Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination

Abstract

Background and Objectives:Pediatric acquired demyelination of the central nervous system associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG-antibody associated disease, MOGAD) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this to the growth trajectories of age- and sex-matched healthy children as well as children with multiple sclerosis (MS, a chronic relapsing disease known to negatively affect brain growth) and monophasic seronegative demyelination.Methods:We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the three largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG antibodies. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination, and negative for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volume was computed through symmetric non-linear registration to templates. We computed age- and sex-normalized z-scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically-developing children, and used mixed-effect models to assess potential deviation from brain growth trajectories.Results:We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p<0.001) age- and sex-expected growth of thalamus, caudate and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year post-onset, and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared to children with MS.Interpretation/discussion:The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months following an acute attack. Further studies are required to better determine the relative impact of monophasic versus relapsing MOGAD, and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord impacts brain volume over time.