The Mismeasure of Change

Cognitive impairment is an intractable and debilitating symptom of multiple sclerosis (MS) for which effective treatments are sorely lacking. We currently have more than 18 FDA-approved disease-modifying therapies (DMTs) with demonstrated efficacy for reducing the risk of relapse and maintaining neurologic function. None is approved for the treatment of cognition, although patients and clinicians commonly identify cognition as a treatment priority when considering DMT use.¹ Increasingly, clinical trials are incorporating cognitive tests as secondary outcome measures; however, a recent meta-analysis that included 41 studies found overall benefits of DMTs for cognition to be only small to moderate.² In this issue of Neurology®, Castrogiovanni et al.³ publish a study that analyzed cognitive outcomes from DECIDE, a randomized controlled trial comparing subcutaneous daclizumab and intramuscular interferon beta-1a in 1,814 patients with relapsing-remitting MS (RRMS). Two cognitive measures were used: the Symbol Digit Modalities Test (SDMT), a cognitive screener and the most common measure of cognition in MS, and the Paced Auditory Serial Addition Test (PASAT), a test involving working memory, math calculation, auditory attention, word retrieval, and speech production. For more than a decade, the use of the PASAT in MS has been discouraged because of poor tolerability and suboptimal psychometric properties.⁴ Patients in both treatment arms showed steady performance improvements across up to 6 time points from baseline to 144-week follow-up on SDMT (mean improvement = +4.9 ± 12.5) and PASAT (+3.3 ± 8.1). Percentage of participants showing cognitive improvement was consistent across several definitions of clinically meaningful change: any change, 4 points, 8 points, and 20% change for SDMT, and any change, 4 points, and 20% change for PASAT. By contrast, performance on the Timed 25-foot Walk Test, a robust and reliable measure of physical disability in RRMS, steadily worsened over the same follow-up periods.