Background: The Symbol Digit Modalities Test (SDMT) is increasingly utilized in clinical trials. A SDMT score change of 4 points is considered clinically important, based on association with employment anchors. Optimal thresholds for statistically reliable SDMT changes, accounting for test reliability and measurement error, are yet to be applied to individual cases. Objective: The aim of this study was to derive a statistically reliable marker of individual change on the SDMT. Methods: This prospective, case–control study enrolled 166 patients with multiple sclerosis (MS). SDMT scores at baseline, relapse, and 3-month follow-up were compared between relapsing and stable patient groups. Using data from the stable group and three previously published studies, candidate thresholds for reliable decline were calculated and validated against other tests and a clinically meaningful anchor—cognitive relapse. Results: Candidate thresholds for reliable decline at the 80% confidence level varied between 6 and 11 points. An SDMT change of 8 or more raw score points was deemed to offer the best balance of discriminatory power and external validity for estimating cognitive decline. Conclusion: This study illustrates the feasibility and usefulness of reliable change methodology for identifying statistically meaningful cognitive decline that could be implemented to identify change in individual patients, for both clinical management and clinical trial outcomes.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system, often presenting with brain atrophy and cognitive impairment (CI). In the relapsing–remitting phenotype, cognitive performance is increasingly recognized to decline acutely during MS relapse, with varying degrees of recovery afterwards. Therefore, CI in MS may result from incomplete recovery from episodes of so-called “cognitive relapse”, gradual neurodegeneration, or both. Among a variety of validated measures of cognitive performance, the Symbol Digit Modalities Test (SDMT) represents the most sensitive measure of cognitive decline and is easily translated to clinical practice. In fact, cognitive relapse identified using the SDMT has been reported in clinically relapsing cohorts as well as in individuals with no other neurological signs, suggesting that routine cognitive assessment may be necessary to fully appreciate the extent of a patient’s disease activity. The aim of this narrative review is as follows: (1) to provide the historical context for neuropsychological assessment in MS, (2) to provide a summation of key studies describing the cognitive relapse phenomenon, and (3) to discuss current gaps in our knowledge and highlight avenues for future research.

Background: Paramagnetic rim lesions (PRL) may be linked to relapse risk of people with relapsing–remitting multiple sclerosis (pwRRMS). Objective: To determine the relationship between presence of PRL lesions and cognitive recovery after relapse. Methods: PRL load was compared between acutely relapsing pwRRMS and matched stable pwRRMS controls (each group n = 21). In addition, cognitive recovery was compared between acutely relapsing pwRRMS with at least one PRL (PRL+) and those without any PRL (PRL−). Results: Acutely relapsing pwRRMS had significantly greater prevalence and number of PRL ( p = 0.004 and p = 0.003) compared with stable controls. These findings remained significant after adjusting for global neuroinflammatory burden (enhancing and non-enhancing lesions). In addition, acutely relapsing PRL + pwRRMS ( n = 10) had worse recovery of verbal memory following relapse compared with acutely relapsing PRL − pwRRMS ( n = 7; p = 0.027). Conclusion: These findings may partially explain previously suggested associations between presence of PRL with more severe disease course.