Early-onset Multiple Sclerosis Research Articles

Multiple sclerosis starting before the age of 18 years: the Brazilian experience

Multiple sclerosis (MS) starting in childhood and adolescence poses a challenge for diagnosis and management of the disease. The aim of the present study was to assess the characteristics of early onset MS in Brazilian patients. Methods Retrospective data collection from specialized MS units. Results From 20 MS units in 11 Brazilian states, 117 cases of MS starting before the age of 18 years were collected. These patients had an average of 10 years of disease duration, still typically with low disability and one relapse every 2.5 years. The mean age for disease onset was 13.7 years. Conclusion The present study introduces a large series of Brazilian cases of pediatric MS. Although some patients presented a very severe form of MS, on the whole the group of patients with MS starting in childhood or adolescence presented a relatively mild form of this disease in Brazil.

Multiple sclerosis: association with the interleukin-1 gene family polymorphisms in the Turkish population

Background: Multiple Sclerosis (MS) is a neurodegenerative disease. It involves inflammation and demyelination. Since cytokines play an important role in the development of MS, genes encoding cytokines such as the Interleukin (IL)-1 family are candidate genes for MS susceptibility. Objective: To determine the relationship between IL-1 gene family and MS in the Turkish population. Methods: A total of 409 MS patients and 256 healthy controls were included in the study. IL-1A −889 (rs1800587), IL-1 RN variable number tandom repeat (VNTR), IL-1B −511 (rs 16944) and IL-1B +3953 (rs 1143634) polymorphisms were investigated from the genomic DNA, obtained via blood samples. Results: No association was found between IL-1A and IL-1RN polymorphisms and susceptibility to MS. However, we have found significantly decreased frequency of IL-1B −511 genotype (p = 0.004) in MS patients compared to controls. In addition, there was a significant association between IL-1B −511 (1/2) genotype and early onset MS (EOMS) (p = 0.0001). Conclusions: Individuals with the 2/2 genotype of IL-1B −511 have significantly decreased incidence of MS, suggesting a protective role for this genotype in the Turkish population. Additionally, IL-1B −511 (1/2) genotype was determined as a possible risk factor for EOMS.

HLA-DRB1* Allele Frequencies in Pediatric, Adolescent and Adult-Onset Multiple Sclerosis Patients, in a Hellenic Sample. Evidence for New and Established Associations

Studies in many populations consistently have showed that the human leukocyte antigens (HLA) and especially the DRB1*15 allele has by far the strongest genetic association with multiple sclerosis (MS). The aim of this study was to investigate the role of HLA-DRB1* alleles in MS risk/resistance and onset. A sample of 165 Hellenic MS patients (18 with pediatric-, 24 with adolescent- and 123 with adult-onset MS) and 107 healthy volunteers were examined with molecular techniques. Comparisons were made according to the Benjamini-Yekutieli method for p value correction. Both adult-onset MS patients and early-onset MS patients (age at onset below 20 years-old) had a significantly higher frequency of the DRB1*15 allele and a significantly lower frequency of the DRB1*11 allele compared to controls. For the early-onset vs. healthy group comparison, subgroup analyses revealed that both the pediatric- and the adolescent-onset MS groups contributed to the aforementioned DRB1*15 significant difference, while the DRB1*11 difference was ascribed solely to the adolescent-MS onset vs. healthy group comparison. Within MS patients comparisons revealed that early-onset MS patients had a tendency for higher DRB1*03 allele and a lower DRB1*16 allele frequency frequencies compared to adult-onset MS patients, although both non-significant. Notably, pediatric-onset MS patients showed complete absence of the DRB1*16 allele, along with a non-significant tendency for higher DRB1*15 allele frequency relative to the adult-onset group. Finally, the adolescent-onset MS group was presented with a lower DRB1*11 allele frequencies compared both to the pediatric- and the adult-onset MS group. Our findings confirm previous studies on the role of HLA-DRB1* in MS. New findings that need to be confirmed by further studies are the pathogenetic role of DRB1*03 for early-onset MS and the putative protective role of the DRB1*16 allele in the pediatric-onset MS.

Copy number variation in pediatric multiple sclerosis

Background: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. Objectives and methods: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. Results and discussion: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. Conclusions: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient’s disease course and prognosis.

The Combined Effect of Nursing Support and Adverse Event Mitigation on Adherence to Interferon Beta-1b Therapy in Early Multiple Sclerosis

There is limited clinical evidence on the impact of nurse support and adverse event (AE) mitigation techniques on adherence to interferon beta-1b (IFNβ-1b) therapy in multiple sclerosis (MS) in a real-world setting. The aim of the Success of Titration, analgesics, and BETA nurse support on Acceptance Rates in MS Treatment (START) trial was to assess the combined effect of titration, analgesics, and BETA (Betaseron Education, Training, Assistance) nurse support on adherence to IFNβ-1b therapy in patients with early-onset MS and to evaluate safety. Participants were instructed to titrate IFNβ-1b and use analgesics to minimize flu-like symptoms. All received BETA nurse follow-up at frequent intervals: live training, two telephone calls during the first month of therapy, and monthly calls thereafter. Participants were considered adherent if they took at least 75% of the total prescribed doses over 12 months (≥75% compliance). Safety was monitored via reported AEs and laboratory test results. Participants who took at least one IFNβ-1b dose over 12 months were analyzed (N = 104); 73.8% of participants completed the study. The mean age of participants was 37.2 years; 72.1% were women and 78.8% were white. Ninety participants had relapsing-remitting MS and 14 had clinically isolated syndrome. The mean compliance rate, reported for 96 participants with complete dose interruption records, was 84.4%. At 12 months, 78.1% of participants were considered adherent. The serious adverse event rate was 9.6%; most events were unrelated to therapy. Thus in the START study, in which participants received nursing support combined with dose titration and use of analgesics, the majority of participants were adherent to therapy.

Epileptic seizures in early-onset multiple sclerosis.

Early-onset multiple sclerosis (EOMS) is defined as the first presentation of symptoms in childhood (before the age of 16 years). EOMS occurs in about 0.4% to 10.5% of multiple sclerosis (MS) patients. In this retrospective population-based study we aimed to describe the clinical/paraclinical details and frequency of epileptic seizures in Iranian EOMS patients registered with the Isfahan Multiple Sclerosis Society (IMSS) from April 2003 to July 2010. EOMS cases were extracted from the Isfahan total MS cohort and included 3522 patients. A total of 117 EOMS patients (19 males and 98 females) with a mean age at onset of 14.2 ± 2.0 years (range: 7-16 years) were extracted from our database (3.3% of the total cohort). Of cases, ten (one male and nine females) had experienced at least two epileptic seizures, providing a crude prevalence of 8.5%. The frequency of epilepsy in EOMS patients (8.5%, 10/117) was significantly greater (P < 0.001) than that of non-EOMS cohort (2.0%, 71/3405). Epileptic seizures occurred before MS onset in two patients, after MS onset in seven, and at MS onset in one as the presenting symptom of the disease. Our findings mostly indicate an excessive prevalence of epileptic seizures in Iranian EOMS patients (8.5%), which is higher than any other report concerning seizures or epileptic seizures in a large MS series.

Characterizing Disability in Early Onset MS Patients: Correlation of Clinical Parameters with Retinal Nerve Fibre Layer Thickness (P01.165)

Characterizing Disability in Early Onset MS Patients: Correlation of Clinical Parameters with Retinal Nerve Fibre Layer Thickness (P01.165)

Clinical prognostic factors after the first attack of early onset multiple sclerosis in iraq

Background: Paediatric-onset multiple sclerosis (MS) has been a focus of great interest in recent years. The prognostic factors in early onset of MS have been evaluated in few studies with various methodologic approaches, and the discussion about the existence of clinical courses different from that of adult-onset MS is still open.

Early Onset Multiple Sclerosis Has Worse Prognosis Than Adult Onset Multiple Sclerosis Based on Cognition and Magnetic Resonance Imaging

Objectives. In the present study, we aimed to compare the childhood and adult onset multiple sclerosis patients prospectively in their adulthood on the basis of clinical and magnetic resonance imaging (MRI) findings and cognitive impairment, which have not been performed before. Patients and Methods. Forty-six patients in whom the disease onset occurred before 16 years of age were included in the present study. Study subjects were compared with 64 randomly included adult onset patients. Results. Mean disease duration, clinical course, and female to male ratio did not differ in the groups. Cerebellar/brainstem and spinal involvement at onset were significantly higher in EOMS than in AOMS. Difference in MSFC between baseline and at the end of the 5th year was significantly worse in EOMS population (P = 0.02). The most significant difference was found in Paced Auditory Serial Addition Test (PASAT) (P = 0.008). Differences between baseline and at the end of the 5th year on the basis of T1 hypointense lesions were significantly higher in early onset MS than in adult onset MS patients (P = 0.02). Conclusions. Early onset MS seems to have worse prognosis than that of adult onset MS on the basis of clinical manifestation, cognitive impairment, and MRI parameters.

Muscular and Gait Abnormalities in Persons With Early Onset Multiple Sclerosis

Muscular and gait abnormalities are common complaints among persons with multiple sclerosis, even in the early stages of the disease. Our aim was to evaluate peak isometric strength, major lower limb muscle fatigue, and spatiotemporal gait parameters in persons with a first neurological event suggestive of multiple sclerosis, defined as a clinically isolated syndrome (CIS). Fifty-two individuals (36 women, 16 men) with CIS, aged 35.2 (SD = 7.2) with an Expanded Disability Status Scale score of 1.7 (SD = 1.3), participated in the study. Peak isometric torque and fatigue index were measured at the knee and ankle bilaterally as well spatiotemporal parameters of gait. Twenty-eight age- and gender-matched healthy subjects served as controls. The CIS group demonstrated increased muscle fatigue, and greater ankle muscle torque asymmetries compared with the control group. The overall fatigue index scores intensified on an average of 40% in the CIS group (27% vs 19% in controls). Participants in the CIS group walked with a larger step length difference, longer step time difference, wider base of support, and prolonged double support period compared with the control group. Positive correlations were identified between double support period and some muscle parameters. At this early stage of clinically isolated syndrome, evidence of a reduction in lower limb motor performance can already be identified. The possibility of early identification and potential for developing an intervention program that may alter treatment outcome warrants further exploration.

The course of early-onset multiple sclerosis in Iraqi children

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system that is increasingly recognized worldwide in children and adolescents. The current study aimed at identifying the clinical characteristics of MS with onset under 18 years of age. This cross-sectional study was conducted in the Multiple Sclerosis Center archive system in Baghdad Teaching Hospital during the period from March 1 to May 15, 2008. The records of 1125 MS patients from 2000 to 2008 were reviewed. Among them 77 patients had the onset of MS under 18 years of age. Two thirds of the patients were female (a female/male ratio of 1.6:1). The mean age of the patients at the onset of the disease was 14.95 ± 3.21 years, and the mean time between the first and second attacks was 3.06 ± 4.09 years. Seventy patients (90.9%) had an initial course of relapse remitting MS. Among them 9 (12.9%) progressed to secondary progressive MS after a mean duration of 9.87 ± 4.14 years. The remaining 7 patients had primary progressive MS associated with optic neuritis and brain stem lesion. Fifty-nine (76.6%) patients had monofocal signs and 18 (23.4%) had polyfocal signs. The mean extended disability status scale score was 4.15 ± 2.17 and the mean progression index was 1.44 ± 2.31. There was a strong inversed correlation between the progression index and interval between the first and second attacks (P=0.0001). The results of the present study show that the course of MS in Iraqi children and adolescents is more aggressive than in children from other countries. This finding needs to be evaluated by further studies.

Early Onset Multiple Sclerosis: A Review for Nurse Practitioners

Research demonstrates that 3.5% to 5% of persons with multiple sclerosis (MS) present before the age of 18 years. MS can present in early childhood through adolescence and must be considered as a differential diagnosis in patients with motor impairment, sensory changes, and cognitive disability. The diagnosis of early-onset MS is based on findings from a complete history and physical examination along with brain and spine imaging. The purpose of this article is to review recent literature on early-onset MS and offer suggestions or clinical practice in the identification and management of patients with this debilitating disease.

Aetiology of multiple sclerosis

When patients are given the news that they have a serious and debilitating condition, one of the questions they ask is ‘what caused this, why me?’ In the case of multiple sclerosis (MS) we can say that while we know that for some patients genetic factors certainly play a role, for many we can only offer broad explanations that allude to multifactorial environmental issues in susceptible individuals. The incidence of MS is increasing worldwide but especially so in the UK; females are more likely to develop the disease. HLA-DR15 serotype confers a significantly higher risk of early onset MS (as well as a variety of other auto-immune conditions) and this may help to explain geographical variation in incidence. However, genetic predisposition cannot by itself be responsible for every case of MS. As with other chronic diseases where auto-immune factors are relevant, it is thought that a double hit hypothesis allows an environmental stimulus to initiate the disease process in individuals with a genetic predisposition. This is the subject of the review by Young which considers some of the environmental factors that have …

Commentary on Immune System Associated Diseases Caused by Viruses: The Role of EBV

In her review using the human Epstein–Barr virus (EBV) as an example, Dr. Chen intends to illustrate how host immune systems have evolved in response to pathogens or in many cases co-evolved with pathogens. She discusses why EBV in most people causes what appears to be a self-limiting lymphoproliferative disease (or is it? See her discussion of autoimmune diseases and EBV), but in a very small proportion of individuals the virus causes malignant diseases of severe consequence. She reviews some of the plausible explanations that may include interactions of environmental and host genetic factors resulting in EBV associated malignancies. She points out that EBV may not merely transform B cells, but it could also impact the host immune system on a much more global basis than previously realized. She also suggests that EBV associated diseases, in lieu of reflecting the pathogenic potential of the virus, are actually a reflection of the genetic predisposition of certain populations to the modulate immune system inappropriately in response to the virus infection. She supports this notion by detailing the abnormal modulation of NKT cells when the host is infected with EBV. For example, she cites a study that shows that the frequencies of regulatory CD8 + NKT, but not CD4 + NKT cells, in EBV associated Burkitt's lymphoma (BL) and nasopharyngeal carcinoma (NPC) patients are much lower than CD8 + NKT levels in healthy EBV carriers (Yuling et al., 2009), concluding that a skewed NKT cell response might modify the pathogenesis caused by the virus. She also supports her supposition that EBV pathogenesis is likely due to improper immune modulation in response to the infection by reviewing the data associating autoimmune diseases with EBV infections, especially focusing on multiple sclerosis (MS). She cites a study by Serafini et al. (2007) in which it was found that that almost 100% of the early onset MS cases with the secondary progressive phase contain dysregulated EBV infected plasma cells in MS brains. She also reviews other studies that describe atypical responses of MS patients who have been exposed to EBV. Nevertheless, the cause and effect link, EBV to MS, is still tenuous, yet intriguing. She concludes that the malignancies associated with EBV infection and especially the autoimmune diseases associated with EBV infection may result from human genetic variations that cause the host to differentially modulate the immune response to EBV infection to the detriment of the host.

Multiple Sclerosis in Iran: A Demographic Study of 8,000 Patients and Changes over Time

Background: Iran was formerly considered to be located in a low prevalence zone for multiple sclerosis (MS). During the last decade the number of patients has increased. This study was conducted to estimate the prevalence of MS in the capital city of the country. Methods: We re-evaluated the files of all patients who had registered at the Iranian Multiple Sclerosis Society during a 10-year period. Results: 8,146 patients (72.3% female, 27.7% male) with a female-to-male ratio of 2.60 had registered. Mean age of disease onset was 27.24 (SD: 8.32). A relapsing-remitting pattern was recognized in 84.9% of the patients. The number of new registrations tripled from 2002 to 2008 and the female-to-male ratio increased from 2 to 3.12. The prevalence of MS in Tehran is estimated to be at least 51.9 per 100,000. Visual impairment was the main presenting symptom. Conclusions: It seems that the prevalence of MS has increased to a medium-to-high risk level in Iran. The mean age of onset was similar to other studies but the calculated prevalence of early onset MS was increased. The cumulative data indicates that the female-to-male ratio is increasing annually.

Clinical profile and HLA-DRB1 genotype of late onset multiple sclerosis in Western Australia

We aimed to characterize the clinical profile and human leukocyte antigen (HLA)-DRB1 genotype of patients with late onset multiple sclerosis (LOMS) in Western Australia. The clinical features, laboratory studies and HLA-DRB1 alleles were analysed in patients with multiple sclerosis (MS) with onset over 50 years of age and compared with 100 patients with early onset MS (EOMS). Of a cohort of 829 patients with MS, 73 (8.8%) presented at over 50 years of age, including 14 (1.7%) over 60 years. Patients with LOMS had a lower female to male ratio, more frequent initial motor dysfunction, less frequent sensory symptoms and optic neuritis, a more frequent primary-progressive course and shorter time to reach Extended Disability Status Scale (EDSS) scores of 3.0 and 6.0. More LOMS patients were initially misdiagnosed compared to patients with EOMS. HLA-DRB1∗1501 was strongly associated with both LOMS and EOMS compared to the Control subjects, while HLA-DRB1∗0801 was over-represented in patients with LOMS. We concluded that patients with LOMS have a different clinical profile when compared to those with EOMS. Carriers of HLA-DRB1∗0801 may be more prone to develop MS at a later age.

A comparative assessment of cerebral white matter by magnetization transfer imaging in early- and adult-onset multiple sclerosis patients matched for disease duration

A more favorable clinical course in early-onset (EO) multiple sclerosis (MS) than adult-onset (AO) disease is reported. Our aim was to assess white matter with/without lesions by magnetization transfer (MT) imaging in EO and AO MS patients matched for duration of the disease. Relapsing-remitting MS patients with disease onset at age < or =18 years and >18 years (n = 11 for each) were matched according to sex, age, disease duration, and 22 sex-and age-matched healthy subjects were studied with MT imaging. MT ratios (MTR) of manually outlined ROIs from T1-hypointense, T1-isointense lesions and perilesional normal appearing white matter (NAWM) as well as NAWM of the left frontal lobe of the patients and healthy subjects were calculated. MTR differences between two patient groups and control subjects, and correlation of MTR with EDSS, disease onset age, disease duration and relapse rate were analyzed statistically. In comparison with NAWM of the patients and healthy subjects, the greatest MTR reductions were observed in T1-hypointense lesions followed by T1-isointense lesions and perilesional NAWM, respectively, in EO and AO MS. Both groups' NAWM MTR were reduced; greater and more significantly in EO patients. No correlation was found between MTR of any ROI and EDSS, duration of the disease, disease onset age, or relapse rate. Although normalization does not occur, abnormality of white matter in MS decreases as distance from the lesions increases. Greater NAWM abnormality in EO MS may relate to inherent myelin abnormalities and different repair/reorganization processes in this particular group.

Early onset multiple sclerosis: The role of gender

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), predominantly affecting young females. A review of the role of gender and early age of onset of this disease will be presented. MS can be difficult to differentiate from other demyelinating diseases when it presents before the adult age, particularly from acute disseminated encephalomyelitis (ADEM). Several working definitions and diagnostic criteria have been proposed to differentiate pediatric MS from ADEM. A male predominance seems to occur in the latter, whereas a female predominance is seen in MS patients from puberty; however, a 1:1 ratio has been observed before the age of 12. Neuromyelitis optica (NMO) in children and adolescents shows a clear female predominance. Some cohort studies have suggested that in the last decades, MS tends to initiate at an older age and that the female:male ratio is increasing. Sex hormones may have immunologic implications, but more data are needed to explain the female predominance and its changes over time.

Assessment of Citrullinated Myelin by1H-MR Spectroscopy in Early-Onset Multiple Sclerosis

Myelin instability and citrullinated myelin basic protein have been demonstrated in the brains of patients with chronic and fulminating forms of multiple sclerosis (MS). Our aim was to trace citrulline in the brains of patients with early-onset MS by using proton MR spectroscopy ((1)H-MR spectroscopy). A short-echo single-voxel (1)H-MR spectroscopy by using the point-resolved proton spectroscopy sequence was performed in 27 patients with MS and 23 healthy subjects. Voxels of interest were chronic demyelinating lesions (CDLs, n = 25) and normal-appearing white matter (NAWM, n = 25) on T2-weighted imaging, and when available in patients with MS, enhancing demyelinating lesions (EDLs, n = 8). Frontal white matter (WM) was studied in control subjects. N-acetylaspartate, choline, and myo-inositol (mIns)-creatine (Cr) ratios and the presence of a citrulline peak were noted. Citrulline peaks were more frequently observed in patients with MS than in control subjects (P = .035), located in the NAWM in 8/25 (32%), in CDLs in 7/25 (28%), and in EDLs of 1/8 (12.5%) patients with MS. The presence of citrulline and measured metabolite/Cr ratios was not related to age at imaging, age at disease onset, duration of disease, or number of relapses. There was no significant metabolic difference between the NAWM of patients with MS and the WM of the control subjects. mIns/Cr was significantly greater in CDLs compared with the NAWM of patients with MS and the WM of healthy subjects. Citrulline was more frequently identified in the brains of patients with early-onset MS than in healthy subjects by (1)H-MR spectroscopy, suggesting an association of increased citrullination of myelin proteins with demyelinating diseases.

Multiple Sclerosis in Childhood: Clinical and Radiological Features

We analyzed the medical records and cerebral imaging of 30 children with early onset multiple sclerosis to compare the clinical and neuro-radiological features with acute demyelinating encephalomyelitis and adult multiple sclerosis. The female:male ratio was 1.3 before the age of 12 years and increased to 4.3 after age 12 years. Optic neuritis and pyramidal dysfunction were the most common presenting clinical features. The most common radiological features at first imaging were periventricular (77.2%), corpus callosal demyelination (63.6%), gadolinium enhancement (62.5%), and Dawson's fingers (40.9%). The median relapse rate per patient year was 1.2 ([IQR] 0.6-2.0). Seven patients reached a moderate Expanded-Disability-Status-Scale score of 3 and 3 patients were more severely affected (score of 6). Expanded-Disability-Status-Scale score increased by 0.7 for every relapse. Ten patients were commenced on immunomodulatory therapy (Interferon beta 1a, n = 9; Interferon beta 1b, n = 3; or Glatiramer acetate, n = 1), the majority of who had minimal side effects and a reduction in relapse rate.