How to Treat Pediatric MS

VANCOUVER—Pediatric multiple sclerosis (MS) presents unique concerns, making appropriate treatment especially important, according to an overview presented at the 45th Annual Meeting of the Child Neurology Society. Currently, disease-modifying therapies with FDA approval in adult MS have not been approved for the treatment of pediatric MS. In addition, brain growth and cognition are adversely affected in pediatric MS. Furthermore, children with MS tend to become disabled at a younger age, compared with adults.

Timothy Lotze, MD

Diagnosis and Initiation of Therapy

Neurologists should be prepared to engage with children and their families to ensure the most efficacious treatment. “Whenever you are having that conversation or you are considering starting the disease-modifying therapy, you need to balance the need to treat the disease with the idea that you are going to be starting a therapy for a lifetime,” said Dr. Lotze.

Disease-modifying therapies target the inflammatory aspects of pediatric-onset MS and should be initiated in children with a confirmed diagnosis, said Dr. Lotze. Children with clinically isolated syndrome who appear to be at high risk for MS and children with positive oligoclonal bands or elevated IgG index may also need to begin a disease-modifying therapy. Distinguishing between MS, acute disseminated encephalomyelitis (ADEM), and neuromyelitis optica (NMO) poses challenges, especially in children under age 10. Certain interferons can exacerbate NMO and may be harmful in children with ADEM or multiphasic ADEM.

Setting Goals

Neurologists are encouraged to counsel patients about the purpose and side effects of treatment, as well as to establish reasonable expectations for treatment. Additionally, children and families should be aware that another attack may occur during treatment and should be informed about what to do if it does.

No therapy is 100% efficacious in pediatric or adult MS, said Dr. Lotze. Research suggests that 50% of adults have no evidence of disease activity (NEDA) at two years of the disease. After seven years, however, 7% of these adults meet NEDA criteria. As a result, minimal disease progression (defined as less than one attack per year, fewer than three new lesions on a yearly MRI, and no progression in disability) may be a more attainable goal. “We would like to see a drug in a single individual or patient that is effective in achieving NEDA. If that is not possible … you might find that ultimately what you can go for is minimal disease progression,” said Dr. Lotze. He added that there appears to be no clear difference in terms of long-term outcome between children with MS who achieve NEDA and those who achieve minimal disease progression.

First-Line Therapies and Follow-Up Appointments

First-line agents for pediatric MS are the injectable drugs known as platform therapies. The International Pediatric MS Society Group (IPMSSG) recommends that all patients start first-line therapy (ie, interferon β or glatiramer acetate) soon after diagnosis.

Positive results from phase IV observational studies suggest that interferon β and glatiramer acetate are safe and efficacious treatments in pediatric MS. When studied in populations ranging in age from 12 to 17, these therapies decreased relapse rate, stabilized disability, and reduced accrual of new lesions. However, injectable treatments are associated with flu-like symptoms and injection-site reactions. Neurologists should start pediatric patients on interferon β with 25% to 50% of full dosing and titrate to a full adult dosing over four to six weeks. When initiating glatiramer acetate, neurologists should start children with a full adult dosing, 20 mg subcutaneous daily or 40 mg subcutaneous three times per week.

Follow-up appointments should occur every three to six months to assess adherence and determine efficacy of treatment. Neurologists are advised to ask patients whether they are comfortable with taking shots. Patients with needle anxiety, a common problem in pediatric MS, may need assistance from a child psychologist or child life specialist. Asking patients how often the patient or family forgets to take the disease-modifying therapy is also necessary, said Dr. Lotze. In addition, the transition from pediatric to adult care should be addressed in follow-up discussions. Teens must understand that certain disease-modifying therapies are contraindicated for pregnant patients. They also should be aware of how alcohol and other drugs interact with treatment.

Treatment Failure

Research indicates that approximately 30% of patients with pediatric-onset MS will not respond to the first-line therapies, and numerous variables may explain why. Age and disease duration can influence treatment efficacy, as can the number of relapses and the level of disease activity before treatment initiation. Patients who are nonadherent because of side effects and who continue to struggle with needle anxiety may experience treatment failure. The IPMSSG defines treatment failure as adherence to treatment for at least six months with no reduction in relapse rate or in new MRI T2 or contrast-enhancing lesions, or with two or more relapses within a 12-month period.

Second-Line Therapies

Trials of several oral agents are currently under way. The IPMSSG, however, urges neurologists to use extreme caution when considering nonplatform therapies for pediatric patients.

Fingolimod is a second-line drug for pediatric MS that blocks the egress of lymphocytes from the lymph nodes. A small percentage of patients taking this oral agent may develop bradycardia. Monitoring is required for the first six hours of treatment to ensure that the patient has no side effects. Some adverse effects associated with the drug include: first dose bradycardia, macular edema, and herpetic infections.

Dimethyl fumarate is an Nrf2 antioxidant pathway modulator that is associated with adverse effects such as flushing and gastrointestinal upset, said Dr. Lotze. Low-dose aspirin may help with flushing, and a proton pump inhibitor can help to manage the gastrointestinal upset. This treatment requires patients to undergo monitoring for blood count and liver function, as does fingolimod.

Teriflunomide, a pyrimidine synthesis inhibitor, is a Pregnancy Category X drug because it increases the risk of birth defects. Rituximab, an anti-CD20 chimeric monoclonal antibody, is gaining popularity for treating MS. Studies suggest that ocrelizumab may be well tolerated in pediatric MS. Natlizumamb, cladribine, and alemtuzumab are typically used to treat more aggressive forms of MS.

Neurologists rarely prescribe cyclophosphamide or mitoxantrone in pediatric MS. Cyclophosphamide has no formal FDA approval for adult MS or pediatric-onset MS and is associated with increased risks of bladder cancer, secondary leukemia, and infertility. Mitoxantrone is FDA-approved for adults with aggressive relapsing-remitting MS and secondary progressive MS. It is associated with increased cancer risk, however, and is highly cardiotoxic.

“After you have initiated a second-line agent, you need to continue to monitor aspects of disease control, including relapse rate, disability, MRI changes, and other adverse events. If you continue to see breakthrough disease, then you may need to consider … changing to another agent or moving to a more aggressive therapy such as rituximab or natalizumab,” said Dr. Lotze.

—Erica Tricarico

Suggested Reading

Chitnis T, Ghezzi A, Bajer-Korneck B, et al. Pediatric multiple sclerosis: Escalation and emerging treatments. Neurology. 2016;87(9 Suppl 2):S10 3-S109.

Jancic J, Nikolic B, Ivancevic N, et al. Multiple sclerosis in pediatrics: Current concepts and treatment options. Neurol Ther. 2016:5(2):131-143.