Early-onset Multiple Sclerosis Research Articles

Maternal smoking during pregnancy and multiple sclerosis amongst offspring

An association between parental smoking and multiple sclerosis (MS) in offspring has been reported. This study examined whether maternal smoking during pregnancy is associated with MS in offspring. Swedish general population registers provided prospectively recorded information on maternal smoking during pregnancy. The study identified 143 cases with MS diagnosed by 2006 and 1730 matched controls. Subjects were born since 1982 and individually matched by year of birth, age, sex and region of residence. Conditional logistic regression assessed the association of maternal smoking with MS in offspring with adjustment for socioeconomic index. Maternal smoking during pregnancy was not associated with MS in offspring, with an odds ratio (and 95% confidence interval) of 0.96 (0.65-1.44). When stratified by paediatric or later MS onset there was no association with maternal smoking in either stratum. It is unlikely that smoking during pregnancy represents a risk for early-onset MS amongst offspring.

Early-onset multiple sclerosis: clinical and evolutive features

Early-onset multiple sclerosis: clinical and evolutive features

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fcgamma receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the development of experimental autoimmune encephalomyelitis (EAE), an accepted animal model for multiple sclerosis (MS). The protection was associated with peripheral increase in CD4+CD25+Foxp3+ regulatory T cell (Treg) numbers and function. The protection was Treg-mediated because IVIg failed to protect against EAE in mice that were depleted of the Treg population. Rather than inducing de novo generation from conventional T cells, IVIg had a direct effect on proliferation of natural Treg. In conclusion, our results highlight a novel mechanism of action of IVIg and provide a rationale to test the use of IVIg as an immunomodulatory tool to enhance Treg in early onset MS and other autoimmune and inflammatory conditions.

A unique case of coincidence of early onset Parkinson's disease and multiple sclerosis

We report on a patient who developed left arm rest/postural tremor at age 24 and responded well to trihexyphenidyl. One year later spastic paraparesis appeared, and multiple sclerosis was diagnosed on the basis of clinical, radiological, and laboratory evidence. Although paraparesis improved after immunosuppressant therapy, a complete picture of an asymmetric parkinsonian syndrome gradually developed. Excellent response to levodopa, drug-induced dyskinesias, and DaTSCAN revealing pathology congruent with Parkinson's disease (PD) indicate a coincidental etiopathogenetic relationship of both clinical entities: multiple sclerosis and PD. Genetic analyses focusing on autosomal recessive parkinsonism (parkin, DJ1, and PINK1) were negative. To the best of our knowledge, only 15 cases of parkinsonism in association with multiple sclerosis have been reported, and their relationship has been interpreted to be either causal or coincidental. This is the first report of a coincidence of both entities, in which the parkinsonian syndrome developed first and before age 30.

Treatment of early-onset multiple sclerosis with intramuscular interferonβ-1a: long-term results

The objective was to evaluate the safety, tolerability and effectiveness of intramuscular (IM) interferon beta-1a (IFNbeta-1a; Avonex, Biogen) 30 mg once a week in patients with onset of symptoms of multiple sclerosis (MS) in childhood or adolescence. Patients with a diagnosis of definite MS according to McDonald's criteria, relapsing course according to Lublin's criteria, onset of symptoms of MS before 16 years of age, and who had received IM IFNbeta-1a therapy before 16 years of age were eligible for the study if they had a pretreatment and treatment duration of at least 6 months. Clinical and laboratory evaluations were performed every 3 months. A total of 52 patients were identified as receiving treatment with IM IFNbeta-1a 30 mg once a week before 16 years of age. Mean age at onset of symptoms of MS was 11.7+/-2.7 years, mean disease duration was 25.9+/-30.3 months, mean annualised relapse rate was 1.9+/-1.1 and mean Expanded Disability Status Scale (EDSS) score was 1.5+/-1.1. After a mean (+/-SD) treatment duration of 42.9+/-19.9 months, annualised relapse rate decreased to 0.4+/-0.5. Final EDSS score was 1.3+/-1.1. Adverse events were recorded for 35 (67%) patients (flulike syndrome, 33%; headache, 29%; myalgia, 21%; fever, 11%; fatigue, 6%; nausea and vomiting, 6%; and skin reaction, 4%); most were transient. IM IFNbeta-1a was effective and well tolerated in these paediatric patients with MS.

Childhood-onset multiple sclerosis: report of 82 patients from Isfahan, Iran.

Although multiple sclerosis is considered as an inflammatory demyelinating disease of young adults, nearly 3% of patients manifest it under the age of 16 years. The aim of this study was to highlight the clinical and demographic features of early-onset multiple sclerosis in Isfahan, Iran. This prospective study concerned multiple sclerosis patients in whom the disease started before the age of 16 years and who were referred to the only clinic of multiple sclerosis in Isfahan from October 1997 through February 2003. All early-onset multiple sclerosis patients underwent magnetic resonance imaging. Magnetic resonance imaging findings were analyzed according to the Barkhof's criteria. All early-onset multiple sclerosis patients were followed for a mean period of 4.7 years. Among 1,238 multiple sclerosis patients, 82 early-onset multiple sclerosis patients were identified. The female to male ratio was 4.5:1. The mean age of onset was 14.1 (range: 5 to 16) years. In 53 (65%) patients, the onset was monosymptomatic; in the remaining 29 (35%), it was polysymptomatic. Sixty-four (78%) patients presented a relapsing-remitting course, 14 (17%) had a secondary-progressive and 4 (5%) had a primary-progressive course. At the last evaluation, the expanded disability status scale score was > or =6 in only 8 (10%) patients. According to Barkhof's criteria, the characteristic magnetic resonance imaging findings were observed in 80 (98%) of early-onset multiple sclerosis patients. In our study, a high rate of childhood multiple sclerosis was observed that may be because of geographical or ethnic differences. Our study also showed that Barkhof's criteria, which is mostly used in adult patients, could be also applied to early-onset multiple sclerosis cases.

Pediatric Multiple Sclerosis

It is becoming ever more recognized that multiple sclerosis (MS) occurs in children and adolescents. Although early-onset MS is a variant in the spectrum of MS phenotypes, the diagnosis and management of MS in children poses a unique set of challenges for the clinician. Moreover, it is increasingly clear that these patients require specialized care, which includes a closely monitored medication program, physical therapy, cognitive and educational evaluation and intervention, and psychosocial support both for the patient and family. The goal of this article is to familiarize the clinician with the clinical and MRI features of pediatric multiple sclerosis and to summarize what is currently known about the clinical disease course. This article highlights important entities in the differential diagnosis of pediatric MS and discusses management strategies based on current literature. Children and adolescents with MS comprise a small but important subset of MS patients who require a multidisciplinary care approach. Additional multicenter studies are required to explore the effects of disease and treatments on physical, psychosocial, educational, and developmental parameters.

Treatment of Early Onset Multiple Sclerosis with Suboptimal Dose of Interferon Beta-1a

Patients with early onset multiple sclerosis may develop disability at a younger age than adults. There are several reports about safety of beta interferons in childhood and juvenile MS with different doses. To determine safety and efficacy of substandard dose of intramuscular interferon beta-1a in a prospective randomized trial in patients with multiple sclerosis under the age of 16. Sixteen patients were divided into two groups randomly. The first group was treated with intramuscular interferon beta-1a 15 micrograms once a week and the second group received no disease-modifying therapy. The patients were followed for four years. There was no significant side effect and none of the treated patients discontinued the drug. There were significant differences between two groups regarding relapse rates (p = 0.04), disability progression (p = 0.01), and new T2 lesions (p = 0.006). Treatment with interferon beta-1a is well tolerated for a long period of time and may be effective in substandard doses in early onset multiple sclerosis.

Early Onset Multiple Sclerosis: More Emphasis on Early Treatment

Multiple sclerosis (MS) is an immune-mediated neurodegenerative disorder of the human central nervous system (CNS) that typically affects young adults. This enigmatic and destructive disorder of both white matter and gray matter of CNS affects individuals with predisposing genetic background and probably requires a provoking environmental factor, such as exposure to a viral agent, to initiate the disease process [[1], [2], [3]]. In the United States, MS is the leading cause of neurological disability in young individuals. Clinically, MS most often follows a relapsing-remitting course during which patients experience various clinical symptoms, usually followed by periods of remission. The neuropathogenesis of MS consists of two parallel destructive arms: inflammatory demyelination and neurodegeneration. During the last two decades, we have learned much about both aspects of the pathogenesis of MS. This expansion of our knowledge had led to development of immunomodulatory agents for more effective management of this previously untreatable disease.

Comparison of the natural history and prognostic features of early onset and adult onset multiple sclerosis in Jordanian population

Objectives To assess the natural history and prognostic features of early onset multiple sclerosis (EOMS) and adult onset multiple sclerosis (AOMS) in Jordanian population. Patients and methods A retrospective analysis of 253 multiple sclerosis (MS) patients treated at the three major referral centers for MS in Jordan was performed. Twenty-six patients were excluded due to lack of follow up details. Patients under (or equal to) the age of 18 years were considered as EOMS. Clinical features of the two groups were compared and statistically analyzed. Time to reach expanded disability status score (EDSS) 3 and time to reach secondary progression were used as end points for survival analysis. Log-rank tests were performed and Kaplan–Meier survival curves were presented. Results About 44 (19.4%) patients had EOMS. The clinical characteristics of EOMS and AOMS were not significantly different. Most patients (about 88%) had relapsing remitting course. Monosymptomatic presentation was the predominant feature in both groups. Median time to reach EDSS 3 and median time to reach secondary progression were significantly longer in EOMS. Kaplan–Meier survival analysis did not show difference between the two groups. Higher EDSS score at diagnosis, shorter first inter-attack interval, and secondary progressive course were significantly unfavorable prognostic factors for both EOMS and AOMS. Conclusions The natural history and prognostic features of EOMS and AOMS are not significantly different in Jordanian population. Therefore, treatment strategies should be the same for the two groups.

Clinical characteristics and long term prognosis in early onset multiple sclerosis

The clinical features, disease course and long term prognosis of early onset multiple sclerosis (EOMS) are variable. A preponderance of female sex, a high incidence of visual and brainstem symptoms at onset and a relapsing-remitting disease course with slower progression rate all have been considered relatively frequent in this subgroup of MS patients. Unfortunately, follow-up in previous studies has usually been limited to less than 10 years, precluding general statements on the long term evolution and prognosis in EOMS. In this retrospective study of EOMS with a substantially longer follow-up of 20.8 years, clinical characteristics, disease course and long term prognosis are described in 49 EOMS patients. In a representative subgroup of 28 patients disability was scored using Kurtzke's Functional System (FS) and Expanded Disability Status Scale (EDSS). The mean period of follow- up for these patients was 28.7 years. The present study confirms that several specific clinical characteristics can be identified in EOMS patients, such as a mainly relapsing-remitting disease onset and frequent presentation with brainstem- cerebellar dysfunction (28.6 %), pyramidal symptoms (18.4 %) and optic neuritis (14.3%). However, after a long period of follow-up the overall disease course and prognosis do not seem to differ from that in adult onset MS. By consequence a young age at onset in MS cannot be considered a favourable prognostic factor.

MRI quantification of gray and white matter damage in patients with early–onset multiple sclerosis

Contrary to what happens in adult-onset multiple sclerosis (MS), in a previous preliminary magnetic resonance imaging (MRI) study we showed only subtle normal-appearing brain tissue changes in patients with earlyonset MS. Our objective was to evaluate the presence and extent of tissue damage in the brain normalappearing white matter (NAWM) and gray matter (GM) from a larger population of patients with earlyonset MS. Using diffusion tensor (DT) and magnetization transfer (MT) MRI, we obtained DT and MT ratio (MTR) maps of the NAWM and GM from 23 patients with early-onset MS and 16 sex- and age-matched healthy volunteers. Compared with healthy volunteers, patients with early-onset MS had significantly increased average MD (p = 0.02) and FA peak height (p = 0.007) and decreased average FA (p <0.0001) of the NAWM. Brain dual-echo lesion load was significantly correlated with average FA (r = -0.48, p = 0.02) and with FA peak height (r = 0.45, p = 0.03) of the NAWM. No MTR and diffusion changes were detected in the GM. This study confirms the paucity of the 'occult' brain tissue damage in patients with earlyonset MS. It also suggests that in these patients GM is spared by the disease process and that NAWM changes are likely to be secondary to Wallerian degeneration of fibers passing through macroscopic lesions.

Immunomodulatory treatment of early onset multiple sclerosis: results of an Italian Co-operative Study

The ITEM study group was organised in Italy to evaluate the effectiveness and safety of interferon-beta (IFNbeta) and glatiramer acetate (GA) in multiple sclerosis (MS) patients treated before 16 years of age. Eighty-six patients (58 females) were included in our database: as subjects with pre- and treatment duration <3 months were excluded, the data of 81 subjects were analysed: 51 were treated with IFNbeta-1a 6 million once weekly (Avonex), 19 with IFNbeta three times weekly (16 with Rebif, 3 with Betaferon) and 11 with GA (Copaxone). The mean age at onset was 12.4 (SD 2.4) years and the mean pre-treatment duration was 19.7 (SD 25.5) months. After a treatment duration of 36.1 (SD 24.2) months, the mean annualised relapse rate decreased from 2.8 (SD 2.6) to 0.5 (SD 0.7). The EDSS score remained unchanged (basal=1.4, final=1,4). Clinical side effects were recorded in 46 subjects of the IFNB group, transient in 35 (flu-like syndrome in 24, headache in 12, myalgia in 10, injection reaction in 5, fever in 3) and persistent in 11 (headache in 5, fever in 4, flu-like syndrome in 3, myalgia in 3, injection reaction in 1). In the GA-treated group, side effects were recorded in 3 cases: injection reaction in 2 and transient chest pain in 1. Abnormal laboratory findings (mainly reduction of WBC) were observed in 24 subjects (transient in 22). Nine subjects treated with Avonex discontinued the treatment: 7 shifted to Rebif, 2 stopped the therapy. Four subjects treated with INFbeta three times weekly shifted to other medications and 2 increased the dose. Four subjects treated with GA discontinued the treatment: 3 shifted to other medications and 1 stopped GA because of injection reaction. On the whole, 3 cases stopped the treatment definitively. To conclude 81, clinically definite MS subjects were treated during childhood or adolescence with immunomodulatory drugs. The treatment was generally well tolerated. It reduced the relapse rate and the progression of the disease in most cases.

Disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an Italian co-operative study

Immunomodulatory drugs (IDs) (interferon beta (IFNgamma) and glatiramer acetate (GA)) reduce relapse rate and disease progression in relapsing remitting multiple sclerosis (RRMS) but extensive data are not available on the effectiveness and tolerability of these drugs in childhood or adolescence. The aim of this study was to evaluate the impact of IFNbeta and GA in MS patients treated before 16 years of age. A research group (Immunomodulatory Treatment of Early onset MS (ITEMS)) was promoted in Italy to collect a large series of patients affected by clinically definite and RRMS and treated with IDs before 16 years of age. Fifteen centres recognized subjects suitable for inclusion: 76 patients (52 females) were collected with a mean age at onset of 12.4 (SD 2.5) years, a mean disease duration of 18.6 (SD 14.7) and a relapse rate of 3.1 (SD 2.9). Results were evaluated in 65 (45 females) subjects with a pretreatment and a treatment duration >3 months: 38 were treated with IFNbeta-1a once weekly (Avonex), 18 with IFNbeta three times weekly (16 with Rebif, 2 with Betaferon) and nine with GA (Copaxone). The mean pretreatment period was respectively 20, 18 and 9.2 months. The treatment duration lasted respectively 23.3, 40.7 and 33.3 months. The mean annualized relapse rate decreased dramatically during the treatment: from 2.4 to 0.4 in the Avonex group, from 3.2 to 0.8 in the Rebif-Betaferon group and from 2.8 to 0.25 in the GA group. The mean final EDSS scores were respectively (in brackets the initial scores): 1.3 (1.4), 1.6 (1.8) and 0.6 (1.1). In the whole group, the final score was unchanged or reduced in all subjects except eight. Clinical side effects were recorded in 41/65 subjects (mainly in subjects treated with IFNbeta), abnormal laboratory findings were observed in 13/65 subjects: they were transient in most cases. IFNgamma was stopped in six cases: in four because of inefficacy and in two cases because of side effects. Sixty-five clinically definite MS subjects were treated during childhood or adolescence with IDs. The treatment reduced the relapse rate and the progression of the disease in most cases. Side effects were common in subjects treated with IFNbeta but were well tolerated in most cases.

Association of Epstein-Barr virus (EBV) infection with multiple sclerosis in pediatric patients

Objective: Epidemiological studies suggest an association between Epstein-Barr virus (EBV) infections and risk of multiple sclerosis (MS)in adults. As children and adolescents had limited contacts to infectious agents in previous life, individuals with early-onset MS are optimal candidates for examining microorganism as co-factors for the development of MS. Aim of our study was to determine the EBV-serostatus in children and adolescents with early-onset MS in comparison to the serostatus of other herpesviruses.

Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a

The authors studied the tolerability of subcutaneous interferon beta-1a (IFNbeta-1a) in 51 patients with early-onset multiple sclerosis. The most frequent systemic adverse effects were flu-like symptoms in 65%. Laboratory abnormalities included asymptomatic leukopenia (27%) and elevated hepatic transaminases (35%). Treatment with IFNbeta-1a was safe and well tolerated in the majority of children and adolescents.

CSF characteristics in early-onset multiple sclerosis

The authors studied CSF characteristics in 136 patients with multiple sclerosis (MS) with a disease onset before age 16. In the initial diagnostic lumbar puncture, CSF-pleocytosis was observed in 66%, blood-CSF barrier dysfunction in 13%, and oligoclonal IgG in 92% of the early-onset MS (EOMS) patients. CSF oligoclonal IgG supports the early diagnosis of MS in childhood with a sensitivity similar to adult-onset MS.

Italian studies on early-onset multiple sclerosis: the present and the future

Italian studies on early-onset multiple sclerosis: the present and the future

Diffusion tensor and magnetization transfer MR imaging of early-onset multiple sclerosis

Multiple sclerosis (MS) is a chronic, demyelinating disease of the central nervous system (CNS) with the onset of symptoms typically occurring between the age of 20 and 40 years. However, in about 3% to 12% of the cases, the onset of the disease is before 16 years of age. This review summarizes the main results obtained by the application of conventional and non-conventional MRI techniques to the assessment of patients with early-onset MS, which showed that the overall amount of CNS damage in these subjects is mild, compared to that typically detected in the adult-form of the disease. This fits with the notion that an early onset of the disease is associated with a more favourable clinical evolution.

Natural History of Early Onset Multiple Sclerosis

The clinical course of multiple sclerosis (MS) in 116 patients with onset before age 16 (prevalence 3.6% in total MS clinic attendees) was evaluated by longitudinal study (mean duration 19.76 +/- 0.9 years) at the University of British Columbia MS Clinic.