BACKGROUND: MRI and laboratory features have been incorporated into 
international diagnostic criteria for multiple sclerosis. We assessed the 
pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum 
antibody findings that best identifies children with multiple sclerosis, and the 
applicability of international diagnostic criteria in the paediatric context.
METHODS: In this prospective cohort study, detailed clinical assessments, serum 
and CSF studies, and MRI scans were done in youth (aged 0·46-17·87 years) with 
incidental acquired demyelinating syndrome. Participants were examined 
prospectively to identify relapsing disease. All MRI scans were assessed using a 
validated scoring method. A random forest classifier identified imaging and 
laboratory features that best predicted a multiple sclerosis or monophasic 
outcome. Performance of the 2001, 2010, and 2017 international McDonald criteria 
for the diagnosis of multiple sclerosis, the 2016 MRI in multiple sclerosis 
(MAGNIMS) criteria, and our 2011 proposed (Verhey) criteria were determined; 
performance was adjudicated with generalised linear models.
FINDINGS: Between Sept 1, 2004, and June 30, 2017, we included 324 participants 
with median follow-up of 72 months (range 6-150), 71 (22%) participants with 
multiple sclerosis, 237 (73%) with monophasic acquired demyelinating syndrome, 
14 (4%) with relapsing non-multiple sclerosis, and two (1%) with alternative 
diagnoses. We scored 2391 brain, 444 spinal, and 67 dedicated orbital MRI scans. 
One or more T1 hypointense lesions plus one or more periventricular lesions 
(Verhey criteria) best predicted multiple sclerosis outcome. Performance of the 
2017 McDonald criteria was comparable to the 2010 McDonald criteria and was 
easier to adjudicate. The ability of CSF oligoclonal bands to substitute for the 
requirement for both enhancing and non-enhancing lesions in the 2017 McDonald 
criteria improved its performance compared with the 2010 criteria. Myelin 
oligodendrocyte testing at baseline did not improve performance of the 2017 
McDonald criteria.
INTERPRETATION: The 2017 McDonald criteria for the diagnosis of multiple 
sclerosis, as applied at the time of incident attack, perform well in 
identifying children and youth with multiple sclerosis, indicating that the same 
diagnostic criteria for multiple sclerosis apply across the age span. The 
presence of so-called black holes on MRI and periventricular lesions at baseline 
(Verhey criteria) also effectively distinguish children with multiple sclerosis 
from children with monophasic demyelination. The presence of CSF oligoclonal 
bands improve diagnostic accuracy. Myelin oligodendrocyte glycoprotein 
antibodies identify children with acute disseminated encephalomyelitis, and 
those with relapsing non-multiple sclerosis, most of whom do not meet 2017 
McDonald criteria at onset.
FUNDING: The Multiple Sclerosis Scientific Research Foundation and The 
Children's Hospital of Philadelphia.