The risk for development of multiple sclerosis has been associated with human leukocyte antigen-DRB1*1501-DQB1*0602 (HLA-DR15) genotype, low infant sibling exposure, and high Epstein-Barr nuclear antigen IgG levels. In a population-based case-control study (Tasmania, Australia), we found that the combined effect of HLA-DR15 positivity and low infant sibling exposure on multiple sclerosis (odds ratio, 7.88; 95% confidence interval, 3.43-18.11) was 3.9-fold greater than expected (test for interaction, p = 0.019) This interaction was observed irrespective of Epstein-Barr nuclear antigen IgG levels. This suggests that immune mechanisms involving HLA class II molecules are susceptible to modulation in early life. Ann Neurol 2009;66:261-265 ANN NEUROL 2010;67:259-263.

OBJECTIVE: The aims of the study were to determine the immune responses to candidate viral triggers of multiple sclerosis (MS) in patients with clinically isolated syndromes (CISs), and to evaluate their potential value in predicting conversion to MS. METHODS: Immune responses to Epstein-Barr virus (EBV), human herpesvirus 6, cytomegalovirus (HCMV), and measles were determined in a cohort of 147 CIS patients with a mean follow-up of 7 years and compared with 50 demographically matched controls. RESULTS: Compared with controls, CIS patients showed increased humoral (p < 0.0001) and cellular (p = 0.007) immune responses to the EBV-encoded nuclear antigen-1 (EBNA1), but not to other EBV-derived proteins. Immunoglobulin G (IgG) responses to other virus antigens and frequencies of T cells specific for HCMV and influenza virus gene products were unchanged in CIS patients. EBNA1 was the only viral antigen with which immune responses correlated with number of T2 lesions (p = 0.006) and number of Barkhof criteria (p=0.001) at baseline, and with number of T2 lesions (p = 0.012 at both 1 and 5 years), presence of new T2 lesions (p = 0.003 and p = 0.028 at 1 and 5 years), and Expanded Disability Status Scale score (p = 0.015 and p = 0.010 at 1 and 5 years) during follow-up. In a univariate Cox regression model, increased EBNA1-specific IgG responses predicted conversion to MS based on McDonald criteria (hazard ratio [95% confidence interval], 2.2 [1.2-4.3]; p = 0.003). INTERPRETATION: Our results indicate that elevated immune responses toward EBNA1 are selectively increased in CIS patients and suggest that EBNA1-specific IgG titers could be used as a prognostic marker for disease conversion and disability progression. ANN NEUROL 2010;67:159-169.

Relapses in multiple sclerosis, associated with significant functional impairment, should be treated with methylprednisolone. In case of repeated relapses or onset cases of multiple sclerosis there is an indication for preventive treatment with interferon-beta/glatiramer acetate (first-line treatment), natalizumab (second-line treatment) or mitoxantrone (third-line treatment).

Mutations in the fused in sarcoma (FUS, also known as translated in liposarcoma) gene have been recently discovered to be associated with familial amyotrophic lateral sclerosis (FALS) in African, European and American populations. In a Japanese family with FALS, we found the R521C FUS mutation, which has been reported to be found in various ethnic backgrounds. The family history revealed 23 patients with FALS among 46 family members, suggesting a 100% penetrance rate. They developed muscle weakness at an average age of 35.3 years, followed by dysarthria, dysphagia, spasticity and muscle atrophy. The average age of death was 37.2 years. Neuropathological examination of the index case revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of the brainstem. We screened 40 FALS families in Japan and found 4 mutations (S513P, K510E, R514S, H517P) in exon 14 and 15 of FUS. Even in Asian races, FALS with FUS mutations may have the common characteristics of early onset, rapid progress and high penetrance rate, although in patients with the S513P mutation it was late-onset. Degeneration in multiple systems and cytoplasmic basophilic inclusion bodies were found in the autopsied cases.Journal of Human Genetics advance online publication, 12 March 2010; doi:10.1038/jhg.2010.16.

BACKGROUND: Sleep supports the consolidation of procedural memory, however patients with major depression show impaired motor memory performance after a night of sleep. It was hypothesized that this impairment is related to hypothalamic-pituitary-adrenal (HPA) axis dysfunction. We tested if high-dose administration of corticosteroids impairs off-line motor memory consolidation in patients with multiple sclerosis (MS). METHODS: Nine patients with MS receiving high-dose corticosteroid therapy (methylprednisolone) and nine MS patients receiving alternative therapy (mitoxantrone) were assessed using a sequential finger tapping task before and after a night with polysomnography. In addition, nine patients with major depression (MD) receiving antidepressants and nine healthy controls were assessed. RESULTS: Although the four groups did not differ in practice-dependent learning, healthy subjects and MS patients receiving mitoxantrone showed markedly overnight-improvements in tapping performance of 17% and 24% while MS patients receiving high-dose corticosteroid therapy and depressed patients showed -9% and -10% overnight decrease. MS patients with and without corticosteroid therapy did not differ in their amount of REM sleep, nor did MD patients and healthy controls. In addition, we did not find any correlation between REM sleep and memory consolidation. CONCLUSION: Our results show that a strong intervention into the HPA system like in MS high-dose corticosteroid therapy impairs off-line motor memory consolidation comparable to the impairments seen in depressed patients. We propose therefore that depression-related changes in plasma corticosteroid levels rather than in sleep per se underlie off-line memory consolidation impairments in MD.

We investigated naïve CD4 T-cell homeostasis in relapsing-remitting multiple sclerosis (RRMS). Quantification of signal joint T-cell receptor excision circles in FACS-isolated CD31hi cells, which correspond closely to CD4 recent thymic emigrants (RTEs), indicates that young patients have reduced generation of CD4 RTEs compared to age-matched controls. In RRMS, compared to controls, CXCR4 analyses indicate age-associated thymic output of progressively immature CD4 RTEs, and Ki-67 data demonstrate altered T-cell proliferative responses that fail to maintain naïve CD4 T-cell numbers with age. Thus, RRMS patients have early thymic involution with compensatory homeostatic peripheral T-cell proliferative responses that may predispose patients to autoreactivity.

OBJECTIVES: Glucosamine has been safely used to relieve osteoarthritis. The aim of this preliminary study was to evaluate the effect of glucosamine sulfate in combination with current disease modifying therapy on the prevention of progression of relapsing-remitting multiple sclerosis (RRMS). METHODS: A phase II double-blind placebo-controlled randomized clinical trial conducted between February and October 2007 included 97 patients with confirmed RRMS aged 17-55 years. They were randomly allocated to receive 6 months of treatment with either oral glucosamine sulfate (1000 mg/day) or placebo combined with disease-modifying therapy. Response to treatment was assessed at 6 months. Primary and secondary outcome measures were number of relapse and changes in mean Expanded Disability Status Scale (EDSS). RESULTS: In 46 patients treated with glucosamine sulfate, mean (SD) relapse rate decreased from 1.1 (0.7) at baseline to 0.4 (0.5) at the end of study period (P < 0.05). In the 51 patients treated with placebo, the mean (SD) relapse rate did not change. After 6 months, 63.0% of patients receiving glucosamine sulfate remained relapse-free compared to 54.9% of those given placebo (P > 0.05). Average EDSS at the end of trial did not differ between groups (mean difference: -0.1; 95% CI: -0.5-0.2). DISCUSSION: Adding glucosamine sulfate to routine disease modifying-therapy had no significant effect on relapse rate or disease progression during the treatment period. A larger phase-III multicenter study of glucosamine sulfate in RRMS is warranted to more assess the efficacy of this intervention.

Research has recently focused on cognitive dysfunction in multiple sclerosis (MS). Cognitive deficits are frequently encountered in patients and account for important impairment in quality of life, therefore posing a major therapeutic challenge for the disease. We presently review studies on cognitive effects of pharmacological treatments in MS. There is evidence for a possible beneficial effect of immunomodulatory treatments, particularly of interferons, and also of acetylcholinesterase inhibitors on cognition in MS, which, however, requires evaluation in larger, multi-centre, longitudinal studies. Methodological issues and future prospects regarding the investigation of this issue are also discussed.

The physical effects of multiple sclerosis (MS) mean participating in research requires considerable effort. Vignettes offer a less fatiguing and more efficient way of gathering preliminary data from such participants as they avoid intrusion into and disruption of healthcare interactions. However, despite their widespread use, no documented process describing how to develop them exists. This paper describes how we designed and crafted vignettes that investigated; how anger in MS patients is affected by nursing and communication styles; how to achieve equivalence; how vignettes should be rated: what statistics should be used to judge their reliability; and how to ensure that vignettes are measuring target variables.

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.