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 </=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.

Coronaviruses infect many species of animal including humans, causing acute and chronic diseases of many organ systems. Murine coronavirus, mouse hepatitis virus (MHV) infection of the mouse, provides animal models for the study of central nervous system disease, including encephalitis and demyelinating diseases such as Multiple Sclerosis and for hepatitis. While there are many studies of the adaptive immune response to MHV, there has until recently been scant information on the type I interferon (IFN) response to MHV. The relationship between MHV and the IFN-alpha/beta response is paradoxical. While the type I IFN response is a crucial aspect of host defense against MHV in its natural host, there is little if any induction of IFN following infection of mouse fibroblast cell lines in vitro. Furthermore, MHV is relatively resistant to the antiviral effects of IFN-alpha/beta in mouse fibroblast cell lines and in human 293T cells. MHV can, under some circumstances, compromise the antiviral effects of IFN signaling. The nucleocapsid protein as well as the nsp1 and nsp3 proteins of MHV has been reported to have IFN antagonist activity. However, in primary cell types such as plasmacytoid dendritic cells (pDC) and macrophages, IFN is induced by MHV infection and an antiviral state is established. Other primary cell types such as neurons, astrocytes and hepatocytes fail to produce IFN following infection and, in vivo, likely depend on IFN produced by pDCs and macrophages for protection from MHV. Thus MHV induction of IFN-alpha/beta and the ability to induce an antiviral state in response to interferon is extremely cell type dependent. IFN induced protection from MHV pathogenesis likely requires the orchestrated activities of several cell types, however, the cell types involved in limiting MHV replication may be different in the liver and in the immune privileged CNS.

CLEC16A, a putative immunoreceptor, was recently established as a susceptibility locus for type I diabetes and multiple sclerosis. Subsequently, associations between CLEC16A and rheumatoid arthritis (RA), Addison's disease and Crohn's disease have been reported. A large comprehensive and independent investigation of CLEC16A variation in RA was pursued. This study tested 251 CLEC16A single-nucleotide polymorphisms in 2542 RA cases (85% anti-cyclic citrullinated peptide (anti-CCP) positive) and 2210 controls (N=4752). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for significant association between CLEC16A variation and RA was observed. This is the first study to fully characterize common genetic variation in CLEC16A including assessment of haplotypes and gender-specific effects. The previously reported association between RA and rs6498169 was not replicated. Results show that CLEC16A does not have a prominent function in susceptibility to anti-CCP-positive RA.Genes and Immunity advance online publication, 11 March 2010; doi:10.1038/gene.2010.7.

Multiple sclerosis (MS) is a common neurological disease, estimated to affect 100,000 people in the UK. Bowel symptoms are reported to be common in MS, with constipation affecting 29-43% and faecal incontinence affecting just over 50%. Both have an impact on quality of life. Very little is known about how people with MS manage their bowels and the effectiveness of different interventions. We conducted a 2-part survey of people with MS and bowel problems. MS Society members were invited to participate in an online survey: 155 replied. 47 people additionally filled in a more detailed postal questionnaire. In this self-selected sample, 34% spend more than 30 minutes a day managing their bowel. Managing bowel function was rated as having an impact equal to mobility difficulties on quality of life. Respondents used a wide range of strategies to manage their bowel but few were rated as very helpful. There is a need for high quality research on all aspects of managing bowel dysfunction in MS in order to improve patients' quality of life.

Background People are not expected to die from multiple sclerosis although, as the condition progresses over a period of time, some people become increasingly disabled and will require assistance with all activities of daily living. Their partners invariably carry out these tasks. Objective To gain a deeper understanding of the experiences of the partner living with and caring for a spouse disabled by multiple sclerosis. Methodology In a qualitative study, eight partners who live and care for a person with multiple sclerosis were interviewed using a semi-structured questionnaire to explore their experience of their role. Results The interview transcripts were analyzed using a thematic framework approach. Codes, themes and five categories were identified, which were worry, planning, frustrations, commitment to marriage and coping strategies. These categories were examined using quotes from the transcripts as evidence. Conclusion This qualitative study identified that these couples had been married for at least 20 years before disability of the spouse significantly affected their lifestyle. Partners felt obliged to continue in their caring role due to a sense of duty and commitment of marriage. Partners felt a sense of loss as they prioritized the health and needs of their spouse above their own and, finally, partners lost their identity as husband/wife as they were called 'the carer'. Partners felt out of control due to the unpredictable and progressive nature of MS and because it consumed their life 24 hours every day. Partners often felt guilty at not being satisfied with their life and wanting some independence.

The increase in the prevalence of long-term conditions (LTCs) represents a growing challenge to healthcare systems worldwide, with LTCs now accounting for more than half of the global disease burden. The World Health Organisation (WHO) predicts that LTCs will become the main worldwide cause of death and disability by the year 2020. More than 3 in 10 people in England suffer from at least one LTC. Long-term conditions are illnesses such as diabetes, asthma, heart failure, dementia, schizophrenia, rheumatoid arthritis, COPD, asthma, multiple sclerosis and motor neurone diseases.

BACKGROUND:: Pediatric multiple sclerosis (MS), once considered a rare childhood illness, has been increasingly identified as an important childhood acquired neurologic disease requiring early recognition and intervention. SUMMARY:: We present a comprehensive review of the current terminology of acquired central nervous system demyelination in children, pertinent investigations, including magnetic resonance imaging and cerebrospinal fluid cerebrospinal fluid studies, and an approach to the differential diagnosis of pediatric onset MS. In addition, the recent studies exploring the epidemiology and pathobiology will be discussed. Finally, we present an algorithm for the treatment of episodes of demyelination along with chronic immunomodulatory therapeutic options in this patient population. CONCLUSIONS:: Although some similarities exist to adult onset MS, MS onset during childhood and adolescence presents unique diagnostic challenges and requires specialized multidisciplinary care for optimal management. National and international collaborative studies are underway to aid in the understanding of the early and ongoing pathogenesis of MS.

OBJECTIVE: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that becomes latent in B-lymphocytes and has been implicated in the pathogenesis of multiple sclerosis (MS). We searched for latent and active EBV infection in MS brain and CSF. METHODS: Nested and non-nested real-time PCR were used to detect cell-specific and EBV-specific transcripts in 15 fresh-frozen and 5 formalin-fixed paraffin-embedded MS plaques and in single MS CSF B-lymphocytes and plasma cells. Intrathecal anti-EBV antibody synthesis was measured by ELISA. Immunocytochemistry was used to detect binding of MS CSF and recombinant antibodies (rAbs) generated from clonally expanded plasma cells in MS CSF to EBV-infected cells. RESULTS: No EBV RNA was found in MS CSF B-lymphocytes or plasma cells. In active MS plaques, EBV-encoded RNA (EBER)-1 was the only and rarely detected transcript. The frequency of detected intrathecal anti-EBV antibody synthesis in patients with MS did not differ from that in non-MS inflammatory CNS disease control patients. Anti-EBV antibodies were detected in the CSF of patients with MS, but MS rAbs did not react with EBV. CONCLUSIONS: Application of real-time PCR to multiple sclerosis brain and single B-lymphocytes in CSF did not reveal any evidence of active Epstein-Barr virus infection.

A number of analysis tools have been developed for the estimation of brain atrophy using MRI. Since brain atrophy is being increasingly used as a marker of disease progression in many neuro-degenerative diseases such as Multiple Sclerosis and Alzheimer's disease, the validation of these tools is an important task. However, this is complex, in the real scenario, due to the absence of gold standards for comparison. In order to create gold standards, we first propose an approach for the realistic simulation of brain tissue loss that relies on the estimation of a topology preserving B-spline based deformation fields. Using these gold standards, an evaluation of the performance of three standard brain atrophy estimation methods (SIENA, SIENAX and BSI-UCD), on the basis of their robustness to various sources of error (bias-field inhomogeneity, noise, geometrical distortions, interpolation artefacts and presence of lesions), is presented. Our evaluation shows that, in general, bias-field inhomogeneity and noise lead to larger errors in the estimated atrophy than geometrical distortions and interpolation artefacts. Experiments on 18 different anatomical models of the brain after simulating whole brain atrophies in the range of 0.2-1.5% indicate that, in the presence of bias-field inhomogeneity and noise, a mean error of 0.64+/-0.53%,4.00+/-2.41% and 1.79+/-0.97% may be expected in the atrophy estimated by SIENA, SIENAX and BSI-UCD, respectively.

Parkinsonism due to multiple sclerosis (MS) is rare. In previously reported patients with MS-induced parkinsonism, MS manifested first, followed a typical clinical course, and parkinsonism developed later in the course of the illness. We report a 52-year-old male presenting with parkinsonism as the initial manifestation of MS, in whom a subsequent MS relapse consisted of marked deterioration in parkinsonism, a clinical pattern not previously described in MS. A brain MRI demonstrated involvement of the substantia nigra and basal ganglia. This patient illustrates that the clinical presentation and progression of MS may rarely be characterised by predominating parkinsonian features which are reversible by treatment with intravenous methylprednisolone and interferon beta1a.

Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) are organ-specific autoimmune diseases leading to an attack of auto-aggressive lymphocytes against the pancreatic beta-cells and central nervous system, respectively. Using four-colour flow cytometry, T-lymphocyte populations having an important function in autoimmune processes were analyzed. T-regulatory cells (Treg) CD4(+)CD25(+)CD127(low), T-suppressor cells (Ts) CD8(+)CD28(-), activated helper CD4(+)CD25(+)CD127(+) and cytotoxic CD8(+)CD25(+) T-cells and also naive CD4(+)CD45RA(+) and memory T-cells CD4(+)CD45RO(+) were compared in the group of patients with T1D (n=30), MS (n=31) and in the group of healthy controls (n=29). Significant differences in Ts cells, activated helper and cytotoxic cells and also memory T-cells were recognized in the group of T1D patients compared to healthy controls. Ts population was significantly lowered in MS patients as well. However, no significant differences were noticed in Treg population. The observed data demonstrate significant differences among patients with T1D and MS in comparison to healthy individuals.

Importance of the field: High-dose, high-frequency IFN beta-1a in multiple sclerosis (MS) can prevent lesion formation, decrease the frequency/severity of relapses and delay progression of disability, with a proven safety profile. Rates of non-adherence are high. There are drugs under investigation that may have greater efficacy and different safety profiles from existing therapies. Areas covered in this review: Evidence supporting the efficacy of IFN beta-1a, factors contributing to non-adherence, and strategies to combat non-adherence. It is hoped that these strategies, coupled with future advances in pharmacogenetics, might lead to better outcomes. The PubMed database was searched using the terms "multiple sclerosis" and "interferon beta-1a", for papers published between 1998 and 2010. Relevant manuscripts and pivotal papers from clinical trials were cited. Searches of abstracts from congresses were also performed to obtain recent findings. What the reader will gain: An overview of early pivotal trials, comparative studies with other treatments, and recent studies assessing the development of this therapy. Take home message: Long-term treatment with IFN beta-1a has benefits in MS and a good safety profile. Although adherence outside of clinical trials can be poor, injection devices, better tolerated drug formulations and education regarding treatment expectations are some of the strategies employed to help patients to adhere to treatment in the hope of improving outcomes.

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis. Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites. What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis. Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.

Zolpidem, a non-benzodiazepine hypnotic, acts selectively via the alpha(1)-subunit of GABA(A) receptors at therapeutic doses. It is therefore thought to lack both benzodiazepine properties such as anxiolysis, anticonvulsion, muscle relaxation, and side effects such as dependency. We report a case of severe dependency of zolpidem taken because of percieved myorelaxation in a patient with multiple sclerosis and paraspasticity. The observations in the patient described here suggest that zolpidem looses alpha1-receptor selectivity at higher doses, thereby leading to the same risks and benefits such as benzodiazepines. This should be taken into account by doctors when prescribing higher doses. Zolpidem may improve symptoms of spasticity in high doses via affection of GABA alpha2-receptor and alpha3-receptor subunits.

Multiple sclerosis (MS) is a chronic immune-mediated, central nervous system (CNS) demyelinating disease. Clinical and histopathological features suggest an inflammatory etiology involving resident CNS innate cells as well as invading adaptive immune cells. Encephalitogenic myelin-reactive T cells have been implicated in the initiation of an inflammatory cascade, eventually resulting in demyelination and axonal damage (the histological hallmarks of MS). Dendritic cells (DC) have recently emerged as key modulators of this immunopathological cascade, as supported by studies in humans and experimental disease models. In one such model, experimental autoimmune encephalomyelitis (EAE), CNS microvessel-associated DC have been shown to be essential for local antigen recognition by myelin-reactive T cells. Moreover, the functional state and compartmental distribution of DC derived from CNS and associated lymphatics seem to be limiting factors in both the induction and effector phases of EAE. Moreover, DC modulate and balance the recruitment of encephalitogenic and regulatory T cells into CNS tissue. This capacity is critically influenced by DC surface expression of co-stimulatory or co-inhibitory molecules. The fact that DC accumulate in the CNS before T cells and can direct T-cell responses suggests that they are key determinants of CNS autoimmune outcomes. Here we provide a comprehensive review of recent advances in our understanding of CNS-derived DC and their relevance to neuroinflammation.

South Staffordshire primary care trust (PCT) has seen a rise in the number of specialist nurses working in the community and the development of a wide range of intermediate care services. The Community Intervention Team (CIT) has offered the patients of East Staffordshire the choice to receive intravenous antibiotics, blood transfusions (Pott, 2009), and other intravenous therapies in their own homes rather than as hospital in-patients, for over five years. The local multiple sclerosis clinical nurse specialist (MS CNS) has worked closely with CIT when any MS patients have needed extra support at home to manage a crisis and this led the authors to consider how they could work together to prevent some of these crises occurring. In this article they authors outline how they used an award from the Queen's Nursing Institute (QNI) to help establish a community-based service to offer patients the option of receiving high-dose steroid therapy at home for treatment of a relapse, within the resources already available in the PCT.

ABSTRACT: Cakit BD, Nacir B, Genç H, Saraçoğlu M, Karagöz A, Erdem HR, Ergün U: Cycling progressive resistance training for people with multiple sclerosis: A randomized controlled study. OBJECTIVE:: To evaluate the effects of cycling progressive resistance training combined with balance exercises on walking speed, balance, fatigue, fear of falling, depression, and quality of life in patients with multiple sclerosis. DESIGN:: In this prospective randomized controlled trial, 45 patients were randomized into two exercise training (n = 30) groups and one control (n = 15) group. The patients in training group 1 (n = 15) underwent progressive resistance training on a bicycle ergometer and balance exercise, whereas group 2 (n = 15) patients received a home-based lower-limb strengthening and balance exercise. Outcome measures, including the duration of exercise, tolerated maximum workload, timed up and go test, Dynamic Gait Index, functional reach, Falls Efficacy scale, 10-m walk test, Fatigue Severity Scale, Beck Depression Inventory, and Short Form 36 scores, were assessed initially and at 8 wks. RESULTS:: After dropouts, the whole study group consisted of 20 women and 13 men (mean age, 37.9 +/- 10.43 yrs). In training group 1, duration of exercise, tolerated maximum workload, timed up and go test, Dynamic Gait Index, functional reach, falls efficacy scale, 10-m walk test, Fatigue Severity scale, and Beck Depression Inventory scores, and in group 2, the mean duration of exercise, tolerated maximum workload, and Falls Efficacy scale scores were significantly improved after the training program (P < 0.05). There were no significant improvements in any of the outcome measurements in the control group (P > 0.05). In between-group comparisons, improvements in outcome measures of group 1 patients were significantly higher than those in other groups, except for 10-m walking test. Group 1 patients showed statistically significant improvement in physical functioning and role-physical functioning scales of the Short Form 36 (P < 0.01 and P < 0.05, respectively), and group 2 patients showed statistically significant improvement in only physical functioning scale of Short Form 36 (P < 0.05) after 8 wks. CONCLUSIONS:: Specific exercise programs, including cycling progressive resistance training, may improve balance, fatigue, and depression and reduce fear of falling in patients with multiple sclerosis without worsening multiple sclerosis signs and symptoms.

This study examined overall and specific symptoms as cross-sectional correlates of physical activity in persons with relapsing-remitting multiple sclerosis (RRMS). We expected that overall symptoms would be inversely associated with physical activity, and that the association would be accounted for by fatigue, depression, and pain. The sample included 269 individuals with a definite diagnosis of RRMS who completed a battery of questionnaires and then wore an accelerometer for 7 days. Data were analyzed using covariance modeling in Mplus. The primary model (chi square = 13.89, df = 10, p = 0.18, SRMR = 0.03, comparative fit index = 0.99) demonstrated that the path between overall symptoms and physical activity was indirect by way of fatigue (indirect path coefficient = -0.15) and depression (indirect path coefficient = -0.10). Such findings provide support for an indirect association between overall symptoms and physical activity by way of fatigue and depression in RRMS.