MS functional composite: relation to disease phenotype and disability strata

OBJECTIVE: The MS Functional Composite (MSFC), a recently developed outcome measure for clinical trials, was applied to 240 patients with MS to explore its utility in different subgroups of MS and for comparison with the Expanded Disability Status Scale (EDSS). METHOD: Three clinical dimensions were examined: arm/hand function, leg function/ambulation, and cognition. Predictions of relative scores on the MSFC and its components in three major MS phenotypes (relapsing-remitting, primary progressive, and secondary progressive) and three strata of disability were developed and tested. Also, correlations with EDSS were calculated and the effect of an external reference population was assessed. RESULTS: Mean MSFC score was positive in the relapsing-remitting (0.4) and mildly disabled (0.4) groups and negative in the secondary progressive (-0.3), primary progressive (-0.4), and moderately (-0.07) and severely disabled (-1.0) groups. The correlation between EDSS and MSFC was strong (-0.68). EDSS correlated strongly with ambulation in secondary and primary progressive patients and severely disabled patients, moderately with arm/hand function for all analyzed groups, and not at all with cognition. Comparison with an external reference population showed changes in MSFC- and Z-scores, but did not result in altered differences between the subgroups. CONCLUSION: Our prospective study in subgroups of MS confirmed and extended the construct validity of the MSFC. The MSFC also showed good concurrent validity with the EDSS, and includes information about cognition.     

Fatigue in multiple sclerosis: relationship to depression, disability, and disease pattern

In order to investigate the associations between fatigue and depression, disability, and disease subtype, 207 individuals with clinically definite Multiple Sclerosis (MS) were administered the Fatigue Severity Scale and the Zung Self-rating Depression Scale during a regular clinic appointment. Their current level of disability was established using the Expanded Disability Status Scale. Fatigue and depression were highly correlated (r=0.58), even when the depression measure was corrected for items overlapping with fatigue and other symptoms or consequences of MS (r=0.44). Fatigue and disability were also correlated (r=0.33). Multiple regression revealed that both depressed mood and disability were significant predictors of fatigue, together accounting for approximately 23% of the variance in patients' self-reported fatigue. The combined groups of primary progressive (n=45) and secondary progressive patients (n=25) appeared to have higher fatigue scores than relapsing-remitting patients (n=137). However, an analysis of covariance revealed that this apparent difference was in fact attributable almost exclusively to differences in disability among the three subtypes of MS. Other reports of differences in fatigue between subtypes of MS should be re-examined in light of this finding.     

Clinical significance of the multiple sclerosis functional composite: relationship to patient-reported quality of life

BACKGROUND: The Multiple Sclerosis Functional Composite (MSFC) was recommended by a task force of the National Multiple Sclerosis Society as a new clinical outcome measure for clinical trials. The task force recommended that the MSFC be validated against other measures of the disease, such as patient-reported quality of life. METHODS: Three hundred patients with multiple sclerosis (MS) representing the spectrum of disease severity were included in this cross-sectional study. The MSFC and Kurtzke Expanded Disability Status Scale (EDSS) were used as measures of disease severity. Clinical relevance of the disease severity scores was analyzed using measures included in the Multiple Sclerosis Quality of Life Inventory. The MSFC and EDSS scores were correlated with self-reported employment status, the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), and the Sickness Impact Profile (SIP). RESULTS: The MSFC and EDSS scores were strongly correlated (r = -0.80, P<.001). The MSFC scores were correlated with patient-reported physical functioning (SIP Physical Summary Scale: r = -0.71, P<.001; SF-36 Physical Component Score: r = -0.41, P<.001). The MSFC scores were significantly but more weakly correlated with emotional functioning (SIP Psychosocial Summary Scale: r = -0.34, P<.001). After controlling for EDSS scores, there were significant residual correlations between the MSFC scores and measures of health-related quality of life, suggesting that the MSFC accounts for the variability in health-related quality of life measures not reflected by the EDSS. CONCLUSIONS: The observed strong correlations between MSFC scores and validated measures of self-reported quality of life indicate that the MSFC scores are clinically relevant. This study supports a recommendation by the National Multiple Sclerosis Society Task Force to use the MSFC as a clinical outcome measure.     

Fatigue in multiple sclerosis: relationship with disease duration, physical disability, disease pattern, age and sex

To evaluate the relationship between disease duration, disability, disease pattern, age and sex with fatigue in MS patients. One hundred and seventy-three clinically definite MS patients and 87 age-matched healthy controls enrolled in this cross sectional study. Demographic data (sex, age), duration of the disease and disease pattern extracted from patient’s files and Kurtzke Expanded Disability Status Scale (EDSS) were recorded for each patient by an expert neurologist. Participants were asked to answer the validated and reliable Persian version of beck depression inventory (BDI) and FSS (fatigue severity score) questionnaires. Mean FSS and BDI scores were significantly different between patients and controls (p < 0.001). Patients with longer disease duration, higher EDSS and progressive type of disease had significantly higher FSS and BDI scores. Although men had higher EDSS, FSS and BDI scores were similar in both sex groups. FSS was significantly correlated with age, disease duration, BDI and EDSS. The analysis of covariance revealed that there is no difference in the covariance-adjusted means for fatigue among two disease groups (relapsing remitting and secondary progressive) except for EDSS. MS patients with longer disease duration, higher EDSS and progressive type of disease suffer from fatigue more than cases with lower EDSS, duration of disease and relapsing type of the disease.     

Axonal pathology in multiple sclerosis: relationship to neurologic disability.

In this review, data is summarized supporting the hypothesis that axonal loss is a major pathologic process responsible for irreversible neurologic disability in patients with multiple sclerosis. Pathologic studies implicate inflammatory demyelination as a principal cause of axonal transection and subsequent axonal degeneration. Axonal degeneration caused by chronic demyelination in the absence of active inflammation may also contribute to progressive disability in the later stages of the disease. Studies using magnetic resonance spectroscopy suggest that axonal loss begins at the onset of the disease, and studies using magnetic resonance imaging have documented brain atrophy in the earliest stages of multiple sclerosis. Brain atrophy increases during the relapsing-remitting disease stage without concurrent disability progression. This suggests that compensatory mechanisms maintain neurologic function, despite progressive brain tissue loss during the early stages of the disease. Beyond a threshold, however, further axonal loss leads to continuously progressive neurologic disability. We hypothesize that the rate and extent of axonal loss during relapsing-remitting multiple sclerosis determines when a patient enters the secondary progressive stage of the disease. This view of disease pathogenesis has several important implications. First, surrogate markers of axonal loss are needed to monitor the disease process for patient care and for clinical trials. We propose brain parenchymal fraction, a precise measure of whole-brain atrophy, as an attractive candidate for this purpose. Second, disease-modifying therapy should be used early in multiple sclerosis patients, before extensive axonal loss has occurred. Third, neuroprotective drugs should be tested in combination with anti-inflammatory drugs in multiple sclerosis patients. Finally, studies of the time course of axonal loss, and its mechanisms are critical for effective therapeutic intervention.     

Correlations between multiple sclerosis functional composite, expanded disability status scale and health-related quality of life during and after treatment of relapses in patients with multiple sclerosis

The measurement of the clinical manifestations of multiple sclerosis (MS) is difficult. In the present study, we examined the changes in measurement of functions during and after pulse methylprednisolon (MP) treatment of MS exacerbations using the MSFC and EDSS. Correlation between multiple sclerosis quality of life (MSQoL)-54, EDSS and MSFC were studied. Thirty-six clinically definite MS patients were included in this study. Because of MSFC's repeating feature, we administered the tests to a control group to exclude practise effects. All patients received 1000-mg intravenous MP for 5 days, followed by tappering dose of 100-mg oral prednisolone. All three scales were assessed on day 0. EDSS and two components of MSFC (nine HPT and T25WT) were administered on the other days of pulse MP treatment. PASAT was not applied before the day 5 to exclude the practise effect. MSQoL-54 was assessed again on day 30. Mean EDSS values significantly decreased after the day 2. MSFC score improved from 0.03 +/- 1.71 on day 0 to 0.79 +/- 1.51 on day 5. Improvement continued on day 30. The mean physical health composite score increased from 66.50 +/- 9.3 on day 0 to 74.34 +/- 8.9 on day 30. Mental health composite had also a significant improvement on day 30. Correlation between the baseline overall MSFC and the EDSS was moderately strong. T25WT correlated most strongly with EDSS. Significant positive correlation was found between MSFC and both components of MSQoL-54. It is more prominent for the MSFC and physical health composite correlation. The same correlation was found for the EDSS and MSQoL-54 composites. Changes in EDSS and MSFC scores and MSQoL-54 were found significantly correlated for the overall score on day 30 compared with day 0. In conclusion, MSFC seems to be more sensitive in detecting changes in function than the EDSS. Hence, EDSS is still useful for daily routine practise. When these results combined with the significant correlation between MSFC and MSQoL-54 measures, which indicated the MSFC reflects the severity of MS as perceived by patients, MSFC seems to be the most useful scale for clinical trials.     

Brain atrophy in relapsing-remitting multiple sclerosis: relationship with 'black holes', disease duration and clinical disability

Recent MRI studies in multiple sclerosis have highlighted the potential role of brain atrophy evaluation as a putative marker of disease progression. In the present study, we evaluated the supratentorial and infratentorial brain volume in patients with relapsing remitting multiple sclerosis (RR MS) and in healthy subjects. Moreover, we determined whether brain volumes of MS patients are associated with different aspects of brain MRI abnormalities and clinical findings. Two-dimensional acquired MRI was performed on 52 relapsing-remitting multiple sclerosis and 30 healthy subjects. The volume of supratentorial and infratentorial structures was measured in selected representative slices. Gd-enhancement, T2 hyperintense, T1 hypointense (i.e. 'black holes') total lesion load, as well as the area of corpus callosum was calculated in the MS group and related to brain volume measures. Correlations between MRI parameters and clinical features were also considered. MS patients had significantly lower supratentorial, infratentorial brain volume and corpus callosum area than healthy subjects (P<0.01). Supratentorial brain volume was significantly related to corpus callosum area (r=0.58; P<0.01) and T1 hypointense lesion load (r=0.48; P<0.01), but not with T2 hyperintense lesion load. Infratentorial/supratentorial ratio was significantly associated with disease duration and EDSS score (r=-0.34; P=0.02 and r=-0.49; P<0.01, respectively). This study documents that brain atrophy is an early MRI finding in RR MS and it is closely related to 'black holes' burden. The use of relative values (infratentorial/supratentorial ratio) may increase the conspicuity of correlation between clinical and MRI findings.     

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS>/=5; n=46) or MS-nonfatigue (MSNF) (FSS相似文献   

Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment

There is convincing evidence that neurological relapses in multiple sclerosis (MS) are the clinical counterpart of acute focal inflammation of the central nervous system (CNS) whereas neurological progression is that of chronic diffuse neurodegeneration. The classical view is to consider that MS is an organ-specific autoimmune disease, i.e. that inflammation is the cause of the neurodegeneration. The succession of relapses eventually leads to accumulation of disability and clinical progression results from subclinical relapses. A series of recent observations tends to challenge this classical concept. Important observations have come from the study of the natural history of MS. In the Lyon MS cohort, accumulation of irreversible disability appeared not to be affected by clinically detectable neurological relapses. This has also been shown to be "amnesic" for the early clinical characteristics of the disease, and essentially age-dependent. Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability. Interferons beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent. Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and cerebral atrophy still progress. The same experience has been reported with cladribine and autologous haematopoietic stem cell transplantation. All these observations give support to the fact that relapses do not essentially influence irreversible disability in the long term in MS. They are consistent with what has been shown at the individual level in the 1970s by performing serial quantitative neurological examinations over several years, and with what is currently emerging from early and serial structural brain MRI studies. These breakthroughs have immediate implications for the counselling of patients with MS. They suggest that MS is as much neurodegenerative as inflammatory, and should cause the modification of disease-modifying therapeutic strategies by focussing on the protection and repair of the nervous system and not only on the control of inflammation.     

New treatment strategies in multiple sclerosis

Multiple sclerosis is the most common, non-traumatic, disabling neurological disease of young adults, affecting an estimated two million people worldwide. At onset multiple sclerosis can be categorised clinically into relapsing remitting MS (RRMS — 85-90% of patients) or primary progressive MS (PPMS). Relapses typically present sub-acutely over hours to days with neurological symptoms persisting for days to weeks before they gradually dissipate. At first full recovery is the norm, later patients accumulate deficits and ultimately most convert to a secondary progressive phase (SPMS), characterised by deficits that increase in the absence of further relapses. The clinical picture reflects the complex interplay of focal inflammation, demyelination and axonal degeneration occurring within the central nervous system.Since the introduction of a genuine disease-modifying drug, interferon-beta1b in 1993, there has been a growing interest from academia and pharmaceutical companies alike in multiple sclerosis therapy. In part this effort has focused on investigating the “window of therapeutic opportunity” within the natural history of the disease: it is becoming increasingly clear that immunotherapies are not useful in the secondary phase of the disease but may offer long-term benefit if given early in the relapsing-remitting phase. In part, attention is being paid to the details of dosing and administration of the various licensed therapies, but there is also a significant research effort to explore new ways to treat the disease. In this review, we first sketch the landscape of novel therapies in multiple sclerosis and then discuss in detail approaches which are likely to emerge over the next few years.     

Immunomodulatory treatment strategies in multiple sclerosis

Journal of Neurology - Multiple sclerosis (MS) represents the prototypic inflammatory autoimmune disorder of the central nervous system and the most common cause of neurological disability in young...     

Mastery,functional disability and perceived health status in patients with multiple sclerosis

Background and purpose: Multiple sclerosis (MS) is a chronic disease that is difficult to predict and to cope with. Mastery refers to the extent to which patients see themselves as being in control of the forces that affect their lives. It may play an important role in perceived health status and well‐being. The purpose of this study was to clarify whether mastery is associated with functional disability and perceived health status in MS patients and how such an association might function. Methods: Two hundred and three MS patients completed the Short‐Form‐36 Health Survey as well as the Pearlin–Schooler Mastery Scale. Functional disability was assessed using the Kurtzke Expanded Disability Status Scale. Hierarchical multiple linear regression analyses were performed on the data from two MS age groups: <45 and ≥45 years of age. Results: Functional disability was negatively associated with perceived physical health status in both age groups and with perceived mental health status in younger age group. Mastery was positively associated with perceived health status in older age group. Discussion: The findings confirm that mastery might be helpful for older MS patients. Education strategies for MS patients aimed at personal empowerment for the maintaining of physical and mental well‐being may be important.     

Evoked potentials and CSF-immunoglobulins in MS: relationship to disease duration, disability, and functional status

In 100 MS patients, BAEP and tibial SEP abnormality rates increased significantly with disease duration and clinical disability. VEP correlated non-linearly with disease duration, and median nerve SEP correlated with disability. In multifactorial analysis, however, BAEP correlated significantly only with clinical brainstem and cerebellar signs. These results suggest that evoked potentials correlate more strongly with neurological status of the functional subsystems than either overall disability or disease duration. These findings indirectly suggest that evoked potentials may be useful monitors during large therapeutical trials in MS patients.     

Relation between functional connectivity and disability in multiple sclerosis: a non-linear model

Objective

To characterize the relation between brain functional connectivity and disability in patients with multiple sclerosis; to investigate the existence of critical values of both disability and functional connectivity corresponding to exhaustion of functional adaptive mechanisms.

Methods

Hundred-and-nineteen patients with no-to-severe disability and 42 healthy subjects were studied via 3T resting state functional MRI. Out of 116 regions extracted from Automated Anatomical Labeling atlas, pairs of regions whose functional connectivity correlated with Expanded Disability Status Score were identified. In patients, mathematical modeling was applied to find the best models describing Expanded-Disability-Status-Score vs structural or functional measures. Functional vs structural models intersecting points were identified.

Results

Disability had direct linear relation with lesion load (r?=?0.40, p?<?5E?6), inverse of thalamic volume (r?=?0.31 p?<?1E?3) and functional connectivity in bi-frontal pairs of regions (r?>?0.40, p?<?0.04), while being non-linearly associated with functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions (F?>?1.73, p?<?0.02). Structural vs functional models intersecting points corresponded to Expanded Disability Status Score of 3.0. 85% of patients scoring more than 3.0 showed functional connectivity in cerebello-temporal and cerebello-frontal pairs of regions below confidence intervals (z?=?[2.28–2.88] 95% CI) measured in healthy subjects.

Conclusions

Functional brain connectivity changes may represent mechanisms of adaptation to structural damage and inflammation and may be not always clinically beneficial. Functional connectivity decreases in comparison with structural measure at Expanded Disability Status Score greater than 3.0, which may be critical and indicate exhaustion of compensatory mechanisms.

     

The relationship between disability and memory dysfunction in multiple sclerosis.

We examined the relationship between memory impairment and functional disability in multiple sclerosis. Tests of memory, sensorimotor ability, and functional capacity were administered to fifty-six subjects with chronic-progressive or remitting-relapsing MS. Sensorimotor impairment, functional disability, and chronicity predicted impairment on various measures of memory acquisition, while age and type of diagnosis did not. After accounting for the effects of initial acquisition, delayed-recall performance was weakly-associated with disability. We suggest that: (1) Functional disability is associated with memory loss in MS; (2) MS-forgetting is caused by defective acquisition, rather by a deficit in consolidation or storage; (3) Level of disease activity, rather than type of MS diagnosis, determines the degree of memory impairment; and (4) MS disability needs to be evaluated multidimensionally, to account for both neurologic and functional impairment.     

Magnetization transfer ratio of the spinal cord in multiple sclerosis: relationship to atrophy and neurologic disability.

The authors compare the spinal cord magnetization transfer ratio (MTR) of multiple sclerosis (MS) patients to healthy volunteers, relate MTR to spinal cord atrophy, and relate these and other magnetic resonance (MR) imaging parameters to disability. Sixty-five patients with MS (14 relapsing remitting [RR], 34 secondary progressive [SP], and 17 primary progressive [PP] MS), and 9 healthy volunteers were studied using MR at 1.0 T. Disability of the patients was assessed using the expanded disability status scale (EDSS). Magnetic resonance parameters were upper spinal cord MTR, number of focal spinal lesions, presence of diffuse abnormalities, and spinal cord cross-sectional area (CSA). Correlations were assessed using Spearman's rank correlation coefficient (r). Magnetization transfer ratio was higher in the controls (median, 33%; range, 30%-38%) than in patients with MS (median, 30%; range, 16-36; p < 0.05). In patients with MS EDSS correlated with spinal cord MTR, albeit weakly (r = -0.25, p < 0.05). Correlation between EDSS and spinal cord CSA was better (SRCC = -0.40, p < 0.01). No correlation was found between MTR and CSA (r = 0.1, p = 0.4). Combining MTR with spinal cord CSA improved correlation with EDSS (r = -0.46, p < 0.001), suggesting an independent correlation between disability and these 2 MR parameters. Expanded disability status scale scores were higher in patients who had diffuse spinal cord abnormality regardless of focal lesions (median, 6; range, 1.5-7.5) than in patients without diffuse abnormalities (median, 3.5; range, 0-8; p < 0.01). CSA was lower in patients with diffuse spinal cord abnormality (median, 62; range, 46-89 mm2) than in patients without diffuse abnormalities (median, 73; range, 47-89 mm2; p < 0.01). MTR was slightly lower in patients with diffuse spinal cord abnormalities (median, 29; range, 21%-33%) than in patients without diffuse abnormalities (median, 31; range, 16-36; t-test, p < 0.05).     

Optimal reference population for the multiple sclerosis functional composite

A reference population is used when integrating the individual components of the Multiple Sclerosis Functional Composite (MSFC) into a single composite score. The choice of reference populations may have a significant impact on the resulting MSFC score, yet the impact of different reference populations has not been evaluated. We evaluated the impact of different reference populations when deriving the Multiple Sclerosis Functional Composite (MSFC) in a group of MS patients followed longitudinally for two years. Reference populations included the study population at baseline (n = 60), a group of healthy controls (n = 18) and the National MS Society Task Force reference population (n = variable). We found that the choice of reference population had a significant impact on the resulting MSFC Z-score, sometimes compromising the statistical sensitivity to change over time. Our results suggest that longitudinal studies employing a multisystem composite Z-score should use a reference population with similar patients, which can most easily be achieved by using the baseline measures of the population under study. These results have significant implications to sample size estimates for longitudinal clinical studies and therapeutic trials.     

Neuropsychological deficits but not coping strategies are related to physical disability in multiple sclerosis

Detailed neuropsychological assessment was performed in 86 women (48 patients with stable relapsing-remitting multiple sclerosis (MS) and 38 matched healthy controls (HC)). Patients were categorized into patients without (EDSS < or =1, n = 26) and with physical disability (EDSS > or =2, n = 22). Patients with EDSS > or =2 scored significantly (P < 0.05) higher in Beck's depression inventory (BDI) and depression scores (DS) compared to HC and patients with EDSS < or =1. No significant differences were found with respect to the use of specific coping strategies between the patient groups, who preferred active (EDSS < or =1) or distracting (EDSS > or =2) strategies. Cognitive deficits were significantly increased in MS with EDSS > or =2 with regard to visuo-construction and visual memory, in particular with respect to geometric figures, compared to MS with EDSS < or =1. Significant positive correlations of depression variables (BDI, DS and BL) and depressive as well as denying coping strategies were found. Our results showed increased depression scores and increased cognitive deficits in advanced physically disabled patients, without selection of specific coping strategies. This supports an individual MS-specific neuropsychological therapeutic approach in order to improve disease related deficits together with social functioning.