The presence and burden of cognitive issues: discordance between the perception of neurologists and people living with multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment is a common symptom of multiple sclerosis (MS) and occurs in more than 40% of people living with MS (plwMS). No real-world study has assessed the perception of neurologists and plwMS on cognitive issues. METHODS: Using data from the 2011-2019 Adelphi MS Disease Specific Programme database, this real-world, retrospective, cross-sectional multi-cohort study included people aged ≥18 years with relapsing-remitting MS and secondary progressive MS from the United States, UK and the EU. Neurologists provided data on the patient record form for plwMS, with the same plwMS invited to voluntarily complete a patient self-completion form: a questionnaire about their experiences with MS. RESULTS: Of 25,374 plwMS, 4817 who provided information on cognitive and mood symptoms were included in the analysis. Of the plwMS, 68% and 59% reported feeling 'mentally fatigued' and having 'difficulty concentrating', respectively. Neurologists reported only 27% of plwMS as having 'difficulty concentrating' and 15% of plwMS as having 'short-/long-term memory problems'. Neurologists reported cognitive or mood symptoms as 'not experienced' by a higher percentage of participants with relapsing-remitting MS than secondary progressive MS. Of the plwMS who experienced 'difficulty concentrating', most had a concomitant feeling of being 'mentally fatigued' (52%), followed by 'feeling anxious or tense' (49%) and 'feeling depressed' (44%). In plwMS, caregivers reported 'difficulty concentrating' (16%) as the most common cognitive issue. CONCLUSION: A clear discordance was observed between neurologists and plwMS regarding the perception of the cognitive and neuropsychiatric issues. These results underline the under-perception of cognitive and emotional affective symptoms in plwMS during neurological consultations.

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis.

BACKGROUND: Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. OBJECTIVE: We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. RESULTS: Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. CONCLUSION: Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.

The importance of pyramidal tract integrity for cortical plasticity and related functionality in patients with multiple sclerosis.

Background: Cortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs). Objective: This study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS. Methods: QPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes. Results: There were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p < 0.001). Conclusion: Our study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease.

Prevalence and prognostic value of neurological affections in hospitalized patients with moderate to severe COVID-19 based on objective assessments.

Neurological manifestations of coronavirus disease 2019 (COVID-19) have been frequently described. In this prospective study of hospitalized COVID-19 patients without a history of neurological conditions, we aimed to analyze their prevalence and prognostic value based on established, standardized and objective methods. Patients were investigated using a multimodal electrophysiological approach, accompanied by neuropsychological and neurological examinations. Prevalence rates of central (CNS) and peripheral (PNS) nervous system affections were calculated and the relationship between neurological affections and mortality was analyzed using Firth logistic regression models. 184 patients without a history of neurological diseases could be enrolled. High rates of PNS affections were observed (66% of 138 patients receiving electrophysiological PNS examination). CNS affections were less common but still highly prevalent (33% of 139 examined patients). 63% of patients who underwent neuropsychological testing (n = 155) presented cognitive impairment. Logistic regression models revealed pathology in somatosensory evoked potentials as an independent risk factor of mortality (Odds Ratio: 6.10 [1.01-65.13], p = 0.049). We conclude that hospitalized patients with moderate to severe COVID-19 display high rates of PNS and CNS affection, which can be objectively assessed by electrophysiological examination. Electrophysiological assessment may have a prognostic value and could thus be helpful to identify patients at risk for deterioration.

Psychological factors and brain magnetic resonance imaging metrics associated with fatigue in persons with multiple sclerosis.

BACKGROUND: Besides demographics and clinical factors, psychological variables and brain-tissue changes have been associated with fatigue in persons with multiple sclerosis (pwMS). Identifying predictors of fatigue could help to improve therapeutic approaches for pwMS. Therefore, we investigated predictors of fatigue using a multifactorial approach. METHODS: 136 pwMS and 49 normal controls (NC) underwent clinical, neuropsychological, and magnetic resonance imaging examinations. We assessed fatigue using the "Fatigue Scale for Motor and Cognitive Functions", yielding a total, motor, and cognitive fatigue score. We further analyzed global and subcortical brain volumes, white matter lesions and microstructural changes (examining fractional anisotropy; FA) along the cortico striatal thalamo cortical (CSTC) loop. Potential demographic, clinical, psychological, and magnetic resonance imaging predictors of total, motor, and cognitive fatigue were explored using multifactorial linear regression models. RESULTS: 53% of pwMS and 20% of NC demonstrated fatigue. Besides demographics and clinical data, total fatigue in pwMS was predicted by higher levels of depression and reduced microstructural tissue integrity in the CSTC loop (adjusted R2 = 0.52, p < 0.001). More specifically, motor fatigue was predicted by lower education, female sex, higher physical disability, higher levels of depression, and self-efficacy (adjusted R2 = 0.54, p < 0.001). Cognitive fatigue was also predicted by higher levels of depression and lower self-efficacy, but in addition by FA reductions in the CSTC loop (adjusted R2 = 0.45, p < 0.001). CONCLUSIONS: Our results indicate that depression and self-efficacy strongly predict fatigue in MS. Incremental variance in total and cognitive fatigue was explained by microstructural changes along the CSTC loop, beyond demographics, clinical, and psychological variables.

Multiple sclerosis and quality of life: The role of cognitive impairment on quality of life in people with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS), a chronic disease of the central nervous system (CNS), affects functional ability and quality of life (QoL). Depression, fatigue, and disability status are among the many factors that have been shown to impact QoL in people with MS, but the extent to which MS-related cognitive impairment is related to QoL is understudied in the literature. OBJECTIVE: The purpose of this study was to determine relevant predictors of QoL from a wide list of symptoms including physical disability, and a multi-dimensional computerized cognitive assessment battery (CAB), depression, fatigue, and demographic variables (including employment status). In addition, the unique predictive power of cognitive impairment on QoL was explored in relation to other common factors of disease impact. METHODS: 171 people with MS (PwMS) were evaluated with a computerized assessment battery (CAB), EDSS examination, and validated Patient Reported Outcome (PRO) measures (Multiple Sclerosis Impact Scale, MSIS-29; Beck Depression Inventory - Second Edition BDI-2; and the Modified Fatigue Impact Scale, MFIS). RESULTS: 171 PwMS were included [Age: 46.02 years ± 9.85, 124 (72.5%) female]. Depression and fatigue scores were highly correlated with MSIS-29. EDSS, unemployment, memory, executive functioning, and motor skills were moderately correlated with MSIS-29. Predictors of QoL were EDSS, depression, fatigue, executive functioning, and attention. Attention and executive functioning were predictive of QoL even after controlling for demographic variables, fatigue, depression, and physical disability status. CONCLUSION: Findings indicate the need for comprehensive and quantified evaluation of all factors associated with disease burden, which will ultimately serve to improve the QoL in PwMS through more targeted and patient-centered care.

Internet-delivered cognitive behavioural therapy programme to reduce depressive symptoms in patients with multiple sclerosis: a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Depression is three to four times more prevalent in patients with neurological and inflammatory disorders than in the general population. For example, in patients with multiple sclerosis, the 12-month prevalence of major depressive disorder is around 25% and it is associated with a lower quality of life, faster disease progression, and higher morbidity and mortality. Despite its clinical relevance, there are few treatment options for depression associated with multiple sclerosis and confirmatory trials are scarce. We aimed to evaluate the safety and efficacy of a multiple sclerosis-specific, internet-based cognitive behavioural therapy (iCBT) programme for the treatment of depressive symptoms associated with the disease. METHODS: This parallel-group, randomised, controlled, phase 3 trial of an iCBT programme to reduce depressive symptoms in patients with multiple sclerosis was carried out at five academic centres with large outpatient care units in Germany and the USA. Patients with a neurologist-confirmed diagnosis of multiple sclerosis and depressive symptoms were randomly assigned (1:1:1; automated assignment, concealed allocation, no stratification, no blocking) to receive treatment as usual plus one of two versions of the iCBT programme Amiria (stand-alone or therapist-guided) or to a control condition, in which participants received treatment as usual and were offered access to the iCBT programme after 6 months. Masking of participants to group assignment between active treatment and control was not possible, although raters were masked to group assignment. The predefined primary endpoint, which was analysed in the intention-to-treat population, was severity of depressive symptoms as measured by the Beck Depression Inventory-II (BDI-II) at week 12 after randomisation. This trial is registered at ClinicalTrials.gov, NCT02740361, and is complete. FINDINGS: Between May 3, 2017, and Nov 4, 2020, we screened 485 patients for eligibility. 279 participants were enrolled, of whom 101 were allocated to receive stand-alone iCBT, 85 to receive guided iCBT, and 93 to the control condition. The dropout rate at week 12 was 18% (50 participants). Both versions of the iCBT programme significantly reduced depressive symptoms compared with the control group (BDI-II between-group mean differences: control vs stand-alone iCBT 6·32 points [95% CI 3·37-9·27], p<0·0001, effect size d=0·97 [95% CI 0·64-1·30]; control vs guided iCBT 5·80 points [2·71-8·88], p<0·0001, effect size d=0·96 [0·62-1·30]). Clinically relevant worsening of depressive symptoms was observed in three participants in the control group, one in the stand-alone iCBT group, and none in the guided iCBT group. No occurrences of suicidality were observed during the trial and there were no deaths. INTERPRETATION: This trial provides evidence for the safety and efficacy of a multiple sclerosis-specific iCBT tool to reduce depressive symptoms in patients with the disease. This remote-access, scalable intervention increases the therapeutic options in this patient group and could help to overcome treatment barriers. FUNDING: National Multiple Sclerosis Society (USA).

Long-term potentiation-like plasticity is retained during relapse in patients with Multiple Sclerosis.

OBJECTIVE: To investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance. METHODS: Facilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse. RESULTS: Synaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity. CONCLUSIONS: QPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies. SIGNIFICANCE: New insights into synaptic plasticity during MS relapses are provided.

Non-pharmacological randomized intervention trial for the management of neuropsychological symptoms in outpatients with progressive multiple sclerosis.

PURPOSE: Despite typically more pronounced cognitive and mental health issues in progressive disease courses of multiple sclerosis (PMS), rehabilitation research in this subgroup is rare. The efficacy of two non-pharmacological interventions with positive results from prior investigations was therefore examined in PMS specifically. METHODS: Persons with PMS (pwPMS) received either computerized cognitive training (BrainStim), standardized cognitive-behavioral group sessions (Metacognitive Training [MaTiMS]), or a combination of both in an ambulatory setting. Neuropsychological assessment was conducted before and after the four-week intervention. RESULTS: 37 participants (13 with primary/24 with secondary PMS, meanage = 52.87, SDage = 7.11, meanEDSS = 4.02, SDEDSS = 1.35) entered analyses. The BrainStim group improved in immediate and delayed verbal memory, recognition, verbal working memory, and perceived cognitive deficits while experiencing increased anxiety post-intervention. MaTiMS participants reported high program satisfaction and less cognitive difficulties at retest. The Combination group performed better in immediate and delayed verbal memory, and in information processing speed after training. Descriptive data further indicated positive effects on anxiety and depression in the MaTiMS and Combination group. CONCLUSIONS: While objective cognitive performance improved when explicitly trained, psychoeducative sessions contributed to subjective mental health. The combination of both approaches is thus suggested, considering the specific needs of pwPMS treated in an ambulatory setting.

Cognitive impairment, fatigue and depression in multiple sclerosis: Is there a difference between benign and non-benign MS?

INTRODUCTION: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). The severity of disability in people with MS (PwMS) is generally measured with the Expanded Disability Status Scale (EDSS). A variant of MS known as 'benign MS' (BMS) has been defined as an EDSS score of 3 or lower, combined with a disease duration of 10 years or longer; however, there is disagreement in the field about whether BMS really exists. Given that the EDSS does not capture cognitive issues, communication dysfunction, fatigue, depression, or anxiety properly, its ability to accurately represent disability in all PwMS, including BMS, remains questionable. METHODS: In this study, 141 persons with BMS (PwBMS) were included, consisting of 115 females (82%) and 26 males (18%) with a mean age of 50.8 (±8.68). A computerized test battery (NeuroTrax®) was used to assess cognition, covering seven cognitive domains (memory, executive function, visual-spatial processing, verbal function, attention, information processing, and motor skills). Fatigue was measured using the Fatigue Severity Scale (FSS). The Beck Depression Inventory (BDI) was used to assess symptoms of depression. Cognitive impairment was defined for this study as when someone has a score lower than 85 in at least two subdomains of the cognitive test battery. Rates of impairment were compared to 158 persons with non-benign MS (PwNBMS; with a disease duration of 10 years and longer and an EDSS score higher than 3) and 487 PwMS with a disease duration of fewer than 10 years. RESULTS: Cognitive impairment was found in 38% of PwBMS and in 66% of PwNBMS (p<0.001). In PwBMS, the lowest rate of impairment was found in the verbal function domain (18%) and the highest rate of impairment in the domain of information processing (32%). Fatigue and depression were found in 78% and 55% of all PwBMS, with no difference in these rates between PwBMS and PwNBMS (p = 0.787 and p = 0.316 resp.) CONCLUSION: Cognitive impairment, fatigue and depression are common among people with an EDSS-based definition of benign MS. These aspects should be incorporated into a new and better definition of truly benign MS.

Supporting brain health in multiple sclerosis: exploring the potential of neuroeducation combined with practical mindfulness exercises in the management of neuropsychological symptoms.

OBJECTIVE: We aimed at examining the effects of a known metacognitive training in MS (MaTiMS) and its modification with an additional neuroeducational module and mindfulness-based exercises (MaTiMS-modified) on neuropsychiatric and cognitive outcomes in people with progressive multiple sclerosis (pwpMS). Exploratively, we investigated whether the modification may show an additional benefit. METHODS: Both interventions were administered in small groups of ambulatory patients. Neuropsychological testing before and after the 3- to 4-week intervention phase comprised patient reported outcomes and cognitive tests. After 3, 6 and 12 months, participants completed online surveys. Analysis of change scores (between baseline and retest) with t-tests (Mann-Whitney U and Wilcoxon tests, respectively) and mixed ANCOVAs with repeated measures for comparison of both interventions were conducted. RESULTS: A total of 65 pwpMS turned to a final sample of 50 (n = 15 excluded due to drop-outs, occurrence of relapse or steroid treatment). Change scores within MaTiMS revealed no significant effect on the PDQ-20 total score and only a significant effect on the subscale retrospective memory lasting 3 months with a moderate effect size. In contrast, MaTiMS-modified revealed a highly significant change in PDQ-20 total compared to baseline and significant improvements with small to moderate effect sizes on all PDQ-20 subscales (lasting until 3 months), in self-efficacy, stress, visuo-spatial working memory (moderate effect sizes), and fatigue (small effect size). While no interaction effect between time and group could be revealed, a significant main effect for time was found in PDQ-20 total. CONCLUSION: Both MaTiMS and MaTiMS-modified positively affected perceived cognitive deficits. However, our data speak in favor of additional benefits by adding neuroeducational and mindfulness-based exercises thus being valuable methods to support brain health including self-efficacy, perceived stress, and fatigue, even in patients with a chronic and progressive brain disease.

Cognitive impairment in people with multiple sclerosis: Perception vs. performance - factors that drive perception of impairment differ for patients and clinicians.

BACKGROUND: Neurologists' perceptions of the presence of cognitive impairment (CI) in people with multiple sclerosis (PwMS) may not always align with findings of objective cognitive assessment. The accuracy of self-reported CI in PwMS can also be highly variable across individuals, and may not align with objective measurement of cognitive disturbances. Research suggests that additional factors impact perceived cognitive ability, such as depression and fatigue. Objective cognitive screening regardless of patient or neurologist perception has been recommended but still is often limited in routine care. Moreover, comprehensive neuropsychological assessment is even less routinely done. OBJECTIVE: To explore how neurologists' perceptions of PwMS' CI compare to the perception of the patient by determining whether PwMS and their clinicians are accurate in detecting the presence and degree of CI as defined by a multi-domain validated computerized test battery in PwMS, as well as investigate what factors influence perception of CI in each group. METHODS: PwMS completed a computerized multi-domain cognitive testing battery, and self-reported measures of disease impact (MSIS-29), fatigue (MFIS), and depression (BDI-II). Disability was assessed by the clinician using the Expanded Disability Status Scale (EDSS). Clinicians and patients also provided an estimation of cognitive deficits along a Likert scale. RESULTS: In this cohort of PwMS (N=202, age range: 20 to 88, gender: 71% female), their level of accuracy in detecting attention deficits (k = -.028, p = .010) was low but statistically significant. In contrast, clinicians' accuracy in detecting global CI (k = -.037, p < .001) and a number of specific domain deficits was moderate. Fatigue (p < .001) and cognitive performance (p = .012) significantly predicted patient perceived cognitive deficits. Clinician perceived cognitive performance was significantly predicted by multiple factors: cognitive scores (p < .001), physical disability (p = .011), age (p = .021), and depression (p = .038). CONCLUSION: The need to objectively screen for CI in PwMS, regardless of perception, can be aided by a better understanding of the agreement and discrepancies between the patient and clinician regarding perceived cognitive disturbances and the presence of CI defined by a multi-dimensional objective screening battery.

The manifestation of affective symptoms in multiple sclerosis and discussion of the currently available diagnostic assessment tools.

INTRODUCTION: In addition to physical and cognitive symptoms, patients with multiple sclerosis (MS) have an increased risk of experiencing mental health problems. METHODS: This narrative review provides an overview of the appearance and epidemiology of affective symptoms in MS such as depression, anxiety, bipolar disorder, euphoria, and pseudobulbar affect. Furthermore, the association between affective symptoms and quality of life and the currently used diagnostic instruments for assessing these symptoms are considered whereby relevant studies published between 2009 and 2021 were included in the review. RESULTS: Patients with mild and moderate disability more frequently reported severe problems with depression and anxiety than severe mobility problems. Apart from the occurrence of depression, little is known about the association of other affective symptoms such as anxiety, bipolar disorder, euphoria, and pseudobulbar affect and subsyndromal symptoms, which fail to meet the diagnostic criteria but are nevertheless a significant source of distress. Although there are a few recommendations in the research to perform routine screenings for diagnosable affective disorders, a standardized diagnostic procedure to assess subsyndromal symptoms is still lacking. As the applied measurements are diverse and show low accuracy to detect these symptoms, patients who experience affective symptoms are less likely to be identified. DISCUSSION: In addition to the consideration of definite psychiatric diagnoses, there is an unmet need for a common definition and assessment of disease-related affective symptoms in MS. Future studies should focus on the improvement and standardization of a common diagnostic procedure for subsyndromal affective symptoms in MS to enable integrated and optimal care for patients.

Performance in information processing speed is associated with parietal white matter tract integrity in multiple sclerosis.

Background: The Symbol Digit Modalities Test (SDMT) is most frequently used to test processing speed in patients with multiple sclerosis (MS). Functional imaging studies emphasize the importance of frontal and parietal areas for task performance, but the influence of frontoparietal tracts has not been thoroughly studied. We were interested in tract-specific characteristics and their association with processing speed in MS patients. Methods: Diffusion tensor imaging was obtained in 100 MS patients and 24 healthy matched controls to compare seed-based tract characteristics descending from the superior parietal lobule [Brodman area 7A (BA7A)], atlas-based tract characteristics from the superior longitudinal fasciculus (SLF), and control tract characteristics from the corticospinal tract (CST) and their respective association with ability on the SDMT. Results: Patients had decreased performance on the SDMT and decreased white matter volume (each p < 0.05). The mean fractional anisotropy (FA) for the BA7A tract and CST (p < 0.05), but not the SLF, differed between MS patients and controls. Furthermore, only the FA of the SLF was positively associated with SDMT performance even after exclusion of the lesions within the tract (r = 0.25, p < 0.05). However, only disease disability and total white matter volume were associated with information processing speed in a linear regression model. Conclusions: Processing speed in MS is associated with the structural integrity of frontoparietal white matter tracts.

Effects of SativexⓇ on cognitive function in patients with multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Cognitive impairment is a common manifestation of multiple sclerosis (MS). OBJECTIVE: To assess by systematic review and meta-analysis available evidence regarding the impact of nabiximols oromucosal spray on cognition in patients with MS. METHODS: A systematic literature search of clinical studies (all types, any comparator) that measured cognitive function in patients with MS spasticity treated with nabiximols. Meta-analysis for cognitive endpoints was not possible due to heterogenous measurement instruments and outcomes. Meta-analysis was performed for adverse events (AEs) of special interest (cognition disorders) reported in randomized controlled trials (RCTs) of nabiximols versus placebo in patients with MS (with or without spasticity). Certainty of evidence and risk of bias were assessed. RESULTS: Seven clinical studies (three RCTs) directly assessing cognitive function were included in the qualitative analysis. There was no consistent evidence to suggest that nabiximols causes cognitive impairment as assessed by a range of specific psychometric instruments across cognitive domains. Thirteen double-blind, placebo-controlled RCTs (nabiximols, n = 964; placebo, n = 904) were included in the meta-analysis of cognitive AEs. Most cognitive AEs (30 of 32 events, 93.8%) reported with nabiximols in MS patients occurred with not in-label use, i.e., dosage >12 sprays per day and/or not administered primarily for treatment of spasticity. CONCLUSIONS: Within the limitations of the review, we can conclude that no detrimental effects of nabiximols on cognitive function were observed in patients with MS spasticity during up to 12 months follow-up and that cognitive AEs were rare and occurred only when nabiximols was not used according to its approved label.

The Seasonal Fluctuation of Fatigue in Multiple Sclerosis.

Background: Fatigue is a common symptom in patients with multiple sclerosis. Several studies suggest that outdoor temperature can impact fatigue severity, but a systematic study of seasonal variations is lacking. Methods: Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC) in a temperate climatic zone with an average outdoor temperature of 8.8°C. This study included 258 patients with multiple sclerosis from 572 visits temporally distributed over the year. The data were adjusted for age, sex, cognition, depression, disease severity, and follow-up time. Linear regression models were performed to determine whether the temporal course of fatigue was time-independent, linearly time dependent, or non-linearly time dependent. Results: Fatigue was lowest during January (mean FSMC: 49.84) and highest during August (mean FSMC: 53.88). The regression analysis showed the best fit with a model that included months + months2, which was a non-linear time dependency. Mean FSMC per month correlated significantly with the average monthly temperature (ρ = 0.972; p < 0.001). Conclusion: In multiple sclerosis, fatigue showed a natural temporal fluctuation. Fatigue was higher during summer compared to winter, with a significant relationship of fatigue with outdoor temperature. This finding should be carefully taken into account when clinically monitoring patients over time to not interpret higher or lower scores independent of seasonal aspects.

Brain age as a surrogate marker for cognitive performance in multiple sclerosis.

BACKGROUND AND PURPOSE: Data from neuro-imaging techniques allow us to estimate a brain's age. Brain age is easily interpretable as 'how old the brain looks' and could therefore be an attractive communication tool for brain health in clinical practice. This study aimed to investigate its clinical utility by investigating the relationship between brain age and cognitive performance in multiple sclerosis (MS). METHODS: A linear regression model was trained to predict age from brain magnetic resonance imaging volumetric features and sex in a healthy control dataset (HC_train, n = 1673). This model was used to predict brain age in two test sets: HC_test (n = 50) and MS_test (n = 201). Brain-predicted age difference (BPAD) was calculated as BPAD = brain age minus chronological age. Cognitive performance was assessed by the Symbol Digit Modalities Test (SDMT). RESULTS: Brain age was significantly related to SDMT scores in the MS_test dataset (r = -0.46, p < 0.001) and contributed uniquely to variance in SDMT beyond chronological age, reflected by a significant correlation between BPAD and SDMT (r = -0.24, p < 0.001) and a significant weight (-0.25, p = 0.002) in a multivariate regression equation with age. CONCLUSIONS: Brain age is a candidate biomarker for cognitive dysfunction in MS and an easy to grasp metric for brain health.