Juvenile multiple sclerosis: addressing epidemiology, diagnosis, therapeutic, and prognostic updates along with cognitive dysfunction and quality of life

Abstract

Juvenile multiple sclerosis (JMS) is a rare but significant subtype of multiple sclerosis (MS) that affects a small percentage of patients under the age of 10 and 3–5% of all MS patients. Despite its rarity, JMS poses unique challenges in terms of diagnosis, treatment, and management, as it can significantly impact a child or adolescent’s physical, cognitive, and emotional development. JMS presents with a varying spectrum of signs and symptoms such as coordination difficulties and permanent cognitive dysfunctions and may include atypical clinical features such as seizures, acute disseminated encephalomyelitis, and optic neuritis, making diagnostic evaluations challenging. Whilst the biology of JMS shares similarities with adult-onset MS, there exist notable distinctions in disease progression, clinical manifestations, and ultimate prognoses. The International Pediatric MS Study Group (IPMSSG) was founded in 2005 to improve understanding of JMS, but there remains a lack of knowledge and guidelines on the management of this condition. This review summarizes the current knowledge on JMS, including its epidemiology, clinical presentations, diagnostic challenges, current treatment options, and outcomes. Current treatment options for JMS include disease-modifying therapies, but JMS can also result in impaired quality of life and psychiatric comorbidity, highlighting the need for comprehensive care for affected children. Through gathering and analyzing scattered studies and recent updates on JMS, the authors aim to address the gaps in current knowledge on JMS and provide an improved understanding of appropriate care for affected children. By doing so, this review hopes to contribute to improving the quality of life and outcomes for JMS patients.

Introduction

Highlights

• Juvenile multiple sclerosis (JMS) is a rare and often overlooked subtype of multiple sclerosis, with only 0.13–0.6 cases per 100 000 children per year.

• Despite sharing similar disease biology, JMS differs from adult-onset multiple sclerosis in terms of its more aggressive course and a greater tendency to involve the spinal cord, as well as presenting with atypical clinical features.

• The review article focuses on the clinical presentations of JMS, with a special emphasis on cognitive dysfunction, and discusses the diagnostic approach, current treatment options, disease course, and updated views on prognosis.

• The article also aims to provide an updated overview of JMS epidemiology, diagnostic challenges, and outcomes, highlighting the need for further research and clinical guidelines for JMS management.

• We also sought to contribute to improving the care and life quality of JMS patients by gathering and analyzing recent updates on the management of such an entity.

Although multiple sclerosis (MS) is most frequently observed in adults, 3–5% of patients and less than 2% of patients younger than 10 years of age have disease onset before the age of 18^1–4. MS in children is quite uncommon compared to MS in adults. According to reports, there are 0.13–0.6 occurrences of juvenile MS (JMS) per 100 000 kids per year^1–3. These results have made JMS one of the most important ignored entities and subtypes of MS, which can present with a varying spectrum of signs and symptoms and permanently disabling the cognitive functions of children for their lifetime. There has been less study, writing, and natural history information on JMS. The IPMSSG was founded in the year 2005, and since then, more is known about JMS.

Despite the similarity in disease biology between juvenile and adult populations, diagnosing, treating, monitoring illness progression, and achieving favorable clinical outcomes pose several challenges. JMS has some differences from adult-onset MS, including a more aggressive course and a greater tendency to involve the spinal cord^2,3. Additionally, JMS may present with atypical clinical features such as seizures, acute disseminated encephalomyelitis (ADEM), and optic neuritis.

In this review, we go over the various clinical presentations of JMS, with a special focus on the cognitive dysfunction associated with it, we discuss the diagnostic approach, current treatment options, disease course, and an updated view on the prognosis. We aim through this study to review the recent literature on JMS, hoping to provide an updated overview of the disease’s epidemiology, clinical presentation, diagnostic challenges, current treatment options, and outcomes. We wanted to identify gaps in the current knowledge regarding such an entity, highlighting the need for further research and clinical guidelines for the management of JMS. By gathering and analyzing the recent updates on JMS, this study seeks to contribute to improving the care and life quality of JMS patients.

Prevalence and incidence of juvenile multiple sclerosis

Although data from specific nations and MS centers are available, the prevalence and incidence of JMS globally are unknown (Table 1). According to several studies^5,6, children make up at least 5% of the total MS population. Between 1.7 and 5.6% of the MS population is under the age of 18, according to demographic studies and case–control series^5–7. Children between the ages of 13 and 16 see the greatest rates of incidence overall.

Table 1.

National cohorts showing the prevalence and incidence of juvenile multiple sclerosis

Country	Number	Age	Diagnostic criteria	Prevalence	Incidence
Italy8	21	0–18 years	Krupp 2013	26.92	2.85
USA9	81	0–18 years	Krupp 2007	–	1.66
Kuwait10	122	<18 years	Krupp 2013	6.0	2.1
Brazil11	125	0–18 years	Krupp 2007	5.5% of the MS population	–
Germany12	126	<15 years	McDonald 2005		0.64

The incidence and prevalence of JMS worldwide were the focus topics in a recent comprehensive review¹³. Regional epidemiologic estimates were derived for North America, Europe, the Middle East, and Asia as a result of the study’s analysis of data from 18 research. According to the study, the incidence of JMS varied from 0.05 to 2.85 cases per 100 000 people a year, with a pooled worldwide incidence estimated to be 0.87 (95% CI: 0.35–1.40). JMS was found to be present in 0.69–26.92 per 100 000 persons overall, with an estimated 8.11 per 100 000 people for the pooled worldwide prevalence. There were significant gaps in the evidence, including the absence of JMS estimates from other sizable parts of the world such as Africa, South America, Russia, and Australia, which were shown to have more varied prevalence than incidence.

A systematic study conducted in 2016 indicated substantial regional variability in the incidence and prevalence of JMS, comparable to the adult MS distribution¹⁴. The lowest prevalence was 0.05 per 100 000 children in Tunisia, while the highest incidence was 2.85 per 100 000 children in Italy¹⁴. It has been determined that there are a minimum of 30 000 children who are currently affected by MS.

Distinguishing features of juvenile multiple sclerosis from adult-onset subtype

Diverse clinical presentations such as optic neuritis, brainstem-cerebellar impairments, and motor and sensory deficits are exhibited by pediatric patients. The adult population diagnosed with MS shows a distinct pattern of clinical presentation as compared to JMS patients (Table 2). The disease has an onset that is more severe in the pediatric age group characterized by debilitating clinical symptoms¹⁶, a multifocal presentation at the onset of the disease¹⁷, and, during the initial course of the disease, a higher frequency of relapses¹⁸. Whilst the majority of these findings have been derived from studies conducted in the US and Europe, there is a notable paucity of data pertaining to epidemiological patterns and clinical features in other regions. In general, pediatric patients exhibit a more favorable prognosis following the initial clinical manifestation¹⁸. Additionally, it has been observed that pediatric patients exhibit a decelerated disease progression, with a delay of 10 years in the onset of the secondary progressive disease phase in comparison to their adult counterparts¹⁹. It is widely postulated that the comparatively gradual onset of permanent physical impairment in pediatric patients²⁰ is attributable to heightened neural plasticity, which facilitates more efficacious recuperation following disease exacerbations. In the context of JMS, the duration between symptom onset and confirmed disability may be comparatively protracted, yet the age at which disability milestones are attained tends to be earlier. What contributes to the extent of clinical disability seen in MS is the early damage that occurs in axons. The research findings suggest that inflammatory demyelinating lesions that occur in children with MS exhibit a greater degree of acute injury to axons compared to adults²¹.

Table 2.

Clinical and characteristic key distinguishing features of juvenile multiple sclerosis (JMS) from adult-onset multiple sclerosis (AOMS)

Distinguishing features	JMS	AOMS
Age of onset	<18 years	>18 years
Gender predominance	Female > Male	Female > Male
Disease course	More likely to have the relapsing-remitting course of MS1–3.	More likely to have primary progressive MS.
Lesion location	More likely to have infratentorial and juxtacortical lesions15.	More likely to have supratentorial lesions.
Cognitive impairment	More common and severe.	Less common and usually mild.
MRI	More likely to have gadolinium-enhancing lesions, T2-hyperintense lesion, and diffuse cerebral atrophy.	More likely to have T1-hypointense lesions, spinal cord lesions, and optic nerve involvement.
Treatment response	Better response to disease-modifying therapies.	Similar response to disease-modifying therapies.

Cognitive dysfunction and its updated evaluation tools in JMS

The domain of cognitive impairment in JMS remained largely uncharted until the past decade. However, in recent years, there has been a significant surge in studies investigating the overall cognitive and neuropsychological status of JMS patients. The prevalence of reported impairments varies between 30 and 80% in different cases. However, the lack of uniformity in the evaluation criteria used in various studies may account for some of the differences in reported prevalence.

The cognitive dysfunction in JMS can be notable during childhood. Cognitive impairment stands out as a crucial factor contributing to the suboptimal quality of life (QoL) among children diagnosed with MS²². Nineteen individuals (39%) have met the established criteria for cognitive impairment out of 62 total cases in a recent cohort²³. The outcomes in cognition among these patients exhibit heterogeneity, with 75% of cases (42 out of 56) showing a decline in cognitive performance after a follow-up of 2 years duration²⁴. According to the findings of our 5-year longitudinal study, it was observed that 56% of patients experienced a decline in their cognitive impairment index, while 25% showed improvement, and 18.8% remained stable²⁵.

A recent study conducted a comprehensive assessment of the Symbol digit modalities test (SDMT) as a cognitive tool for screening patients with JMS²⁶. The study analyzed various predictive factors that may contribute to impairment in cognition in such patients. The study encompassed a group of 500 individuals who received a diagnosis of JMS, as well as 116 patients who presented with clinically isolated syndrome. 13.5 years was the mean age of onset of symptoms, and 3.0 years was the duration of the disease. The findings indicate that there was a prevalence of reduced processing speed among JMS and clinically isolated syndrome patients, with 23.4 and 16.4%, respectively, displaying this impairment during the initial evaluation. Furthermore, the study findings indicate that a clinically significant decrease in serial testing was observed in 14.1% of patients, which was associated with the male sex and older age of MS onset. The transient exacerbation observed in the SDMT can be attributed to either the recurrence of the ailment or the administration of steroids.

The association between MRI metrics and neuropsychological performance in JMS individuals relative to healthy controls matched for age and sex was examined in a recent investigation¹⁵. The findings were that individuals who exhibited impairment in cognition were of 29% within the MS group. The cognitive domains that were primarily affected include the speed of processing, attention, visuomotor cooperation, and expressive language. In comparison to the healthy subjects, a reduction in the volume of the brain, gray matter, and thalamus was noted in the MS group. The use of comprehensive neuropsychological testing and neuroimaging techniques for the assessment and monitoring of cognitive functioning in JMS patients was emphasized by such studies.

Genetic and environmental risk factors

MS risk is influenced by modifications in the major histocompatibility complex. The allele HLA-DRB1×15:01 was found to increase the likelihood of MS diagnosis among children who have incident demyelination, with an odds ratio of 2.7²⁷. The modulation of ancestral origin such as Hispanic or African descent affects the impact of HLA alleles²⁸. Increased susceptibility to JMS in the pediatric population has been linked also to several single-nucleotide variations (SNVs). Interestingly, some of these SNVs overlap with those detected in the adult population²⁹.

Breastfeeding

The risk that breastfeeding could implement to pediatric-onset MS development has been a topic of debate in the scientific literature. A case–control study was conducted to check if there could be a potential relationship between breastfeeding and MS development in childhood. The study compared 36 JMS patients to a control of 72 subjects. Interestingly, females who did not breastfeed their infants had a significantly greater risk of their children getting diagnosed with JMS, with an odds ratio of 4.43 and a 95% CI³⁰. These findings are consistent with previous research as several other studies provided supporting evidence of a correlation between reduced breastfeeding and the possibility of developing JMS^31,32.

The proposed hypothesis suggests that the similarity between cow milk proteins and human self-antigens could potentially trigger early onset of MS. However, breast milk may offer a safeguard against this self-reactivity to cow milk. This theory has been previously documented in the literature³⁰. Nevertheless, a comprehensive investigation conducted by the US network of pediatric MS centers has revealed that there is no correlation between breastfeeding and the likelihood of JMS, even after accounting for pregnancy-related variables³³. Despite this, it is plausible that breastfeeding could mitigate autoimmune dysregulation and confer additional advantages to the developing offspring. Consequently, providing early breastfeeding counseling could serve as a promising prophylactic measure against the onset of MS, particularly for expectant mothers with a familial predisposition to the disease.

Obesity in childhood

There appears to be a potential correlation between childhood obesity and the likelihood of developing juvenile/pediatric MS. Based on the findings of a case–control study, it was observed that children diagnosed with MS exhibited a comparatively higher BMI in comparison to the control subjects. The correlation exhibited notable prominence among female subjects³⁴. The same results were in another case–control study that reported the same findings³⁵. Another study found that the trajectories of BMI in JMS patients displayed heightened levels not only at the point of diagnosis but also early in childhood³⁶. Adipokines, which are secreted by lipid cells, were found to be involved in immune regulation³⁷. Obesity has been identified as a low vitamin D level risk factor and an earlier onset of menarche³⁴. Although there has been considerable attention given to the role of dietary elements, such as salt consumption, in relation to the susceptibility of children to MS, no conclusive links have been established as of yet³⁸.

Smoking and air pollution exposure

Various data have linked exposure to second-hand smoke with the potential development of JMS. According to a case–control study, the risk of MS diagnosis after adjustment was found to be twice as high in children with at least one smoker at home. The adjusted risk ratio of 2.49 indicates that the risk is greater for older children, implying that a lengthier exposure duration amplifies the risk. Another study observed that among children with incident demyelination, 37% of those with MS had reported exposure to second-hand smoke, while the corresponding figure for those with monophasic demyelination was 30%^39,40. The primary hypothesized pathways linking cigarette smoking exposure to the onset of MS involve direct neurotoxicity, immune modulation, and demyelination. These mechanisms were extensively studied and documented in the literature^39,40. The experimental evidence suggests that the presence of cyanide in cigarette smoke induces demyelination in rat models⁴¹.

Apart from the inhalation of cigarette smoke, the potential correlation between the risk of developing MS and air pollution exposure, including sulfur dioxide and carbon monoxide has been examined⁴². A case–control study was conducted, and its findings indicated a significant relationship between the presence of certain air pollutants, such as carbon monoxide and lead, and an increased chances of developing JMS. The results of the study were statistically significant, with a P-value less than 0.01. This suggests that there is a correlation between exposure to these air pollutants and the risk of developing JMS.

Viral Infections and the role of Epstein-Barr virus

It is probable that the risk of juvenile MS development is influenced by exposure to prevalent viruses during the early stages of life. In a multicenter study, exposure to Epstein-Barr virus (EBV) was evident serologically in JMS patients compared to controls. Additionally, another study found that such evidence was linked to an increased MS diagnosis risk (hazard ratio: 2.04)^16,27. Moreover, it was observed in a longitudinal investigation that children with MS who were previously exposed to EBV exhibited a significantly elevated frequency of EBV reactivation in comparison to children exposed to the EBV without a diagnosis of MS. This study involved the use of monthly oral swabs to identify the DNA of EBV⁴³.

On the other hand, in a recent study conducted on children with incident demyelination, it was observed that exposure to cytomegalovirus (CMV) in the past was linked with a reduced risk of being diagnosed with MS. This association was found to be significant, with an adjusted hazard ratio of 0.42. In contrast, no such association was observed with exposure to EBV. In a study conducted in the United States, it was observed that children with MS had a lower likelihood of exhibiting serological evidence of remote CMV infection in comparison to the control group (odds ratio: 0.27)^44,45. Collectively, these investigations suggest the hypothesis that exposure to CMV could potentially confer a protective effect. Two studies conducted in the United States have reported that the risk of MS in white children without the HLA-DRB1×15:01 risk allele is increased by herpes simplex virus 1 seropositivity^46,47.

Vitamin D deficiency

The risk factor for MS development has been extensively investigated in relation to serum levels of 25-hydroxyvitamin D (calcidiol). Numerous studies have established a correlation between serum levels of calcidiol and the likelihood of MS development. In fact, certain studies have suggested that low calcidiol levels may play a causal role in the pathogenesis of juvenile/pediatric MS^48–50. In a particular investigation, the Mendelian randomization approach was employed to establish a plausible causal association between levels of calcidiol and the susceptibility to JMS by leveraging genetic associations to evaluate the impact of biomarkers on disease risk. A noteworthy negative correlation has been observed between serum calcidiol concentrations and the likelihood of JMS. The establishment of this association was predicated on a vitamin D genetic risk score that was formulated utilizing three SNVs that have been previously linked to vitamin D levels. The findings indicate that there is an inverse relationship between the likelihood of developing JMS and the rise in serum calcidiol levels, as identified by the genetic risk score^48,49.

Sex hormones

In instances where the onset of MS occurs prior to puberty, there is a similar occurrence rate of the disease between males and females. However, MS is observed to be more prevalent in women, following puberty, by a factor of two to three, indicating the potential involvement of sex hormones⁵¹. One case–control study has demonstrated an association between a delayed onset of menarche and a reduced likelihood of being diagnosed with MS during childhood³⁴. Additionally, a longitudinal study also reported the same findings⁵². According to the study, boys who experienced the onset of MS symptoms during the peripubertal period had a 2.4 times higher rate of relapses compared to those who experienced symptoms postpuberty⁵³. This finding is specific to children who already have an MS diagnosis. In a study involving girls diagnosed with JMS, it was observed that the rates of relapse were comparatively higher during peri-menarche as opposed to post-menarche. The incidence rate ratio was found to be 8.5⁵⁴.

Diagnostic updates of juvenile multiple sclerosis

Diagnosing JMS is challenging, as the symptoms may mimic those of other disorders, and the disease is relatively rare in children. However, clinicians use specific diagnostic criteria to identify JMS. Diagnosing JMS requires the fulfillment of at least two of the four criteria, with one being the first or second criterion. The following are the diagnosis criteria for JMS:

First criterion: presence of demyelinating clinical symptoms

The first criterion for diagnosing JMS is the presence of clinical symptoms suggestive of demyelination. These symptoms include optic neuritis, transverse, cerebellar ataxia, and other neurological deficits. The symptoms should last at least 24 h and not be attributable to other causes⁵⁵.

Second criterion: presence of lesions in the white matter on MRI

The second criterion is the detection of lesions in the white matter on an MRI of the brain and/or spinal cord. These lesions are usually ovoid or periventricular and demonstrate the characteristic features of demyelination, such as gadolinium enhancement and T2 hyperintensity⁵⁶. The lesions should be disseminated in time and space, meaning they should be present in different areas of the brain and/or spinal cord at different times⁵⁷.

Third criterion: exclusion of other potential causes of symptoms and MRI findings

The third criterion excludes other possible causes of the symptoms and MRI findings. This includes ruling out infectious, inflammatory, vascular, and neoplastic disorders that can mimic MS⁵⁶. The clinician should also consider genetic and metabolic disorders that can cause demyelination, such as leukodystrophies and mitochondrial diseases⁵⁶.

Fourth criterion: presence of oligoclonal bands in CSF

The fourth criterion is the presence of oligoclonal bands (OCBs) in the CSF. OCBs are immunoglobulin G (IgG) proteins that are produced by plasma cells in the CNS⁵⁸. Their presence in the CSF is a marker of intrathecal IgG synthesis, a feature of MS. Nevertheless, it should be noted that OCBs are not exclusive to MS and may also manifest in other CNS inflammatory disorders⁵⁶.

Diagnostic difficulties and differential diagnoses

A neurologist with expertise in MS and pediatric neurology should also make the diagnosis. In addition, the clinician should consider the age of onset, the family history, and the presence of other autoimmune or inflammatory disorders in the patient.

One distinction that should be made is that children under the age of 12 differ clinically from adolescent MS. This group of children under the age of 12 has been shown to more likely to differ clinically from adolescent type MS⁵⁵. Individuals with MS onset in adulthood exhibit distinct clinical features compared to those with JMS. Specifically, they present a higher likelihood of experiencing an initial attack resembling ADEM, display larger and less defined lesions in the early stages of the disease, and demonstrate a lower prevalence of CSF OCBs⁵⁶.

ADEM is a monophasic demyelinating disorder that can present with a variety of symptoms. The most common include seizures, behavior disorders, and motor deficits. Frequently, prior infection with a virus or certain vaccinations such as those administered for measles or varicella-zoster virus is required for the development of such a condition⁵⁵. Distinguishing between ADEM and the initial MS episode can pose a challenge when relying solely on clinical assessment. Therefore, the MRI presentation is a crucial factor in determining the diagnosis^57,58. MRI can show lesions that are more diffuse and larger than those seen in MS⁵⁸. It can also reveal lesions in the deep gray matter, which is not typically seen in MS. By using MRI, physicians can better differentiate ADEM from MS and other demyelinating disorders.

Recent modifications and updates

In 2017, the IPMSSG revised the diagnostic criteria for JMS to improve its accuracy and efficiency⁵⁶. The updated criteria reflect the growing knowledge of JMS and its unique features compared to adult MS.

The new criteria retain the four original diagnostic criteria: clinical symptoms, MRI findings, exclusion of alternative diagnoses, and OCBs in CSF. However, the IPMSSG modified these criteria in several ways⁵⁶:

1. Firstly, the clinical criteria now require at least two non-febrile clinical attacks, rather than a single episode, to reflect the variable and unpredictable nature of JMS. The attacks should be separated by at least 30 days and not be explained by other causes⁵⁶.

2. Secondly, the MRI criteria now include the presence of juxtacortical lesions, which are MS lesions located near the cortex of the brain. Juxtacortical lesions are common in JMS and can be missed by traditional MRI protocols⁵⁶.

3. Thirdly, the exclusion criteria have been expanded to consider a wider range of infectious and inflammatory disorders that can mimic MS⁶⁰. These include autoimmune encephalitis, chronic disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, and progressive multifocal leukoencephalopathy⁵⁶.

4. Lastly, the CSF criteria now allow for the detection of intrathecal IgG synthesis by either OCBs or elevated IgG index, which is a ratio of CSF to serum IgG levels⁵⁹. This change acknowledges that OCBs may not always be present in JMS and that an elevated IgG index can be a reliable alternative⁵⁶.

The diagnostic criteria for JMS have been updated to reflect the unique clinical, radiological, and immunological features of this disease in children and adolescents.⁶⁰ The new criteria require at least two clinical attacks, considering juxtacortical lesions on MRI, expanding the exclusion criteria, and allowing for alternative markers of intrathecal IgG synthesis⁵⁶. These changes are expected to improve the accuracy and consistency of pediatric MS diagnosis and facilitate earlier treatment and intervention for affected children.

Therapeutic and treatment updates

MS in children can present with symptoms such as fatigue, weakness, cognitive impairment, and visual disturbances, which can seriously impact a child’s QoL. Despite its rarity, the incidence of pediatric MS is surging, and there is a growing need for effective therapies and treatment strategies. We summarized the latest updates on the therapeutic and treatment options for JMS.

Disease-modifying therapies (DMTs)

The mainstay of pediatric MS treatment is disease-modifying therapies (DMTs). As a result of these drugs, relapses are reduced, disability progress is delayed, and QoL is improved⁶¹. Among the DMTs available for pediatric MS are interferon beta, glatiramer acetate, teriflunomide, dimethyl fumarate, fingolimod, natalizumab, and rituximab⁶².

Interferon beta and glatiramer acetate are the oldest and most widely used DMTs for JMS. They are administered via subcutaneous injections and have a favorable safety profile⁶³. The oral medications teriflunomide, dimethyl fumarate, and fingolimod are approved for use in adults with MS, and they have also shown promising results in pediatric patients⁶⁴. Natalizumab and rituximab are intravenous medications that are reserved for more severe cases of JMS⁶⁵. A prospective cohort study evaluated the use of natalizumab for at least 12 months in pediatric MS patients. The study included patients with a mean age of onset of 14.9 and a disease duration of 5.1 years⁶⁶. The majority of the patients experienced disease activity despite receiving first-line DMTs. The study reported an average of 34.5±18 infusions of natalizumab⁶⁶. At the last follow-up visit, the mean expanded disability status score improved, significantly reducing the annual rate of relapse. The statistical analysis revealed a significant decrease in the percentage of patients exhibiting MRI activity, with a reduction from 93.8 to 12.5% (P<0.001)⁶⁶. The study overall showed that treatment with natalizumab reduced clinical and radiologic disease activity in a JMS cohort with aggressive or breakthrough disease.

The efficacy and safety of DMTs in JMS have recently been reviewed and meta-analyzed, with interferon beta and glatiramer acetate effectively reducing relapse rates and delaying disability progression with few adverse events⁶⁷. However, the review also found that some children may develop neutralizing antibodies to interferon beta, which can reduce its efficacy over time⁶⁷. At 1 year of age, the renal glomerular filtration rate reaches adult levels, which makes it less of a concern⁶¹. As a result of variability, the pharmacokinetics of a particular agent must be considered as well as potential differences based on an individual’s age⁶¹. As a result of the review, it was recommended that JMS patients be evaluated for their safety and efficacy over a longer period of time.

Symptomatic management

It is important to improve the life’s quality for kids and adolescents with MS through symptomatic management as well as DMTs. Physical therapy, occupational therapy, cognitive behavioral therapy, and medications can all be used to treat symptoms, including fatigue, spasticity, and bladder dysfunction. The most common MS symptom is fatigue, which can impact life quality negatively. In order to minimize fatigue in the pediatric population of MS, it is important to eliminate unnecessary energy demands, improve sleep hygiene, and optimize symptomatic medications and DMTs.

In a recent randomized controlled trial, dalfampridine slightly improved walking speed and endurance in MS compared to placebo⁶⁸. It was also found to have a favorable safety profile. Dalfampridine is a potassium channel blocker that has been approved for use in adults with MS⁶⁸. It is starting to be used in studies with JMS to see if the same results apply.

Management of relapses

In JMS, relapses are common and often debilitating. Relapses may be treated with corticosteroids, plasmapheresis, or intravenous immunoglobulin.

In a systematic review of corticosteroids in JMS, the administration of intravenous methylprednisolone has been demonstrated to effectively decrease both the severity and duration of relapses, while exhibiting minimal adverse events⁶⁹. However, the review also highlighted the need for more long-term studies to evaluate the safety and efficacy of corticosteroids in JMS.

A recent investigation examining ADEM in pediatric patients revealed that IV administration of corticosteroids at dosages ranging from 20–30 mg/kg/day for a period of 3–5 days frequently led to a remarkable amelioration of clinical symptoms⁷⁰. The administration of intravenous immunoglobulin, divided over 2–5 days, may help children who fail to respond to corticosteroids⁷⁰. According to a recent retrospective study, plasmapheresis reduced disability and improved life quality in a subset of children with JMS⁷¹.

Prognostic updates

The largest data reporting long-term JMS outcomes came from the EDMUS project. The objective of this investigation was to delineate the trajectory and prognostic indicators of MS in individuals who experienced the onset of symptoms at or before 16 years of age and to contrast these findings with those of individuals who developed MS in adulthood. The research involved a group of 394 individuals diagnosed with MS during childhood and a comparison group of 1775 individuals diagnosed with MS during adulthood. The findings indicate that individuals with MS onset during childhood exhibit a delayed progression towards irreversible disability, albeit at a relatively younger age compared to those with adult-onset MS. The study findings indicate that the median time from onset to secondary progression was 28 years among individuals with childhood-onset MS, with a median age of 41 years at the time of conversion to secondary progression. The study found that the median durations from the onset of symptoms to disability scores of 4, 6, and 7 were 20.0, 28.9, and 37.0 years, respectively. Additionally, the median ages at which these disability scores were reached were 34.6, 42.2, and 50.5 years. Patients with childhood-onset MS were more likely to be female than male and were more likely to have an exacerbating-remitting initial course. Overall, the findings suggest that childhood-onset MS has a unique disease course compared to adult-onset MS¹⁹.

According to recent reports, there exist supplementary variables that could potentially serve as prognosticators for enduring consequences in individuals afflicted with demyelinating disorders. In particular, the occurrence of the initial two demyelinating episodes within the same year of the onset of the disease is correlated with an increased probability of encountering fresh relapses and advancing toward an expanded disability status scale (EDSS) disability score of 4.0⁷². Additionally, it has been observed that patients with JMS who experience their initial demyelinating episode in the brainstem exhibit a markedly higher likelihood of developing further disability progression (up to fivefold) in comparison to those with lesions located in other areas of the CNS⁷³.

According to a recent longitudinal study spanning 9 years, prompt administration of high-potency medication was found to be associated with a considerably prolonged duration until the occurrence of a subsequent relapse⁷⁴. The study findings indicate that the occurrence of cerebellar lesions during the initial phase and the administration of high-efficacy medications are linked to a reduced long-term annualized rate of relapse. On the contrary, the presentation of transverse myelitis is correlated with an increased frequency of relapse over time⁷⁴. The study findings suggest that the emergence of two fresh T2 hyperintensities and an EDSS rise within the initial 24 months of the disease can be indicative of a long-term disability progression over a period of 9 years⁷⁴.

Quality of life of patients with juvenile multiple sclerosis

JMS has the potential to exert a considerable influence on the QoL of those who are affected by it, including children. Children with MS may experience physical symptoms such as weakness, spasticity, and fatigue, as well as cognitive and emotional symptoms such as memory problems, depression, and anxiety²⁵. The impact of these symptoms on the child’s QoL can be substantial and may persist even during periods of disease remission.

The objective of a recent investigation was to provide material for integration into a novel condition-specific assessment tool that gauges the life consequences of MS in minors and young adults, utilizing a patient engagement model⁷⁵. The study utilized the patient generated index to create an online survey that was filled out by 20 participants, with 11 being adolescents aged 14–22 years who had MS. The results revealed that more than 75% of the areas identified by adolescents with MS pertained to activities and participation, while roughly 20% pertained to body function. Conversely, 60% of the areas nominated by parents were related to body function. Thus, a measurement tool for the impact of MS on the QoL would need to incorporate both impairments caused by MS and significant activities and roles. The new approach involves using the patient generated index system, wherein the individual chooses disability areas affected by MS, rates and prioritizes each area for improvement, and identifies the areas that are going well. The study concluded that this novel measurement approach could be beneficial in creating specific measures for conditions like JMS, which are rare.

In a recent study, the objective was to assess the QoL in adults diagnosed with JMS or adult-onset multiple sclerosis and investigate the factors that impact QoL in both cohorts⁷⁷. The nationwide Swedish MS registry data from 2011 to 2019 was gathered by the researchers. The data included demographic characteristics, EQ-5D-3 level, nultiple sclerosis impact scale-29 score, EDSS score, SDMT score, relapses, and DMT exposure. The study comprised 5094 patients who were diagnosed with confirmed MS, out of which 354 individuals were identified as having POMS. The primary measure of interest was the EQ-5D visual analog scale score.

Upon adjusting for confounding factors, the research findings indicate that there is no statistically significant variation in the QoL between patients diagnosed with JMS and those with adult-onset multiple sclerosis. The results indicate that relapse, severe neurologic disability (EDSS ≥6.0), and higher multiple sclerosis impact scale-29 psychological scores are consistently associated with lower QoL. On the other hand, higher information processing efficiency and exposure to first-line DMTs are correlated with higher QoL scores in both groups.

The findings of these studies indicate that pediatric patients with MS experience adverse effects on their academic and emotional domains. The findings underscore the importance of addressing these domains of existence among individuals with MS, with a particular emphasis on devising interventions aimed at enhancing their QoL. The findings of the study underscore the necessity for forthcoming research endeavors to incorporate affirmative factors and their influence on the QoL of pediatric patients with MS. It is recommended by the authors that in order to enhance the precision of QoL evaluations in this demographic, employment of MS-targeted instruments should be considered in forthcoming investigations.

Conclusion

JMS is a rare but significant subtype of MS that can have a permanent and disabling impact on the cognitive functions of children. Despite being an uncommon condition, it presents with a varying spectrum of signs and symptoms that can pose a challenge in diagnosis and management. By gathering and analyzing the recent updates on JMS, this study highlights the need for further research and clinical guidelines for the management of JMS. The current literature on JMS emphasizes the importance of early recognition and timely intervention in the management of the disease, which can significantly improve the care and QoL of JMS patients (Table 3).

Table 3.

Documented and potential risk factors for the development of juvenile multiple sclerosis and their proposed mechanisms.

Risk factor	Proposed mechanism
Breastfeeding	Triggering of an early immune reaction due to similarities in proteins in cow milk and self-antigens in humans.
Obesity	Proinflammatory properties of increased leptin production from adipose tissue.
Smoking	Neurotoxicity that has a direct effect on the nervous system, damage to the protective covering of nerve fibers, and regulation of the immune response.
Poor air quality	Activation of autoreactive T-cells to enter the CNS through the release of proinflammatory cytokines, promotion of oxidative stress, and stimulation of immune responses.
EBV and other viruses	Priming of T-cells after a chronic and latent infection of human B cells, leading to cross-reactivity.
Vitamin D	T-cell response attenuation towards auto-antigens suppresses the production of the proinflammatory cytokines, along with an increase in T-regulatory cells.

Ethical approval

Ethical approval was not required for this review.

Consent

Informed consent was not required for this review.

Sources of funding

No funding obtained.

Author contribution

P.P.: conceptualization, methodology, writing- original draft preparation, validation; M.D.M.M.: methodology, writing- original draft preparation, review and editing; S.G.: resources, visualization, supervision; P.I.: writing original draft preparation, review and editing; D.S.: review and editing, visualization; J.J.: review and editing, visualization; R.A.: review and editing, visualization; B.N.: writing- original draft preparation, review and editing; H.V.: original draft preparation, validation; A.D.M.M.: writing- original draft preparation, review and editing; O.A.H.: writing- review and editing.

Conflicts of interest

All authors do not have any conflict of interest.

Research registration unique identifying number (UIN)

1. Name of the registry: Not applicable.

2. Unique identifying number or registration ID: Not applicable.

3. Hyperlink to your specific registration (must be publicly accessible and will be checked): Not applicable.

Guarantor

Priyadarshi Prajjwal.

Data availability statement

No data is available for this review.

Provenance and peer review

Not commissioned, externally peer-reviewed.