Pediatric-Onset Multiple Sclerosis (POMS)

Pediatric-onset multiple sclerosis (POMS) occurs when MS is diagnosed before 18 years of age. Approximately 3-5% of all individuals with MS experience disease onset before the age of 16 (Belman et al., 2016; Chitnis et al., 2009; Boiko et al., 2002; Duquette et al., 1987). POMS 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 stark contrast to adult-onset MS, in which primary progressive MS is much more frequent.

• There are environmental, genetic, and familial factors associated with the development of MS. This review discusses genetic and environmental risk factors in POMS.
• Maternal illness during pregnancy, pesticide exposure due to paternal occupation and use of pesticides in the household during pregnancy may increase the chance an unborn child will go on to develop MS. Delivery by Cesarean section may decrease the risk of developing MS in childhood (Graves et al., 2016).
• The onset of puberty seems to increase the likelihood of developing MS in those assigned female at birth, as they are 2-3 times more likely than those assigned male at birth to develop MS once puberty begins. Interestingly, there is no sex difference prior to pubertal onset, suggesting the potential role hormonal differences may play in MS pathophysiology (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).
• The gut microbiome has been implicated in small studies, but still needs validation in larger cohorts (Tremlett et al., 2016). A large study looking at how diet might affect relapse rate in POMS was recently completed, with results forthcoming.
• Ancestry appears to play a role in adult MS. However, place of birth, regardless of ancestry, appears to factor more into POMS compared to adult-onset MS (Kennedy et al., 2006).
• Children with a first-degree relative with MS (i.e. parent or sibling) have been shown to have a 2-4% increased risk of developing MS (Esposito et al., 2015; Nielsen et al., 2005).

Social determinants of health

In addition to the factors highlighted above, according to the World Health Organization, numerous studies suggest that social determinants of health (SDoH) account for between 30-55% of health outcomes overall. Addressing SDoH is, therefore, crucial to improve the health and lives of people living with chronic disease, like MS. Some social determinants of health, which can influence the trajectory of one’s healthcare journey include:

• Income and social protection
• Education
• Employment status and job security
• Work life conditions
• Food security
• Housing, basic amenities and the environment
• Early childhood development
• Social inclusion and non-discrimination
• Structural conflict
• Access to affordable and adequate healthcare services

The ability to access care, which is affected by these SDoH, can impact the course of disease. Addressing SDoH issues can, therefore, help improve disease-specific outcomes and quality of life for your patients. Utilizing your healthcare team is an important step in recognizing and addressing these factors with the pediatric onset MS patient and family.

• POMS patients experience 2-3 times more frequent relapses in the first 6 years post-diagnosis than adults with early-onset MS (Gorman et al., 2009; Benson et al., 2014).
  • Disability accrual is slower in children compared to adults (Chitnis 2020).
  • On average, POMS patients show significant disability at an age 10 years younger than their early adult-onset MS counterparts (Harding et al., 2012; Renoux et al., 2007).).
• POMS patients 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). POMS patients have a higher MRI 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, at least early on (Pfeifenbring et al., 2015).
• Approximately one-third of POMS patients 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, there was the potential for compensation and improvement in some subjects which showcase the importance of systemic cognitive screening and development of effective treatment strategies (Amato et al., 2014). Further study is needed to better understand the variables that positively influenced the improvement seen in some subjects.

It is important to diagnose and treat POMS as early as possible to prevent disease progression. As is true in adults, any child or adolescent with a demyelinating event should be evaluated for MS. Diagnostic confirmation depends on history, examination, interpretation of paraclinical testing, and exclusion of mimics and alternative etiologies. This is best achieved by a pediatric MS specialist. The Network of Pediatric Multiple Sclerosis Centers allows you to search for local pediatric MS specialists.
 
Two consensus reports – one by neurologists in the United States and one by the International Pediatric MS Study Group (IPMSSG) 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 IPMSSG, provides a comprehensive review of pediatric demyelinating disorders, including MS.

See tools for making a diagnosis.

Differential diagnosis

The challenge in differential diagnosis lies in distinguishing MS from the numerous other disorders in children that can also present with demyelinating events. In order to distinguish other demyelinating events from POMS, the International Pediatric MS Study Group (IPMSSG) (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 spectrum disorder (NMOSD)
• clinically isolated syndrome (CIS)

The IPMSSG 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 experiencing an acute CNS demyelinating event, followed by a second episode of neurologic dysfunction. Historically, <10% of children presenting with ADEM were eventually diagnosed with MS. However, the relatively recent discovery of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), a common presentation of which is ADEM, will likely alter the landscape as more research is conducted on MOGAD.

Clinically isolated syndrome (CIS) occurs when there is a clinical demyelinating event without sufficient radiologic findings to satisfy an MS diagnosis. In several studies utilizing the IPMSSG criteria, the risk of MS after an episode of pediatric-onset CIS was shown to range from 26% to 62% (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.

Radiologically isolated syndrome (RIS) occurs when a patient’s MRI is consistent with MS, but the patient has not experienced a clinical demyelinating event. Long-term treatment of CIS or RIS patients can be considered on a case-by-case basis.

Treatment options

Fingolimod (Gilenya®, Tascenso ODT®) is indicated for the treatment of children and adolescents 10 years of age or older with relapsing-remitting MS. Other DMTs are frequently used off-label in this population.

• A study looking at the use of teriflunomide (Aubagio ®) in treating POMS did not meet its primary endpoint of decreasing time to first confirmed clinical relapse, however, it did meet its secondary endpoint of reducing disease activity on MRI scans significantly more than placebo.
• Other oral therapies for MS, including dimethyl fumarate (Tecfidera®) continue to be studied in clinical trials for the treatment of POMS.

Prior to oral and high efficacy therapies becoming available, many of the older disease modifying therapies prescribed for adults with MS were also prescribed in children. These included interferon beta-1a (Avonex®, Betaseron®) and glatiramer 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).
• Initial treatment of POMS with newer DMTs (oral and infusible medications) has shown better disease activity control compared to 1^st generation injectables in clinical trials, showcasing the effectiveness of newer therapies. However, long-term safety data for newer DMTs are still needed (Krysko et al., 2020).

With regards to infusion therapies, 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). Additional infusion trials are currently underway.

In addition to the adult FDA-approved therapies used in POMS, 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 safety profile similar to other B-cell depleting agents widely used in adults (e.g. ocrelizumab) (Dale et al., 2014).

Treatment strategies

POMS is usually 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 1^st-generation injectables in POMS patients or those with CIS, newer DMTs provided better disease control and safety profiles were similar to what has been observed in adults. However, long-term safety data are still needed in children (Krysko et al., 2020). Due to the highly active nature of POMS and earlier age of conversion to secondary progressive MS, initial treatment with newer, higher-efficacy DMTs is being increasingly recommended (Hacohen et al., 2020). 

Starting or switching disease modifying therapies

Ultimately, starting or switching a disease modifying therapy in children and adolescents requires an in-depth discussion between the provider, patient and family. It should include:

• Understanding the goals and expectations of the child and family
• Sharing the safety, efficacy and monitoring profile of the various treatment options
• Proactively discussing factors that could affect adherence (cost, route of administration, dosage, transportation)

By understanding what is important to the child and family and addressing concerns, fears, and potential challenges, 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 (IPMSSG) 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.

Social and emotional dimensions of well-being

In any patient diagnosed with POMS, poor academic performance, difficulty with peer relations, low self-esteem, difficulty with accepting the diagnosis, fatigue and psychiatric comorbidities (especially anxiety and depression) are all important considerations. While a detailed neuropsychological evaluation by a trained professional can be helpful, POMS support groups also can provide additional crucial information, resources and networks for both patients and their families faced with this complex and life-long disease. Other resources to consider as part of the care team include:

• Pediatric or adolescent psychologists and psychiatrists
• School guidance counselors, psychologists, teachers, mentors, and administrators
• Support groups with other patients and families facing this disease
• Neuropsychologist to objectively characterize any neurocognitive deficits and track them over time

Wellness and lifestyle modification strategies

• Good sleep hygiene (≥ 8 hours of restorative sleep each night)
• Healthy diet that is high in fruits, vegetables, whole grains, lean protein, polyunsaturated fats while minimizing processed foods, refined sugars, and saturated fats from meat or dairy
• Staying well hydrated (depends on body weight and daily activity level)
• Daily aerobic exercise (≥ 30 minutes or more as tolerated)
• Rehab services such as physical and occupational therapy
• Stress reduction techniques and emotional wellness activities (e.g. yoga, meditation, mindfulness)
• Avoiding tobacco exposure (active and passive), alcohol and drugs
• Addressing and treating comorbid medical problems such as obesity, ADHD, headaches, and psychiatric conditions by meeting regularly with a Psychologist and/or Psychiatrist
• Routine health maintenance screening and vaccination (non-live vaccines if on certain DMTs) through a primary care provider
• Vitamin D supplementation with a goal total vitamin D level of 40-60 ng/mL
• Other vitamin supplementation as appropriate (e.g. iron or B12) (Petrin et al., 2018)

Considerations

• Depending on where the patient receives care, an MS specialist may want to transition a child’s care to an adult provider once they reach a certain age. In such cases, it is important to develop a transition of care plan ahead of time.
• Evaluate the patient’s ability to make and keep appointments independently, without requiring family involvement. The team can then determine if additional education or resources are needed.
• Assess patient’s ability to take and refill medications in order to determine if additional education or resources are needed (e.g. setting reminders on a patient’s phone).
• Discuss importance of reporting new or worsening symptoms in a timely manner.
• Discuss potential benefit of permitting parents/caregivers to discuss protected health information on the patient’s behalf depending on age and level of independence (Castillo, Kitsos, 2017).
• The Child Neurology Foundation has tools and resources for healthcare professionals on the topic of transitioning out of the pediatric care team.

The Network of Pediatric Multiple Sclerosis Centers (NPMSC) is a United States-based network with international collaborations. It is comprised of adult and child neurologists, scientists and other research professionals with a unifying mission to uncover the causes, investigate determinants of remyelination and neuroprotection, advance therapeutics and improve outcomes in pediatric-onset MS. Through ongoing studies, the NPMSC is measuring clinical, environmental, and cognitive manifestations of pediatric-onset MS and growing the largest collection of pediatric onset MS cases in the world to further the field and improve the outcomes and quality of life of patients and families.

If you are interested in collaborating with the network, please submit a collaborator interest form.

• Pediatric MS webpage (includes links to pediatric videos, articles, and resources)
• New to Pediatric MS: Navigating Your Journey Program Flyer
• Kids Get MS Too: A Guide For Parents Of A Child Or Teen With MS
  • Spanish version
• Pediatric MS Resource Guide (includes links to pediatric MS information and resources for parents, preteens and teens)
  • English (web version)
  • English (printable version)
  • Spanish
• Pediatric MS Alliance

Reviewed by Aaron Abrams, MD, March 2023