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      Drugs & Diseases > Pediatrics: General Medicine

      Pediatric Multiple Sclerosis Treatment & Management

      Updated: Jan 03, 2022
      • Author: Alice K Rutatangwa, DO, MSc; Chief Editor: Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA  more...
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      Treatment

      Disease-Modifying Therapies

      Ten disease-modifying therapies (DMT) have been approved for treatment of relapsing-remitting multiple sclerosis (MS) in the adult population, including 6 first-line therapies (glatiramer acetate [GA], intramuscular [IM] and subcutaneous [SC] interferon [IFN] beta-1a, and SC interferon-beta-1b, fingolimod [also approved in children], teriflunomide, and dimethyl fumarate) and two second-line therapies (mitoxantrone, alemtuzumab, natalizumab, and ocrelizumab). In addition, therapies such as rituximab and cyclophosphamide have been evaluated in phase II trials in adults with breakthrough disease, as have add-on therapies such as monthly steroids and intravenous immunoglobulin (IVIG).

      Oral therapies

      Fingolimod, teriflunomide, and dimethyl fumarate are oral disease-modifying therapies to achieve FDA approval for treatment of relapsing and remitting MS in adults. Fingolimod was also approved for children aged 10 years or older with relapsing MS in May 2018. Approval of fingolimod in children was based on the Phase 3 PARADIGMS study (n=215) that compared fingolimod to interferon beta-1a in children and adolescents. Patients were randomized to receive once-daily oral fingolimod (n=107, 0.5 mg or 0.25 mg, dependent on patients' body weight) or intramuscular interferon (IFN) beta-1a (n=108) once weekly. Compared with IFN beta-1a, fingolimod reduced the annualized rate of n/neT2 lesions by 52.6% (p< 0.001) and number of Gd+T1 lesions per scan by 66.0% (p< 0.001). Treatment with fingolimod up to Month 24 compared with IFN beta-1a significantly reduced brain atrophy (ARBA: −0.48% vs. −0.80%, p=0.014), Fingolimod significantly reduced MRI activity and slowed brain volume loss for up to 2 years compared with IFN beta-1a. [80]

      Safety and efficacy of teriflunomide and dimethyl fumarate are not established in pediatric patients with MS. Off-label use of these medications should be pursued cautiously given the known adverse effects in adults. Teriflunomide labeling includes a boxed warning regarding severe liver injury and teratogenicity. Dimethyl fumarate cautions include lymphopenia, flushing, PML, angioedema, and liver injury.

      Interferon-beta therapy

      Interferon-beta-1a and 1b appear to be safe and well tolerated in this population, although discontinuation rates are high (30%-50%) [47] and side effects common. For example, many children on interferon (35%-65%) report flulike symptoms. Other relatively frequently observed side effects include leukopenia (8%-27%), thrombocytopenia (16%), anemia (12%), and transiently elevated transaminases (10%-62%). Injection-site reactions are very common.

      Dosing of interferon-beta is not established in the pediatric population. However, most patients tolerate doses titrated following adult protocols or gradual titration to 30 µg once weekly for interferon-beta-1a IM and 22–44 µg SC 3 times/week for interferon-beta-1a. Children older than 10 years tolerate full doses of interferon-beta-1b, although decreased tolerance may exist in the younger population. [48] Limited data are available on the efficacy, effect on disability progression, and MRI effect.

      Glatiramer acetate therapy

      Only three published retrospective studies have evaluated the use of glatiramer acetate in pediatrics. [49, 50, 51] The medication appears well tolerated except for the typical injection-site reactions and rare and transient chest pain. The mean annualized relapse rate decreased during treatment, but the study was limited by small sample size.

      Immunomodulatory and cytotoxic therapies

      A small number of children continue to have MS relapses despite treatment with the first-line DMT described above, although no consensus criteria exist for the definition of breakthrough disease in pediatric MS. In general, practitioners allow at least 6 months of observation on a given treatment prior to deeming the treatment suboptimal.

      Immunomodulatory and cytotoxic agents that are used in adult MS in the event of suboptimal response to interferon-beta and/or glatiramer acetate have been used in a small number of pediatric patients. There are no reports on the use of fingolimod in pediatric MS.

      Natalizumab appears well tolerated by children with MS in whom first-line therapies have failed. Patients experience less clinical relapses, and MRI scans show no enhancing lesions. [52] There have been no reports to date of PML in association with natalizumab use in children. [53]

      There have been no published reports of mitoxantrone use in the pediatric population except for a few cases followed at the US Pediatric MS Centers of Excellence. [54] The authors suggest caution with its use given the reported significant side effects of leukemia and cardiomyopathy.

      In the pediatric MS population, only one case report of rituximab has been published. [55]

      There is limited evidence to support the use of cyclophosphamide in children. Caution should be exercised given the risks of infertility and secondary neoplasm.

      Next:

      Symptomatic Treatments in Pediatric Multiple Sclerosis

      Optimizing quality of life and function can be aided by treatment of persistent symptoms. Rehabilitative techniques, adaptive equipment, and medications can all contribute. Spasticity, fatigue, tremor, paroxysmal symptoms, cognitive impairment, and bowel and bladder dysfunction can all be improved with symptomatic treatment. Very few clinical studies have been performed in children with MS; therefore, the treatments discussed in this article are empirically derived and, in general, not FDA-approved. [56]

      Spasticity

      Spasticity can be moderated with stretching and range-of-motion exercises. Greater degrees of spasticity benefit from oral agents, including baclofen, tizanidine, or benzodiazepines; however, dosing may need to be balanced with side effects, including sedation. [53]

      Fatigue

      Fatigue is a frequent symptom in children with MS and is noted more frequently than can be easily explained by depression, exhaustion from physical disability or heat exposure, sleep disturbance, or poor bowel/bladder control. Ameliorating these potential underlying causes of fatigue is a critical first step. Medications that have been anecdotally used to address fatigue in children with MS include amantadine, [57] modafinil, [58, 59] and methylphenidate.

      Bladder dysfunction

      Bladder dysfunction can be treated with medications to treat or suppress infection and to decrease detrusor hyperreflexia. Intermittent bladder catheterization for urinary retention and desmopressin acetate nasal spray at bedtime for sleep-depriving nocturia unresponsive to fluid management are beneficial in some children.

      Constipation

      Constipation occurs frequently, particularly in children with MS-related decreases in mobility. Management includes manipulating the diet, increasing fluid intake, maximizing activity levels, and adding stool softeners and additional fiber/bulk to diet.

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