Cited by 3,166Autoimmune Neurological Disorders and TreatmentsPeripheral Neuropathies and DisordersInfectious Encephalopathies and Encephalitis

The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index; 17 of the 23 sources its claims cite were checked for support.

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

Open access

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.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In this multi-institutional observational cohort of 577 patients with anti-NMDAR encephalitis, immunotherapy and tumor removal produced good outcome (mRS 0–2) in 394/501 within 24 months, and second-line immunotherapy improved outcomes after first-line failure. Early treatment and no ICU admission predicted good outcome.

Key findings

  • 577 patients (1–85 years, median 21) were studied; 211 (37%) were younger than 18 in the Results (the abstract states 212 children). Of 501 assessable patients, 472 (94%) received first-line immunotherapy or tumor removal, and 251 (53%) improved within four weeks.
  • Of 221 patients who failed first-line therapy, 125 (57%) received second-line immunotherapy, which was associated with better outcome than no second-line therapy (OR 2·69, CI 1·24–5·80, p=0·012).
  • During the first 24 months, 394/501 reached mRS 0–2 (median 6 months); at 24-month follow-up 203/252 (81%) had good outcome, and 24 (9·5%) died in the Results (the abstract reports 30 died). 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 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 second-line immunotherapy effect were comparable to the entire cohort (OR 3·35, CI 0·86–12·98, p=0·081).

Methods

  • Multi-institutional observational study (2007–2012) of patients with GluN1 antibodies from the Universities of Pennsylvania and Barcelona and samples from 200 centers worldwide (32 countries); 577 patients were included for demographic analyses, and 501 had follow-up of at least 4 months (median 24 months, range 4–186).
  • Patients were assessed at symptom onset and 4, 8, 12, 18, and 24 months using the modified Rankin Scale (mRS); symptoms were categorized into 8 groups. First-line immunotherapy was steroids, IVIg, or plasma exchange; second-line was rituximab or cyclophosphamide; tumor removal was also assessed. Treatment failure was no sustained improvement within four weeks and mRS ≥4.
  • Statistical analysis used Fisher exact, Fisher-Freeman-Halton, or Mann-Whitney U tests; univariable binary logistic regression followed by generalized linear mixed models with binary distribution, subject as random effect, and time point from disease onset included; SAS GLIMMIX version 9.3.

Limitations

  • The paper states the study was not randomized, was observational, and selection bias cannot be ruled out; individual treatments (e.g., plasma exchange vs IVIg or rituximab) could not be compared side-by-side statistically.
  • The paper states there was no predefined protocol establishing order or combination of treatments, and treatment decisions were made by treating physicians based on clinical symptoms, family acceptance of side effects, and drug availability.
  • The paper states that ending follow-up at 24 months likely underestimates recovery and overestimates mortality; imputation analysis estimated 7% mortality at 24 months. The text also shows inconsistent counts between abstract and Results for deaths, children, and 24-month good outcome, which is evident from the paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/s1474-4422(12)70310-1

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

66 Own result · 11 Own interpretation · 10 Partly supported · 9 Own method · 2 Supported · 2 Sources not found · 2 No basis given · 1 Supported so far · accuracy not yet measured

Show all 41 claims

  • Probably not a substantial claim. 27
  • It may state two separate claims as one. 44
62 of 62
  • The paper relies on this without support.

    The use of immunotherapy and the long-term outcome in anti-NMDAR encephalitis have not been defined.

    “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.”
  • The paper relies on this without support.

    The efficacy of immunotherapy and its impact in the long-term outcome have not been established.

    “However, the efficacy of immunotherapy and its impact in the long-term outcome have not been established.”
  • The paper relies on this without support.

    A substantial number of patients fail to respond to first-line immunotherapy, and for these patients the treatment strategy and outcome are unknown.

    “A substantial number of patients fail to respond to first-line immunotherapy, such as steroids, plasmapheresis, and intravenous immunoglobulins (IVIg) and for these patients the treatment strategy and outcome are unknown.”
  • The authors state this as an assumption.

    A systematic analysis of the effects of sequential immunotherapy and their impact on long-term outcome has not been previously done in any of these disorders or other antibody-mediated neurological diseases.

    “To our knowledge, a systematic analysis of the effects of sequential (first-, second-line) immunotherapy and their impact on long-term outcome has not been previously done in any of these disorders or other antibody-mediated neurological diseases.”
4 of 4

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

2 of 2

Citations

Cites

Show all 28 references

Cited by

Sorted by citations

Items 2,401–2,500 of 3,166

Metadata

Authors
Titulaer, M. J., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., Honig, L. S., Benseler, S. M., Kawachi, I., Martinez-Hernandez, E., Aguilar, E., Gresa-Arribas, N., Ryan-Florance, N., Torrents, A., Saiz, A., Rosenfeld, M. R., Balice-Gordon, R., Graus, F., & Dalmau, J.
Affiliations
  • Hospital of the University of Pennsylvania (US)
  • Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
  • California Department of Public Health (US)
  • Kitasato University Hospital (JP)
  • Columbia University (US)
  • University of Toronto (CA)
  • Brain Research Institute, Niigata University (JP)
  • Hospital Clínic de Barcelona (ES)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Dalmau, Josep
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2013-02
Volume
12
Issue
2
Pages
157-165
ISSN
1474-4422 (ISSN-L)
OpenAlex
W2163022996
Cited by
3,165
References
28
Citations by year
2026: 225 · 2025: 231 · 2024: 249 · 2023: 239 · 2022: 287 · 2021: 329 · 2020: 296 · 2019: 274 · 2018: 222 · 2017: 193 · 2016: 202 · 2015: 169 · 2014: 152 · 2013: 90
FWCI
129.68
Type
journal article
Language
en
Open access
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Japan Society for the Promotion of Science (23591236)
  • National Institute on Aging (P50AG008702)
  • National Institute of Mental Health (R01MH094741)
  • National Cancer Institute (R01CA089054, R56CA089054, R01CA107192)
  • National Institute of Neurological Disorders and Stroke (RC1NS068204, R01NS077851)
Topics
  • Health Sciences › Medicine › Clinical Neurology › Autoimmune Neurological Disorders and Treatments
  • Health Sciences › Medicine › Clinical Neurology › Peripheral Neuropathies and Disorders
  • Health Sciences › Medicine › Infectious Diseases › Infectious Encephalopathies and Encephalitis
Keywords
anti-NMDA receptor encephalitis, NMDA receptor antibodies, immunotherapy, rituximab, cyclophosphamide, plasmapheresis, intravenous immunoglobulin, corticosteroids, tumor resection, long-term outcomes, prognostic factors, modified Rankin Scale, autoimmune encephalitis, children, adults
MeSH terms
Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Analysis of Variance, Autoantibodies, Child, Child, Preschool, Female, Humans, Immunotherapy, Infant, Male, Middle Aged, Retrospective Studies, Time Factors, Cohort Studies, Logistic Models, Receptors, N-Methyl-D-Aspartate, Immunoglobulins, Intravenous, Treatment Outcome, Observation, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis

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