Reports of patients and relatives from the CogniCIS study about cognition in clinically isolated syndrome: what are our patients telling us?

OBJECTIVE: To assess the Multiple Sclerosis Neuropsychological Questionnaire (MSNQ) in patients with clinically isolated syndrome (CIS). METHODS: 130 European CIS patients and 60 relatives completed the MSNQ. RESULTS: The mean (SD) MSNQ score for CIS patients was 15.5 (10.8) and for their informants 11.3 (9.6). Neither the CIS patient nor relative MSNQ report scores correlated with any of the cognitive test scores in the Brief Repeatable Battery of Neuropsychological Tests, but they were significantly related to psychosocial scales including depression. CONCLUSIONS: In CIS, patient and relative MSNQ scores are influenced by psychosocial variables rather than actual objective cognitive status. Formal cognitive test assessment is recommended for CIS patients.

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.

Long-term effects of prolonged-release fampridine in cognitive function, fatigue, mood and quality of life of MS patients: The IGNITE study.

BACKGROUND: Studies have reported conflicting results regarding the potential benefit of prolonged release (PR) fampridine in other domains besides walking. Moreover, only a small number of studies have explored long- term effects of PR fampridine. The aim of this study was to assess cognitive function, quality of life, mood and fatigue in MS patients treated with fampridine after 6 and 12 months of treatment. METHODS: IGNITE was an observational, open label study. Subjects were examined with the timed 25-ft walk (T25FW) and the BICAMS battery and were asked to complete the Multiple Sclerosis Impact Scale (MSIS-29), Modified Fatigue Impact Scale (MFIS), Beck Depression Inventory-II (BDI-II) and MS International Quality-of-Life questionnaire (MUSIQOL) at baseline and at weeks 24 and 48. Patients were sub-grouped into responders (n:40) and non-responders (n:20) according to T25FW performance after 2 weeks on treatment. RESULTS: After 6 months, statistically significant improvement was observed on T25FW (p < .001), SDMT (p < .001) and MSIS29 (p < .001), for responders. After 1 year on treatment, statistically significant improvement was observed in T25FW (p < .001), MSIS29 (p = .004), SDMT (p < .001) and MUSIQOL (p = .03) for responders. There were no statistically significant improvements for the non-responders. CONCLUSIONS: PR Fampridine may have a beneficial effect on information processing speed though not on memory. Study data provide some evidence that fampridine treatment may reduce the impact of MS on daily activities and improve quality of life but has no effect on subjective fatigue and mood.

A longitudinal study of cognition in primary progressive multiple sclerosis.

There are few longitudinal studies of cognition in patients with multiple sclerosis, and the results of these studies remain inconclusive. No serial neuropsychological data of an exclusively primary progressive series are available. Cross-sectional analyses have revealed significant correlations between cognition and magnetic resonance imaging (MRI) parameters in primary progressive multiple sclerosis (PPMS). This study investigated cognitive and MRI change in 99 PPMS patients from five European centres for 2 years. They were assessed at 12 month intervals using the Brief Repeatable Battery, a reasoning test, and a measure of depression. The MRI parameters of T1 hypointensity load, T2 lesion load, and partial brain volume were also calculated at each time point. There were no significant differences between the mean cognitive scores of the patients at year 0 and year 2. However, one-third of the patients demonstrated absolute cognitive decline on individual test scores. Results indicated that initial cognitive status on entry into the study was a good predictor of cognitive ability at 2 years. There was only a small number of significant correlations between changes in cognition and changes on MRI, notably T1 hypointensity load with the two attentional tasks (r = -0.266, P = 0.017; r = -0.303, P = 0.012). It is probable that multiple factors underlie this weak relation between the cognitive and MRI measures.

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.

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.

Rehabilitation of incomplete spinal cord pathology: factors affecting prognosis and outcome.

To determine the factors affecting the outcome of patients with incomplete spinal cord lesions, a retrospective study was performed of all such patients (n = 49) admitted to the neurorehabilitation unit of the National Hospital for Neurology and Neurosurgery, London, over a 2-year period. Disability on admission and discharge as measured by the Functional Independence Measure (FIM), change in disability, presence or absence of neurological recovery, patient age, level of the lesion and length of inpatient stay were the main outcome measures. Data were complete on 39 patients. There were 20 patients with cervical myelopathy, 15 with intrinsic cord abnormalities including syrinxes, 7 with spinal cord infarcts and 7 with other conditions such as tropical spastic paraparesis and hereditary paraparesis. Age ranged from 17 to 88 years (mean 53). Mean duration of stay was 40 days and the duration was related to the diagnosis. Nineteen of the patients made some neurological improvement, while all but one improved on the FIM. This functional gain did not correlate with the patients' age, initial disability or level of the lesion, but was related to the length of stay in the unit, and neurological improvement. We conclude that the needs of patients with progressive incomplete spinal cord lesions due to neurological disease differ from those of patients with acute traumatic spinal cord lesions and are best managed in a neurological rehabilitation unit. Efficacy appears to be related to neurological recovery and the duration of rehabilitation. This study underlines the value of combined neurological and rehabilitation expertise in the management of this patient group and the need to incorporate both disciplines in planning service provision.

Discrepantly poor verbal skills in poor readers: a failure of learning or ability?

Poor verbal skills in poor readers have long been reported in the literature. There have been many attempts to understand the interaction between poor verbal ability and poor verbal achievement. The methodological problems are considerable, including the measurement of verbal ability, which has been confounded by previous learning. A new reasoning test, the VESPAR, has been designed to measure novel problem solving and thus to be less reliant on acquired verbal skills. One hundred and seventy 14-year-olds completed the VESPAR, the Cognitive Abilities Test (CAT) and a single-word reading test. Overall, verbal scores were weaker than spatial scores. A subgroup of 38 pupils with particularly marked discrepancies between verbal and non-verbal CAT was identified. The especially discrepant pupils were matched with other non-discrepant pupils from the year group for either verbal or non-verbal CAT. The discrepant group's reading was at the same level as the matched verbal CAT group. However, the primary verbal ability of the discrepancy group, as measured on the VESPAR, was greater than the matched verbal CAT group. This raises the possibility that CAT- but not VESPAR-discrepant pupils may be at particular risk of under-achievement in the verbal domain.

Cerebellar information processing in relapsing-remitting multiple sclerosis (RRMS).

Recent research has characterized the anatomical connectivity of the cortico-cerebellar system - a large and important fibre system in the primate brain. Within this system, there are reciprocal projections between the prefrontal cortex and Crus II of the cerebellar cortex, which both play important roles in the acquisition and execution of cognitive skills. Here, we propose that this system also plays a particular role in sustaining skilled cognitive performance in patients with Relapsing-Remitting Multiple Sclerosis (RRMS), in whom advancing neuropathology causes increasingly inefficient information processing. We scanned RRMS patients and closely matched healthy subjects while they performed the Paced Auditory Serial Addition Test (PASAT), a demanding test of information processing speed, and a control task. This enabled us to localize differences between conditions that change as a function of group (group-by-condition interactions). Hemodynamic activity in some patient populations with CNS pathology are not well understood and may be atypical, so we avoided analysis strategies that rely exclusively on models of hemodynamic activity derived from the healthy brain, using instead an approach that combined a 'model-free' analysis technique (Tensor Independent Component Analysis, TICA) that was relatively free of such assumptions, with a post-hoc 'model-based' approach (General Linear Model, GLM). Our results showed group-by-condition interactions in cerebellar cortical Crus II. We suggest that this area may have in role maintaining performance in working memory tasks by compensating for inefficient data transfer associated with white matter lesions in MS.

Cerebellar contributions to working memory.

Anatomical studies show the existence of two well-characterized cortico-cerebellar 'loops' that connect prefrontal and cortical motor areas each with their own modules in the cerebellar cortex. The involvement of the cerebellar 'motor' modules in motor skills is well established, but little is understood about the way that cerebellar prefrontal modules process information from the prefrontal cortex. This question is particularly important for understanding the human cortico-cerebellar system because the prefrontal loop appears to have expanded significantly during the course of evolution. Here, we investigate whether cerebellar modules known to be connected with the prefrontal cortex (specifically within cerebellar cortical lobule VII) become engaged by the execution of skilled cognitive operations. We tested the anatomically specific hypothesis that this area would be activated by the skilled maintenance and manipulation of items within verbal working memory. We used the Paced Auditory Serial Addition Test (PASAT) in combination with a sparse sampling method to avoid artefact caused by speech-related head movement on the BOLD timecourse. Consistent with our hypothesis, we report that activity in the experimental condition was evoked in medial portions of cerebellar cortical lobule VII (relative to a closely matched control task). As would be anticipated, the motor demands common to experimental and control tasks activated face areas of the motor cortex as well as connected motor areas of the cerebellar cortex. We discuss this evidence in the context of theories of cortico-cerebellar information processing.

The abstraction of numerical relations: a role for the right hemisphere in arithmetic?

Arithmetical reasoning ability has been investigated in a group study of patients with unilateral cerebral lesions. Two series of 38 and 39 patients, who had suffered unilateral cerebral lesions of the right and left cerebral hemisphere, respectively, were investigated. They completed a neuropsychological battery that included a test of computation (Graded Difficulty Arithmetic, GDA; Jackson & Warrington, 1986), and a new test of numerical series completion (Arithmetical Reasoning Test, ART). Whereas the left-hemisphere lesion group were markedly more impaired on the GDA compared to both the right-hemisphere lesion group and a standardization sample, both lesion groups were equally severely impaired on the ART. It is suggested that the abstraction of numerical relations, which is essential to numerical series completion, relies on the integrity of the right hemisphere. A global model of arithmetic processing that incorporates these findings is proposed.

Multiple sclerosis: a preliminary study of selected variables affecting rehabilitation outcome.

PROBLEM: The diversity of physical and cognitive impairments seen in progressive multiple sclerosis (MS), make it difficult to identify the factors that influence neurorehabilitation outcome. Improvements in a motor disability scale must be considered in the context of the patient's physical and cognitive starting points, if the process of neurorehabilitation is to be properly understood. METHOD: Data was collected from 38 patients (mean age 41 years, 16 men and 22 women) with clinically definite MS (of whom all but one were in the progressive phase of the disease), who were consecutively admitted to a neurorehabilitation unit. Patients' physical disability was assessed on the motor scale of the Functional Independence Measure (FIM) on admission and discharge. Cognitive and neurological assessments were completed on admission. The cognitive battery comprised the WAIS-R, NART, RMT, CVLT CMT, GNT, GDA, and VOSP (some in short form). Emotional measures were the STAI, STAXI and BDI. RESULTS: The mean improvement on the FIM was 6 points. A multiple regression analysis was performed to determine which cognitive and neurological variables related to reduced disability after neurorehabilitation. To take account of each patient's starting point, the model included their FIM admission score. This variable, together with vocabulary skills and cerebellar function accounted for 57% of the variance in the patients' improvements. These results suggest that verbal intelligence and cerebellar function are influential in determining rehabilitation outcome. Although these findings will be unsurprising to clinicians, this is the first quantitative demonstration of these effects.

Relation of impairment to everyday competence in visual disorientation syndrome: evidence from a single case study.

OBJECTIVE: To determine the relation of neurology and neuropsychology to everyday competence. DESIGN: The association of these three domains was investigated using a single case multiple baseline design with two phases. Phase A comprised 6 weeks that coincided with an inpatient admission. Phase B comprised 3 months spent at home. A battery of visual spatial tests was completed every fortnight during the A phase and at the end of the B phase. Two new tests of relevant neurologic function with control data were developed and used weekly during the A phase and at the end of the B phase. The first test recorded the speed, accuracy, and efficiency of her walking, and the second test recorded her depth perception. SETTING: Tertiary care center. PARTICIPANT: A 35-year-old woman who suffered a venous sinus thrombosis with visual disorientation syndrome. RESULTS: During Phase A, she achieved significant functional gains in mobility, dressing, bathing, and domestic tasks, in the context of unchanging psychometric test scores and static relevant neurologic function. During Phase B, she achieved few functional gains, despite improvements in neurologic status, demonstrated by depth perception. CONCLUSIONS: Everyday function can progress without improvement in neurologic and cognitive status.

A new test of memory for multiple sclerosis I: format development and stimuli design.

Memory tests were often developed for healthy populations. The accuracy of these measures is reduced when administered to patients with neurological diseases, who may experience physical and/or cognitive symptoms. Also, methodological factors, for example, spanning the ability spectrum, and content/format artefacts, may contribute to a decline in test precision. The aim of this study was to develop a new test of memory, which addresses these issues. The new memory test comprises assessments of recall, paired association, and recognition, at a Task Familiarisation stage and two difficulty levels, for both the verbal and spatial modalities. It was administered to 85 healthy individuals and 100 patients with multiple sclerosis (MS). All patients were able to attempt each task of the new assessment and there was no influence of visual integrity or manual dexterity on memory test performance, supporting the applicability of the tasks to patients with multiple sclerosis. Both the standardisation and validation samples demonstrated a wide range of scores on each section of the new test suggesting that the measure spanned an acceptably broad range of abilities. It seems probable, therefore, that the new assessment offers a more exact measure of verbal and spatial recall, paired association, and recognition memory.

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.

Resolution of left hemisphere cognitive dysfunction in multiple sclerosis with magnetic resonance correlates: a case report.

Cognitive impairment is common in multiple sclerosis and although deterioration has been observed in individual patients at the time of relapse, improvement in cognitive function in parallel with remission of neurological impairment has proved more difficult to document. We describe a 21-year-old women with a one-year history of relapsing remitting multiple sclerosis, who was admitted to hospital following a severe relapse which rendered her quadriplegic. Detailed psychometric assessment was carried out during relapse and on recovery of neurological function, eight weeks later. There were improvements in arithmetic, naming, and comprehension tasks. The patient had T2 weighted and gadolinium-enhanced magnetic resonance imaging and magnetic resonance spectroscopy. These showed a reduction in lesion size, lesion enhancement, and changes in brain chemistry which parallel the improvement in cognitive performance.

The impact of inpatient rehabilitation on progressive multiple sclerosis.

One of the primary aims of rehabilitation for patients with multiple sclerosis (MS) is to reduce their levels of disability and handicap, yet little systematic research into the outcomes of this intervention has been undertaken. This stratified, randomized, wait-list controlled study evaluated the effectiveness of a short period of multidisciplinary inpatient rehabilitation in people with MS. Sixty-six patients in the progressive phase of the disease were assessed at 0 and 6 weeks with validated measures of impairment (Expanded Disability Status Scale and Functional Systems), disability (Functional Independence Measure), and handicap (London Handicap Scale). Both groups were comparable in terms of age, sex, disease duration and severity, disability, and handicap. At the end of 6 weeks, although the level of impairment in both groups remained the same, those who participated in a short period of inpatient rehabilitation (average of 25 days) significantly improved their level of disability and handicap compared with those in the wait-list control group. Despite unchanging impairment, inpatient rehabilitation resulted in reduced disability and handicap in patients with progressive 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. Multiple Sclerosis (2000) 6 280 - 285

Cognitive function in primary progressive and transitional progressive multiple sclerosis: a controlled study with MRI correlates.

The relative rarity of primary progressive (PP) and transitional progressive (TP) multiple sclerosis has meant that little documentation of cognitive function in such patients is currently available. The aim of this study was to investigate the cognitive skills of patients with PP and TP multiple sclerosis relative to matched healthy controls, and to examine the relationship of this impairment to MRI parameters. Sixty-three patients (43 PP, 20 TP) were individually matched with healthy controls, who undertook the same cognitive tasks as the patient group. The neuropsychological assessment comprised Rao's brief repeatable battery, a reasoning test, and a measure of depression. Patients also underwent T1- and T2-weighted brain MRI. These patients were taken from a larger cohort (158 PP, 33 TP) in whom it had been demonstrated that the re were no significant differences between the mean scores of the PP and TP groups on any of the cognitive variables. The 63 patients were therefore taken as one group for comparison with the healthy controls. These patients performed significantly worse than the controls in tests of verbal memory, attention, verbal fluency and spatial reasoning. An impairment index was constructed and applied to the patient data. This correlated modestly with T2-lesion load (r = 0.45, P = 0.01), T1-hypointensity load (r = 0.45, P = 0.01) and cerebral volume (r = -0.35, P = 0.01). Thus, PP and TP multiple sclerosis patients demonstrate significant cognitive dysfunction when compared with matched healthy controls. The relationship between this impairment and MRI parameters is moderate, suggesting that cognitive dysfunction in PP and TP multiple sclerosis has a complex and multifactorial aetiology, which is not adequately explained by pathology as demonstrated on conventional MRI.