Heather Rosehart

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.

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.

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.

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.

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.

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.

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.

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. Pearsons 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.