Can children develop multiple sclerosis?

Children less than 18 years of age who develop MS are diagnosed with pediatric-onset multiple sclerosis (POMS) and make up approximately 3-5% of all MS worldwide. The estimated yearly incidence of POMS in the United States is 0.183 to 0.651 per 100,000 children per year, although true rates are likely higher. Diagnostic delays are common, as MS is often viewed exclusively as an adult disease. MS mimics, overlap syndromes, and infectious etiologies occur more frequently in children, making the diagnosis even more challenging. Diagnosing MS before puberty is rare, although a patient as young as 2 years old has been reported. Pre-pubertal POMS affects males and females almost equally, while after puberty girls are affected 2 to 3 times more than boys, similar to adult MS. This suggests hormonal factors may play an important role in MS pathophysiology, a notion further supported by the protective effect pregnancy has on relapse rates in adult MS.

What are the risk factors for POMS?

Aside from pubertal hormones, several other genetic, environmental, and epigenetic risk factors have been implicated in the development of MS in children, although more research is needed on the topic. Monozygotic twin studies demonstrate 25% concordance, compared to 2-5% in dizygotic twins (similar to the risk in first-degree relatives). Similar to adult MS, low vitamin D is associated with an increased risk of developing POMS and of disease activity, possibly secondary to decreased immune system function. Previous Epstein-Barr Virus (EBV) exposure also increases POMS risk, similar to adults. Other factors specifically implicated in the development of POMS include exposure to maternal illness and pesticides during gestation, exposure to cigarette smoke, place of birth (as opposed to ancestry in adult MS), and obesity, particularly in patients with certain HLA-DRB1*15 susceptibility haplotypes. HLA DR15 has been shown to contribute to the development of early-onset MS. In one study, delivery by C-section and later age at menarche were associated with decreased POMS risk. In the United States, children with MS represent a diverse group, with 67% White, 21% Black, 2% American Indian/Alaskan Native, and 7% multiracial reported in one large cohort. The potential impact of social determinants of health during childhood (e.g. socioeconomic and psychosocial factors such as schooling and employment, underlying mood disorders, early life stressors including trauma) on POMS risk is an area of active research. Possible susceptibility related to variation in gut microbiome and diet is also under investigation.

What are the symptoms of POMS?

Like adult MS, focal neurological symptoms and signs in children develop according to the neuroanatomical region affected by each neuroinflammatory attack in the central nervous system (CNS). Children are more likely than adults to present with multifocal symptoms during relapse, and particularly at disease onset. Isolated optic neuritis, isolated brainstem syndromes, and constitutional symptoms (such as headache) are more common in POMS. Antecedent events such as infections are more frequent in children less than 12 compared to those greater than or equal to 12. Children less than 12 are also more likely to present with encephalopathy and coordination problems, while children greater than 12 are more likely to present with sensory symptoms. POMS patients are less likely to readily report symptoms, which can further delay the diagnosis and treatment. For example, children are often embarrassed to discuss bowel or bladder issues with their parents or doctors. Young children may not yet fully comprehend or be able to effectively communicate their symptoms, especially when they are subtle or difficult to describe (e.g. fatigue, numbness and tingling, visual disturbance). Furthermore, POMS patients tend to recover from individual relapses more quickly and completely than adults, making neurological deficits harder to detect. Since infections are so common in children, MS symptoms are often mistakenly attributed to infectious etiologies (e.g. eye pain and blurry vision misdiagnosed as viral conjunctivitis instead of optic neuritis). We at the Mellen Center therefore recommend evaluation by a POMS specialist for any child presenting with demyelinating symptoms.

Are there differences in the clinical course of POMS compared to adult MS?

POMS is almost exclusively relapsing-remitting at onset, contrasting with adult-onset MS in which a significant proportion are initially diagnosed with primary progressive MS. Children and adolescents experience more relapses and new lesions early on in the disease course than adults, with more than twice as many relapses per year over at least the first 6 years. However, most POMS patients show minimal deficits on neurological examinations and very low EDSS scores after an acute attack. They also recover more rapidly from relapses, with a mean symptom duration of 4 weeks compared to 6-8 weeks in adults. Long-term follow up analysis, however, reveals that POMS patients still reach significant levels of neurological disability approximately 10 years earlier than young adult-onset MS patients, even after controlling for disease duration. This is why we at the Mellen Center advocate for early initiation of highly effective disease modifying therapies (DMTs) for all newly diagnosed POMS patients.

Are there differences in MRI findings between POMS and adult MS?

In addition to more frequent relapses, POMS patients demonstrate greater radiologic disease activity early on than adults. At initial diagnosis, children show a greater number of T2 hyperintense lesions, large (>1 cm) T2 hyperintense lesions, and gadolinium-enhancing (active) lesions than adults. In addition, they form new T2 hyperintense and gadolinium-enhancing lesions at faster rates on follow up MRIs. Children are, however, more likely to have spontaneous reduction in the size of existing lesions on serial scans. POMS patients preferentially show a higher lesion burden in the posterior fossa, although the distribution across the other CNS regions is similar to adults. Brain volume loss correlates with clinical disease activity, specifically more infratentorial lesions, relapses, and higher EDSS scores. Studies demonstrate a reduction in age-expected brain growth in POMS, particularly in the thalamus.

Are there neurodevelopmental consequences to POMS?

Since young brains are still rapidly maturing, there may be greater impact on neurogenesis secondary to MS-related neuroinflammation and neurodegeneration in POMS than in adult MS. Longitudinal data suggest a level of cognitive impairment out of proportion to physical disability in POMS, resulting in poorer academic and career performance. These deficits can be subtle, which is why formal objective testing is important. The reason why greater neuroplasticity in children during periods of rapid neurodevelopment translates into better physical recovery from individual MS attacks but greater impairment in higher cortical functioning is an area of active investigation. POMS patients suffer from neurocognitive and mood changes out of proportion to other neurological deficits, with up to half struggling academically within the first 2 years of diagnosis. Neurocognitive disability in POMS tends to be more severe than in adult-onset MS, as evidenced by greater impairment in information processing speeds and faster rates of decline. These measures also correlate with future lower income and decreased likelihood of job advancement. Children with MS show more problems with linguistic skills and general intelligence than adults, although they exhibit similar severe deficits in complex attention, information processing speeds, visuomotor integration, and verbal and visual memory. As a result, we at the Mellen Center advocate for early and repeated formal neuropsychological testing in all POMS patients.

What is the differential diagnosis for POMS?

Since MS is relatively uncommon in the pediatric population, mimics must be considered, particularly at first attack. Alternate etiologies include other demyelinating disorders such as myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), neuroinflammatory diseases (e.g. neurosarcoidosis), systemic autoimmune diseases (e.g. lupus), histiocytic disorders (e.g. hemophagocytic lymphohistiocytosis and Langerhans), lymphoproliferative and neoplastic disorders, other neuronal antibody-mediated syndromes (e.g. GFAP, although these are rarely reported in children), nutritional and vitamin deficiencies, toxic exposures, connective tissue diseases (e.g. scleroderma en coup de sabre), and CNS vasculitis. Many genetic and metabolic etiologies (e.g. leukodystrophies) first present in childhood and can closely resemble acquired demyelinating syndromes. They should therefore be considered in any child with developmental delays or regression, intellectual disability, neurocutaneous stigmata, a strong family history of genetic or metabolic disease, parental consanguinity, or early unexplained death in a family member. Symptoms, signs, and radiologic features atypical of MS should prompt a thorough investigation into these alternative etiologies. If encephalopathy, encephalitis, or seizures are present, acute disseminated encephalomyelitis (ADEM) should be strongly considered, of which MOGAD is an increasingly recognized cause, including in children.

Is POMS diagnosed differently than adult MS?

In 2013, the International Pediatric MS Study Group (IPMSSG) published diagnostic criteria for POMS, which incorporated many aspects of the 2010 Revised McDonald criteria used in adult-onset MS. Although there have been no official updates to the pediatric criteria since then, the newer 2017 Revised McDonald criteria are nonetheless also widely used to diagnose MS in children. A large 2018 prospective study demonstrated 71% sensitivity and 95% specificity when applying the 2017 Revised McDonald criteria to POMS. Predictors helping to differentiate POMS from other monophasic demyelinating disorders included the presence of at least one T1 hypointense lesion (black hole), gadolinium-enhancing lesion, and periventricular lesion. The absence of periventricular lesions was a strong negative predictor of POMS. We at the Mellen Center apply similar diagnostic testing in children as we do in adults to confirm MS. Please see the Mellen Center Approach articles on diagnosing MS for further details. Figure 1 provides a comparison of pediatric- and adult-onset MS.

How do you differentiate MS from MOGAD and NMOSD in children?

ADEM is a more common demyelinating presentation in children than adults. Although MOGAD should be highest on the differential, a first presentation of MS should also be considered. This is because behavioral changes in a young, acutely ill, or developmentally delayed child can easily be mistaken for encephalopathy, a required feature of ADEM but not one typically seen in MS. There are, however, key radiologic and serologic findings to help differentiate MOGAD from MS, similar to adults. For further information on ADEM and MOGAD, please refer to the Mellen Center Approach article “Understanding MOG Antibody Disease”. Another important disorder to consider, although even rarer in children, is NMOSD. Key differences in pediatric-onset NMOSD compared to adults include a greater number of brain lesions and shorter-segment spinal cord lesions. Please see the Mellen Center Approach article “Neuromyelitis Optica” for more details. Due to the diagnostic complexities, we recommend evaluation by a clinician with expertise in POMS and related pediatric neuroinflammatory disorders at the first sign of a demyelinating or neuroinflammatory event in a child. This helps ensure prompt and thorough workup, diagnosis, and treatment.

How do you monitor children after a first demyelinating event?

As discussed above, a first demyelinating event in childhood may represent the initial presentation of MS or another disorder altogether. The terms clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) are applied similarly to children as they are in adults. Even if a definitive diagnosis cannot be made following a first event, close clinical and MRI monitoring is critical to risk-stratify patients and identify early on those children who will convert to MS (or a related disorder) necessitating treatment.

What treatments are available for relapses in POMS?

Acute relapses in POMS are treated similarly to adults, keeping in mind the possible need for weight-based dosing, particularly in young children. All attempts should be made in any child presenting with acute relapse concerns to be evaluated as soon as possible in person by an experienced POMS specialist for a thorough neurological examination to confirm deficits, screen for mimics and pseudo-relapse (oftentimes infection), and determine next steps. For true relapses, similar to adults, first-line treatment is with high dose glucocorticoids in the form of IV methylprednisolone 30 mg/kg/day, with a maximum dose of 1000 mg daily, for 3 or 5 days. We typically reserve 5 days for patients who do not respond quickly to initial treatment or have particularly severe symptoms and signs. In incomplete responders, a 2nd round of high-dose glucocorticoids may be required, followed by an oral taper. All pediatric patients treated with high dose glucocorticoids must be counseled and monitored for potential side effects. Prophylactic treatment with an H2 blocking medication or proton pump inhibitor should be provided for the duration of treatment to prevent steroid-related gastritis. Side effects of long-term steroid use in children can be particularly severe and may include adrenal insufficiency, hormonal and growth effects, hyperactivity, insomnia, weight gain, acne, and increased risk of infections. Consultation with a pediatric endocrinologist can be helpful in this regard. Outpatient treatment with high-dose oral glucocorticoids is often not possible for young children who cannot yet swallow pills, so outpatient infusion center or inpatient admission is often required. Similar to adults, steroid-refractory cases may need escalation to plasmapheresis or plasma exchange (PLEX).

What treatments are available to prevent relapses in POMS?

Given the greater disease activity and earlier onset of significant disability in POMS patients, it is critical to initiate treatment promptly with a highly effective disease-modifying therapy (DMT). Since there is currently no cure for MS, POMS patients (like adults) require lifelong treatment to prevent relapses, lesion accrual, and long-term disability. It has been shown that the risk of reaching disability milestones in POMS is mitigated by earlier and longer treatment, particularly with higher efficacy DMTs. An increasingly important outcome measure in MS is no evidence of disease activity (NEDA). NEDA-3 (absence of relapses, absence of disability progression, and no new or enlarging T2 or gadolinium-enhancing lesions) was achieved more frequently in POMS patients on high-efficacy therapies. We therefore advocate for the use of highly effective DMTs as first-line to help prevent MS-related disability in POMS (see Table 1). Of the available DMTs, only fingolimod is FDA approved (in 2018) for the treatment of POMS (in ages 10 and up), largely due to challenges with conducting clinical trials in uncommon pediatric disorders. Fortunately, more trials are underway. There is robust real-world prospectively-collected retrospective data analyses demonstrating very similar efficacy and safety profiles of DMTs in POMS as compared to adults. Some exceptions apply, such as an increased rate of seizures in children on fingolimod, although this is thought to be due to higher rates of symptomatic primary generalized genetically-mediated epilepsy syndromes that may go undiagnosed and untreated during childhood. In very young children, we typically use rituximab due to its long track record of overall safety in its weight-based dosing guidelines in pediatric rheumatological disorders.

What other factors should be considered when treating POMS?

Other factors to consider when treating POMS patients with DMTs include route of administration, medication adherence, keeping up to date with vaccinations, patient and parental preference, logistical considerations (e.g. distance to a capable infusion facility), cost (e.g. insurance companies often deny coverage due to the lack of clinical trial data in POMS), side effects, medical comorbidities, psychosocial and socioeconomic factors, potential teratogenicity, the need for safety monitoring through frequent blood draws, and potential long-term effects on the developing immune system and CNS. Such complexities can be difficult to navigate for anyone, but particularly a child. This is why we encourage all POMS patients to be active participants in all treatment and management decisions as early as possible. This also provides them with the skills necessary to become independent, responsible, and health-conscious individuals, which can improve outcomes. While parental consent is required for most medical decision-making in children, assent and understanding on the part of the child should be sought after whenever possible.

When should POMS patients transition to adult neurologists and other adult specialists?

Discussions surrounding transition of care from pediatric to adult treatment teams should start as early as possible. While many neurologists continue to care for their POMS patients until age 21 and beyond, provider-initiated transition conversations should take place early on and include the patient and legal guardian. Most teenagers are inexperienced when it comes to scheduling and keeping appointments, taking medications, paying for medical expenses, and identifying and reporting new symptoms. This is often because parents or adult legal guardians have been in charge of their medical care up until this point. Teenagers in particular are at a developmental phase that tends to under-emphasize the long-term consequences of their decisions and actions. This is why it is especially important to encourage POMS patients to develop these skills early on, so they are better equipped to overcome barriers when transitioning to the adult medical world. Transition discussions become even more critical for children with cognitive impairment, as conversations surrounding medical decision-making, legal guardianship, and continuation of insurance coverage will help prevent lapses in care and treatment. It can be helpful to involve social workers, case managers, and patient financial and insurance advocates to help navigate these complexities.

What other resources can POMS patients and their families benefit from?

Like many chronic neurological diseases of childhood, POMS management is complex and requires a multidisciplinary approach. We therefore recommend considering involving the following team members:

  • Pediatric or adult neurologist with experience treating POMS.
  • Primary care physician, such as a pediatrician or family doctor, to provide routine screening, vaccinations, and other preventative medical practices, as recommended by the American Academy of Pediatrics.
  • Pediatric or adolescent psychologists and psychiatrists to address depression, anxiety, and other mood and stress-related conditions commonly experienced by POMS patients.
  • Depending on the degree of physical disability, pain specialists, physiatrists, speech, physical and occupational therapists may be needed for rehabilitation following an acute MS relapse, and for chronic symptom management.
  • Neuropsychologist for formal testing to identify and monitor cognitive deficits and learning disorders and help guide appropriate school and class placement, educational programs, future job planning, and interventional services.
  • Ophthalmologist to monitor vision due to the effects MS has on the optic nerves.
  • Endocrinologist for monitoring of glucocorticoid-related side effects.
  • Immunologist for monitoring of immunosuppression.
  • Social workers, case managers, and patient/family financial and insurance advocates.
  • School guidance counselors, psychologists, teachers, and administrators are important allies in establishing school-based supports for POMS patients. Given the significant impact POMS can have on neurocognitive functioning, parents are encouraged to request in writing an evaluation for an Individualized Education Plan (IEP) and/or 504 services to help ensure their child is receiving the services they need to help them thrive.

Additional POMS Information and Resources

National MS Society (NMSS)

Following an MS diagnosis, many children, teens, and families feel isolated, and are in need of support beyond what is available from their healthcare team. In addition to a family’s social and emotional support system, the National MS Society (NMSS) offers free online resources through their Pediatric MS Support page. They offer free, downloadable information for parents of children and teens with MS, resources for educational and school-related issues in MS, and links to the Network of Pediatric MS Centers (including Cleveland Clinic’s Mellen Center), where patients can find clinicians and support networks with experience in POMS. The NMSS also has a Patient Navigator program to help guide POMS patients and families through the multitude of questions and challenges that arise over the course of their MS journey. Please click on the following links for more information:

https://www.nationalmssociety.org/What-is-MS/Who-Gets-MS/Pediatric-MS
https://www.nationalmssociety.org/Resources-Support/Find-Support/Ask-an-MS-Navigator
https://usnpmsc.org/

International Pediatric MS Study Group (IPMSSG)

The International Pediatric MS Study Group (IPMSSG) is a valuable resource to find further information about diagnosis and research updates related to POMS.

https://www.ipmssg.org

Research Opportunities

For information on POMS clinical trials (including at the Mellen Center), please visit the ClinicalTrials.gov website and type “pediatric MS” into the “Condition/disease” entry form, or click on the following link:

https://clinicaltrials.gov/search?cond=pediatric%20MS

Summary

Pediatric-onset MS (POMS) occurs in roughly 3-5% of all MS cases, although true rates are likely higher. Evaluating for other etiologies is critical, as alternative diagnoses and overlap syndromes are more common in children. Compared to adults, POMS patients show higher clinical and radiologic disease activity early on. Although they typically recover from individual relapses more quickly and fully than adults, they may experience more neurocognitive and mood challenges. They also still show significant disability on average 10 years earlier than adult-onset MS patients. This is why prompt and effective treatment is important. The treatment options and management approach to POMS are similar (although not identical) to adult MS, which is why establishing with a provider with experience in POMS is recommended. Treatment for acute relapses and long-term prevention are also similar to adult-onset MS, with high-efficacy therapies recommended early on. Children with MS benefit similarly to adults in optimization of vitamin D levels, engaging in healthy lifestyle habits, and establishing with appropriate mental health specialists and support networks.

References

  1. Scolding NJ, Pasquini M, Reingold SC, Cohen JA, on behalf of attendees at the International Conference on Cell-Based Therapies for Multiple Sclerosis. Cell-based therapeutic strategies for multiple sclerosis. Brain 2017;140:2776-2796 Amato MP, Goretti B, Ghezzi A, Hakiki B, Niccolai C, Lori S, Moiola L, Falautano M, Viterbo RG, Patti F, et al. Neuropsychological features in childhood and juvenile multiple sclerosis: five-year follow-up, Neurology, 2014; 83:1432-1438.
  2. Baroncini D, Simone M, Iaffaldano P, Brescia Morra V, Lanzillo R, Filippi M, Romeo M, Patti F, Chisari CG, Cocco E, Fenu G, Salemi G, Ragonese P, Inglese M, Cellerino M, Margari L, Comi G, Zaffaroni M, Ghezzi A; Italian MS registry. Risk of Persistent Disability in Patients With Pediatric-Onset Multiple Sclerosis. JAMA Neurol. 2021 Jun 1;78(6):726-735. doi: 10.1001/jamaneurol.2021.1008. PMID: 33938921; PMCID: PMC8094039.
  3. Bartels F, Nobis K, Cooper G, Wendel E, Cleaveland R, Bajer-Kornek B, Blaschek A, Schimmel M, Blankenburg M, Baumann M, Karenfort M, Finke C, Rostásy K. Childhood multiple sclerosis is associated with reduced brain volumes at first clinical presentation and brain growth failure. Mult Scler. 2019 Jun;25(7):927-936. doi: 10.1177/1352458519829698. Epub 2019 Apr 4. PMID: 30945587.
  4. Benson LA, Healy BC, Gorman MP, Baruch NF, Gholipour T, Musallam A, Chitnis T. Elevated relapse rates in pediatric compared to adult MS persist for at least 6 years, Mult Scler Relat Disord, 2014; 3:186- 193.
  5. Castillo Villagrán D, Yeh EA. Pediatric Multiple Sclerosis: Changing the Trajectory of Progression. Curr Neurol Neurosci Rep. 2023 Oct 4. doi: 10.1007/s11910-023-01300-3. Epub ahead of print. PMID: 37792206.
  6. Chitnis T. Pediatric demyelinating diseases, Continuum (Minneap Minn), 2013; 19:1023-1045.
  7. Chitnis T, Tenembaum S, Banwell B, Krupp L, Pohl D, Rostasy K, Yeh EA, Bykova O, Wassmer E, Tardieu M, et al. Consensus statement: evaluation of new and existing therapeutics for pediatric multiple sclerosis, Mult Scler, 2012; 18:116-127.
  8. Palavra F, Silva D, Fernandes C, Faustino R, Vasconcelos M, Pereira C, Costa C, Ribeiro JA, Amaral J, Robalo C. Clinical predictors of NEDA-3 one year after diagnosis of pediatric multiple sclerosis: an exploratory single-center study. Front Neurosci. 2023 Sep 14;17:1259306. doi: 10.3389/fnins.2023.1259306. PMID: 37781240; PMCID: PMC10536233.
  9. Fisher KS, Cuascut FX, Rivera VM, Hutton GJ. Current Advances in Pediatric Onset Multiple Sclerosis. Biomedicines. 2020 Mar 28;8(4):71. doi: 10.3390/biomedicines8040071. PMID: 32231060; PMCID: PMC7235875.
  10. Graves JS, Chitnis T, Weinstock-Guttman B, Rubin J, Zelikovitch AS, Nourbakhsh B, Simmons T, Waltz M, Casper TC, Waubant E; Network of Pediatric Multiple Sclerosis Centers. Maternal and Perinatal Exposures Are Associated With Risk for Pediatric-Onset Multiple Sclerosis. Pediatrics. 2017 Apr;139(4):e20162838. doi: 10.1542/peds.2016-2838. PMID: 28562303; PMCID: PMC5369674.
  11. Hanwell, H. E. and B. Banwell (2011). “Assessment of evidence for a protective role of vitamin D in multiple sclerosis.” Biochimica et biophysica acta 1812(2): 202-212.
  12. Kanda T, Ishii K, Kawaguchi H, Kitajima K, Takenaka D. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material, Radiology, 2014; 270:834-841.
  13. Kornbluh AB, Kahn I. Pediatric Multiple Sclerosis. Semin Pediatr Neurol. 2023 Jul;46:101054. doi: 10.1016/j.spen.2023.101054. Epub 2023 May 11. PMID: 37451754.
  14. Krupp LB, Tardieu M, Amato MP, Banwell B, Chitnis T, Dale RC, Ghezzi A, Hintzen R, Kornberg A, Pohl D, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions, Mult Scler, 2013; 19:1261-1267.
  15. Pfeifenbring, S., R. F. Bunyan, et al. (2015). “Extensive acute axonal damage in pediatric multiple sclerosis lesions.” Annals of neurology 77(4): 655-667.
  16. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria, Ann Neurol, 2011; 69:292-302.
  17. Waldman A., Ghezzi A., Bar-Or A., Mikaeloff Y., Tardieu M., Banwell B. Multiple sclerosis in children: An update on clinical diagnosis, therapeutic strategies, and research. Lancet Neurol. 2014;13:936–948. doi: 10.1016/S1474-4422(14)70093-6.
  18. Waubant, E., D. Chabas, et al. (2009). “Difference in disease burden and activity in pediatric patients on brain magnetic resonance imaging at time of multiple sclerosis onset vs adults.” Archives of neurology 66(8): 967-971.
  19. Yeh EA, Waubant E, Krupp LB, Ness J, Chitnis T, Kuntz N, Ramanathan M, Belman A, Chabas D, Gorman MP, et al. Multiple sclerosis therapies in pediatric patients with refractory multiple sclerosis, Arch Neurol, 2011; 68:437-444.
  20. Yeh EA, Weinstock-Guttman B. The management of pediatric multiple sclerosis, J Child Neurol, 2012; 27:1384-1393.