The current understanding of cognitive dysfunction in multiple sclerosis (MS) was informed by research conducted prior to the development of moderate-to-high efficacy disease-modifying treatments (DMTs) and based on earlier less sensitive diagnostic criteria for MS. Therefore, the objective of this study was to reevaluate the pattern of MS-related cognitive deficits in the context of higher efficacy DMTs and updated diagnostic criteria by examining rates of impairment across cognitive domains in current MS patients, and to compare those to a historical MS sample before the moderate-to-high efficacy DMT era.

This cross-sectional study incorporated data from 740 patients aged 18-69 years (M_age=44.3±12.2; 72.0% female, 28.0% male; 59.3% non-Hispanic White; 8.0±6.7 years diagnosed) diagnosed with relapse-onset MS in 1995 or after (i.e., DMT era) at a Northeastern academic medical center. All patients underwent a cognitive screening between 2018-2021, which assessed processing speed (WAIS-IV Symbol Search), verbal memory (Hopkins Verbal Learning Test-Revised), and nonverbal memory (CANTAB Paired Associate Learning). Rates of cognitive impairment (defined as ≤5th percentile vs. healthy standardization samples) were examined. Rates of impairment were also evaluated within unbiased subsamples for auditory attention (n=641, Brief Test of Attention, 2nd-9th percentile) and executive functioning (n=360, Tower of London, 2nd Ed. Total Move Score, ≤5th percentile). Chi-square analyses were conducted to compare relapsing-remitting MS (RRMS; n=628) and secondary progressive MS (SPMS; n=112) phenotypes on rates of cognitive impairment. Finally, the rate of processing speed impairment in current MS patients was compared to a historical sample of 215 relapse-onset patients (162 RRMS, 53 SPMS) published in 2004, before moderate-to-high efficacy DMTs. 

Rates of impairment were 9.3% for processing speed, 25.0% for verbal memory, 15.5% for nonverbal memory, 10.0% for auditory attention, and 13.1% for executive functioning. Impairment rate was significantly higher in SPMS than RRMS across cognitive domains, p’s < 0.05. Specifically, rates of impairment in SPMS were nearly double that of RRMS patients for processing speed (25.9% vs. 6.4%), auditory attention (15.5% vs. 8.9%), verbal memory (42.9% vs. 21.8%), nonverbal memory (29.5% vs. 13.1%), and executive functioning (26.4% vs. 10.7%). Relative to the historical comparison group (M_age=45.3±9.0; 71% female, 29% male; 92% non-Hispanic White; 6.0±6.3 years diagnosed), rate of processing speed impairment was much lower in the current vs. 2004 sample for RRMS (6.4% vs. 15.4%) and SPMS (25.9% vs. 58.5%) patients. 

Processing speed impairment in RRMS and SPMS appears less common with access to higher-efficacy DMTs, which challenges extant models of MS cognitive dysfunction. In fact, despite prevalent memory deficits, rates of impairment in processing speed and auditory attention among patients with RRMS did not differ from normative expectations. These findings challenge the common speed-centric belief that patients with RRMS have memory deficits because of slower processing speed or attention difficulty. Further work to elucidate and engender a model of MS cognition is a critical first step to inform appropriate cognitive interventions for MS patients.