A total of 7,565 records were identified through the database searches. After de-duplication, 7,447 unique records were selected for title and abstract review. After assessing all records based on title and abstract, 258 records were selected to be reviewed in full-text format. Of these records, 103 were found to fulfill the inclusion criteria. Results of each stage of the screening process are presented in Figure 1. Of the included articles, 9 (8.7%) examined epidemiological metrics (incidence, prevalence), 47 (45.6%) evaluated disease characteristics (disease course, relapse rate, disability, comorbidities), 52 (50.5%) investigated effects on daily living (QoL, mood, etc.), and 4 (3.9%) reported direct healthcare cost or resource use (Figure 2).
Epidemiology
Incidence
The systematic literature review identified nine studies that reported on the incidence of pediatric MS. Only one of these studies estimated the incidence of pediatric MS in the USA, reporting 0.57 cases per 100,000 children and adolescents in the state of Utah (Table 2)(7). Eight studies reported incidence rates for specific countries within Europe (8-15). In the most commonly reported age group, 0- to 15-year-olds, incidence rates ranged from 0.3 (16) to 0.64 (17) per 100,000 person-years. The incidence of pediatric MS increased with age, reaching a high of 2.64 per 100,000 person-years among 14- to 15-year-olds in one German nationwide surveillance study(17).
Prevalence
Prevalence rates for pediatric MS were reported in nine of the included studies(7, 8, 19-25). Three studies reported rates in the USA(7, 19, 20), providing the number of cases per 100,000 persons. Across these studies, prevalence rates ranged from 0.035 to 14.6 cases per 100,000 persons, with the highest rate reported for patients aged 15 to 19 years. Six studies reported prevalence rates for pediatric MS for specific countries in Europe(8, 21-25), all of which reported rates as a percentage of all MS patients. The estimated prevalence of pediatric MS across European countries ranged from 0.7% to 9.6% of all MS patients. In all studies that reported prevalence by age group, higher rates were reported for older age groups than for younger age groups.
Disease Characteristics
Relapse Rates
Twenty-two publications were identified that reported relapse rates and/or the number of relapses in the past year experienced among North American patients with pediatric MS (see Additional File 2). Seventeen publications reported continuous measures, mostly in the form of annualized relapse rates (ARR). ARRs ranged from a low of 0.36 ± 0.16(29) to a high of 2.76(30). The highest rate was noted for the pediatric-onset population (≤18 years old) in the pre-treatment period. Post-treatment ARR was lower in the study that compared pre- and post-treatment ARR (30). In addition, relapse rates were highest in the early course of the disease decreasing with increasing disease duration (30-32).
Similar trends were observed in the European studies. Twenty-one publications were identified that reported relapse rates for European pediatric patients with MS (see Additional File 2). Eleven publications reported continuous measures; these were mostly in the form of ARRs and ranged from 0.65(33, 34) to 1.8 (35). Two studies reported relapse rates over 5 years after disease manifestation (36, 37). The highest relapse rate was 2.1 and was reported in Year 1 for patients with pediatric MS who were younger than 11 years of age(37). When Year 1 and Year 2 relapse rates were compared, the rates were always lower in Year 2. In addition, one study conducted a subgroup analysis comparing outcomes among ≤11-year-old and 14- to 16-year-old patients. In both Year 1 and Year 2, the 14- to 16-year-old sub-group had a lower relapse rate than the ≤11 year-olds (37). Overall, the results of the European studies were in alignment with those of the North American studies, showing higher relapse rates among younger patients.
Three studies compared relapse rates amongst pediatric and adult patients with MS, finding that ARRs were consistently higher among pediatric patients(30, 38, 39). As expected, for both the pediatric and the adult population, ARRs were higher before treatment (2.76; 1.78) than after treatment (1.12; 0.35). In addition, another study concluded that relapse rates were more frequent early in the disease and became infrequent or absent over time (40). Overall, the results showed higher rates and number of relapses in the past year in younger patients and in the pre-treatment period, highlighting the importance of early diagnosis and treatment.
Humanistic Burden
Quality of Life
Ten studies reported QoL outcomes among North American patients with pediatric MS(41-50) (see Additional File 3). The most frequently used scale for assessment of QoL was the Pediatric Quality of Life Inventory (PedsQL); other scales included the Short Form-36 (SF-36) and Child Health Questionnaires (CHQ). Although several studies included the PedsQL, various versions were used or results from different domains were reported, thereby complicating the ability to make comparisons across the studies. Four studies compared the outcomes of patients with pediatric MS to those of healthy controls (42, 46, 47, 49). Three of these studies found that QoL was reduced in patients with pediatric MS compared with QOL in healthy controls(46, 47, 51), with two reporting significant differences(46, 47). Whereas one study reported that patients with pediatric MS have a similar QOL as the healthy population(52). Only one publication compared QoL between pediatric and adult patients with MS, finding no significant difference between groups(50).
Five studies reported QoL outcomes among European patients with pediatric MS (see Additional File 3) using various scales for assessment, including SF-36, PedsQL, and CHQ. Three studies compared outcomes among patients and healthy controls(53-55), reporting reduced QoL for children with MS; the reductions were significant in two studies. One of these studies compared the self-reported QoL scores of patients with those of their parents, while another only presented parent-reported scores(53, 55). All of the studies concluded that the QoL of both patients and their families is negatively impacted by the physical and cognitive manifestations of MS(53-55).
Fatigue
Thirteen studies reported fatigue outcomes among North American patients with pediatric MS using a variety of measures (see Additional File 4). The most common assessment tool was the PedsQL Multidimensional Fatigue Scale (PedsQL MFS), which was used in three studies. In addition, three studies compared pediatric MS patients with healthy controls reporting higher fatigue scores in pediatric MS patients in various assessment tools (49, 56, 57). Furthermore, one study compared fatigue outcomes among patients with MS or with monophasic acquired demyelinating syndrome, finding that patients with MS reported higher levels of general and total fatigue(58). Another study compared fatigue between pediatric and adult MS patients and observed no significant differences between groups (59).
Ten studies reported fatigue-related outcomes among European patients with pediatric MS (see Additional File 4). Nine of these publications reported categorical outcomes, most of which assessed the percentage of patients experiencing fatigue, which ranged from 20%(60, 61) to as high as 79.5%(38). Two publications reported continuous outcomes using either the Checklist Individual Strength fatigue score or the PedsQL MFS. These studies reported that patients with pediatric MS experience significantly worse fatigue than healthy controls. Overall, the results of the European studies were similar to those from the North American studies, highlighting fatigue as a common symptom experienced by patients with pediatric MS.
Cognitive Function
A variety of measures were used for evaluation, including the Expressive One-Word Picture Vocabulary Test (EOWPVT), the Symbol Digit Modalities Test (SDMT), and the Wechsler Abbreviated Scale of Intelligence (WASI). Cognitive function tests included but were not limited to assessments of learning, memory, information processing speed, attention, language, and executive functioning. Twenty-six studies reported cognitive function outcomes among North American patients with pediatric MS(41-45, 50, 56, 57, 62-72) (see Additional File 5). Ten publications compared outcomes among patients with those of healthy controls and presented the number and percentage of cognitively impaired children or those with below-average scores on several cognitive performance scales(32, 59, 73-80). In these studies, the percentage of patients with cognitive impairment ranged from 32% to 35%. Further, cognitive performance was reduced among patients with pediatric MS compared with healthy children, with five reporting statistical significance (63, 76, 80-82). In particular, patients with MS had lower scores in processing speed, visuomotor speed, and executive control. One publication compared outcomes among patients with pediatric-onset MS and those with adult-onset MS, finding that patients with pediatric-onset MS had a lower mean cognitive performance measure than patients with adult-onset MS(59).
Ten studies reported cognitive function outcomes among European patients with pediatric MS (see Additional File 5). Four publications compared outcomes with healthy controls and all four reported reduced IQ or lower performance on various cognitive tests in patients with MS compared to healthy controls (83-86). One study reported that the cognitive impairment associated with pediatric MS deteriorates over time (83). Two studies included patients with adult MS as a comparator; one of these studies found that patients with pediatric-onset MS are at a higher risk of developing cognitive impairment in adulthood than patients with adult-onset MS (38). Across studies, the percentage of patients with pediatric MS and cognitive impairment ranged between 18% and 70% (37, 85-89).
School Performance
Finally, 11 studies reported school performance outcomes among North American patients with pediatric MS (see Additional File 6). Most of these publications reported varying indicators of reduced academic performance or difficulties in school. One study reported that 35.1% of patients with MS needed assistance with school work and a change in school curriculum. Two publications compared school performance results with those of healthy controls, with one finding that academic difficulties were increased in patients with pediatric MS(90). Seven publications reported outcomes relating to school performance among European patients with pediatric MS (37, 86, 87, 91-94) (see Additional File 6). Of these studies, three reported that 10% of patients required support from a teacher because of cognitive difficulties. No comparisons were made between patients and healthy controls.