**2. Epidemiology**

In the pediatric MS population diagnosed before puberty, the number of males and females diagnosed is relatively equivalent [6,7]. In adolescents, the ratio of females to males with MS increases to 2 to 3:1, which may sugges<sup>t</sup> that the onset of menarche plays some role in the pathogenesis of MS [6]. Additionally, the prevalence of MS increases after age 10 [8]. A diverse racial and ethnic population are diagnosed with pediatric MS, one study reporting 67% self-identifying as white and 20.6% as African

American [9]. In this cohort, 30.2% identified as Hispanic, while other cohorts have reported up to 52% of pediatric patients with MS or CIS as Hispanic [9,10]. There has been a significant link to the role of obesity in MS and it has been shown that adolescent obesity is a risk factor for pediatric MS [11]. Not only was adolescent obesity a risk to develop MS, but one study found that in pediatric MS, obesity was present in early childhood years [12]. Obesity has been shown to promote an inflammatory state, which could contribute to not only the pathogenesis of MS, but could also play a role in the risk of relapse and long-term management. A retrospective cohort study performed comparing pediatric MS patients who were obese vs. those with normal BMI showed that obese patients had statistically significant higher relapse rates on first-line treatments, and higher relapse rates on second-line treatments [13]. Low levels of vitamin D have been associated with an increased risk of pediatric MS and with increased rates of relapse [14,15]. In the adult population it has been shown that there is an increased risk of MS in those who smoke cigarettes, and coinciding with this, children who are exposed to smoking in the home have been shown to be more likely to develop pediatric MS than a control population [16,17]. Epstein-Barr virus (EBV) may play a role in pathogenesis and risk of MS and pediatric MS, although the mechanism remains unclear at this time [15,18]. Historically, a correlation between EBV and MS was proposed due to the similarities in the epidemiology of the diseases, and studies have shown a strong correlation in support of this [19]. EBV infection can occur at any age, and is generally asymptomatic in young children. The presence of MS-mimics such as Neuromyelitis Optica Spectrum Disorder (NMOSD) and anti-myelin oligodendrocyte antibody syndrome, may contribute to a higher frequency of EBV seronegative- antibody children diagnosed with MS. One of the main genetic risk factors found in pediatric MS is HLA DRB1\*1501 [20,21]. HLA DRB1\*1501 is additionally seen as a genetic risk factor in adult MS, and postulated to be associated with earlier age of onset in the adult population, although there has been varying evidence in support of this, and thus at this time cannot be attributed to age of onset. The HLA class II proteins play a role in cell-mediated immunity, leading to the suspicion that it could be a genetic marker or predisposition to developing MS [22]. There are 57 previously identified single nucleotide polymorphisms that have been associated with adult-onset MS that have also been identified in a large cohort of children with demyelinating diseases and found to be associated with increased risk of pediatric-onset MS [23]. One recently published cohort identified 32% of patients with at least one relative with MS [22], with a report of incidence in a first-degree relative of 2–5% [24]. In monozygotic twins, a concordance rate of 27% is reported vs. dizygotic twins with a rate of 2.3% [24]. There have been numerous correlated factors in pediatric MS, and likely more that have ye<sup>t</sup> to be determined. Many of these factors also overlap, and more studies are needed in order to determine if there are additional genetic etiologies that may lead to a predisposition to development of pediatric MS in the context of certain environmental factors.

### **3. Clinical Presentation**

In a subset of patients at the initial presentation of a demyelinating event, a diagnosis of pediatric MS can be made. Younger children will often present with multifocal symptoms, but entering adolescence it becomes more common to present with single focal symptoms more similar to that of adults [25,26]. The most commonly reported symptoms in children include sensory (15–30%), motor (30%), and brainstem dysfunction (25–41%) [27]. The clinical course in 95–98% of pediatric MS patients is relapsing remitting, compared to 85–90% in adults [27–29]. Less than 3% of pediatric MS cases are reported as primary progressive, compared to 10–15% in the adult population [28–30]. In children with a progressive course, other diagnoses should be considered. Children have been reported to have a higher relapse rate compared to adult-onset MS, especially within the first few years of diagnosis [31,32]. Studies have reported 2.3–2.8 times higher relapse rate in pediatric MS, and higher rates of relapse early in the disease if without treatment or on lower e fficacy treatment [32–34]. These findings sugges<sup>t</sup> that those with pediatric MS have a more significant inflammatory component than those with adult-onset MS [32]. Due to these factors, more recent treatment has trended toward

initiation with higher efficacy medications at time of diagnosis to help target this increased inflammatory state, decrease relapse rate, and prevent accrual of disability.
