Pediatric multiple sclerosis




Pediatric multiple sclerosis (MS) comprises a small proportion (4%-5%) of the multiple sclerosis population. Multiple sclerosis is typically considered to be a disease of young adults. However, pediatric MS, defined as onset of MS before the age of 18, is increasingly recognized.

Pediatric multiple sclerosis represents a particular MS subgroup with unique diagnostic challenges.

While some aspects of the clinical disease in children resemble those of adults, children can also dramatically differ in clinical, radiological, and laboratory features. The family unit plays a different role in pediatric MS than in adult MS. Management is complicated by the lack of clinical trials in this age group.

The National Multiple Sclerosis Society (NMSS) has recognized that pediatric multiple sclerosis (and other acquired central nervous system demyelinating disorders) have not been studied adequately. The natural history and best practices with respect to evaluation and treatment are unknown.


Children present with a wide variety of symptoms including sensory deficits, ON, brainstem-related deficits, motor deficits, and gait disorders.

Several clinical features are more common in young MS patients (those under 11 years of age). These include a history of preceding infection, more frequent severe cognitive problems, seizures, optic nerve dysfunction, and brainstem or cerebellar involvement. In contrast, it is less common for younger to have isolated spinal cord presentations. Younger patients also have more confluent disease on brain MRI with lesions that tend to vanish more quickly. One study found that those under the age of 12 years had a longer relapse-free interval and lower number of relapses in the first two years of disease compared to those older than 12 years.

Fatigue that limits recreational and scholastic activities is a common symptom of pediatric MS. Children also appear to be exceptionally vulnerable to cognitive disability. The most common impairments are complex attention, visuomotor integration, confrontation naming, receptive language, and executive function while verbal fluency tends to be relatively intact. The frequency of cognitive impairment ranges in different studies from 30 to 66%. Unfortunately, preliminary data suggest that as many as 70% of children decline in cognitive ability over two years. This is in contrast to adults where cognitive decline is typically more gradual.


MS is a Disease of the Immune System.

MS is a disease that involves an immune system attack against the central nervous system (brain, spinal cord, and optic nerves). The disease is thought to be triggered in a genetically susceptible individual by a combination of one or more environmental factors. Although MS is thought by some scientists to be an autoimmine disease, others disagree strongly because the specific target of the immune attack in MS has not yet been identified. For this reason, MS is referred to as an immune-mediated disease.

As part of the immune attack on the central nervous system, myelin (the fatty substance that surrounds and protects the nerve fibers in the central nervous system) is damaged, as well as the nerve fibers themselves. The damaged myelin forms scar tissue (sclerosis), which gives the disease its name. When any part of the myelin sheath or nerve fiber is damaged or destroyed, nerve impulses traveling to and from the brain and spinal cord are distorted or interrupted, producing the variety of symptoms that can occur.


Five therapies have been approved by the Food and Drug Administration for use as first-line therapies for the prevention of relapses in adults with relapsing-remitting multiple sclerosis. These include 4 injectable therapies (interferon β-1a intramuscular [once a week], interferon β-1a subcutaneous [3 times a week], interferon β-1b subcutaneous [every other day], and glatiramer acetate subcutaneous [daily]), and one oral agent, fingolimod. Second-line therapies that have been approved for use in the adult multiple sclerosis population include natalizumab and mitoxantrone.

The therapies noted above have not received Food and Drug Administration approval for use in pediatric multiple sclerosis, as no randomized controlled studies have been performed in the pediatric multiple sclerosis population. However, retrospective studies evaluating their use in the pediatric population with multiple sclerosis have been published:

Interferon β (IFNβ). Several retrospective case series have described the use of subcutaneous and intramuscular interferon β-1a and -1b in the pediatric population with limited follow-up (up to 48 months)

Glatiramer acetate in pediatric relapsing-remitting multiple sclerosis (Kornek et al.) reported on 7 patients with pediatric-onset relapsing-remitting multiple sclerosis (ages 9-16 years) who were treated with glatiramer acetate for 24 months.

In adults, new evidence suggests that vitamin D plays a vital role in maintaining innate immunity and has been implicated in the prevention of certain disease states including infection, autoimmune diseases (multiple sclerosis).


An essential feature of the diagnosis of MS is that there is dissemination in time and space.

Diagnostic testing:

A standard diagnostic evaluation beyond imaging and CSF should include: CBC, ESR, and ANA, whereas extended testing for specific conditions might include Lyme antibody titers, MR angiography, MR spectroscopy, evoked potentials, CSF lactate, serum vitamin levels (B12, D, E, folate), anti-Ro, anti-La, serum angiotensin-converting enzyme levels, HIV, rapid plasma reagent, HTLV-1 PCR, serum EBV and mycoplasma titers, NMO antibody, very long chain fatty acids, and GFAP mutation.

Differential Diagnosis:

Acute disseminated encephalomyelitis: The most common and perhaps the most difficult differential on first presentation is acute disseminated encephalomyelitis (ADEM). Considered a post- or parainfectious demyelinating process, this disorder also presents with multiple lesions and multiple neurological deficits.

Neuromyelitis optica: Is another inflammatory disorder of the CNS that can mimic MS. Neuromyelitis optica (NMO) formerly referred to as Devic's disease. The criteria for its diagnosis require optic neuritis and transverse myelitis, and either a longitudinally extensive lesion on spinal cord MRI or a positive NMO IgG antibody titer. The presence of brain involvement is not uncommon in children and does not exclude the diagnosis.

Infection and other disorders: Encephalitic or meningo-encephalitic infectious etiologies must be ruled out in patients with acute presentations, particularly when there is fever and CSF leukocytosis. CNS Lyme disease may manifest with multifocal white matter lesions and a relapsing/remitting clinical course. Similar patterns may be seen with HIV encephalomyelitis, HTLV-1, neurosyphilis, progressive multifocal leukoencephalopathy (PML), Whipple's disease, subacute sclerosing panencephalitis (SSPE), and various parasites.

Vascular and autoimmune disorders: CNS vasculitis can be difficult to distinguish from MS. The presence of beading on CT angiograms can suggest the diagnosis, as can an elevated C-reactive protein level or erythrocyte sedimentation rate (ESR). A brain biopsy may be necessary in cases of isolated CNS angiitis. Other disorders to include in the differential diagnosis are systemic lupus erythematosus (SLE), Behçet disease, neurosarcoidosis, and Sjogren's disease. Vascular diseases mimicking MS are fortunately rare in younger individuals and would include moyamoya disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). In some cases of CADASIL, there is marked overlap on brain MRI with MS. The family history, stroke-like events, and migraines help lead to the correct diagnosis with confirmation of a Notch3 mutation. Other disorders to consider are Langerhans cell histiocytosis and hemophagocytic lymphohistiocytosis.

Neoplasms: Cranial neoplasms, particularly CNS lymphoma, may mimic a tumefactive presentation of MS on neuroimaging and complicate the diagnosis. Including MRS studies with the routine MRI might help in the differential diagnosis in these instances.

Leukodystrophies: Leukodystrophies can be subdivided into myelination failure, delay or breakdown, and those associated with malformations. Key features are bilateral and symmetric involvement on MRI that appears fairly homogenous. Adrenoleukodystrophy and adrenomyeloneuropathy can be confusing as they show preferential involvement of the peritrigonal white matter, splenium of the corpus callosum, posterior limb of the internal capsule, the crus cerebri, and the cerebellar white matter. The inclusion of very long chain fatty acids in the laboratory work-up of suspected cases leads to the correct diagnosis.

Mitochondrial disorders: The course for mitochondrial disorders is typically progressive and may be marked by bilateral basal ganglia involvement on MRI. Further red flags, such as visual loss, bilateral hearing deficit, short stature, ophthalmoplegia (Kearns-Sayre), cardiac involvement (Kearns-Sayre/CPEO), stroke-like events (MELAS), myoclonic epilepsy (MERRF), or bone marrow failure (Pearson), can help reveal the specific cytopathy. Brainstem involvement is a feature seen in Leigh syndrome.


Over time, children with MS develop repeated relapses and accumulate increasing disability. Annual relapse rates vary in different studies from 0.5 to 2.8, depending on differences in prospective vs. retrospective design of the studies and duration of follow-up. Overall, when compared to adults, children with MS have a higher rate of relapse within the first two years of disease but progress more gradually. In several retrospective studies, the time to reach an EDSS of 6.0 from diagnosis varied from 19 to 29 years. At higher levels of EDSS, the likelihood is that the course will have transitioned to secondary progressive MS. The risk of secondary progressive MS in children (as in adults) is associated with a higher frequency of relapses and shorter intervals between attacks in the first few years of the disease.


Management of relapses:

The usual treatment for an acute relapse is corticosteroids with doses of parenteral methylprednisolone ranging from 10 to 30 mg/kg. In most instances, the maximum dose is 1000 mg administered intravenously (IV) once daily in the morning for 3–5 days; an oral prednisone taper is optional. An alternative to IV steroids is high-dose, oral prednisone (same dose as IV therapy) which in adults may be as effective as IV treatment in managing acute relapses. High-dose oral prednisone (up to 1200 mg/day) in adults has been found to have good bioavailability compared to IV therapy but is untested in children or adolescents. Adverse effects of steroids such as insomnia as well as mood disturbances including psychosis, hyperglycemia, and hypertension need to be monitored. Prolonged steroid use can also possibly retard growth in youngsters. Despite its long-term risks, short courses of steroid therapy are reasonably safe and well tolerated by most children.

Plasmapheresis or intravenous immunoglobulin (IVIG) are options for when IV steroids fail to improve a severe relapse. The use of either modality is based on its success in a limited number of cases of children or adults. Usually five exchanges every other day are administered. IVIG treatment can also be used at a dose of 0.4 g/kg for five days and be continued one day per month at 0.4 g/kg. This therapeutic approach has been studied in only small samples of ADEM and its variants.

Interferon (IFN):

IFN-beta 1a intramuscular (IM) injection at a dose of 30 micrograms (μg) once weekly is usually well tolerated in children with MS. Adverse events and laboratory changes were similar to those of treated adults. The standard adult dose of 30 micrograms (μg) IM once per week has been used effectively even in some ten year-old children but half the dose is often used for very young children aged three years and younger.

Interferon beta 1a subcutaneous (SC) injection has also been successfully administered to pediatric MS patients. The dose for IFN-beta 1a SC for children can be the same as adults: 44 μg three times a week with a minimum of 48 hours between each dose at a lower dose of 22 μg three times a week.

Glatiramer acetate (GA):

In a study of seven patients aged 9–16 years who were treated with GA, all did well at standard doses of 20 mg daily and without escalation. In controlled clinical trials of adults, the most commonly observed adverse experiences associated with the use of GA were: injection site reactions, vasodilatation, chest pain, asthenia, infection, pain, nausea, arthralgia, anxiety, and hypertonia. These side effects have also been reported in children.

Breakthrough disease:

Unfortunately, many children treated with first-line DMTs experience breakthrough disease and need to be switched to either another first-line treatment or to second-line therapies.

Natalizumab in pediatric MS:

A total of four children treated with natalizumab have been reported who were 12–13 years of age at the time of therapy and had failed first-line DMTs (interferons and glatiramer acetate). A dose of 3–5 mg/kg of body weight was administered, leading to a decrease in disease activity and, in three patients in whom it was recorded, improved quality of life. All patients tolerated the treatment well, but none at the time of the report had been followed for more than 24 months. The potential development of PML remains a substantial concern in choosing this treatment option.

Symptomatic therapy:

There are no clinical trials of symptomatic therapy in children with MS. There have been studies showing efficacy of oral and intrathecal baclofen for spasticity in children with other neurological disorders.


  • NIH