Wednesday, February 6, 2019

Pediatric-onset multiple sclerosis

Multiple sclerosis (MS) most commonly presents in adulthood; however, in 3% to 5% of patients with MS, the first clinical attack occurs prior to age 18 years. The first demyelinating attack in childhood is termed an acquired demyelinating syndrome (ADS), which may be a monophasic illness or a first attack of a relapsing demyelinating disorder, such as MS. The proportion of children with ADS who have MS ranges from 15% to 45%. Pediatric-onset MS (POMS) follows a relapsing-remitting course at onset, with fewer than 2% of pediatric patients presenting with a primary progressive form of MS. More frequent relapses in early disease stages compared with adults is characteristic of POMS. Children tend to have more complete recovery after attacks, and disability accumulation is slower compared with adult-onset MS. Secondary progressive disability usually does not occur until approximately 20 years after onset. Treatment is largely based on data obtained from clinical trials in adult patients; however, there are 2 recent randomized clinical trials performed in children that provide high-quality efficacy and safety data. In this review, we discuss the clinical features, neuroimaging, disease course, and available treatments for children with MS….

Risk factors for POMS and adult-onset MS include having 1 or more HLA-DRB* alleles, Epstein-Barr virus (EBV) exposure, low serum vitamin D levels, obesity, and second-hand smoke exposure. HLA-DRB1* is the strongest genetic risk factor for MS. In a study of 266 children presenting with ADS, those with HLA-DRB*15 were more likely to be diagnosed with MS than controls (odds ratio [OR] = 2.7)….

Children with MS have lower disability scores early in the course of disease and on average do not experience significant ambulation deficits until 20 or more years after the initial attack. Patients with POMS generally take 10 years longer to convert to secondary progressive MS (SPMS) compared with adults. Due to the early age of onset, patients with POMS do reach SPMS on average 10 years earlier than those with adult-onset MS. Potential indicators for poor outcomes include a short interval (< 1 year) between the first 2 attacks, incomplete recovery after first attack, and brainstem involvement at onset…

The criteria for the diagnosis of MS were recently updated in 2017 with the following important revisions to the 2010 McDonald criteria.

1. Presence of 2 or more oligoclonal bands in CSF that are not present in serum can be used as evidence of dissemination in time;

2. Symptomatic and asymptomatic MRI lesions can be included to provide evidence for dissemination in space (DIS) or dissemination in time (DIT); and

3. Cortical lesions can be used to fulfill MRI criteria for DIS.

The 2017 McDonald criteria have been validated in a large pediatric cohort and shown to be comparable to the 2010 McDonald criteria…

The natural history of POMS, with high relapse rates and higher volume of brain lesions early in the disease, supports a role for prompt initiation of effective disease-modifying therapy…

For chronic disease management, traditional first-line therapies have included interferon β and glatiramer acetate. Both demonstrated a 29% to 34% reduction in ARR and decrease in new MRI lesion development in adult patients. Although there have been no treatment trials of interferon β in children, safety and tolerability have been demonstrated and published in retrospective reviews. In a study of 65 patients with POMS, the mean ARR decreased during treatment with either interferon β-1a (from 2.4 to 0.4) or glatiramer acetate (from 2.8 to 0.25).22 The limitations of retrospective data to inform on efficacy, however, must be considered.

A recent randomized, double-blind, placebo controlled 2-year trial compared oral fingolimod with weekly intramuscular interferon β-1a. Fingolimod was associated with a lower rate of relapse and less lesion accumulation on MRI, leading to approval by the Food and Drug Administration (FDA) and regulatory agencies in other countries for use of fingolimod to treat children with MS who are over age 10 years. For patients weighing less than 40 kg, a dose of 0.25 mg daily is used; the standard adult dose of 0.5 mg daily is used for those weighing more than 40 kg. Currently active clinical trials are evaluating efficacy and safety of dimethyl fumarate,24 teriflunomide, and alemtuzumab for POMS…

Other treatments used to treat patients with POMS include natalizumab and rituximab. Natalizumab is a humanized monoclonal antibody against α4β1 and α4β7 integrins. Blocking these molecules prevents immune cells from crossing the blood-brain barrier. Proven efficacious in adults, the best data in pediatric patients is limited to prospective cohort studies. In a study of 55 patients with POMS using the adult dosing regimen of 300 mg intravenously every 4 weeks, ARR decreased to 0.1 ± 0.2 during treatment from an ARR of 2.4 ± 1.6 in the year preceding treatment (P < .001).26 Rituximab is a monoclonal antibody against CD20, a surface marker found on the majority of B cells. Rituximab has demonstrated a favorable safety profile in children and appears promising for use in neuroimmunologic diseases in children, including POMS.

Another monoclonal antibody directed against CD20, ocrelizumab, has shown efficacy in treatment of adults with relapsing-remitting MS in 2 large clinical trials. Studies are being planned to investigate this medication for treatment of POMS…

In children, MS has a relapsing-remitting course with frequent relapses early in the disease but with minimal disability accrual. Cognitive impairment and continued cognitive decline, however, are of major concern and have the potential to negatively impact long-term quality of life. Effective therapy reduces relapse rates, brain lesions, and brain atrophy. The long-term benefit of early therapy remains to be seen, and close monitoring for potential therapy-mediated morbidities is necessary.

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