White matter changes in paediatric multiple sclerosis and monophasic demyelinating disorders.
See Hacohen et al. (doi:10.1093/awx075) for a scientific commentary on this article. Most children who experience an acquired demyelinating syndrome of the central nervous system will have a monophasic disease course, with no further clinical or radiological symptoms. A subset will be diagnosed with multiple sclerosis, a life-long disorder. Using linear mixed effects models we examined longitudinal diffusion properties of normal-appearing white matter in 505 serial scans of 132 paediatric participants with acquired demyelinating syndromes followed for a median of 4.4 years, many from first clinical presentation, and 106 scans of 80 healthy paediatric participants. Fifty-three participants with demyelinating syndromes eventually received a diagnosis of paediatric-onset multiple sclerosis. Diffusion tensor imaging measures properties of water diffusion through tissue, which normally becomes increasingly restricted and anisotropic in the brain during childhood and adolescence, as fibre bundles develop and myelinate. In the healthy paediatric participants, our data demonstrate the expected trajectory of more restricted and anisotropic white matter diffusivity with increasing age. However, in participants with multiple sclerosis, fractional anisotropy decreased and mean diffusivity of non-lesional, normal-appearing white matter progressively increased after clinical presentation, suggesting not only a failure of age-expected white matter development but also a progressive loss of tissue integrity. Surprisingly, patients with monophasic disease failed to show age-expected changes in diffusion parameters in normal-appearing white matter, although they did not show progressive loss of integrity over time. Further analysis demonstrated that participants with monophasic disease experienced different post-onset trajectories in normal-appearing white matter depending on their presenting phenotype: those with acute disseminated encephalomyelitis demonstrated abnormal trajectories of diffusion parameters compared to healthy paediatric participants, as did patients with non-acute disseminated encephalomyelitis presentations associated with lesions in the brain at onset. Patients with monofocal syndromes such as optic neuritis, transverse myelitis, or isolated brainstem syndromes in whom multifocal brain lesions were absent, showed trajectories more closely approximating normal-appearing white matter development. Our findings also suggest the existence of sexual dimorphism in the effects of demyelinating syndromes on normal-appearing white matter development. Overall, we demonstrate failure of white matter maturational changes and progressive loss of white matter integrity in paediatric-onset multiple sclerosis, but also show that even a single demyelinating attack-when associated with white matter lesions in the brain-negatively impacts subsequent normal-appearing white matter development.
Neuroimaging Research Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Giulia
G
Longoni
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Robert A
RA
Brown
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Parya
P
MomayyezSiahkal
Centre for Intelligent Machines, Department of Electrical and Computer Engineering, Faculty of Engineering, McGill University, Montreal, QC, Canada.
Colm
C
Elliott
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Sridar
S
Narayanan
Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Amit
A
Bar-Or
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Ruth Ann
RA
Marrie
Department of Pediatrics, University of Toronto; Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada.
E Ann
EA
Yeh
Neuroimaging Research Unit, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.|Department of Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.
Massimo
M
Filippi
Division of Neurology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Brenda
B
Banwell
McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.|Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.
Douglas L
DL
Arnold
D000293:Adolescent; D016880:Anisotropy; D001921:Brain / Q000473:pathology*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003711:Demyelinating Diseases / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000473:pathology*; D059906:Neuroimaging; D012727:Sex Characteristics; D066127:White Matter / Q000473:pathology*
acute disseminated encephalomyelitis; clinically isolated syndrome; demyelination; multiple sclerosis: imaging; neuroinflammation