Association between limbic system lesions and anxiety in persons with multiple sclerosis.

BACKGROUND: Persons with Multiple Sclerosis (PwMS) have a higher rate of anxiety and depression than the general population. Depression has been associated with clinical relapses; temporal lesions were shown to predict depression severity. Anxiety is considerably understudied. The role of MS lesions in the limbic system is also understudied, partly due to difficulties identifying limbic lesions on standard 1.5 and 3 Tesla MRI. METHODS: This is a retrospective study of 23 PwMS who underwent 7T MRI on the same day as completing the Hospital Anxiety and Depression Scale (HADS). MRI was performed on a Siemens 7T MRI Plus and an 8-channel transmit coil with 32 receiver channels operating in pTx mode. MP2RAGE and DIR-SPACE sequences were analyzed to determine the number of lesions within the limbic system. RESULTS: The median number of lesions in the limbic system was 2.0 (range 0-7). When comparing the presence or absence of lesions in the limbic system, there was a significant relationship with anxiety (X2 (1, N = 23)=4.44, p = 0.035), but not for depression. CONCLUSION: Although only a small sample size, this study provides preliminary evidence that lesions in the limbic system are associated with the presence of anxiety in PwMS. This relationship warrants further investigation.

Does multilingualism act as a protective factor (cognitive reserve) against cognitive impairment in multiple sclerosis?: A retrospective cohort study.

BACKGROUND: Cognitive impairment (CI) is common in multiple sclerosis (MS), affecting half of persons with MS (PwMS). Cognitive reserve has been associated with delaying the onset and slowing the progression of CI in PwMS. Multilingualism has been demonstrated to be a protective factor against CI in Alzheimer's disease (AD) but has never been studied in PwMS. OBJECTIVE: To explore if multilingualism is a protective factor against CI in PwMS. METHODS: This is a retrospective cohort study of PwMS aged 18-59, with a confirmed diagnosis of relapsing MS, fluent in English, who completed the Minimal Assessment of Cognitive Function in MS (MACFIMS) at the London (ON) MS Clinic. Any PwMS with a history of dementia or developmental delay, daily marijuana use, a major psychiatric disorder, or less than grade 9 education was excluded. We focused on the Brief Visuospatial Memory Test (BVMTR), immediate recall (-IR) and delayed recall (-DR) as it would be the least affected by language, as well as the Symbol Digit Modalities Test (SDMT), as information processing speed is the most commonly affected domain in PwMS. One-way ANOVA was used to compare raw scores on the BVMTR and SDMT between groups (uni- vs. multillingual), while chi-square was used to compare impairment on BVMTR and SDMT between groups. RESULTS: The cohort consisted of 678 subjects. The mean age was 39.7 (± 9.6) years with 501 (73.9 %) females (sex at birth), the mean duration of disease of 5.9 (± 6.9) years, and mean years of education was 13.9 (±2.2). The majority of subjects (563, 83 %) were unilingual and (115, 17 %) were multilingual; 102 subjects were bilingual and 13 subjects fluent in ≥ three languages. English was the first language was in most of subjects (614, 90.6 %). There was no significant difference on the BVMTR-IR scores (p = 0.189) or BVMTR-DR (p = 0.096) between groups. Similarly, there was no difference in the number of subjects impaired on the BVMTR-IR (X2 (1, N = 678) = 3.167, p = 0.057) or BVMT-DR between groups (X2 (1, N = 678) = 2.996, p = 0.083). Further, there was no significant difference on the SDMT (p = 0.506) between groups, or in number of subjects impaired on the SDMT between groups (X2 (1, N = 678) = 1.023, p = 0.312). CONCLUSION: This study shows that multilingualism does not have a protective effect against CI in PwMS and does not play a role in enriching the cognitive reserve, in contrast to studies in AD. This difference may be explained by a different underlying pathological mechanism in these diseases and warrants further study.

Is there a multiple sclerosis personality? Personality characteristics in newly diagnosed multiple sclerosis and association with mood and cognition.

BACKGROUND: Neuropsychiatric changes are common in multiple sclerosis (MS). Personality in persons with MS (pwMS) is understudied despite its implications for health behaviours, symptoms, and quality of life (QOL). OBJECTIVE: To assess baseline personality characteristics and their relationship to information processing speed (IPS) and mood in persons with early MS. METHODS: A retrospective chart review of 384 pwMS who had psychometric testing within 2 years of diagnosis between February 2012 and May 2021. Testing included the NEO-Five Factor Inventory, Symbol Digit Modalities Test, and Hospital Anxiety and Depression Scale (HADS). RESULTS: Participants were highly agreeable (53.7%). Most had impaired IPS (60.5%). Anxiety and depression were present in 194 (50.5%) and 87 (22.6%) participants, respectively. Females were more agreeable and conscientious. Neuroticism, conscientiousness, and extraversion had moderate-high correlations with anxiety and depression. Despite weak correlations with conscientiousness, extraversion, and openness, pwMS with impaired versus normal IPS had no significant personality differences. CONCLUSIONS: Individuals with recently diagnosed MS are agreeable, typically have impaired IPS, and often have anxiety or depression. Significant personality differences exist between sexes and between pwMS with or without anxiety or depression. Early identification of these neuropsychiatric traits in pwMS may improve treatment adherence, symptoms, and QOL.

Predictors of cognitive fatigue and fatigability in multiple sclerosis.

BACKGROUND: Persons with multiple sclerosis (PwMS) commonly experience cognitive fatigue (CF), defined as a decrease in cognitive performance with sustained activity, yet CF remains understudied. Further, the relationship between subjective CF and objective CF, or cognitive fatiguability, has not been fully elucidated in previous studies. Understanding the predictors of cognitive fatigue may scaffold the development of interventions that target this symptom. The objective of this prospective study was to evaluate the extent to which depression, anxiety, information processing speed, and sleep quality predict subjective and objective CF. METHODS: PwMS were recruited from one academic MS clinic in London (ON) Canada. Objective CF was measured by the Paced Auditory Serial Addition Test (PASAT), where performance on the last third of the PASAT is compared to performance on the 1st third, a validated measurement of objective CF. Subjective CF was measured by the cognitive component of the Modified Fatigue Impact Scale (MFIS). Additionally, depression, anxiety, information processing speed, and sleep quality data was collected. All assessments took place on the same day. Pearson's r was calculated to examine the relationship among all continuous outcome measures while linear regression analyses were used to examine predictors of subjective and objective CF. RESULTS: The sample consisted of 53 subjects who were mostly female (37; 69.8%) with a mean age of 44.2 years; the majority (47; 88.7%) had relapsing MS. Objective CF and subjective CF were not significantly related (r = - 0.16). Further, there was no statistically significant predictors of objective CF noted. In contrast, subjective CF demonstrated a statistically significant relationship with the Symbol Digit Modalities Test (SDMT; r = - 0.29, p = .05), Hospital Anxiety and Depression Scale (HADS), depression subscale (r = 0.61, p < .001), HADS anxiety subscale (r = 0.54, p < .001), and sleep quality (r = 0.33, p = .02). Additionally, all variables predicted subjective CF, R2adj = 0.384 [F (6, 40) = 5.783, p = .0002]. In particular, anxiety significantly predicted subjective CF when controlling for depression, information speed, and sleep quality. CONCLUSION: This study demonstrated that subjective CF is significantly predicted by anxiety, and strongly influenced by information processing impairment and depression. Addressing underlying affective factors, such as anxiety or depression, may help alleviate perceived or subjective CF among PwMS, thus improving their function and quality of life. Further studies with a larger sample size or longitudinal follow up may help define predictors of objective CF.

A mindfulness group intervention in newly diagnosed persons with multiple sclerosis: A pilot study.

BACKGROUND: Relapsing MS (RMS) is a lifelong disease without a cure, usually diagnosed between 20-40 years of age. Being newly diagnosed with RMS is a highly stressful event due to the unpredictable disease course after diagnosis. Thus, it is imperative that persons with MS have the skills and support to cope with the negative physical and emotional effects of the disease. The objective of this study was to assess whether a mindfulness-based intervention (MBI) would improve coping skills and thus lessen the negative consequences of stress due to being newly diagnosed with RMS. METHODS: This was a single-blind (assessor), randomized, prospective study of a 10-week MBI vs. usual standard of care in persons newly diagnosed (within 1 year) with RMS, recruited from one tertiary care MS clinic in London (ON), Canada. The MBI was administered in group format with a trained MBI facilitator. Primary outcomes included the Brief COPE measure and the Hospital Anxiety and Depression Scale (HADS) subscales. Secondary outcomes included measures of perceived stress, cognitive function, fatigue, and quality of life. Exploratory (tertiary) outcomes included serum markers of inflammation and stress. Subjects were assessed at baseline, post intervention (or equivalent) and 6 months later. A repeated measures multivariate analysis of covariance (MANCOVA) was used, with baseline scores employed as covariates and the test scores, to compare longitudinal changes, immediately after the MBI sessions and 6 months later. RESULTS: Twenty-five subjects were recruited (16 MBI, 9 controls) for two (Fall and Spring) MBI interventions over 1.5 years. All controls completed the study, while 4 MBI participants did not, leaving 21 subjects in the analysis. Most were women (17, 81%), with a mean age of 37.1 ± 9.4 years. Two thirds had already started a DMT at the time of consent; the median EDSS was 2.0 (0.0-4.0). The groups were well matched on baseline characteristics, with the exception of months since diagnosis (MBI 6.4 ± 6.5 vs. control 3.6 ± 2.8, p=0.023). All controls completed the study, while 4 MBI participants did not. The MBI group improved significantly on the COPE measure when compared to the control group (p=0.024) pre and post intervention; the MBI group also improved significantly on the HADS depression subscale (p=0.007). There was no significant difference over time on the HADS anxiety subscale (p=0.179). The effect size on COPE was 0.56 and 0.40 on HADS-D. On the secondary outcomes, there was a significant improvement on the Perceived Stress Scale (p=0.015). The exploratory outcomes were not significantly different. None of the outcomes were significant at the six-month follow-up. CONCLUSION: This pilot study demonstrates that an MBI may improve coping, depression and perceived stress in newly diagnosed (within one year) persons with RMS in the short term. Future research to confirm these results, as well as further investigate measures to extend the benefit beyond the immediate intervention.

Does cognitive training improve attention/working memory in persons with MS? A pilot study using the Cogmed Working Memory Training program.

BACKGROUND: Cognitive deficits, especially in attention, are common in persons with MS (PwMS) and are associated with clinically meaningful outcomes, such as work disability and lower quality of life (QOL). In this study, we aimed to determine whether Cogmed Working Memory Training (CWMT) improves attention/working memory in PwMS displaying impairment in these domains. METHODS: This single blind, randomized controlled, pilot study compared the effects of CWMT, a five-week evidenced-based computer-assisted training program that is supported by weekly meetings with a coach, to standard medical care (treatment as usual). We recruited PwMS from one MS center (London (ON) Canada), aged 18-64, with an Expanded Disability Status Scale (EDSS) score of ≤ 7.0, and a visual acuity (corrected) of at least 20/70. Potential subjects had to demonstrate impaired attention on at least two of three measures (Paced Auditory Serial Addition Test [PASAT], Symbol Digit Modalities Test [SDMT], and/or DKEFS Color-Word Interference Test); these measures also served as the primary study outcomes. Subjects were randomized to either the CWMT or treatment as usual. Secondary cognitive outcomes included other measures of attention, memory, as well as a self-reported cognitive function measure. Self-reported measures of mood (depression and anxiety), pain, and QOL were also included as other secondary outcomes. Subjects received assessments at baseline, post-treatment, and 6-month follow-up, or an equivalent time period for the treatment as usual group. The two groups were compared at baseline on background measures using independent samples t-tests, Chi-Square tests, and Mann-Whitney U tests. To analyze primary and secondary outcomes, a non-parametric approach was used due the small sample size and that many of our outcomes did not meet assumptions for parametric analyses. Friedman's test was conducted followed by post hoc pairwise comparisons within each group using Wilcoxon Signed-Rank tests with Bonferroni corrected post hoc contrasts, which allowed us to examine for differences between time points. RESULTS: Of 30 subjects, 15 were assigned to CWMT. Significant training effects were noted in 1 of 3 primary attentional outcomes (DKEFS Color-Word Interference Test), 2 of 3 secondary attentional outcomes (Letter-Number Sequencing, Digit Span), and 1 mood scale (Hospital Anxiety and Depression scale (HADS) - Depression Subscale), ps < .025. No significant changes were observed in the treatment as usual group. CONCLUSION: This pilot study demonstrates that cognitive training with CWMT has the potential to improve attention/working memory in PwMS, as well as a potential positive effect on mood, in PwMS. Further exploration of this intervention in PwMS with attention/working memory impairment is warranted.

Predictors of vocational status among persons with multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a common cause of neurological disability in young to middle-aged adults, resulting in physical, psychosocial, and cognitive impairments. Manifestation of these symptoms during crucial work-life years can greatly influence the ability of persons with (PwMS) to retain employment. It is unknown what factors are most important in leading to work disability, and if/how these different factors interact with each other and result in work disability. OBJECTIVE: To determine significant predictors of vocational status among PwMS using a structural equation modeling approach. METHODS: A retrospective chart review identified PwMS at an academic tertiary care hospital. The following data was collected: demographics and disease characteristics, vocational status, physical disability status (Expanded Disability Status Scale, EDSS), fine motor function (Nine Hole Peg Test, NHPT), generalized fatigue (Fatigue Severity Scale, FSS), mood and anxiety symptoms (Hospital Anxiety and Depression Scale, HADS) and cognitive function (Symbol Digit Modalities Test, SDMT). An exploratory structural equation model (SEM) was developed to examine the predictive utility of clinical and psychosocial variables on vocational status after controlling for demographic and disease characteristics. The fit of the model to the data was examined using the comparative fit index (CFI), normal fit index (NFI), root-mean-squared error of approximation (RMSEA), and standardized root mean residual (SRMR). RESULTS: There were 158 PwMS included in the analysis. The final model demonstrated that SDMT (ß = 0.16), EDSS (ß = -0.33), and HADS-D (ß = -0.23) significantly predicted vocational status (ps < 0.05). It explained 37% of the variance and provided a good fit to the data (χ2(11) = 13.01, p > 0.05, SRMR = 0.055, RMSEA = 0.034, NFI = 0.94, CFI = 0.99. CONCLUSIONS: Physical disability, depressive symptoms, and reduced information processing affect work-related disability and vocational status among PwMS. Interventions targeting these factors should be prioritized by clinicians.

Posterior Fossa Lesion Load and Pathological Laughing and Crying in Multiple Sclerosis.

BACKGROUND: Pathological laughing and crying (PLC) encompasses episodes of involuntary laughing, crying, or both that are contextually incongruous with the individual's subjective mood. Despite a 10% to 46% prevalence in people with multiple sclerosis (MS) and reduced quality of life, localization of neuroanatomical lesions associated with PLC remains poorly delineated. METHODS: The relationship between posterior fossa lesions and PLC in people with MS was examined using a retrospective medical record review of people with MS (2012-2016) who had completed the Center for Neurologic Study-Liability Scale (CNS-LS) and had undergone 1.5-T magnetic resonance imaging within 6 months of each other. RESULTS: Medical record review identified 80 potential cases, with 77 included. Brainstem and cerebellar lesions were counted, measured, and compared between people with MS who had positive results on the CNS-LS (scores ≥17, n = 22) with those who had negative results on the CNS-LS (scores ≤16, n = 55). Initial χ2 analysis showed no significant difference in lesion numbers in people with MS without (CNS-LS score ≤16) versus with (CNS-LS score ≥17) PLC. When analyzing only people with MS without evidence of depression, a significant inverse relationship was identified such that fewer posterior fossa lesions on automated magnetic resonance imaging was associated with the presence of PLC. CONCLUSIONS: Posterior fossa lesion load is not indicative of which individuals could develop PLC. Further investigations to delineate the primary source of PLC symptoms would aid in diagnosis and treatment of this condition.

Effect of Treating Acute Optic Neuritis With Bioequivalent Oral vs Intravenous Corticosteroids: A Randomized Clinical Trial.

Importance: Intravenous (IV) administration of corticosteroids is the standard of care in the treatment of acute optic neuritis. However, it is uncertain whether a bioequivalent dose of corticosteroid administered orally, which may be more cost-efficient and convenient for patients, is as effective as IV administration in the treatment of acute optic neuritis. Objective: To determine whether recovery of vision following treatment of acute optic neuritis with a high-dose IV corticosteroid is superior to that with a bioequivalent dose of an oral corticosteroid. Design, Setting, and Participants: This single-blind (participants unblinded) randomized clinical trial with 6-month follow-up was conducted at a single tertiary care center in London, Ontario, Canada. Participants were enrolled from March 2012 to May 2015, with the last participant's final visit occurring November 2015. Patients 18 to 64 years of age presenting within 14 days of acute optic neuritis onset, without any recovery at time of randomization and without history of optic neuritis in the same eye, were screened. Inclusion criteria included best-corrected visual acuity (BCVA) of 20/40 or worse and corticosteroids deemed required by treating physician. In total, 89 participants were screened; 64 were eligible, but 9 declined to participate. Thus, 55 participants were enrolled and randomized. Primary analysis was unadjusted and according to the intention-to-treat principle. Interventions: Participants were randomized 1:1 to the IV methylprednisolone sodium succinate (1000-mg) or oral prednisone (1250-mg) group. Main Outcomes and Measures: Primary outcome was recovery of the latency of the P100 component of the visual evoked potential at 6 months. Secondary outcomes were the P100 latency at 1 month and BCVA as assessed with Early Treatment Diabetic Retinopathy Study letter scores on the alphabet chart and scores on low-contrast letters at 1 and 6 months. Results: Of 55 randomized participants, the final analyzed cohort comprised 23 participants in the IV and 22 in the oral treatment groups. The mean (SD) age of the cohort was 34.6 (9.5) years, and there were 28 women (62.2%). At 6 months' recovery, P100 latency in the IV group improved by 62.9 milliseconds (from a mean [SD] of 181.9 [53.6] to 119.0 [16.5] milliseconds), and the oral group improved by 66.7 milliseconds (from a mean [SD] of 200.5 [67.2] to 133.8 [31.5] milliseconds), with no significant difference between groups (P = .07). Similarly, no significant group difference was found in the mean P100 latency recovery at 1 month. For BCVA, recovery between the groups did not reach statistical significance at 1 month or 6 months. In addition, improvements in low-contrast (1.25% and 2.5%) BCVA were not significantly different between treatment groups at 1 or 6 months' recovery. Conclusions and Relevance: This study finds that bioequivalent doses of oral corticosteroids may be used as an alternative to IV corticosteroids to treat acute optic neuritis. Trial Registration: clinicaltrials.gov Identifier: NCT01524250.

Anti-cholinergic medications for bladder dysfunction worsen cognition in persons with multiple sclerosis.

Bladder dysfunction is common in persons with MS (PwMS), often due to detrusor muscle overactivity. Anticholinergic medications are considered the first line treatment for bladder dysfunction and are known to worsen cognition in healthy older adults and in persons with dementia. Yet, it is not known if these medications have the same effect on PwMS. Thus, the Objective of this prospective matched-cohort study was to determine if anticholinergic medications affect objective measures of cognition in PwMS. We recruited PwMS starting either oxybutynin or tolterodine (cases). Cases and controls were tested with the Brief International Cognitive Assessment for MS (BiCAMS) battery prior to starting anticholinergic medications and 12weeks later. The primary outcome was change on the Symbol Digit Modalities Test (SDMT) between groups; secondary outcomes were changes on the other BiCAMS measures. Analysis of Covariance with baseline measures as covariates to assess the significance of between group differences was performed at 12weeks. Forty eight PwMS starting anticholinergic medications and 21 matched PwMS controls were recruited. There was a significant difference (p<0.001) in the change on the cognitive measures over 12weeks between groups. The controls demonstrated improvement, consistent with practice effect, while the cases remained unchanged. This study demonstrates that anticholinergic medications may have a negative effect on cognition in PwMS; further confirmatory studies are needed.

On-road assessment of fitness-to-drive in persons with MS with cognitive impairment: A prospective study.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS). In other populations, cognitive impairment is known to affect fitness-to-drive. Few studies have focused on fitness-to-drive in MS and no studies have solely focused on the influence of cognitive impairment. OBJECTIVE: To assess fitness-to-drive in persons with MS with cognitive impairment and low physical disability. METHODS: Persons with MS, aged 18-59 years with EDSS ⩽ 4.0, impaired processing speed, and impairment on at least one measure of memory or executive function, were recruited. Cognition was assessed using the Minimal Assessment of Cognitive Function battery. A formal on-road driving assessment was conducted. Chi-square analysis examined the association between the fitness-to-drive (pass/fail) and the neuropsychological test results (normal/impaired). Bayesian statistics predicting failure of the on-road assessment were calculated. RESULTS: Of 36 subjects, eight (22.2%) were unfit to drive. Only the BVMTR-IR, measuring visual-spatial memory, predicted on-road driving assessment failure ( X2 ( df = 1, N = 36) = 3.956; p = 0.047) with a sensitivity of 100%, but low specificity (35.7%) due to false positives (18/25). CONCLUSION: In persons with MS and impaired processing speed, impairment on the BVMTR-IR should lead clinicians to address fitness-to-drive.

Visual Correlates of Fitness to Drive in Adults With Multiple Sclerosis.

The impact of visual and visual-cognitive impairments on fitness to drive in persons with multiple sclerosis (PwMS) are not well studied. We quantified visual correlates of fitness to drive in 30 PwMS. PwMS completed visual ability and visual attention assessments, and a standardized on-road assessment, and were compared with 145 older volunteer drivers. PwMS (vs. older volunteer drivers) made more total ( W = 12,139, p = .03) and critical driving errors (predictive of crashes) in adjustment to stimuli ( W = 11,352, p < .0001), vehicle positioning ( W = 11,449, p < .0001), and wide lane turns ( W = 9,932, p < .0001). PwMS who failed (vs. passed) made more total ( W = 325, p = .04), adjustment to stimuli ( W = 321.5, p = .02), and gap acceptance errors ( W = 333, p = .03). For PwMS, adjustment to stimuli errors moderately correlated with visual acuity (ρ = .50, p = .006), and gap acceptance errors moderately correlated with visual processing speed (ρ = .40, p = .03). Visual-cognitive impairments may be indicative of critical driving errors and help identify PwMS at-risk for fitness to drive.

Driving Errors That Predict On-Road Outcomes in Adults With Multiple Sclerosis.

Driving errors that predict on-road outcomes for persons with multiple sclerosis (PwMS) are not well studied. The objective of this study was to determine whether adjustment-to-stimuli and gap acceptance errors significantly predict passing/failing a standardized on-road assessment of PwMS. Thirty-seven participants completed visual ability and visual attention assessments, and participated in an on-road assessment, where seven types of driving errors and pass/fail outcomes were determined. Adjustment-to-stimuli (No.) and gap acceptance errors (commit/did not commit) significantly predicted passing/failing the on-road assessment, with an area under the curve of 91.6% ( p < .0001). With no gap acceptance errors committed, five adjustment-to-stimuli errors optimally determined pass/fail outcomes in PwMS. Furthermore, with no adjustment to stimuli errors committed, committing any gap acceptance errors also optimally determined pass/fail outcomes in PwMS. Further research may focus on visual, cognitive, and/or motor impairments underlying adjustment-to-stimuli and gap acceptance errors for eventual development of rehabilitation strategies for PwMS.

The effect of Fampridine-SR on cognitive fatigue in a randomized double-blind crossover trial in patients with MS.

BACKGROUND: Cognitive fatigue (CF) is a common complaint in persons with MS (PwMS). Fampridine-SR improves ambulation, fatigue and endurance, due to enhancing action potential formation by blocking potassium channels in demyelinated axons. Thus, through this same mechanism, it is hypothesized that Fampridine-SR could improve CF. OBJECTIVE: To determine if Fampridine-SR objectively improves CF in PwMS. METHODS: Sixty PwMS of any type with CF, defined as 3 or less correct responses when comparing the last third to the first third on the Paced Auditory Serial Addition Test (PASAT), were recruited from a tertiary care MS clinic in London (ON) Canada. Subjects also had to be between 18 and 64 years of age, inclusive, not had a relapse in the last 60 days or corticosteroids in the last 30 days, EDSS 0.0-7.0, and no other diagnosis that could cause cognitive impairment. A randomized double blind crossover design was used: subjects were randomized to either placebo or Fampridine-SR for 4 weeks, then after at least a one week washout, received the opposite treatment. Subjects were assessed before and after each treatment block. The primary outcome was the PASAT CF score after treatment with Fampridine-SR compared to placebo. T-tests and chi-square were used to compare demographics between the two groups (placebo-Fampridine-SR vs. Fampridine SR-placebo). Treatment effects were assessed using factorial ANOVA, with treatment (Fampridine-SR vs. placebo) and time (before and after treatment) as within-subject variables. RESULTS: Of the 60 subjects randomized, 48 completed the study; three were removed due to an adverse event while in the treatment arm (one due to relapse while on placebo, one due to urinary retention and one due to dizziness and headache while on Fampridine-SR). The subjects had a mean age of 46.5±10.0 years, education of 13.6±1.9 years, and were diagnosed with MS 10.6±9.6 years ago. The majority were female (46, 76.7%), had relapsing remitting MS (41, 68.3%) with median EDSS of 3.5 (range 1.0-7.0). There were no significant demographic differences between the two groups. The treatment x time interaction within the factorial ANOVA on PASAT CF scores was statistically significant, F(1, 45)=8.28, p=0.006, suggesting there is a difference between the treatments (placebo vs. Fampridine-SR), over the course of the study. An evaluation of the mean scores suggests, however, that subjects saw a greater improvement when they were given the placebo, than when they were given the active medication. Similarly, individuals showed a greater increase in their information processing speed (as measured by the PASAT) over the course of treatment when they were given the placebo, as compared with the active medication F(1,45)=4.17, p=0.047. CONCLUSION: Although this small pilot study does not suggest that Fampridine-SR results in a statistically significant improvement of CF in MS patients, as compared to placebo, individuals demonstrated an improvement in both information processing speed and CF, suggesting further studies are warranted.

Developing easy to perform routine MRI measurements as potential surrogates for cognitive impairment in MS.

OBJECTIVES: One of the most frequently disabling symptoms in Multiple Sclerosis (MS) is cognitive impairment which is often insidious in onset and therefore difficult to recognize in the early stages, for both persons with MS and clinicians. A biomarker that would help identify those at risk of cognitive impairment, or with only mild impairment, would be a useful tool for clinicians. Using MRI, already an integral tool in the diagnosis and monitoring of disease activity in MS, would be ideal. Thus, this study aimed to determine if simple measures on routine MRI could serve as potential biomarkers for cognitive impairment in MS. PATIENTS AND METHODS: We retrospectively identified 51 persons with MS who had a cognitive assessment and MRI within six months of the MRI. Simple linear measurements of the hippocampi, bifrontral and third ventricular width, bicaudate width and the anterior, mid and posterior corpus callosum were made. Pearson's correlations examined the relationship between these MRI measures and cognitive tests, and MRI measures were compared in persons with MS who were either normal or cognitively impaired on objective cognitive tests using Analysis of Covariance (ANCOVA). RESULTS: Bicaudate span and third ventricular width were both negatively correlated, while corpus callosal measures were positive correlated with cognitive test performance. After controlling for potential confounders, bicaudate span was significant different on measures of immediate recall. Both anterior and posterior corpus collosal measure were significantly different on measures of verbal fluency, immediate recall and higher executive function; while the anterior corpus callosum was also significantly different on processing speed. The middle corpus collosal measure was significantly different on immediate recall and higher executive function. CONCLUSION: This study presents data demonstrating that simple to apply MRI measures of atrophy may serve as biomarkers for cognitive impairment in persons with MS. Further prospective studies are needed to validate these findings.

Anxiety and Depressive Symptoms Are Associated With Worse Performance on Objective Cognitive Tests in MS.

Cognitive impairment, anxiety, and depressive symptoms are common in multiple sclerosis (MS) and are known to interact in non-MS populations. This retrospective chart review examined this relationship in a relapsing-remitting MS population. A significant difference on measures of processing speed/working memory and visual-spatial memory was found in MS patients with anxiety compared with nonanxious MS patients, while a significant difference was found on measures of processing speed, visual-spatial memory and executive function in MS patients with depressive symptoms compared with those without. Further research is needed to determine the causal relationship between anxiety and depressive symptoms and cognitive impairment.

Depression and hypomania symptoms are associated with high dose corticosteroids treatment for MS relapses.

BACKGROUND: Psychiatric side effects are known to occur with low dose corticosteroids. Standard of care for Multiple Sclerosis (MS) relapses is high dose corticosteroids (HDC), at least 1g/day for 3-5 days, and yet the relationship between this treatment and mood is not known. We sought to determine the frequency and potential predictors of (hypo)manic and depressive symptoms with HDC treatment for MS relapses. METHODS: Consecutive MS subjects requiring HDC treatment were identified. The Mood Disorders Questionnaire (MDQ) and the Beck Depression Inventory-Fast Screen (BDIFS) were administered for (hypo)manic and depressive symptoms, respectively, prior to HDC, 3 days and one month post-HDC. RESULTS: Eighty eight subjects completed the study. At relapse diagnosis, the mean BDIFS score was 4.2 (SD 3.1); the mean number of (hypo)manic symptoms endorsed on the MDQ was 4.3 (SD 3.5). Three days after completing HDC, 22.5% had an increase on the BDIFS and 38.2% endorsed more symptoms on the MDQ. A history of depression (p=0.006) and low reported quality of life (p=0.029) predicted an increase on the MDQ; the odds of an increase in (hypo)manic symptoms was 5.6 times higher with a history of any psychiatric disease/substance abuse (p=0.005). No predictors for worsening on the BDIFS were found. LIMITATIONS: Self-reported measures were used, anxiety was not evaluated and 17 subjects were lost to follow up. CONCLUSION: Depressive and hypo(manic) symptoms are commonly associated with HDC for MS relapses. It is important for clinicians and MS patients to be aware of this risk.

Effects of single dose mixed amphetamine salts--extended release on processing speed in multiple sclerosis: a double blind placebo controlled study.

RATIONALE: Multiple sclerosis (MS) commonly affects cognitive function, most frequently presenting as impaired processing speed (PS). There are currently no approved treatments for PS in this population, but previous studies suggest amphetamines may be beneficial. OBJECTIVE: The objective of this study is to determine if mixed amphetamine salts, extended release (MAS-XR) has the potential to improve impaired PS in MS patients in a randomized controlled pre- and post-dose testing study. METHODS: Fifty-two MS patients demonstrating PS impairment on either the Symbol Digit Modalities Test (SDMT) or Paced Auditory Serial Addition Test (PASAT) were randomized to a single dose of 5 mg MAS-XR (n = 18), 10 mg MAS-XR (n = 20), or placebo (n = 14). Subjects were evaluated a second time, after taking the blinded medication. ANOVA was used to compare the change on the SDMT and PASAT in each of the treatment groups compared to the placebo. Cohen's d was used to calculate effect size. RESULTS: At baseline, the mean SDMT score was 43.3 ± 7.2 and the mean PASAT was 34.8 ± 13.4, with 47 (90.4 %) and 25 (48.1 %) categorized as impaired on the SDMT and PASAT, respectively. The change in SDMT scores from baseline to post-treatment demonstrated significant improvement for the MAS-XR 10-mg dose compared to placebo, increasing by 5.2 ± 4.5 vs. 0.6 ± 4.4 points (p = 0.043), with a medium effect size of 0.47. Change on the PASAT was not significantly different in either treatment group. CONCLUSIONS: This study supports MAS-XR 10 mg as a potential treatment for MS patients with demonstrated PS impairment, warranting a larger longitudinal study.

Diagnosis and quantification of cognitive fatigue in multiple sclerosis.

OBJECTIVE: To standardize a method to measure cognitive fatigue in patients with multiple sclerosis (MS). BACKGROUND: Many patients with MS complain of cognitive fatigue, defined as a decline in cognitive performance during a task requiring sustained activity. Until now there has not been a standardized way to detect cognitive fatigue or determine its severity. METHODS: We administered the Paced Auditory Serial Addition Test (PASAT) to 130 normal controls and 100 randomly selected patients with MS, and compared the number of correct responses between the first third and last third of the test. RESULTS: The controls averaged 2 more correct responses in the last third of the PASAT than in the first third. The patients with MS averaged 2 to 3 fewer correct responses in the last third than the first third. CONCLUSIONS: Our study showed that comparing responses between the first and last thirds of the PASAT is a reliable method to measure cognitive fatigue in patients with MS. We also present normative data to be used to determine whether patients with MS have cognitive fatigue.