Diagnostic criteria for multiple sclerosis in children
The diagnosis of multiple sclerosis in both children and adults depends on the evidence of inflammatory disease activity in some parts of the CNS and its temporal distribution. Although previous diagnostic criteria have included multiple sclerosis with onset after the age of 10 years in the Department of Neurology, Huashan Hospital, Fudan University, the current 2010 McDonald Diagnostic Criteria formally address the diagnosis of multiple sclerosis in children and provide specific remarks on the use of MRI in pediatric multiple sclerosis patients.
The ability to make a definitive diagnosis of multiple sclerosis in a single disseminated episode is unique among the McDonald criteria, which indicate the typical clinical features of multiple sclerosis and the presence of 2 T2 lesions in the 4 most common sites of MRI involvement (periventricular, subcortical, brainstem, or spinal cord) and at least one clinically resting enhancing lesion as well as a nonenhancing lesion.
The sensitivity and specificity of the 2010 McDonald diagnostic criteria have been evaluated in the pediatric population, particularly when applied to baseline scans. All studies showed an increased sensitivity of the 2010 McDonald criteria and suggested that early diagnosis of multiple sclerosis could be made using the 2010 McDonald criteria.
In a study including 212 patients with childhood acquired demyelinating syndrome, after prospective clinical and MRI evaluation over 2 years, the 2010 criteria applied at baseline were found to have a sensitivity of 100%, specificity of 86%, positive predictive value of 59%, and negative predictive value of 100% for subsequent diagnosis of multiple sclerosis.
When children presenting with acquired demyelinating syndrome were excluded and the criteria were applied to pediatric patients older than 11 years of age, the positive predictive value of the criteria increased to 76%, which is consistent with the results observed in the adult first-episode population. 2010 McDonald diagnostic criteria include spinal cord lesions as one of the four spatially scattered lesions. However, spinal cord imaging is not routinely performed in children with demyelination, unless the clinical presentation suggests spinal cord involvement.
However, even when examined, T2 high signal lesions in the spinal cord are usually clinically quiescent lesions, and only 10 (27%) of the 36 children studied had extended lesions. An imaging study of children with episodes of acquired demyelinating syndrome showed that spinal cord imaging increased the diagnostic power of the 2010 diagnostic criteria by 10%.
A comparison of children with multiple sclerosis who met the 2010 McDonald diagnostic criteria at baseline and those who did not meet the criteria on MRI showed similar relapse rates and no significant differences in Expanded Disability Status Scale scores between the two groups within the first few years of disease onset. This suggests that the 2010 McDonald diagnostic criteria are not selective for children with more clinically severe multiple sclerosis.
Clinical features and outcomes
Ninety-seven percent of patients with onset of MS before the age of 18 years present with a relapsing-remitting course, and primary progressive MS is rare in children and adolescents, and if present requires more detailed evaluation to rule out other diagnoses.
In a study of clinical presentation in a population with different age of onset, patients younger than 11 years may be more likely to present with multifocal features, more likely to involve the brainstem or develop motor deficits, and more likely to have more acute damage than older patients. However, the ability of younger children to clearly articulate minor sensory deficits or alert parents to symptoms of minor visual impairment is also an issue to consider.
One study showed that 21 pediatric MS patients had a higher frequency of relapses within the first few years after onset compared to 110 adult onset MS patients. A retrospective analysis of 88 pediatric MS patients conducted in Germany showed that the highest average number of relapses per year during the first year after the first attack was 2.2. in the pediatric group and 1.8 in the 14-16 year old group; the annual relapse rate decreased significantly in both groups by year 5. In this German study, the impact of treatment was not fully evaluated, but more than 80% of children received immunomodulators.
The time interval between first onset and onset of disability (assessed by EDSS scores) was longer in MS patients with childhood onset compared with adult MS patients, although the biological age of onset of disability was 10 years earlier in patients with childhood onset. In the German study mentioned above, 88 pediatric patients had a median EDSS score of less than 1 at 2 years after onset, 1.2 at 10 years, and 2.5 at 15 years.
Childhood MS occurs during the critical formative educational period and during active brain maturation. Results from three studies collecting more than 300 pediatric MS patients found that 30% had cognitive dysfunction, including executive function, processing speed, and visuomotor integration, with attention being the most frequently involved function. Younger age of onset and lower intellectual functioning scores were predictors of more severe impairment in the area of cognitive function.
Indicators of academic performance were also affected in MS patients, with one study showing that 26% of children with MS performed worse in math. Results from two longitudinal studies showed that 28 patients showed cognitive decline after 1 year in 7 patients and 56 patients showed cognitive decline after 2 years in 42 patients. The correlation between cognitive function and MRI characteristics will be discussed later. Cognitive rehabilitation is also an active area of current discussion, but no effective interventions to enhance cognitive reserve and improve cognitive function have been reported.
MRI in children with multiple sclerosis
MRI analysis of disease activity
It has been hypothesized that patients with childhood-onset MS have a lower burden of lesions at the time of first attack compared to those with adult-onset MS because of the younger age of many pediatric MS patients and the age-related self-imposed limitations in the natural growth of MRI subclinical lesions over time.
However, analysis of T2 lesion volumes in patients with childhood onset versus those with adult onset (who were matched for disease duration and had early imaging) revealed that the volumes of T2 lesions were similar in both groups. The volume of T1 lesions was larger in patients with adult onset disease, but the T1 image of submural lesions was larger in patients with childhood onset disease. The findings of these MRI studies are consistent with the reported higher incidence of brainstem symptoms in MS patients with childhood onset.
More combined studies are needed to further assess lesion burden as well as lesion assessment in larger cohort studies. Standardized MRI scoring methods have been proposed for the evaluation of children with MS in clinical practice. An analysis of imaging data from the US Pediatric MS Network re-emphasizes the importance of standardized MRI protocols.
MRI analysis of focal and whole brain integrity
Studies using non-conventional MRI sequences such as diffusion tensor imaging (DTI) or magnetic resonance transfer imaging (MTI) have provided new perspectives and insights into the structural integrity of brain tissue. In a cohort study of pediatric MS patients undergoing DTI, reduced anisotropy fraction (FA) in the white matter of the brain, which appears normal externally in MS patients compared to age-matched healthy children, was found within the lobes as well as in the corpus callosum. Consistent FA differences were observed in both groups, but differences in diffusivity were not consistent in both groups.
Decreased FA was shown to be associated with poor math performance as well as impaired processing speed in a study that included 34 young MS patients. Results from two fiber bundle-based analyses showed a decrease in FA in 14 children with MS and 10 children with MS with external viewing of normal white matter, respectively. Overall, the results from these studies suggest that there is disruption of myelin structure in early MS, but larger series of assessments as well as fiber bundle analyses are needed to further evaluate changes in myelin over time in MS.
Magnetization transfer rate (MTR) imaging can be used as a method to assess myelin integrity. MTR imaging is primarily based on the ability of hydrogen ions to bind to macromolecules with different transfer excitability than free hydrogen ions when activated by magnetic resonance pulses. MTR is reduced in demyelinating lesions compared to normal white matter, but rises when myelin is remyelinated.
A study including 11 adolescents and 11 adults with MS showed abnormal MTR in brain tissue that appeared normal in appearance in MS patients compared to 22 healthy controls. Longer-term, larger cohort studies are needed to further fully understand the application of MTR analysis in pediatric MS patients.
The effect of MS on brain volume, particularly in pediatric patients, on age-expected mature brain development has been investigated. In a cross-sectional analysis that included 38 children with MS with a mean age of 15.2 years, it was shown that whole brain volumes in MS patients decreased by 1 SD from their age-expected counterparts.
Thalamic volume, even when corrected for whole-brain volume, was more likely to be involved in pediatric MS patients, suggesting a susceptibility of the thalamus in early MS. In MS patients with childhood onset, decreased thalamic and corpus callosum volumes can distinguish those with cognitive impairment from those with intact cognitive function.
Functional MRI
The potential of functional MRI to provide relevant information on neural network activity, both in terms of resting-state imaging and specific neuronal connections, is an area of increasing interest in MS research. A study of 17 pediatric MS patients applying functional MRI showed normal connectivity coefficients in children with MS compared to adult patients with increased connectivity under specific tasks. When analyzed for specific sensorimotor tasks, MS patients with childhood onset showed preserved functional reserve. The authors hypothesized that preserved connectivity may account for the lower level of early disability in patients with childhood onset MS.
Functional MRI studies in pediatric MS patients may have limitations, including normal changes in neural networks with increasing age in developing children, individual differences in neural network capacity across patients, and MS-related changes that may lead to compensatory increases in intracerebral connectivity followed by decreases in connectivity as the disease progresses. Methods to identify these different types as well as increased sample sizes are needed for further study.
Pathophysiologic insights
Genetic and environmental risk factors
For both pediatric and adult MS patients, the strongest genetic risk factor is an HLA-DR allele-specific haploinsufficiency mutation located in the major histocompatibility complex (MHC), while the less potent genetic risk factor is a partial gene single nucleotide polymorphism for most immune-related functions. In a study evaluating the frequency of HLA-DRB15 alleles, which included 64 pediatric MS patients, 206 children with monophasic acquired demyelinating syndrome, and 196 controls, the results showed that children with at least one DRB1*15 allele were more likely to be diagnosed with MS. The association between childhood multiple sclerosis, viral infection, and HLA-DR15*01 was also reported in a US cohort study.
In a study that included 188 cases of childhood acquired demyelinating syndrome (53 of which were diagnosed with multiple sclerosis) compared to 466 adult-onset multiple sclerosis and 2046 adult controls, 57 single nucleotide polymorphisms (SNPs) were clarified by genome-wide association analysis (GWAS).
The frequency of these SNPs was more likely to be detected in children diagnosed with MS than in children with monophasic acquired demyelinating syndrome, similar to adult onset MS. Although the results of large GWAS studies performed in adult MS patients will not be replicated in pediatric patients, candidate gene regions involved in adult studies can be evaluated in children.
Several cohort studies have shown vitamin D deficiency to be a risk factor for MS in children and have shown a correlation between vitamin D concentrations and relapse rates. Increased risk of multiple sclerosis has also been associated with adolescence, and this association may be confounded by the association of obesity with low serum vitamin D levels. However, in a multinational study of adults that included 1830 patients and 2015 controls, low vitamin D levels were shown to be associated with an increased risk of multiple sclerosis in patients with a history of obesity in adolescence.
Although there is no clear evidence that specific infections are the cause of MS, exposure to specific viral as well as parasitic infections is associated with increased as well as decreased risk of MS development. 85-88% of MS patients with childhood onset had serologic evidence of distant EBV infection compared to 44-77% of healthy controls in the same region. Results of a study showed that anti-EBNA1 serum titers were higher in MS patients with childhood onset compared to EBV-exposed healthy controls.
In a 1-year study of immune control in potentially EBV-infected individuals, the incidence of monthly oral swabs for EBV DNA was found to be 66% in EBV-positive children with MS, compared with 20% in age-matched controls in the same region. There was a negative predictive correlation between cytomegalovirus exposure and risk of MS onset in childhood-onset and adult-onset disease. Although herpes zoster virus (HSV) exposure alone did not affect the risk of MS, MS risk was increased in patients with HSV exposure and the presence of one or more HLA-DRB15 alleles.
A prospective follow-up study including children with sporadic acquired demyelinating syndrome analyzed genetic factors, viral exposure, and the coexistence of vitamin D. Results showed that all three HLA-DRB15 alleles, distant EBV infection, and low serum vitamin D levels were associated with a final diagnosis of MS in 16 patients (28 patients in total).
The remaining 12 patients ended up with a monophasic course despite having all three categories of risk factors. Of the 20 children without any of the risk factors, only 1 was ultimately diagnosed with MS, suggesting a protective effect when none of the three risk factors were present.
Cerebrospinal fluid analysis
In a study that included 107 patients with MS starting in childhood, 40 pediatric patients with an elevated cerebrospinal fluid leukocyte count who started under 11 years of age had an elevated cerebrospinal fluid count compared with 67 patients who started in adolescence (11-18 years). Neutrophils were also more likely to be present in the cerebrospinal fluid of pediatric patients at younger ages (<11 years) than those with an 11-18 year old onset.
Immunoglobulin (OCB) synthesis in the subarachnoid space, strictly limited to CSF (but not in serum), is a marker of multiple sclerosis. In the same study, CSF OCB was detectable in 49 (63%) children with MS aged 11-18 years and in 21 (43%) younger patients.
In a study that included pediatric patients with acquired demyelinating syndrome, OCB was detectable in 44 of 170 patients, a proportion that increased by 60% when the patients were subsequently diagnosed with MS. In a German study including 88 children with MS, OCB was detectable in 28 of 47 patients <11 years of age and in 30 of 41 patients >11 years of age. repeat CSF analysis in subsequent episodes showed that OCB was present in 43 of 47 younger patients and in 35 of 41 older patients OCB was seen in 35 of 41 older patients.
The study also analyzed cerebrospinal fluid IgM and showed that 44 of 70 pediatric patients had intrathecal synthesis of IgM. The presence of CSF IgM was associated with increased recurrence rates, particularly in the first two years of disease and in female patients. These findings were not replicated in the next cohort study and were less consistent with the results regarding CSF IgM in adults.
Cerebrospinal fluid proteomic analysis of 19 pediatric patients with acquired demyelinating syndrome showed that nine patients were eventually diagnosed with multiple sclerosis during a mean follow-up period of 4.88 years. In contrast to children with persistent monophasic acquired demyelinating syndrome, no dense myelin antigens (which are often considered potential disease targets for MS) were detected in the cerebrospinal fluid of children who eventually developed MS.
Among all cerebrospinal fluid proteins, the concentration of proteins known to be localized in the axonal glial junction region was 41 times higher in MS patients than in patients with monophasic acquired demyelinating syndrome. Several axonal glial apparatus proteins, such as OMGP, neuroglial protein, ADAM22, TENASCIN-R, and CASPR4, distinguish patients with monophasic disease from those who develop MS. It would be interesting to replicate these findings and to investigate their correlation with anti-axonal gliadin serum antibodies such as contactin-2, neurotubulin-155, and neurotubulin-186.
Serological analysis of 65 children with acquired demyelinating syndrome revealed no antibodies against contact protein 2 or contact protein-associated protein 2 (CASPR2). In an analysis of 25 MS patients with childhood onset and 67 pediatric and adult controls, no differences were found in the concentrations of non-myelin proteins such as tau, phosphorylated tau or S-100B, which can be increased in the presence of CNS damage.
Analysis of cerebrospinal fluid from nine pediatric MS patients during acute episodes showed increased concentrations of CSF tau protein, suggesting either a transient increase during acute injury or a more severe CNS injury in patients with active disease.
Serum antibodies
Serum antibodies directed against myelin proteins can be detected in 25-50% of pediatric patients with acute CNS demyelination. In a study enrolling children with multiple sclerosis (25 of whom had both serum and cerebrospinal fluid samples) and 106 age-matched controls, antibodies directly against mature and immature myelin matrix proteins (MBP) were detected in 22 of 91 children with multiple sclerosis (24%), similar to the proportion of controls (20%).
In the same study, some patients who presented with positive serum MBP antibodies also presented with anti-MBP antibodies in the cerebrospinal fluid. The high affinity of serum anti-MBP antibodies detected in these pediatric patients was based on soluble phase as well as plasmon resonance analysis.
Several studies have explored antibodies against the MOG response, a myelin protein expressed in the outermost layer of myelin that may serve as a target for antigens. Methods for detecting myelin antibodies vary from study to study, even for cell-based analyses. When using a cell-based analysis, MOG can be presented in its most natural conformational form, with high titers of IgG antibody responses detectable in 9 of 19 patients with acute disseminated encephalomyelitis compared to 9 of 25 patients with clinically isolated syndromes and no patients in healthy controls or other neurological disease controls.
In addition, using a different cell-based assay, Rostasy and colleagues detected anti-MOG antibodies in 2 children with monophasic optic neuritis (10 in total, all with normal brain MRI), 12 children with recurrent optic neuritis (15 in total, with recurrent optic nerve symptoms only and MRI not meeting diagnostic criteria for MS), and 3 children with MS with optic neuritis as the first symptom (12 in total). Anti-MOG antibodies were detected.
In a second study by the same authors, 8 patients with optic neuromyelitis optica spectrum disease were described, of whom 3 were positive for MOG, 2 were positive for aquaporin-4, and 3 were negative for both MOG and aquaporin-4. Cell-based analysis of anti-MOG antibodies in 126 patients with childhood acquired demyelinating syndrome revealed the presence of anti-MOG antibodies in 31 patients.
Serial serologic analysis revealed persistent anti-MOG antibodies in 6 of the 8 pediatric patients with acquired demyelinating syndrome with subsequent confirmation of MS, but not in the 16 children with acute disseminated encephalomyelitis, who had detectable MOG antibodies only during the acute phase of the disease. Thus, anti-MOG antibodies may be able to distinguish children with CNS demyelination from those with encephalitis.
The dense myelin component may not be the only target of the immune response in CNS demyelinating patients. Using an ELISA-based assay, antibodies directly against the potassium rectifier channel KIR4.1 were detected in 27 of 47 patients (57%) with acquired demyelinating syndrome, whereas they were not detected in all 62 controls (44 with other diseases and 18 healthy children).
The pattern of staining of human brain histology sections in KIR4.1-positive children was similar to that in adult KIR4.1-positive multiple sclerosis patients. Serum MOG antibodies were not detected in KIR4.1 positive children, suggesting that this is a unique serologic feature. However, a recent study showed that neither KIR4.1 antibodies were detected in serum and cerebrospinal fluid of adult multiple sclerosis patients, nor was a deficiency of KIR4.1 expression from glial cells in multiple sclerosis lesions detected.
Cellular response
Several studies have explored the T-cell profile and functional responses in pediatric MS patients. In a study focusing on regulatory T cell subsets, the ratio of primary and regulatory T cells in circulating blood and recent thymic transplantation was compared in 30 pediatric MS patients, 67 age-matched control children, and 26 adults.
The findings revealed that the T-cell characteristics of pediatric MS patients were significantly different from those of children of the same age group, with a relatively high proportion of primary T cells compared to regulatory T cells and a relative absence of recent thymic transplantation; however, these characteristics were similar to those seen in adults, suggesting a tendency toward earlier maturation of immune system function in pediatric MS patients. In addition, pediatric MS patients have reduced regulatory T-cell suppression compared with age-matched controls, suggesting a defect in immune control.
In a study focusing on effector cell immune responses, T cell responses to myelin were evaluated in 10 untreated pediatric-onset MS patients, 10 adult-onset MS patients, and 20 age-matched controls. The results of the study showed that although T-cell responses against myelin were seen in all three groups, this response was most pronounced in pediatric MS patients. Childhood MS patients had higher T-cell expression of interleukin factor 17 compared with multiple controls, suggesting a role for a central memory response to Th17 in childhood MS.
Treatment
The treatment of childhood and adolescent MS requires the intervention of a multidisciplinary team. Internal medicine, psychology, cognitive assessment, and psychiatric treatment are needed, as well as social support to be able to participate in treatment, and education of the school system about MS-related diseases is also important.
The overall safety and tolerability of first-line immunomodulator therapy currently used in pediatric patients is good. The most common adverse effect of interferon beta therapy is a temporary increase in hepatic transaminases, although there are fewer side effects if treatment is started at a starting dose of ¼ of the full dose and titrated gradually. Dose reductions may alleviate transaminase elevations, and such patients may tolerate increases to the full dose after a period of time.
In a study that included more than 300 pediatric patients, the safety profile of interferon beta-1a treatment was similar to that of treatment in adults, even in children younger than 12 years of age. No major adverse reactions have been reported in patients treated with glatiramer acetate, although hepatotoxicity has been reported in one patient.
The International Pediatric Multiple Sclerosis Study Group (IPMSSG) and a European consensus group reviewed the principles for initiating first-line therapy in children and adolescents. The consensus statement advocates offering treatment to all patients diagnosed with multiple sclerosis, as there is no reliable way to be certain that patients will not relapse.
There are a number of drugs approved for the treatment of adult MS (not all drugs are approved in all countries), including oral and injectable treatments. However, none have been studied in children with MS so far, although further studies can be expected in the future. A number of recent reviews and IPMSSG have also discussed some important considerations regarding the use of these drugs in pediatric MS patients.
Three considerations support the use of new treatments: approximately 30% of pediatric MS patients do not tolerate first-line injectable therapy; pediatric MS patients generally prefer oral drug therapy to injectable therapy; and drugs with novel mechanisms of action may have better efficacy in patients who have had an inadequate response to interferon beta or glatiramer acetate therapy. There are no uniform criteria for defining poor patient response to first-line therapy.
The IPMSSG has proposed guidelines for evaluating the efficacy of first-line therapy, which state that patients need to receive at least a full dose of therapy for 6 months for the first time. At the end of the first treatment cycle, three factors determine poor response: increased or no reduction in relapse rate between 12 months of treatment follow-up compared to pre-treatment; new T2 or enhancing lesions on MRI; or 2 or more clinical relapses within 12 months.
The decision to initiate second-line therapy requires a detailed assessment of the risk-benefit of treatment. Currently, the most promising therapeutic agent is natalizumab because of its clear efficacy in reducing relapse rates and significantly reducing MRI active lesions, although no studies of this agent have been conducted in pediatric MS patients.
The most significant risk of natalizumab treatment is active JC virus infection of the brain, leading to the development of progressive multifocal white matter encephalopathy. The risk of progressive multifocal leukoencephalopathy is almost negligible in patients who have never been exposed to JC virus and who have not had JC virus included in the course of treatment with natalizumab. Because initial JC virus infection is generally thought to occur in late adolescence or early adulthood, a subset of pediatric MS patients may be at low risk for exposure.
Detection of anti-JC virus antibodies in a high-quality laboratory is important for risk estimation in patients undergoing treatment and for ongoing monitoring. The risk of developing progressive multifocal leukoencephalopathy in patients exposed to JC virus can be estimated by the duration of treatment with natalizumab, with the highest risk occurring in patients treated with other immunosuppressive agents (e.g., cyclophosphamide, mitoxantrone, azathioprine) prior to treatment with natalizumab. Because of acute toxic effects and long-term cancer risk, treatment with cyclophosphamide and mitoxantrone is not commonly used in pediatric MS patients in countries where natalizumab is available.
Conclusion and outlook
To date, data on the clinical features and prognosis of children with acquired demyelinating syndrome have been obtained from studies in areas with a high prevalence of multiple sclerosis, and it would be interesting to investigate whether the clinical features and prognosis of patients with acquired demyelinating syndrome differ in other countries with a low prevalence of multiple sclerosis, such as Africa and countries around the equator.
The use of standardized MRI manipulation methods and scoring methods for clinical and study quality imaging are essential for multicenter collaborative studies. The use of advanced imaging techniques provides a window into the effects of multiple sclerosis on local tissue damage, age-expected brain developmental damage, and its relevance to cognition. Finally, functional MRI studies provide additional insight and understanding of compensatory neural network activation as well as dysfunction and can serve as a novel approach to understand the development of immature neural network structures at the onset of multiple sclerosis.
Research over the past few years supports the notion that multiple sclerosis with childhood onset shares common risk factor profiles with multiple sclerosis with adult onset. Serum and cerebrospinal fluid antibody profiles suggest the need to focus on the immunologic response against MOG, which is most pronounced in young pediatric patients, may be transiently present in patients with acute disseminated encephalomyelitis, and is particularly prevalent in children with recurrent optic neuritis.
Studies of immune cell subpopulations have shown a relative decrease in primary immune cells, a decrease in the number of recent thymic grafts, and a disturbed pool of regulatory immune cells, and the study observations raise the interesting possibility that premature aging of specific immune cell subpopulations occurs in MS patients with childhood onset.
The treatment of pediatric MS patients will be improved by high-quality data on treatment efficacy and safety, and we need to ensure that these treatments are applied to pediatric patients similarly to adult patients before starting treatment. North American and European authorities require that all treatments already approved in the adult MS treatment area be proposed for pediatric MS research. Pediatric MS clinical studies require multicenter, multinational patient recruitment to achieve sufficient patient numbers for analysis, one of several challenges identified in an international conference on the subject.
Pivotal clinical phase 3 studies generally require a series of clinical endpoints to assess effectiveness, such as relapse rates, EDSS scores, or the proportion of patients with confirmed disability progression. In pediatric MS patients, although the relapse rate early in the disease can exceed that of adult patients, the number of patients required to demonstrate treatment efficacy is very high when relapse is used as a primary endpoint assessment. New lesions are detected using MRI much more frequently than clinically identified relapses in adult MS patients, and therefore, new or enlarged T2 lesions can be used as a key prognostic assessment metric in clinical phase 2 studies of MS.
An analysis of lesion development in patients with multiple sclerosis followed up after the first attack budgeted the number of patients needed to show differences in treatment efficacy in a clinical study of pediatric multiple sclerosis. Secondary MRI metrics, such as brain volume, may also be used to measure this, although there are limited changes in brain volume that can be detected in short clinical studies and potential confounding factors due to acute relapse treatment and transient increases in brain volume associated with corticosteroid therapy need to be considered.
Childhood multiple sclerosis is a relatively uncommon disease, which severely limits the possibility of recruiting enough patients for meaningful clinical studies with multiple drugs, or even multi-national combined studies. The need for sound management guidance for pediatric and adolescent MS clinical research is a major area of concern for the IPMSSG and its members.
The increased awareness of childhood multiple sclerosis is our improved understanding of the clinical features, especially in those children who are particularly young. Genetic, serum, cerebrospinal fluid, and cell-based analyses for the most part support that patients with MS with childhood onset share a common biological basis with those with adult onset MS; and when studied in children with their first episode, can provide a unique understanding of the biological features of the disease.
Tests of cognitive impairment in children with MS and MRI evidence regarding whole brain and focal age-expected brain volume damage suggest that the neurodegenerative features of MS are not a long-term late complication of the disease and that this degeneration is not mitigated by age, emphasizing the need to develop neuroprotective treatment strategies for all patients with MS.
Although current evidence suggests that multiple sclerosis is a disease that can occur at all ages, age does play an important role in the impact of the disease. Just as children are not the same as young adolescents, adolescents are not the same as young adults. From a biological perspective, major myelin formation continues into early adulthood and may affect focal lesion formation as well as the ability to repair myelin.
The maturation of neural networks throughout childhood and adolescence largely influences the expression of focal excitatory and inhibitory synapses, so that intracerebral connections and compensatory network formation in children with MS differ from connections in adults with multiple sclerosis whose CNS has matured. Functional MRI studies that directly address myelin integrity and analysis are exciting areas of ongoing research.
Finally, as multiple sclerosis treatments continue to proliferate, clinicians should ensure a better understanding of each treatment’s mechanism of action, immune effects, monitoring measures, infection and other risks, principles of treatment selection, and treatment adjustment or dosing. Most pediatric training programs do not currently provide such education, and further medical education for clinicians is needed to establish linkages with other specialists familiar with immunosuppressive therapy.