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Pediatric Multiple Sclerosis

  • Author: Teri L Schreiner, MD, MPH; Chief Editor: Amy Kao, MD  more...
 
Updated: Dec 03, 2015
 

Background

Multiple sclerosis (MS) is primarily a disease of adults. However, MS onset in children accounts for up to 10% of all MS cases.

Over the last 10 years, much has been learned about the epidemiology, pathophysiology, diagnosis, and treatment of MS in children. Several exciting discoveries have stressed the importance of genetic and environmental factors. Notable examples include human leukocyte antigen (HLA) subtypes and viral exposures, among others. There are phenotypic differences, including clinical, MRI, and laboratory findings, between adults and children, especially before puberty.

For example, in young children, the first presentation of MS can be indistinguishable from acute disseminated encephalomyelitis (ADEM). In addition, the initial brain MRI scan in younger patients shows more frequent involvement of the posterior fossa and higher numbers of ill-defined T2-bright foci that often partially resolve on the follow-up scan, thereby challenging early diagnosis. Finally, the spinal fluid in younger patients may fail to reveal oligoclonal bands (OCBs) or elevated immunoglobulin G (IgG) index at disease onset.

The treatment of pediatric patients with MS is based on randomized controlled data in adults. No randomized controlled trials of disease-modifying therapies in children have been conducted. Retrospective data have shown them to be effective. This is one of the several areas that require more study.

Definitions

MS is historically defined as neurologic symptoms disseminated in time (DIT) and space (DIS). The diagnostic criteria for MS in adults have been refined over time.[1, 2, 3] The current McDonald diagnostic criteria may be applied to children if the initial presentation is not characterized by encephalopathy.

MS is a challenging diagnosis in children—especially in prepubescent children—because of the atypical clinical, biological, and MRI presentations and the broader spectrum of potential differential diagnoses specific to that age range.[4]

In 2007, the International Pediatric MS Study Group published operational definitions for acquired demyelinating diseases of the CNS in children.[5] According to these definitions, ADEM (monophasic) requires the presence of both encephalopathy and polysymptomatic presentation. ADEM may last up to 3 months, with fluctuating symptoms or MRI findings. In contrast, a clinically isolated syndrome can be either monofocal or polyfocal but usually does not include encephalopathy. The original definitions were reviewed and updated in 2013.[6]

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Pathophysiology

Data concerning the pathophysiology of pediatric MS and how it may differ from adult MS are limited. Pathologic studies have offered some insights; however, brain biopsy is undertaken only in the most severe cases, so results may be biased toward a more severe phenotype. Most cases involve tumefactive demyelination. Cases with detailed pathology report a dense accumulation of lymphocytes and macrophages in a prominent perivascular distribution, with rare B cells. Axonal damage is typically limited.[7]

As in adults, identification of a self-antigen as an immunologic trigger is elusive, but T cells are believed to play a major role in CNS inflammation.[8] Several groups have studied T-cell responses to various antigenic stimuli in pediatric MS. A 2008 study of a large cohort of children with CNS inflammatory demyelination, type 1 diabetes, or CNS injury demonstrated that children with these conditions exhibited heightened peripheral T-cell responses to a wide array of self-antigens.[9] Anti–myelin oligodendrocyte glycoprotein (MOG) and anti–myelin basic protein (MBP) have been studied in both adults and children. In children, these anti-myelin antibodies seem to be associated with encephalopathy at onset.

CSF studies have demonstrated that children younger than 11 years exhibit a distinct cellular profile when compared with older children. Younger children with their first MS event were more likely to lack evidence of intrathecal antibody production (OCBs or an elevated IgG index) and had a higher percentage of neutrophils in their CSF, suggesting prominent activation of the innate immune response, as opposed to the typical activation of the adaptive response seen in older patients.

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Etiology

Triggers

Several environmental factors have been shown to play a role in MS susceptibility in adults. In children, very few studies have addressed these issues. Studying the role of common viruses in the pediatric MS population provides a unique opportunity given the close temporal relationship between the infection and MS onset and the fact that exposure to those viruses is lesser in children than in adults. Several studies examining viral exposures in pediatric MS have consistently identified significantly increased frequencies of Epstein-Barr virus (EBV) seropositivity in children with MS compared to matched controls.[10, 11, 12, 13] This association is independent of age at blood draw, sex, race, ethnicity, and HLA-DRB1 status.[14]

The novel observations in this study are that a remote infection with cytomegalovirus (CMV) decreases the risk of MS by more than 70%, and, in HLA-DRB1 –positive individuals, a remote infection with herpes simplex virus -1 (HSV-1) decreased the MS risk by 90%. In contrast, in HLA-DRB1 –negative individuals, HSV-1 seropositivity increased the MS risk fourfold.

Concern over the use of vaccinations, most recently hepatitis B vaccine, and the subsequent development of MS has been raised. Mikaeloff et al found no increased risk of developing a first episode of childhood MS up to 3 years postvaccination in the French population.[15]

Interestingly, the same group evaluated the risk of childhood-onset MS as related to exposure to passive smoking.[16] The relative risk for a first episode of MS was found to be over twice that in the control population and was even higher in those with prolonged exposure (≥10 years).

Finally, unlike in adult MS, the effect of vitamin D status on MS susceptibility is unknown, although levels of 25(OH) vitamin D have been found to be independently associated with subsequent relapse rate in patients with pediatric MS (for each 10 ng/mL increment of 25(OH) vitamin D3, risk of subsequent MS relapse was decreased by 34%).[17]

A few studies have evaluated genetic risk factors in pediatric MS. The US Pediatric MS Network has also reported that HLA-DRB1, as in adult MS, may be a risk factor for pediatric MS. In multivariate models adjusted for age, race, ethnicity, and remote viral exposures, the risk of developing MS if carrying at least one HLA-DRB1 allele was increased by 2- to 4-fold, depending on the model used.[4, 14]

Further studies on genetic and environmental risk factors are ongoing to explore the precise mechanisms that lead to disease onset. The discovery of gene-environment interactions may also shed new light on the understanding of molecular mechanisms involved in disease processes and might lead to the development of new therapeutic strategies.

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Epidemiology

While the worldwide prevalence of pediatric MS is unknown, data are available from individual countries or MS centers. Several large series[18, 19, 20, 21] report prevalence rates of MS onset in childhood or adolescence ranging from 2.2%-4.4% of all MS cases, while some MS referral centers report that up to 10% of their patients with MS experienced symptom onset prior to age 18 years.[22] In general, pediatric MS onset prior to age 10 years is rare and constitutes approximately 20% of the reported pediatric cases in large series.[8]

In 2011, a population based study in Southern California showed that, in the multiethnic cohort of Kaiser Permanente, the incidence rate of pediatric MS was 0.51 per 100,000 person-years (95% confidence interval [CI], 0.33-0.75), and the incidence of other forms of acute demyelinating syndrome, including optic neuritis, transverse myelitis, other forms of clinically isolated syndromes, and ADEM, was 1.56 per 100,000 person-years (95% CI, 1.23-1.95), for an overall incidence of acute demyelinating syndrome of 1.66 per 100,000 person-years (95% CI 1.32-2.06).[23]

It is unclear whether the incidence of pediatric MS has increased in the past decades or is merely being increasingly recognized owing to improved diagnostic criteria and medical awareness.

The sex ratio of pediatric MS varies by age. Before age 6 years, the ratio of MS in girls to boys is 0.8:1. It increases closer to the ratio observed in adults as children age.[5] The effect of ethnicity on risk of childhood-onset MS is poorly understood.

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Prognosis

The psychosocial complications of pediatric MS encompass various problems, including feelings of self-consciousness, worries related to the future, problems with family and friends, mood disorders, and cognitive impairment.

The Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (KSADS)[24] revealed that approximately 30%-48% of children with MS or related conditions have affective disorders.[25] The most common psychiatric conditions include major depression, anxiety disorder, a combination of anxiety and depressive disorders, panic disorder, bipolar disorder, and adjustment disorder.

When the scores from the pediatric MS group were compared to age-matched healthy controls and the fifth percentile of the healthy controls was used as the cutoff for fatigue, a total of 73% of the pediatric MS group met this criterion for severe fatigue.[25]

Cognitive impairment occurs in an estimated 30%-75% of children with MS depending on which definition of impairment is applied and at what point in their course the children undergo evaluations.[25, 26, 26, 24] Similar to prior reports, the domains more frequently affected included memory, complex attention, verbal comprehension, and executive functioning. Younger age at symptom onset correlated with lower intelligence quotient (IQ) scores.[25, 27]

Children with MS appear to be more vulnerable to cognitive decline over short periods than adults with MS. In school-aged children, cognitive decline is demonstrated by poor school performance. A significant percentage of pediatric patients with MS require some type of help or altered school curriculum owing to cognitive impairments, and up to 14% are homeschooled because of their illness. Some children need classroom seating accommodations, tutoring, and in-class assistance with implementation of 504 or individualized education plans.

Disability scores are lower in pediatric patients than in adults, even when adjusted for disease duration. The median time to reach an Expanded Disability Status Scale (EDSS) score of 4 (defined as a visible, often irreversible, neurologic deficit in a patient who is still able to ambulate at least 500 meters without assistance) was approximately 20 years in pediatric MS versus 10 years in adult MS.[28] Thus, despite a slower development of irreversible disability in patients with pediatric MS, the age when these patients are confronted with disease progression and neurological deficits is 10 years younger than the population with adult-onset MS, at the time when they are expected to have a family and enter the workforce.[29]

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Contributor Information and Disclosures
Author

Teri L Schreiner, MD, MPH Instructor, Fellow in Neuroimmunology, Children's Hospital Colorado, University of Colorado School of Medicine

Teri L Schreiner, MD, MPH is a member of the following medical societies: American Academy of Neurology, Child Neurology Society

Disclosure: Received grant/research funds from National MS Society for employment; Received consulting fee from Questcor Pharmaceuticals for consulting; Received grant/research funds from Teva Pharmaceuticals for other.

Coauthor(s)

Emmanuelle L Waubant, MD, PhD Professor of Clinical Neurology and Pediatrics, Director, Regional Pediatric MS Clinic at UCSF, Director, MS Fellowship Program at UCSF, University of California, San Francisco, School of Medicine; Medical Director, Nancy Davis Center Without Walls

Emmanuelle L Waubant, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Neurological Association

Disclosure: Received grant/research funds from Roche for research project; Received grant/research funds from Biogen Idec for fellowship grant; Received honoraria from Teva for speaking and teaching; Received consulting fee from Novartis for board membership; Received honoraria from Genzyme for speaking and teaching; Received honoraria from Questcor for speaking and teaching.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD Attending Neurologist, Children's National Medical Center

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Have stock from Cellectar Biosciences; have stock from Varian medical systems; have stock from Express Scripts.

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Periventricular increased T2 signal, as shown in this FLAIR image, can be seen in neuromyelitis optica given the dense concentration of aquaporin 4 water channels in this area.
Increased T2 signal at the cervicomedullary junction, as seen in a pediatric patient with MS.
An enhancing lesion in the right superior frontoparietal region. Image 4 shows the same lesion on FLAIR imaging.
FLAIR image of lesion in the right superior frontoparietal region.
This sagittal T2 image of the cervical spine shows small hyperintense lesions typical of MS at C2 C3.
This axial FLAIR image shows bilateral, left predominant confluent signal change. There is also an area of gray matter involvement in the right frontal region. This image would not be sufficient to distinguish an episode of ADEM from pediatric MS in a pre-pubertal child.
 
 
 
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