Remotely-delivered cognitive remediation in multiple sclerosis (MS): protocol and results from a pilot study.

BACKGROUND: Cognitive impairment represents a critical unmet treatment need in multiple sclerosis (MS). Cognitive remediation is promising but traditionally requires multiple clinic visits to access treatment. Computer-based programs provide remote access to intensive and individually-adapted training. OBJECTIVE: Our goal was to develop a protocol for remotely-supervised cognitive remediation that enables individuals with MS to participate from home while maintaining the standards for clinical study. METHODS: MS participants (n = 20) were randomized to either an active cognitive remediation program (n = 11) or a control condition of ordinary computer games (n = 9). Participants were provided study laptops to complete training for five days per week over 12 weeks, targeting a total of 30 hours. Treatment effects were measured with composite change via scores of a repeated neuropsychological battery. RESULTS: Compliance was high with an average of 25.0 hours of program use (80% of the target) and did not differ between conditions (25.7 vs. 24.2 mean hours, p = 0.80). The active vs. control participants significantly improved in both the cognitive measures (mean composite z-score change of 0.46 ± 0.59 improvement vs. -0.14 ± 0.48 decline, p = 0.02) and motor tasks (mean composite z-score change of 0.40 ± 0.71improvement vs. -0.64 ± 0.73 decline, p = 0.005). CONCLUSIONS: Remotely-supervised cognitive remediation is feasible for clinical study with potential for meaningful benefit in MS.

Longitudinal evaluation of cognitive functioning in pediatric multiple sclerosis: report from the US Pediatric Multiple Sclerosis Network.

BACKGROUND: Approximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time. OBJECTIVE: Changes in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers. METHODS: A total of 67 individuals with pediatric MS (n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8-17 years of age (mean age ± standard deviation (SD)=14.37 ± 2.02) completed initial and follow-up neuropsychological testing after an average of 1.64 ± 0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning. RESULTS: Rate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure. CONCLUSION: Findings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

Social cognition in pediatric-onset multiple sclerosis (MS).

BACKGROUND: Pediatric-onset multiple sclerosis (MS) patients represent a subpopulation who are diagnosed during the course of development. Social cognitive deficits have recently been recognized in adults with MS. It is critical to identify whether these youngest patients with the disorder are also at risk. OBJECTIVE: To determine whether pediatric-onset MS is associated with social cognitive deficits. METHODS: Consecutively-recruited participants with pediatric-onset MS were compared to a group of age- and gender-matched healthy controls on Theory of Mind (ToM) task performance. Tasks measured facial affect recognition (Reading the Mind in the Eyes Test), detecting social faux pas (Faux Pas Test), and understanding the perspective of another (False Beliefs Task). RESULTS: Twenty-eight (28) pediatric-onset MS participants (median age 17 years) and 32 healthy controls (median age 16 years) completed the study. The MS participants performed worse than controls on all three ToM tasks: Reading the Mind in the Eyes Test (p = 0.008), the Faux Pas Test (p = 0.009), and the False Beliefs Task (p = 0.06). While more MS than control participants were impaired on a measure of information processing speed (the Symbol Digit Modalities Test; 38% versus 6%), it did not account for the differences in ToM performance. CONCLUSIONS: Social cognition may represent an area of cognitive functioning affected by MS in the pediatric-onset population. These processes are especially important to study in younger patients as they may have long range implications for social adjustment, employment, and well-being.

Copy number variation in pediatric multiple sclerosis.

BACKGROUND: Pediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions. OBJECTIVES AND METHODS: The objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array. RESULTS AND DISCUSSION: We identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS. CONCLUSIONS: This is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis.

OBJECTIVES: The goal of this study was to determine if memory would be improved by donepezil as compared to placebo in a multicenter, double-blind, randomized clinical trial (RCT). METHODS: Donepezil 10 mg daily was compared to placebo to treat memory impairment. Eligibility criteria included the following: age 18-59 years, clinically definite multiple sclerosis (MS), and performance ≤ ½ SD below published norms on the Rey Auditory Verbal Learning Test (RAVLT). Neuropsychological assessments were performed at baseline and 24 weeks. Primary outcomes were change on the Selective Reminding Test (SRT) of verbal memory and the participant's impression of memory change. Secondary outcomes included changes on other neuropsychological tests and the evaluating clinician's impression of memory change. RESULTS: A total of 120 participants were enrolled and randomized to either donepezil or placebo. No significant treatment effects were found between groups on either primary outcome of memory or any secondary cognitive outcomes. A trend was noted for the clinician's impression of memory change in favor of donepezil (37.7%) vs placebo (23.7%) (p = 0.097). No serious or unanticipated adverse events attributed to study medication developed. CONCLUSIONS: Donepezil did not improve memory as compared to placebo on either of the primary outcomes in this study. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence which does not support the hypothesis that 10 mg of donepezil daily for 24 weeks is superior to placebo in improving cognition as measured by the SRT in people with MS whose baseline RAVLT score was 0.5 SD or more below average.

Visual-cognitive processing deficits in pediatric multiple sclerosis.

BACKGROUND: Children with multiple sclerosis (MS) can suffer significant cognitive deficits. This study investigates the sensitivity and validity in pediatric MS of two visual processing tests borrowed from the adult literature, the Brief Visuospatial Memory Test-Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT). OBJECTIVE: To test the hypothesis that visual processing is disproportionately impacted in pediatric MS by comparing performance with that of healthy controls on the BVMTR and SDMT. METHODS: We studied 88 participants (43 MS, 45 controls) using a neuropsychological assessment battery including measures of intelligence, language, visual memory, and processing speed. Patients and demographically matched controls were compared to determine which tests are most sensitive in pediatric MS. RESULTS: Statistically significant differences were found between the MS and control groups on BVMTR Total Learning (t (84) = 4.04, p < 0.001, d = 0.87), BVMTR Delayed Recall (t (84) = 4.45, p < 0.001, d = 0.96), and SDMT (t (38) = 2.19, p = 0.035, d = 0.69). No significant differences were found between groups on confrontation naming or general intellectual ability. Validity coefficients exploring correlation between BVMTR, SDMT, and disease characteristics were consistent with the adult literature. CONCLUSIONS: This study found that BVMTR and SDMT may be useful in assessing children and adolescents with MS.

Younger children with MS have a distinct CSF inflammatory profile at disease onset.

BACKGROUND: The clinical and MRI presentation differs between earlier- and later-onset pediatric multiple sclerosis (MS), whereas the effect of age on the CSF inflammatory profile is unknown and may contribute to delayed diagnosis. OBJECTIVES: To compare the CSF cellular and immunoglobulin G (IgG) profiles between earlier- and later-onset pediatric MS. METHODS: We queried the databases of 6 pediatric MS centers for earlier-onset (onset <11 years) and later-onset (> or = 11 and <18 years) patients with MS or clinically isolated syndrome who underwent CSF analysis within the first 3 months of presentation (observational study). We compared CSF white blood cell (WBC) differential count, IgG index, and IgG oligoclonal bands between age groups. RESULTS: We identified 40 earlier-onset (mean age at onset = 7.2 +/- 2.7 years, 60% females) and 67 later-onset pediatric MS patients (15.1 +/- 1.7 years, 63% females). Although WBC count tended to be higher in earlier-onset patients (median = 9/mm(3) [0-343] vs 6 [0-140], p = 0.15), they had a lower proportion of lymphocytes (70% [0-100] vs 93% [0-100] of WBCs, p = 0.0085; difference = +3% per 1-year increase of age, p = 0.0011) and higher proportion of neutrophils than later-onset patients (0.5% [0-75] vs 0% [0-50] of WBCs, p = 0.16; difference = -1% per 1-year increase of age, p = 0.033). In earlier-onset disease, fewer patients had an elevated IgG index than in the later-onset group (35% vs 68% of patients, p = 0.031). CONCLUSION: Age modifies the CSF profile at pediatric multiple sclerosis (MS) onset, which may mislead the diagnosis. Our findings suggest an activation of the innate rather than the adaptive immune system in the earlier stages of MS or an immature immune response.

Protein expression profiles in pediatric multiple sclerosis: potential biomarkers.

The diagnosis of pediatric multiple sclerosis (MS) is challenging due to its low frequency and the overlap with other acquired childhood demyelinating disorders of the central nervous system. To identify potential protein biomarkers which could facilitate the diagnosis, we used two-dimensional gel electrophoresis (2-DE) in combination with mass spectrometry to identify proteins associated with pediatric MS. Plasma samples from nine children with MS and nine healthy subjects, matched in aggregate by age and gender, were analyzed for differences in their patterns of protein expression. We found 12 proteins that were significantly up regulated in the pediatric MS group: alpha-1-acid-glycoprotein 1, alpha-1-B-glycoprotein, transthyretin, apoliprotein-C-III, serum amyloid P component, complement factor-I, clusterin, gelsolin, hemopexin, kininogen-1, hCG1993037-isoform, and vitamin D-binding protein. These results show that 2-DE in combination with mass spectrometry is a highly sensitive technique for the identification of blood-based biomarkers. This proteomic approach could lead to a new panel of diagnostic and prognostic markers in pediatric MS.

Longitudinal correlates of fatigue in multiple sclerosis.

OBJECTIVE: To determine the predictors of longitudinal changes in fatigue based on pain, mood, and neurological impairment across multiple sclerosis (MS) subtypes. BACKGROUND: Fatigue is the most common symptom of MS but remains poorly understood. The New York State Multiple Sclerosis Consortium (NYSMSC) database offers a unique opportunity to longitudinally assess a variety of potential fatigue correlates in a very large and diverse MS sample. DESIGN/METHODS: This study examined baseline and 1-year follow-up data on 2768 patients drawn from the NYSMSC database regarding fatigability, pain, depressive symptoms, MS subtype, and expanded disability status scale (EDSS). Correlates and predictors of fatigue were assessed in correlational and multiple regression analyses. RESULTS: Baseline fatigue, pain, and depression accounted for 34.6% of the variance in 1-year follow-up fatigue scores. Fatigue was lower in relapsing-remitting subjects than in other MS subtypes. Fatigue consistently correlated at baseline and follow-up with depressive symptoms, pain severity, and EDSS. Changes in fatigue correlated with changes in other variables. CONCLUSIONS: Predictors of fatigue at 1 year include baseline fatigue, pain, mood, and EDSS. These symptoms are also correlated at baseline, follow-up, and in change scores. Identifying predictors of fatigue may facilitate patient management.

Dose comparison trial of sustained-release fampridine in multiple sclerosis.

OBJECTIVE: To examine the efficacy and safety of three different doses of sustained-release fampridine in people with multiple sclerosis (MS). METHOD: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. RESULTS: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo (p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more "consistent responders" in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. CONCLUSIONS: This phase 2 study suggests that a subgroup of patients, when treated with fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.

The psychosocial consequences of pediatric multiple sclerosis.

Although psychological distress and cognitive dysfunction are well documented in adults with multiple sclerosis (MS), they are poorly understood in children with the disease. Psychosocial difficulty experienced by children and adolescents with MS involves factors common to all chronic illnesses in children, as well as MS-specific factors. The psychosocial manifestations of the disease may affect the patient's self-image, role functioning, mood, and cognition to adversely affect schooling, interpersonal relationships, and treatment compliance. Furthermore, the impact of having a family member with MS may affect overall family functioning. Assessment and interventions for psychosocial and cognitive problems in pediatric MS should be multidisciplinary in nature and address the child's functioning at home, school, and among peers, as well as the effect on the family.

Cognitive functioning in children and adolescents with multiple sclerosis.

OBJECTIVE: To examine cognitive functioning in children with multiple sclerosis (MS). METHODS: The authors examined the neuropsychological profile of 37 children with a diagnosis of clinically definite MS and assessed the associations between cognitive function and clinical features. RESULTS: Of 37 children and adolescents evaluated, 35% demonstrated significant cognitive impairment. Cognitive functioning was strongly related to several clinical variables, including current Expanded Disability Status Scale, total number of relapses, and total disease length. The consequences of MS adversely affected academic functioning in over a third of the children. CONCLUSIONS: Cognitive deficits occur in children with multiple sclerosis. Comprehensive treatment planning should involve recognition that they may require academic accommodations for their education.

Donepezil improved memory in multiple sclerosis in a randomized clinical trial.

OBJECTIVE: To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). METHODS: This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. RESULTS: Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). CONCLUSIONS: Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

Cognitive performance and MR markers of cerebral injury in cognitively impaired MS patients.

OBJECTIVE: To relate neuropsychological performance to measures of cerebral injury in persons with MS selected for cognitive impairment. METHODS: Participants were 37 individuals with relapsing-remitting (59.5%) and secondary progressive (40.5%) MS. They were tested at baseline as part of a clinical trial to enhance cognition with an acetylcholinesterase inhibitor. Eligibility criteria included at least mild cognitive impairment on a verbal learning and memory task. A modified Brief Repeatable Battery of Neuropsychological Tests formed the core of the behavioral protocol. Neuroimaging measures were central (ventricular) cerebral atrophy, lesion volume, and ratios of N-acetyl aspartate (NAA) to both creatine and choline. RESULTS: A clear, consistent relation was found between cognitive and MR measures. Among neuroimaging measures, central atrophy displayed the highest correlations with cognition, accounting for approximately half the variance in overall cognitive performance. NAA ratios in right hemisphere sites displayed larger correlations than those on the left. Multiple regression models combining the MR measures accounted for well over half the variance in overall cognitive performance. The Symbol Digit Modalities Test was the neuropsychological task most strongly associated with the neuroimaging variables. CONCLUSIONS: If a strong and stable association can be firmly established between cognitive and MR variables in appropriate subsets of MS patients, it might aid in the investigation of interventions to enhance cognition and modify the course of the disease.

Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial.

OBJECTIVE: To determine whether post Lyme syndrome (PLS) is antibiotic responsive. METHODS: The authors conducted a single-center randomized double-masked placebo-controlled trial on 55 patients with Lyme disease with persistent severe fatigue at least 6 or more months after antibiotic therapy. Patients were randomly assigned to receive 28 days of IV ceftriaxone or placebo. The primary clinical outcomes were improvement in fatigue, defined by a change of 0.7 points or more on an 11-item fatigue questionnaire, and improvement in cognitive function (mental speed), defined by a change of 25% or more on a test of reaction time. The primary laboratory outcome was an experimental measure of CSF infection, outer surface protein A (OspA). Outcome data were collected at the 6-month visit. RESULTS: Patients assigned to ceftriaxone showed improvement in disabling fatigue compared to the placebo group (rate ratio, 3.5; 95% CI, 1.50 to 8.03; p = 0.001). No beneficial treatment effect was observed for cognitive function or the laboratory measure of persistent infection. Four patients, three of whom were on placebo, had adverse events associated with treatment, which required hospitalization. CONCLUSIONS: Ceftriaxone therapy in patients with PLS with severe fatigue was associated with an improvement in fatigue but not with cognitive function or an experimental laboratory measure of infection in this study. Because fatigue (a nonspecific symptom) was the only outcome that improved and because treatment was associated with adverse events, this study does not support the use of additional antibiotic therapy with parenteral ceftriaxone in post-treatment, persistently fatigued patients with PLS.

Metabolic differences between multiple sclerosis subtypes measured by quantitative MR spectroscopy.

We used quantitative magnetic resonance (MR) spectroscopic imaging with T1-based image segmentation to evaluate the subtypes of multiple sclerosis (MS) (eight patients each group of relapsing-remitting [RR], secondary progressive [SP] and primary progressive [PP]). There was no significant difference in age between the PP group with the RP, SP or control group. We found that the metabolite ratio of choline/NA from the periventricular white matter region was not significantly different between the RR and SP groups. Using an ANOVA, the ratios of periventricular choline/NA or creatine/NA of these combined groups were significantly higher than the PP and control groups. Quantification of these data suggest that the major cause of the elevation of these parameters is due to an increase in choline and creatine in the RR group while NA is decreased in the SP group. Thus, early PP disease appears to be relatively intact with respect to neuronal loss.

Cognitive dysfunction lateralizes with NAA in multiple sclerosis.

Recent studies have demonstrated the utility of magnetic resonance (MR) spectroscopic imaging to evaluate axonal integrity in patients with multiple sclerosis (MS). Patient status in MS is frequently assessed by the Expanded Disability Status Scale, which emphasizes ambulation but underestimates the contribution of cognitive factors. Yet, cognitive functions of memory and processing are known to be impaired in MS. We used quantitative MR spectroscopy to determine this relation between cognitive function and N-acetyl aspartate (NAA) levels. We find a significant correlation (r = .63, p < .005) for the left periventricular (PV) NAA concentrations with performance on the verbal Selective Reminding Test. Right PVNAA was significantly (p < .02) correlated with the Tower of Hanoi performance, with r = .58.

Fatigue in multiple sclerosis.

Fatigue is among the most common, yet least understood, symptoms of multiple sclerosis (MS) [1.]. It can profoundly disrupt the occupational and social functioning of patients, and is recognized as a criterion for MS disability by the Social Security Administration. Most approaches to fatigue assessment can be classified as either self-report scales or performance-based measures of motor or cognitive output. During the clinical management of fatigue, it is important to consider the role of other MS symptoms on fatigue, as well as that of non-MS-related medical conditions. Management of fatigue in MS often entails both pharmacologic and behavioral components. This article reviews recent developments in the assessment, treatment, and pathogenesis of MS fatigue.

Fatigue and declines in cognitive functioning in multiple sclerosis.

OBJECTIVE: To determine whether cognitive fatigue, defined as a decline in cognitive performance over a single testing session, could be identified in MS. METHODS: Forty-five individuals with MS and 14 healthy control participants completed a 4-hour session of cognitive testing that involved a baseline neuropsychological battery, a continuous effortful cognitive task (completing mental arithmetic problems administered on a computer), and a repeat neuropsychological battery. Self-report measures of fatigue and affect were completed before each step of the testing session. RESULTS: The pattern of change in cognitive performances over the testing session significantly differed between the MS and control participants. Individuals with MS showed declines on measures of verbal memory and conceptual planning, whereas the control participants showed improvement. Although there were no significant differences between the groups on any of the baseline cognitive measures, the MS participants performed worse than the control subjects on tests of visual memory, verbal memory, and verbal fluency that were repeated following the continuous effortful cognitive task. Both MS and control participants reported increased mental and physical fatigue across the testing session compared with their baseline values. CONCLUSION: Individuals with MS show declines in cognitive performance during a single testing session and fail to show the improvement exemplified by healthy control subjects.