Outcome Measure In Multiple Sclerosis Research Articles

Magnetic resonance imaging as a surrogate outcome measure of disability in multiple sclerosis: Have we been overly harsh in our assessment?

The validity of magnetic resonance imaging (MRI) as a surrogate outcome measure in multiple sclerosis (MS) clinical trials has been greeted skeptically both by the US Food and Drug Administration and by clinical researchers because the correlation between current MRI measures and clinical disability, although significant, has generally been low. Thus, the reported correlations have varied between rho = 0.09 and rho = 0.60, and have often been at the lower end of this range. Nevertheless, it still appears possible that this apparently poor correlation is due not to any deficiency either with our current MRI measures or with our disability scale, but rather to the intrinsic variability in the clinical expression of MS plaques in different anatomical locations. This article explores this possibility through the development of a general mathematical model for the relation between MRI changes and clinical disability in patients with MS. Under the conditions of this general model, the maximum expected correlation between clinical disability and MRI will typically be quite low (eg, rho = 0.2-0.3), even when it is assumed that the MRI changes are the sole determinant of disability and, furthermore, that the scale used to measure disability is ideal. These observations, together with the significant relations already reported between MRI and disability (with observed correlations in the range of 0.2-0.6), actually suggest that our available clinical and MRI measures are considerably better than is currently believed and, in fact, that the MRI may be a valid surrogate marker in the assessment of treatment efficacy in MS.

Padronização da Multiple Sclerosis Functional Composite Measure (MSFC) na população brasileira

The Multiple Sclerosis Functional Composite Measure (MSFC) is an outcome measure in multiple sclerosis developed by USA National Multiple Sclerosis Society (1994), a three-part composite clinical measure--9-Hole Peg Test, Timed 25-Foot Walk and PASAT. It should be multidimensional in order to reflect the principal ways MS affects an individual. The MSFC was applied in 91 Brazilian subjects and standardized to be use in MS centers.

The Paced Auditory Serial Addition Test: to what extent is it performed as instructed, and is it associated with disease course?

One commonly used outcome measure in multiple sclerosis (MS) clinical trials is the Multiple Sclerosis Functional Composite, which includes the Paced Auditory Serial Addition Test (PASAT) as a measure of cognitive function. Concerns have been raised about the standard PASAT scoring method, whereby the number of correct responses is summed. This method does not take into account whether the test is performed as intended, which may affect interpretation of the results. Accordingly, another scoring method has been proposed, which examines the number of times a correct response is immediately preceded by another correct response (termed a dyad). We compared the two scoring methods for the PASAT, and found that the mean percentage of correct responses not accounted for by dyads ranged from 27.5% to 49.5%, indicating that much of the time the test is not performed as instructed. We also examined disease course and the PASAT score, as studies have produced conflicting results as to whether disease course is associated with cognitive impairment. Although disease course was significantly associated with the PASAT score, it accounted for little of the variation in scores, even when adjusting for other predictors. Finally, as 14.2% of participants refused to do the PASAT or failed to complete it, we also examined whether the Perceived Deficits Questionnaire (PDQ), a self-reported measure of cognitive function, is a potential proxy measure for the PASAT. The correlation between the two tools was low (-0.14), suggesting that the PDQ is not a useful substitute for the PASAT.

Reproducibility and Accuracy of Quantitative Magnetic Resonance Imaging Techniques of Whole-Brain Atrophy Measurement in Multiple Sclerosis

Background and Purpose. Whole-brain atrophy is of growing interest as an outcome measure in multiple sclerosis (MS) clinical trials. The authors compared the reproducibility and accuracy of 3 quantitative techniques of measurement in patients with MS. Methods. Thirty-four patients with relapsing-remitting MS (median Expanded Disability Status Scale disability score = 1.5) were studied. Brain parenchymal fraction (BPF) was quantified on spin-echo 2-dimensional T1-weighted axial 5-mm slice thickness sequences by semiautomated (Buffalo, Trieste) or automated (SIENAX) algorithms. Results. Mean ± SD BPFs were 0.830 ± 0.04 with Buffalo, 0.824 ± 0.04 with Trieste, and 0.826 ± 0.04 with SIENAX methods (P= nonsignificant [NS]). Mean BPF scan-rescan coefficient of variation (COV) was 0.41% for Buffalo, 0.44% for Trieste, and 0.32% for SIENAX (P=NS).The semiautomated methods showed higher accuracy than the auto-mated method in brain extraction (masking; P= .001). The errors of skull stripping included scalp, skull bone marrow, inferior parts of temporal lobes anterior to the brain stem, face structures, sagittal sinuses, eyes, and optic nerves. Buffalo (r=−0.37, P= .034) and Trieste (r=−.36, P= .039) BPFs showed stronger cor relation with disability than SIENAX (r=−0.16, P= .219). These differences were statistically significant (P= .0031 for Buffalo and P= .0037 for Trieste BPF). Conclusions. This study showed a high reproducibility of both semiautomated and automated methods for brain atrophy measurement. The semiautomated methods showed higher accuracy than the automated SIENAX method did in the evaluation of brain extraction, especially in infratentorial and cortical regions, where operator interaction dur ing the masking processes was essential.

Reproducibility and Accuracy of Quantitative Magnetic Resonance Imaging Techniques of Whole-Brain Atrophy Measurement in Multiple Sclerosis

Whole-brain atrophy is of growing interest as an outcome measure in multiple sclerosis (MS) clinical trials. The authors compared the reproducibility and accuracy of 3 quantitative techniques of measurement in patients with MS. Thirty-four patients with relapsing-remitting MS (median Expanded Disability Status Scale disability score = 1.5) were studied. Brain parenchymal fraction (BPF) was quantified on spin-echo 2-dimensional T1-weighted axial 5-mm slice thickness sequences by semiautomated (Buffalo, Trieste) or automated (SIENAX) algorithms. Mean +/- SD BPFs were 0.830 +/- 0.04 with Buffalo, 0.824 +/- 0.04 with Trieste, and 0.826 +/- 0.04 with SIENAX methods (P = nonsignificant [NS]). Mean BPF scan-rescan coefficient of variation (COV) was 0.41% for Buffalo, 0.44% for Trieste, and 0.32% for SIENAX (P =NS).The semiautomated methods showed higher accuracy than the automated method in brain extraction (masking; P = .001). The errors of skull stripping included scalp, skull bone marrow, inferior parts of temporal lobes anterior to the brain stem, face structures, sagittal sinuses, eyes, and optic nerves. Buffalo (r = -0.37, P = .034) and Trieste (r = -.36, P = .039) BPFs showed stronger cor relation with disability than SIENAX (r = -0.16, P = .219). These differences were statistically significant (P = .0031 for Buffalo and P = .0037 for Trieste BPF). This study showed a high reproducibility of both semiautomated and automated methods for brain atrophy measurement. The semiautomated methods showed higher accuracy than the automated SIENAX method did in the evaluation of brain extraction, especially in infratentorial and cortical regions, where operator interaction during the masking processes was essential.

Development of the Brazilian version of the Multiple Sclerosis Functional Composite Measure (MSFC-BCTRIMS): pilot study

Initial efforts are reported to develop and validate a Brazilian version of the Multiple Sclerosis Functional Composite Measure (MSFC-BCTRIMS). MSFC is an outcome measure in multiple sclerosis (MS) which assesses motor functions of legs and arms/hands besides cognitive function. MSFC was designed to have better sensitivity and sounder psychometric foundations than traditional measures in detecting therapeutic benefits of disease-modifying agents. Results from the pilot study indicate that the MSFC-BCTRIMS discriminates between MS individuals and a control group. An initial approach to construct validation, intercorrelating the MSFC-BCTRIMS scores with several other measures, suggests speed of information processing is important for both arm/hand and cognitive function.

Therapy with glatiramer acetate for multiple sclerosis.

Some clinical data have shown that glatiramer acetate (Copaxone), a synthetic amino acid polymer empirically found to suppress experimental allergic encephalomyelitis (EAE), an animal model of MS, might help improve the outcome of patients with multiple sclerosis (MS). We performed a Cochrane review of all randomised, placebo-controlled trials of glatiramer acetate in MS, whatever the disease course. We searched the Cochrane MS Group trials register (June 2003), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2, 2003), MEDLINE (PubMed) (January 1966 to June 2003), EMBASE (January 1988 to June 2003) and hand searching of symposia reports (1990-2002) from the neurological Associations and MS Societies in both Europe and America. All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review. Both patients with relapsing-remitting (RR) and chronic progressive (CP) MS were analysed. Study protocols were comparable across trials as to patient entry criteria and outcome definition. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against well-known side effects, including injection-site reactions in glatiramer acetate-treated patients. A total of 646 patients contributed to this review, as it is summarised in Table 01. Glatiramer acetate did not show any significant effect on disease progression, measured as a sustained worsening in the Expanded Disability Status Scale (EDSS). On the other hand, a slight decrease in the mean EDSS score, driven by a major study, should be considered in the light of the limited validity of this outcome measure. No benefit was shown in CP MS patients (progression at two years: RR=0.69, 95% CI [0.33 to 1.46]). The frequency of reported adverse events does not support any major toxicity associated with glatiramer acetate administration. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety (relative risk = 3.40 (95% CI [2.22 to 5.21], p <0.00001]). Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable. Glatiramer acetate did not show any beneficial effect on the main outcome measures in MS, i.e. disease progression, and it does not substantially affect the risk of clinical relapses. Therefore its routine use in clinical practice is not currently supported. More investigations are needed. Further research should also develop more reliable measures of patient disability over time and include quality of life among primary outcomes.

Sensory Temporal Thresholds and Interhemispheric Transfer Times in Multiple Sclerosis: A Preliminary Study of a New Outcome Measure

This preliminary study investigated the potential of a cerebral lateralization technique that measures both, temporal judgements to sensory stimuli and interhemispheric transfer time (IHTT), as an outcome measure in multiple sclerosis (MS). Tactile stimulation was delivered to one or both hands by mechanical tactile stimulators. Pairs of light emitting diodes were presented to hemifields for visual stimulation. Response consisted of a binary forced-choice (YES/NO) judgement as to the simultaneity of the onset of pairs of stimuli. Both tactile and visual temporal thresholds were significantly higher in MS patients than controls in every presentation condition. IHTT estimates (threshold differences between unilateral and bilateral presentations) for the tactile and visual tasks were also significantly longer in patients than controls. Age correlated with sensory temporal thresholds for the control group only. These findings suggest that this technique may be a useful outcome measure in MS. We hypothesize that myelin injury slows central conduction therefore impairing the ability to judge the onset of sensory stimuli and increasing IHTTs.

The role of MRI as a surrogate outcome measure in multiple sclerosis

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sclerosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on clinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration. Multiple Sclerosis (2002)8, 40-51

The role of MRI as a surrogate outcome measure in multiple sclerosis.

The need for more specific and more sensitive outcome measures for use in testing new therapies in multiple sderosis (MS) is generally accepted. This need has been accentuated by the realization that the ability to conduct large placebo-controlled trials will be limited in the future. From the first use of magnetic resonance imaging (MRI) to study MS, the ability of this imaging technique to identify areas of the central nervous system damage by the disease process in MS has been impressive. Thus, the possibility that MRI could serve as a surrogate outcome measure in clinical trials in MS has been attractive. The use of MRI as a surrogate outcome measure has been examined by an international group of investigators with expertise in clinical aspects of MS, the use of MRI in MS, and in experimental therapeutics. The group agreed that MRI does not represent a validated surrogate in any clinical form of MS. It was also agreed, however, that MRI does provide a reflection of the underlying pathology in the disease, but no single MRI measurement in isolation was seen as sufficient to monitor disease. The use for multiple imaging techniques, especially new, emerging techniques that may better reflect the underlying pathology, was seen as particularly important in monitoring studies of patients with either secondary or primary progressive MS. The choice of MRI techniques used to monitor new therapies needs to be consistent with the proposed mechanisms of the new therapy and phase of the disease. It was also noted, however, that additional validation is required for nonconventional imaging techniques. Finally, the participants noted that clinical trials using MRI as a primary outcome measure may fail to fully identify the effects of the therapy on dinical measures and that the risk and cost-benefit ratio of the treatment might be unresolved. Thus, before MRI is used as a primary outcome measure, new approaches to trial design must be given careful consideration.

Disease specific quality of life instruments in multiple sclerosis: Validation of the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS)

Quality of life (QoL) is discussed as an additional outcome measure in multiple sclerosis (MS). However, few questionnaires assessing disease specific QoL in MS have been published. On the basis of the literature and interviews with clinicians and MS patients, we have developed a disease specific QoL instrument and validated it in a broad range of patients with MS. In this study, a heterogeneous sample of n = 237 MS patients completed the newly developed Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS, in German language) and a battery of already validated questionnaires. They further underwent neurological scoring and objective tests. By these means, we investigated its validity, appropriateness, internal consistency, and retest reliability. Internal consistency and retest coefficients were high and satisfied psychometric standards. Convergent and discriminant validity was supported by direction, magnitude and pattern of correlations with other health measures. HAQUAMS subscales and its total score distinguished between patient groups of varied disease severity, cognitive impairment, and affective symptomatology. No floor or ceiling effects were found in either of the HAQUAMS subscales. The HAQUAMS is a reliable, valid and appropriate instrument for QoL assessment in multiple sclerosis. Data of responsiveness are currently being obtained.

Kurtzke scales revisited: the application of psychometric methods to clinical intuition.

When developing his disability scales for multiple sclerosis, Kurtzke demonstrated perception and insight. However, 45 years later, the evaluation of his clinically derived scales remains limited, particularly for more disabled patients. Indeed, many of Kurtzke's assumptions underpinning the development of the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) are untested. This study aims to build on previous work and provide a more detailed examination using psychometric methods of the EDSS and FS. There are three study objectives: (i) to examine comprehensively the psychometric properties of the EDSS in more disabled people with multiple sclerosis undergoing in-patient rehabilitation; (ii) to examine the reliability of the FS and test Kurtzke's assumptions that they measure different aspects of the neurological examination and measure different constructs from that measured by the EDSS; and (iii) to examine whether the FS can be summed to generate a summary score. The EDSS was examined for its acceptability (score distributions), reliability (inter- and intra-rater reproducibility, standard error of measurement), validity (convergent and discriminant validity, measurement precision, discrimination between individuals) and responsiveness (effect size). The FS were examined for their reliability (inter- and intra-rater reproducibility), intercorrelations, correlations with the EDSS and the extent to which they satisfy Likert's criteria as a summed rating scale. In this more disabled sample of people with multiple sclerosis, the EDSS is an acceptable measure but demonstrates limited variability. Inter-rater reproducibility (intraclass correlation coefficient; ICC = 0.78) is adequate for group comparison studies, but intra-rater reproducibility is variable (ICC = 0.62-0.94). Convergent and discriminant validity for the EDSS is supported, but its measurement precision relative to the Functional Independence Measure is limited (56%). Also, the EDSS has a limited ability to distinguish between individuals in terms of their disability and its responsiveness is poor (effect size = 0.10). Results indicate that the FS measure constructs distinct from each other (intercorrelations = -0.23 to +0. 52) and from the EDSS (correlations = -0.10 to +0.59). Intra-rater, but not inter-rater reproducibility is adequate for group comparison studies. The FS do not satisfy criteria as an eight-, seven- or six-item summed rating scale. Despite being based on sound clinical intuition, the lack of psychometric input into the development of the EDSS and FS has limited their usefulness as evaluative outcome measures in multiple sclerosis.

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

OBJECTIVESUnderstanding 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)...

More Evidence for the Benefit of Interferon-β in Relapsing-Remitting MS

MRI is playing an increasingly important role as an outcome measure in multiple sclerosis. Studies with different preparations of interferon-β have shown a substantial reduction in new disease activity as seen on MRI. Although the relation between measures of disease activity on MRI and disease progression is complex and not completely understood, both natural history studies and …

Neuropsychiatric assessment as a secondary outcome measure in a multiple sclerosis intravenous immunoglobulin L(IMg) trial

Multiple sclerosis (MS) patients often suffer from abnormalities of mood including euphoria, depression, anxiety, pathological laughing and crying (PLC), and psychoses. We assessed neuropsychological functions (NF) as secondary outcome measures in relapsing-remitting multiple sclerosis (RRMS) patients treated by intravenous immunoglobulin (IVIg). Forty RR-MS patients (mean age 34.5±2.4; M : F=8: 32) were randomized to receive either IVIg or placebo in a double-blind trial for 2 years. NF evaluation at baseline, 1 and 2 years included the Goldberg Anxiety and Depression scales, the Brief Psychiatric Rating Scale, the Hamilton Anxiety Scale, the Beck Depression Inventory, and the Mini-Mental State Examination. Baseline anxiety, depression and general psychopathology scores were similar for the IVIg and placebo groups. At 1 and 2 years, anxiety, depression and general psychopathology had decreased similarly in both groups compared with baseline. No significant cognitive changes were observed in either group. In the IVIg group PLC emerged in one patient and one patient developed clinically overt depression necessitating antidepressant treatment. In the placebo group, two patients developed a hypomanic episode, and PLC emerged in two patients. IVIg treatment is safe, according to psychiatric outcome measures, and these measures should be routinely used in RR-MS drug trials.

Evoked Potentials As Outcome Measures in Multiple Sclerosis

Evoked Potentials As Outcome Measures in Multiple Sclerosis

Magnetic Resonance Imaging (MRI) As an Outcome Measure in Multiple Sclerosis

Magnetic Resonance Imaging (MRI) As an Outcome Measure in Multiple Sclerosis