Optic neuritis (ON) is a common inflammation of the optic nerve associated with numerous autoimmune conditions, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), chronic relapsing autoimmune optic neuritis (CRION) and autoimmune optic neuritis (AON)[1]. NMOSD is further subdivided into aquaporin-4 (AQP4) antibody positive disease and a seronegative form[2]. A subset of ON patients have serum IgG autoantibodies to myelin oligodendrocyte glycoprotein (MOG)[3]. Glial fibrillary acidic protein levels were elevated in the cerebrospinal fluids of patients with AQP4-IgG positive NMOSD, but absent in MOG-IgG positive cases (including those MOG-IgG positive patients who met diagnostic criteria for NMOSD), suggesting that astrocyte damage is a prominent feature of AQP4-IgG positive NMOSD[4].

Certain clinical and radiological features are suggestive of MOG-IgG positive ON, such as bilateral ON, disc edema and a predilection for the retrobulbar portion of the optic nerve[3,5]. ON in the context of MOG-IgG antibodies has been associated with a better clinical outcome than AQP4 IgG- positive ON[6,7], which commonly leaves permanent residual deficits[8].

Average retinal nerve fiber layer thickness (RNFL) correlates with visual outcome after ON[9]. The aim of this study was to examine whether MOG-IgG positive ON is associated with a better average RNFL measurement compared to AQP4-IgG positive ON, corresponding with the reported better visual outcome, after adjusting for the number of ON events.

In this cohort study of ON outcomes; average RNFL was better preserved in eyes of MOG-IgG positive patients compared to those with AQP4-IgG positive antibodies, even after adjusting for the number of ON attacks. The improved anatomical outcome in MOG-IgG positive patients closely correlated with a better visual acuity and visual field outcome.

Favorable visual outcome [15] and relative RNFL preservation (as seen in this study) may possibly be explained by the difference in the underlying autoimmune mechanism, since MOG-IgG antibodies target the myelin sheath [4,16], while AQP4-Ig-G antibodies cause an astrocytopathy [4]. Such astrocytopathy and neuroaxonal damage could explain a worse prognosis after ON in AQP4-IgG positive patients[17].

In addition to the different antibody targets; MOG-IgG optic neuropathy may be more sensitive to treatment because it involves secondary immune processes. An animal model of AQP4-IgG infused into the CSF has been shown that AQP-IgG is directly pathogenic[18]. This model suggests that some of the injury in AQP-IgG-associated NMO is a result of direct AQP4-IgG damage to the myelin and axons, without major complement activation or immune cell infiltration. The visual loss in MOG-IgG-associated injury may be more reversible due to a greater role of a secondary immune process, making it more amenable to immunosuppression, than AQP-IgG disease in which the antibody directly targets the axons and myelin [18].

A limitation of this study is the difference in disease duration between the two groups. This difference is a direct result of the fact that the first reports of MOG-associated disease [7] began almost a decade after AQP-4 antibodies were related to NMOSD [19]. Thus, the length of follow-up available for MOG-positive disease is shorter (20 mo) than that available for patients with AQP-positive NMOSD.

The results of the largest study on MOG-IgG ON to date[20,21], published in 2016, includes 50 cases of MOG-IgG positive disease and may partially contradict with ours. The authors concurr that while each episode of ON in MOG-IgG results in less optic nerve damage than single episodes of AQP4-IgG ON, the final deficits over time are comparable to those in AQP4-IgG ON, due to damage accrual driven by a higher relapse rate in MOG-IgG disease [21]. However, this study included 14 untreated attacks in 11 patients [20], which may have affected results of long-term visual outcome. Additionally, this study does not report how soon after ON symptoms did patients receive treatment, nor how closely these patients were monitored after steroid cessation for signs of relapse. We observed that MOG-IgG related ON is exquisitely steroid-sensitive and believe that time to treatment and close monitoring are important factors in visual preservation. Kleiter et al. [8], speculated that poorer visual outcome may be associated with lack of frequent short-term follow-up following an ON attack, leading to delayed escalation of therapy [8]. In each of the cases described in our report, very close short-term follow-up was maintained. For each ON attack, visual functions were monitored to ensure response after 3–5 days of high dose intravenous solumedrol, then again within a week of oral steroids, to ensure that no drop in vision occurred, and periodically every 2–6 weeks thereafter. Patients were instructed to monitor their own vision and report immediately if visual deterioration occurs. Two of the patients indeed returned earlier than planned for treatment after noting that ON relapsed when steroids were tapered. Close monitoring allows rapid escalation of therapy when needed. The small distances required for travel in Israel may facilitate close monitoring and early initial treatment with IVMP

Despite the caution needed in interpreting analyses from this small cohort, our finding are consistent with prior reports [3,22]. Whether the difference in outcomes between MOG and AQP4-IgG positive disease result from an inherent difference in the pathological mechanism of injury and response to treatment, requires further studies on the long term course of MOG-IgG positive ON and NMOSD [23].

The results of this study also highlight the fact that visual acuity alone is a poor indicator of residual deficit after ON. There was an insignificant difference in visual acuity outcome between ON eyes of MOG-IgG and AQP-IgG positive patients. However, both the mean RNFL and the mean visual field defect were better indicators of residual deficit after ON (Fig 1). We did not have complete visual evoked potential study or contrast sensitivity results to analyze whether these would be significantly different between the two groups.

We recognize the inherent statistical flaws stemming from the separate-eyed nature of our analysis, leading to a possible overstatement of statistical estimates [24]. MOG-positive optic neuritis is a rare disease, making a large-scale study of OCT findings a challenge that is not easy to overcome. We have begun to address this challenge by calling for international collaboration to pool OCT data from centers worldwide. Another approach with which we plan to correct for the difficulties in interpreting data from a rare disease is to collect and analyze repeated measures from each eye [24].

In conclusion, RNFL is better preserved in eyes following ON of patients with MOG-IgG antibodies compared to those with AQP4-IgG antibodies, correlating with visual outcome. Recognizing MOG-antibody positive associated disorders is not only an issue of nomenclature, but of potential clinical importance.