Pediatric MS

Pediatric MS refers to multiple sclerosis with disease onset in childhood. Approximately 3-5% of all individuals with MS will experience disease onset before age 16 (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 International Pediatric MS Study Group published in 2016, provides a comprehensive review of pediatric demyelinating disorders including MS.

• Environmental risk factors may include past exposure to Epstein-Barr Virus, second-hand tobacco smoke exposure, and vitamin D insufficiency (Ascherio 2013; Banwell et al., 2011; Tenembaum 2010).
• Vitamin D appears to play an important role in immune function. Low vitamin D levels are associated with increased risk for developing MS, and in those already diagnosed, low vitamin D increases risk for relapses (Gianfrancesso et al 2017; Hanwell & Banwell 2011).
• The onset of puberty seems to increase risk for developing MS in girls, who are 2-3 times more likely than post-pubertal boys to develop MS. There is no gender inequality prior to puberty (Belman 2016; Chitnis 2013).
• Though no single gene has been identified 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 increased risk of pediatric-onset MS in children of European ancestry (Disanto et al., 2011).
• Obesity may exacerbate risk for developing MS in patients with genetic susceptibility to MS (i.e. with HLA-DRB1*15 alleles) (Gianfrancesco et al 2017; 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 above the general population (Esposito et al., 2015; Nielsen et al., 2005).
• Gut microbiome has been implicated in smaller studies but still need validation in larger cohorts (Tremlett et al 2016)

• Pediatric-onset MS is similar to adult-onset relapsing-remitting MS.
• 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).
• Approximately one-third of children show evidence of significant cognitive impairment early on (Amato et al., 2008), with significant progression within two years (Amato et al., 2010), and over half demonstrate declines in cognitive indices over 5 years. However, a subset of patients can show improvement over time, suggesting that early intervention may mitigate cognitive impact of pediatric-onset MS (Amato et al., 2014).
• Progression of motor disability (as measured by EDSS) takes longer in children than in adults (Harding et al, 2012; Simone et al., 2002).
• Pediatric-onset MS patients reach disability milestones at a younger age than their adult-onset counterparts (Harding et al, 2012; Renoux et al., 2007).
• Pediatric MS patients have a higher T2 lesion burden than adult MS patients (Waubant et al., 2009). Post-mortem comparison of pediatric and adult MS patients’ brains found more extensive axonal injury in demyelinating lesions in the pediatric brains. Taken together, these data support the conclusion that MS in children is more inflammatory (Pfeifenbring et al. 2015).

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 ruling out other disorders that could be mistaken for MS, and distinguishing between MS and various transient demyelinating syndromes that can occur in children.

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), variants of ADEM associated with a repeat episode, neuromyelitis optica (NMO), clinically isolated syndrome (CIS) and pediatric MS, and updated those definitions in 2013. 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 and then has a subsequent second episode of neurologic dysfunction. Note that a subset of patients with ADEM (which typically follows a self-limited disease course) experience relapses of disease activity. Some of these patients are reclassified as MS based on the nature of the clinical events, laboratory findings, and subsequent MRI changes. While the risk of developing MS following an episode of ADEM in childhood is <10%, the risk following an episode of CIS has been shown to be 26% to 62% in several studies using 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 are reviewed by Banwell et al in 2007.

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-injected disease modifying MS 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 must prompt use of other newer therapies.
 
In 2018 the U.S. Food and Drug Administration approved the use of the oral MS therapy fingolimod (Gilenya®, Novartis AG) for treatment of children and adolescents 10 years of age or older with relapsing MS.

Other oral therapies for MS, including dimethyl fumarate (Tecfidera®) and teriflunomide (Aubagio®), are currently under study 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 in the adult MS population (Ghezzi et al 2015)
 
In addition to the FDA approved therapies used for pediatrics, another treatment that is not FDA approved for MS, known as rituximab (Rituxan®), has been studied in small trials of pediatric patients and showed that it was safe and effective. Rituximab has been 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 that the provider, child and family have an in-depth discussion. This discussion should include the goals and expectations of the child and family, how the drug is expected to control the MS, the side effects, the risks and any monitoring (blood tests, MRI and other tests) after the therapy is started. In this way, providers, patients and families can participate in a shared decision-making process to determine the therapy that best meets individual needs.

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 in a supplement to the journal Neurology. 
 
A publication from the MS International Federation (MSIF) summarizes the key points from each of these articles.
 
In addition to above, in pediatric MS, poor academic performance, difficulty with peer relations,  low self esteem, difficulty with acceptance of diagnosis and even depression can be co-existing morbidities. While detailed psychosocial evaluation by a trained professional is warranted, pediatric MS support groups can provide helpful information, resources and a network for teens and families.


Reviewed by Kavita Thakkar, MD, February 2019

• 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