Pediatric MS

Approximately 3-5% of all individuals with MS 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 (IPMSSG) – provide helpful insights into the management of MS in the pediatric population.

Read the free-access Neurology supplement on Pediatric Demyelinating Disorders, published in 2016, from the International Pediatric MS Study Group.

• 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 multiple sclerosis, and in those already diagnosed, low vitamin D increases risk for relapses (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 (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) (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).

• 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 intervention early on 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).
• 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 the decision path for diagnosing a child who has experienced an acute CNS demyelinating event and then experiences a 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 recent 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 acquired inflammatory CNS demyelination in children (.pdf), including the first attack of demyelination and further demyelinating attacks

Prognostic factors after a first attack of inflammatory CNS demyelination in children by Branwell et al (2007)

In 2018 the U.S. Food and Drug Administration approved the expansion of the use of the oral MS therapy Gilenya® (fingolimod, Novartis AG) to include the treatment of children and adolescents 10 years of age or older with relapsing MS.  In addition, many of the disease modifying therapies prescribed for adults with MS are also prescribed for pediatric 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 showed that the safety and efficacy in children were similar to that in the adult MS population.  Smaller retrospective studies, case studies and unblinded controlled trials have demonstrated safety and efficacy of the self-injected MS disease modifying therapies.

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.

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 Multiple Sclerosis International Federation (MSIF) summarizes the key points from each of these articles.