Pediatric MS

Pediatric-onset multiple sclerosis (POMS) typically refers to MS onset before 18 years of age. Approximately 3-5% of all individuals diagnosed with MS will experience disease onset before 16 years of age (Belman et al., 2016; Chitnis et al., 2009; Boiko et al., 2002; Duquette et al., 1987). Two recent consensus reports – one by neurologists in the United States and one by the International Pediatric MS Study Group provide helpful insights into the diagnosis and management of MS in the pediatric population.

The Free-access Neurology supplement on Pediatric Demyelinating Disorders, from the 2016 International Pediatric MS Study Group, provides a comprehensive review of pediatric demyelinating disorders, including MS.

• A recent review discusses genetic and environmental risk factors in pediatric MS.
• Environmental risk factors may include past exposure to Epstein-Barr Virus and second-hand tobacco smoke  (Ascherio 2013; Banwell et al., 2011; Tenembaum 2010; Waubant et al., 2016).
• Vitamin D appears to play an important role in immune function. A low total vitamin D level is associated with an increased risk of developing MS. In someone already diagnosed, a low vitamin D may increase the risk of relapse. (Gianfrancesco et al., 2017;  Hanwell & Banwell 2011).
• Low dietary iron may increase the risk of MS in children (Pakpoor et al., 2017).
• The gut microbiome has been implicated in small studies, but still needs validation in larger cohorts (Tremlett et al., 2016).
• Obesity may increase the risk of developing MS in patients with certain genetic susceptibilities  (i.e., HLA-DRB1*15 alleles) (Gianfrancesco et al., 2017; Langer-Gould et al., 2013; Hedstrom et al., 2014).
• 15-20% of MS patients report having a family member with MS. Children with a first-degree relative with MS (i.e. parent or sibling) have a 2-4% increased risk of developing MS. (Esposito et al., 2015; Nielsen et al., 2005).
• Though no single gene has been shown to cause MS, many single nucleotide polymorphisms (SNPs) across the genome have been associated with increased risk in children and adults (van Pelt et al., 2013). One susceptibility allele in particular, HLA-DRB1*15, has been associated with an increased risk of MS in children of European ancestry (Disanto et al., 2011). There also appears to be an interaction between negative DRB1*15 status and remote HSV-1 infection for increased MS risk (Waubant et al., 2013).
• Ancestry appears to play a role in adult MS. Place of birth, regardless of ancestry, appears to factor more into pediatric MS. (Kennedy et al., 2006).
• Maternal illness during pregnancy, pesticide exposure due to paternal occupation and use of pesticides in the household during pregnancy may increase the chance the unborn child will go on to develop MS. Delivery by Cesarean section may decrease the risk of developing MS in childhood by 60%. (Graves et al., 2016).
• The onset of puberty seems to increase the likelihood of developing MS in girls, as they are 2-3 times more likely than boys to develop MS after puberty begins. There is no gender difference prior to pubertal onset (Ahn et al., 2015; Belman et al., 2016; Chitnis 2013).
• Later age at menarche may decrease the risk of developing MS (Ahn et al., 2015).

• Children experience 2-3 times more frequent relapses than adults with early MS (Gorman et al., 2009). This increased relapse frequency appears to persist over at least the first 6 years of the disease (Benson et al., 2014).
• Children tend to be polysymptomatic at presentation but recover from relapses more quickly than adults, on average over 4 weeks compared to 6-8 weeks in adults (Chitnis 2013).
• Pediatric patients with MS are more likely to experience more frequent relapses compared to adults with MS. However, disability accrual is slower in children compared to their adult counterparts (Chitnis 2020). Pediatric MS patients show disability at a younger age than their adult counterparts (Harding et al., 2012; Renoux et al., 2007).
• Pediatric MS patients have a higher T2 lesion burden than adults (Waubant et al., 2009). Post-mortem comparison found more extensive axonal injury in the demyelinating lesions of pediatric brains than adults. Therefore, childhood MS appears to be more inflammatory (Pfeifenbring et al., 2015).
• Ancestry appears to play a role in adult MS. Place of birth, regardless of ancestry, appears to factor more into pediatric MS. (Kennedy et al., 2006).
• Approximately one-third of children show evidence of significant cognitive impairment early on (Amato et al., 2008), with significant progression within 2 years (Amato et al., 2010). Over half demonstrate a decline in cognitive indices over 5 years. However, a subset of patients can show improvement over time, suggesting that early intervention may mitigate the cognitive impact of pediatric-onset MS (Amato et al., 2014).

As is true in adults, children with two discrete demyelinating events separated in time and space meet criteria for a diagnosis of MS. The challenge lies in distinguishing MS from the numerous other disorders in children that can also present with transient demyelinating episodes.

The Pediatric International Study Group (Krupp et al., 2007) proposed consensus definitions for monophasic acute disseminated encephalomyelitis (ADEM – an essential feature of which is the presence of encephalopathy), neuromyelitis optica (NMO) and clinically isolated syndrome (CIS) to distinguish them from pediatric MS. The group updated those definitions in 2013. To help facilitate this,  the International Study Group has also proposed a minimum diagnostic battery for use in pediatric patients with an initial inflammatory demyelinating event.

This chart (modified from Wingerchuk et al., 2015; Krupp et al., 2013; Sadaka et al., 2012; Banwell et al., 2011) demonstrates a diagnostic pathway for a child who has experienced an acute CNS demyelinating event who then has a second episode of neurologic dysfunction. Note that a subset of patients with ADEM (which is typically a self-limited disease) experience relapses. Some of these patients are subsequently reclassified as MS based on the nature of the clinical events, laboratory findings, and MRI changes. While the risk of developing MS following an episode of ADEM in childhood is <10%, the risk after an episode of CIS has been shown to be 26% to 62% in several studies that utilized the International Study Group criteria (Alper G et al., 2009; Neuteboom RF et al., 2008; Banwell et al., 2007; Dale RC et al., 2007). Classification of first and subsequent episodes of acquired CNS demyelination, along with its differential diagnoses, clinical features and outcomes, were reviewed by Banwell et al. in 2007.

Pediatric MS is almost exclusively diagnosed as a relapsing remitting course with frequency of primary progressive MS estimated at 0-7% (Abdel-Mannan, 2020). This is in contrast to adult MS in which primary progressive MS is more frequent

Many of the disease modifying therapies prescribed for adults with MS are also prescribed for pediatric MS. These include conventional first line therapies like interferon beta 1A (Avonex®, Betaseron®) and Glatirimer acetate (Copaxone®). Safety and efficacy of these self-injectable  drugs have been demonstrated in small retrospective studies, case studies and unblinded controlled trials (Banwell et al., 2006, Tenenbaum et al., 2013, Kornek et al., 2003). Lack of tolerability or continued progression of disease despite these therapies may necessitate the use of other, newer therapies.

Pediatric MS is considered highly active, characterized by more frequent relapses, rapid lesion accrual early in the disease course and more cognitive and physical disability at an earlier age than in adult-onset MS (Hacohen et al., 2020). In a cohort study comparing initial treatment with newer DMTs versus older injectables in children with MS/CIS, newer DMTs provided better disease control, though long-term safety data are still needed (Krysko et al., 2020). Due to the highly active nature of pediatric MS, and earlier age of conversion to secondary progressive MS, initial treatment with  newer, higher-efficacy DMTs has been recommended by some (Hacohen et al., 2020).
 
In 2018 the U.S. Food and Drug Administration approved the use of the oral MS therapy fingolimod (Gilenya®, Novartis AG) for the treatment of children and adolescents 10 years of age or older with relapsing-remitting MS.

Other oral therapies for MS, including dimethyl fumarate (Tecfidera®) and teriflunomide (Aubagio®), are currently under investigation in clinical trials for the treatment of pediatric MS. 
 
An observational study of natalizumab (Tysabri®) showed that the safety and efficacy in children was similar to that seen in the adult MS population (Ghezzi et al., 2015).
 
In addition to the adult FDA-approved therapies used in pediatric MS, another treatment that is not FDA-approved for MS, known as rituximab (Rituxan®), has been studied in small trials of pediatric patients, demonstrating both safety and efficacy. Rituximab is widely used in other pediatric autoimmune disorders and has a favorable safety profile (Dale et al., 2014).

Ultimately, starting or switching a disease modifying therapy in children and adolescents requires an in-depth discussion between the provider, child and family. It should include the goals and expectations of the child and family, how the drug is expected to control MS and the side effects, risks, alternatives and any monitoring that must be performed before and during therapy. In this way, providers, patients and families can participate in a shared decision-making process to determine the therapy that best meets the individual needs of each patient.

The International Pediatric MS Study Group has written a series of articles highlighting the advances, unanswered questions and challenges in diagnosing and treating MS in children. These articles have been published as a supplement in the journal, Neurology. 
 
A publication from the MS International Federation (MSIF) summarizes the key points from each of these articles.
 
In any patient diagnosed with pediatric MS, poor academic performance, difficulty with peer relations,  low self-esteem, difficulty with accepting the diagnosis and psychiatric comorbidities are all important considerations. While a detailed psychosocial evaluation by a trained professional should always be pursued, pediatric MS support groups can provide additional crucial information, resources and networks for both patients and their families who are faced with this complex and life-long disease.


Reviewed by Carla Francisco, MD and Aaron Abrams, MD, February, 2021

• Child Neurology Foundation - Transition to Adult Care
• The educational impact of childhood-onset multiple sclerosis: Why assessing academic achievement is imperative - MS Journal, 2020
• Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis - Journal of Neurology, Neuroimmunology, Neuroinflammation, 2020
• Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline - MS Journal, 2020
• Clinical trials of disease-modifying agents in pediatric MS - Neurology, 2019
• Use of newer disease-modifying therapies in pediatric multiple sclerosis in the US - Neurology, 2018