The Expanding Clinical Spectrum of Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Associated Disease in Children and Adults

Abstract

The ability of MOG antibody (MOG-Ab) to induce autoimmune disease in animals has been known for decades (1), but it is only recently since the cell-based assay for MOG-Ab IgG₁ has been developed and commercialized, that it became possible to characterize clinical syndromes associated with MOG-Ab in humans. Early reports of MOG Associated Disease (MOGAD) emphasized its similarity to Neuromyeliits Optica Spectrum Disorder (NMOSD) (2–4). Indeed, a minority of patients with Aquaporin-4 antibody (AQ4-ab)-seronegative NMOSD−42% in one series–test positive for MOG-Ab (5). However, because the spectrum of MOGAD encompasses many NMOSD-atypical presentations, and because of differences in pathophysiology–AQ4-ab-positive NMOSD being an astrocytopathy and MOGAD being an oligodendrocytopathy—there is an increasing tendency to recognize AQ4-Ab-positive NMOSD and MOGAD as distinct entities (6–10). In this review, we organize the clinical presentations of MOGAD by neuroanatomic compartments, while emphasizing the wide range of reported presentations. While this organization is useful for didactic purposes, it should be borne in mind that MOGAD may involve multiple regions of the CNS simultaneously– much more often than other CNS inflammatory diseases, and that half of MOGAD patients have active lesions in more than one location at the time of initial presentation (11–14). While no phenotype is restricted to any specific age group, some generalizations about clinical presentations of MOGAD in children and adults are possible. In children under the age of 11, ADEM-like phenotypes (encephalopathy, multifocal neurologic deficits and “fluffy” supratentorial cerebral lesions in a bilateral distribution) predominate, while in adolescents and adults, focal syndromes of optic neuritis or longitudinally extensive myelitis are more common (11, 15, 16). Unlike Multiple Sclerosis (MS), where relapse rates are higher in children and decline with older age, in MOGAD the majority of children are not prone to frequent relapses, with 80% of having a monophasic course (17). However, the high rate of monophasic disease may be an overestimate due short follow up (right censoring) as recent case reports documented disease reemergence years and even decades after the initial episode in childhood (18, 19). Given the important differences in pediatric and adult MOGAD, we will qualify discussion of specific syndromes with reference to the respective age group (with the caveat that the clinical distinctions across age groups are only generalizations). Optic neuritis (ON) is the most common initial presentation of MOGAD in adolescence and adulthood, and a frequent presentation in pediatric patients (11, 16, 20). It is associated with a higher risk of subsequent relapse compared to other clinical presentations (11–13, 18). At the onset, vision loss is often severe and up to 80% of patients have bilateral optic nerve involvement, which is highly unusual in MS (12, 14, 21–24). Despite the severity of vision loss in the acute phase, recovery is usually good, especially in children: 89–98% of children had visual acuity to 20/25 or better at 6 months (14, 25). In adults, 6–14% of patients had permanent loss of vision (≤ 20/200) in the affected eye (11, 13, 24). Optic disc edema is rare in MS or NMOSD but is present in up to 86% of patients with MOGAD-ON (13, 21, 22, 24, 26, 27). Rarely, bilateral ON with disc edema can be mistaken for idiopathic intracranial hypertension especially if the patient also complains of headache and has elevated opening pressure on lumbar puncture; however lymphocytic pleocytosis in CSF and enhancement of optic nerve on orbital MRI point toward an inflammatory etiology and should prompt testing for MOG-Ab (28). Fulminant disc edema with peripapillary hemorrhages and “macular star” have been described in MOGAD-ON (29–31). Both of these findings are considered highly atypical for other inflammatory-demyelinating diseases and are more often associated with infectious and ischemic etiologies (29, 30). Up to 50% of adults with MOG-ON have a recurrence of optic neuritis (11–13, 18), which may be the only manifestations of MOGAD. Two rare previously described phenotypes, chronic relapsing inflammatory optic neuropathy (CRION)– a rare condition characterized by relapsing, steroid-dependent optic neuritis (32), and relapsing isolated optic neuritis (RION), have been associated with MOG-Ab in some cases (33, 34). MRI of the orbits during acute MOG-ON typically shows longitudinally extensive optic nerve enhancement with a predilection for the anterior portion of optic nerves; the chiasm and optic tracts are less frequently affected (21, 31). “Optic perineuritis,” characterized by inflammation of the optic nerve sheath and surrounding structures on MRI (35), is seen in up to 50% of cases of MOGAD-ON (Figure 1A) (13, 21, 25, 36, 37). Perineural enhancement is a feature that can help differentiate MOGAD from NMOSD or MS (13, 21, 25, 36, 37). Isolated cases of MOGAD perineuritis, involving the nerve sheath and surrounding structures but not the optic nerve, have also been reported (38, 39). Rarely, uveitis and keratitis can occur simultaneously or subsequently to MOG-ON (38). Figure 1. (A) MRI brain T1 coronal post gadolinium contrast showing contrast enhancement of bilateral optic nerves and right optic nerve sheath consistent with perioptic neuritis. (B) MRI spine sagittal STIR showing longitudinal extensive patchy lesion spaning from cervical to thoracic cord. (C) MRI spine sagittal T2 showing hyperintense longitudinally extensive “pseudo-dilation” of central canal. (D) MRI spine sagittal T1 post gadolinium contrast showing patchy enhancement of the conus medullaris. (E) MRI brain...