Pediatric multiple sclerosis: a review

Children can present with a wide variety of manifestations including optic neuritis (ON), sensory, brainstem-cerebellar, and motor symptoms. The MS course in cases with onset at < 16 years of age is very similar in among populations from Italy, Russia, France, USA, and Kuwait [1‐3, 6‐10]. The clinical phenotype differs from that of adult patients, in that pediatric MS patients generally experience a more aggressive disease onset with disabling clinical symptoms [11], a polyfocal presentation at disease onset [12] and a higher relapse rate early in the disease course [13]. Though these findings are mostly from the USA and Europe, no were major regional differences in the epidemiological patterns or clinical features, meaning data outside of these regions are scarce. Overall, children tend to have a more favorable outcome after a first clinical event [13]. They also have slower disease progression over time: they take 10 years longer to reach secondary progressive disease phase compared to adults [2]. The relatively slow development of irreversible physical disability in children [14] is believed to result from better plasticity, allowing better recovery from relapses. In pediatric MS time from onset to confirmed disability may be relatively long, but disability milestone is reached at an earlier age.

Axonal damage occurs early in MS and contributes to the degree of clinical disability. In children with MS, there is more pronounced acute axonal damage in inflammatory demyelinating lesions than in adults [15]. Similar heightened axonal damage was observed in a case study of a 12-year-old patient [16]. Evidence was found in a study that was performed on archival biopsy and autopsy tissue of 19 children with demyelinating diseases: MS (n = 11) or clinically isolated syndrome (CIS) (n = 8). Median age at biopsy/autopsy was 13 years (range 4 – 17 years). The most important outcome was the significant increase, by 50%, of acute axonal damage in early active demyelinating lesions of pediatric patients (median = 1665 Amyloid Precursor Protein (APP) -positive axons/mm²) compared to adult patients (median = 1100 APP-positive axons/mm², p = 0.0455). The numbers of APP-positive axons/mm² were significantly higher in the prepubertal age group (< 11 years of age) compared to the pubertal age group (11–17 years, p = 0.0061) and adult patients (≥18 years, p = 0.0044). Furthermore, significantly more children showed multifocal MRI T2 lesions (71.4% vs 54.5%, p > 0.05). Also, the index lesion was larger in pediatric patients (81.8% vs 50% size > 2 cm). There was an increased inflammatory infiltration in pediatric MS lesions, which was shown to be associated with the extent of acute axonal damage in pediatric and adult patients (r = 0.5381, p = 0.0098).

Besides clinical features that are typical for demyelination, MS is associated with significant cognitive impairment in childhood. In a study in 63 patients, 19 (31%) fulfilled criteria for cognitive impairment [17]. Cognitive outcome in these patients can be heterogeneous, as cognitive performance deteriorated in 42 of 56 cases (75%) after 2 years of follow-up [18]. In a 5-year longitudinal study, cognitive impairment index deterioration was observed in 56% of patients, improvement in 25%, and stability in 18.8% [19].

One of two methodological approaches to calculate the prevalence and incidence of pediatric MS are usually conducted in scientific publications, which could explain the variation in published data. Subtraction of POMS cases from the total MS cohort, or calculating an age-specific, population-based risk are the common methodological approaches. Other reasons for the variation in the prevalence and incidence are the use of different diagnostic criteria and of a different cut-off age among the studied pediatric cohorts, ranging from 15 to 18 years.

The worldwide prevalence and incidence of pediatric MS is unknown, but data from individual countries and MS centers are available (see Table 1). Several studies indicate that at least 5% of the total population with MS comprises of pediatric patients [6, 7]. Population studies and case-control series show that between 1.7% and 5.6% of the MS population is younger than 18 years of age [2, 6‐8]. A recent study showed that incidence and prevalence of pediatric MS in Kuwait in 2013 were 2.1 and 6.0, respectively [20]. Incidence in general is highest in children between the age of 13 and 16.

There is a possible role for Epstein-Barr virus (EBV) in MS pathogenesis. This was suggested by the results of a multinational observational study, which included 137 pediatric MS patients from 17 sites across North- and South-America and Europe [11]. Non-MS controls were matched 1:1 by year of birth with an MS participant enrolled from the same region. The participants underwent standardized assays (ELISA) for IgG antibodies directed against EBV, cytomegalovirus, parvovirus B19, varicella zoster virus, and herpes simplex virus. Over 108 (86%) of children with MS, irrespective of geographical residence, were seropositive for remote EBV infection, compared to only 64% of matched controls (p = 0.025). The hazard ratio (HR) to be in the MS group in case of seropositivity for remote EBV was 2.8 (confidence interval (CI): 1.4 – 5.8) (p = 0.005). Only anti-EBV nuclear antigen titers were higher in the EBV-positive MS patients compared to EBV-positive non-MS controls (p = 0.003).

One of the main risk factors of MS, also confirmed in pediatric MS, is HLA DRB1*1501 [21]. DNA from 56 children with MS (< 16 years of age) was used for HLA-DRB1 typing and compared to healthy controls (n = 328), MS patients from the same population (n = 234), and 76 parents of 39 pediatric MS patients. Only the frequencies of DR2(15) alleles were higher in both sets of MS patients than in controls. Transmission disequilibrium test (TDT) results showed significant difference in transmission of DR2(15) and non-DR2(15) alleles (p = 0.00002).

High-quality studies of the natural history of pediatric MS are scarce due to methodological issues. In a comparative study analyzing data collected from two different pediatric cohorts, clinical characteristics and progression of pediatric onset MS (< 16 years) over time were assessed. In the Moscow cohort, 67 cases of newly diagnosed MS were prospectively observed for 2 - 13 years, while the Vancouver cohort consisted of 116 MS cases who were retrospectively observed for 1 - 47 years [1, 9]. The pediatric cohorts were compared with an historical adult cohort to assess the risk of disability progression assessed by expanded disability status scale (EDSS) scores. There were a number of significant differences between pediatric and adult-onset MS [10]. The 50% risks to reach EDSS 3 and 6 were 23 and 28 years after MS onset, compared to 10 and 18 years in the comparator group.

In a longitudinal prospective population-based study the risk of disease progression in POMS was assessed [22]. The interval to second relapse was longer in pediatric patients (5.0 vs 2.6 years, p = 0.04) PPMS was less common (0.9% vs 8.5%, p = 0.003). Pediatric patients took longer to develop secondary progressive MS (SPMS) (32 vs 18 years, p = 0.0001) and to reach disability milestones (EDSS 4.0, 23.8 vs 15.5 years, p < 0.0001; EDSS 6.0, 30.8 vs 20.4 years, p < 0.0001; EDSS 8.0, 44.7 vs 39 years, p = 0.02), but did so between 7.0 and 12 years younger than in adult-onset MS. A high relapse rate predicted faster progression. Complete recovery on the other hand, reduced the risk of progression (reaching EDSS 4) on the long term.

In a large cohort from a network of French and Belgian centers, patients with pediatric MS reached secondary-progression and disability milestones at ages approximately 10 years younger than patients with adult-onset disease, despite a slower development of irreversible disability [2]. Among the 17,934 patients, 394 (2.2%) had MS starting at 16 years of age or younger, and 290 (73.6%) of these patients were women. The mean age at onset was 13.7 years. Onset occurred at the age of 14 years or younger in 159 patients (40.4%), and at 10 years or younger in 30 patients (7.6%). The estimated median time between the first two neurologic episodes was 2.0 years.

A more aggressive disease course may be predicted by relapse severity and residual disability in early pediatric MS. In a retrospective study of 105 patients with MS or CIS onset prior to 18 years of age, optic nerve involvement was associated with a severe initial demyelinating event (IDE) (OR 4.30, p = 0.007) [28]. A severe initial demyelinating event was associated with incomplete recovery (OR 6.90, p < 0.001), with similar trends for second and third events. Incomplete recovery from the first event predicted incomplete second event recovery (OR 3.36, p = 0.055).

The importance of presentation at onset for the prognosis is underlined by a study of prognostic indicators of SPMS in a cohort of 127 pediatric MS patients (< 18 years of age) from Kuwait [29]. Twenty patients (15.8%) developed SPMS. At MS onset, brainstem involvement (adjusted HR 5.71; p = 0.010) and age at MS onset (adjusted HR 1.38; p = 0.042) were significantly associated with the risk of SPMS.

Many different diagnostic criteria for pediatric MS have been proposed. It is challenging to rule out other disorders that may mimic MS, and to distinguish pediatric MS from various demyelinating syndromes that can occur in childhood. The criteria by the Pediatric International Study Group have been applied in most studies. This is because they have classified the various acquired demyelinating syndromes (ADSs) that may be the first clinical sign of pediatric MS. The classification of ADSs, which dates from 2007 [30] and has been updated in 2013 [31] is as follows (see Table 2 for diagnostic criteria):

There are a number of important changes when comparing the 2007 and 2012 definitions for pediatric acute demyelinating disorders of the CNS [30, 31].

As in adults, dissemination in time and space is an essential feature. In general, the more atypical the case and the younger the child, the more consideration is necessary before making a diagnosis of MS [32]. MS must not only be differentiated from acute ADEM or NMO, but there is also an extensive list of other disorders that can mimic MS which need to be excluded. Examples of such disorders are systemic lupus erythematosus (SLE), neurosarcoidosis, Sjögren syndrome, leukodystrophies, hereditary metabolic disorders, and encephalitic or meningo-encephalitic infectious etiologies.

It is especially challenging to determine whether a child with an initial demyelinating event (IDE) will develop subsequent events that are consistent with MS or not. A list of “red flags” in the differential diagnosis in children presented with their initial demyelinating event have been suggested [32]. It includes encephalopathy and fever, progression from the onset, involvement of the peripheral nervous system or other organs, absence of CSF oligoclonal IgG (40-50% of pediatric MS patients exhibit oligoclonal bands, which is less than in adults) and markedly elevated CSF white blood cells or proteins.

ADEM typically presents as a monophasic demyelinating disease. It may be induced by preceding viral infections or vaccination, e.g. concerning measles or varicella zoster virus (VZV). Seizures or behavioral disorders as common presenting symptoms in ADEM. It can be difficult to differentiate ADEM from the first MS attack based on clinical evaluation. MRI appearance plays a major role in the diagnosis. Two or more periventricular lesions, absence of a diffuse bilateral lesion pattern, and the presence of black holes are frequently seen in MS patients compared to patients with ADEM [33].

The appearance of new lesions in different locations on follow-up MRI strongly suggests MS. Recently it was shown that susceptibility-weight imaging (SWI) may be useful in differentiating initial presentation of pediatric MS from ADEM [34].

Studies in adult MS patients suggest significant benefit of early institution of DMTs. The available efficacy data for pediatric MS patients is scarce and mostly based on retrospective studies. An international consensus highlighted the importance of initiating DMT in children and adolescents with MS [35]. A rationale for early institution of DMT in pediatric MS patients was supported by several facts related to natural history data:

Evidence of the effectiveness of DMTs in reducing relapse rate and disease progression in pediatric MS patients is exclusively based on observational studies. Four randomized controlled trials are either recruiting or reaching final stages: PARADIGMS (fingolimod), TERIKIDS (teriflunomide), FOCUS (dimethyl fumarate) and CONNECT (dimethyl fumarate vs. Interferon beta 1a).

The current first-line treatment of MS in children consists of either interferon beta (IFNB) or glatiramer acetate (GA). The safety profile of IFNB / GA remains favourable in children. No unexpected adverse events and no serious adverse events were documented in 44 pediatric MS patients from 7 countries who were treated with interferon beta-1b [36]. The mean age at the start of therapy was 13 years; 8 patients were ≤ 10 years of age. Most common adverse events included flu-like syndrome (35%), abnormal liver function test (26%), and injection site reaction (21%).

Adult doses of subcutaneous (sc) IFNB-1a (44 and 22 μg, three times weekly) were generally well tolerated by children and adolescents, with no new or unexpected adverse drug reactions, in a large retrospective study, named REPLAY [37]. It is the largest multicenter, multinational review of safety, tolerability, and efficacy outcomes with sc IFNB-1a in pediatric MS patients. Reviewed were records of 307 patients aged between 2 and 17 years, who had received at least 1 injection of sc IFNB-1a for demyelinating events. Despite the lack of a control group, beneficial effects were observed. Annualized relapse rates were 1.79 before and 0.47 during treatment. On the other hand, the experience with glatiramer acetate is very limited. It has roughly the same efficacy as IFNB [38].

In children with breakthrough disease (defined as relapses while on first-line therapies), escalation to higher efficacious second-line therapies, such as natalizumab, fingolimod, mitoxantrone, cyclophosphamide, rituximab, and daclizumab may be considered based on the extrapolated data from adult cohorts. However, data on the safety, efficacy, and tolerability of most of these treatments are scarce and have been reported only in small-size retrospective case series [40].

Large observational studies have shown that natalizumab is an effective treatment in children with breakthrough disease, with a good safety and efficacy profile, comparable to those in adult populations [39‐44]. A strong suppression of disease activity was observed in all subjects during follow-up in a study of 19 patients (mean age 14.6 +/− 2.2 years) [41]. The mean EDSS score decreased from 2.6 ± 1.0 to 1.9 ± 1.0 (p < 0.001). EDSS remained stable in 5 cases, decreased by ≥0.5 point in 6 cases, and decreased by ≥ 1 point in 8 cases. There were no relapses during follow-up (p < 0.001), nor new gadolinium-enhanced (Gd+) lesions (p = 0.008). A study by the same group of 55 patients showed a dramatic decrease in the number of relapses [42]. The mean number of relapses before treatment was high: 4.4. During follow-up only 3 relapses in all occurred. Mean EDSS scores decreased from 2.7 to 1.9 at the last visit (p < 0.001). During follow-up, the majority of patients remained free from MRI activity. Transient and mild clinical adverse events occurred in 20 patients. Anti-JCV antibodies were detected in 20 of 51 tested patients. In a retrospective study of 9 pediatric patients with highly active MS, the use of natalizumab completely halted the inflammatory process [43]. Two patients still had relapses, but they both had neutralizing antibodies against natalizumab. The median EDSS score decreased from 3.0 to 1.0, the median ARR decreased from 3.0 to 0.0. A recent study revealed that treatment with natalizumab was associated with reductions in mean ARR (3.7 vs 0.4; p < 0.001), n median EDSS scores (2 vs 1; p < 0.02), and in mean number of new T2-lesions per year (7.8 vs 0.5; p < 0.001) in children with active relapsing MS.