Multiple sclerosis (MS) is typically detected in young adulthood or middle age, although it can also occur in childhood. An estimated 3% to 10% of patients with MS may experience their first clinical event at <16 years of age and 1% at <10 years of age.1,2

Although the demyelinating features are the same in pediatric vs adult MS, pediatric MS has distinctive patterns that distinguish it from later disease. MS in children is equally distributed among boys and girls, which in adulthood shifts to a 3:1 bias toward women.3 The first attack is often multifocal, involving motor and brainstem function, sphincter control, and cognitive disturbances, compared with the usual presentation of isolated symptoms of optic neuritis and sensory symptoms in postpubertal onset.4

Cerebellar and brainstem involvement are more common in pediatric MS, and up to 30% of patients have cognitive impairment significant enough to affect academic performance and social functioning.5 Deficits may span domains of working memory, speech processing, and executive function.6

These patterns generally continue throughout the first 2 years after onset, with frequent relapses.4 “In general, [those with] pediatric MS have a higher relapse rate and lower response to some therapies than adults,” explained Benjamin M. Greenberg, MD, MHS, FAAN, FANA, CRND, director of the Transverse Myelitis and Neuromyelitis Optica Program, and co-director of the Pediatric CONQUER Program at the University of Texas Southwestern O’Donnell Brain Institute.

The vast majority of pediatric MS cases (>95%) follow a relapsing-remitting course; as such, primary progressive and secondary progressive forms of MS in children are very rare.1,7

At the same time, the frequency of relapses in pediatric patients is significantly greater, at a rate of 2 to 3 times higher than in adults.2,7,8 Unlike adults, children generally achieve full recovery from relapse with little or no cumulative disability.8 Prognostically, brainstem involvement in the early attacks signifies a poor outcome, with more than 5 times the risk for secondary progressive disease compared with children without brainstem involvement.8

Diagnosing MS in Children

As with adults, diagnosis of pediatric MS rests largely on magnetic resonance imaging evidence of dissemination through time and space, along with evidence of a clinical attack. In very young patients, however, these first symptoms may not be easily identified as MS.

Pediatric MS is predominantly inflammatory in nature, with a presentation that is similar to a number of other conditions, including central nervous system infection or vasculitis, macrophage activation syndromes, metabolic and mitochondrial disorders, and rheumatologic diseases such as systemic lupus erythematosus and sarcoidosis.2 Careful history, physical examination, and laboratory and cerebrospinal fluid workups are typically used for differential diagnosis, with mixed results.

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Acute disseminated encephalomyelitis (ADEM) is the most common type of acquired demyelinating syndrome  that closely mimics the initial presentation of MS in children.

“In pediatric multiple sclerosis the differential is broad and includes other autoimmune disorders of the [central nervous system] including ADEM, [neuromyelitis optica], and anti-[myelin oligodendrocyte glycoprotein] antibody-related syndrome. It also includes non-immune mediated disorders such as leukodystrophies,” Dr Greenberg said. Studies indicate that approximately one-third of children first diagnosed with ADEM will have the diagnosis revised to MS within 3 years. This number was reduced when stricter criteria for ADEM were implemented.7,9 

Biomarker Strategies for Diagnosis

As early therapy is recommended to prevent development of longer-term disability, particularly from cognitive effects of pediatric MS, it is especially important to separate MS from other inflammatory conditions accurately. Biomarkers may offer the most effective way to differentiate pediatric MS attacks from similar presentations.

According to Dr Greenberg, “relative to ADEM and [neuromyelitis optica], there is a higher rate of anti-[myelin oligodendrocyte glycoprotein antibody]-associated disease in children than in adults. Patients with this antibody can present with ADEM or with a [neuromyelitis optica spectrum disorder] syndrome.” A 2018 study found that diffusion tensor imaging was also effective in differentiating MS from ADEM, marked by comparatively lower fractional anisotropy and higher radial diffusivities values.6

A recent study by Ganelin-Cohen et al10 reported that high levels of free light chain monomers and dimers were indicative of MS with higher specificity (91.4%) and sensitivity (90.5%) than oligoclonal bands typically used for diagnosis. Further, analysis of 3 specific patterns of monomers/dimers were of prognostic value; mixed patterns of increased λ-monomers plus increased dimers or λ-dimers predicted an aggressive course of disease.10 Similarly, Boesen and colleagues11 reported that levels of inflammatory biomarker chitinase 3-like 1 and neurofilament light chain ≥ 283 μg/L were 75% sensitive and 93% specific for a diagnosis of MS vs ADEM.

“For pediatric MS, confirming the accurate diagnosis is key. From there, once on therapy, monitoring for evidence of new disease activity with physical examinations, [magnetic resonance imaging], and academic assessments is key,” Dr Greenberg stated, adding that, “There are no fluid-based biomarkers to assess response for therapy, so follow-up is based on confirming clinical and radiographic stability.”


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