Ralph H. B. Benedict

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.

Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS)

Cognitive impairment occurs in roughly 50% of patients with multiple sclerosis (MS). It is well known that processing speed and episodic memory deficits are the most common neuropsychological (NP) sequelae in this illness. Consensus has emerged about the specific tests that prove most helpful for routine monitoring of MS associated cognitive impairment. The purpose of this study was to examine the validity of the Minimal Assessment of Cognitive Function in MS (MACFIMS), a recommended battery based on the findings of an international conference held in 2001. We tested 291 MS patients and 56 healthy controls. Frequencies of impairment paralleled those reported in previous work for both individual cognitive domains and general impairment. All tests were impaired in the MS group, and distinguished relapsing-remitting (RR) from secondary progressive (SP) course. Principle components analysis showed a distinct episodic memory component. Most of the MACFIMS tests discriminated disabled from employed patients. However, in regression models accounting for all NP tests, those emphasizing verbal memory and executive function were most predictive of vocational status. We conclude that the MACFIMS is a valid approach to routine NP assessment of MS patients. Future work is planned to determine its psychometric properties in a longitudinal study.

Predicting quality of life in multiple sclerosis: accounting for physical disability, fatigue, cognition, mood disorder, personality, and behavior change.

Health-related quality of life (HQOL) is poor in multiple sclerosis (MS) but the clinical precipitants of the problem are not well understood. Previous correlative studies demonstrated relationships between various clinical parameters and diminished HQOL in MS. Unfortunately, these studies failed to account for multiple predictors in the same analysis. We endeavored to determine what clinical parameters account for most variance in predicting HQOL, and employability, while accounting for disease course, physical disability, fatigue, cognition, mood disorder, personality, and behavior disorder. In 120 MS patients, we measured HQOL (MS Quality of Life-54) and vocational status (employed vs. disabled) and then conducted detailed clinical testing. Data were analyzed by linear and logistic regression methods. MS patients reported lower HQOL (p<0.001) and were more likely to be disabled (45% of patients vs. 0 controls). Physical HQOL was predicted by fatigue, depression, and physical disability. Mental HQOL was associated with only depression and fatigue. In contrast, vocational status was predicted by three cognitive tests, conscientiousness, and disease duration (p<0.05). Thus, for the first time, we predicted HQOL in MS while accounting for measures from these many clinical domains. We conclude that self-report HQOL indices are most strongly predicted by measures of depression, whereas vocational status is predicted primarily by objective measures of cognitive function. The findings highlight core clinical problems that merit early identification and further research regarding the development of effective treatment.

Revision of the Brief Visuospatial Memory Test: Studies of normal performance, reliability, and validity.

There is an increasing demand for alternate-form neuropsychological tests that can be used in clinical trials with little risk of direct practice effect. Although the Brief Visuospatial Memory Test (BVMT) includes six equivalent alternate forms, its administration is limited to an immediate and 25-min delayed free-recall trial. We now present a revised version of the BVMT called the Brief Visuospatial Memory Test-Revised (BVMT-R) that includes three learning trials, a 25-min delayed recall trial, and a delayed yes/no recognition task. A new scoring system, which accounts for the location of test stimuli as well as the accuracy of recall, is also introduced. Using these new administration and scoring procedures, we administered the BVMT-R to 261 neuropsychiatric patients and 456 normal healthy adults. The results indicated that the test has excellent interform reliability, and the construct and criterion-related validity of the test were supported in studies using clinical samples. Although the BVMT-R is not without its limitations, the tests brevity and alternate-form capacity make it a valuable instrument for serial neuropsychological assessments.

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.

The Goldman Consensus statement on depression in multiple sclerosis

Background. In January 2002 the New York City Chapter of the National Multiple Sclerosis Society convened a panel of experts to review the issue of depressive affective disorders associated with multiple sclerosis (MS). This Consensus Conference was supported by a grant from the Goldman family of New York City. Results. The panel reviewed summaries of current epidemiologic, neurobiologic, and therapeutic studies having to do with depressive disorders among MS patient populations. Depressive disorders occur at high rates among patients with MS, and there is reason to believe that the immunopathology of the disease is involved in the clinical expression of affective disorders. The depressive syndromes of MS have a major, negative impact on quality of life for MS sufferers, but are treatable. At the present time, most MS patients with depression do not receive adequate recognition and treatment. Conclusions. The Goldman Consensus Conference Study Group provides recommendations for improved screening, diagnosis, and clinical management for depressive affective disorders among patients suffering from MS.

Risk factors for and management of cognitive dysfunction in multiple sclerosis

Cognitive impairment is common in multiple sclerosis (MS), especially when assessed by neuropsychological tests that emphasize mental processing speed, episodic memory, and some aspects of executive function. In this Review, we question why some MS patients develop severe impairment in cognitive abilities, while cognitive ability remains intact in others. We find that the heterogeneity in neuropsychological presentation among patients with MS reflects the influence of many factors, including genetics, sex, intelligence, disease course, comorbid neuropsychiatric illness, and health behaviors. Neuropsychological deficits are also robustly correlated with brain MRI metrics. Male patients with early evidence of cerebral gray matter atrophy are most prone to impairment, whereas high premorbid intelligence improves the neuropsychological prognosis. Routine evaluation of cognition is useful for helping patients to navigate problems related to activities of daily living and work disability and, if reliable methods are employed, cognitive decline can be detected and included among the many clinical signs of disease progression or treatment failure. Pharmacological treatments for neuropsychological impairment are on the horizon, although presently no firm medical indications exist for the condition.

Gray and white matter brain atrophy and neuropsychological impairment in multiple sclerosis

Background: The relationship of gray and white matter atrophy in multiple sclerosis (MS) to neuropsychological and neuropsychiatric impairment has not been examined. Methods: In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain whole brain normalized volumes of gray and white matter, as well as measured conventional lesion burden (total T1 hypointense and FLAIR hyperintense lesion volume). The whole brain segmentation was corrected for misclassification related to MS brain lesions. To compare the effects of gray matter, white matter, and lesion volumes with respect to brain-behavior relationships, the MS group (disease duration = 11.2 ± 8.8 years; EDSS score = 3.3 ± 1.9) underwent neuropsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83). Results: The MS group had smaller gray (p = 0.009) and white matter volume (p = 0.018), impaired cognitive performance (verbal memory, visual memory, processing speed, and working memory) (all p < 0.0001), and greater neuropsychiatric symptoms (depression, p < 0.0001; dysphoria, p < 0.0001; irritability, p < 0.0001; anxiety, p < 0.0001; euphoria, p = 0.006; agitation, p = 0.02; apathy, p = 0.02; and disinhibition, p = 0.11) vs controls. Hierarchical stepwise regression analysis revealed that whole gray and white matter volumes accounted for greater variance than lesion burden in explaining cognitive performance and neuropsychiatric symptoms. White matter volume was the best predictor of mental processing speed and working memory, whereas gray matter volume predicted verbal memory, euphoria, and disinhibition. Conclusion: Both gray and white brain matter atrophy contribute to neuropsychological deficits in multiple sclerosis.

Reliable screening for neuropsychological impairment in multiple sclerosis

In an earlier study, we developed the Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ) to assist in the screening for neuropsychological (NP) impairments. Self-report MSNQ scores correlated significantly with measures of depression, whereas informant-report MSNQ scores correlated with cognitive performance, but not depression. This study was criticized for use of a small sample and lack of data regarding normal performance and test -retest reliability. The present study was designed to replicate the earlier work with a larger sample of patients and normal controls obtained from multiple sites. We also evaluated the test -retest reliability and predictive validity of the MSNQ. The sample included 85 multiple sclerosis (MS) patients and 40 normal controls, matched on demographic variables. All participants completed the MSNQ and underwent NP testing. Thirty-four patients were re-examined at one week. Pearson and ANOVA techniques were utilized for univariate comparisons. Bayesian statistics were calculated to assess predictive validity. Patient self- and informant-report MSNQ scores differed from normal and test -retest reliability indices were high. Both self- and informant-reports were correlated with cognitive dysfunction and depression scales. Self-report MSNQ scores correlated more strongly with depression than cognitive performance, whereas the opposite pattern was observed with informant-report scores. Bayesian statistics showed that informant-report MSNQ scores predict cognitive impairment and patient self-report scores identify patients with cognitive impairment or depression. It is concluded that the MSNQ is useful, although patient self-reports may be exaggerated in depressed patients or reduced in patients with severe cognitive impairment.

The thalamus and multiple sclerosis Modern views on pathologic, imaging, and clinical aspects

The paired thalamic nuclei are gray matter (GM) structures on both sides of the third ventricle that play major roles in cortical activation, relaying sensory information to the higher cortical centers that influence cognition. Multiple sclerosis (MS) is an immune-mediated disease of the human CNS that affects both the white matter (WM) and GM. A number of clinical observations as well as recent neuropathologic and neuroimaging studies have clearly demonstrated extensive involvement of the thalamus, basal ganglia, and neocortex in patients with MS. Modern MRI techniques permit visualization of GM lesions and measurement of atrophy. These contemporary methods have fundamentally altered our understanding of the pathophysiologic nature of MS. Evidence confirms the contention that GM injury can be detected in the earliest phases of MS, and that iron deposition and atrophy of deep gray nuclei are closely related to the magnitude of inflammation. Extensive involvement of GM, and particularly of the thalamus, is associated with a wide range of clinical manifestations including cognitive decline, motor deficits, fatigue, painful syndromes, and ocular motility disturbances in patients with MS. In this review, we characterize the neuropathologic, neuroimaging, and clinical features of thalamic involvement in MS. Further, we underscore the contention that neuropathologic and neuroimaging correlative investigations of thalamic derangements in MS may elucidate not heretofore considered pathobiological underpinnings germane to understanding the ontogeny, magnitude, and progression of the disease process.