Waubant E, Chabas D, Okuda DT, Glenn O, Mowry E, Henry RG, Strober JB, Soares B, Wintermark M, Pelletier D. Difference in Disease Burden and Activity in Pediatric Patients on Brain Magnetic Resonance Imaging at Time of Multiple Sclerosis Onset vs Adults. Arch Neurol. 2009;66(8):967-971. doi:10.1001/archneurol.2009.135
Copyright 2009 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2009
To compare initial brain magnetic resonance imaging (MRI) characteristics of children and adults at multiple sclerosis (MS) onset.
Retrospective analysis of features of first brain MRI available at MS onset in patients with pediatric-onset and adult-onset MS.
A pediatric and an adult MS center.
Patients with pediatric-onset <18 years) and adult-onset (≥18 years) MS.
Main Outcome Measures
We evaluated initial and second (when available) brain MRI scans obtained at the time of first MS symptoms for lesions that were T2-bright, ovoid and well defined, large (≥1cm), or enhancing.
We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS. Children had a higher number of total T2- (median, 21 vs 6; P < .001) and large T2-bright areas (median, 4 vs 0; P < .001) than adults. Children more frequently had T2-bright foci in the posterior fossa (68.3% vs 31.4%; P = .001) and enhancing lesions (68.4% vs 21.2%; P < .001) than adults. On the second brain MRI, children had more new T2-bright (median, 2.5 vs 0; P < .001) and gadolinium-enhancing foci (P < .001) than adults. Except for corpus callosum involvement, race/ethnicity was not strongly associated with disease burden or lesion location on the first scan, although other associations cannot be excluded because of the width of the confidence intervals.
While it is unknown whether the higher disease burden, posterior fossa involvement, and rate of new lesions in pediatric-onset MS are explained by age alone, these characteristics have been associated with worse disability progression in adults.
Multiple sclerosis (MS) onset before the age of 18 years occurs in up to 10% of all MS cases.1 The lower incidence of MS in childhood contributes to decreased awareness and delayed diagnosis. Other factors that delay diagnosis in children include the different clinical phenotype at disease presentation in pediatric-onset MS compared with adult-onset MS.2
While it is possible that the magnetic resonance imaging (MRI) phenotype in children with pediatric-onset MS might also contribute to delayed diagnosis, the MRI characteristics that define MS in this age group are unclear. One report has suggested that pediatric patients with clinically definite MS may less often meet McDonald criteria for dissemination in space on initial brain imaging.3,4 Up to 40% of patients with pediatric-onset MS may have tumefactive T2-bright lesions defined as 2 cm or more in diameter on their initial scan.5,6 Although pediatric patients with MS onset before age 11 years have similar numbers of T2-bright foci on their initial brain MRI scan than patients with an onset between 11 and 18 years of age, these lesions tend to be less often ovoid and well defined and resolve more frequently at follow-up in the younger than 11 years age group.7 This suggests the possibility of different underlying biological mechanisms at play in younger patients. Finally, pediatric patients with an initial demyelinating event, including first MS event; acute demyelinating encephalomyelitis and possibly other demyelinating disorders, such as neuromyelitis optica; and complete acute transverse myelitis may have a greater infratentorial lesion volume than adults with relapsing-remitting MS.8 However, these reports have not compared MRI features in children vs adults seen at the same initial stage of the disease.
We sought to determine if quantitative differences exist on brain MRI scans obtained at MS onset between children and adults. More specifically, as children more frequently have clinical brainstem/cerebellar involvement at MS onset than adults,2 we hypothesized that infratentorial involvement on the initial brain MRI would be more prominent in children at disease onset.
We queried the University of California, San Francisco (UCSF), pediatric MS database for patients with disease onset before 18 years of age who were diagnosed with MS or clinically isolated syndrome (CIS) according to recently published operational definitions.4,9,10 Patients with acute demyelinating encephalomyelitis, neuromyelitis optica, recurrent optic neuritis with normal cerebrospinal fluid and normal brain and spinal MRI scans, or complete acute transverse myelitis were excluded. Participation in the study was restricted to patients with an initial brain MRI scan obtained within 3 months of symptom onset before intravenous steroid therapy and initiation of disease-modifying therapy. The clinical disease course of most of these patients (31 of 41) has been described elsewhere.7 The MRI scans were performed in various facilities but were stored on the UCSF computerized PACS system. All patients had axial or coronal T2-weighted fluid-attenuated inversion recovery (FLAIR) images available for review. Follow-up MRI scans consisted of the first repeated scans obtained after the first event available in the UCSF PACS system. All MRI scans were performed at a magnet field strength of 1.5 T except for 2 follow-up scans performed at 3 T that showed nearly complete resolution of the previously observed T2-bright foci. Only 8 of 41 first scans and 7 of 40 second scans were performed with overlapping slices on T2-weighted FLAIR sequences. The scans performed with nonoverlapping slices had a gap between slices of no more than 2 mm.
Adult patients with CIS seen at the UCSF Adult Multiple Sclerosis Center were part of a natural history study11; entry criteria included at least 2 T2-bright foci in the deep white matter on a clinical brain MRI scan, age 18 years or older, no exposure to intravenous steroid therapy for at least 1 month, and no disease-modifying therapy at the time of baseline scan. Brain MRI scans were obtained using a standardized protocol at baseline and every 3 months during the first year. All brain MRIs were acquired on a 1.5-T GE scanner (General Electric Medical Systems, Milwaukee, Wisconsin) using a quadrature head coil. Each MRI examination included an axial, T1-weighted, 3-dimensional, spoiled gradient echo imaging sequence (echo time = 6 milliseconds, repetition time = 27 milliseconds, flip angle = 40°, 192 × 256 × 124 matrix, 180 mm × 240 mm × 186 mm field of view) and slice thickness of 1.5 mm (with pixel resolution of 0.94 × 0.94 × 1.5 mm) and axial, T2-weighted spin-echo images (echo time = 80 milliseconds, repetition time = 2500 milliseconds, 192 × 256 matrix, 180 × 240 mm field of view, 3-mm-thick slices, no gap, 47 slices). Study scans obtained approximately 6 months after study entry were used for follow-up evaluation. The closest available scan was used when the scan at month 6 was not performed.
All scans were independently and blindly reviewed. For both groups, the overall number of T2-bright lesions (defined as foci ≥3 mm2 of increased signal on the T2-weighted FLAIR or T2-weighted spin-echo images), the number of well-defined ovoid and large (≥1 cm) lesions, and the number of gadolinium-enhancing (Gd+) lesions were compared between the 2 age groups. Operational definitions were provided elsewhere.7 The number of Gd+ lesions was determined by comparing precontrast and postcontrast T1-weighted sequences. All Gd+ lesions were also seen on T2-weighted FLAIR or T2-weighted sequences. Areas of confluent T2-weighted FLAIR hyperintensity, defined as involving the white matter of greater than 2 adjacent gyri, were also compared. Lesion resolution (defined as ≥50% decrease in the number of T2-bright areas) between the first and second MRI scans was evaluated as detailed elsewhere.7 No steps were taken to minimize the impact of differences in acquisition between the first and the second scans as this is not customarily used for clinic and trial scans.
Calculations and statistical analyses were performed using Stata 10.0 statistical software (StataCorp, College Station, Texas). Means (SD) or medians (with ranges) were used to summarize demographic, clinical, and MRI data. Because the number of T2-bright foci were not normally distributed, results are presented as median with range or proportion of patients with lesions in specific locations. Nonparametric tests were used to compare number of lesions between both groups (Mann-Whitney). Proportions were compared with the χ2 test. Multivariate logistic regression was performed, adjusted for race, to evaluate if children were more likely than adults to have the involvement of various regions on initial brain MRI. The effect of race/ethnicity on lesion number and location was evaluated in children. Patients with mixed race/ethnic ancestry (n = 4) were dropped from these analyses.
We identified 41 patients with pediatric-onset MS and 35 patients with adult-onset MS for whom initial brain scans were available. Patient characteristics are presented in Table 1. The main differences between groups included sex ratio, race, and proportion of patients with spinal cord and polyregional presentations.
Time between symptom onset and first available brain MRI scan was longer in adults because their first available scan was in fact the baseline scan of the natural history study, while in patients with pediatric-onset MS, the first clinical scan was used. The MRI baseline differences for children and adults are summarized in Table 2 and Table 3. All but 1 patient with pediatric-onset MS and all patients with adult-onset MS had at least 1 T2-bright area on the initial scan. The number of T2-bright foci at presentation was substantially higher in patients with pediatric-onset MS than adult-onset MS. In addition, children had a higher number and proportion of poorly defined T2-bright areas, large T2-bright areas, brainstem/cerebellar and corpus callosum involvement, and Gd+ lesions. Deep gray matter involvement was similar in adults and children.
In the multivariate analysis, pediatric patients had more than 4-fold increased odds of having infratentorial T2-bright foci compared with adults (odds ratio, 4.23; 95% confidence interval, 1.29-13.83; P = .02). There appeared to be no independent effect of race/ethnicity on infratentorial involvement (white non-Hispanic vs others: odds ratio, 0.57; 95% confidence interval, 0.17-1.93; P = .36). Among patients with pediatric-onset MS, no effect of race/ethnicity on the initial brain MRI was found in terms of total number of T2-, large T2-, and location of T2-bright foci (data not shown). White non-Hispanic patients tended to have less deep gray matter involvement (16.7% vs 41.7%; P = .13) but more corpus callosum involvement (91.7% vs 54.2%; P = .02) than others.
All but 1 patient in each group had follow-up scans available. Data pertaining to the second brain MRI scans are presented in Table 4. The statistical analysis was repeated after removing the second scans obtained less than 1 month and more than 1 year after the first one. The results were not meaningfully changed (data not shown). Patients with pediatric-onset MS had more new T2-bright foci and more Gd+ lesions on the second scan than adults. The proportion of patients receiving disease-modifying therapy at the time of the follow-up scan was 10% in patients with pediatric-onset MS vs 36% in patients with adult-onset MS. Among patients with pediatric-onset MS, there was no difference in terms of the number of new T2-bright foci and Gd+ lesions according to race/ethnicity (data not shown).
We report that patients with pediatric-onset MS have a higher MRI disease burden at presentation and higher disease activity on follow-up scans than adults at the same disease stage seen at the same institution. This challenges the notion that clinical onset of pediatric-onset MS may be closer to the biological disease onset3 and that patients with pediatric-onset MS may experience a more benign clinical course than patients with adult-onset MS.1,12
Pediatric-onset MS brain MRI scans at disease onset exhibit remarkable features compared with adult-onset MS. First, our patients with pediatric-onset MS had more frequent radiological infratentorial involvement than adults at the same disease stage. The more frequent radiological infratentorial involvement in children questions if the underlying biological processes at play are different in younger patients. It is unclear whether the timing of myelin maturation in pediatric-onset MS explains the selective infratentorial involvement. There appears to be a clear T2 relaxation time age dependency in brains from birth to early age (<5 years of age),13 which could affect the sensitivity of detecting T2-weighted lesions in very young children compared with adults. However, this relaxation dependency is present in both the supratentorial and infratentorial brain parenchyma,13 thus not likely to influence the proportion of infratentorial/supratentorial lesions we observed in our study between patients with adult-onset MS and pediatric-onset MS. Furthermore, whether the inflammatory response in pediatric-onset MS selectively targets antigens predominantly located in the posterior fossa remains to be determined. The selective infratentorial involvement on the initial brain MRI scan in pediatric-onset MS is consistent with our findings that patients with pediatric-onset MS demonstrate more frequent clinical involvement of the brainstem or cerebellum at onset than adults.2 Second, pediatric patients with MS exhibit more ill-defined and large T2-bright foci on their initial scans than adults. This finding suggests that inflammatory processes in children may be less circumscribed than in adults, possibly as a result of more edematous reactions. We cannot exclude that differences at the level of the immature microglia and blood-brain barrier also contribute to these phenomena. Third, a significant resolution of the initial T2 lesion burden occurs in patients with pediatric-onset MS, which was not demonstrated in adult-onset MS. This is consistent with less destructive/more reversible lesions in children that could be explained by more edematous phenomenon, less axonal loss and demyelination, or better remyelination. The use of sophisticated imaging techniques, such as multicomponent T2 relaxometry, diffusion tensor imaging, and spectroscopy, may further characterize the main underlying processes.
Our findings have several implications. First, they suggest that at our institution, a large proportion of patients with pediatric-onset MS may actually meet adult criteria for MS4,10 in terms of dissemination in space but also in terms of dissemination in time, consistent with a recent report.14 The higher disease activity in pediatric-onset MS compared with adult-onset MS is also consistent with the observation in adults that younger patients have more frequent new Gd+ lesions on brain MRI scans than older patients.15 Second, the higher disease burden, frequency of infratentorial lesions, and occurrence of new lesions at MS onset in children compared with adults are worrisome, as these features have been associated with more rapid accrual of disability in adults with MS.16- 18 It remains to be confirmed by long-term follow-up whether our patients with pediatric-onset MS will have a worse prognosis in terms of disability progression, as we cannot rule out that better central nervous system plasticity in younger patients may in fact attenuate clinical progression in patients with pediatric-onset MS with very active disease.
We report that nearly all patients with pediatric-onset MS have abnormal brain MRI scans at disease onset. This is consistent with a previous publication.3 Although the total number of T2-bright foci at onset is not available from previous pediatric studies, the proportions of patients with various lesion locations reported for our pediatric-onset MS cohort match well with previous studies.3,6,14 Similarly, the proportion of pediatric patients with large lesions is within reported ranges.5,6 Finally, median numbers of T2-bright areas reported in several CIS studies in adults are in line with our adult-onset MS findings.17,19,20 The median number of T2-bright foci on the initial scan of our patients with pediatric-onset MS remains higher than values reported for patients with adult-onset MS in CIS studies.
Our study has several limitations. A referral bias may exist that could account for some of the reported group differences. Pediatric patients are seen at the Regional Pediatric Multiple Sclerosis Center at UCSF that serves the entire West Coast, while adults seen at UCSF tend to come from a smaller referral area, as several adult MS centers are available in California. This difference could bias the referral toward more severe pediatric patients being referred to our pediatric MS clinic. In addition, because of limited awareness that MS can affect children, it is possible that children with milder cases may be undiagnosed for longer periods and therefore are not referred to us. Second, the MRI protocols used for children and adults were nonuniform. This difference, however, cannot explain the significant differences observed. The use of dedicated and conventional T2-weighted images in the adult MRI protocol and the predominant use of nonoverlapping T2-weighted FLAIR sequences (less sensitive in the posterior fossa) in children should have biased our findings toward detecting more posterior fossa lesions in adults, not the contrary. Third, that the MRI scans used for this analysis were obtained later in adults should also have biased toward higher T2 lesion burden in adults since most T2-bright foci tend to remain visible indefinitely in that age group.
The MRI differences between pediatric and adult MS onset reported herein occur in the context of several demographic and clinical differences between groups (age, ethnic background, sex ratio, clinical onset location, monoregional vs polyregional onset). It is unclear if any of these demographic/clinical differences explain most of the reported MRI phenotype. Clearly, age was the main independent predictor for infratentorial involvement in the multivariate analysis, but also for other locations. Race/ethnicity may be associated with some specific lesion location but this has to be confirmed in a larger cohort. The higher frequency of infratentorial involvement on MRI of patients with pediatric-onset MS is striking, as clinical presentation involved brainstem/cerebellum equally in our 2 groups. These findings did not change substantially after removing polyregional presentations (data not shown).
The findings reported herein need to be replicated with a standardized MRI protocol in larger cohorts. In the future, the use of more sophisticated imaging techniques may help to further dissect biological differences related to age that pertain to qualitative and quantitative tissue injury and repair.
Correspondence: Emmanuelle Waubant, MD, PhD, UCSF Regional Pediatric Multiple Sclerosis Center, 350 Parnassus Ave, Ste 908, San Francisco, CA 94117 (email@example.com).
Accepted for Publication: March 7, 2009.
Author Contributions:Study concept and design: Waubant and Pelletier. Acquisition of data: Waubant, Chabas, Okuda, Henry, Soares, and Pelletier. Analysis and interpretation of data: Waubant, Chabas, Glenn, Mowry, Henry, Strober, Soares, Wintermark, and Pelletier. Drafting of the manuscript: Waubant. Critical revision of the manuscript for important intellectual content: Waubant, Chabas, Okuda, Glenn, Mowry, Henry, Strober, Soares, Wintermark, and Pelletier. Statistical analysis: Waubant and Mowry. Obtained funding: Waubant, Henry, and Pelletier. Administrative, technical, and material support: Waubant, Okuda, Wintermark, and Pelletier. Study supervision: Waubant, Glenn, and Pelletier.
Financial Disclosure: None reported.
Funding/Support: The UCSF Regional Pediatric Multiple Sclerosis Center belongs to the Pediatric MS Network initiated by the National Multiple Sclerosis Society (NMSS). The adult natural history study was supported by grant RG3240 from the NMSS. Dr Mowry has an NMSS Sylvia Lawry Fellowship Award and a Partners Clinical Fellowship Award. Drs Waubant and Chabas are supported by the Nancy Davis Foundation. Dr Pelletier is a Harry Weaver Neuroscholar of the NMSS.