Pediatric-onset Multiple Sclerosis Patients Research Articles

Imaging Pediatric Multiple Sclerosis-Challenges and Recent Advances.

Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task-based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS.

Attitudes, perceptions, and use of marijuana in youth with multiple sclerosis.

Studies have shown a negative impact on cognition and brain volume in marijuana-using adult multiple sclerosis (MS) patients and healthy adolescents. Given that onset of MS during childhood and adolescence negatively impacts brain growth and the normal maturation of neuronal networks, the addition of marijuana exposure in these youth may be even more harmful. Determine attitudes toward and prevalence of recreational marijuana use in MS youth. We surveyed 52 consecutive pediatric-onset MS patients from three pediatric MS centers in the UnitedStates. Participants answered a structured questionnaire to capture attitudes toward marijuana and personal use habits, if present. Nearly half reported use of marijuana, with the majority beginning to use in mid-to-late adolescence. The most popular reasons for using marijuana were relaxation (72%), improvement of medical problems (64%), and stress reduction (52%). Over half (64%) of marijuana users perceived it to have negative effects on memory and focus. Cost and access were not barriers to use, despite all respondents being less than age 21. Youth with MS endorse recreational marijuana as safe, and many use marijuana frequently despite appreciating a negative impact on memory. More detailed understanding of the long-term impact of marijuana use in youth with MS is needed.

Pronounced Structural and Functional Damage in Early Adult Pediatric-Onset Multiple Sclerosis with No or Minimal Clinical Disability.

Pediatric-onset multiple sclerosis (POMS) may represent a model of vulnerability to damage occurring during a period of active maturation of the human brain. Whereas adaptive mechanisms seem to take place in the POMS brain in the short-medium term, natural history studies have shown that these patients reach irreversible disability, despite slower progression, at a significantly younger age than adult-onset MS (AOMS) patients. We tested for the first time whether significant brain alterations already occurred in POMS patients in their early adulthood and with no or minimal disability (n = 15) in comparison with age- and disability-matched AOMS patients (n = 14) and to normal controls (NC, n = 20). We used a multimodal MRI approach by modeling, using FSL, voxelwise measures of microstructural integrity of white matter tracts and gray matter volumes with those of intra- and internetwork functional connectivity (FC) (analysis of variance, p ≤ 0.01, corrected for multiple comparisons across space). POMS patients showed, when compared with both NC and AOMS patients, altered measures of diffusion tensor imaging (reduced fractional anisotropy and/or increased diffusivities) and higher probability of lesion occurrence in a clinically eloquent region for physical disability such as the posterior corona radiata. In addition, POMS patients showed, compared with the other two groups, reduced long-range FC, assessed from resting functional MRI, between default mode network and secondary visual network, whose interaction subserves important cognitive functions such as spatial attention and visual learning. Overall, this pattern of structural damage and brain connectivity disruption in early adult POMS patients with no or minimal clinical disability might explain their unfavorable clinical outcome in the long term.

Breastfeeding During Infancy Is Associated With a Lower Future Risk of Pediatric Multiple Sclerosis

BackgroundRisk of multiple sclerosis (MS) is influenced by environment and genetics. Infant breastfeeding appears protective against some childhood autoimmune disorders, but its impact on risk of MS in childhood is unknown. The objective of this study is to analyze the association of breastfeeding in infancy on future risk of pediatric-onset MS. Basic ProceduresBiological mothers of 36 consecutive pediatric-onset MS patients completed a questionnaire on history of breastfeeding and various birth and demographic factors. The control group consisted of 72 otherwise healthy patients with a diagnosis of migraine and normal brain magnetic resonance imaging obtained less than 12 months before enrollment. Inverse probability of treatment weighting was used to reduce selection bias and balance the covariates between breastfed and non–breastfed children. Main FindingsDemographics (with the exception of body mass index) and birth factors were not significantly different between groups. Whereas 36% of cases were breastfed, 71% of controls were breastfed (P = 0.001). The median duration of breastfeeding was 0 weeks (range: 0 to 40 weeks) for cases and 16 weeks (range: 0 to 216 weeks) for controls. Lack of infant breastfeeding was associated with future diagnosis of pediatric-onset MS (odds ratio = 4.43; 95% confidence interval, 1.68 to 11.71; P = 0.003). This association remained significant after correcting for covariates, such as body mass index and age at diagnosis. ConclusionsThese data demonstrate that absence of infant breastfeeding has an association with an increased risk of pediatric-onset MS diagnosis.

7T MRI Visualization of Cortical Lesions in Adolescents and Young Adults with Pediatric-Onset Multiple Sclerosis.

Cortical pathology in multiple sclerosis (MS) has been associated with prolonged and progressive disease. 7T magnetic resonance imaging (MRI) provides enhanced visualization of cortical lesions (CLs). Hence, we conducted a pilot study to explore whether CLs occur early in MS, as evidenced by pediatric-onset patients. A total of 8 pediatric-onset MS patients were imaged using 7T MRI. CLs were annotated on T1-weighted magnetization-prepared rapid acquisition of gradient echoes images as leukocortical (LC), intracortical, or subpial. Total CLs, age at onset, age at scan, disease duration, total relapses, and Expanded Disability Status Scale (EDSS) score were recorded. A median of 120 (range: 48-144) CLs was identified in 8 MS patients (3 female, all with relapsing remitting MS, mean age at scan 21 years ± 3.5 SD, mean age of disease onset 15 years ± 2.3 SD, mean disease duration 5.3 years ± 3.4 SD, median EDSS 2.0). Nearly all the lesions identified were LC. Many CLs are detectable using 7T MRI in patients with pediatric-onset MS despite relatively brief disease duration, absence of progressive disease, and very limited physical disability-supporting early cortical involvement in MS.

The cognitive reserve theory in the setting of pediatric-onset multiple sclerosis

Background: The study of cognitive reserve (CR) in relationship with cognitive impairment (CI) in pediatric-onset multiple sclerosis (POMS) may provide cues to identifying subjects at higher risk of impairment and scope for therapeutic strategies. Objectives: To assess the potential impact of CR on cognition in a cohort of POMS patients. Methods: In all, 48 POMS patients were followed up for 4.7 ± 0.4 years. CI was defined as the failure of ⩾3 tests on an extensive neuropsychological battery. Change of neuropsychological performance was assessed through the Reliable Change Index (RCI) method. At baseline, CR was estimated by measuring the intelligence quotient (IQ). The relationships were assessed through multivariable regression analyses. Results: At baseline, CI was detected in 14/48 (29.2%) patients. Two out of 57 healthy control (HC; 3.5%) met the same criteria of CI (p < 0.001). A deteriorating cognitive performance using the RCI method was observed in 18/48 patients (37.6%). Among the 34 cases who were cognitively preserved at baseline, a higher reserve predicted stable/improving performance (odds ratio (OR) = 1.11; 95% confidence interval (CI): 1.03–1.20; p = 0.006). Conclusion: Our results suggest that higher CR in POMS patients may protect from CI, particularly in subjects with initial cognitive preservation, providing relevant implications for counseling and rehabilitation strategies.

Sex differences and subclinical retinal injury in pediatric-onset MS

Objective: To assess retinal ganglion cell (RGC) injury and sex differences in axon loss in pediatric multiple sclerosis (MS). Methods: This is a cross-sectional evaluation of consecutive pediatric MS subjects and controls. Eyes with acute optic neuritis (ON) within 6 months of visit were excluded. Spectral domain optical coherence tomography (OCT) included peripapillary ring and macular scans with post-acquisition segmentation of retinal layers using automated software (Heidelberg v1.8.6.0). Generalized estimating equations (GEEs) measured associations of sex, history of ON, disease duration, and age with OCT outcomes. Results: In all, 53 MS subjects (100 eyes, median disease duration = 1.0 years, interquartile range (IQR) = 0.3, 2.5) were compared to 19 control subjects (38 eyes). Eyes with history of ON showed reduced retinal nerve fiber layer (RNFL: −26.8 µm, 95% confidence interval (CI) = −38.9, −14.8, p < 0.001) and 26% lower ganglion cell layer (GCL) volumes (−0.12 mm3, 95% CI = −0.16, −0.072, p < 0.001) compared to control eyes. Non-ON MS eyes had lower temporal RNFL (−11.9 µm, 95% CI = −18.6, −5.3, p < 0.001) and GCL volumes (−0.036 mm3, 95% CI = −0.06, −0.011, p = 0.004) than control eyes. In MS eyes, males versus females had lower global RNFL (−9.4 µm, 95% CI = −17.4, −1.33, p = 0.022) and in ON eyes had lower temporal quadrant RNFL (−9.6 µm, 95% CI = −15.1, −4.15, p = 0.001). Conclusion: Subclinical retinal injury occurs in pediatric-onset MS patients without a history of ON. As in adult-onset MS, substantial GCL thinning is present in eyes with prior ON. Finally, greater retinal axonal injury occurs in boys compared to girls.

Dimethyl Fumarate Is Well Tolerated in a Small Cohort of Pediatric-Onset Multiple Sclerosis Patients (P3.010)

Dimethyl Fumarate Is Well Tolerated in a Small Cohort of Pediatric-Onset Multiple Sclerosis Patients (P3.010)

Brain activation patterns and cognitive processing speed in patients with pediatric-onset multiple sclerosis

ABSTRACTObjective: This study aimed to determine the extent and pattern of brain activation elicited by a functional magnetic resonance imaging version of the Symbol Digit Modalities Test (fMRI–SDMT), a task of information processing speed, in pediatric-onset multiple sclerosis (MS) patients as compared to sex- and age-matched non-MS self-reported healthy individuals. Method: Participants included 20 right-handed individuals aged 13–24 years with pediatric-onset MS (mean age = 19 years, 15 female) and 16 non-MS self-reported healthy individuals. All participants underwent a 3.0-tesla MRI scan with structural (T1; T2; proton density, PD; fluid-attenuated inversion recovery, FLAIR) and fMRI–SDMT acquisition. Participants were instructed to indicate with a button press whether a single pairing of a symbol to a number matched any of those shown in a key that displays nine possible pairings. Results: Response time (p = .909) and accuracy (p = .832) on the fMRI–SDMT did not differ between groups. However, the MS group demonstrated lower overall activation than the non-MS group in the right middle frontal gyrus (p = .003). Within the MS group, faster response time was associated with greater activation of the right inferior occipital, anterior cingulate, right superior parietal, thalamus, and left superior occipital cortices (all p < .05). A significant interaction effect was demonstrated, indicating that faster response time was associated with greater activation of the left superior occipital region in the pediatric MS group than in the non-MS group (p = .002). Conclusions: Attenuated activation of frontal regions was observed in this cohort of pediatric-onset MS patients when performing the fMRI–SDMT, even in the absence of behaviorally detectable deficits. Within the MS group only, faster response time elicited greater activation, suggesting this to be an adaptive mechanism that may contribute to limiting the impact of disease-related structural pathology.

Medication utilization among pediatric-onset multiple sclerosis patients in the United States

Medication utilization among pediatric-onset multiple sclerosis patients in the United States

Altered resting-state functional connectivity in cognitively preserved pediatric-onset MS patients and relationship to structural damage and cognitive performance

Objective: To evaluate resting-state functional connectivity (FC) and relationship to brain volumes and cognition in a sample of cognitively preserved pediatric-onset multiple sclerosis (MS) patients. Methods: Sixteen cognitively intact pediatric-onset MS patients and 15 healthy age- and sex-matched controls underwent cognitive testing and 3T anatomical and functional MRI. Resting-state FC patterns were examined using region-of-interest-based timeseries correlations. Results: Compared to controls, pediatric-onset MS patients demonstrated higher FC of the precuneus, particularly with the anterior cingulate cortex (z=4.21, p<.001), frontal medial cortex (z=3.48, p<.001), and cerebellum (z=3.72, p<.001). Greater T2 lesion volume and lower normalized thalamic volume were associated with reduced FC of the thalamus, especially for FC with the right superior occipital region (t=−2.87, p=.0123 and t=2.27, p=.04 respectively). FC of the left frontal medial cortex was negatively correlated with composite cognitive z-score in the pediatric-onset MS group (p<.05). Conclusions: Greater resting-state FC between posterior and anterior brain regions is present in pediatric-onset MS. With greater disease-related structural pathology, there is a disruption of thalamo-cortical FC. In the absence of actual cognitive impairment, heightened FC of the frontal medial cortex was associated with lower cognitive performance, suggesting that greater functional resources are recruited during resting-state in patients with reduced cognitive efficiency.

Pediatric-Onset Multiple Sclerosis Disease Progression in Kuwait: A Retrospective Analysis

BackgroundPediatric and adults patients share basic aspects of multiple sclerosis; however, pediatric patients may have distinctive clinical features and disease course. ObjectiveTo compare the demographic and clinical characteristics between patients of pediatric-onset and adult-onset multiple sclerosis. MethodsUsing the Kuwait National Multiple Sclerosis Registry , multiple sclerosis patients with disease onset at age ≤17 years (pediatric-onset multiple sclerosis) or >17 years (adult-adult multiple sclerosis) were identified. Several demographics and clinical characteristics were analyzed. Disability measures and time to reach secondary progressive multiple sclerosis were compared between the two cohorts using chi-square and Student t tests. ResultsA total of 984 records of multiple sclerosis patients were assessed, of which 111 (11.3%) had disease onset at age ≤17 years. The female to male ratio did not differ between the two groups (P = 0.19). The mean age at onset of pediatric- and adult-onset multiple sclerosis was 14.9 and 27.68 years, respectively. Pediatric-onset multiple sclerosis patients were more likely to have brainstem/cerebellar (P < 0.03) and multifocal (P < 0.01) presentations at onset. The mean number of relapses did not differ between the two cohorts (3.4 ± 2.1 versus 3.05 ± 2.2; P = 0.14). The mean expanded disability status scale score at last visit was lower in the pediatric-onset cohort compared with the adult-onset cohort (2.38 ± 1.72 versus 3.02 ± 2.18; P = 0.003). The time to develop secondary progressive multiple sclerosis was longer in the pediatric-onset cohort (14.6 ± 4.6 years versus 11.0 ± 5.3 years; P < 0.04). ConclusionsPediatric-onset multiple sclerosis patients were more likely to have brainstem/cerebellar and multifocal symptoms at onset. Although the number of relapses was comparable to the adult-onset cohort, multiple sclerosis patients with pediatric-onset had lower expanded disability status scale scores and a longer time to reach secondary progressive course at last follow-up visits.

Pediatric onset multiple sclerosis patients tend to have slower disease progression (P1.109)

Pediatric onset multiple sclerosis patients tend to have slower disease progression (P1.109)

P012 - Pediatric onset multiple sclerosis patients tend to have slower disease progression

Background Data on the difference between pediatric and adult onset multiple sclerosis (MS) in terms of disease course and progression is scare in our region. Objective To compare the demographic and clinical characteristics between pediatric-onset and adulthood-onset MS. Methods Utilizing the national MS registry, we conducted a cross-sectional study to dichotomize MS patients based on age of disease onset (under 17 years or above). Demographics and clinical characteristics (age, symptoms presentation at onset, disease duration, disease course, relapses, EDSS score, and use of disease modifying therapies) were collected. Simple descriptive statistical tests were used to describe numerical and non-numerical values. Variables of both groups were compared using chi-square and Student t -tests. Results A total of 984 records of MS patients were assessed; of whom 111 (11.3%) had the disease onset before 17 years of age. Pediatric onset MS patients were more likely to be female (female:male ratio 2.5 vs. 1.85; p p p p p p p p Conclusions MS patients, who had their disease onset before age 17, tend to be female and have brainstem/cerebellar and multifocal symptoms at disease onset. Despite the comparable relapse rate and disability measures between the two cohorts, patients with pediatric onset had slower disease progression.

The Symbol Digit Modalities Test is an effective cognitive screen in pediatric onset multiple sclerosis (MS)

ObjectiveTo evaluate the Symbol Digit Modalities Test (SDMT) as a tool for identifying pediatric-onset MS patients at risk for cognitive impairment. BackgroundThe SDMT is a brief measure of cognitive processing speed that is often used in adult MS patients. Approximately one-third of pediatric-onset MS patients have cognitive impairment and there is a need for an effective screening instrument. Design/methodsSeventy (70) consecutive outpatients with pediatric-onset MS underwent clinical evaluations including the SDMT and were compared to those with other pediatric neurological diagnoses (OND, n=40) and healthy controls (HC, n=32). A subset of the MS group and all healthy controls completed neuropsychological evaluation within one year of SDMT administration. ResultsThe MS group performed worse on the SDMT compared to the HC group (p=0.02). Thirty-seven percent (37%) of the MS, 20% of the OND, and 9% of HC groups scored in the impaired range. For MS participants who underwent neuropsychological testing (n=31), the SDMT showed 77% sensitivity and 81% specificity for detecting neuropsychological impairment when administered within one year and reached 100% sensitivity when the interval was under two months (n=17). Overall, older age and increased disability predicted poorer SDMT performance (age r=−0.26, p=0.03) and the Expanded Disability Status Scale score or EDSS (r=−0.47, p<0.001), while a history of optic neuritis predicted better performance (p=0.04). Optical coherence tomography measures were not related to SDMT performance. ConclusionIn this preliminary study, the SDMT was an effective brief screen for detecting cognitive impairment in pediatric-onset MS.

Interhemispheric cooperation in global–local visual processing in pediatric multiple sclerosis

Impairments in visuospatial abilities are commonly reported in children and adolescents with multiple sclerosis (MS). Corpus callosum (CC) pathology occurs in patients with MS and may contribute to impairment in visuospatial perception, particularly when interhemispheric information transfer is required. This study used a global–local hierarchical letter paradigm to examine the relationship between interhemispheric information transfer and white matter integrity in the CC assessed using diffusion tensor imaging. Thirteen cognitively preserved pediatric-onset MS patients and 15 age-matched healthy controls were asked to determine whether a target letter E appeared at the attended level of the stimulus. As expected, both groups processed global and local information more slowly under divided than selective attention conditions. The MS group performed similarly to the control group with respect to reaction time and accuracy on selective and divided attention conditions, with one exception. Specifically, the presence of a global target when attending to a local target caused greater response conflict in the MS group than in controls (p = .01). Pooling both the patient and control data, greater response conflict was associated with reduced white matter integrity as indicated by lower fractional anisotropy in the anterior body of the CC (r = –.33, p < .05). Results suggest that reduced white matter integrity in anterior regions of the CC may lead to less efficient inhibition of task-irrelevant global information in the hierarchal processing of visual information.

Magnetization transfer ratio recovery in new lesions decreases during adolescence in pediatric-onset multiple sclerosis patients.

Children and adolescents diagnosed with multiple sclerosis rarely accrue physical disability early in their disease. This could be explained by greater remyelination in children, a capacity that may be lost in adolescence or early adulthood. Magnetization transfer ratio (MTR) MRI can be used to quantify changes in myelin in MS. We used serial MTR imaging and longitudinal random effects analysis to quantify recovery of MTR in acute lesions and to evaluate MTR changes in normal-appearing tissue in 19 adolescent MS patients. Our objective was to determine whether younger adolescents have a greater capacity for remyelination and whether this decreases as patients approach adulthood. We detected a significant decrease in MTR recovery between ages 16 and 20 years (p = 0.023), with older subjects approaching typical recovery levels for adult-onset MS. MTR recovery in acute MS lesions decreases with age in adolescents, suggesting loss of remyelination capacity. This may be related to the conclusion of primary myelination or other developmental factors.

Increased leptin and A-FABP levels in relapsing and progressive forms of MS

BackgroundLeptin and adipocyte-fatty acid binding protein (A-FABP) are produced by white adipose tissue and may play a role in chronic inflammation in Multiple Sclerosis (MS). To assess leptin and A-FABP in relapsing and progressive forms of MS.MethodsAdipokine levels were measured in untreated adult relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS) and Healthy control (HC). Pediatric-onset MS (POMS) and pediatric healthy controls (PHC) were also assessed. Leptin and A-FABP levels were measured in serum by ELISA. Groups were compared using linear mixed-effects model.ResultsExcluding two patients with Body Mass Index (BMI) > 50, a significant difference in leptin level was found between RRMS and HC controlling for age (p = 0.007), SPMS and HC controlling for age alone (p = 0.002), or age and BMI (p = 0.007). A-FABP levels were higher in SPMS than HC (p = 0.007), controlling for age and BMI. Differences in A-FABP levels between POMS and PHC was observed after controlling for age (p = 0.019), but not when BMI was added to the model (p = 0.081).ConclusionLeptin and A-FABP levels are highest in SPMS compared to HC, suggesting a role in pathogenesis of this disease subtype. A-FABP levels are increased in POMS patients and may play a role in the early stages of disease.

Pediatric onset multiple sclerosis: McDonald criteria 2010 and the contribution of spinal cord MRI

Background: Diagnostic magnetic resonance imaging (MRI) criteria have not been sufficiently validated in pediatric multiple sclerosis (MS) despite differences in epidemiologic data and clinical disease courses between pediatric and adult MS. Objective: The objective of this paper is to evaluate the diagnostic applicability and validity of the revised McDonald diagnostic criteria 2010 in a large cohort of pediatric-onset MS patients (POMS) and compare them to previously recommended MRI-based classifications. Furthermore, we aimed to investigate the contribution of spinal cord lesions to the revised McDonald criteria 2010. Methods: A cohort of 85 patients with definite MS, age at onset 2.8–18 years, was analyzed in a retrospective multicenter study. Number and regional distribution of T2w and contrast-enhancing T1w lesions at initial and follow-up MRIs were main outcome measures. Results: In 62% of POMS the initial MRI within four weeks after symptom onset was sufficient to diagnose MS according to the revised McDonald criteria 2010. In a subcohort of patients with spinal MRI at first presentation, 10% reached the dissemination in space (DIS) and dissemination in time (DIT) criteria only by the inclusion of contrast-enhancing spinal lesions. Conclusions: The revised McDonald criteria 2010 facilitate the diagnosis of POMS already at first presentation. The addition of a spinal cord MRI was helpful only in selected cases.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1*15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1* alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent- and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1*15 allele and a significantly lower frequency of the DRB1*11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric- and the adolescent-onset MS groups contributed to the aforementioned DRB1*15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1*03 allele and a lower DRB1*16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1*16 allele, along with a non-significant tendency for higher DRB1*15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1*11 allele frequencies compared both to the pediatric- and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1* in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1*03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.