Evaluation of the symbol digit modalities test (SDMT) and MS neuropsychological screening questionnaire (MSNQ) in natalizumab-treated MS patients over 48 weeks.

BACKGROUND AND OBJECTIVES: Brief cognitive tests to monitor cognitive impairment in patients with multiple sclerosis (MS) are needed. METHODS: Performance on monthly administrations of the Symbol Digit Modalities Test (SDMT) and the MS Neuropsychological Questionnaire (MSNQ) was assessed in 660 patients with MS in 21 countries (109 sites) for 48 weeks in an open-label, safety-extension study of natalizumab. RESULTS: At baseline, the cohort's mean age was 40.1 years, 67.6% were female and the median Expanded Disability Status Scale score was 2.5. Test-retest correlations were high for both SDMT (range 0.89 for weeks 0-4 to 0.96 for weeks 44-48) and MSNQ (0.82 for weeks 0-4 to 0.93 for weeks 44-48). There were no statistically significant effects of geographic region. While SDMT scores improved by 15 points over 48 weeks (p < 0.0001), incremental monthly changes were small (effect size d < 0.3). Similar results were obtained on the MSNQ except that scores moved downward, suggesting fewer cognitive complaints over 48 weeks (p < 0.0001), but again the incremental monthly changes were small (d <-0.2). CONCLUSIONS: These results replicate earlier work in a smaller cohort treated with conventional disease-modifying therapy, and support the reliability of the SDMT and MSNQ as potential screening for monitoring tools for cognition over time.

Effects of acute relapses on neuropsychological status in multiple sclerosis patients.

Little is known about neuropsychological status changes in multiple sclerosis (MS) patients experiencing a relapse. The Symbol Digit Modalities Test (SDMT) and MS Neuropsychological Screening Questionnaire (MSNQ) are brief measures of cognitive performance and self-reported status, respectively. We retrospectively identified relapses in subjects participating in the 48-week open-label, safety-extension study of natalizumab (STRATA) to determine if changes in cognitive ability occurred during acute relapses. SDMT and MSNQ were administered prior to infusions. We analyzed SDMT and MSNQ scores pre- and post-relapse in 53 MS patients with relapses (cases) and 115 MS patients without relapses (controls) matched on age, gender, baseline SDMT and time from study initiation. ANOVA and GLM were used to compare cases versus controls overall, and stratified by EDSS cerebral functional status (cFS) scores. SDMT change pre- to post-relapse in cases was significantly lower than difference between similar time points in controls (p = 0.003). When comparing visit 2 (two visits pre-relapse) to visit 1 (first visit post-relapse), MSNQ change was significantly different between cases and controls (p = 0.012). For cFS ≤ 1, the change in SDMT was significantly different between cases and controls but not for cFS ≥ 2. These results confirm the involvement of cognitive function during some MS relapses suggesting the SDMT or MSNQ can be used to identify transitory neuropsychological status changes and cognitive relapses.

Canadian treatment optimization recommendations (TOR) as a predictor of disease breakthrough in patients with multiple sclerosis treated with interferon beta-1a: analysis of the PRISMS study.

BACKGROUND: Early intervention with an effective disease-modifying drug (DMD) offers the best chance of limiting the inflammatory process that contributes to irreversible axonal damage correlating with disability in multiple sclerosis (MS). It is equally important to ascertain fairly quickly whether patients are responding positively to the choice of therapy to allow time for either a treatment modification or a switch in treatment, a process we termed "treatment optimization". Various treatment optimization recommendations (TOR) have been proposed to help decide when a patient taking an MS DMD might be showing a sub-optimal response. We have applied the clinical scheme proposed by the Canadian TOR to the patients involved in the Prevention of Relapses and disability by Interferon Subcutaneously in MS 4-year (PRISMS-4) study, who received interferon beta-1a treatment for 4 years, with the TOR applied retrospectively at year 1. OBJECTIVE: The aim of this investigation was to examine whether these TOR were able to predict which patients would go on to develop disease breakthrough (defined as any relapses or disease progression), indicative of a sub-optimal response over the ensuing 3 years of study and therefore might have benefited from a change in treatment. RESULTS: We found 39% of patients receiving therapy experienced either a medium or high level of concern of breakthrough after a year of treatment, and 89% of these patients went on to develop further breakthrough over years 2-4. Although 67% of the 61% of patients having no or low-level concern after a year of treatment also experienced further disease breakthrough, it was significantly less than the medium or high group. CONCLUSION: This study shows that the Canadian TOR may be an important tool for early treatment optimization.

Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.

OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.