Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research(19/08/14)
Amy Waldman MD, Prof Angelo Ghezzi MD, Amit Bar-Or MD, Yann Mikaeloff MD, Prof Marc Tardieu PhD, Prof Brenda Banwell MD
The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have been informed by many new insights in the past 7 years.
National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis.
The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume.
Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis.
Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
Source: The Lancet Neurology, Volume 13, Issue 9, Pages 936 - 948, September 2014 Copyright © 2014 Elsevier Ltd (19/08/14)
Quantitative determination of regional lesion volume and distribution in children and adults with RRMS.
INTRODUCTION: Onset of MS occurs during childhood in about 5% of cases. It is unclear whether very young age at MS onset, when the nervous system is still myelinating, affects MS lesion accrual or regional distribution.
OBJECTIVE: To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS).
METHODS: Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration.
RESULTS: All subjects exhibited T2-weighted brain lesions. Children had higher whole-brain T2-weighted-lesion-volume (T2LV) compared to adults (mean (SD) in cm(3): 12.76(2.7) vs. 10.03(3.4), p<0.0013). The supratentorial-T2LV was similar in children and adults (8.45(1.7) vs. 7.94(1.7), mean (SD), p?=?0.2582), but adults were more likely to have supratentorial lesions (96.5% vs. 68.9%, p<0.012). Children were more likely to have infratentorial-T2-weighted lesions (75.9% vs. 43.4%, p<0.03), specifically in the brainstem (62.1% vs. 26.7%, p<0.019) and the pons (48.3% vs. 17.24%, p<0.024), had higher infratentorial-T2-weighted-lesion counts (4.1(5.6) vs. 1.45(2.3), p<0.021), a greater infratentorial-T2LV (4.31(2.7) vs. 2.08(2.4), p<0.0013), and a greater infratentorial-T1-weighted-lesion-volume (T1LV) (3.7(2.5) vs. 1.08(1.9), p<0.0007). Whole-brain-T1LV was higher in children (9.3(2.5) vs. 6.43(2.1), p>0.001). Adult MS patients had higher supratentorial-T1LV (5.5(0.92) vs. 6.41(2.1), mean (SD), p<0.034), whereas children were more likely to have infratentorial-T1-weighted lesions (58.6% vs. 23.3%, p<0.015).
DISCUSSION: Onset of MS during childhood is associated with a higher volume of brain lesions in the first few years of disease relative to adults. Children with MS are more likely than adults to have T2 and T1 lesions in the infratentorial white matter, raising the possibility of preferential immune targeting of more mature myelin. Children with MS have a lower supratentorial T1 lesion burden, possibly reflecting more effective remyelination and repair in brain regions that are still engaged in active primary myelination.
Ghassemi R, Narayanan S, Banwell B, Sled JG, Shroff M, Arnold DL; Canadian Pediatric Demyelinating Disease Network.
Source: PLoS One. 2014 Feb 26;9(2):e85741. doi: 10.1371/journal.pone.0085741. eCollection 2014. & PMID: 24586244 (14/04/14)
Objective: To investigate Epstein-Barr virus (EBV) oral shedding frequency and EBV genetic diversity in pediatric patients with multiple sclerosis (MS).
Methods: This was a prospective case-control study. We used PCR-based assays to detect viral DNA in the monthly mouth swabs of 22 pediatric patients with MS and 77 age- and sex-matched healthy controls. EBV-positive samples were further analyzed for sequence variation in the EBV BCRF1 (ebvIL-10) gene using direct DNA sequencing methods, and in the EBV LMP1 gene by mass spectrometry.
Results: Nineteen of the 22 (86.4%) children with MS were seropositive for remote EBV infection compared to 35 out of 77 (45.5%) healthy controls (p = 0.008). Baseline analysis of mouth swabs revealed a higher proportion of EBV-positive samples from EBV-seropositive patients with MS compared to EBV-seropositive healthy controls (52.6% vs 20%, p = 0.007). Longitudinal analysis of monthly swabs revealed average EBV detection rates of 50.6% in patients with MS and 20.4% in controls (p = 0.01). The oral shedding frequencies of Herpesviruses herpes simplex virus–1, cytomegalovirus, human herpesvirus (HHV)-6, and HHV-7 did not differ between groups. Changes in the predominant EBV genetic variants were detected more frequently in patients with MS; however, no specific EBV genetic variant was preferentially associated with MS.
Conclusion: Children with MS demonstrate abnormally increased rates of EBV viral reactivation and a broader range of genetic variants, suggesting a selective impairment in their immunologic control of EBV.
Carmen Yea, MSc, Raymond Tellier, MD, Patrick Chong, PhD, Garrett Westmacott, PhD, Ruth Ann Marrie, MD, PhD, Amit Bar-Or, MD, Brenda Banwell, MD; On behalf of the Canadian Pediatric Demyelinating Disease Network
Source: Neurology © 2013 American Academy of Neurology (30/10/13)
OBJECTIVE: The purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS).
METHODS: A retrospective analysis on pediatric MS patients treated with MX was performed with regards to demographic/clinical parameters and magnetic resonance imaging (MRI) findings.
RESULTS: 19 definite pediatric MS cases with mean ± SD age of 15.4 ± 2.8 years underwent 20 mg MX for control of their severe/frequent relapses, high EDSS score or new and active brain MRI lesions. After a median [IQR] follow-up period of 30[12-60] months, 14 cases (73%) were relapse free; the EDSS score decreased by at least 0.5 in 16 cases (84.2%); and gadolinium-enhancing lesion volume fell by 84.2% in 16 cases. Adverse events included nausea and vomiting, fatigue, alopecia, palpitation, cardiomyopathy and mild leukopenia. All adverse events were mild and transient.
CONCLUSION: Our results suggest MX is a good candidate for treatment of children with worsening RRMS and SPMS. Recommendations regarding patient selection, treatment administration, and close follow-up should be considered. Continuing research is needed to establish its efficacy and safety profile in a multinational collaboration with careful follow-up of adverse events.
Etemadifar M, Afzali P, Abtahi SH, Ramagopalan SV, Nourian SM, Murray RT, Fereidan-Esfahani M.
Department of Neurology, Medical School, Isfahan University of Medical Sciences, Isfahan, Iran; Isfahan Research Committee of Multiple Sclerosis (IRCOMS), Isfahan University of Medical Sciences, Isfahan, Iran.
Sources: Eur J Paediatr Neurol. 2013 Oct 7. pii: S1090-3798(13)00131-1. doi: 10.1016/j.ejpn.2013.09.001. [Epub ahead of print] Copyright © 2013 European Paediatric Neurology Society & Pubmed PMID: 24139067 (28/10/13)
Stressful life events in childhood did not appear to increase the subsequent risk for multiple sclerosis (MS), researchers said here.
In large Danish cohort study, children who experienced stressful life events had a weak 1.11-fold risk (95% CI 1.02-1.20) of later developing MS compared to unexposed children, according to Nete Munk Nielsen, MD, PhD, from Statens Serum Institut in Copenhagen, and colleagues.
However, there was a "slightly increased risk of MS" for kids who experience parental divorce (relative risk 1.13, 95% CI 1.04-1.23) compared to children who did not, they wrote in their poster presentation at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting.
While stressful events are often associated with risk for MS in adults, studies that have looked for an association between stress and MS in children have turned in mixed results.
The authors pointed out that a recent study found that adults exposed to emotional or sexual abuse as children were at 2.2- to 3.4-fold increased risk of MS. However, another study reported no association between physical or sexual abuse in childhood and risk for MS.
The authors analyzed Danish public health records that included nearly 3 million individuals born between 1968 and 2011. The Danish Civil Registration System contains updated information on family relations, marital status, and vital statistics on every Danish person since April 1, 1968. The researchers compiled data on parental and sibling deaths as well as parental divorce. Information about cases of MS in the study cohort was obtained from the Danish MS Registry.
The cohort represented 63 million person-years of follow-up. The records showed that 15.8% of the population was exposed to at least one stressful life event before the age of 18, with most of those events being parental divorce.
The researchers identified 3,260 individuals in the cohort who were later diagnosed with MS.
The death of a parent had a nonsignificant 4% increased risk (95% CI 0.90-1.21) of a later MS diagnosis, while death of a sibling before age 18 had a similar nonsignificant 4% impact (95% CI 0.81-1.32).
"There have been conflicting studies over whether stressful events in a person's childhood leads to MS, but in our analysis, we did not find strong evidence for this," Nielsen said during her poster presentation.
"We cannot exclude a biological effect of stress on the susceptibility to MS, but do consider adoption of unhealthy behaviors more likely to explain our findings," she added.
That may be particularly true in the findings on parental divorce. Nielsen said that children's lives may be impacted by living with one parent with reduced income, resulting in less access to healthier lifestyles. Unhealthy lifestyles have been linked to a higher MS risk.
She added that her group will continue to research which life events may confer a risk for MS and disease development.
Nielsen reported no conflicts of interest. A co-author reported relationships with Biogen Idec, Novartis, and Teva.
Primary source: European Committee for Treatment and Research in Multiple Sclerosis
Source reference: Nielsen N, et al. "Stressful life-events in childhood and risk of multiple sclerosis" ECTRIMS 2013; Abstract P302.
Source: MedPage Today © 2013 MedPage Today, LLC (07/10/13)
For young people, type 1 diabetes may raise the likelihood of having multiple sclerosis. Scientists now suspect that certain environmental factors may play a role.
Type 1 diabetes and multiple sclerosis (MS) are both autoimmune diseases, meaning a person's immune system causes damage to their own body.
Type 1 diabetes (sometimes called juvenile diabetes because it is usually diagnosed in childhood) is an autoimmune attack against the beta cells in the pancreas while, with multiple sclerosis, the immune system attacks the brain and spinal cord.
Recent research backed up previous studies which found that children and adolescents with diabetes face greater odds of getting MS. Investigators discovered that environmental factors, including when a person is born, may heighten this risk.
Susanne Bechtold, MD, in the Department of Pediatrics, Medical University Munich, Germany, and a team of researchers analyzed data on 56,653 children and adolescents with type 1 diabetes under the age of 21 from Germany and Austria.
The authors discovered 19 of these patients had MS.
Researchers compared MS prevalence rates from the Mid-European and German MS pediatric and adult registers with their data. They calculated an MS prevalence of 7 to 10 patients per 100,000 with type 1 diabetes, compared with 3 to 5 cases per 100,000 in a non-diabetes population.
The risk of the diabetes patients having MS was three to almost five times greater.
The investigators also cited three possible influencing factors that could be adding to the risk of developing MS—immigration status, thyroid antibodies (only in males) and month of birth.
There was a higher MS risk in patients with an immigrant background. The authors wrote "...we assume that variations in their genetic, environmental or cultural background caused this significantly increased risk to simultaneously develop type 1 diabetes and MS."
Male patients with thyroid specific antibodies also had a higher chance of developing MS. Thyroid antibodies are an immune response of the body, which is considered to be abnormal.
Also, researchers noted that among the diabetes-MS patients, dates of birth peaked in June and August.
Dr. Bechtold told dailyRx News, “We think that environmental factors might influence the immunological system, like by vitamin D level during early pregnancy. The theory regarding month of birth is that vitamin D has immune-modulating capacities.”
This study found that two-thirds of patients with type 1 diabetes and MS had a birth month consistent with the fetus having experienced lower levels of ultraviolet exposure during early pregnancy. Exposure to sunlight can be a source of vitamin D.
“Overall this is speculation and I am not aware on any study investigating the influence of different environmental factors in detail on the fetus,” said Dr. Bechtold.
The authors qualified their results, writing that the low number of MS patients did not reach statistical significance.
“In the next step, we are going to contact each of the 19 patients to get more detailed information of history, family history and immunological data,” Dr. Bechtold told dailyRx News. “Only with these hopefully more detailed knowledge we may give advice.”
The study was published online in September in Diabetes Care ahead of print.
Source: dailyRX © 2013 dailyRx, Inc (30/09/13)
OBJECTIVE: To evaluate the practical application of International Pediatrics Multiple Sclerosis study group definitions in children with inflammatory demyelination of the central nervous system and to identify predictors of multiple sclerosis.
METHODS:Baseline data on 123 children with a first episode of acute central nervous system demyelination were collected. The initial diagnosis according to the International Pediatrics Multiple Sclerosis study group was recorded and compared with final diagnosis.
RESULTS:Forty-seven (38.2%) children met International Pediatrics Multiple Sclerosis study group criteria for acute disseminated encephalomyelitis and 67 (54.4%) had clinically isolated syndrome at the initial presentation. Four (3.2%) had the diagnosis of neuromyelitis optica and five (4%) did not meet any specific diagnosis per the study group criteria. Clinical follow-up was available on 118 of 123 children (95.9%), with a median of 61.5 months (quartile range 23, 110 months). Conversion from clinically isolated syndrome to multiple sclerosis occurred in 26 of 67 children (38.8%); acute disseminated encephalomyelitis to multiple sclerosis occurred in 4 of 47 children (8.5%). Adjusted multivariate logistic regression analysis for an outcome of future development of multiple sclerosis showed the following predictors: female gender (odds ratio 12.44; 95% confidence interval 1.03-149.3); initial diagnosis of monofocal brain stem or hemispheric dysfunction (odds ratio 24.57; 95% confidence interval 3.06-196.78); and Callen magnetic resonance imaging criteria if met (odds ratio 122.45; 95% confidence interval 16.57-904.57).
CONCLUSION:International Pediatrics Multiple Sclerosis study group criteria affirm that children with initial clinically isolated syndrome are more likely to develop future multiple sclerosis compared with those with an acute disseminated encephalomyelitis initial diagnosis. In addition, female gender, brain stem or hemispheric involvement, and Callen magnetic resonance imaging criteria predict the diagnosis of multiple sclerosis.
Peche SS, Alshekhlee A, Kelly J, Lenox J, Mar S.A Long-Term Follow-Up Study Using IPMSSG Criteria in Children With CNS Demyelination.
Sources: Pediatr Neurol. 2013 Aug 27. doi:pii: S0887-8994(13)00401-3. 10.1016/j.pediatrneurol.2013.06.023& Pubmed PMID: 23993834 (04/09/13)
To compare relapse rates in paediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (AOMS) over the first 6-years of disease.
Patients with relapsing-remitting disease onset were identified from the Partners Pediatric MS Center, Massachusetts General Hospital and Partners MS Center, Brigham and Women's Hospital. 84 POMS and 258 AOMS patients were included. Annualized relapse rates (ARR) for each individual year from year 1 to year 6, after first attack were compared using Poisson regression, as was expanded disability status scale (EDSS) score at the visit closest to each year interval.
ARR was significantly higher in POMS compared to AOMS at individual years (except year 4), and was not significantly affected by adjustment for gender, race and proportion of time on treatment. Despite a 2.30 times higher relapse rate over 6-years, EDSS between groups did not differ. ARR in years 1–5 did not impact year 5 disability measured by EDSS in POMS.
Our findings demonstrate that higher ARR in POMS relative to AOMS is sustained over 6-years, suggesting a more inflammatory nature and potential disconnect between relapses and disability measured by EDSS early in POMS. This data may be useful when designing clinical trials for POMS.
L.A. Benson, B.C. Healy, M.P. Gorman, N.F. Baruch, T. Gholipour, A. Musallam, T. Chitnis. Source: Multiple Sclerosis and Related Disorders © 2013 Elsevier B.V. (25/07/13)