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Figure.
Identification of Antibodies (Ab) to the Glycine Receptor α1 Subunit (GlyR) Concurrent With Aquaporin 4 (AQP4) Ab or Myelin-Oligodendrocyte Glycoprotein (MOG) Antibodies
Identification of Antibodies (Ab) to the Glycine Receptor α1 Subunit (GlyR) Concurrent With Aquaporin 4 (AQP4) Ab or Myelin-Oligodendrocyte Glycoprotein (MOG) Antibodies

We transfected HEK293 cells with GlyR (row 1), the full-length MOG C-terminal fused to enhanced green fluorescent protein (EGFP; row 2), and the AQP4-M23 isoform (row 3). Column 1 shows the serum immunostaining; column 2, commercial Abs to GlyR and AQP4 in red and MOG-EGFP–expressing cells in green; and column 3, merged reactivities and the nuclei of the cells revealed with 4',6-diamidino-2-phenylindole (DAPI). A, Serum from patient 1 shows reactivity with GlyR- and MOG-transfected cells (rows 1 and 2) but not with AQP4-transfected cells (row 3). B, Serum from patient 5 shows reactivity with GlyR- and AQP4-transfected cells (rows 1 and 3) but not with MOG-transfected cells (row 2). C, In contrast, serum from a control individual yields negative findings on all 3 transfected cells (rows 1-3).

Table 1.  
Clinical Comparison of Patients With ON Based on Antibody Status
Clinical Comparison of Patients With ON Based on Antibody Status
Table 2.  
Clinical Features of Patients With Antibodies
Clinical Features of Patients With Antibodies
1.
Pirko  I, Blauwet  LA, Lesnick  TG, Weinshenker  BG.  The natural history of recurrent optic neuritis. Arch Neurol. 2004;61(9):1401-1405.
PubMedArticle
2.
Toosy  AT, Mason  DF, Miller  DH.  Optic neuritis. Lancet Neurol. 2014;13(1):83-99.
PubMedArticle
3.
Matiello  M, Lennon  VA, Jacob  A,  et al.  NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology. 2008;70(23):2197-2200.
PubMedArticle
4.
Reindl  M, Di Pauli  F, Rostásy  K, Berger  T.  The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol. 2013;9(8):455-461.
PubMedArticle
5.
Sato  DK, Callegaro  D, Lana-Peixoto  MA,  et al.  Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82(6):474-481.
PubMedArticle
6.
Kitley  J, Waters  P, Woodhall  M,  et al.  Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283.
PubMedArticle
7.
McKeon  A, Martinez-Hernandez  E, Lancaster  E,  et al.  Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol. 2013;70(1):44-50.
PubMedArticle
8.
Carvajal-González  A, Leite  MI, Waters  P,  et al.  Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137(pt 8):2178-2192.
PubMedArticle
9.
Polman  CH, Reingold  SC, Edan  G,  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Ann Neurol. 2005;58(6):840-846.
PubMedArticle
10.
Pittock  SJ, Weinshenker  BG, Lucchinetti  CF, Wingerchuk  DM, Corboy  JR, Lennon  VA.  Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
PubMedArticle
11.
Krupp  LB, Banwell  B, Tenembaum  S; International Pediatric MS Study Group.  Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology. 2007;68(16)(suppl 2):S7-S12.
PubMedArticle
12.
Wingerchuk  DM, Lennon  VA, Pittock  SJ, Lucchinetti  CF, Weinshenker  BG.  Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489.
PubMedArticle
13.
Dalmau  J, Tüzün  E, Wu  HY,  et al.  Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):25-36.
PubMedArticle
14.
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.
PubMedArticle
15.
Rostásy  K, Mader  S, Hennes  EM,  et al.  Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica. Mult Scler. 2013;19(8):1052-1059.
PubMedArticle
16.
Banwell  B, Tenembaum  S, Lennon  VA,  et al.  Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology. 2008;70(5):344-352.
PubMedArticle
17.
McKeon  A, Lennon  VA, Lotze  T,  et al.  CNS aquaporin-4 autoimmunity in children. Neurology. 2008;71(2):93-100.
PubMedArticle
18.
Woodhall  M, Çoban  A, Waters  P,  et al.  Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci. 2013;335(1-2):221-223.
PubMedArticle
19.
Hacohen  Y, Absoud  M, Woodhall  M,  et al; UK & Ireland Childhood CNS Inflammatory Demyelination Working Group.  Autoantibody biomarkers in childhood-acquired demyelinating syndromes: results from a national surveillance cohort. J Neurol Neurosurg Psychiatry. 2014;85(4):456-461.
PubMedArticle
20.
Ariño  H, Gresa-Arribas  N, Blanco  Y,  et al.  Cerebellar ataxia and glutamic acid decarboxylase antibodies: immunologic profile and long-term effect of immunotherapy. JAMA Neurol. 2014;71(8):1009-1016.
PubMedArticle
Original Investigation
February 2015

Antibodies to Aquaporin 4, Myelin-Oligodendrocyte Glycoprotein, and the Glycine Receptor α1 Subunit in Patients With Isolated Optic Neuritis

Author Affiliations
  • 1Department of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain
  • 2Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  • 3Division of Pediatric Neurology, Department of Pediatrics IV, Innsbruck Medical University, Innsbruck, Austria
  • 4Pediatric Neurology, Children’s Hospital Datteln, Witten/Herdecke University, Witten, Germany
  • 5Institute of Neurology, Medical University of Vienna, Vienna, Austria
  • 6Department of Pharmacology, UCL School of Pharmacy, London, England
  • 7Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
JAMA Neurol. 2015;72(2):187-193. doi:10.1001/jamaneurol.2014.3602
Abstract

Importance  In patients with isolated optic neuritis (ON), the presence of antibodies to aquaporin 4 (AQP4) has diagnostic and prognostic value. In the same clinical setting, the significance of antibodies to myelin-oligodendrocyte glycoprotein (MOG) or the glycine receptor α1 subunit (GlyR) is unclear.

Objectives  To investigate the frequency of antibodies to AQP4, MOG, and GlyR in patients with unilateral or bilateral, severe, or recurrent isolated ON and to determine their clinical and prognostic correlates.

Design, Setting, and Participants  Retrospective case-control study from November 1, 2005, through May 30, 2014 with the detection of autoantibodies in a neuroimmunology referral center. We included 51 patients with ON but without clinical and magnetic resonance imaging findings outside the optic nerves and 142 controls (30 healthy individuals, 48 patients with neuromyelitis optica, and 64 patients with multiple sclerosis).

Main Outcomes and Measures  Clinicoimmunologic analysis. We determined the presence of antibodies to AQP4, MOG, and GlyR using cell-based assays.

Results  The median age of the patients at the onset of ON symptoms was 28 (range, 5-65) years; 36 patients (71%) were female. Antibodies were identified in 23 patients (45%), including MOG in 10 patients, AQP4 in 6 patients, and GlyR in 7 patients (concurrent with MOG in 3 and concurrent with AQP4 in 1). Patients with AQP4 antibodies (median visual score, 3.5 [range, 1-9]) had a worse visual outcome than patients with MOG antibodies alone (median visual score, 0 [range, 0-5]; P = .007), patients with seronegative findings (n = 28) (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies alone (n = 3) (median visual score, 0 [range, 0-2]; P = .10).The median age of the 7 patients with GlyR antibodies was 27 (range, 11-38) years; 5 (71%) of these were female. Among the 3 patients with GlyR antibodies alone, 1 patient had monophasic ON, 1 had recurrent isolated ON, and 1 had conversion to multiple sclerosis. The 3 patients with GlyR antibodies concurrent with MOG antibodies had recurrent isolated ON, and the patient with concurrent AQP4 antibodies had conversion to neuromyelitis optica. Of the 48 controls with neuromyelitis optica, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. Of the 64 controls with multiple sclerosis, 5 (8%) had GlyR antibodies.

Conclusions and Relevance  Forty-five percent of patients with unilateral or bilateral, severe, or recurrent isolated ON had antibodies to MOG, AQP4, or GlyR. Patients with AQP4 antibodies had the poorest visual outcomes, whereas patients with MOG antibodies had a better outcome that was similar to that of patients with seronegative findings. The significance of GlyR antibodies in the setting of ON is unclear and deserves further study.

Introduction

Optic neuritis (ON) is often the presenting symptom of multiple sclerosis (MS) or neuromyelitis optica (NMO).1 However, after extensive diagnostic workup and prolonged follow-up, some patients are diagnosed as having idiopathic monophasic or recurrent isolated ON.2 The presence of autoantibodies may help to differentiate these disorders. As many as 20% of patients with recurrent ON have antibodies to aquaporin 4 (AQP4), and their presence conveys the risk for developing transverse myelitis and a poor outcome.3 A subset of patients with NMO or suspected limited forms (including ON) without AQP4 antibodies have antibodies to myelin-oligodendrocyte glycoprotein (MOG).4 Patients with MOG antibodies seem to have a better outcome than those with AQP4 antibodies.5,6

In a previous study examining the presence of antibodies to the glycine receptor α1 subunit (GlyR) in patients with stiff person syndrome, McKeon and colleagues7 found among 100 control individuals a patient with a 2-year history of visual deficits (visual acuity [VA], 20/400) and bilateral optic atrophy in association with GlyR antibodies. Despite the prolonged duration of symptoms, the VA improved after a trial of corticosteroids (20/100 OD and 20/150 OS).7 Since then, several of us (E.M.-H., M.S., and A.S.) have seen another patient with bilateral progressive inflammatory optic neuropathy and GlyR antibodies, and similar observations have been made by other investigators.8 These findings suggested that GlyR antibodies may be associated with ON as relevant pathogenically related antibodies or as an epiphenomenon. We report herein our experience with 51 patients who presented with unilateral or bilateral, severe, or recurrent isolated ON, a clinical profile that is usually suspected of being related to AQP4 antibodies.1,3 We tested serum or cerebrospinal fluid (CSF) samples from each patient systematically for all 3 antibodies (AQP4, MOG, and GlyR), with the goal of determining their frequency and the clinical and prognostic correlates.

Methods
Patients and Samples

We obtained written informed consent for this study from all patients, and the study was approved by the review board of the Hospital Clínic, University of Barcelona, Barcelona, Spain. We included patients with the following criteria: (1) new onset of unilateral or bilateral, severe (VA, worse than 20/200), or recurrent ON, suspected to be of demyelinating origin, treated by the authors or with serum or CSF samples sent to our laboratory from November 1, 2005, through May 30, 2014, for antibody studies; (2) absence of central nervous system abnormalities outside the optic nerves and normal or nonspecific abnormal magnetic resonance imaging findings that did not fulfill criteria for MS,9 NMO,10 or acute disseminated encephalomyelitis11 at the time the patient or the samples underwent initial assessment; and (3) adequate clinical information with a follow-up of at least 12 months.

Visual acuity was assessed using an ordinal scale as previously reported1,3 on which 0 indicates normal; 1, scotoma but with a VA better than 20/30; 2, a VA of 20/30 to 20/59; 3, a VA of 20/60 to 20/199; 4, a VA of 20/200 to 20/800; 5, counting fingers; 6, light perception only; and 7, no light perception. The final visual outcome was the sum of the last assigned visual score for each eye.

Overall, we included 51 patients with isolated ON (36 adults and 15 children). Serum samples were available from all 51 patients, and CSF samples were available from 4 patients. Control samples included serum from 30 healthy individuals, 48 patients with definite NMO according to the criteria of Wingerchuk et al,12 and 64 patients (including 8 children) with definite MS9 (at the time of sample collection, the clinical phenotypes included clinically isolated syndrome [n = 28], relapsing remitting [n = 17], secondary progressive [n = 9], and primary progressive [n = 10]).

Cell-Based Assays

For the detection of GlyR antibodies, we used a live cell–based assay. In brief, HEK293 cells were transfected with a plasmid (pRK5) containing the human GlyR α1 subunit complementary DNA, as reported.13 The next day, cells were incubated with patients’ serum samples (diluted 1:40 in growth medium containing culture medium [Dulbecco Modified Eagle Medium; Life Technologies], 5% fetal bovine serum, 5% horse serum, 1% penicillin-streptomycin, 1% glutamate, and 1% sodium pyruvate) or patients’ CSF samples (diluted 1:5) for 1 hour at 37°C. After being fixed and permeabilized for 5 minutes (4% paraformaldehyde and 0.3% Triton X-100 [polyethylene glycol tert-octylphenyl ether; Sigma-Aldrich]), the cells were serially incubated with a monoclonal mouse antibody recognizing the GlyR α1 subunit (mAb4a, diluted 1:1000 in 1% bovine serum albumin; Synaptic Systems) for 1 hour at room temperature, followed by the secondary goat antihuman and goat antimouse antibodies (A11013 [Alexa Fluor 488] and A11005 [Alexa Fluor 594]; Molecular Probes/Life Technologies], each diluted 1:1000 in 1% bovine serum albumin). Coverslips were then applied with mounting medium (Vectashield H-1200; Vector Laboratories) and examined under a fluorescence microscope using a commercially available imaging system (Axiovision; Zeiss). All positive samples and 11 randomly selected negative samples underwent similar testing with live cells at room temperature and at 4°C to determine whether changes in the temperature of incubation modified the immunostaining results.

Antibodies to AQP4 and MOG were similarly examined using live HEK293 cells transfected with the AQP4-M23 isoform or the full-length MOG C-terminal fused to enhanced green fluorescent protein, as reported.14 For detection of AQP4 antibodies, serum samples were used at a dilution of 1:20; and for MOG antibodies, 1:160. Cerebrospinal fluid samples were used at a dilution of 1:2. The titer of GlyR and MOG antibodies was obtained by serial dilutions of samples until the reactivity was no longer visible.

Results
Demographics and General Clinical Features

The median age of the patients at symptom onset was 28 (range, 5-65) years; 36 patients (71%) were female. The initial episode was severe unilateral ON in 13 patients (25%), severe bilateral ON in 14 patients (27%), nonsevere bilateral ON in 8 patients (16%), and nonsevere unilateral in 16 (31%). The findings of magnetic resonance imaging of the brain at symptom onset were normal in 36 patients (71%) and had nonspecific abnormalities in 15 patients (29%). The CSF studies available in 37 patients showed CSF-specific IgG oligoclonal bands in 3 (8%). Long-term immunosuppressive therapy with azathioprine, prednisone, or rituximab was administered only in adults (14 of 36 [39%]).

At the last follow-up (median, 33.5 months; interquartile range, 22-68 months), 43 patients retained the diagnosis of idiopathic isolated ON (monophasic in 17 [40%] and recurrent in 26 [60%]), 1 patient had conversion to MS (magnetic resonance imaging criteria of dissemination in space and time9 and 2 relapses of ON), and 7 patients had conversion to NMO or NMO spectrum disorder. Of these 7 patients, 3 had recurrent ON, 2 had episodes of transverse myelitis,12 1 had an episode of brainstem dysfunction, and 1 had bilateral and severe monophasic ON.

Antibody Findings

Serum antibodies were detected in 23 patients (45%). Of these, 10 patients had MOG antibodies, 6 patients had AQP4 antibodies, and 7 patients had GlyR antibodies (3 with concurrent MOG antibodies and 1 with concurrent AQP4 antibodies) (Figure). The change of temperature during the incubation with patients’ samples did not modify the results. Paired serum and CSF samples were available from 4 patients, of whom 1 had MOG antibodies in serum and CSF and 1 had concurrent MOG and GlyR antibodies only in serum. In the remaining 2 patients, both samples were negative.

Among the 48 controls with NMO, 37 (77%) had AQP4 antibodies, 4 (8%) had MOG antibodies, 2 (4%) had AQP4 antibodies concurrent with MOG antibodies, and 5 (10%) were seronegative. None of the controls with NMO had GlyR antibodies. Among the 64 controls with MS, 5 (8%) had GlyR antibodies, including 3 with relapsing remitting MS, 1 with a clinically isolated syndrome of myelitis, and 1 with primary progressive MS. The CSF samples of 4 of these 5 patients were available for study, and all were negative for GlyR antibodies. All controls with MS were negative for AQP4 and MOG antibodies. None of the 30 healthy individuals had detectable antibodies.

Clinicoimmunologic Correlates

The 4 patients with 2 antibodies were excluded from the analysis, and we compared the seronegative patients (n = 28), the patients with MOG antibodies only (n = 10), those with APQ4 antibodies only (n = 6), and those with GlyR antibodies only (n = 3) (Table 1). The only significant differences found among subgroups were the final visual scores (P = .04, Kruskal-Wallis test) and the use of long-term immunosuppressive therapy (P < .001, χ2 test). Patients with AQP4 antibodies had a worse visual outcome (median visual score, 3.5 [range 1-9]) than patients with MOG antibodies (median visual score, 0 [range, 0-5]; P = .007), seronegative patients (median visual score, 1.0 [range, 0-14]; P = .08), and patients with GlyR antibodies (median visual score, 0 [range, 0-2]; P = .10) (all comparisons, Mann-Whitney test) (Table 1). Patients with AQP4 antibodies also received long-term immunosuppressive therapy more frequently (6 of 6 patients [100%]) compared with patients with MOG antibodies (2 of 10 [20%]), seronegative patients (3 of 28 [11%]), and patients with GlyR antibodies (0 of 3).

Other differences did not reach statistical significance on multiple comparisons, probably owing to the low number of patients in each subgroup. However, compared with the patients with AQP4 antibodies, those with MOG antibodies were less frequently female (5 of 10 [50%] vs 6 of 6 [100%]) and were younger (median age, 18 vs 44 years). No differences were found in the frequency of severe or bilateral first episodes of ON or recurrent ON. The AQP4 antibodies were not detected in children.

The clinical features of the 7 patients with GlyR antibodies are shown in Table 2. Median age was 27 (range, 11-38) years; 5 of these (71%) were female. Among the 3 patients with GlyR antibodies alone, 2 had idiopathic isolated ON (recurrent in one and monophasic bilateral in the other) and 1 experienced conversion to MS.9 The 3 patients with GlyR antibodies concurrent with MOG antibodies had idiopathic recurrent isolated ON, and the patient with concurrent AQP4 antibodies experienced conversion to definite NMO.12 At the last follow-up for the 7 patients with GlyR antibodies (median, 41 months; interquartile range, 33-72 months), the 5 patients with idiopathic isolated ON (excluding those with conversion to NMO and MS) achieved normal VA. The frequency of GlyR antibodies alone in patients with ON was not different from that observed in controls with MS (3 of 47 [6%] vs 5 of 64 [8%]; P > .99). The follow-up of serum GlyR antibody titers was available from 5 patients with ON; in 4 patients the titers remained unchanged, and in 1 patient the antibodies were no longer detectable.

Discussion

This study shows that 45% of patients with new-onset unilateral or bilateral, severe, or recurrent ON, in the absence of clinical and magnetic resonance imaging findings outside the optic nerves, had antibodies to MOG, AQP4, or GlyR. Moreover, when one considers the patients who at the last follow-up retained the diagnosis of idiopathic isolated ON, 15 of 43 (35%) had MOG, GlyR, or both antibodies. The identification of autoantibodies was important for 2 reasons. First, it showed the presence of specific autoimmune mechanisms, and second, it had clinical and prognostic implications. Indeed, compared with patients with AQP4 antibodies, those with MOG antibodies were younger and, despite the similar frequency of severe or bilateral first episodes of ON or recurrent ON, had a better visual outcome. Some of these antibody-associated features are similar to those reported in the context of NMO or NMO-related syndromes. For example, in patients with NMO or limited forms of NMO, the presence of MOG antibodies has been shown to be associated with a better outcome than the presence of AQP4 antibodies.5,6 In another study examining the presence and prognostic value of AQP4 antibodies in patients with recurrent ON, seropositive patients had a worse final visual score than that of seronegative patients, similar to our study.3 The more frequent use of long-term immunosuppressive therapy in patients with AQP4 antibodies likely is explained by the availability of this antibody in routine clinical tests (MOG and GlyR antibodies were examined retrospectively) and the awareness that detection of AQP4 antibodies is associated with a high risk for accumulating disability. We did not find AQP4 antibodies in children with ON15; this finding is in contrast to that of the studies of children with NMO, in whom the frequency of AQP4 antibodies is similar to that of the adults.16 However, our study focused on isolated ON, leading to the exclusion of patients with AQP4 antibodies that frequently occur with additional symptoms or radiologic findings beyond the optic nerves.17

To our knowledge, the presence of GlyR antibodies has not been investigated previously in patients with isolated ON. In the present study, 7 patients with ON (14%) had GlyR antibodies, and these were associated with other antibodies in 4 patients (57%). Moreover, GlyR antibodies were identified in 5 controls with MS (8%). These patients represented all the clinical phenotypes of MS, and none of them developed symptoms of stiff person syndrome or progressive encephalomyelitis with rigidity and myoclonus. The GlyR antibodies are abundantly expressed in inhibitory synapses of the brainstem, spinal cord, and retina, and the association with demyelinating diseases has been suggested in other reports, including 2 patients with NMO18 and a child with transverse myelitis and deep brain white matter abnormalities.19 A pathogenic link among GlyR antibodies, ON, and demyelinating disorders has not been established, but these antibodies can occur in several different disorders. Indeed, in a recent study of patients with cerebellar ataxia and glutamic acid decarboxylase 65 antibodies,20 GlyR antibodies were identified in 4 of 34 patients (12%), and their presence did not correlate with any specific clinical feature. These findings are in contrast to a recent report8 suggesting a high specificity of GlyR antibodies for progressive encephalomyelitis with rigidity and myoclonus; however, the control samples used in that report included only serum samples from patients with N-methyl-d-aspartate receptor– and AQP4 antibody–associated syndromes or CSF samples from patients with MS. In our study, the persistence of unchanged titers of GlyR antibodies in 4 of the 5 patients after recovering visual function suggests that the presence of these antibodies may be a bystander effect.

Conclusions

Overall, this study indicates that a substantial number of patients with unilateral or bilateral, severe, or recurrent isolated ON have autoantibodies and that their significance varies with the type of autoantibody. Patients with AQP4 antibodies had the poorest visual outcome, whereas patients with MOG antibodies had a more favorable outcome that was similar to that of seronegative patients. The GlyR antibodies can occur in patients with ON, but their significance in this clinical setting is unclear. Studies with more patients should determine whether GlyR antibodies have a role as biomarkers of immune-mediated ON. In addition, future studies should determine whether patients with milder forms of ON have similar antibody findings.

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Article Information

Accepted for Publication: October 6, 2014.

Corresponding Author: Josep Dalmau, MD, PhD, Neuroimmunology Program, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Casanova 143, Cellex Bldg, Floor 3A, 08036 Barcelona, Spain (jdalmau@clinic.ub.es).

Published Online: December 15, 2014. doi:10.1001/jamaneurol.2014.3602.

Author Contributions: Drs Saiz and Dalmau had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Martinez-Hernandez, Dalmau.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Martinez-Hernandez, Sepulveda, Rostásy, Höftberger, Saiz, Dalmau.

Critical revision of the manuscript for important intellectual content: Rostásy, Graus, Harvey, Saiz, Dalmau.

Statistical analysis: Martinez-Hernandez, Sepulveda.

Obtained funding: Martinez-Hernandez, Dalmau.

Administrative, technical, or material support: Harvey.

Study supervision: Graus, Saiz, Dalmau.

Conflict of Interest Disclosures: Dr Saiz has received compensation for consulting services and speaking from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, Sanofi-Aventis, and Teva Pharmaceutical Industries, Ltd. Dr Dalmau receives royalties from Athena Diagnosis for a patent for the use of Ma2 as an autoantibody test and a licensing fee from Euroimmun for a patent for the use of N-methyl-d-aspartate receptor as an autoantibody test. No other disclosures were reported.

Funding/Support: This study was supported by grant CM12/00055 from the Instituto de Salud Carlos III (Dr Martinez-Hernandez), by grant 14158 from Jubilaeumsfonds of the Austrian Bank, by grant 101530 (Dr Dalmau) and grant 101610 (Dr Saiz) from Fundació la Marató TV3, by grant RD12/0032/0002 from Red Española de Esclerosis Múltiple (Dr Saiz) by grant PI11/01780 from the Fondo de Investigaciones Sanitarias (Dr Dalmau), and by grant RO1NS077851 from the National Institute of Neurological and Communicative Disorders and Stroke, National Institutes of Health (Dr Dalmau).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: Eva Caballero, BS, Neuroimmunology Laboratory, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain, provided excellent technical support. The neurologists of the Spanish Group of Neuromielitis óptica and Red Española de Esclerosis Múltiple provided clinical information. These contributors received no compensation for their roles. We thank all the patients for their generous contribution to research.

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Pirko  I, Blauwet  LA, Lesnick  TG, Weinshenker  BG.  The natural history of recurrent optic neuritis. Arch Neurol. 2004;61(9):1401-1405.
PubMedArticle
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Toosy  AT, Mason  DF, Miller  DH.  Optic neuritis. Lancet Neurol. 2014;13(1):83-99.
PubMedArticle
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Matiello  M, Lennon  VA, Jacob  A,  et al.  NMO-IgG predicts the outcome of recurrent optic neuritis. Neurology. 2008;70(23):2197-2200.
PubMedArticle
4.
Reindl  M, Di Pauli  F, Rostásy  K, Berger  T.  The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol. 2013;9(8):455-461.
PubMedArticle
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Sato  DK, Callegaro  D, Lana-Peixoto  MA,  et al.  Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology. 2014;82(6):474-481.
PubMedArticle
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Kitley  J, Waters  P, Woodhall  M,  et al.  Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. 2014;71(3):276-283.
PubMedArticle
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McKeon  A, Martinez-Hernandez  E, Lancaster  E,  et al.  Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. JAMA Neurol. 2013;70(1):44-50.
PubMedArticle
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Carvajal-González  A, Leite  MI, Waters  P,  et al.  Glycine receptor antibodies in PERM and related syndromes: characteristics, clinical features and outcomes. Brain. 2014;137(pt 8):2178-2192.
PubMedArticle
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Polman  CH, Reingold  SC, Edan  G,  et al.  Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald criteria”. Ann Neurol. 2005;58(6):840-846.
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Pittock  SJ, Weinshenker  BG, Lucchinetti  CF, Wingerchuk  DM, Corboy  JR, Lennon  VA.  Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expression. Arch Neurol. 2006;63(7):964-968.
PubMedArticle
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