Frederick Munschauer

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.

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis

Background: Interferon beta is an effective treatment for relapsing multiple sclerosis(MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. Objectives: To determine the incidence and biological significance of NAB to interferon beta-1a (IFN-β-1a; Avonex; Biogen, Cambridge, MA) in MS patients. Methods: A two-step assay for NAB to IFN-β-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-β-1a, and from patients in an ongoing open-label study of IFN-β1a. The biological significance of NAB to IFN-β-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and β-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-β-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-β-1a with the incidence in MS patients who had used only IFN-β-1b. Results: In patients in the open-label study, development of NAB to IFN-β-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in β-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-β-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-β-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-β-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-β-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. Conclusions: NAB directed against IFN-β have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-β is significantly greater with IFN-β-1b therapy compared with IFN-β-1a therapy. Treatment decisions in MS patients treated withIFN-β should take into account development of NAB.

A longitudinal study of brain atrophy in relapsing multiple sclerosis

Objective: To determine if progressive brain atrophy could be detected over 1- and 2-year intervals in relapsing MS, based on annual MR studies from the Multiple Sclerosis Collaborative Research Group (MSCRG) trial of interferon β-1a (Avonex). Methods: All subjects had mild to moderate disability, with baseline expanded disability status scores ranging from 1.0 to 3.5, and at least two relapses in the 3 years before study entry. Atrophy measures included third and lateral ventricle width, brain width, and corpus callosum area. Results: Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at 1 and 2 years. Significant decreases in corpus callosum area and brain width were also observed at 1 and 2 years. Multiple regression analyses suggested that the number of gadolinium-enhancing lesions at baseline was the single significant contributor to change in third ventricle width. Atrophy over 1 and 2 years as indicated by enlargement of the third and lateral ventricle and shrinkage of the corpus callosum was greater for patients entering the trial with enhancing lesions. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. Conclusion: In patients with relapsing MS and only mild to moderate disability, significant cerebral atrophy is already developing that can be measured over periods of only 1 to 2 years. The course of cerebral atrophy in MS appears to be influenced by prior inflammatory disease activity as indicated by the presence of enhancing lesions. Brain atrophy measures are important markers of MS disease progression because they likely reflect destructive and irreversible pathologic processes.

Screening for cognitive impairment in multiple sclerosis using the Symbol digit Modalities Test.

Cognitive impairment is common in multiple sclerosis (MS), yet difficult to detect duringroutine neurologic examination. Therefore, briefscreening tests that identify patients who may benefit from a more thorough assessment or treatment are needed. We investigated the utility of the Symbol Digit Modalities Test (SDMT) as a screen for cognitive dysfunction because it can be administered and scored in about 5 minutes. One hundred MS patients and 50 healthy controls, matched on demographic variables, participated in the study. Examination procedures included the neuropsychological (NP) tests included in the Minimal Assessment of Cognitive Function in MS (MACFIMS) battery. Patients were considered impaired if they performed one and a half standard deviations below controls on two or more MACFIMS variables, excluding theSDMT. Bayesian statistics showed that a total score of 55 or lower onthe SDMT accurately categorized 72% of patients, yielding sensitivityof 0.82, specificity of 0.60, positive predictive value (PPV) of 0.71, and negative predictive value (NPV) of 0.73. These results suggest that the effectiveness of the SDMT as a screen for cognitive impairment in MS is roughly equal to that of other psychometric and questionnaire methods.

Screening for multiple sclerosis cognitive impairment using a self-administered 15-item questionnaire

Since there is a need for cost-effective screening techniques to identify neuropsychological impairment in multiple sclerosis (MS) patients, and because existing methods require cognitive testing with subsequent interpretation by a neuropsychologist, a brief self-report procedure was developed to screen for neuropsychological impairment in MS. In the first phase of the study, a pool of 80 items was generated based on a literature review and consultation with healthcare professionals. The set was reduced to 15 via Rasch analysis. Using these items, a brief (five minute) MS Neuropsychological Screening Q uestionnaire (MSNQ), including patient- and informant-report forms, was composed. In phase II, 50 MS patients and their caregivers completed the MSNQ. A comprehensive neuropsychological test battery was also administered. A nalyses covered the reliability of the MSNQ and correlations between both patient- and informant-report scores and objective neuropsychological testing. C ronbach’s a coefficients were 0.93 and 0.94 for the patient- and informant-report forms, respectively, and both forms of the test were strongly correlated with a more general cognitive complaints questionnaire. The patient MSNQ form correlated significantly with measures of depression but not with objective tests of cognitive function. In contrast, the informant form was correlated with patient cognitive performance but not depression. A cut-off score of 27 on the informant form of the MSNQ optimally separated patients based on a neuropsychological summary score encompassing measures of processing speed and memory. There were two false-negatives and one false-positive, giving the test a sensitivity of 0.83 and a specificity of 0.97. It is concluded, therefore, that this self-administered neuropsychological screening test is reliable and predicts neuropsychological impairment in MS patients with a reasonable degree of accuracy.

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.

Hyperglycemia, Insulin, and Acute Ischemic Stroke. A Mechanistic Justification for a Trial of Insulin Infusion Therapy

Background and Purpose— Hyperglycemia is associated with increased mortality and morbidity in acute ischemic stroke. Summary of Review— Hyperglycemia induces a pro-oxidative and proinflammatory state that can cause direct neuronal toxicity. Hyperglycemia-mediated increase in matrix metalloproteinase-9 can cause neuronal damage by an increase in cerebral edema. Moreover, hyperglycemia may be responsible for a procoagulant state that can further compromise blood supply to the penumbral areas in acute ischemic stroke. Insulin infusion has an effect that is opposite to that of hyperglycemia. It not only lowers blood glucose levels but also exerts an antioxidant and anti-inflammatory effect. Insulin also improves NO production and results in improved blood circulation to the ischemic areas. This article focuses on the potential mechanisms underlying the injurious effects of glucose and the beneficial effects of insulin. Conclusions— In the absence of other potential beneficial therapies, there is an urgency to institute trials with insulin infusion in acute ischemic stroke.

Psychometrics and normative data for the Multiple Sclerosis Functional Composite: replacing the PASAT with the Symbol Digit Modalities Test

The MS Functional Composite (MSFC) is a continuous scale of neurological disability for patients with multiple sclerosis (MS). Cognition is represented by the Paced Auditory Serial Addition Test (PASAT), although the Symbol Digit Modalities Test (SDMT) has been proposed as a promising alternative. MSFC scores were calculated using either the PASAT or the SDMT with the following reference populations: National Multiple Sclerosis Society (NMSS) Task Force, 400 MS patients, and 100 normal controls. A subgroup of 115 patients was followed longitudinally, with a test—retest interval of 2.3 ± 1.2 years. Pearson correlations were calculated and analyses of variance (ANOVAs) were used to assess relationships among the MSFC components and composite scores, and differences in performance between patients and controls. Longitudinal changes were also assessed. Logistic regression was performed to determine which MSFC scores are most predictive of diagnosis, course, and work disability. All MSFCs had similar test—retest reliability and correlations with other measures including neurological disability, depression, and fatigue. The SDMT showed slightly better validity with respect to predicting diagnosis, course, and work disability, although the amount of variance accounted for was similar for each version of the MSFC. Our data, derived from a large sample of MS patients and normal controls, supports the validity of both PASAT and SDMT versions of the MSFC. Because the SDMT has slightly better predictive validity and has a relatively easier administration procedure, some clinicians and researchers may wish to replace the PASAT with the SDMT in future calculations of the MSFC using the calculation methods provided in this manuscript.