Description

Definition and epidemiology. Multiple sclerosis is a chronic inflammatory, immune-mediated disorder of the central nervous system that starts in early adulthood in the majority of cases but can occur in childhood, age 16 or younger, in approximately 5% (64; 70). The earliest described age of onset is prior to 24 months of age (66). The etiology is unknown, though a parainfectious immune response at onset may initiate cross-reactive nerve or myelin immunity that becomes self-sustained in susceptible individuals. The HLA-DRB1 genetic locus and environmental factors, such as vitamin D levels, Epstein-Barr virus infection, and smoking, influence the risk and development of both pediatric and adult multiple sclerosis (10; 54; 55; 26; 79). Overall, it ranged from 0.69 to 26.92 per 100,000 individuals, differing between countries and increasing with older age (25; 81).

Pathology. Multiple sclerosis is characterized by chronic, recurrent inflammation with demyelination; loss of neurons, axons, and oligodendrocytes; as well as gliosis, remyelination, and synaptic changes (40; 80; 28). Inflammation is focal, multifocal, and diffuse. It is not limited to the white matter, but has also been demonstrated in cortical demyelinating lesions and meninges in early multiple sclerosis (48). In addition, grey matter loss with cortical and thalamic neuronal loss occurs from the onset of disease (75; 74; 17). The inflammatory process is followed, often after 15 to 20 years, by slowly progressive disability that appears to represent cumulative neuronal and synaptic loss as a consequence of the chronic inflammatory milieu.

Epidemiology

Genetics. The HLA-DRB1 locus is the most important genetic risk factor for developing multiple sclerosis, conferring increased susceptibility for whites (-DRB1*1501) and African Americans (-DRB1*1503) (61). It may also contribute to an approximately 3-fold increase in the risk of multiple sclerosis susceptibility in childhood (-DRB1*15) (12; 43). Conversely, variations in the HLA-A gene confer decreased risk susceptibility for developing multiple sclerosis (43). Other genetic loci, including IL2RA and IL7R, have been identified in genome-wide association studies as being important for multiple sclerosis susceptibility (42; 43). Furthermore, these genetic risk loci are associated with increased propensity to childhood onset multiple sclerosis (73). However, among all the single nucleotide polymorphisms identified, the genetic effects of any locus on the risk for developing multiple sclerosis are significantly less potent compared to the major histocompatibility complex (61; 21; 43). The role of epigenetics in multiple sclerosis has not been clearly defined. However, it is possible that epigenetic mechanisms, including DNA methylation and histone modification, may modulate the interaction between genes and the environment and explain some of the differences in multiple sclerosis susceptibility (15). They may also account for some of the differences in disease activity, including the effects of histone modification on remyelination through regulation of oligodendrocyte differentiation, a process that may be impaired in older individuals (68).

Environmental factors. There are differences in the frequency of multiple sclerosis in different parts of the world. The frequency in Europe, North America, and Australia is high compared with Asia and tropical regions, where it is low. The incidence correlates positively with increased distance from the equator, and this cannot be fully explained by genetic differences (05; 06). There is also a risk modification for developing multiple sclerosis that is associated with geographic migration, with risk dependent on both age at the time of migration and direction of migration. The younger the age of migration, the more likely it is that the incidence of multiple sclerosis in migrants is closer to the multiple sclerosis incidence of their resident destination (05). Environmental factors in children as well as in adults, especially Epstein-Barr virus infection and vitamin D levels, contribute significantly to multiple sclerosis risk and may explain some of the geographic variation and differences associated with migration (05). An age-matched case-control study showed that pediatric multiple sclerosis patients who were seropositive for Epstein-Barr nuclear antigen-1 had an increased risk for multiple sclerosis (odds ratio 3.78, 95% confidence interval 1.52-9.38, p = 0.004), whereas those with remote infection with cytomegalovirus had a decreased risk of multiple sclerosis (odds ratio 0.27, 95% confidence interval 0.11-0.67, p = 0.004) (79). Infection with herpes simplex virus (HSV) 1 was associated with a decreased multiple sclerosis susceptibility in those who were positive for the DRB1*15 allele (odds ratio 0.07, 95% confidence interval 0.02-0.32, p = 0.001) and increased susceptibility in those who were negative for the allele (odds ratio 4.11, 95% confidence interval 1.17-14.37, p = 0.03). This suggests that although infection with Epstein-Barr virus may increase risk for developing multiple sclerosis, other infections such as cytomegalovirus may actually reduce it. HSV-1 may either increase or decrease multiple sclerosis susceptibility depending on the absence or presence of the DRB1*15 allele, respectively (79). However, a multinational observational study of age- and region-matched pediatric multiple sclerosis patients and non-demyelinating neurologic disorder control participants showed that 86% of pediatric multiple sclerosis patients compared with 64% of controls had positive Epstein-Barr nuclear antigen-1 and viral capsid antigen consistent with remote Epstein-Barr virus infection, regardless of geographical location (p = 0.025, adjusted for multiple comparisons) (10a). The multiple sclerosis patients did not show any difference from controls in the seroprevalence of IgG antibodies directed against cytomegalovirus, HSV, parvovirus B19, or varicella zoster virus. Seropositivity for remote Epstein-Barr virus infection in children was associated with a nearly 3-fold increase in the likelihood of multiple sclerosis compared with age- and region-matched controls (95% confidence interval 1.4-5.8, p = 0.025 after adjustment for multiple comparisons) (10a).

The association between Epstein-Barr virus and increased multiple sclerosis susceptibility is established, but the association with other viral and bacterial antigens proposed to be important triggers in the etiology of multiple sclerosis, including Chlamydia pneumoniae and human herpes virus (HHV) 6, is debatable. Antibodies to C pneumoniae detected in the CSF of 28% of pediatric multiple sclerosis patients comprised less than 1% of total intrathecal IgG, suggesting their presence may be part of a polyspecific oligoclonal response (65). The presence of C pneumoniae DNA in the CSF of adult multiple sclerosis patients has not been confirmed (13). Whereas an important role in the etiology of multiple sclerosis cannot be ruled out, the ubiquitous HHV-6 found in autopsy specimens of multiple sclerosis lesions and evidence of HHV-6 infection in the serum and CSF of multiple sclerosis patients is unlikely to explain the epidemiology of multiple sclerosis (05).

Vitamin D insufficiency is associated with increased risk for multiple sclerosis. Based on a case control study using the Department of Defense Serum Repository database, there was a 41% reduction in multiple sclerosis risk in whites for each 50 nmol/L increase in 25-hydroxy vitamin D (relative risk 0.59, 95% confidence interval 0.36-0.97, p = 0.04) (58). Low levels of vitamin D are associated with increased disease activity. In a retrospective study, pediatric multiple sclerosis or clinically isolated syndrome patients with lower serum 25-hydroxy vitamin D3 levels had an increased relapse rate, with each 10 ng/mL increase in the adjusted 25-hydroxy vitamin D3 level associated with a decrease in the rate of future relapses by one third (incidence rate ratio 0.66, 95% confidence interval 0.46-0.95, p = 0.024) (55). Moreover, in a study of multiple sclerosis patients treated with interferon beta-1b after a clinically isolated syndrome, a 20 ng/mL increase in the average serum 25-hydroxy vitamin D levels during the first 12 months predicted decreased multiple sclerosis disease activity, characterized by a 57% lower relapse rate during the following 4 year period, whereas levels greater than or equal to 20 ng/mL at 12 months predicted reduced disability in subsequent months 12 through 60 as measured by the expanded disability status score (07).

Although cigarette smoking and exposure to secondhand smoke from tobacco use may not provide an explanation for the geographic variation and altered multiple sclerosis susceptibility associated with migration, it is a significant risk factor for multiple sclerosis. In a prospective Nurses Health study of women in the United States, women who smoked 25 or more packs a year had an increased incidence of multiple sclerosis (relative risk 1.7, 95% confidence interval 1.2-2.4, p < 0.01) (41). In a population-based case-control study in France, children with exposure to parental cigarette smoking had an adjusted relative risk of 2.12 of having multiple sclerosis (relative risk 2.1, 95% confidence interval 1.43-3.15), an effect that was greater in those with multiple sclerosis onset after 10 years of age (relative risk 2.49, 95% confidence interval 1.53-4.08) (54).

Obesity is another environmental risk factor for multiple sclerosis. A large study using cohorts from 2 separate Nurses’ Health Studies showed that obesity at 18 years of age doubles the risk of multiple sclerosis (57). Childhood and adolescent obesity has been identified as a risk factor for childhood multiple sclerosis, which is similar to adults (56; 46). A case cohort study of Kaiser Permanente Southern California patients showed that obesity was associated with an increased risk of multiple sclerosis and clinically isolated syndrome in girls 11 to 18 years of age (46). A large prospective study of body mass index in children ages 7 to 13 showed that girls with a 95th or greater percentile for BMI had a 1.61- to 1.95-fold increased risk for multiple sclerosis compared with girls below the 85th percentile for BMI (56).

It is unclear as to whether increased sodium intake may increase the risk for developing multiple sclerosis, and there are conflicting data as to whether it increases disease activity. Based on an observational study, increased sodium intake increased the rate of multiple sclerosis exacerbations in adults between the ages of 28 and 52 (30). However, 1 study looking at the effects of salt intake on multiple sclerosis disease activity in patients treated with interferon beta1b did not show that salt intake has any significant effect on disease activity, disability, or conversion to clinically definite multiple sclerosis in patients treated with interferon beta1b (33). Furthermore, in pediatric-onset multiple sclerosis patients, the odds of increased sodium intake were similar to controls based on the results of a case-control multicenter study (51), and a separate case-cohort study reported that increased dietary sodium intake did not affect time to developing a multiple sclerosis relapse in patients with pediatric-onset multiple sclerosis (60).

Clinical characteristics of multiple sclerosis in children

The majority of pediatric multiple sclerosis patients have relapsing-remitting disease. A primary progressive course is rare in pediatric multiple sclerosis, unlike adult multiple sclerosis in which 10% to 15% of patients have a primary progressive course (10a). The ratio of females to males is age-dependent. The gender ratio is nearly equal with a female to male ratio of 0.8:1 in children under 6 years of age, then increases to 1:6:1 in children between ages 6 through 10, and then increases again to 2:1 for onset after 10 years of age (10b). A prospective population-based study in South-East Wales showed that the female to male ratio was 4:1 at adolescence, 2.5:1 in adults until age 45 to 49, and then 1:1.5 after age 50 (23). Exacerbations of inflammation may be manifested clinically with focal neurologic deficits. An initial clinical presentation of optic neuritis, brainstem, or cerebellar symptoms may be characteristic of a monofocal attack, whereas monofocal transverse myelitis is infrequent in pediatric multiple sclerosis (10a). Acute transverse myelitis occurs in 20% of children who initially present with an acquired demyelinating syndrome. The majority have longitudinally extensive transverse myelitis spanning 3 or more vertebral segments on MRI, which is more typically associated with a neuromyelitis optica spectrum disorder (02). Inflammatory responses in children are more likely than those in adults to be associated with intense focal inflammation resulting in mass lesions, often with vascular permeability with marked interstitial edema. Altered and loss of consciousness may represent a consequence of raised intracranial pressure. The size of the focal inflammatory lesions along with the extent of the acute inflammation appears to be a function of age, with the more severe vascular inflammation in children with progressively less likelihood for vascular inflammation with increasing age (50; 08; 78). The presentation with large solitary or multifocal lesions may cause diagnostic difficulties. A monophasic disease process such as acute disseminated encephalomyelitis may present in a similar manner. Episodes of focal neurologic deficits in children, including severe deficits, appear to be followed by recovery more often than similar episodes in adults. Earlier age at onset of multiple sclerosis is associated with an increased likelihood of complete recovery from an initial relapse (23). This may represent the potential for improved recovery in the context of resolution of edema. In addition, however, greater neural plasticity and synaptic changes may contribute at least initially to the tendency for improved recovery from acute deficits in children. Chronic ongoing pathological processes in children often have the potential of disrupting the developmental process. As a consequence, cognitive dysfunction is frequent even in the absence of physical disability. In a multicenter, cross-sectional study of 187 pediatric multiple sclerosis patients and 44 patients with clinically isolated syndrome, patients younger than 18 years of age showed that 35% of pediatric multiple sclerosis patients and 18% of clinically isolated syndrome patients had neuropsychological testing results consistent with cognitive impairment, highlighting problems with fine motor coordination (54%), difficulty with visual-motor integration (50%), and slowness of information processing (35%) (44). Processing speed, 1 of the cognitive domains that is often impacted in children with multiple sclerosis, as measured by the Symbol Digit Modalities Test, was found to increase with age in patients with childhood multiple sclerosis, and then it subsequently decreased over time in these patients (03). The prevalence of seizures in multiple sclerosis patients is 3% to 4% based on 6 population-based studies (45). The prevalence of seizures in pediatric onset multiple sclerosis (5.5%) is higher than in adult multiple sclerosis patients (1.3%, which is similar to the general population), based on a large population-based study in Turkey (27). Pediatric onset of multiple sclerosis at less than 16 years of age (p = 0.01) and increased mean expanded disability status scale score (p = 0.004) were both associated with an increased likelihood of having seizures (27).

The period of time to onset of progressive disability appears to be longer in patients with onset of disease at an early age (64). At the same time, age at onset appears to represent an independent variable that determines the course of disease. Progression in multiple sclerosis patients with onset as children tends to overlap with that whose onset is in adulthood, although the onset of progression generally occurs 10 years younger in patients with pediatric-onset disease compared with adults (64). This suggests that multiple sclerosis in children represents a disease process that overlaps with that in adults. It is possible that there are unique precipitating factors in children. At the same time, distinctions pertinent to the disease in children may be a function of age. Furthermore, there has been some work on the microbiome in children with multiple sclerosis, indicating that the gut microbiota in children with multiple sclerosis is different from age matched controls without multiple sclerosis, allowing some insight into the mechanism of disease close to the onset of disease (72). Different amino acid tryptophan metabolism pathways resulting in changes in the levels of distinct tryptophan metabolites may affect the incidence and the disease activity of pediatric onset multiple sclerosis. Higher levels of tryptophan and indole lactate, a metabolite of tryptophan, produced by intestinal bacteria within the gut decreased the risk of developing pediatric multiple sclerosis. Every 1 mcg/mL increase in serum tryptophan was associated with a 20% reduction in the adjusted odds of developing multiple sclerosis (95% confidence interval 4%-34%) (59). On the other hand, increased levels of kynurenine, which is not produced by the gut microbiota but via liver derived enzymes such as tryptophan 2,3-dioxygenase or indoleamine 2,3-dioxygenase enzymes (34), were associated with an increased relapse rate with incident rate ratio of 5.8 (P-value =0.003) (59).

Pathogenesis and immunobiology

Multiple sclerosis pathogenesis involves T-cell and B-cell autoreactivity, as well as innate immune responses involving macrophages and resident central nervous system cells, including microglia (80). Differentiation between acute multiple sclerosis and acute disseminated encephalomyelitis does not appear clear-cut based on pathological findings. A retrospective cohort study of perivenous demyelination cases at the Mayo Clinic showed that both confluent demyelination characteristics of acute multiple sclerosis lesions and perivenous demyelination typically associated with acute disseminated encephalomyelitis were found on brain biopsy or autopsy samples in 3 of the 13 perivenous demyelination cases, indicating that these disorders overlap pathologically (83). The genes related to susceptibility to multiple sclerosis are immune related. Lesions in children tend to be more inflammatory, with more edema than those of adults. Early diagnosis and effective therapy with monitoring are important. Diffusion tensor imaging indicates early changes in neuronal connectivity in pediatric multiple sclerosis (76).

Nevertheless, there are some important biological differences between pediatric and adult multiple sclerosis that may affect disease severity and response to treatment. Importantly, in recent years, distinction between demyelinating syndromes of the central nervous system has led to 4 main phenotypes: multiple sclerosis, AQP4-positive neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein associated disorders (MOGAD), and antibody-negative demyelinating syndromes. The proportion of patients positive for MOG-IgG appears to be higher in pediatric cohorts compared to adults (14; 52; 76). Furthermore, myelin oligodendrocyte glycoprotein appears to predict a disease course other than that of multiple sclerosis (38; 31). Presentations of MOGAD vary with age, with older children more likely to present with optic neuritis or transverse myelitis versus acute disseminated encephalomyelitis more commonly in younger children. The proportion of pediatric CNS demyelinating syndrome patients who had anti-MOG antibodies was about one third. The percentage of these individuals who then became seronegative for the anti-MOG antibody was about 57%, typically within 1 year. This was the median time to conversion to seronegative in a prospective multicenter cohort study conducted between 2004 and 2017 (77). About 53% of pediatric CNS demyelinating syndrome patients who had anti-MOG antibodies had full resolution of their baseline MRI changes and only 38% who remained seropositive for anti-MOG antibodies subsequently developed a clinical relapse, indicating that the majority of individuals with anti-MOG antibodies in this cohort study had a monophasic course of illness (77).

On a cellular level, there is an increased proportion of memory T cells in the setting of reduced percentages of naïve T cells in pediatric onset multiple sclerosis patients compared with healthy controls of the same age, similar to adult multiple sclerosis (09). However, alterations in B cell subsets during acute relapses in pediatric onset multiple sclerosis differ from those in adult multiple sclerosis. Pediatric onset multiple sclerosis is characterized by an increase in the proportions of plasmablasts as well as non-class switched memory B cells in the cerebrospinal fluid versus the presence of primarily class-switched memory B-cells and plasma cells in adult multiple sclerosis patients (67). Furthermore, there are some data that suggest that cerebrospinal fluid plasmablasts are associated with increased IgG synthesis and acute central nervous system inflammation as demonstrated by an increase in the number of gadolinium enhancing lesions on brain MRI in multiple sclerosis patients (18). The increased percentages of cerebrospinal fluid plasmablasts in pediatric onset multiple sclerosis patients are consistent with the finding of increased central nervous system inflammation in childhood multiple sclerosis compared with adult multiple sclerosis.

There is a greater likelihood of finding neutrophils in the CSF of pediatric multiple sclerosis patients 11 years of age or younger (20). Although the role of neutrophils has not been clearly defined in multiple sclerosis pathogenesis, there is some evidence from animal studies that CXCR2-positive neutrophils may be essential for mediating central nervous system demyelination in the cuprizone model of demyelination and in the animal model of experimental autoimmune encephalomyelitis (47). Furthermore, neutrophil infiltration controlled by opposing effects of IL-17 and interferon-gamma cytokines on CXCL2-induced neutrophil recruitment is necessary for brain but not spinal cord inflammation in the experimental autoimmune encephalomyelitis model (69). It is possible that neutrophils may play an important role in central nervous system demyelination and that cytokine-specific regulation of neutrophil infiltration is required for the localization of inflammation to specific regions of the central nervous system at the biological onset of multiple sclerosis.

Gray matter atrophy has been found to be associated with disability in adult multiple sclerosis (32). A study looking at cortical lesions in pediatric multiple sclerosis patients showed that there are relatively fewer cortical lesions in pediatric compared to adult multiple sclerosis (01). However, some studies have shown that pediatric multiple sclerosis patients have significant grey matter loss in the thalamus, which correlates with cognitive impairment but does not appear to be associated with physical disability as measured by the Expanded Disability Status Scale (53; 71). Acute axonal damage is increased by more than 50% in early active demyelinating lesions in pediatric patients compared to adult patients with multiple sclerosis (63).

There is some evidence that there is greater central nervous system remyelination in early versus chronic multiple sclerosis, although the mechanism through which this occurs is not well delineated (36). Abnormal central nervous system remyelination in multiple sclerosis may involve dysregulation of the Wnt pathway. Signaling through the Wnt/beta-Catenin pathway, known to be critical in anterior-posterior patterning in vertebrates, is thought to play an important role in normal developmental myelination in mammals (29). Increased levels of Wnt pathway mRNA and proteins have been found in multiple sclerosis lesions, suggesting that this pathway may also be important in inhibiting remyelination in multiple sclerosis (29). Impaired axonal regeneration in multiple sclerosis may be multifactorial, involving both extrinsic factors, including myelin-associated inhibitors and signaling pathways that may transduce inhibitory signals for axonal regeneration, and intrinsic factors that may be age-dependent (16; 62).

Clinical applications

Monitoring of clinical disease activity and the use of effective immune-based therapies are important for preventing long-term disability in multiple sclerosis patients. There may be a decreased likelihood for pediatric multiple sclerosis patients presenting with a clinically isolated syndrome suggestive of multiple sclerosis to be treated with disease-modifying drugs compared to adults with clinically isolated syndrome, and a greater tendency for pediatric multiple sclerosis to be mistaken for acute disseminated encephalomyelitis. Consequently, delays in treatment with disease-modifying drugs may contribute to the greater number of relapses in pediatric multiple sclerosis compared to adult multiple sclerosis. However, a study demonstrated that pediatric multiple sclerosis patients have a greater number of relapses than adult multiple sclerosis patients after controlling for treatment with disease-modifying medications, suggesting that there may be increased central nervous system inflammation in pediatric multiple sclerosis compared to adult multiple sclerosis (37).

Phase III studies of therapeutic agents in patients with multiple sclerosis have excluded individuals under the age of 18 years in the past. Consequently, there is considerably less information regarding the efficacy and safety of immune agents in children compared to adults with multiple sclerosis. Nevertheless, treatment options for acute exacerbations are the same in both pediatric and adult multiple sclerosis, with the use of intravenous corticosteroids as first-line therapy and the addition of intravenous immunoglobulin or plasmapheresis for patients with acute exacerbations that are refractory to intravenous corticosteroids.

Disease-modifying therapies, including beta interferon and glatiramer, have been used as first-line treatments for both adult and pediatric multiple sclerosis and adults presenting with a clinically isolated syndrome suggestive of multiple sclerosis. The use of disease-modifying treatment in children presenting with a clinically isolated syndrome may delay a second attack corresponding to the onset of clinically definite multiple sclerosis, although there are no published clinical data showing benefit of early treatment in pediatric clinically isolated syndrome.

PARADIGMS, a phase 3 double-blind study of fingolimod, enrolled 215 pediatric multiple sclerosis patients and showed that fingolimod treatment for up to 2 years reduced the annualized relapse rate and new or newly enlarged T2-weighted MRI lesions compared to interferon-beta-1-a, including in treatment-naïve and younger patients (24). The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a, corresponding to an absolute difference of 0.55 relapses and a relative difference of 82%.

Another randomized, double-blind, placebo-controlled phase III trial, TERIKIDS, examined the safety and efficacy of teriflunomide in 166 children aged 10 to 17 years with relapsing multiple sclerosis for up to 96 weeks, followed by an open-label extension period continuing for up to 192 weeks after randomization, in which all patients received teriflunomide (22). The primary endpoint was time to first confirmed clinical relapse by the end of the double-blind period, and key secondary imaging endpoints were number of new or enlarged T2 lesions and number of gadolinium-enhancing lesions per MRI scan. Although the primary endpoint findings did not reach statistical significance, the median time to first confirmed relapse was 75 weeks in the teriflunomide group and 39 weeks in the placebo group, translating to a 34% reduction in clinical relapse risk. Furthermore, MRI brain lesions were significantly fewer with teriflunomide than placebo. This led to teriflunomide becoming the first approved first-line oral disease modifying drug (DMD) in the European Union for children and adolescents in relapsing-remitting multiple sclerosis. FDA approval in the United States is still pending.

FOCUS, a phase II trial, evaluated the safety, efficacy, and pharmacokinetics of dimethyl fumarate in 22 pediatric patients aged 10 to 17 years with relapsing-remitting multiple sclerosis (04). The primary end point was the change in T2 hyperintense lesion incidence from the baseline period to the final 8 weeks of treatment. Secondary end points were pharmacokinetic parameters and adverse event incidence. Dimethyl fumarate treatment was associated with a reduction in magnetic resonance imaging activity in pediatric patients with pharmacokinetic and safety profiles consistent with those in adults.

Natalizumab has also been used to treat pediatric multiple sclerosis refractory to first-line disease-modifying therapies. Based on the experience of 24 pediatric multiple sclerosis patients in a network of pediatric multiple sclerosis centers in the United States, the majority of patients showed good response to natalizumab after 18 months of treatment based on MRI and clinical measures of disease activity (82). A prospective cohort study of 55 pediatric multiple sclerosis patients in Italy receiving a median of 26 monthly infusions of natalizumab showed that the mean expanded disability status scale score decreased from 2.7 to 1.9 (p< 0.0001); the majority of patients developed no new T2 or gadolinium enhancing lesions on MRI; and clinical adverse effects were relatively mild (35). Although 21 out of 50 patients tested serologically were positive for the JCV antibody, there were no confirmed cases of progressive multifocal leukoencephalopathy. Although it is possible that pediatric multiple sclerosis patients have a lower risk of developing progressive multifocal leukoencephalopathy than adults, further studies are necessary to determine the risk of progressive multifocal leukoencephalopathy in children with multiple sclerosis. Safety, tolerability, and efficacy studies are necessary in pediatric multiple sclerosis of other newer therapies such as teriflunomide, dimethyl fumarate, and ocrelizumab. In patients with aggressive disease courses, treatment with cyclophosphamide has been shown to reduce the relapse rate and prevent further disability 1 year after starting treatment in the majority of pediatric multiple sclerosis patients with severe disease refractory to first-line disease-modifying treatments (49). However, there may be long-term risks.

The distinction between the different CNS demyelinating phenotypes is important as it affects the management of these patients. Although there are currently no evidence-based guidelines for the treatment of patients with MOG-Ig associated disorders, typical immunomodulatory treatments used in multiple sclerosis appear to be ineffective in MOG-IgG associated disorders, whereas azathioprine, mycophenolate mofetil, rituximab, and particularly, intravenous immunoglobulins appear to be associated with a reduction in relapse frequency (39).

The relapsing-remitting course of multiple sclerosis in childhood may be slower compared to adults. A natural history study of pediatric multiple sclerosis showed that the time to secondary progression is longer in pediatric compared to adult multiple sclerosis, although age at onset of secondary progression was earlier in pediatric multiple sclerosis (64). The slower course of pediatric multiple sclerosis may, in part, be due to greater capacity for central nervous system remyelination and axonal regeneration in pediatric compared to adult multiple sclerosis. However, it is unclear whether these processes, versus reduced edema, correlate with the disappearance of MRI lesions in pediatric multiple sclerosis (19). Furthermore, the relative lack of physical disability in pediatric multiple sclerosis compared with adult multiple sclerosis may be associated with the paucity of cortical lesions in pediatric multiple sclerosis (01).

Multiple sclerosis in children may represent a form of the disease close to its onset and, in this context, may allow insights into the etiopathogeneses. It is likely that the initial inflammatory CNS event occurs as a parainfectious disorder, possibly involving various infectious agents in some patients. In this context, the initial episode of CNS inflammation may occur as an episode of molecular mimicry, whereas subsequent episodes of recurrent inflammation characteristic of multiple sclerosis occur in individuals rendered susceptible on the basis of the repertoire of immune molecule polymorphisms they possess.

Multiple sclerosis is rare in children, in part, because it is underdiagnosed and often mistaken for other diseases mimicking multiple sclerosis. Furthermore, age-dependent changes in the immune responses to environmental triggers and greater plasticity of the developing target central nervous system in children may also contribute to the decreased incidence of pediatric compared to adult multiple sclerosis. Modifying risk factors in childhood through the supplementation of vitamin D, immunization by vaccination against Epstein-Barr virus, promoting tobacco cessation, weight reduction to prevent obesity, and dietary changes to modify the gut microbiome to decrease central nervous system inflammation are strategies that can be developed to prevent multiple sclerosis, augmenting current treatment strategies of reducing central nervous system inflammation to stop further disease activity and progression.

Disclaimer. The views expressed in this article do not necessarily reflect the views of the Department of Veterans Affairs or the United States Government.