PART V. SPECIAL ISSUES
33
Pediatric Multiple Sclerosis
Amy T. Waldman
KEY POINTS FOR CLINICIANS
• Pediatric and adult multiple sclerosis (MS) have similar clinical symptoms.
• The presence of encephalopathy and a polysymptomatic presentation with diffuse central nervous system (CNS) involvement is more suggestive of acute disseminated encephalomyelitis (ADEM).
• For children presenting with transient neurological symptoms, such as paresthesias, the diagnosis of MS may not be recognized by a pediatrician or other healthcare professional, especially if the symptoms self-resolve, the neurological examination is normal, or limited imaging is performed. Therefore, a high index of suspicion for pediatric MS is required.
• In children with clinical symptoms consistent with MS (vision changes, paresthesias, weakness, balance, and gait difficulties), the MRI criteria for dissemination in space and dissemination in time proposed by the 2017 revisions to the McDonald Criteria are applicable to children, especially those older than 11 years.
• Children with MS have more frequent relapses early in the disease course and a greater T2 lesion volume at disease onset than adults; however, they generally have a slower progression to disability.
• Primary progressive MS is exceedingly rare in children and should prompt consideration of alternative diagnoses such as metabolic, mitochondrial, or neurodegenerative disorders (including leukodystrophies).
• In pediatric MS, relapse management is similar to adult MS, typically beginning with methylprednisolone, 20 to 30 mg/kg/d (maximum of 1,000 mg) for 3 to 5 days.
• Adult dosing of disease-modifying therapy (interferon beta and glatiramer acetate) is generally prescribed, although interferons should be titrated up to the full dose to minimize potential side effects.
• Pediatric MS clinical trials are helping to understand the efficacy, safety, and tolerability of MS therapies in pediatric patients.
• While disability can be minimal in pediatric MS, cognitive evaluation is a key aspect of care.
Pediatric MS was first described in 1922. Thirty-six years later, one of the first retrospective studies on pediatric MS, which enrolled 40 children with MS between 1920 and 1952, concluded that children and adults with MS have similar clinical profiles including symptoms and physical and laboratory (cerebral spinal fluid [CSF]) findings. Shortly thereafter, pediatric MS was recognized by the first expert panel organized to establish a definition of clinically definite MS. In 1961, Dr. George Schumacher and colleagues permitted the inclusion of children (older than 10 years) in their clinical description of the disease (1).
297Although pediatric MS has been recognized for almost a century, dedicated pediatric MS centers, facilitated by national collaborative programs, have been established mostly over the past decade. Pediatric MS research has also grown substantially. Although many similarities exist between pediatric- and adult-onset MS, there are notable differences, too. Such differences, which have raised questions about the impact of age, genetic susceptibility, and environmental exposures on the developing immune system, will hopefully lead to a greater understanding of the pathophysiology of the disease. This chapter highlights these unique issues relevant to the diagnosis and prognosis for MS in our youngest patients.
DEFINITIONS OF ACQUIRED DEMYELINATING SYNDROMES IN CHILDREN
Perhaps the greatest challenge in diagnosing MS in children is the growing recognition of the spectrum of demyelinating and neuroinflammatory conditions affecting the brain and spinal cord. In 2007, the International Pediatric MS Study Group proposed working definitions to allow for greater consistency in the diagnosis of ADEM, pediatric MS, and other acquired demyelinating syndromes in childhood (2). By creating a uniform language, the group hoped for more accurate diagnostic and prognostic data. These definitions were updated in 2013 (see Table 31.1), and additional phenotypes (see Table 33.2) have been further characterized since the 2013 revisions.
As in adults, pediatric MS is a chronic disease defined by neurological events separated in time and space affecting any age (including those younger than 10 years). The consensus definitions allow for the diagnosis of MS using MRI scans to confirm dissemination in time and space. The 2017 McDonald Criteria are applicable to children (see Diagnosis and MRI section in this chapter) (3). Ninety-five percent of children have relapsing–remitting MS (4); secondary progression rarely occurs during childhood or adolescence. Primary progressive MS is exceedingly rare in children; therefore, a progressive clinical course in a child should prompt consideration of genetic, metabolic, mitochondrial, neoplastic, and other disorders.
TABLE 33.1 International Pediatric MS Study Group Definitions
ACQUIRED DEMYELINATING SYNDROMES | PROPOSED CONSENSUS DEFINITIONS | COMMENTS |
ADEM (monophasic) | • A first polyfocal clinical CNS event with presumed inflammatory cause • Encephalopathy that cannot be explained by fever is present • MRI typically shows diffuse, poorly demarcated, large, >1–2 cm lesions involving predominantly the cerebral white matter; T1 hypointense white matter lesions are rare; deep gray matter lesions (e.g., thalamus or basal ganglia) can be present • No new symptoms, signs, or MRI findings after 3 mo following the incident ADEM | • Encephalopathy is defined as an alternation in consciousness (e.g., stupor, lethargy) or behavioral change unexplained by fever, systemic illness, or postictal symptoms • A single clinical event of ADEM can evolve over a period of 3 mo, with fluctuations in clinical symptoms and severity • MRI findings alone are insufficient for the diagnosis of ADEM • Documentation of a prior infection and isolation of an infectious agent are not required for diagnosis |
Multiphasic ADEM | • New event of ADEM 3 m or more after the initial event that can be associated with new or reemergence of prior clinical and MRI findings | • The new event must meet the clinical criteria for ADEM, including the presence of encephalopathy. Serial MRIs of patients with multiphasic ADEM, obtained following resolution of the second demyelinating event, should ultimately show a complete or partial resolution in the MRI lesions, in contrast to serial MRI findings in patients with MS that typically demonstrate ongoing accrual of asymptomatic lesions |
Neuromyelitis optica (IPMSSG definitions publishied in 2013) | • Must have optic neuritis and acute myelitis as major criteria • Must have at least two of three supportive criteria: (a) contiguous spinal MRI lesion extending over three or more segments, (b) brain MRI not meeting diagnostic criteria for MS, or (c) anti-aquaporin-4 IgG seropositive status | • Brain lesions, located in the hypothalamus, brain stem, or diffuse cerebral white matter, have been described in children who have typical features of NMO • NMO should be considered in the differential diagnosis of children with ADEM due to overlapping clinical features (e.g., diffuse cerebral lesions and contiguous spinal cord MRI lesions) • These criteria were published before NMO Spectrum Disorder was further classified by the presence or absence of NMO-IgG antibodies (5) |
CIS | • A first monofocal or multifocal CNS demyelinating event; encephalopathy is absent, unless due to fever | 298• The term CIS is applied to the first clinical demyelinating event (i.e., isolated in time) that does not meet the criteria for another syndrome • Examples include isolated optic neuritis, transverse myelitis, and brainstem syndromes • The study group elected to define CIS as multifocal if the clinical features could be attributed to more than one CNS site and monofocal if the clinical symptoms could be attributed to a single CNS lesion. These distinctions are based solely on clinical findings. The term multifocal cannot be applied to a clinically monofocal presentation in which the MRI shows multiple asymptomatic lesions |
Pediatric MS | Any of the following: • Two or more nonencephalopathic CNS clinical events separated by more than 30 d, involving more than one area of the CNS • One nonencephalopathic episode typical of MS which is associated with MRI findings consistent with 2010 Revised McDonald criteria for DIS and in which a follow-up MRI shows at least one new enhancing or nonenhancing lesion consistent with DIT MS criteria • One ADEM attack followed by a nonencephalopathic clinical event, 3 or more months after symptom onset, that is associated with new MRI lesions that fulfill 2010 Revised McDonal DIS criteria • A first, single, acute event that does not meet criteria for ADEM and whose MRI findings are consistent with the 2010 Revised McDonald criteria for DIS and DIT (applies only to children ≥12 y old) | • The DIS criteria have less predictive value in younger children, thus caution must be used in applying these criteria to confirm an MS diagnosis in children younger than 12 y |
ADEM, acute disseminated encephalomyelitis; CIS, clinically isolated syndrome; CNS, central nervous system; CSF, cerebrospinal fluid; DIS, dissemination in space; DIT, dissemination in time; FLAIR, fluid attenuated inversion recovery; IgG, immunoglobulin G; NMO, neuromyelitis optica; NMOSD, neuromyelitis optica spectrum disorder; MS, multiple sclerosis.
Source: Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19:1261–1267.
INCIDENCE OF PEDIATRIC MS
Approximately 3% to 5% of adults with MS experience their first attack prior to 18 years of age (6). The incidence of pediatric MS in the United States is 0.5 per 100,000 children, or 379 new cases each year according to a study performed using a large health maintenance organization database in southern California (7). The same study estimated the incidence of all demyelinating diseases (including ADEM, optic neuritis, and transverse myelitis) to be 1.6 per 100,000, or 1,246 new cases per year (7). In comparison, a prospective national Canadian study reported an incidence of an initial demyelinating syndrome of 0.9 per 100,000 children (8). Another prospective national study determined the incidence of pediatric MS (<16 years) in Germany to be 0.3 per 100,000 children (9). The variation between studies may reflect different methodologies or may be due to different environmental and genetic factors. For example, age, race, ethnicity, and residence may alter susceptibility for pediatric MS.
Three percent of MS patients experience their first symptom in childhood.
DEMOGRAPHICS
The risk of pediatric MS increases with age. Multiple studies have shown an increased risk in pediatric MS after 10 to 11 years of age (9–11) (see section on Risk of MS after a first demyelinating event), whereas ADEM commonly occurs between 3 and 8 years of age (12–14). Although younger children are more likely to present with ADEM and older children have monofocal or multifocal clinically isolated syndromes (Table 33.1), there are exceptions, and the proposed International Pediatric MS Study Group criteria, not age, should be used to diagnose acquired demyelinating syndromes in children.
299TABLE 33.2 Additional Pediatric Disorders
ACQUIRED DEMYELINATING SYNDROMES | PROPOSED CONSENSUS DEFINITIONS | COMMENTS |
ADEM followed by recurrent optic neuritis | All of the following are present: • Initial presentation fulfills criteria for ADEM • ON diagnosed after ADEM with objective evidence of loss of visual function • The ON occurs after a symptom-free interval of 4 wk and not as part of the ADEM or recurrent ADEM • Diagnostic criteria for pediatric MS are not fulfilled • Oligoclonal bands are not detected in the CSF (a pleocytosis may be present) • MRI reveals typical brain or spinal cord T2 lesions consistent with ADEM initially; however, subsequent imaging shows resolution or near-complete resolution of lesions and new brain or spinal cord lesions do not appear during the ON attacks | • Initial clinical features and imaging are typical of ADEM; however, with time, there is resolution of clinical symptoms, examination findings, and MRI abnormalities extrinsic to the optic nerves. Attacks of only recurrent optic neuritis occur |
Chronic relapsing inflammatory optic neuropathy | • Optic neuritis and at least one relapse • Objective evidence for loss of visual function • Response to immunosuppressive treatment and relapse on withdrawal or dose reduction of immunosuppressive treatment – NMO-IgG seronegative – MRI confirms contrast enhancement of the acutely inflamed optic nerves | • In this disorder, recurrent attacks isolated to the optic nerves occur without any other CNS involvement |
ADEM, acute disseminated encephalomyelitis; CNS, central nervous system; CSF, cerebral spinal fluid; MS, multiple sclerosis; NMO-IgG, neuromyelitis optica immunoglobulin G; ON, optic neuritis.
Source: Krupp LB, Tardieu M, Amato MP, et al. International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions. Mult Scler. 2013;19:1261–1267; Huppke P, Rostasy K, Karenfort M, et al. Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients. Mult Scler. 2013;19(7):941–946; Petzold A, Plant GT. Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J Neurol. 2013;261(1):17–26. (15,16).
The risk of pediatric MS increases after 11 years of age.
Overall, the proportion of males and females presenting with demyelinating diseases is approximately equal; however, the female:male ratio is approximately 2:1 in pediatric MS whereas there is perhaps a male predominance in ADEM (12,13).
Many pediatric studies have demonstrated a lower proportion of white/Caucasian race among pediatric-onset MS compared to adult-onset disease (6,15–17). Although referral bias may influence the proportion of minorities at some centers, there is growing evidence to suggest that the risk of MS is increased in African American and Asian children as well as those with a Hispanic background. The influence of race and ethnicity on disease severity is addressed later in the chapter (see section on Relapses).
The difference in demographics between children and adults with MS may be due to differences in susceptibility among different races and ethnicities in children or may reflect more diverse populations living in areas of higher MS risk. In fact, a Canadian study demonstrated a higher proportion of patients with Caribbean, Asian, or Middle Eastern ancestry than the adult MS population from the same area, suggesting that risk of MS may be determined in part by disease risk in the place of residence during childhood, in addition to ancestry (17).
OTHER RISK FACTORS
Environmental risk factors for MS have been the subject of much research. As noted earlier, the place of residence during childhood influences the risk of MS. The prevalence of 300MS increases proportionate to distance from the equator, perhaps owing to decreased sun exposure. Lower serum levels of vitamin D increase the risk of pediatric and adult MS (10,18) and have been linked to an increased relapse rate in pediatric MS (see subsequent section on Relapses) (19). Large-scale retrospective analyses have also shown an increased risk for MS in children of mothers with lower levels of exposure to ultraviolet (UV) radiation in the first trimester of pregnancy (20).
Other factors contributing to adult MS also have been investigated in children. The HLA-DRB1*1501/1503 allele linked to increased susceptibility in adult MS has been shown to confer similarly increased risk upon pediatric patients of European ancestry presenting with acquired demyelinating syndromes (21). A remote Epstein–Barr virus (EBV) infection is also associated with an increased risk of MS. The presence of antibodies against EBV nuclear antigen along with the presence of the HLA-DRB1*1501 allele markedly increases MS risk in adults (22). However, a genetic–environmental interaction has not been shown in children. Rather, the HLA-DRB1*15 genotype, remote EBV infection, and vitamin D insufficiency (defined as <75 nmoL/L which corresponds to 30 ng/mL) are independent risk factors for pediatric MS (10). Absence of these three risk factors is associated with a low risk of MS (5%) (10). In a national prospective study of children with acquired demyelinating syndromes, approximately 57% of the children with all the three factors have been diagnosed with MS (10). Higher body mass index is also a risk factor for pediatric MS (23).
Although the HLA-DRB1 allele and Epstein–Barr nuclear antigen-1 seropositivity are independent risk factors, the HLA-DRB1 allele may be implicated in the role of herpes simplex virus (HSV) in MS. One study showed that HSV played a protective role against MS in children with the HLA-DRB1 allele, and that the risk of MS was increased in those with HSV who did not have the allele (23). The same study demonstrated a decreased risk of MS in children previously exposed to cytomegalovirus (CMV) (23).
A French study linked parental smoking at home to increased risk (adjusted relative risk [RR] = 2.12) of pediatric-onset MS as compared to controls. The investigators also found that the risk was higher still with longer duration of exposure in children older than 10 years (RR = 2.49) (24). Though several studies pointed to a possible relationship between Hepatitis B vaccination and subsequent development of pediatric MS, more stringent analyses have found vaccination to have no effect on risk (25).
The presence of the HLA-DRB1 allele, remote EBV infection, vitamin D deficiency, and parental smoking increase the risk of pediatric MS.
CLINICAL FEATURES
Signs and Symptoms
The clinical symptoms in pediatric MS are very similar to adult-onset disease. CNS demyelination may result in visual disturbances, sensory manifestations, weakness or spasticity, balance difficulties, gait abnormalities, or bowel and bladder dysfunction localizing to the brain or spinal cord. Lhermitte’s sign and Uhthoff’s phenomenon also occur in children.
One of the most common presenting symptoms of MS in both children and adults is optic neuritis, characterized by decreased visual acuity, red color desaturation, and visual field deficits. Compared to adults, children are more likely to have bilateral involvement, especially children younger than 10 years. Children often present with significant vision loss (visual acuities of 20/200 or worse); however, the visual recovery is favorable as most achieve a visual acuity of 20/40 or better (26,27). Many of the children in these studies received intravenous corticosteroids, which may have helped improve outcome (see section on Relapses). Children with bilateral optic neuritis are not at higher risk for MS compared to those presenting with unilateral optic neuritis. Rather, risk of MS after optic neuritis increases with age at presentation, regardless of whether the child has unilateral or bilateral disease. The presence of asymptomatic MRI lesions outside the visual system markedly increases the risk of MS (11) (see Figure 33.1 and section on risk of MS after a first demyelinating event).
Optic neuritis is also a presenting symptom of neuromyelitis optica spectrum disorder (NMOSD) (see section on Differential Diagnosis). Bilateral or chiasm involvement at any age should prompt the clinician to consider further evaluation for NMOSD.
FIGURE 33.1 Probability of developing MS after optic neuritis according to age at presentation and MRI findings (defined as ≥1 lesion on T2-weighted imaging outside of the visual system) in children.
MS, multiple sclerosis.
Source: Waldman AT, Stull LB, Galetta SL, et al. Pediatric optic neuritis and risk of multiple sclerosis: meta-analysis of observational studies. J AAPOS. 2011;15:441–446.
Bilateral optic neuritis is more common than unilateral optic neuritis in children younger than 10 years.
Laboratory Studies
CEREBROSPINAL FLUID
A lumbar puncture is routinely recommended for all children presenting with demyelinating disease, although some physicians are less inclined to order a spinal tap for isolated optic neuritis (28). Only about 70% of physicians routinely obtain CSF studies in isolated optic neuritis (28).
