A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.

Predictors and dynamics of postpartum relapses in women with multiple sclerosis.

BACKGROUND: Several studies have shown that pregnancy reduces multiple sclerosis (MS) relapses, which increase in the early postpartum period. Postpartum relapse risk has been predicted by pre-pregnancy disease activity in some studies. OBJECTIVE: To re-examine effect of pregnancy on relapses using the large international MSBase Registry, examining predictors of early postpartum relapse. METHODS: An observational case-control study was performed including pregnancies post-MS onset. Annualised relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) scores were compared for the 24 months pre-conception, pregnancy and 24 months postpartum periods. Clustered logistic regression was used to investigate predictors of early postpartum relapses. RESULTS: The study included 893 pregnancies in 674 females with MS. ARR (standard error) pre-pregnancy was 0.32 (0.02), which fell to 0.13 (0.03) in the third trimester and rose to 0.61 (0.06) in the first three months postpartum. Median EDSS remained unchanged. Pre-conception ARR and disease-modifying treatment (DMT) predicted early postpartum relapse in a multivariable model. CONCLUSION: Results confirm a favourable effect on relapses as pregnancy proceeds, and an early postpartum peak. Pre-conception DMT exposure and low ARR were independently protective against postpartum relapse. This novel finding could provide clinicians with a strategy to minimise postpartum relapse risk in women with MS planning pregnancy.

The Kurtzke EDSS rank stability increases 4 years after the onset of multiple sclerosis: results from the MSBase Registry.

BACKGROUND: The Expanded Disability Status Scale (EDSS) is widely used to rate multiple sclerosis (MS) disability, but lack of disease duration information limits utility in assessing severity. EDSS ranking at specific disease durations was used to devise the MS Severity Score, which is gaining popularity for predicting outcomes. As this requires validation in longitudinal cohorts, we aimed to assess the utility of EDSS ranking as a predictor of 5-year outcome in the MSBase Registry. METHODS: Rank stability of EDSS over time was examined in the MSBase Registry, a large multicentre MS cohort. Scores were ranked for 5-year intervals, and correlation of rank across intervals was assessed using Spearman's rank correlation. EDSS progression outcomes at 10 years were disaggregated by 5-year EDSS scores. RESULTS: Correlation coefficients for EDSS rank over 5-year intervals increased with MS duration: years 1-6=0.55, years 4-9=0.74, years 7-12=0.80 and years 10-15=0.83. EDSS progression risk at 10 years after onset was highly dependent on EDSS at 5 years; one-point progression risk was greater for EDSS score of >2 than ≤2. Two-point progression was uncommon for EDSS score of <2 and more common at EDSS score of 4. CONCLUSIONS: EDSS rank stability increases with disease duration, probably due to reduced relapses and less random variation in later disease. After 4 years duration, EDSS rank was highly predictive of EDSS rank 5 years later. Risk of progression by 10 years was highly dependent on EDSS score at 5 years duration. We confirm the utility of EDSS ranking to predict 5-year outcome in individuals 4 years after disease onset.

Abdominal massage for the alleviation of constipation symptoms in people with multiple sclerosis: a randomized controlled feasibility study.

BACKGROUND: Constipation affects many people with multiple sclerosis (MS), negatively impacting on their quality of life. The use of abdominal massage has been reported in several populations and has been shown to increase the frequency of defaecation. OBJECTIVE: The objective of this study was to determine the feasibility of undertaking abdominal massage in people with MS. METHODS: Following ethical approval, 30 patients with MS and constipation were recruited. After providing informed written consent and completion of baseline outcome measures, participants were randomly allocated to a massage group or a control group. The massage group participants were provided with advice on bowel management, and they or their carers were taught how to deliver abdominal massage and were recommended to perform it daily during the 4-week intervention period. The control group received bowel management advice only. Outcomes were measured pre (Week 0) and post treatment (Week 4), and at Week 8 and included: the Constipation Scoring System (CSS) (primary outcome), the Neurogenic Bowel Dysfunction Score, and a bowel diary. RESULTS: Both groups demonstrated a decrease in CSS score from Week 0 to Week 4, indicating an improvement in constipation symptoms; however, the massage group improved significantly more than the control groups (mean difference between groups in score change -5.0 (SD 1.5), 95% CI -8.1, -1.8; t = -3.28, df = 28, p = 0.003). CONCLUSION: The results of this small study suggest a positive effect of the intervention on the symptoms of constipation, and support the feasibility of a substantive trial of abdominal massage for the alleviation of the symptoms of constipation in people with MS.

"The Brain Society": The First Two Years of an Undergraduate Neuroscience Society in Northern Ireland.

The Queen's University Belfast Brain Society was set up in September 2018 to promote interest in the human brain. There were three main goals: firstly to provide opportunities for medical students to learn from neurologists and neurosurgeons outside their formal curriculum; secondly the Brain Society aimed to organise events that included students from other disciplines and to members of the general public who were interested in learning about aspects of neuroscience; thirdly to tackle neurophobia. In the last two years, there have been 14 events, ranging from formal lectures, to practical sessions and to patient-focused information evenings. We have sold over 1,600 tickets. This article covers how the Brain Society was set up, to inform students in other universities about the Belfast experience.

The neuropeptide genes TAC1, TAC3, TAC4, VIP and PACAP(ADCYAP1), and susceptibility to multiple sclerosis.

The related immunomodulatory neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase activating peptide (PACAP; gene symbol ADCYAP1) have recently been proposed as novel therapeutics for the treatment of multiple sclerosis (MS). These neuropeptides, as well as those belonging to the tachykinin family exert pleiotropic effects, many of which are of relevance to central nervous system inflammation. In the present study, we have analysed 14 single nucleotide polymorphisms (SNPs) and 4 microsatellite markers in the VIP, ADCYAP1, TAC3 and TAC4 genes for susceptibility to MS in a case-control collection from Northern Ireland. Following correction for multiple comparisons, we did not find any significant associations between single polymorphic markers or multiple-marker haplotypes and susceptibility to MS. Furthermore, we analysed 2 SNPs in the TAC1 gene in a set of Sardinian trio MS families, based on our previous observation of association of these SNPs with MS in the Northern Irish (Genes Immun. 2005, 6, 265-270). Analysis of these SNPs in the Sardinians was not significant though a similar trend to that originally observed in the Northern Irish was present. Meta-analysis of the Sardinian and Northern Irish TAC1 SNP genotype data revealed a Mantel-Haenszel Common OR Estimate for the TAC1 intron 1 SNP rs2072100 of 0.76 (95% CI 0.63-0.92; P=0.005; A allele) and for the TAC1 promoter SNP rs7793277 of 0.76 (95% CI 0.615-0.95; P=0.014; C allele). Our data advocate a need for further exploration of the TAC1 gene region in MS.

CTLA4 gene polymorphisms and multiple sclerosis in Northern Ireland.

Four CTLA4 polymorphisms were investigated in a Northern Irish collection of relapsing-remitting (RR) and primary-progressive (PP) multiple sclerosis (MS) patients. The CTLA4 promoter (-318 C/T), exon 1 (+49 A/G) and intergenic CT60 SNPs, as well as a microsatellite found in the 3' UTR (AT(n)) were analysed in 246 RRMS, 84 PPMS and 158 healthy controls. The A allele of the exon 1 +49 A/G SNP (OR=1.36; 95% CI=1.11-1.81; P=0.038), and more so the AA genotype (OR=1.70; 95% CI=1.11-2.60; P=0.015) were associated with RR, but not PPMS. In the PPMS population, overall allele distribution of the AT(n) microsatellite was significantly different from that in the healthy controls. We did not find any association with the promoter (-318 C/T) or intergenic CT60 SNPs in either of the disease cohorts. In concordance with several recent studies, we detected a trend toward higher carriage rates of the +49 G allele in PP vs RR MS patients (66.7% vs 58.9%), though this was not significant. Our data highlight the CTLA4 +49 A/G and 3'UTR polymorphisms as potential modifiers of disease course in MS.

Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans.

By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.

Neurology assessment by objective structured video examination.

BACKGROUND: The ability to carry out a neurological examination and make an appropriate differential diagnosis is one of the mainstays of our final Bachelor of Medicine (MB) exam; however, with the introduction of objective structured clinical examinations (OSCEs) it has become impossible to arrange for adequate numbers of suitable real patients to participate in the exam. CONTEXT: It is vital that newly qualified doctors can perform a basic neurological examination, interpret the physical signs and formulate a differential diagnosis. It is vital that newly qualified doctors can perform a basic neurological examination INNOVATION: Since 2010 we have introduced an objective structured video examination (OSVE) of a neurological examination of a real patient as part of our final MB OSCE exam. The students view clips of parts of the examination process. They answer questions on the signs that are demonstrated and formulate a differential diagnosis. IMPLICATIONS: This type of station is logistically a lot easier to organise than a large number of real patients at different examination sites. The featured patients have clearly demonstrated signs and, as every student sees the same patient, are perfectly standardised. It is highly acceptable to examiners and performed well as an assessment tool. There are, however, certain drawbacks in that we are not examining the student's examination technique or their interaction with the patient. Also, certain signs, in particular the assessment of muscle tone and power, are more difficult for a student to estimate in this situation.

Time- and Region-Specific Season of Birth Effects in Multiple Sclerosis in the United Kingdom.

IMPORTANCE: The reports of seasonal variation in the births of people who later develop multiple sclerosis (MS) have been challenged and attributed to the background pattern in the general population, resulting in a false association. OBJECTIVE: To study the seasonality of MS births after adjusting for temporal and regional confounding factors. DESIGN, SETTING, AND PARTICIPANTS: A study was conducted using case-control data from 8 MS-specialized centers from the United Kingdom, MS cases from a population-based study in the Lothian and Border regions of Scotland, and death records from the UK Registrar General. Participants included 21 138 patients with MS and control data from the UK Office of National Statistics and the UK government office regions. The seasonality of MS births was evaluated using the Walter and Elwood test, after adjusting for temporal and regional variations in the live births of the UK population. The study was conducted from January 16, 2014, to September 2, 2015. MAIN OUTCOMES AND MEASURES: Diagnosis of multiple sclerosis. RESULTS: Analysis of the general population indicated that seasonal differences are present across time and region in the United Kingdom, with both factors contributing to the monthly distribution of live births. We were able to demonstrate that, when adjusting for the temporal and regional variations in the live births of the UK population, there was a significant season of birth effect in patients with MS, with an increased risk of disease in the peak month (April) compared with the trough month (November) (odds ratio, 1.24; 95% CI, 1.10-1.41) and 15.68% fewer people who developed MS being born in November (observed to expected birth ratio, 0.840; 95% CI, 0.76-0.92). CONCLUSIONS AND RELEVANCE: Season of birth is a risk factor for MS in the United Kingdom and cannot be attributed to the background pattern in the general population. The reasons for the variations in birth rates in the general population are unclear, but not taking them into consideration could lead to false-positive associations.

Pharmacogenomics of responsiveness to interferon IFN-beta treatment in multiple sclerosis: a genetic screen of 100 type I interferon-inducible genes.

OBJECTIVES: Interferon IFN-beta is indicated for the treatment of multiple sclerosis. A significant proportion of patients show a poor clinical response to therapy. Type I interferon exerts its effect at least partially through interaction of specific transcription factors with interferon-stimulated response elements (ISREs), mostly located in promoter regions of its target genes. We hypothesized that polymorphisms may occur within or close to ISRE elements, altering type I interferon inducibility and ultimately leading to a modified clinical response in carriers. METHODS: We selected 100 ISRE-containing genes and sequenced their promoter regions in small genomic deoxyribonucleic acid pools of responding and nonresponding patients, as well as healthy control subjects. A selection of polymorphisms discovered by this approach was scrutinized subsequently in a collection of individual deoxyribonucleic acid samples. RESULTS: We identified 4 genes containing polymorphisms associated with response to recombinant IFN-beta: IFNAR1 (P = .036), LMP7 (P = .002; odds ratio [OR], 6.37 [95% confidence interval (CI), 1.84-24.1]), CTSS (P = .02; OR, 0.38 [95% CI, 0.18-0.84]), and MxA (P = .015; OR, 3.37 [95% CI, 1.11-11.4]). Logistic regression analysis with treatment outcome used as the dependent variable and genotype as the independent variable revealed 2 genes, LMP7 (OR, 0.55 [95% CI, 0.34-0.89]) and MxA (OR, 0.41 [95% CI, 0.19-0.88]), that were independently associated with treatment response. CONCLUSIONS: Our work confirms and extends previous indications for a polygenic mechanism involved in bringing about responsiveness to recombinant IFN-beta. The identification of 2 genes active in the antigen processing and presentation cascade; that is, LMP7, coding for the proteasome subunit beta, and CTSS, coding for cathepsin S; as potential response modifiers may identify this pathway as being of particular relevance to phenotypic expression of response heterogeneity.

Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic susceptibility effect in vicinity to the protachykinin-1 gene.

Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged from the recent American genome screen in multiple sclerosis (MS) as the most promising region genome-wide for harboring a disease susceptibility gene. We tested association between D7S554 and MS in 217 Sardinian trio MS families by the transmission disequilibrium test (TDT), and in a Northern Irish case-control study comprising 542 individuals. In both populations, we found evidence for significant allelic association (P(c)=0.04 and P(c)=0.0002, respectively). In a second stage, we analysed five microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the same set of Sardinian families. Parental transmission of a single allele of one of these markers, i.e. D7S3126, was significantly distorted (P(c)=0.008). D7S554 and D7S3126 are located at distances of, respectively, 40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that the previous finding of linkage with D7S554 refers possibly to the presence of an MS susceptibility effect in vicinity to TAC1. In addition, a second independent association was uncovered between a microsatellite polymorphism in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall, the analysis presented here may contribute to the increasingly refined genomic map of MS and underscores the requirement for a further high-resolution screening of chromosome 7q21-22.

A genome wide scan for association with multiple sclerosis in a N. Irish case control population.

In order to screen the genome for linkage disequilibrium (LD) in multiple sclerosis (MS), we typed 2537 microsatellite markers in separately pooled DNA from 200 cases and 200 controls from N. Ireland. Twenty two markers showing significant evidence of association were identified including three from the HLA region on chromosome 6p21. Putative candidate genes mapping close to the 19 novel markers include the IL10RA and CD3E genes on 11q23 (which both lie close to the marker D11S1998). Individual typing of the marker D11S1998 confirmed its association.

Participation in general practice health screening by people with multiple sclerosis.

We examined the effect of mobility on health screening for people with multiple sclerosis. General practice records were searched for blood pressure and cholesterol measurements, lifestyle advice, cervical smears, and mammograms. Blood pressure measurement decreased with decreasing mobility (P <0.001). Lifestyle advice was also related to mobility (P <0.01), with those with a moderate disability most likely to receive lifestyle advice. Overall, wheelchair users received fewer preventative services. Findings were similar for men and women.

Locked-in, walked out.

Locked in syndrome is typically associated with significant morbidity and mortality. We report a patient who had an unusually good recovery from locked in syndrome due to pontine infarction. The good recovery exhibited by our patient may have resulted from resolution of oedema at the site of infarction and brainstem plasticity being augmented by initial supportive measures in the intensive care unit and early, intensive rehabilitation.