Abstract
Objective:
To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies.
Methods:
Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells.
Results:
Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack.
Conclusions:
Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.
Neuromyelitis optica (NMO) is characterized by severe attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM) with 3 or more vertebral segment spinal cord lesions observed on MRI.1 Limited forms of the disease are known as NMO spectrum disorders (NMOSD). NMOSD currently include patients with either ON or LETM (single or recurrent events of LETM or recurrent or simultaneous bilateral ON).2 Approximately 90% of the patients with NMO and more than half of the patients with NMOSD are positive for autoantibodies against aquaporin-4 (AQP4).3,4 Therefore, a proportion of patients with NMO or NMOSD remains AQP4 antibody-negative despite the use of the best assays available on serum samples collected during an acute attack before any treatment.
Recently, autoantibodies against myelin oligodendrocyte glycoprotein (MOG) were reported in 4 patients who were clinically diagnosed with NMOSD and negative for AQP4 antibodies.5 High-titer MOG antibodies are predominantly of the immunoglobulin G (IgG) 1 subtype and efficiently mediate complement-dependent cytotoxicity in vitro.6 However, none of these previous studies investigated comprehensively the features that may distinguish patients with AQP4 antibodies from those with high-titer MOG antibodies or those who are negative for both antibodies, even though such information is useful for clinical practice. In this study, we compared the clinical, MRI, and laboratory characteristics of patients with high-titer MOG antibodies with those of patients with AQP4 antibodies and seronegative patients.
METHODS
Patients and serum samples.
We enrolled a total of 215 patients from 3 tertiary centers for this study: 1) Hospital das Clínicas, Faculty of Medicine, University of Sao Paulo, Brazil; 2) Center for the Investigation of MS at Federal University of Minas Gerais, Belo Horizonte, Brazil; and 3) Tohoku University Hospital, Sendai, Japan. We included pediatric and adult patients who had received a clinical diagnosis of definitive NMO or NMOSD, which currently includes patients with one attack or recurrent LETM and those with bilateral simultaneous or recurrent ON. For simplicity, we use the term NMOSD to encompass both NMO and NMOSD. We only included consecutive patients followed up in one of the 3 centers for whom information regarding the clinical attacks, brain and spinal cord MRIs, and serum for antibody testing were available; 7 patients were excluded because of a lack of information (5 patients with AQP4 antibodies and 2 seronegative patients). All patients seronegative for both AQP4 and MOG antibodies were fully investigated, and alternative diagnoses were ruled out. The serum samples from the Brazilian centers were stored at −80 °C after centrifugation in each center, shipped on dry ice to Sendai, Japan, and stored again at −80 °C until analysis.
AQP4 and MOG antibody assays.
All serum samples were analyzed at Tohoku University to detect AQP4 and MOG antibodies. The cell-based assay (CBA) for AQP4 antibody detection in living cells has been described7 using HEK-293 cells stably transfected with the M23 isoform of AQP4. Two investigators (D.K.S. and T.T.) scored the assays. These samples were also analyzed for the presence of MOG antibodies using a CBA with live HEK-293 cells transiently transfected with a plasmid containing full-length human MOG cDNA (pIRES2-Dsred2 vector, BD Biosciences, San Jose, CA; provided by P.J.W.) using the FUGENE6 transfection agent (Promega Corp., Madison, WI). Goat anti-human IgG labeled with Alexa488 (Invitrogen, Carlsbad, CA) was used as a secondary antibody after the transfected cells were exposed to the patients’ diluted serum. The samples were tested for MOG antibodies at least twice at dilution of 1:128, and only patients whose samples were judged to be positive by 2 observers (D.K.S. and T.T.) were considered positive with high titers. See details of the patients tested during the validation of MOG antibody assay in the e-Methods on the Neurology® Web site at www.neurology.org. Later, positivity for the MOG antibodies was also confirmed by P.J.W. at Oxford University in a blinded fashion. The titers from both assays were calculated semiquantitatively using consecutive twofold dilutions.
Statistical analysis.
Nonparametric tests (Wilcoxon tests) were used to compare the clinical data and CBA titers among the groups of patients. The categorical data from the study were analyzed using Fisher exact test, and p < 0.05 was considered to be significant.
Standard protocol approvals, registration, and patient consent.
This study was approved by the ethics committee of each center and conducted in accordance with internationally recognized ethical standards. All study participants provided written informed consent.
RESULTS
In total, 215 patients with NMOSD were included: 152 from Brazil (Sao Paulo and Belo Horizonte) and 63 from Japan (Sendai). Among these patients, 7.4% (16/215) were positive for MOG antibodies, 64.7% (139/215) were positive for AQP4 antibodies, and the remaining 27.9% (60/215) were seronegative. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of AQP4-antibody seronegative cases.
The clinical characteristics of each patient with MOG antibodies are summarized in table 1. None of the patients had encephalopathy or seizures. In the acute phase, all patients with MOG antibodies received IV high-dose methylprednisolone (1 g/d for 3–5 days) as the first-line treatment for acute attacks, and 87.5% (14/16) of them experienced good recovery. Only one patient with a severe LETM attack, with tetraparesis, urinary retention, and a sensory level of Th10 and below, was further treated with 5 sessions of plasmapheresis. However, this patient had only a partial recovery of motor strength in the trunk and upper limbs, remaining paraplegic and without bowel/bladder control.
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