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To evaluate the practical application and psychometric properties of three health utility measures in a sample of MS patients with a broad range of neurological disability as measured by the Extended Disability Status Scale (EDSS).Patients randomly selected from two MS clinic registries were assessed using standard clinical methods and completed three generic measures of health utility (EQ-5D, HUI Mark III, SF-6D). The proportion of missing data, test/retest reliability, and construct validity of each health utility measure were examined.The assessments were completed by 187 patients. Less than 10% of data were missing for the subscales of the SF-6D (3.2%), HUI Mark III (1.6%), and EQ-5D (or =7.5%). Severely disabled patients were more likely to omit physical function questions for the SF-6D (20%), and EQ-5D (43%). Retest reliability for the SF-6D (ICC = 0.83), EQ-5D (ICC = 0.81), and HUI Mark III (ICC = 0.87) were adequate for population surveys. Correlations between assessment of clinical function and each health utility measure were strongest for the HUI Mark III (HUI Mark III EDSS rho = -0.77, HUI Mark III ambulation index rho = -0.76, HUI Mark III timed 25 foot walk rho = -0.73, HUI Mark III nine hole peg test rho = -0.65).The health utility measures were generally feasible and reliable but the HUI Mark III demonstrated highest concordance with the EDSS across the full range of neurological disability. Of the three measures studied, the HUI Mark III may be the most appropriate for cost effectiveness evaluations of MS therapies.

Background: Measuring perfusion provides a potential indication of metabolic activity in brain tissue. Studies in multiple sclerosis (MS) have identified areas of decreased perfusion in grey matter (GM) and white matter (WM), but the pattern in clinical subgroups is unclear. Objectives: This study investigated perfusion changes in differing MS clinical subgroups on or off β-interferon therapy using a non-invasive MRI technique (continuous arterial spin labelling) to investigate whether different clinical MS subtypes displayed perfusion changes and whether this could give a further insight into the pathological mechanisms involved. Methods: Sixty patients (21 relapsing remitting, 14 secondary progressive, 12 primary progressive, 13 benign) and 34 healthy controls were compared. Statistical parametric mapping (SPM ’99) was used to investigate regional variations in perfusion in both GM and WM. Global WM perfusion was derived by segmenting WM from images using T 1 relaxation times. Results: Regions of lower perfusion in predominantly GM were observed in the primary and secondary progressive cohorts, particularly in the thalamus. Increased WM perfusion was seen in relapsing remitting and secondary progressive cohorts. Conclusions: Low GM perfusion could reflect decreased metabolism secondary to neuronal and axonal loss or dysfunction with a predilection for progressive forms of MS. Increased WM perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation. Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and cognitive impairment.

Objectives: This study aimed to develop further a diary originally devised to measure the impact of multiple sclerosis (MS) as part of a cost utility study of beta interferon, and to evaluate its reliability, validity, and responsiveness in an outpatient sample of people with MS. Methods: The original diary was further developed using qualitative and quantitative methods to ensure that it addressed the views of people with MS. The psychometric properties of the MS Symptom and Impact Diary (MSSID) were evaluated in a sample of 77 people who completed the MSSID daily for 12 weeks. Internal and test–retest reliability, discriminant and convergent validity, and responsiveness were assessed using traditional psychometric methods. Results: The MSSID formed three, internally consistent scales that measured mobility, fatigue, and the overall impact of MS. The test–retest reliability of the mobility scale was adequate for individual comparisons (ICC>0.90) and the fatigue and overall impact scales were adequate for group comparisons (ICC>0.70). The MSSID was able to distinguish between clinical groups depending on clinical course, indoor ambulation status, and relapse status. It demonstrated associations with other single point instruments in the expected direction. Compared with single point instruments, its responsiveness was similar or better, especially in detecting short term improvements in functioning. Conclusions: The MSSID may provide a useful complement to currently available instruments to measure the outcomes of MS within clinical trials. Further research is needed to explore its feasibility in the context of a randomised controlled trial and its utility for clinicians.

Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose−response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 μg subcutaneously once weekly, in patients with secondary progressive MS. Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 μg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 μg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose−response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.

BACKGROUND: Some multiple sclerosis (MS) patients treated with interferon beta (IFN beta) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN beta are expensive and the clinical relevance of the results has been debated. OBJECTIVE: To establish a cheap, sensitive, and reliable assay for antibodies to (125)I-IFN beta, and to correlate levels of antibodies with clinical response to IFN beta treatment. METHODS: We established a radioimmunoprecipitation assay (RIPA) using (125)I-IFN beta. We tested NAB positive sera, healthy control sera, and serial samples of 33 IFN beta-1b treated MS patients from the Vancouver cohort of the Berlex pivotal trial who had a high incidence of NABs. RESULTS: We found that the RIPA was highly sensitive for the detection of antibodies to IFN beta-1a and -1b, and that there was a strong correlation between reactivity of NAB positive sera for (125)I-IFN beta-1b and for (125)I-IFN beta-1a. The RIPA was more sensitive and consistent than the NAB. Moreover, there was a trend towards poorer MRI outcomes in RIPA positive patients, but not in NAB-positive patients. CONCLUSIONS: The RIPA assay is sensitive and easy to perform. It should be of value in assessing the clinical impact of IFN beta antibodies, and its use could help target expensive INF beta treatments to those who will respond best.

Background: Pathology in the cervical spinal cord is considered an important cause of disability in multiple sclerosis. However, the majority of serial studies have failed to find a correlation between spinal cord atrophy and disability. Objectives: To use a highly reproducible and accurate method to quantify spinal cord area change on three dimensional magnetic resonance imaging and relate this to disability change in patients with multiple sclerosis. Methods: 38 patients with multiple sclerosis (20 with the relapsing–remitting (RRMS) form and 18 with the secondary progressive (SPMS) form) were imaged at baseline and at months 6, 12, 18, and 48 during two treatment trials of the high dose subcutaneous thrice weekly interferon s-1a (IFNs, Rebif). Thirty one healthy subjects were also imaged at baseline. Upper cervical cord area (UCCA) was measured using Sobel edge detection. Results: The intraobserver coefficient of variation of the method was 0.42%. A significant reduction in UCCA was detected at month 6 in the placebo group (p = 0.04) and at month 12 for INFs (p = 0.03). The mean reduction of UCCA at month 48 was 5.7% for patients initially on placebo who received treatment at 24 months (RRMS) or at 36 months (SPMS), and 4.5% for those on IFNs throughout the study (p = 0.35). The change in UCCA was significantly correlated with change in the expanded disability status scale at month 12 (r = 0.4, p = 0.016), month 18 (r = 0.32, p = 0.05), and month 48 (r = 0.4, p = 0.016) in the total cohort. Conclusions: Despite the small number of patients studied and the possible confounding effects of interferon treatment, this study showed that edge detection is reproducible and sensitive to changes in spinal cord area, and that this change is related to changes in clinical disability. This suggests a role for measurement of spinal cord atrophy in monitoring disease progression and possible treatment effects in clinical trails.

Objective: To evaluate the incidence and the prevalence of neutralising antibodies (NABs) to three interferon beta (IFNβ) products in patients with multiple sclerosis (MS). Methods: Sera were tested from 125 patients with relapsing-remitting MS. Patients were treated with IFNβ-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFNβ-1a (Avonex, n = 44) 30 µg intramuscularly once weekly, or IFNβ-1a (Rebif, n = 36) 22 µg subcutaneously three times weekly for 6 to 18 months. An additional 16 patients were treated with Rebif 22 µg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment. Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+). Results: At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18. Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04). In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07). At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif. Conclusion: The three IFNβ preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest. These differences should be considered by neurologists when selecting treatment for their patients with MS because NABs can reduce both bioavailability and clinical efficacy of IFNβ.