Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4–IgG in Patients in the Optic Neuritis Treatment Trial

Abstract

Importance

Autoantibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) are recently established biomarkers of autoimmune optic neuritis whose frequency and accompanying phenotype, especially for MOG-IgG, are still being characterized. The Optic Neuritis Treatment Trial (ONTT) was a well-known randomized clinical trial in optic neuritis; therefore, knowledge of the serostatus and accompanying phenotype of these patients would be useful to determine the frequency of these antibodies in patients presenting with typical monocular optic neuritis and their outcomes.

Objectives

To determine the AQP4-IgG and MOG-IgG serostatus of patients within the ONTT and describe the clinical features of seropositive patients.

Design, Setting, and Participants

In this follow-up study of the randomized clinical trial, ONTT, conducted between July 1, 1988, and June 30, 1991, analysis of serum for AQP4-IgG and MOG-IgG was performed from January 1 to April 30, 2017. A total of 177 patients from the ONTT with acute optic neuritis and serum available for analysis were enrolled from 13 academic referral centers.

Interventions

Analysis of serum for AQP4-IgG and MOG-IgG was performed at Mayo Clinic Neuroimmunology Laboratory in 2017 with a flow cytometry, live cell, AQP4- and MOG-transfected cell-based assay.

Main Outcomes and Measures

Aquaporin-4–IgG and MOG-IgG serostatus.

Results

Of the 177 patients in the study (135 women and 42 men; mean [SD] age, 32.8 [6.9] years), 3 were positive for MOG-IgG (1.7%) and none were positive for AQP4-IgG. All 3 patients positive for MOG-IgG had disc edema at presentation. Two patients later had a single episode of recurrent optic neuritis. All 3 patients had complete recovery of visual acuity, and none were corticosteroid dependent, although peripheral visual field loss persisted in 1 patient. None of the 3 patients positive for MOG-IgG had demyelinating lesions on magnetic resonance imaging scans, and none had developed multiple sclerosis at the 15-year follow-up.

Conclusions and Relevance

Frequency of MOG-IgG was rare in the ONTT, and AQP4-IgG was not found in patients in the ONTT. Characteristics of patients positive for MOG-IgG in the ONTT support the previously described phenotype of MOG-IgG optic neuritis. Myelin oligodendrocyte glycoprotein–related disease appears to be a different entity than multiple sclerosis. Overall, AQP4-IgG and MOG-IgG may be less common in isolated optic neuritis than previously reported.

This case report examines the aquaporin-4–IgG and myelin oligodendrocyte glycoprotein–IgG serostatus of patients within the Optic Neuritis Treatment Trial and describes the clinical features of seropositive patients.

Key Points

Question

What is the prevalence of myelin oligodendrocyte glycoprotein–IgG and aquaporin-4–IgG in patients in the Optic Neuritis Treatment Trial?

Findings

In this case report, no patients were positive for aquaporin-4–IgG, and only 3 were positive for myelin oligodendrocyte glycoprotein–IgG. Patients positive for myelin oligodendrocyte glycoprotein–IgG presented with optic disc edema, and 2 of 3 had recurrent optic neuritis while none developed multiple sclerosis.

Meaning

Aquaporin-4–IgG and myelin oligodendrocyte glycoprotein–IgG may be less common than previously reported in isolated unilateral optic neuritis.

Introduction

The Optic Neuritis Treatment Trial (ONTT) is a well-known multicenter, randomized, placebo-controlled clinical trial (conducted between July 1, 1988, and June 30, 1991) that has provided guidance for the treatment and natural history of optic neuritis. The last follow-up study was published in 2008, detailing the 15-year outcomes of the trial. There was variability in the outcome, with approximately 50% of participants developing multiple sclerosis (MS) and some developing recurrent optic neuritis.

Since the initiation of the ONTT, 2 novel glial autoantibodies have been discovered that better characterize a subset of patients with inflammatory demyelinating disease, including optic neuritis. The first, aquaporin-4–IgG (AQP4-Ig), an antibody targeting the astrocytic water channel, is recognized as the pathogenic antibody causing neuromyelitis optica, whereby patients tend to have both optic neuritis and longitudinally extensive transverse myelitis but can have other neurologic symptoms as well. More recently, antibodies to myelin oligodendrocyte glycoprotein (MOG) have been found in a subset of patients with optic neuritis, which is still being characterized.

It would be of interest to evaluate these antibodies in the ONTT cohort because it is the most recognizable study of optic neuritis and has excellent longitudinal follow-up of 15 years; thus, the frequency of these antibodies in patients presenting with typical monocular optic neuritis, as well as their outcomes, could be determined. The goal of this study was to reanalyze the sera of patients from the ONTT cohort for antibodies against AQP4 and MOG and define the clinical phenotype of seropositive cases.

Methods

Among the 448 patients assessed in the initial ONTT study, serum samples were obtained from 181 at entry into the ONTT, prior to any treatment, and stored within a deidentified database. Four samples did not have sufficient serum available for testing, leaving 177 available for testing. Among these 177 patients, the mean (SD) age was 32.8 (6.9) years, 135 were female (76.3%), and 156 were white (88.1%), demographics that are identical to the overall cohort. This study was approved by the Mayo Clinic institutional review board.

Aquaporin-4–IgG and MOG-IgG testing was performed from January 1 to April 30, 2017, in the Mayo Clinic Neuroimmunology Laboratory by technicians blinded to diagnosis. Aquaporin-4–IgG testing was performed using a clinically validated flow cytometry, live cell, AQP4-transfected cell-based assay. The MOG-IgG1 flow cytometry assay is based on the assay previously published by Waters et al.

Results

Among the 177 patients tested, 3 were seropositive for MOG-IgG (1.7%) and none were positive for AQP4-IgG. All 3 patients seropositive for MOG-IgG had disc edema at presentation, 1 case of which was described as severe (Table). The MOG-IgG seropositive patient with severe disc edema (patient 1, Table) had a visual acuity of hand motion at presentation, while the remaining 2 patients seropositive for MOG-IgG had a visual acuity of 20/50. All 3 patients had pain at onset of optic neuritis. The patient with visual acuity of hand motion was randomized to receive placebo, while the other 2 patients were treated with oral prednisone. Two of the 3 patients seropositive for MOG-IgG had a single recurrence of optic neuritis 3 years after the initial optic neuritis, 1 in the same eye and 1 in the contralateral eye. All 3 patients seropositive for MOG-IgG had complete recovery of visual acuity at the 15-year follow-up, and none were corticosteroid dependent or placed on chronic immunosuppression. Two patients had complete recovery of visual fields, while 1 had a residual visual field defect with a mean deviation of –8.27 dB, which was the patient who initially presented with visual acuity of hand motion. Two patients had severe optic nerve pallor, and 1 had mild optic nerve pallor at the most recent 15-year follow-up. None of the patients seropositive for MOG-IgG had demyelinating lesions on magnetic resonance imaging scans, and none developed MS or any other neurologic symptoms.

Table. Characteristics of Optic Neuritis Treatment Trial Patients Seropositive for Myelin Oligodendrocyte Glycoprotein–IgG.

Patient No./Sex/Age at Diagnosis, y	Disc Edema at Presentation	VA at Presentation	Treatment	Final VA	Final Visual Fields	Final Optic Disc Appearance	Recurrent Optic Neuritis	Multiple Sclerosis at 15 y
1/M/28	Severe	HM	Placebo	20/20	MD, –8.27 dB	Severe pallor	Yes	No
2/F/30	Mild	20/50	Oral prednisone	20/20	Full	Mild pallor	No	No
3/F/45	Mild	20/50	Oral prednisone	20/20	Full	Severe pallor	Yes	No

Abbreviations: HM, hand motion; MD, mean deviation; VA, visual acuity.

Discussion

Evaluation of AQP4-IgG and MOG-IgG antibodies in the ONTT cohort showed that no patients were positive for AQP4-IgG, but 3 patients were positive for MOG-IgG. All 3 patients seropositive for MOG-IgG had optic disc edema at presentation, 1 case of which was severe. In comparison, 35% of patients in the overall ONTT cohort had optic disc edema at presentation. Optic disc edema is also seen more commonly in patients seropositive for MOG-IgG when compared with MS-related optic neuritis in other series.

Although prior studies show that MOG-IgG can be associated with chronic relapsing inflammatory optic neuropathy, no patients seropositive for MOG-IgG in the ONTT fulfilled the criteria for chronic relapsing inflammatory optic neuropathy. Treatment may not be required in all patients who are seropositive for MOG-IgG. For example, the patient in the ONTT cohort seropositive for MOG-IgG who presented with severe disc edema and visual acuity of hand motion had marked spontaneous improvement with placebo.

None of the patients seropositive for MOG-IgG developed MS compared with 50% within the overall ONTT cohort. Therefore, MOG positivity has a negative predictive value for future development of MS in patients presenting with their first episode of optic neuritis, which is consistent with other studies that have shown that MOG-IgG is a distinct disease entity from MS.

The low rate of AQP4-IgG and MOG-IgG positivity in the ONTT cohort was surprising because other studies evaluating AQP4-IgG and MOG-IgG in single-center or multicenter cohorts of optic neuritis have shown a much higher percentage of positivity of these antibodies. Two prior studies evaluating the frequency of AQP4-IgG in unilateral isolated optic neuritis found that 6% to 10% of patients were positive for AQP4-IgG. The largest study of MOG-IgG found that 21% of patients with isolated optic neuritis tested positive for MOG-IgG. The high frequency of AQP4-IgG and MOG-IgG positivity in prior studies may be a reflection of referral bias, as prior studies were performed at tertiary referral centers where more severe or atypical optic neuritis cases that are more likely to have one of these autoantibodies may be overrepresented.

Limitations

There are some limitations of this study. Only 177 of the 448 patients enrolled in the ONTT had serum available for analysis, but demographics were similar between those with serum available and the rest of the cohort. Because the patient information was deidentified, we could not request further follow-up information beyond the 15 years of the study. Although the evaluation of AQP4-IgG and MOG-IgG was performed 20 years after completion of the ONTT, in previously evaluating the AQP4-IgG assay, we have found that samples stay positive over time; and, similarly, in our experience, the same is true for MOG-IgG. The ONTT included patients between the ages of 18 and 45 years; therefore, these findings are most applicable to young adults, which is important to note because MOG-IgG positivity is much more frequent in pediatric optic neuritis and demyelinating disease. Last, the patients enrolled in the ONTT were predominantly white (85%), which could contribute to the lack of patients seropositive for AQP4-IgG because neuromyelitis optica has been shown to be more prevalent in Asian and African populations. Despite these limitations, this study yields important results because the ONTT is the most well-known study on optic neuritis and, therefore, contributes to our understanding of AQP4-IgG and MOG-IgG serostatus in isolated optic neuritis.

Conclusions

Clinical characteristics of MOG-IgG–related optic neuritis in the ONTT are similar to prior descriptions: patients were more likely to have disc edema, recurrent optic neuritis, and a clinical course distinct from MS. However, none of the patients developed chronic relapsing inflammatory optic neuropathy or had other neurologic symptoms. In addition, this study suggests that AQP4-IgG and MOG-IgG may be less common than previously reported in isolated unilateral optic neuritis.