Cognitive functions over the course of 1 year in multiple sclerosis patients treated with disease modifying therapies

Abstract

Objectives: Disease-modifying therapies (DMTs) are applied to delay or prevent disease progression in multiple sclerosis (MS). While this has mostly been proven for physical symptoms, available studies regarding long-term effects of DMTs on cognitive functions are rare and sometimes inconsistent due to methodological shortcomings. Particularly in the case of fingolimod, comprehensive data on cognitive functions are not yet available. Therefore, we set out to reliably assess cognitive functions in patients with relapsing-remitting MS (RRMS) treated with DMTs over 1 year. Methods: Cognitive functions were assessed with eight tests at three timepoints: baseline, 6-month follow up and 12-month follow up. First, we investigated whether the stability of cognitive functions (i.e. not falling below the 5% cut-off in more than one test) over 1 year in RRMS patients (n = 41) corresponds to the stability in healthy individuals (n = 40) of a previous study. Second, we compared the percentage of declined and improved patients in the different tests. Third, we compared patients treated with fingolimod (n = 22) with patients treated with natalizumab (n = 11) with regard to cognitive stability. Fourth, based on the patient data, the Reliable Change Index was applied to compute cut-offs for reliable cognitive change.Results: Approximately 75% of RRMS patients treated with DMTs remained stable over the course of 1 year. The Paced Auditory Serial Addition Test (PASAT) and the Spatial Recall Test (SPART), produced improvements in 12.5% and 30.6%, respectively, probably due to practice effects. Patients treated with fingolimod did not differ from patients treated with natalizumab with regard to cognitive stability. Conclusions: Cognitive functions remain relatively stable under DMT treatment over 1 year, irrespective of the type of medication. Furthermore, the tests PASAT and SPART should be interpreted cautiously in studies examining performance changes over time. The provided RCI norms may help clinicians to determine whether a difference in two measurements observed in a RRMS patient is reliable.

Baseline characteristics and effects of fingolimod on cognitive performance in patients with relapsing‐remitting multiple sclerosis

“…The fact that a significant difference in mean PASAT-3 score emerges at 6 months and remains for the 24 months of double-blind phases of the trials, and that a clear difference is maintained till the end of the study, indicates that early treatment with fingolimod was effective in preserving cognitive function in the long term. The 2.1-point difference in mean PASAT-3 score at 24 months is close to the reported 2.5 mean difference between MS patients with stable and deteriorated work status after 40 months [37], and is therefore arguably clinically meaningful [22]. PASAT mean scores also significantly differentiate work-stable, work-challenged and work-disabled MS patient groups [38], clearly linking PASAT performance to real-world function.…”

“…Observational, often uncontrolled, studies provide evidence supporting the treatment effect on cognitive dysfunction for interferon‐beta [ 19 ] and natalizumab [ 20 , 21 ]. There are several other, open‐label studies with varying findings [ 22 , 23 , 24 ]. Recently, more randomized clinical trials have been evaluating cognitive performance; however, very limited data are available.…”

Practice effects in performance outcome measures in patients living with neurologic disorders – A systematic review

“…Practice effects can also be quantified by computing the ratio between the test scores at retest and at baseline to obtain a progression ratio ( Prince et al., 2018 ). An alternative approach to estimate a reliable change index from a normative or reference population ( Duff et al., 2017 ; Rosas et al., 2020 ; Turner et al., 2016 ; Utz et al., 2016 ). The reliable change index can be applied on an individual patient level and compared against the observed change.…”

“…', however, do not take differences in practice effects between individual patients into account. Only few studies acknowledged that practice effects may differ from patient to patient and performed their analyses in subgroups of patients defined by their practice effects response or on an individual patient level (Duff et al 2014;Duff et al 2017;Pham et al, 2021;Prince et al, 2018;Rosas et al 2020;Sormani et al, 2019;Turner et al 2016;Utz et al 2016). Analyses of longitudinal data in daily clinical practice could however benefit from methods to study practice effects on an individual patient level.…”

Mechanisms of neurobehavioral abnormalities in multiple sclerosis: Contributions from neural and immune components

“…Evidence shows that these divisions are artificial and that both processes occur throughout the natural history of the disease ( Glanz et al, 2007 , Potagas et al, 2008 , Rao et al, 1991 ). For instance, the disease-modifying treatments (DMTs), which target inflammatory demyelination, not only diminish the frequency of relapses but also ameliorate some of the NBAs associated with MS ( Mattioli et al, 2015 , Utz et al, 2016 , Ozakbas et al, 2016 ). This suggests that both processes operate simultaneously and that their understanding could point to novel therapeutic targets to achieve an integral management of the disease.…”