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 CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; 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 with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) 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 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. 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 results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized 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-expected 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 postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS.

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 after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

Figure 1. Flowchart of Patient Recruitment

Figure 2. Growth Trajectories in Children With MOGAD, MS, and Seronegative Mono-ADS

Trajectories of Z scores over time and model fits are plotted for each diagnostic group (from left to right: MOGAD, MS, and seronegative mono-ADS) and for each structure (from top to bottom: whole brain, normalized thalamus, normalized caudate, normalized putamen, and normalized globus pallidus). The vertical dashed line marks 1 year from clinical presentation. The solid blue lines indicate the fitted values of the linear mixed-effect model, while the gray shaded area indicates 95% CI. The model coefficients for the comparisons between groups are reported in Table 2. NIHPD = NIH Study of Normal Brain Development; MOGAD = MOG antibody–associated disease; PNC = Philadelphia Neurodevelopmental Cohort; POMS = pediatric-onset multiple sclerosis.

Figure 3. Growth Trajectories in Children With Monophasic MOGAD

Trajectories of Z scores over time and model fits for participants with MOGAD with monophasic disease course and for each structure. The vertical dashed line marks 1 year from clinical presentation. The solid blue lines indicate the fitted values of the linear mixed-effect model, while the gray shaded area indicates 95% CI. MOGAD = MOG antibody–associated disease.