Gavin McDonnell

Multiple Sclerosis Severity Score Using disability and disease duration to rate disease severity

Background: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. Methods: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. Results: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. Conclusion: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

Pharmacogenomics of responsiveness to interferon IFN‐β treatment in multiple sclerosis: A genetic screen of 100 type I interferon‐inducible genes

Interferon IFN‐β 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.

Serum soluble adhesion molecules in multiple sclerosis: raised sVCAM-1, sICAM-1 and sE-selectin in primary progressive disease.

Abstract Leucocyte invasion into the central nervous system in multiple sclerosis (MS) is complex, involving T-cell/endothelium interaction dependent upon initial adhesion mediated by molecules such as E-selectin, L-selectin, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Circulating levels of these can be measured by sensitive enzyme-linked immunoassay (ELISA) techniques. To assess whether serum concentrations of soluble adhesion molecules vary across the spectrum of patients with relapsing-remitting (RR), secondary progressive (SP) and primary progressive (PP) MS, we measured circulating levels of soluble (s)E-selectin, sL-selectin, sICAM-1 and sVCAM-1 in serum obtained from 78 PPMS patients, 71 patients with RRMS, 65 patients with SPMS and 66 patients with other neurological disease using commercially available ELISA systems. Levels of serum sVCAM-1 were significantly elevated in PPMS compared with RRMS in remission (P = 0.0001) and in relapse (P = 0.0001), whilst sICAM-1 was significantly elevated in PPMS compared with all other MS groups (vs SPMS, P = 0.006; vs RRMS in relapse, P = 0.003; vs RRMS in remission, P = 0.0001). Serum sE-selectin levels were significantly higher in PPMS compared with all other groups except inflammatory neurological disease (IND) [vs SPMS, P = 0.029; vs RRMS in relapse, P = 0.002; vs RRMS in remission, P = 0.001; vs non-inflammatory neurological disease (NIND), P = 0.002; vs IND, P = 0.076]. In PPMS there was no correlation between levels of any adhesion molecule and disability or disease duration. These results provide evidence for significant immunological heterogeneity in MS and suggest that different leucocyte/endothelial cell interactions may be active in various MS subgroups. It also challenges the hypothesis that PPMS is a less inflammatory form of the disease.

Factors in the rising prevalence of multiple sclerosis in the north-east of Ireland

Background Northern Ireland is recognized as an area of high risk for multiple sclerosis. The original study of Allison and Millar in 1951 found a prevalence of 51/100,000 and mean annual incidence of 2.74/100,000/year. Subsequent studies in 1961, 1986, and 1996 suggested rising prevalence – 80, 138, and 168.2/100,000, respectively. Methods In 2004, we surveyed the North-East of Northern Ireland (population 160,446, area 2030 km2) using multiple sources of case ascertainment, all satisfying the Poser criteria for definite or probable multiple sclerosis (MS) or the McDonald criteria. Results From a provisional list of 469 cases, 370 (123 males, 247 females) were identified. The prevalence was 230.6 per 100,000 (95% CI 207.0–255.4) with significantly higher prevalence in females (300.8/100,000) than males (157.0/100,000). Direct standardization to the 1961 Northern Ireland population reduced the overall prevalence rate to 200.5/100,000 (95% CI 193.2–208.0), in females to 270.2/100,000 (95% CI 258.8–282.4) and in males to 131.1/100,000 (95% CI 122.8–139.9). In 1996, incidence had risen to 9.3/100,000/year (14 cases in population of 151,000) with a higher incidence in females (10.3/100,000/year) than males (8.3/100,000/year). Conclusions Northern Ireland continues to have a rising prevalence of MS. The increase in incidence suggests a true increase in the disease.

Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course.

The C C R5 chemokine receptor has been implicated in the patho genesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the C C R5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. O f the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the C C R5 d32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the d32 allele. In the population-based group of RR/SPMS patients, carriage of the C C R5 d32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P =0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the C C R5 d32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between C C R5 d32 carriage and a better prognosis.

Raised CSF levels of soluble adhesion molecules across the clinical spectrum of multiple sclerosis

Endothelial activation is considered an important step in multiple sclerosis (MS) lesion formation, elevated cerebrospinal fluid (CSF) and serum levels of certain adhesion molecules being associated with varying stages of disease activity and clinical course. CSF and serum sVCAM-1, sICAM-1, sE-selectin and sL-selectin were measured by ELISA in 16 primary progressive (PPMS), 16 secondary progressive (SPMS) and 43 relapsing-remitting MS patients (RRMS) and compared with 20 inflammatory (IND) and 46 non-inflammatory neurological disease (NIND) controls. CSF sVCAM-1 and sICAM-1 were increased in all MS groups vs. NIND with no significant differences between the MS groups. CSF sE-selectin (p = 0.007) and the sE-selectin index (p = 0.01) were elevated in PPMS vs. RRMS in relapse, whilst serum sE-selectin was significantly raised in PPMS compared to RRMS in remission (p = 0.005), RRMS in relapse (p = 0.004), NIND (p = 0.03) and IND (p = 0.05). Adhesion molecule levels in both progressive MS groups were similar. These results provide evidence for a distinct inflammatory component in PPMS and for immunological heterogeneity between the clinical subgroups of MS.

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.

Tried and tested: the psychometric properties of the multiple sclerosis impact scale (MSIS-29) in a population-based study.

Objective To investigate the psychometric properties of the Multiple Sclerosis Impact Scale (MSIS-29) and to assess the relationship between the Kurtzke Expanded Disability Status Scale and the physical and psychological parts of this score. Methods A population-based study identified cases with definite multiple sclerosis (MS) in the north-east region of Ireland. They were examined and completed the MSIS-29. Cases were classified as mild (Expanded Disability Status Score (EDSS) 0–3.0), moderate (EDSS 3.5–5.5), or severe (6.0–9.5) MS. Results The 248 participants (82 male, 166 female) had a mean age of 49.1 years (SD 12.4). EDSS ranged from 0 to 9.5 (median 6.0). Data quality was excellent (0.02% missing data), physical and psychological scores spanned the entire range with low floor and ceiling effects. Internal consistency was high (Cronbach’s alpha 0.97 – physical score, 0.93 – psychological score). The convergent validity of the physical impact score of the MSIS-29 with the Kurtzke EDSS was confirmed with a high Spearman’s rank coefficient correlation of 0.63 (P = 0.01). Physical impact scores for mild, moderate, and severe disability as were statistically different at 25.9%, 48.0%, and 63.9%, respectively. Mean psychological score was non-significantly higher in the moderately disabled group at 47.4% compared with the severely disabled at 44.3% (P = 0.58). Conclusions The MSIS-29 is an acceptable, reliable, and valid method of recording quality of life. A significant relationship between higher physical impact scores of the MSIS-29 and higher Kurtzke EDSS values suggests that is may be of use in clinical trials to monitor progression.

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 Spearmans 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.

Genetic association studies of tumour necrosis factor α and β and tumour necrosis factor receptor 1 and 2 polymorphisms across the clinical spectrum of multiple sclerosis

Abstract Allelic association studies with microsatellite markers around the tumour-necrosis factor (TNF) genes have demonstrated significantly different allele distributions of TNF markers (a and b) between relapsing-remitting/secondary progressive multiple sclerosis (MS) (RR/SPMS) patients and normal controls. Considering the suspected genetic and immunological heterogeneity in MS, we tested this association in primary progressive MS (PPMS) patients. Elevated levels of serum soluble TNF receptors (sTNF-R) are reported in patients with gadolinium enhancing lesions, and animal models suggest a possible therapeutic role of sTNF-RI in MS. Thus we performed similar association studies using markers for the TNF-R genes. Gene association studies were carried out on 199–216 normal controls, 174 RR/SPMS patients and 102 PPMS patients using polymorphic dinucleotide repeat TNF markers (a, b and d), and separate markers for TNF-RI and TNF-RII. Forward primers were fluorescently labelled, polymerase chain reaction (PCR) products were analysed on a fluorescent fragment analyser, and Genescan 672 software was used for allele sizing. Samples were typed for HLA-DR antigens using PCR technology and sequence-specific oligonucleotide probes. TNFa marker allele distributions differed significantly between PPMS patients and controls (P = 0.028), largely attributable to an increase in the 118-bp TNFa allele in PPMS patients (P = 0.00024). Allele distributions were similar in PPMS and RR/SPMS patients (P = 0.91). Logistic regression analysis, however, indicated that these associations were not independent of that with HLA-DRB1*15. For the TNFb marker, the 127-bp allele showed association with both patient categories (PPMS vs. controls, P = 0.010; RR/SPMS vs. controls, P = 0.027), whilst the 128-bp allele occurred more frequently in controls (PPMS vs. controls, P = 0.036: RR/SPMS vs. controls, P = 0.0009). As with the TNFa 118 bp allele, the association with TNFb was not independent of the HLA association. No association occurred with the TNFd marker, and there were also no significant differences in allele frequencies between MS groups and controls regarding the marker for TNF-RI or TNF-RII. In Northern Irish patients the TNF contribution to MS genetic susceptibility is therefore similar across the clinical spectrum of the disease but is not independent of the association with HLA-DRB1*15.