Growing Up with MS: The Adolescent Experience of Pediatric-Onset Multiple Sclerosis

Cognitive reserve is a determinant of social and occupational attainment in patients with pediatric and adult onset multiple sclerosis

Disease-modifying therapies in managing disability worsening in paediatric-onset multiple sclerosis: a longitudinal analysis of global and national registries

Pediatric-onset multiple sclerosis (POMS) patients often exhibit a wide range of cognitive deficits. Therefore, therapeutic approaches should aim not only to prevent cognitive decline but also to promote cognitive improvement. This study aimed to explore the effects of natalizumab (NTZ) on cognitive function, as measured by the Symbol Digit Modalities Test (SDMT), in both POMS and adult-onset multiple sclerosis (AOMS) patients. A total of 63 patients (34 AOMS and 29 POMS) were enrolled in this retrospective, single-center study. Patients were clinically and radiologically assessed every 6 months, and they completed the SDMT at baseline and after at least 24 months of follow-up. SDMT values were reported as corrected values (cSDMT) and z-scores (zSDMT). Annualized cSDMT and zSDMT scores were calculated by dividing the change in scores by the length of the follow-up period (expressed in years). Both POMS and AOMS groups showed improvement in annualized cSDMT and zSDMT scores, but the improvement was significantly greater in the POMS group compared to the AOMS group (+3.85 ± 4.32 vs. +1.76 ± 2.80, p = 0.010 for cSDMT; 0.41 ± 0.40 vs. 0.25 ± 0.34, p = 0.026 for zSDMT). After re-baselining at 6 months, 93% of POMS patients (27 patients) and 85.3% of AOMS patients (29 patients, p = 0.84) achieved NEDA-3 (no evidence of disease activity). The NEDA-3 status, along with clinical and demographic parameters at baseline, did not account for the observed SDMT improvement. The favorable clinical, radiological, and neuropsychological outcomes observed in this study support the use of natalizumab as a viable treatment option in POMS.

Multiple sclerosis (MS) is the most common neuroimmunological disease in young adults. Data on its clinical onset before the age of 18 (paediatric-onset MS (POMS)) are limited. This observational study present data on >1000 POMS compared with adult-onset MS (AOMS) and analysed patients regarding diagnostic delay, initial symptoms and long-term outcome using generalised additive models and adjustment for relevant confounders. The results showed a diagnostic delay and a higher proportion of women with POMS vs AOMS. Sensory (57%) and visual (48%) disturbances were the most common initial symptoms of POMS. Relapse rates were higher in POMS than in AOMS within the first 15 years after the clinical onset. The proportion of patients reaching an Expanded Disability Status Scale (EDSS) score of 3.0 by 15 years was lower in POMS (41%) than in AOMS (age-dependent, 48%-71%). A plateau phase in EDSS was observed in patients with POMS after age 40, which was not seen in those with AOMS. This plateau phase was responsible for the equalisation of the EDSS score with advanced age between POMS and AOMS. Cerebellar and polysymptomatic symptoms at clinical onset and male sex were predictors of higher EDSS scores in POMS, whereas in AOMS, pyramidal dysfunction was a predictor of worse outcomes. This largest and longest follow-up study of POMS to date revealed that women are more likely to develop MS at younger ages and experience different symptoms than men. Patients with POMS tend to have higher relapse rates but may recover more quickly from relapses and experience a more stable disease course later in life.

Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73 564 patients from 120 MS centers were available in the register. The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.

Pediatric-onset multiple sclerosis (POMS) is characterized by high inflammatory activity, aggressive course and early development of physical and cognitive disability. A highly effective early treatment must be considered in POMS. To evaluate safety and efficacy of natalizumab (NTZ) in naïve POMS. 20 naïve POMS (13F, 7M; mean age: 13.8 ± 2.7years) were treated with NTZ for at least 24months (mean number of infusions: 42 ± 20). No evidence of disease activity (NEDA)-3 plus status, i.e., no relapse, no disease progression (EDSS score), no radiological activity and no cognitive decline, was evaluated. After 2years of NTZ treatment, a significant reduction in the mean EDSS score (p < 0.0001) was observed in the whole cohort. During the follow-up, evidence of disease activity on MRI was observed in two patients (10%) and a mild decline in cognition was observed in other two. No patient had clinical relapse. At the time of last visit NEDA-3 plus status was maintained in 16 (80%) patients. No major adverse event was observed. Early treatment of aggressive POMS with NTZ proved to be highly effective in achieving and maintaining the NEDA-3 plus status. Our data support the use of NTZ as first treatment choice in POMS.

The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis. Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p=0.044), younger age (mean=8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p=0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p=0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001). MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284.

<h3>Background</h3> Age of onset of multiple sclerosis (MS) peaks in the 3rd and 4th decades and is rarely less than 18. Robust longitudinal studies in paediatric-onset MS (POMS) are limited, and a clearer understanding of outcome could optimise management strategies. <h3>Methods</h3> Patients with disease onset &lt;18 years were identified from a prospective population-based register. Clinical features including presenting symptoms, time to Expanded Disability Status Scale (EDSS) 4.0, 6.0 and 8.0 and onset of secondary progression were compared with patients with adult-onset MS (AOMS). <h3>Results</h3> 111 POMS patients were identified from a cohort of 2068. No significant differences in sex ratio, familial recurrence, relapse rate, ethnicity or clinical symptoms at presentation were identified between POMS and AOMS. However, interval to second relapse was longer (5 vs 2.6 years, p=0.04) and primary progressive disease was less common (0.9% vs 8.5%, p=0.003) in POMS than in AOMS. POMS patients also took longer to develop secondary progressive disease (32 vs 18 years, p=0.0001) and to reach disability milestones (EDSS 4.0, 23.8 vs 15.5 years, p&lt;0.0001; EDSS 6.0, 30.8 vs 20.4 years, p&lt;0.0001; EDSS 8.0, 44.7 vs 39 years, p=0.02), but did so between 7.0 and 12 years younger than in AOMS. <h3>Conclusions</h3> 5.4% of patients with MS have POMS (2.7% &lt;16 years; 0.3% &lt;10 years) and have distinct phenotypic characteristics in early disease. Furthermore, while patients with POMS take longer to reach disability milestones, they do so at a younger age than their adult counterparts and could be considered to have a poorer prognosis. Management strategies for these patients should take account of these data.

BackgroundAge of onset of multiple sclerosis (MS) peaks in the 3rd and 4th decades and is rarely less than 18. Robust longitudinal studies in paediatric-onset MS (POMS) are limited, and...

Pediatric Multiple Sclerosis

Background: Little is known about long-term cognitive and patient-reported outcomes of pediatric-onset multiple sclerosis (POMS). Objective: The objective of this paper is to compare cognitive and patient-reported outcomes in adults with POMS vs. adult-onset MS (AOMS). Methods: We compared standardized patient-reported measures MSQOL54, MFIS, CES-D and SDMT in adult patients with MS onset prior to and after age 18, using data gathered in the Comprehensive Longitudinal Investigations in MS at Brigham and Women’s Hospital (CLIMB) study. Results: Fifty-one POMS and 550 AOMS patients were compared. SDMT scores were significantly lower in POMS after adjusting for age (−7.57 (−11.72, −3.43; p < 0.001), but not after adjusting for disease duration. Estimated group difference demonstrated lower normative z scores in POMS vs. AOMS in unadjusted analysis (−0.74 (95% CI: −1.18, −0.30; p = 0.0009) and after adjusting for disease duration (−0.60; 95%CI: −1.05, −0.15; p = 0.0097). Findings were unchanged in a subset of POMS diagnosed prior to age 18. In unadjusted and adjusted analyses, no significant differences were observed in health-related quality-of-life, fatigue, depression or social support between POMS and AOMS. Conclusions: Younger age of onset was associated with more impairment in information-processing speed in adults with POMS compared to AOMS, and remained significant when controlling for disease duration in age-normed analysis. The two groups were similar in terms of patient-reported outcomes, suggesting similar qualitative experiences of MS.

ObjectiveTo evaluate long-term disability progression in pediatric-onset multiple sclerosis (POMS) and compare to adult-onset multiple sclerosis (AOMS).MethodsThis was a retrospective cohort study using prospectively collected clinical information from the Swedish MS Registry. Clinical features were compared and Kaplan-Meier and Cox proportional hazards regression were used to assess the risk of reaching sustained Expanded Disability Status Scale (EDSS) 3, 4, and 6 in POMS (multiple sclerosis [MS] onset <18 years) and AOMS (MS onset ≥18 years).ResultsA total of 12,482 persons were included; 549 (4.4%) were classified as POMS. The POMS cohort took longer to reach all 3 disability milestones from their MS onset, but did so at a younger age than the AOMS cohort. Primary progressive course (hazard ratio [HR] 4.63; 95% confidence interval [CI] 1.46–14.7), higher relapse rate in the first 5 years of disease (HR 5.35; 95% CI 3.37–8.49), and complete remission from the initial relapse (HR 0.41; 95% CI 0.18–0.94) were associated with an altered risk of progression to EDSS 4 among POMS cases. The same pattern emerged for the risk of reaching EDSS 3 and 6.ConclusionsPatients with pediatric-onset MS follow a distinctive clinical course, which should be considered in the treatment and management of the disease.

Detecting cognitive decline in pediatric MS: The significance of personal measures for high-achievers.

Social determinants of health (SDOH) affect patient health outcomes, but the impact on patients with pediatric-onset multiple sclerosis (POMS) has not been well studied. Study objectives were to (1) describe the frequency of adverse SDOH, (2) evaluate social hardships as a potential barrier to the initiation of disease-modifying therapy (DMT), and (3) explore the association between adverse SDOH and disease outcomes in POMS, as well as study attrition. This was a retrospective multicenter observational study conducted through the United States Network of Pediatric MS Centers database. Participants were patients diagnosed with POMS (excluding primary progressive MS). The primary outcome was time to initiation of DMT. Secondary outcomes included most recent Expanded Disability Status Scale (EDSS) score, steroid treatment for the first event, time to second event, and study attrition. Demographic variables and clinical outcomes were compared between patients with and without hardships (maternal education of high school or less, public insurance/no insurance, or single/no-income household). Multivariable regression models were used to assess the impact of social hardship on study outcomes. There were 996 total participants (69% female, mean age at symptom onset and EDSS score [±SD] were 14.2 ± 3 and 1.2 ± 1.1, respectively). Of 768 patients with complete demographic information, 66% reported a hardship. Hardship was associated with younger age at symptom onset and diagnosis. While there was no difference in time to DMT initiation, patients with hardship were more likely to receive steroids for the first event (odds ratio [OR] 1.66, 95% CI 1.21-2.26, p = 0.002). Lack of private insurance was associated with increased risk of study attrition (OR 1.85, 95% CI 1.14-3.00, p = 0.012) and higher EDSS score (β = 0.15, 95% CI 0.01, 0.28). Living in a no-income household (vs dual-income) was associated with a shorter time to second event (hazard ratio 1.33, 95% CI 1.02-1.74, p = 0.034). The experience of hardships is common and associated with younger age at symptom onset and diagnosis, as well as shorter time to second event. Lack of private insurance is associated with study attrition and a higher EDSS score despite no difference in time to initiating DMT. There may be differences in early disease pathophysiology related to social hardship, and future studies are needed to better understand this complex relationship.