Dawn Langdon

Minimal Neuropsychological Assessment of MS Patients: A Consensus Approach

Cognitive impairment is common in multiple sclerosis (MS), yet patients seen in MS clinics and neurologic practices are not routinely assessed neuropsychologically. In part, poor utilization of NP services may be attributed to a lack of consensus among neuropsychologists regarding the optimal approach for evaluating MS patients. An expert panel composed of neuropsychologists and psychologists from the United States, Canada, United Kingdom, and Australia was convened by the Consortium of MS Centers (CMSC) in April, 2001. Our objectives were to: (a) propose a minimal neuropsychological (NP) examination for clinical monitoring of MS patients and research, and (b) identify strategies for improving NP assessment of MS patients in the future. The panel reviewed pertinent literature on MS-related cognitive dysfunction, considered psychometric factors relevant to NP assessment, defined the purpose and optimal characteristics of a minimal NP examination in MS, and rated the psychometric and practical properties of 36 candidate NP measures based on available literature. A 90-minute NP battery, the Minimal Assessment of Cognitive Function in MS (MACFIMS), emerged from this discussion. The MACFIMS is composed of seven neuropsychological tests, covering five cognitive domains commonly impaired in MS (processing speed/working memory, learning and memory, executive function, visual-spatial processing, and word retrieval). It is supplemented by a measure of estimated premorbid cognitive ability. Recommendations for assessing other factors that may potentially confound interpretation of NP data (e.g., visual/sensory/motor impairment, fatigue, and depression) are offered, as well as strategies for improving NP assessment of MS patients in the future.

Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS)

Background: Cognitive impairment in MS impacts negatively on many patients at all disease stages and in all subtypes. Full clinical cognitive assessment is expensive, requiring expert staff and special equipment. Test versions and normative data are not available for all languages and cultures. Objective: To recommend a brief cognitive assessment for multiple sclerosis (MS) that is optimized for small centers, with one or few staff members, who may not have neuropsychological training and constructed to maximize international use. Methods: An expert committee of twelve members representing the main cultural groups that have so far contributed considerable data about MS cognitive dysfunction was convened. Following exhaustive literature review, peer-reviewed articles were selected to cover a broad spectrum of cultures and scales that targeted cognitive domains vulnerable to MS. Each was rated by two committee members and candidates scales were rated on psychometric qualities (reliability, validity, and sensitivity), international application, ease of administration, feasibility in the specified context, and acceptability to patients. Results: The committee recommended the Symbol Digit Modalities Test, if only 5 minutes was available, with the addition of the California Verbal Learning Test – Second Edition and the Brief Visuospatial Memory Test – Revised learning trials if a further 10 minutes could be allocated for testing. Conclusions: A brief cognitive assessment for MS has been recommended. A validation protocol has been prepared for language groups and validation studies have commenced.

Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci

To perform a 1‐stage meta‐analysis of genome‐wide association studies (GWAS) of multiple sclerosis (MS) susceptibility and to explore functional consequences of new susceptibility loci.

Evidence-based measurement Which disability scale for neurologic rehabilitation?

Objective: To compare the 10-item Barthel Index (BI), 18-item Functional Independence Measure (FIM), and 30-item Functional Independence Measure + Functional Assessment Measure (FIM+FAM) as measures of disability outcomes for neurologic rehabilitation. Methods: A total of 149 inpatients from two rehabilitation units in South England specializing in neurologic disorders were studied. Traditional psychometric methods were used to evaluate and compare acceptability (score distributions), reliability (internal consistency, intrarater reproducibility), validity (concurrent, convergent and discriminant construct), and responsiveness (standardized response mean). Results: All three rating scales satisfied recommended criteria for reliable and valid measurement of disability, and are acceptable and responsive in this study sample. The FIM and FIM+FAM total scales are psychometrically similar measures of global disability. The BI, FIM, and FIM+FAM motor scales are psychometrically similar measures of physical disability. The FIM and FIM+FAM cognitive scales are psychometrically similar measures of physical disability. Conclusions: In the sample studied, the BI, FIM, FIM+FAM have similar measurement properties, when examined using traditional psychometric analyses. Although instruments with more items and item response categories generate more qualitative information about an outcome, they may not improve its measurement. Results highlight the importance of using recognized techniques of scale construction to develop health outcome measures.

Survival in MS A randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial

Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314–0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg–treated patients (46.0% among IFNβ-1b 50 μg–treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality. Classification of Evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Inpatient rehabilitation in multiple sclerosis Do the benefits carry over into the community

Objective: To determine the duration and pattern of carry-over of benefits gained after a short period of multidisciplinary inpatient rehabilitation. Background: Few studies have evaluated the outcome of rehabilitation after discharge. Long-term follow-up is required to establish whether gains made during the inpatient stay are sustained over time and in the patient’s own environment. Methods: Prospective single-group longitudinal study. Fifty consecutive patients with progressive MS undergoing inpatient rehabilitation were followed for 12 months after discharge. Assessments were undertaken on admission (A), at discharge, and subsequently at 3-month intervals for 1 year (1Y) with a battery of measures addressing neurologic status, disability, handicap, quality of life, and emotional well-being. The time taken to return to baseline level was calculated using summary measures, and trends in performance levels were plotted. Results: Twelve-month data were collected for 92% of patients. Although neurologic status declined (median Expanded Disability Status Scale scores: A = 6.8, 1Y = 8.0), improvements were maintained in disability and handicap for 6 months, emotional well-being for 7 months, and health-related quality of life (physical component) for 10 months. Conclusions: The benefits gained from rehabilitation were partly maintained after discharge despite worsening neurologic status. Carry-over of benefits, however, declined over time, reinforcing the need for continuity of care between the inpatient setting and the community.

Treatment of cognitive impairment in multiple sclerosis: position paper

Cognitive impairment in multiple sclerosis (MS) is common, debilitating and burdensome. Key evidence from trials was reviewed to enable recommendations to be made to guide clinical practice and research. Behavioural and pharmacological interventions on cognition reported in published studies were reviewed. Most studies evaluating behavioural treatment for impairment in learning and memory, deficits of attention and executive function have demonstrated some improvement. Controlled studies in relapsing remitting MS indicate interferon (IFN) β-1b and IFN β-1a were associated with modest cognitive improvement. The effects of symptomatic therapies such as modafinil and donepezil are inconsistent. Most studies yielding positive findings have significant methodological difficulties limiting the confidence in making any broad treatment recommendations. There are no published reports of glatiramer acetate, natalizumab and fingolimod being effective in improving cognition in controlled trials. The effects of disease modifying therapies in other forms of MS and clinically isolated syndrome have not yielded positive results. Data linking behavioural therapy, symptomatic treatment or disease modifying treatment, to either reducing cognitive decline or improving impaired cognition are limited and inconsistent. The treatment and prevention of cognitive impairment needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.

Clinical appropriateness: a key factor in outcome measure selection: the 36 item short form health survey in multiple sclerosis

OBJECTIVES Understanding the properties of an outcome measure is essential in choosing the appropriate instrument and interpreting the information it generates. The MOS 36 item short form health survey questionnaire (SF-36) is widely acknowledged as the gold standard generic measure of health status; few studies however have evaluated its use for clinical trials in multiple sclerosis. Its clinical appropriateness, internal consistency reliability, validity, and responsiveness was investigated across a broad range of patients with multiple sclerosis. METHODS A prospective study in which 150 adults with clinically definite multiple sclerosis completed a battery of questionnaires evaluating generic health status, disability, handicap, and emotional wellbeing. Of these, 44 patients undergoing inpatient rehabilitation completed the questionnaires before and after intervention to evaluate responsiveness. RESULTS Score distributions demonstrated significant floor and ceiling effects in four of the eight dimensions which were particularly marked when patient selection was restricted to a narrow band of disease severity (as is the case in most clinical trials). Internal consistency exceeded the standard for group comparisons for all dimensions. Convergent and discriminant construct validity was supported by the direction, magnitude, and pattern of correlations with other health measures. In comparison with instruments measuring associated constructs, the responsiveness of the SF-36 was poor in evaluating change in moderate to severely disabled patients participating in a programme of inpatient rehabilitation. CONCLUSIONS The SF-36 has some limitations as an outcome measure in multiple sclerosis. The results highlight the need for all instruments to be examined in the specific sample population under question and for the specific research question being investigated. In multiple sclerosis clinical trials, the SF-36 should be supplemented with other relevant measures.

Brief International Cognitive Assessment for MS (BICAMS): international standards for validation

An international expert consensus committee recently recommended a brief battery of tests for cognitive evaluation in multiple sclerosis. The Brief International Cognitive Assessment for MS (BICAMS) battery includes tests of mental processing speed and memory. Recognizing that resources for validation will vary internationally, the committee identified validation priorities, to facilitate international acceptance of BICAMS. Practical matters pertaining to implementation across different languages and countries were discussed. Five steps to achieve optimal psychometric validation were proposed. In Step 1, test stimuli should be standardized for the target culture or language under consideration. In Step 2, examiner instructions must be standardized and translated, including all information from manuals necessary for administration and interpretation. In Step 3, samples of at least 65 healthy persons should be studied for normalization, matched to patients on demographics such as age, gender and education. The objective of Step 4 is test-retest reliability, which can be investigated in a small sample of MS and/or healthy volunteers over 1–3 weeks. Finally, in Step 5, criterion validity should be established by comparing MS and healthy controls. At this time, preliminary studies are underway in a number of countries as we move forward with this international assessment tool for cognition in MS.

Neuropsychological impairment in multiple sclerosis patients: the role of (juxta)cortical lesion on FLAIR:

In this study we evaluated the correlation between neuropsychological impairment (measured with the Brief Repeatable Battery Neuropsychological Tests) and (juxta)cortical lesions detected with FLAIR and the relative sensitivity of the FLAIR sequence compared to spin-echo MRI sequences in detecting (juxta)cortical MS lesions. A total of 39 patients with definite MS were evaluated by MRI with a conventional and fast spin echo sequence and fast FLAIR sequence, and neuropsychological tests of the Brief Repeatable Battery Neuropsychological tests were performed. The Z-score of all subtests were used to calculate a Cognitive Impairment Index. The results show that a high number of (juxta)cortical lesions is detected with thin slice FLAIR (30% of all lesions seen). This percentage was not superior to spin-echo, reflecting the thin slice thickness (3 mm) we used. The lesions detected with FLAIR were to a certain degree different ones than the lesions detected with the other techniques. While the number of non-cortical lesions correlated with the expanded disability status scale (r=0.32, P=0.045), the number of (juxta)cortical lesions detected with the FLAIR showed a correlation (r=0.34, P=0.035) with the Cognitive Impairment Index. Our study underlines the high number of (juxta)cortical lesions in MS and the value of thin slice FLAIR sequence to detect such lesions with MRI. It also stresses the importance of (juxta)cortical lesions on determining neuropsychological impairment.