Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes

MINI REVIEW published: 20 March 2019 doi: 10.3389/fneur.2019.00261 Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes Bruno Brochet 1,2* and Aurélie Ruet 1,2 1 Service de Neurologie, CHU de Bordeaux, Bordeaux, France, 2 Team Glia-Neuron Interactions, Neurocentre Magendie, INSERM U1215, Université de Bordeaux, Bordeaux, France Edited by: Dawn Wendy Langdon, Royal Holloway, University of London, United Kingdom Reviewed by: Niels Bergsland, University at Buffalo, United States Ralf Lürding, University of Regensburg, Germany *Correspondence: Bruno Brochet Specialty section: This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology Received: 06 November 2018 Accepted: 27 February 2019 Published: 20 March 2019 Citation: Brochet B and Ruet A (2019) Cognitive Impairment in Multiple Sclerosis With Regards to Disease Duration and Clinical Phenotypes. Front. Neurol. 10:261. doi: 10.3389/fneur.2019.00261 Frontiers in Neurology | www.frontiersin.org The relationships between cognitive impairment that exist during the clinical course of multiple sclerosis (MS) remain poorly described. The effect of disease duration has been studied in a few longitudinal cohorts and some cross-sectional studies that suggest that cognitive deficits tend to extend with disease duration. However, the effect of disease duration seems to be confounded by the effect of age. At the pre-clinical stage, cognitive deficits have been observed in patients with radiologically isolated syndromes, and their profile is similar than in clinically isolated syndromes (CIS) and relapsing-remitting MS (RRMS). The frequency of cognitive impairment tends to be higher in RRMS than in CIS. In these phenotypes, slowness of information processing speed (IPS) and episodic verbal and visuo-spatial memory deficits are frequently observed, but executive functions, and in particular verbal fluency, could also be impaired. More frequent and severe deficits are reported in SPMS than in RRMS with more severe deficits for memory tests, working memory and IPS. Similarly to what is observed in SPMS, patients with primary progressive MS (PPMS) present with a wide range of cognitive deficits in IPS, attention, working memory, executive functions, and verbal episodic memory with more tests and domains impaired than RRMS patients. Altogether these data suggested that not only the duration of the disease and age play an important role in the cognitive profile of patients, but also the phenotype itself, probably because of its specific pathological mechanism. Keywords: multiple sclerosis, neuropsychology, cognition, phenotypes, cognition INTRODUCTION The relationships between cognitive impairment (CI) associated with multiple sclerosis (MS) that exist during the clinical course of the disease remain poorly described. When considering the prevalence of CI in the different phenotypes, the respective effects of disease duration and age (and consequently the accumulation of pathology) and of the clinical phenotypes (meaning the different pathological mechanisms underlying these phenotypes) have to be considered. These two dimensions overlapped largely, since in relapsing-onset MS the clinical phenotypes such as clinically isolated syndromes (CIS), relapsing-remitting (RR), and secondary progressive (SP) occur successively. Methodological issues have to be taken into account when comparing the different studies. First, the NP tests could vary notably between studies. The number of tests, the domains studied, and the psychometric properties of the tests used could affect the results. Second, the definition of CI could also vary; for example, the number of NP scores need to be abnormal and different statistical thresholds were used. In this paper we provide details about the main studies, summarized in tables. 1 March 2019 | Volume 10 | Article 261 Brochet and Ruet Cognitive Impairment in MS Phenotypes COGNITIVE IMPAIRMENT AND DISEASE DURATION performed in another purpose, the so-called RIS, CI has been observed with a similar cognitive profile than in RRMS affecting information processing speed (IPS) and memory (11, 12). So far, only small studies are available, and it is not possible to conclude on the prevalence of CI in RIS. The impact of disease duration on CI has been a matter of debate for many years. This question has been addressed in a few longitudinal studies (1–4), but also in several cross-sectional studies taking disease duration as a covariate (5–8). Table 1 summarizes the longitudinal studies. In a long-term controlled study, Amato et al. (3) and (4) examined 50 MS patients with short disease duration and 70 matched healthy controls (HC). After 10 years, impairment was confirmed for short-term verbal memory, abstract reasoning and linguistic abilities, but attention and short-term spatial memory were also involved (4). This study suggests that as the disease progresses, cognitive deficits tend to extend. Moreover, the proportion of patients who were cognitively preserved decreased over time from 74% at baseline to 44% after 10 years, while the proportion of patients with mild or moderate impairment tended to increase. Early cross-sectional studies concluded with a weak correlation between CI and disease duration (5, 6), or no correlation (7). In a large cross-sectional study including 1,500 MS patients evaluated by computerized NP testing, Achiron et al. (8) studied the effect of disease duration and observed that the proportion of CI increased over 25 years. In another study performed in 168 patients examining the different phenotypes using the Brief-Repeatable Battery of NP tests (BRBN), an effect of disease duration was observed on all tests (9). A recent multi-center study in a large sample of 1,040 patients with MS tested using the BRB-N and the Stroop test, showed an association of CI with disease duration but also age and disability (10). However, when adjusting disease duration and clinical course to age and disability, the association with CI was no longer significant but it is quite obvious that age and disease duration are strongly associated. Clinically Isolated Syndromes It is difficult to compare studies performed in different clinical phenotypes in different settings, with various NP batteries. Studies evaluating MS patients with different phenotypes using a similar methodology are necessary for comparing CI according to these phenotypes. However, the demographic characteristics of the different phenotypes, such as age and gender in particular, are different, and this needs to be taken into account by using appropriate controls. Two of the earliest studies conducted on CI in the MS spectrum were, in fact, in patients with optic neuritis, one of the most common type of CIS (13) and in CIS in general (14, 15). Many studies have been performed since, but only controlled studies with a healthy cont (...truncated)