Anti-NMDAR Antibodies in Demyelinating Diseases

Česká verzia

Authors: M. Elišák ¹; E. Meluzínová ¹; J. Hanzalová ^1,2; P. Lišková ¹; D. Krýsl ³; I. Doležalová ⁴; I. Štětkářová ⁵; P. Marusič ¹
Authors place of work: Neurologická klinika 2. LF UK a FN Motol, Praha ¹; Ústav imunologie, 2. LF UK a FN Motol, Praha ²; Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden ³; 1. neurologická klinika LF MU a FN u sv. Anny v Brně ⁴; Neurologická klinika 3. LF UK a FN Královské Vinohrady, Praha ⁵
Published in the journal: Cesk Slov Neurol N 2017; 80/113(3): 332-335
Category: Short Communication
doi: https://doi.org/10.14735/amcsnn2017332

Summary

Introduction:
Antibodies against N-methyl D-aspartate receptor (anti-NMDAR) are directly pathogenic autoantibodies associated with encephalitis. Cases reporting the presence of anti-NMDAR antibodies associated with a demyelinating disease have been published, some without symptoms of NMDAR encephalitis. The aim of our study was to describe characteristics of a demyelinating disease in patients with anti-NMDAR antibodies.

Material and methods:
Anti-NMDAR antibodies were investigated in the serum and cerebrospinal fluid of patients with clinically suspected autoimmune encephalitis by indirect immunofluorescence using cell-based assay on fixed cells transfected for the antigen. The clinical course and MRI findings consistent with a demyelinating disease were assessed in accordance with the current diagnostic criteria.

Results:
Eleven patients with autoimmune encephalitis and positive anti-NMDAR were identified between 2012 to 2015. Ten of them met criteria of NMDAR encephalitis, one patient had an acute onset (de novo status epilepticus) with MRI and CSF findings corresponding with acute disseminated encephalomyelitis and regression following corticosteroid treatment. Subsequently, due to MRI dynamics, this patient met the criteria of multiple sclerosis. One patient with NMDAR encephalitis developed an optic neuritis 20 months later and MRI showed demyelinating changes with dissemination in time and space. Following corticosteroid and azathioprine treatment, the patient is clinically stable but with persisting MRI disease activity. In both patients, demyelinating lesions were also identified in the spinal cord.

Conclusion:
In patients with an atypical manifestation of a demyelinating disease (prominent psychiatric or cognitive symptoms, seizures or extrapyramidal signs) anti-NMDAR testing should be performed and an appropriate immunotherapy should be started in positive cases. In some patients, NMDAR encephalitis may result in an onset of a demyelinating disease.

Key words:
demyelinating disease – anti-NMDAR

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Chinese summary - 摘要

抗NMDAR抗体在脱髓鞘疾病中的应用

介绍：

针对N-甲基D-天门冬氨酸受体（抗NMDAR）的抗体是与脑炎症相关的直接致病性自身抗体。报告了与脱髓鞘疾病相关的抗NMDAR抗体的存在的病例已经出版，一些没有NMDAR脑炎的症状。我们研究的目的是描述抗NMDAR抗体患者脱髓鞘疾病的特征。

材料和方法：

通过间接免疫荧光法检测临床疑似自身免疫性脑炎患者的血清和脑脊液中的抗NMDAR抗体，使用基于细胞的测定法将固定的细胞转染入抗原。根据目前的诊断标准评估与脱髓鞘疾病一致的临床过程和MRI结果。

结果：

在2012年至2015年期间，确定了11例自身免疫性脑炎和阳性抗NMDAR患者。其中10例符合NMDAR脑炎症标准，其中1例发生急性发作（从头状癫痫），MRI和CSF发现与急性播散性脑脊髓炎和回归皮质类固醇治疗后。随后，由于MRI动力学，该患者符合多发性硬化症的标准。一名NMDAR脑炎患者20个月后出现视神经炎症，MRI显示随着时间和空间传播的脱髓鞘变化。在皮质类固醇和硫唑嘌呤治疗后，患者临床稳定但持续存在MRI疾病活动。在两名患者中，脊髓中也鉴定出脱髓鞘病变。

结论：

在具有脱髓鞘疾病（突出的精神病或认知症状，癫痫发作或锥体外系征象）的非典型表现的患者中，应进行抗NMDAR检测，并在阳性情况下开始适当的免疫治疗。在一些患者中，NMDAR脑炎可能导致脱髓鞘疾病的发作。

关键词：

脱髓鞘疾病 - 抗NMDAR

Zdroje

1. Ekizoglu E, Tuzun E, Woodhall M, et al. Investigation of neuronal autoantibodies in two different focal epilepsy syndromes. Epilepsia 2014;55(3):414– 22. doi: 10.1111/ epi.12528.

2. Kayser MS, Titulaer MJ, Gresa-Arribas N, et al. Frequency and characteristics of isolated psychiatric episodes in anti– N-methyl-d-aspartate receptor encephalitis. JAMA Neurol 2013;70(9):1133– 9.

3. Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/ B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren‘s syndrome, schizophrenia, mania or stroke. These autoimmune anti-glutamate receptor antibodies can bind neurons in few brain regions, activate glutamate receptors, decrease glutamate receptor‘s expression, impair glutamate-induced signaling and function, activate blood brain barrier endothelial cells, kill neurons, damage the brain, induce behavioral/ psychiatric/ cognitive abnormalities and ataxia in animal models, and can be removed or silenced in some patients by immunotherapy. J Neural Transm (Vienna) 2014;121(8):1029– 75. doi: 10.1007/ s00702-014-1193-3.

4. 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– 28.

5. Lekoubou A, Viaccoz A, Didelot A, et al. Anti-N-metyl-D-aspartate receptor encephalitis with acute disseminated encephalomyelitis-like MRI features. Eur J Neurol 2012;19(2):e16– 7. doi: 10.1111/ j.1468-1331.2011.03617.x.

6. 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.

7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 2011;69(2):292– 302. doi: 10.1002/ ana.22366.

8. Wingerchuk DM, Banwell B, Bennett JL, et al; International Panel for NMO Diagnosis. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85(2):177– 89. doi: 10.1212/ WNL.0000000000001729.

9. Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133(6):1655– 67. doi: 10.1093/ brain/ awq113.

10. Kruer MC, Koch TK, Bourdette DN, et al. NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. Neurology 2010;74(18):1473– 5. doi: 10.1212/ WNL.0b013e3181dc1a7f.

11. Pennington C, Livingstone S, Santosh C, et al. N-methyl D-aspartate receptor antibody encephalitis associated with myelitis. J Neurol Sci 2012;317(1– 2):151– 3. doi: 10.1016/ j.jns.2012.02.034.

12. Fleischmann R, Prüss H, Rosche B, et al. Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis. JAMA Neurol 2015;72(1):96– 9. doi: 10.1001/ jamaneurol.2014.1817.

13. Ramberger M, Bsteh G, Schanda K, et al. NMDA receptor antibodies: a rare association in inflammatory demyelinating diseases. Neurol Neuroimmunol Neuroinflamm 2015;2(5):e141. doi: 10.1212/ NXI.0000000000000141.

14. Spadaro M, Gerdes LA, Krumbholz M, et al. Autoantibodies to MOG in a distinct subgroup of adult multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016;3(5):e257. doi: 10.1212/ NXI.0000000000000257.

15. Kim SH, Kim W, Li XF, et al. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Mult Scler 2012;18(10):1480– 3.

16. Sørensen PS, Fazekas F, Lee M. Intravenous immunoglobulin G or the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 2002;9(6):557– 63.

17. 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– 65. doi: 10.1016/ S1474-4422(12)70310-1.