Myelin oligodendrocyte glycoprotein (MOG)-IgG associated optic neuritis as a new issue in the differential diagnosis of optic neuropathy

PATHOPHYSIOLOGY

Optic neuritis (ON) is a cardinal manifestation of inflammatory conditions of the central nervous system (CNS). It can be the first symptom of multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Neuromyelitis optica spectrum disorders are inflammatory demyelinating diseases of the CNS that cause optic neuritis, transverse myelitis and some other CNS syndromes. In more than 80% of cases, NMOSD is caused by immunoglobulin G autoantibodies to aquaporin 4 (AQP4), the most frequent water channel protein in the CNS. A subset of AQP4-negative cases may be associated with myelin oligodendrocyte glycoprotein (MOG) antibodies even in 42% of patients [1-4].
Oligodendrocytes are a type of glial cells present in the optic nerves. They form a myelin sheath on their axons (Figure 1). Myelin oligodendrocyte glycoprotein is a surface protein located on the oligodendrocytes; it is involved in maintaining the myelin structure. Unlike AQP4, MOG is closely related to the CNS and does not occur in other tissues of the body [4]. It is known to be highly immunogenic with the potential of causing autoimmune diseases, which confirms its use for the induction of experimental autoimmune encephalitis in laboratory animals [5]. Autoantibodies to MOG can activate the complement system and induce a cytotoxic reaction, leading to primary demyelinating damage, sparing axons and astrocytes in the initial stage of the disease [6, 7]. Meanwhile, AQP4 antibodies at first lead to massive astrocyte destruction, disturbance of the blood-brain barrier function and secondary damage to the myelin sheath [3, 8].

EPIDEMIOLOGY

Myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD) is generally observed more often in younger individuals (compared to AQP4-IgG NMOSD) and affects females and males equally. The overall incidence is estimated at 0.16 per 100,000 per year (0.31 for children and 0.13 for adults) [9].

CLINICAL PRESENTATION

Overall, the most common clinical presentation of MOGAD is ON [10]. MOG-IgG positive ON tends to be more often recurrent (in approximately 50% of patients) and bilateral (72.7% of MOG-IgG patients vs 24% of AQP4-IgG patients) [10, 11]. Significant eye pain is common in the acute phase. It is also more often associated with optic disc oedema than other causes of acute demyelinating ON, which can sometimes be severe and include peripapillary haemorrhages. That is why it may lead to misdiagnosis of papilloedema from elevated intracranial pressure in bilateral cases or nonarteritic anterior optic neuropathy in unilateral ones. Overall, optic disc oedema is reported in up to 86% [12-14]. Optic nerve MRI reveals longitudinal, extensive (involving > 50% of the length of the optic nerve) and anterior (usually seen in the orbital and intracranial region of the optic nerve) enhance ment, while AQP4-IgG positive ON tends to have more poste- rior, often optic chiasm involvement. Another common finding is optic perineuritis with optic nerve sheath enhancement, in contrast to MS-related ON, where parenchymal optic nerve enhancement is usually seen [13, 15]. Brain MRI in MOGAD reveals non-specific white matter lesions in the brainstem, adjacent to the fourth ventricle or a normal appearance, but not the ovoid, periventricular (adjacent to the lateral ventricles), white matter lesions typical of MS. However, MRI of the spinal cord may present swelling and contrast enhancement that can resemble the transverse myelitis of NMOSD [10]. MOG-IgG positive ON typically causes severe vision loss at the onset in the form of central scotomas to complete visual loss in up to 95% of patients [16]. Despite that, as many as 75-80% of cases show a complete or significant visual recovery [10]. By comparison, over one-third of AQP4-IgG positive ON cases lead to the final visual acuity of Snellen 0.1 or worse [17]. Optical coherence tomography (OCT) studies reported greater peripapillary retinal nerve fibre layer (RNFL) and ganglion cell complex (GCC) thickness in MOG-IgG pos- itive ON compared to AQP4-IgG positive ON [18, 19]. Subsequently, optic nerve injury results in thinning of the RNFL and GCC after the acute phase, whose severity is generally similar and more pronounced in both mentioned types of ON than in MS-related ON [20, 21]. However, despite a similar seriousness of RNFL and GCC thinning in MOG-IgG and AQP4-IgG positive ON, visual outcomes clearly diverged, with relatively preserved visual acuity in the first case and markedly worse visual outcomes in the latter [21]. Pattern visual evoked potentials (PVEPs) were employed to separate MS from inflammatory and demyelinating CNS diseases, in- cluding NMOSD. The studies indicate that P100 latency is more delayed in MS than NMOSD, with a greater proportion of absent responses and less frequent subclinical altera- tions in the latter group [22]. Prolongation of P100 latency persists after the acute phase, even when visual acuity returns to normal [23]. The characteristics of MOG-IgG positive ON in comparison to AQP4-IgG positive ON and MS-related ON are presented in Table I. Other manifestations of MOGAD are acute disseminating encephalomyelitis (ADEM) and transverse myelitis (TM), less frequently isolated brainstem syndromes (e.g. eye movement disorder, hearing loss, trigeminal neuralgia, dysphagia, hemiparesis, dizziness, breathing prob- lems), rarely encephalitis or seizures. The clinical presentation of MOGAD varies based on age at onset. A recent study suggested that ADEM is the most common clinical presentation in younger children, followed by ON and ON with TM [9]. In adults, the most common presentation was ON, followed by TM and simultaneously ON and TM. Acute disseminating encephalomyelitis, especially accompanied with ON, strongly suggests MOGAD, as it is not common in MS and AQP4-IgG positive NMOSD. Transverse myelitis can appear similar to AQP4-IgG positive NMOSD but more commonly affects the conus medullaris [15, 24].

DIAGNOSTICS

The gold standard in MOGAD suspected cases is serological diagnostics of MOG-IgG. Characteristics of cerebrospinal fluid are neither sensitive nor specific. Very few patients were found to have oligoclonal bands seen with MS. Usually, analyses yield normal results or show a pleocytosis with a range of white blood cell counts [10, 11]. Cases of ON with bilateral ON, recurrent ON or optic disc swelling on fundoscopy should be primarily considered for cell-based assays. The differential diagnosis includes MS, NMOSD (caused by AQP4-IgG), nonarteritic anterior optic neuropathy, sarcoidosis, Lyme disease and granulomatosis with polyangiitis (Wegener’s granulomatosis) [25].

TREATMENT

Randomized, controlled treatment trials are limited for MOG-IgG positive ON, but based on available results, it is recommended to use 1 g per day of intravenous methylprednisolone for 3-5 days for treatment of acute MOG-positive ON. Patients usually show rapid and significant improvement. However, the recovery increase after intravenous steroids is rated at 10-20% compared to no treatment [15, 26]. In patients who do not respond to steroid treatment, intravenous immunoglobulin or plasma exchange can be used [10, 15]. There are no prospective trials to guide the maintenance therapy for MOG-positive ON, but observational open-label work sug- gests its role in preventing recurrent attacks. Notably, the majority of individuals in all studies had a recurrence within the first year of attack [13, 15]. In one study, 95% of patients receiving doses of at least 20 mg of prednisone for 6 months following an acute phase treatment had no recurrent ON episodes at follow-up of over a year [14]. High dose and longer length of treatment were strongly associated with remittance, and patients who were given a tapered dose or discontinued therapy earlier had relapse rates comparable to those with no treatment [14, 15]. There are also data pointing to the role of immunosuppressive drugs, such as azathioprine, mycophenolate mofetil, rituximab and intravenous immunoglobulin, in reducing the relapse rate of MOGAD [14, 15]. These drugs should be considered in the absence of the therapeutic effect of steroids, the necessity of their limitation or the most severe cases [27]. As the pathophysiology of MOGAD is better explained, target therapies are expected to be developed.

CONCLUSIONS

In conclusion, MOG-IgG positive optic neuritis is a new subset of optic neuropathy. It usually responds well to steroid therapy, and visual acuity outcomes are favourable. However, significant visual field defects, damage of the retinal ganglion cells, reduction of the peripapillary retinal nerve fibre layer thickness and prolonged PVEPs may remain. The risk of recurrence is high during the first year, and subsequent attacks are associated with an increased risk of permanent neurologic deficit. Further research is needed to determine the optimal management and therapy for MOGAD.

DISCLOSURE

The authors declare no conflict of interest.

References