Pediatric Multiple Sclerosis Population Research Articles

Preventing Multiple Sclerosis: The Pediatric Perspective.

Pediatric-onset multiple sclerosis (MS) is a predominantly relapsing-remitting neuroinflammatory disorder characterized by frequent relapses and high magnetic resonance imaging (MRI) lesion burden early in the disease course. Current treatment for pediatric MS relies on early initiation of disease-modifying therapies designed to prevent relapses and slow progression of disability. When considering the concept of MS prevention, one can conceptualize primary prevention (population- or at-risk population interventions that prevent the earliest facet of MS pathobiology and hence reduce disease incidence), or secondary prevention (prevention of disease consequence, such as reducing relapse frequency and lesion accrual, enhancing focal lesion repair, promoting CNS resilience against the more global facets of disease injury, and ultimately, preventing progression of neurological disability). Studying the pediatric MS population provides a unique opportunity to explore early-life exposures that contribute to the development of MS including perinatal and environmental risk determinants. Research is ongoing related to targeting these risk factors for potential MS primary prevention. Here we review these key risk factors, their proposed role in the pathogenesis of MS, and their potential implications for primary MS prevention.

Quality of Life of Children and Adolescents with Multiple Sclerosis-A Literature Review of the Quantitative Evidence.

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system that also develops in patients under 18 years of age. The disease negatively affects the quality of life (QoL) of children and adolescents. We conducted a literature review. The aim of the review was to identify the QoL of pediatric patients with MS and assess the factors determining their QoL. Methods: We analyzed studies published between 2000 and 2020 in PubMed, Scopus, Science Direct, Web of Science, and EBSCO databases. Results: In all, 17 studies were included in the review. The most common tool in assessing QoL was the generic module PedsQL. The range of mean/median global score of QoL was 53.8–81.7. The worst QoL was dominantly reported in the school and emotional spheres, on the contrary, the disease’s least determined area of QoL was the social and physical dimension. In particular, disability and fatigue were important predictors of QoL. Conclusions: MS negatively affects the school and emotional spheres in particular, so it is important to pay greater attention to these spheres of life of MS patients. As the review studies pay insufficient attention to the analysis of positive factors and their impact on the QoL of MS patients, research should integrate these phenomena. The use of MS-targeted tools in future research in the pediatric MS population is also appropriate.

A Review of Available Treatments, Clinical Evidence, and Guidelines for Diagnosis and Treatment of Pediatric Multiple Sclerosis in the United States.

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

TNFRSF1A and MEFV mutations in childhood onset multiple sclerosis.

To investigate frequency and phenotype of TNFRSF1A and MEFV mutations in childhood-onset multiple sclerosis (MS). Twenty-nine clinically well characterized patients were investigated for mutations in exons 2, 3, 4, and 6 of the TNFRSF1A gene and in exons 2, 3, 9, 10 of the MEFV gene. Standardized morbidity ratio (SMR) was used to assess whether the number of observed mutations was higher than expected. Eleven out of 29 patients tested positive for mutations. Heterozygosity for the TNFRSF1A R92Q (rs4149584) variant was found in 6/11 mutation-positive patients. The SMR for R92Q in our pediatric MS population was 4.6 (95% CI 1.7-10.0), 7.0 (95% CI 2.6-15.2), and 13.6 (95% CI 5.0-29.7), depending on reference population. Six patients carried atleast one heterozygous MEFV mutation with SMRs of 21.4 (95% CI 7.9-46.6) and 14.6 (95% CI 5.4-31.9). Clinical characteristics of childhood MS patients with or without mutations did not differ significantly. Conclusion One third of our childhood MS patients had a heterozygous mutation in the TNFRSF1A and/or MEFV gene. This proportion by far exceeds the number of mutations expected and was higher than in adult MS patients, suggesting that these mutations might contribute to the pathogenesis of childhood MS.

Management of Children with Multiple Sclerosis

The care of children and adolescents with multiple sclerosis (MS) requires appreciation of the impact of the disease on the developing brain and, in particular, the risk for cognitive impairment and academic challenges. Relapse rates in the first three years from onset are high, with an average of 1.5 relapses per year, and often require hospitalization for acute corticosteroid therapy. Disease modulatory therapies are typically prescribed, although formal clinical trials in the pediatric MS population are only just now being realized. In this review, we discuss strategies to optimize therapy for an individual child or teenager, including utilization of a multidisciplinary approach to care.

Pediatric multiple sclerosis: Clinical features and outcome.

Multiple sclerosis (MS) in children manifests with a relapsing-remitting MS (RRMS) disease course. Acute relapses consist of new neurologic deficits persisting greater than 24 hours, in the absence of intercurrent illness, and occur with a higher frequency early in the disease as compared to adult-onset RRMS. Most pediatric patients with MS recover well from these early relapses, and cumulative physical disability is rare in the first 10 years of disease. Brainstem attacks, poor recovery from a single attack, and a higher frequency of attacks portend a greater likelihood of future disability. Although prospective pediatric-onset MS cohorts have been established in recent years, there remains very limited prospective data detailing the longer-term clinical outcome of pediatric-onset MS into adulthood. Whether the advent of MS therapies, and the largely off-label access to such therapies in pediatric MS, has improved prognosis is unknown. MS onset during the key formative academic years, concurrent with active cognitive maturation, is an important determinant of long-term outcome, and is discussed in detail in another article in this supplement. Finally, increasing recognition of pediatric MS worldwide, recent launch of phase III trials for new agents in the pediatric MS population, and the clear imperative to more fully appreciate health-related quality of life in pediatric MS through adulthood highlight the need for standardized, validated, and robust outcome measures.

Natalizumab in the pediatric MS population: results of the Italian registry.

BackgroundNatalizumab is a promising option for pediatric multiple sclerosis (MS) patients with active evolution and a poor response to Interferon-beta or Glatiramer Acetate. However, no data are available in large cohorts of patients and after a long-term follow up. Our study was planned to shed lights on this topic.MethodsA registry was established in 2007 in Italy to collect MS cases treated with Natalizumab (NA) before 18 years of age.Results101 patients were included (69 females), mean age of MS onset 12.9 ± 2.7 years, mean age at NA initiation 14.7 ± 2.4 years. Mean treatment duration was 34.2 ± 18.3 months.During NA treatment, a total of 15 relapses were recorded in 9 patients, annualized relapse rate was 2.3 ± 1.0 in the year prior to NA and decreased to 0.1 ± 0.3 (p < 0.001) at last NA infusion.Mean Expanded Disability Status Scale (EDSS) decreased from 2.6 ± 1.3 at initiation of NA to 1.8 ± 1.2 at the time of last visit (p < 0.001). At brain MRI, new T2 or Gd enhancing lesions were observed in 10/91 patients after 6 months, 6/87 after 12 months, 2/61 after 18 months, 2/68 after 24 months, 3/62 after 30 months, and 5/43 at longer follow up. At the time of last observation, 58 % of patients were free from clinical (relapses/increased EDSS) and/or MRI activity (new T2 or gadolinium-enhancing lesions). No relevant adverse events were recorded.DiscussionNA was safe, well tolerated and very efficacious in the large majority of patients. Our data support the use of this medication in subjects with pediatric MS and an aggressive course.ConclusionsA relevant reduction of relapse rate and EDSS was observed during NA treatment, compared to pre-treatment period. No evidence of disease activity (NEDA) occurred in 58 % of cases.

Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials

To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints. Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters. Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (ϑ), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative ϑ, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction. Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration.

Current Therapeutic Options in Pediatric Multiple Sclerosis

Therapies for relapsing-remitting pediatric multiple sclerosis (MS) are aimed at preventing relapses (disease modifying therapies), treating acute attacks, and managing disabling cognitive and physical symptoms. Initial disease modifying therapy to prevent relapses should use one of four first-line injectable therapies that are approved for adult relapsing-remitting MS: interferon beta 1a IM, interferon beta 1a SC, interferon beta 1b SC, or glatiramer acetate. If breakthrough disease occurs or the medication is poorly tolerated, the next step should be to try one of the other first-line therapies. If the first-line therapies have been exhausted, second-line therapies such as natalizumab, cyclophosphamide, or mitoxantrone may be considered. One must use caution when choosing these potent therapies, as secondary effects may include serious infection or malignancy. Phase III studies in adult MS have been published on two oral agents, fingolimod and cladribine, and fingolimod has received FDA approval for use in relapsing-remitting MS in adults. These drugs have not been evaluated in the pediatric MS population, nor have any of three other oral agents now in phase III development: laquinimod, BG-12, and teriflunomide. Acute relapses can be treated with pulse methylprednisolone at a dosage of 20 to 30mg/kg per day (maximum 1g per day) for 3 to 5days. If this is ineffective, intravenous immunoglobulin (2g/kg divided over 2-5days) or plasmapheresis may be considered. Neuropsychological, physical therapy, and occupational therapy screening should be performed on patients with pediatric MS. Interventions focusing on visual motor integration may be particularly useful in this group Spasticity may be treated with symptomatic therapies, but one must be aware of potential adverse effects of agents such as baclofen and diazepam. Headache, fatigue, anxiety, and depression are frequently seen, and patients may need a psychiatry consultation and counseling.

Cognitive test results in pediatric MS

Heterogeneity in physical and cognitive outcomes is a well-recognized but little understood feature of multiple sclerosis (MS). Such heterogeneity likely reflects the contribution of multiple factors including genetics, physical environment, social environment, comorbid diseases, and health behaviors. Increasingly, race and ethnicity are being studied as possible factors influencing MS-related outcomes.1 In this issue of Neurology ®, Ross et al.2 examined 42 patients with pediatric-onset MS to determine whether race is associated with differences in cognition. Each study participant underwent testing to evaluate global functioning, complex attention, verbal fluency, confrontation naming, and verbal memory. The 20 African American (AA) subjects did not perform as well as the 22 Caucasian American (CA) subjects on tests of complex attention and language. Previous studies of the pediatric MS population showed a high burden of cognitive impairment and difficulties with complex attention and language; the burden of impairment increased with longer disease duration, earlier age at onset, increasing number of relapses, and level of physical disability.3,4 Ross et al. extend earlier findings by focusing on a patient-related characteristic, race, on cognitive impairment rather than on disease-related characteristics such as age …

Natalizumab in pediatric multiple sclerosis patients

Pediatric multiple sclerosis (MS) comprises 2-5% of all cases of MS. Although first-line disease-modifying therapy (DMT) including interferons and glatiramer acetate appear to be well tolerated in this population, recent work has suggested that a growing number of children suffer from disease which is resistant to treatment with these therapies. Natalizumab is a therapy which, although associated with a 1 : 1000 risk for progressive multifocal leukoencephalopathy (PML), has been shown to be well tolerated in the adult population and may lead to disease remission in adults with highly active disease. Reports of use of this therapy in the pediatric population with highly active disease have been published. This paper reviews current experience with the use of natalizumab in the pediatric MS population, with attention to potential risks and possible long-term outcomes in this population.

Therapeutic strategies in childhood multiple sclerosis.

Multiple sclerosis (MS) in children and adolescents accounts for 3-10% of the whole MS population, and is characterized by a relapsing course in almost all cases. The frequency of relapses is higher than in adult onset MS, at least in the first years of evolution. The objective of treatment is to speed the recovery after a relapse, to prevent the occurrence of relapses, and to prevent disease progression and neurodegeneration. The use of drugs for MS in children and adolescents has not been studied in clinical trials, so their use is mainly based on results from trials in adults and from observational studies. There is a consensus to treat acute relapses with intravenous high-dose corticosteroids. The possibility of preventing relapses and disease progression is based on the use of immunomodulatory agents. Interferon-beta (IFNB) and glatiramer acetate (GA) have been demonstrated to be safe and well tolerated in pediatric MS patients, and also to reduce relapse rate and disease progression. Cyclophosphamide and natalizumab could be offered as second-line treatment in patients with a poor response to IFNB or GA. New oral and injectable drugs will be available in the near future: if safe and well tolerated in the long-term follow up of adults with MS, they could be tested in the pediatric MS population.

Management of multiple sclerosis in adolescents &amp;ndash; current treatment options and related adherence issues

Multiple sclerosis (MS) is a progressive inflammatory demyelinating disorder of the central nervous system that is increasingly recognized in children and adolescents. This realization comes with additional concerns about existing therapeutic options and the impact of the disease on health-related outcomes of adolescents with MS. This five-part review provides an update on management strategies relevant to the pediatric MS population. The first section gives an overview on the epidemiology and natural history of early onset MS. The second section outlines currently available MS treatments, including medications during acute relapses and long-term immunomodulatory therapies. The third section highlights adherence issues pertaining to MS, including the challenges uniquely faced by adolescents. The fourth section provides a summary of research into quality of life and psychosocial consequences of pediatric onset MS. Attention is drawn to the grief experience of affected adolescents and the importance of peer relationships. Finally, the family resilience framework is presented as a conceptual model to facilitate optimal adaptation of adolescents with MS. Healthcare professionals can promote resilience and treatment adherence by ensuring that these individuals and their families are sufficiently informed about available MS treatments, providing instrumental support for managing potential medication side effects, and addressing age-appropriate developmental needs.

Hepatitis vaccines and pediatric multiple sclerosis

Pediatric multiple sclerosis (MS) accounts for fewer than 5% of MS cases. Nevertheless, these young patients with MS may provide invaluable insights regarding the pathogenesis of the disorder. Children with MS are closest to the onset of their disease, enabling detailed examination of potential environmental, viral, and genetic triggers. An ongoing controversy well-suited for study in a pediatric MS population is whether immunizations, particularly hepatitis B (HB) virus vaccine, increase the risk of MS and other forms of CNS demyelinating disease. In this issue of Neurology ®, Mikaeloff et al.1 examine the timing and type of HB vaccine with respect to pediatric MS risk. Despite the benefits of HB prevention, implementation of universal HB immunization has been controversial. Case reports raising the concern of CNS demyelinating disease following HB vaccination emerged in the mid-1990s, but no association between HB vaccination and MS was found in a retrospective cohort study.2 Subsequent case–control studies also failed to identify an association between recent HB immunization and MS3–5 or subsequent relapse. …

Age at Onset of Multiple Sclerosis May Be Influenced by Place of Residence during Childhood Rather than Ancestry

Multiple sclerosis (MS) most commonly affects individuals of Northern European descent who live in countries at high latitude. The relative contributions of ancestry, country of birth and residence as determinants of MS risk have been studied in adult MS, but have not been explored in the pediatric MS population. In this study, we compare the demographics of pediatric- and adult-onset MS patients cared for in Toronto, Ontario, Canada, a multicultural region. The country of birth, residence during childhood, and ancestry were compared for 44 children and 573 adults. Our results demonstrate that although both the pediatric and adult cohorts were essentially born and raised in the same region of Ontario, Canada, children with MS were more likely to report Caribbean, Asian or Middle Eastern ancestry, and were less likely to have European heritage compared with individuals with adult-onset MS. The difference in ancestry between the pediatric and adult MS cohorts can be explained by two hypotheses: (1) individuals raised in a region of high MS prevalence, but whose ancestors originate from regions in which MS is rare, have an earlier age of MS onset, and (2) the place of residence during childhood, irrespective of ancestry, determines lifetime MS risk – a fact that will be reflected in a change in the demographics of the adult MS cohort in our region as Canadian-raised children of recent immigrants reach the typical age of adult-onset MS.

Pediatric multiple sclerosis.

The onset of multiple sclerosis (MS) in childhood is being increasingly recognized. Despite this, there currently exist several barriers to the prompt diagnosis of MS in children. Many clinicians view MS as an exclusively adult-onset disease, and thus they may not entertain the diagnosis in a child. Also, the clinical and radiographic criteria for the diagnosis of MS have not been validated in a pediatric MS population. The available literature, as well as experience gained in a dedicated pediatric MS clinic, is used here to describe features of pediatric MS and contrast these with adult MS. The rationale and importance of future studies in pediatric MS is highlighted.