Identification of Medium-Length Antineurofilament Autoantibodies in Patients with Anti-N-Methyl-D-Aspartate Receptor Encephalitis

다국어 초록 (Multilingual Abstract)

Background and Purpose Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe central nervous system disorder mediated by NMDAR antibodies that damages neurons.
We investigated the correlation between cytoskeletal autoantibodies and the clinical severity in patients with anti-NMDAR encephalitis.
Methods Non-NMDAR autoantibodies were identified by screening matched cerebrospinal fluid (CSF) and the serum samples of 45 consecutive patients with anti-NMDAR encephalitis and 60 healthy individuals against N-methyl-D-aspartate receptor 1-transfected and nontransfected human embryonic kidney 293T cells. Immunocytochemistry was performed to assess antibody binding in rat brain sections and primary cortical neurons. Cell-based assays and Western blotting were applied to identify autoantibodies targeting medium neurofilaments (NFMs). We compared clinical characteristics between patients with NMDAR encephalitis who were positive and negative for anti-NFM-autoantibodies.
Results Anti-NFM autoantibodies were detected in both the serum and CSF in one patient (2%) and in the serum only in six patients (13%). No antibodies were detected in the serum of healthy controls (7/45 vs. 0/60, p=0.0016). Four of the seven patients with anti-NFM autoantibodies in serum were children (57%), and three (43%) had abnormalities in brain magnetic resonance imaging. These patients responded well to immunotherapy, and either no significant or only mild disability was observed at the last follow-up. Anti-NMDAR encephalitis did not differ with the presence of anti-NFM autoantibodies.
Conclusions Anti-NFM autoantibodies may be present in patients with anti-NMDAR encephalitis, indicating underlying neuronal damage. A large cohort study is warranted to investigate the clinical differences between patients with NMDAR encephalitis according to their anti- NFM antibody status.

참고문헌 (Reference)

1 Mariotto S, "Serum neurofilament light chain in NMOSD and related disorders : comparison according to aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies status" 3 : 2055217317743098-, 2017

2 Disanto G, "Serum neurofilament light : a biomarker of neuronal damage in multiple sclerosis" 81 : 857-870, 2017

3 Barro C, "Serum neurofilament as a predictor of disease worsening and brain and spinal cord atrophy in multiple sclerosis" 141 : 2382-2391, 2018

4 Shu Y, "Serum complement levels in anti-N-methyl-d-aspartate receptor encephalitis" 25 : 178-184, 2018

5 Piehl F, "Plasma neurofilament light chain levels in patients with MS switching from injectable therapies to fingolimod" 24 : 1046-1054, 2018

6 Fiumelli H, "Phosphorylation of neurofilament subunit NF-M is regulated by activation of NMDA receptors and modulates cytoskeleton stability and neuronal shape" 65 : 495-504, 2008

7 Dalmau J, "Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma" 61 : 25-36, 2007

8 Al-Chalabi A, "Neurofilaments and neurological disease" 25 : 346-355, 2003

9 Kim OJ, "Neurofilament-M interacts with the D1 dopamine receptor to regulate cell surface expression and desensitization" 22 : 5920-5930, 2002

10 Martínez-Morillo E, "Neurofilament medium polypeptide(NFM)protein concentration is increased in CSF and serum samples from patients with brain injury" 53 : 1575-1584, 2015

11 Yilmaz A, "Neurofilament light chain protein as a marker of neuronal injury : review of its use in HIV-1 infection and reference values for HIVnegative controls" 17 : 761-770, 2017

12 Bacioglu M, "Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases" 91 : 56-66, 2016

13 Matute-Blanch C, "Neurofilament light chain and oligoclonal bands are prognostic biomarkers in radiologically isolated syndrome" 141 : 1085-1093, 2018

14 Bartos A, "Lower serum antibodies against tau protein and heavy neurofilament in Alzheimer’s disease" 64 : 751-760, 2018

15 van Swieten JC, "Interobserver agreement for the assessment of handicap in stroke patients" 19 : 604-607, 1988

16 Kreye J, "Human cerebrospinal fluid monoclonal N-methyl-D-aspartate receptor autoantibodies are sufficient for encephalitis pathogenesis" 139 : 2641-2652, 2016

17 Flanagan EP, "Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy : analysis of 102 patients" 81 : 298-309, 2017

18 Bartos A, "Elevated intrathecal antibodies against the medium neurofilament subunit in multiple sclerosis" 254 : 20-25, 2007

19 Liem RK, "Dysfunctions of neuronal and glial intermediate filaments in disease" 119 : 1814-1824, 2009

20 Dalmau J, "Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis" 10 : 63-74, 2011

21 Hughes EG, "Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis" 30 : 5866-5875, 2010

22 Granerod J, "Causes of encephalitis and differences in their clinical presentations in England : a multicentre, population-based prospective study" 10 : 835-844, 2010

23 Körtvelyessy P, "Biomarkers of neurodegeneration in autoimmune-mediated encephalitis" 9 : 668-, 2018

24 Fang B, "Autoimmune glial fibrillary acidic protein astrocytopathy : a novel meningoencephalomyelitis" 73 : 1297-1307, 2016

25 Wandinger KP, "AntiNMDA-receptor encephalitis : a severe, multistage, treatable disorder presenting with psychosis" 231 : 86-91, 2011

26 Dalmau J, "Anti-NMDA-receptor encephalitis : case series and analysis of the effects of antibodies" 7 : 1091-1098, 2008

27 Chapman MR, "Anti-NMDA receptor encephalitis : diagnosis, psychiatric presentation, and treatment" 168 : 245-251, 2011

28 Loughan AR, "Anti-N-methyl-D-aspartate receptor encephalitis : a review and neuropsychological case study" 30 : 150-163, 2016

29 Oron L, "Animal model and in vitro studies of anti neurofilament antibodies mediated neurodegeneration in Alzheimer’s disease" 49 : 77-84, 1997

30 Zhou J, "An unusual case of anti-MOG CNS demyelination with concomitant mild anti-NMDAR encephalitis" 320 : 107-110, 2018

31 Graus F, "A clinical approach to diagnosis of autoimmune encephalitis" 15 : 391-404, 2016