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Introduction
Acute optic neuritis (ON) typically presents with ocular pain and low visual acuity (VA), and there is a risk of permanent vision loss if ON is not managed properly.1 ON may be the first symptom of inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD).
Recently, we reported some distinct characteristics between seropositive anti-aquaporin-4 (anti-AQP4) patients and seropositive antimyelin oligodendrocyte glycoprotein (anti-MOG) patients with NMOSD, using our in-house cell-based assays (CBA). However, patients with a single attack of unilateral ON were not included in our previous study. None of the previous studies of anti-MOG+ patients performed orbital MRI or optical coherence tomography (OCT) segmentation analyses, which may have diagnostic and prognostic implications. To address these issues, we evaluated the diagnostic utility of the anti-MOG assay and compared the MRI and OCT findings of anti-MOG+ and anti-AQP4+ patients with isolated ON.
Patients and methods
Patients
We investigated 28 affected ON eyes from 21 consecutive anti-AQP4 seronegative patients aged 12 years or older who presented with isolated ON (4 cases with simultaneous bilateral ON, 3 cases with relapsing unilateral ON, and 14 cases with a single attack of unilateral ON) and were admitted to Tohoku University Hospital between 2011 and 2013. We excluded patients with ON already associated with brain and/or spinal cord MRI lesions. We compared anti-MOG+ ON eyes with nine affected ON eyes from eight anti-AQP4+ patients with isolated ON (one simultaneous bilateral ON). Severe VA loss was set at 0.1 in the decimal Japanese chart (equivalent to 20/200).2
Orbital MRI
All patients performed orbital imaging using a 1.5 T MRI. We measured the short τ inversion recovery (STIR) and/or T2-weighted image hyperintense lesions in anatomical segments of the optic nerve.3 We also evaluated the presence of contrast-enhancing lesions.
Spectral domain OCT
Spectral domain OCT with automated retinal segmentation was performed using a three-dimensional OCT-2000 with system software V.8.11 (Topcon Corp, Tokyo, Japan) during the follow-up (6 months after ON episodes). We evaluated ganglion cell-inner plexiform layer (GCIPL) and retinal nerve fibre layer (RNFL) thickness.
Anti-MOG CBA
Sera collected during acute ON attacks from the 21 idiopathic isolated ON patients were tested blindly for anti-MOG using our in-house CBA as previously reported with slight modifications.4 We used stably transfected full-length MOG-expressing cells and a goat antihuman Fc-specific IgG cross-adsorbed secondary antibody (Pierce Biotechnology, Rockford, Illinois, USA) to reduce the risk of light chain cross-reactivity from other immunoglobulin subclasses.
Statistical analysis
Non-parametric tests (Wilcoxon tests) were used to compare the clinical data and CBA titres between patient groups. Categorical data from the study were analysed using Fisher's exact test and p<0.05 was considered significant.
Standard protocol approval and patient registration and consent
The ethics committee of Tohoku University approved this study and all participants provided written informed consent.
Results
Anti-MOG serological status and clinical recovery after treatment
Thirteen (61.9%) of the 21 examined patients with isolated ON, who were anti-AQP4 seronegative, were anti-MOG+ based on CBA, with a median titre of 1:2048 (range=1:128–1:16 384). Four patients had simultaneous bilateral ON, all of whom were anti-MOG+. The other two anti-MOG+ patients and one seronegative patient had unilateral ON relapses. All anti-MOG+ cases responded well to intravenous methylprednisolone (MP) treatment, except one patient who was anti-MOG+ with a 20-year history and three previous untreated ON attacks (2 right ON and 1 left ON).
Comparison of MRI findings between anti-MOG+ and anti-AQP4+ ON eyes
Overall, the anti-MOG+ ON eyes more frequently exhibited severe optic nerve swelling and contrast-enhancing lesions of the optic nerve, which were occasionally associated with the extension of inflammation to tissues surrounding the intraorbital portion of the optic nerve. Long STIR lesions in anti-MOG+ ON affected multiple segments of the optic nerve, but spared the optic chiasm compared with anti-AQP4+ ON, as summarised in table 1. Four anti-AQP4+ ON eyes also displayed long STIR lesions on MRI, but five ON eyes displayed only focal lesions, restricted to the orbital portion of the optic nerve.
MRI findings of anti-MOG+ and seronegative ON eyes with isolated ON
Comparison of OCT parameters between anti-MOG+ and anti-AQP4+ ON eyes
The average circumpapillary RNFL thickness (mean±SD) was greater in the anti-MOG+ ON eyes compared with the anti-AQP4+ ON eyes (90.2±10.5 vs 74.1±14.9 µm, respectively, p=0.0228), with a pronounced difference in the superior (109.6±19.3 and 80.0±19.8 µm, respectively, p=0.0068) and inferior (115.4±12.6 and 83.1±23.5 µm, respectively, p=0.0028) quadrants and the GCIPL thickness (57.0±6.2 vs 46.1±12.3 µm, respectively, p=0.0277). There were no differences in the macular RNFL thickness between anti-MOG+ and anti-AQP4+ ON (26.5±5.4 and 23.7±11.6 µm, respectively).
Discussion
This study demonstrated that a significant proportion of patients with anti-MOG antibodies as detected by CBA who experienced ON attacks typically exhibited good recovery after intravenous MP treatment. The MRI abnormalities indicate severe and extensive inflammation in the optic nerve of the anti-MOG+ ON eyes. Anti-MOG+ ON should be distinguished from anti-AQP4+ ON, which also presents with extensive ON lesions in half of our patients, by prompt testing for anti-AQP4 and anti-MOG. The anti-MOG+ ON lesions spared the optic chiasm, which was detected in anti-AQP4+ ON. Anti-MOG+ ON patients typically exhibit better VA recovery than anti-AQP4+ ON patients, who also carry a higher risk of further attacks.4
GCIPL and circumpapillary RNFL thickness measured by OCT in anti-MOG+ ON suggested that these patients experience less retinal neuronal loss than anti-AQP4+ ON despite severe optic nerve swelling. Further long-term prospective follow-up studies should clarify whether the extent of GCIPL and circumpapillary RNFL thinning correlates with visual outcomes in such cases.
Isolated ON without brain or spinal cord lesions requires extensive investigation because many inflammatory CNS diseases can present with ON as the initial attack.5 We acknowledge that our study results have some limitations due to the small number of patients, but we focused on isolated ON because it represents a diagnostic challenge. Therefore, anti-MOG may identify a subgroup of isolated ON patients with a distinct prognosis from the anti-AQP4+ ON, which can potentially guide long-term therapeutic decisions.
Footnotes
Contributors TA, DKS and IN contributed to the study design and conceptualisation. TA, DKS, IN and KF drafted the manuscript. TA, DKS, IN, TaT, ToT, HD, KKu, KKa, HK, SN, TM, TN, KF and MA contributed to the acquisition, analysis and interpretation of data. TA, DKS and IN contributed to the statistical analysis. TA, DKS, IN, TaT, ToT, HD, KKu, KKa, HK, SN, TM, TN, KF and MA contributed to a critical revision of the manuscript.
Funding This study was supported by KAKENHI (22229008) of The Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and by the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan.
Competing interests DKS has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, research support from CAPES/Brasil and the Ichiro Kanehara Foundation, and speaker honoraria from Novartis. IN reports grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Ministry of Health, Labour and Welfare of Japan, personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd, and grants from LSI Medience Corporation. HK reports grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. SN reports grant from JSPS KAKENHI Grant (Grant-in-Aid for Research Activity Start-up) Number 24890017. TM has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co., and Astellas Pharma Inc. and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co., The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan. KF has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc., Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc., Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co., Daiichi Sankyo, and Nihon Pharmaceutical and research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, and Genzyme Japan; he is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present).
Patient consent Obtained.
Ethics approval Tohoku University Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.