Antibody-Negative Autoimmune Encephalitis: A Single-Center Retrospective Analysis
Language English Country United States Media electronic-print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
37879962
PubMed Central
PMC10605954
DOI
10.1212/nxi.0000000000200170
PII: 10/6/e200170
Knihovny.cz E-resources
- MeSH
- Autoimmune Diseases of the Nervous System * diagnosis therapy MeSH
- Autoimmune Diseases MeSH
- Autoantibodies MeSH
- Adult MeSH
- Encephalitis * diagnosis therapy MeSH
- Hashimoto Disease MeSH
- Middle Aged MeSH
- Humans MeSH
- Limbic Encephalitis MeSH
- Neoplasms * MeSH
- Retrospective Studies MeSH
- Aged MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Autoantibodies MeSH
BACKGROUND AND OBJECTIVES: Autoimmune encephalitis (AE) refers to a heterogenous group of inflammatory CNS diseases. Subgroups with specified neural autoantibodies are more homogeneous in presentation, trigger factors, outcome, and response to therapy. However, a considerable fraction of patients has AE features but does not harbor detectable autoantibodies and is referred to as antibody-negative AE. Our aim was to describe clinical features, trigger factors, treatments, and outcome of a cohort of comprehensively tested antibody-negative AE patients. METHODS: This retrospective monocentric study recruited adult patients whose serum and/or CSF was sent to our tertiary center for neural antibody testing between 2011 and 2020, who entered the diagnostic algorithm as possible antibody-negative AE and had the following: (1) probable antibody-negative AE, definite antibody-negative acute disseminated encephalomyelitis (ADEM), or definite autoimmune limbic encephalitis (LE) according to diagnostic criteria; (2) available data on MRI of the brain, CSF, and EEG; and (3) stored serum and/or CSF samples. These samples were reanalyzed using a comprehensive combination of cell-based and tissue-based assays. RESULTS: Of 2,250 patients tested, 33 (1.5%) were classified as possible antibody-negative AE. Of these, 5 were found to have antibodies by comprehensive testing, 5 fulfilled the criteria of probable AE (3F:2M, median age 67, range 42-67), 4 of definite autoimmune LE (2F:2M, median age 45.5, range 27-60 years), one of definite antibody-negative ADEM, 2 of Hashimoto encephalopathy, one had no samples available for additional testing, and 15 had no further categorization. Of 10 probable/definite AE/LE/ADEM, one had a malignancy and none of them received an alternative diagnosis until the end of follow-up (median 18 months). In total, 80% (8/10) of patients received immunotherapy including corticosteroids, and 6/10 (60%) patients received rituximab, azathioprine, cyclophosphamide, plasma exchange, or IV immunoglobulins. Five (50%) patients improved, one (10%) stabilized, one (10%) worsened, and 3 (30%) died. All deaths were considered to be related to encephalitis. We did not observe differences of immunotherapy-treated patients in likelihood of improvement with or without nonsteroidal immunotherapy (with 2/6, without 1/2). DISCUSSION: Antibody-negative AE should be diagnosed only after comprehensive testing. Diagnostic effort is important because many patients benefit from immunotherapy and some have malignancies.
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Leypoldt F, Wandinger KP, Bien CG, Dalmau J. Autoimmune encephalitis. Autoimmune encephalitis. Eur Neurol Rev. 2012;8:31-37. PubMed PMC
Dubey D, Pittock SJ, Kelly CR, et al. . Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol. 2018;83(1):166-177. doi:10.1002/ana.25131 PubMed DOI PMC
Titulaer MJ, McCracken L, Gabilondo I, et al. . Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157-165. doi:10.1016/s1474-4422(12)70310-1 PubMed DOI PMC
Gadoth A, Pittock SJ, Dubey D, et al. . Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG-positive patients: LGI1/CASPR2-IgG + patients. Ann Neurol. 2017;82(1):79-92. doi:10.1002/ana.24979 PubMed DOI
Thaler FS, Zimmermann L, Kammermeier S, et al. . Rituximab treatment and long-term outcome of patients with autoimmune encephalitis: real-world evidence from the GENERATE registry. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1088. doi:10.1212/nxi.0000000000001088 PubMed DOI PMC
Wickel J, Chung H-Y, Platzer S, et al. . Generate-Boost: study protocol for a prospective, multicenter, randomized controlled, double-blinded phase II trial to evaluate efficacy and safety of bortezomib in patients with severe autoimmune encephalitis. Trials. 2020;21(1):625. doi:10.1186/s13063-020-04516-7 PubMed DOI PMC
Blackburn KM, Denney DA, Hopkins SC, Vernino SA. Low recruitment in a double-blind, placebo-controlled trial of ocrelizumab for autoimmune encephalitis: a case series and review of lessons learned. Neurol Ther. 2022;11(2):893-903. doi:10.1007/s40120-022-00327-x PubMed DOI PMC
Dogan Onugoren M, Golombeck KS, Bien C, et al. . Immunoadsorption therapy in autoimmune encephalitides. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e207. doi:10.1212/nxi.0000000000000207 PubMed DOI PMC
Flanagan EP, Geschwind MD, Lopez-Chiriboga AS, et al. . Autoimmune encephalitis misdiagnosis in adults. JAMA Neurol. 2023:80(1):30-39. PubMed PMC
Abboud H, Probasco J, Irani SR, et al. . Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry. 2021;92(8):897-907. doi:10.1136/jnnp-2020-325302 PubMed DOI PMC
von Rhein B, Wagner J, Widman G, Malter MP, Elger CE, Helmstaedter C. Suspected antibody negative autoimmune limbic encephalitis: outcome of immunotherapy. Acta Neurol Scand. 2016;135(1):134-141. doi:10.1111/ane.12575 PubMed DOI
Hacohen Y, Wright S, Waters P, et al. . Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens. J Neurol Neurosurg Psychiatry. 2013;84(7):748-755. doi:10.1136/jnnp-2012-303807 PubMed DOI PMC
Ahmad SAB, Archer HA, Rice CM, Gerhand S, Bradley M, Wilkins A. Seronegative limbic encephalitis: case report, literature review and proposed treatment algorithm. Pract Neurol. 2011;11(6):355-361. doi:10.1136/practneurol-2011-000084 PubMed DOI
Karaaslan Z, Mercan Ö, Tüzün E, Mısırlı H, Türkoğlu R. A Case of seronegative limbic encephalitis with multiple sclerosis: a possible overlapping syndrome. Am J Case Rep. 2017;18:64-66. doi:10.12659/ajcr.901391 PubMed DOI PMC
Storey K, Matěj R, Rusina R. Unusual association of seronegative, nonparaneoplastic limbic encephalitis and relapsing polychondritis in a patient with history of thymectomy for myasthenia: a case study. J Neurol. 2011;258(1):159-161. doi:10.1007/s00415-010-5691-4 PubMed DOI
Sequeira C, Lopes P. Antibody negative autoimmune encephalitis: a case report. Acta Médica Portuguesa. 2021;34(5):378-382. doi:10.20344/amp.13793 PubMed DOI
Najjar S, Pearlman D, Zagzag D, Devinsky O. Spontaneously resolving seronegative autoimmune limbic encephalitis. Cogn Behav Neurol. 2011;24(2):99-105. doi:10.1097/wnn.0b013e3182248193 PubMed DOI
Graus F, Escudero D, Oleaga L, et al. . Syndrome and outcome of antibody‐negative limbic encephalitis. Eur J Neurol. 2018;25(8):1011-1016. doi:10.1111/ene.13661 PubMed DOI PMC
Lee W-J, Lee H-S, Kim D-Y, et al. . Seronegative autoimmune encephalitis: clinical characteristics and factors associated with outcomes. Brain. 2022;145(10):3509-3521. doi:10.1093/brain/awac166 PubMed DOI
Orozco E, Valencia-Sanchez C, Britton J, et al. . Autoimmune encephalitis criteria in clinical practice. Neurol Clin Pract. 2023;13(3):e200151. doi:10.1212/cpj.0000000000200151 PubMed DOI PMC
Cellucci T, Van Mater H, Graus F, et al. . Clinical approach to the diagnosis of autoimmune encephalitis in the pediatric patient. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e663. doi:10.1212/nxi.0000000000000663 PubMed DOI PMC
Graus F, Titulaer MJ, Balu R, et al. . A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404. doi:10.1016/s1474-4422(15)00401-9 PubMed DOI PMC
Balu R, McCracken L, Lancaster E, Graus F, Dalmau J, Titulaer MJ. A score that predicts 1-year functional status in patients with anti-NMDA receptor encephalitis. Neurology. 2019;92(3):e244-e252. doi:10.1212/wnl.0000000000006783 PubMed DOI PMC
Lim J, Lee S, Moon J, et al. . Development of the clinical assessment scale in autoimmune encephalitis. Ann Neurol. 2019;85(3):352-358. doi:10.1002/ana.25421 PubMed DOI
Graus F, Delattre JY, Antoine JC, et al. . Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75(8):1135-1140. doi:10.1136/jnnp.2003.034447 PubMed DOI PMC
Ances BM, Vitaliani R, Taylor RA, et al. . Treatment-responsive limbic encephalitis identified by neuropil antibodies: MRI and PET correlates. Brain. 2005;128(8):1764-1777. doi:10.1093/brain/awh526 PubMed DOI PMC
Déchelotte B, Muñiz-Castrillo S, Joubert B, et al. . Diagnostic yield of commercial immunodots to diagnose paraneoplastic neurologic syndromes. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e701. doi:10.1212/nxi.0000000000000701 PubMed DOI PMC
Höftberger R, Sepulveda M, Armangue T, et al. . Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler J. 2014;21(7):866-874. doi:10.1177/1352458514555785 PubMed DOI PMC
Lancaster E, Lai M, Peng X, et al. . Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9(1):67-76. doi:10.1016/s1474-4422(09)70324-2 PubMed DOI PMC
van Coevorden-Hameete MH, Titulaer MJ, Schreurs MWJ, de Graaff E, Sillevis Smitt PAE, Hoogenraad CC. Detection and characterization of autoantibodies to neuronal cell-surface antigens in the central nervous system. Front Mol Neurosci. 2016;9:37. doi:10.3389/fnmol.2016.00037 PubMed DOI PMC
Reindl M, Schanda K, Woodhall M, et al. . International multicenter examination of MOG antibody assays. Neurol Neuroimmunol Neuroinflamm. 2020;7(2):e674. doi:10.1212/nxi.0000000000000674 PubMed DOI PMC
Titulaer MJ, Höftberger R, Iizuka T, et al. . Overlapping demyelinating syndromes and anti–N‐methyl‐D‐aspartate receptor encephalitis. Ann Neurol. 2014;75(3):411-428. doi:10.1002/ana.24117 PubMed DOI PMC
Valencia Sanchez C, Theel E, Binnicker M, Toledano M, McKeon A. Autoimmune encephalitis after SARS-CoV-2 infection: case frequency, findings, and outcomes. Neurology. 2021;97(23):e2262-e2268. doi:10.1212/wnl.0000000000012931 PubMed DOI PMC
Dalmau J, Graus F, Rosenblum Mk, Posner JB. Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy a clinical study of 71 patients. Medicine. 1992;71(2):59-72. doi:10.1097/00005792-199203000-00001 PubMed DOI
Park S-H, Kim Y-C. Case report: the use of rituximab in antibody-negative autoimmune encephalitis. Front Neurol. 2021;12:686009. doi:10.3389/fneur.2021.686009 PubMed DOI PMC
Lee S, Kim HD, Lee JS, Kang H-C, Kim SH. Clinical features and treatment outcomes of seronegative pediatric autoimmune encephalitis. J Clin Neurol. 2021;17(2):300-306. doi:10.3988/jcn.2021.17.2.300 PubMed DOI PMC
Singh V, Zhao C, Gupta V, Chu Y. Combination checkpoint inhibitor-induced antibody negative autoimmune encephalitis in non-small cell lung cancer. Neurol India. 2021;69(1):222. doi:10.4103/0028-3886.310070 PubMed DOI
Maniscalco GT, Manzo V, Napolitano M, et al. . Autoimmune encephalitis: a retrospective monocentric experience. Mult Scler Relat Disord. 2021;55:103191. doi:10.1016/j.msard.2021.103191 PubMed DOI
Abboud H, Probasco JC, Irani S, et al. . Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry. 2021;92(7):757-768. doi:10.1136/jnnp-2020-325300 PubMed DOI PMC
