The care of children and adolescents with multiple sclerosis (MS) requires appreciation of the impact of the disease on the developing brain and, in particular, the risk for cognitive impairment and academic challenges. Relapse rates in the first three years from onset are high, with an average of 1.5 relapses per year, and often require hospitalization for acute corticosteroid therapy. Disease modulatory therapies are typically prescribed, although formal clinical trials in the pediatric MS population are only just now being realized. In this review, we discuss strategies to optimize therapy for an individual child or teenager, including utilization of a multidisciplinary approach to care.
Pediatric multiple sclerosis, immunomodulation, safety, efficacy, relapse, treatment
Anusha K Yeshokumar has no relevant conflicts of interest to declare. Brenda Banwell has received remuneration for work as a central MRI reviewer for Novartis. No funding was received in the publication of this article.
Compliance with Ethics: This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.
Authorship:All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
December 19, 2016 Accepted
February 07, 2017
Anusha K Yeshokumar, Division of Child Neurology, Children's Hospital of Philadelphia, Colket Translational Research Building, 10th Floor, 35th Street and Civic Center Boulevard, Philadelphia, PA 19104-4399, US. E: firstname.lastname@example.org
This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Multiple sclerosis (MS) onset during childhood or adolescence follows a relapsing-remitting pattern, with a high early relapse frequency, and is associated with a risk for cognitive impairment and future physical disability. Acute management of relapses, modulation of chronic disease course, cognitive evaluations and strategies for academic modifications, and multidisciplinary team approaches to the management of fatigue, bladder issues, and coping and emotional health are also key components of care. While the vast majority of MS patients experience onset in adulthood, up to 10% of patients experience symptom onset prior to 18 years of age.1,2
Relapses in pediatric MS patients, including the sentinel first “attack,” are characterized by optic neuritis, transverse myelitis, brainstem syndromes, or rarely, an acute disseminated encephalomyelitis- (ADEM) like (encephalopathy and polyfocal deficits) syndrome. By definition, an individual attack is defined by a new neurological deficit persisting more than 24 hours, and not better explained by another etiology, and occurring more than 30 days from the last recorded attack.3 MS diagnosis is confirmed by recurrent attacks and supported by magnetic resonance imaging (MRI) evidence for new lesions involving different regions of the central nervous system (CNS). The 2010 McDonald MS diagnostic criteria also allow for diagnosis to be made at the time of the first acute demyelinating attack if MRI demonstrates clinically silent lesions in two of the four regions typical for MS, at least one of which enhances with gadolinium.4 Application of the 2010 McDonald MS diagnostic criteria at the time of a first attack in a pediatric cohort requires consideration of the patient’s age. When applied to patients over the age of 11, the criteria very accurately identify children who later experience further MS attacks. Children who do not demonstrate the MRI features described in the 2010 McDonald criteria did not experience further disease and were not diagnosed with MS.5 In younger children, however, lesions are typically larger with less well-defined margins and may completely resolve.6,7 The positive predictive value of the 2010 McDonald criteria at the time of a first attack is only 55%, and thus caution must be used in applying the criteria in this age group, often requiring evidence of new disease over time on serial clinical and MRI examinations before confirming MS.8 Of note, a normal brain MRI at the time of a first demyelinating attack (in presentations of optic neuritis or transverse myelitis) strongly suggests a monophasic illness, with less than 3% of such children being diagnosed with MS over time.9
Over 90% of patients will experience near complete neurological recovery from relapses early in the disease.10 However, secondary disease progression, in which accrual of neurological disability occurs independent of relapses, may occur over time. While pediatric MS patients may take longer to develop secondary disease progression, they do so at a younger age than patients with onset in adulthood.11
Fundamental to the diagnosis of MS is the exclusion of other diagnoses. Progressive symptoms from onset would not be typical of the relapsing-remitting course seen in over 97% of pediatric MS patients and should lead to consideration of leukodystrophies, mitochondrial disease, compressive
myelopathy, or rarely, severe nutritional deficiencies.12,13 Infectious etiologies must be excluded, particularly at the time of acute presentation and in all children with an ADEM-like first event.
Immunomodulatory therapies for multiple sclerosis
In the last several years, an increasing number of treatment options have been made available for the treatment of MS. There are currently ten medications that have been approved by the US Food and Drug Administration (FDA) for use in adults. There are currently no medications that have been approved by the European Medicines Agency (EMA) or the FDA for use in children, however, treatment studies in pediatric MS are currently underway as discussed below. Here, we review many of the medications that have been used off-label in pediatric MS (see Table 1). Information on their efficacy, tolerability, and safety in children has mostly resulted from anecdotal experience and retrospective analyses. The most commonly used treatments for MS in children include interferon beta and glatiramer acetate. These medications were initially approved for use in adults in the 1990s and have a favorable safety profile in children and adults. These medications are injectables (either subcutaneous or intramuscular), and many children struggle with adherence to frequent needles.
Glatiramer acetate is a heterogenous mixture of synthetic polypeptides found in myelin basic protein. It is thought to act as an immunomodulatory agent by inhibiting specific regulatory and effector T-cells and by altering function of antigen-presenting cells.14,15 Glatiramer acetate is administered as a subcutaneous injection dosed at 20 mg daily or 40 mg three times a week. There is no reduction in dose required for children. Small retrospective studies in children have shown that glatiramer acetate is overall very well tolerated with no concerning or lasting side effects, even when used long-term.16,17 Patients may experience a transient hypersensitivity reaction with flushing and tachycardia lasting 30–90 seconds. These reactions are not dangerous and typically only occur a few times. Injection site skin reactions, particularly persistent skin dimpling (lipoatrophy), can occur. Careful teaching about injection technique is essential.
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Pediatric multiple sclerosis, immunomodulation, safety, efficacy, relapse, treatment