequency of abnormal behavior, movement disorder, and seizures is different among the three age groups (p<0·0001) Panel C: Distribution by age of cumulative symptoms during the first month of the disease. For each color, the first dark column refers to patients < 12 years, the middle column to patients 12-17 years, and the right, light column to patients ≥ 18 years. *p = 0·002; **p < 0·0005; ^#p = 0·024.

Figure 1. Demographic information, distribution by age of initial symptom, and cumulative symptoms during the first month of the disease

Panel A: Patient’s age at disease onset Panel B: Symptom presentation according to patients’ age (age <12 = 111 patients; 12-17 years = 99; ≥ 18 years = 364; 3 unknown). The frequency of abnormal behavior, movement disorder, and seizures is different among the three age groups (p<0·0001) Panel C: Distribution by age of cumulative symptoms during the first month of the disease. For each color, the first dark column refers to patients < 12 years, the middle column to patients 12-17 years, and the right, light column to patients ≥ 18 years. *p = 0·002; **p < 0·0005; ^#p = 0·024.

Figure 1. Demographic information, distribution by age of initial symptom, and cumulative symptoms during the first month of the disease

Panel A: Patient’s age at disease onset Panel B: Symptom presentation according to patients’ age (age <12 = 111 patients; 12-17 years = 99; ≥ 18 years = 364; 3 unknown). The frequency of abnormal behavior, movement disorder, and seizures is different among the three age groups (p<0·0001) Panel C: Distribution by age of cumulative symptoms during the first month of the disease. For each color, the first dark column refers to patients < 12 years, the middle column to patients 12-17 years, and the right, light column to patients ≥ 18 years. *p = 0·002; **p < 0·0005; ^#p = 0·024.

Figure 1. Demographic information, distribution by age of initial symptom, and cumulative symptoms during the first month of the disease

Panel A: Patient’s age at disease onset Panel B: Symptom presentation according to patients’ age (age <12 = 111 patients; 12-17 years = 99; ≥ 18 years = 364; 3 unknown). The frequency of abnormal behavior, movement disorder, and seizures is different among the three age groups (p<0·0001) Panel C: Distribution by age of cumulative symptoms during the first month of the disease. For each color, the first dark column refers to patients < 12 years, the middle column to patients 12-17 years, and the right, light column to patients ≥ 18 years. *p = 0·002; **p < 0·0005; ^#p = 0·024.

Figure 2. Flowchart of treatment groups

Figure 3. Clinical outcome after extended follow-up

Panel A: All patients Panel B: Patients who responded to first-line immunotherapy (steroids, IVIg, plasmapheresis) Panel C: Patients who failed first-line immunotherapy and did not receive second-line therapy Panel D: Patients who failed first-line immunotherapy and received second-line therapy (rituximab, cyclophosphamide, or both) Outcome was measured by mRS. Twenty-nine patients included in panel A did not have immunotherapy or tumor removal.

Figure 3. Clinical outcome after extended follow-up

Panel A: All patients Panel B: Patients who responded to first-line immunotherapy (steroids, IVIg, plasmapheresis) Panel C: Patients who failed first-line immunotherapy and did not receive second-line therapy Panel D: Patients who failed first-line immunotherapy and received second-line therapy (rituximab, cyclophosphamide, or both) Outcome was measured by mRS. Twenty-nine patients included in panel A did not have immunotherapy or tumor removal.

Figure 3. Clinical outcome after extended follow-up

Panel A: All patients Panel B: Patients who responded to first-line immunotherapy (steroids, IVIg, plasmapheresis) Panel C: Patients who failed first-line immunotherapy and did not receive second-line therapy Panel D: Patients who failed first-line immunotherapy and received second-line therapy (rituximab, cyclophosphamide, or both) Outcome was measured by mRS. Twenty-nine patients included in panel A did not have immunotherapy or tumor removal.

Figure 3. Clinical outcome after extended follow-up

Panel A: All patients Panel B: Patients who responded to first-line immunotherapy (steroids, IVIg, plasmapheresis) Panel C: Patients who failed first-line immunotherapy and did not receive second-line therapy Panel D: Patients who failed first-line immunotherapy and received second-line therapy (rituximab, cyclophosphamide, or both) Outcome was measured by mRS. Twenty-nine patients included in panel A did not have immunotherapy or tumor removal.

Figure 3. Clinical outcome after extended follow-up

Panel A: All patients Panel B: Patients who responded to first-line immunotherapy (steroids, IVIg, plasmapheresis) Panel C: Patients who failed first-line immunotherapy and did not receive second-line therapy Panel D: Patients who failed first-line immunotherapy and received second-line therapy (rituximab, cyclophosphamide, or both) Outcome was measured by mRS. Twenty-nine patients included in panel A did not have immunotherapy or tumor removal.

Figure 4. Frequency of relapses

Panel A: Patients with tumor had fewer relapses than those without tumor (p = 0·0007). Panel B: The use of immunotherapy associated with fewer relapses (p = 0·038). Second-line immunotherapy associated with fewer relapses in patients without tumor (see Figure S2).

Figure 4. Frequency of relapses

Panel A: Patients with tumor had fewer relapses than those without tumor (p = 0·0007). Panel B: The use of immunotherapy associated with fewer relapses (p = 0·038). Second-line immunotherapy associated with fewer relapses in patients without tumor (see Figure S2).