MOG and AQP4 Antibodies among Children with Multiple Sclerosis and Controls

Abstract

Objective: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis.

Methods: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays.

Results: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001).

Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

Figure 1.

Orbital and brain MRI examples in patients with myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD) and multiple sclerosis (MS). Row 1. A to B3: two patients with MOGAD Row 2. C to E2: three patients with MS negative for AQP4-IgG and MOG-IgG Row 3 & 4. F to J: five patients with MS and false positive MOG-IgG and negative AQP4-IgG (A) Orbital MRI with axial T1-weighted fat-suppression images post-gadolinium reveals bilateral optic nerve enhancement involving the anterior optic pathway (A, arrows) with the left side extending ≥50% of the length of the nerve in a patient with MOGAD. (B) Axial fluid attenuated inversion recovery (FLAIR) images reveal faint left-sided deep grey matter T2-hyperintensities (B, arrowheads) along with some additional white matter T2-hyperintensities (B1, arrows); subsequent Axial FLAIR images in the same MOGAD patient during a separate attack reveal a large, poorly demarcated, expansile T2-hyperintense lesion in the right middle cerebellar peduncle and cerebellum (B2, arrow) that resolved completely in follow-up 9 months later (B3). (C) Orbital MRI with axial T1-weigthed fat-suppression images post-gadolinium reveals unilateral left optic nerve enhancement of the intracranial segment of the optic nerve extending <50% of the nerve (C, arrows) in a patient with MS seronegative for MOG-IgG and AQP4-IgG. (D) Axial FLAIR images reveal multiple periventricular lesions with characteristic morphology for MS (D, arrows) in a patient with MS seronegative for MOG-IgG and AQP4-IgG. (E) Axial FLAIR images reveal a well circumscribed T2-hyperintense lesion in the left lateral pons and middle cerebellar peduncle (E1, arrow) in a patient with MS seronegative for MOG-IgG and AQP4-IgG that persisted 7 months after initial MRI (E2, arrow). (F) Orbital MRI with gadolinium reveals a short segment of enhancement in the left proximal optic nerve (F1, arrow) in a patient with MS with an accompanying low titer MOG-IgG felt to represent a false positive; the MRI brain in this same patient (F) reveals multiple focal white matter lesions with a morphology consistent with MS (F2, arrows). (G) Axial FLAIR reveals innumerable periventricular T2-lesions (G, arrows) some of which are ovoid or perpendicular to the ventricles highly consistent with MS in a patient with low titer MOG-IgG that was felt to represent a false positive result. (H) Axial FLAIR reveals two small foci of T2-hyperintensity (arrows) in the pons and cerebellum in a patient with MS and low titer MOG-IgG felt to be a false positive. (I) Axial FLAIR reveals multiple ovoid T2-hyperintensities, some of which are periventricular in a patient with MS and low titer MOG-IgG felt to be a false positive. (J) Axial FLAIR reveals multiple periventricular T2-hyperintense lesions (J1, arrows) with corresponding T1-hypointensity (J2, arrow) in a patient with MS and MOG-IgG positivity, felt to be a false positive. Abbreviations: AQP4-IgG, Aquaporin-4-IgG; FLAIR, fluid attenuated inversion recovery; MOG-IgG, myelin-oligodendrocyte-glycoprotein-IgG; MOGAD, myelin oligodendrocyte glycoprotein antibody associated disease; MRI, magnetic resonance imaging; MS, multiple sclerosis.