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ABSTRACT: BACKGROUND: The increasing influence of patient-reported outcome (PRO) measurement instruments indicates their scrutiny has never been more crucial. Above all, PRO instruments should be valid: shown to assess what they purport to assess. OBJECTIVES: To evaluate a widely used fatigue PRO instrument, highlight key issues in understanding PRO instrument validity, demonstrate limitations of those approaches and justify notable changes in the validation process. METHODS: A two-phase evaluation of the 40-item Fatigue Impact scale (FIS): a qualitative evaluation of content and face validity using expert opinion (n=30) and a modified Delphi technique; a quantitative psychometric evaluation of internal and external construct validity of data from 333 people with multiple sclerosis using traditional and modern methods. RESULTS: Qualitative evaluation did not support content or face validity of the FIS. Expert opinion agreed with the subscale placement of 23 items (58%), and classified all 40 items as being non-specific to fatigue impact. Nevertheless, standard quantitative psychometric evaluations implied, largely, FIS subscales were reliable and valid. CONCLUSIONS: Standard quantitative 'psychometric' evaluations of PRO instrument validity can be misleading. Evaluation of existing PRO instruments requires both qualitative and statistical methods. Development of new PRO instruments requires stronger conceptual underpinning, clearer definitions of the substantive variables for measurement and hypothesis-testing experimental designs.
Multiple Sclerosis 04/2013; · 4.26 Impact Factor
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Multiple Sclerosis 07/2012; 18(7):913. · 4.26 Impact Factor
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ABSTRACT: Traumatic spinal cord injury is often disabling and recovery of function is limited. As a consequence of damage, both spinal cord and brain undergo anatomical and functional changes. Besides clinical measures of recovery, biomarkers that can detect early anatomical and functional changes might be useful in determining clinical outcome-during the course of rehabilitation and recovery-as well as furnishing a tool to evaluate novel treatment interventions and their mechanisms of action. Recent evidence suggests an interesting three-way relationship between neurological deficit and changes in the spinal cord and of the brain and that, importantly, noninvasive magnetic resonance imaging techniques, both structural and functional, provide a sensitive tool to lay out these interactions. This review describes recent findings from multimodal imaging studies of remote anatomical changes (i.e., beyond the lesion site), cortical reorganization, and their relationship to clinical disability. These developments in this field may improve our understanding of effects on the nervous system that are attributable to the injury itself and will allow their distinction from changes that result from rehabilitation (i.e., functional retraining) and from interventions affecting the nervous system directly (i.e., neuroprotection or regeneration).
The Neuroscientist 06/2012; · 4.57 Impact Factor
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Multiple Sclerosis 04/2012; 18(4):384-6. · 4.26 Impact Factor
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ABSTRACT: Purpose. To compare the quality of life (QoL) and emotional well-being of the offspring of parents with Parkinson's disease (PD) and multiple sclerosis (MS) and to consider results in light of current UK clinical guidelines. Methods. 143 adolescent and adult children of parents with PD and MS were postally administered the Parental Illness Impact Scale and a measure of emotional well-being. Results. Minimal differences were observed between the two groups in both QoL and emotional well-being. Levels of mild to moderate depression were substantially greater than those of the general population. Conclusions. The nonsignificant differences reported indicate a similar degree of impact across the two conditions assessed. A significant body of evidence demonstrates the considerable impact of parental MS, with the needs of children being acknowledged in current clinical guidelines. There is a need to similarly acknowledge the potential impact of parental Parkinson's in UK guidelines for PD.
Parkinson's disease. 01/2011; 2011:951874.
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ABSTRACT: The aim of this study was to determine whether the diffusion tensor-derived radial diffusivity and axial diffusivity, measured in the cortico-spinal tract in the cervical cord, predict clinical recovery after a cord relapse in patients with multiple sclerosis, and change over time.
Fourteen patients were clinically assessed at the onset of a cervical cord relapse and after 1, 3 and 6 months. Patients and 13 age-matched healthy controls underwent spinal cord diffusion tensor imaging at each time point. The directional diffusivities from diffusion tensor imaging, termed radial diffusivity and axial diffusivity, were calculated in regions of interest placed in the lateral columns, where the cortico-spinal tract is located, and in the anterior and posterior columns. Regression analyses identified predictors of clinical outcome, adjusting for age, gender, cord cross-sectional area and baseline clinical score, and estimated the differences in the rate of change in diffusion tensor imaging measures between groups over time, adjusting for changes in cord cross-sectional area.
Lower radial diffusivity of the cortico-spinal tract at baseline was associated with better clinical outcome. As patients improved clinically during the follow-up, they showed greater decrease in radial diffusivity of the cortico-spinal tract than controls.
The predictive role of radial diffusivity and its dynamic changes over time suggest that this index reflects spinal cord pathological processes, including resolution of inflammation and remyelination, that contribute to clinical recovery in multiple sclerosis. This suggests that radial diffusivity may be useful in trials that promote recovery after spinal cord injury and could be applied to other neurological diseases affecting the spinal cord.
Multiple Sclerosis 10/2010; 16(10):1193-202. · 4.26 Impact Factor
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Multiple Sclerosis 07/2010; 16(7):770. · 4.26 Impact Factor
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Multiple Sclerosis 03/2010; 16(3):281. · 4.26 Impact Factor
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ABSTRACT: The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex. Eleven multiple sclerosis patients with a history of hemiparesis attributable to a lesion within the contralateral corticospinal tract, and 12 controls were studied. We used two advanced imaging techniques: (i) diffusion-based probabilistic tractography, to obtain connectivity and fractional anisotropy of the corticospinal tract; and (ii) FreeSurfer, to measure volume, thickness, surface area, and curvature of precentral and paracentral cortices. Differences in these measures between patients and controls, and relationships between each other and to clinical scores, were investigated. Patients showed lower corticospinal tract fractional anisotropy and smaller volume and surface area of the precentral gyrus than controls. In patients, corticospinal tract connectivity and paracentral cortical volume, surface area, and curvature were lower with increasing disability; lower connectivity of the affected corticospinal tract was associated with greater surface area of the ipsilateral paracentral cortex. Corticospinal tract connectivity and new measures of the primary motor cortex, such as surface area and curvature, reflect the underlying white and grey matter damage that contributes to disability. The correlation between lower connectivity of the affected corticospinal tract and greater surface area of the ipsilateral paracentral cortex suggests the possibility of cortical adaptation. Combining tractography and cortical measures is a useful approach in testing hypotheses which are specific to clinically relevant functional systems in multiple sclerosis, and can be applied to other neurological diseases.
Multiple Sclerosis 03/2010; 16(5):555-65. · 4.26 Impact Factor
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Thomas Jenkins,
Olga Ciccarelli,
Ahmed Toosy,
Katherine Miszkiel,
Claudia Wheeler-Kingshott,
Daniel Altmann,
Laura Mancini,
Steve Jones,
Gordon Plant,
David Miller, Alan Thompson
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ABSTRACT: Structural MRI, electrophysiology, and functional MRI (fMRI) elucidate different aspects of damage and repair in demyelinating diseases. We combined them to investigate why patients with optic neuritis (ON) exhibit a wide variation in severity of acute visual loss, with the following objectives: (1) To determine how structural and electrophysiological changes in the anterior and posterior visual pathways contribute to acute visual loss. (2) To combine these data with fMRI, to investigate whether cortical activity modulates visual acuity. The visual system of 28 patients with acute unilateral ON was assessed. Linear regression modeling was used to identify parameters associated with acute visual loss, and to determine whether fMRI activity was associated with vision, after accounting for structural and electrophysiological predictors, age, and gender. Optic nerve lesion length and visual evoked potential (VEP) amplitude were associated with visual loss. Bilateral activation in the extra-striate occipital cortex correlated directly with vision, after adjusting for optic nerve lesion length, VEP amplitude, and demographic characteristics. These data suggest that acute visual loss is associated with the extent of inflammation and conduction block in the optic nerve, but not with pathology in the optic radiations or occipital cortex. The association of better vision with greater fMRI responses, after accounting for factors which reduce afferent input, suggests a role for adaptive neuroplasticity within the association cortex of the dorsal stream of higher visual processing. Longitudinal studies will clarify whether different extra-striate cortical regions play a role in adaptive plasticity in the acute and chronic stages of injury.
Human Brain Mapping 09/2009; 31(2):276-86. · 5.88 Impact Factor
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ABSTRACT: This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.
MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.
42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65-0.93 and 0.66, 95% CI: 0.48-0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72-0.96 and 0.71, 95% CI: 0.56-0.87 for the psychological scale)
Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level.
BMC Neurology 04/2009; 9:12. · 2.17 Impact Factor
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The Lancet 03/2009; 373(9665):697-8. · 38.28 Impact Factor
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ABSTRACT: To explore the patient's experience of clinical research with a view to improving its conduct.
Qualitative analysis of focus groups, semi-structured telephone interviews and questionnaires undertaken with subjects of clinical research.
265 patients enrolled in two therapeutic and four non-therapeutic clinical studies were invited to take part. 95 agreed; 32 took part in focus groups, 34 in telephone interviews and 29 returned a questionnaire. Response rate (36%).
Most patients are channeled into research by the health care professionals treating them. Benefits of taking part were seen as: extra care; increased surveillance; obtaining expert information; and being able to help others. Participants also had criticisms which included lack of information about research findings, problems in making sense of adverse events, insufficient attention to their comfort and 'unscientific' aspects of particular studies.
Participation in clinical research is not entirely altruistic. Patients expected reciprocity in their on-going relationship with the researcher. Therefore to help ensure that patients continue to support clinical research, we suggest that: time should be allowed for providing information; greater attention should be paid to physical comfort; opportunities should be provided for involvement in research design, in the excitement of research and for giving feedback on the findings; and contact between patients taking part in the same study should be facilitated. By investing in the idea of scientific progress through research, some subjects are able to transform their suffering into hope for the future.
Journal of the Royal Society of Medicine 09/2008; 101(8):416-22. · 1.41 Impact Factor
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ABSTRACT: The United States Food and Drug Administration (FDA) are currently producing guidelines for the scientific adequacy of patient reported outcome measures (PROMs) in clinical trials, which will have implications for the selection of scales used in future clinical trials. In this study, we examine how the Cervical Dystonia Impact Profile (CDIP-58), a rigorous Rasch measurement developed neurologic PROM, stands up to traditional psychometric criteria for three reasons: 1) provide traditional psychometric evidence for the CDIP-58 in line with proposed FDA guidelines; 2) enable researchers and clinicians to compare it with existing dystonia PROMs; and 3) help researchers and clinicians bridge the knowledge gap between old and new methods of reliability and validity testing.
We evaluated traditional psychometric properties of data quality, scaling assumptions, targeting, reliability and validity in a group of 391 people with CD. The main outcome measures used were the CDIP-58, Medical Outcome Study Short Form-36, the 28-item General Health Questionnaire, and Hospital and Anxiety and Depression Scale.
A total of 391 people returned completed questionnaires (corrected response rate 87%). Analyses showed: 1) data quality was high (low missing data < or = 4%, subscale scores could be computed for > 96% of the sample); 2) item groupings passed tests for scaling assumptions; 3) good targeting (except for the Sleep subscale, ceiling effect = 27%); 4) good reliability (Cronbach's alpha > or = 0.92, test-retest intraclass correlations > or = 0.83); and 5) validity was supported.
This study has shown that new psychometric methods can produce a PROM that stands up to traditional criteria and supports the clinical advantages of Rasch analysis.
Health and Quality of Life Outcomes 09/2008; 6:58. · 2.11 Impact Factor
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ABSTRACT: Diffusion-based tractography enables the graphical reconstruction of the white matter pathways in the brain and spinal cord of living humans. This technique has many potential clinical applications, including the investigation of stroke, multiple sclerosis, epilepsy, neurodegenerative diseases, and spinal cord disorders, and it enables hypotheses to be tested that could not previously be considered in living humans. This Review will outline the limitations of tractography, describe its current clinical applications in the most common neurological diseases, and highlight future opportunities.
The Lancet Neurology 08/2008; 7(8):715-27. · 23.46 Impact Factor
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Zhaleh Khaleeli,
Olga Ciccarelli,
Francesco Manfredonia,
Frederik Barkhof,
Bruno Brochet,
Mara Cercignani,
Vincent Dousset,
Massimo Filippi,
Xavier Montalban,
Chris Polman,
Marco Rovaris,
Alex Rovira,
Jaume Sastre-Garriga,
Machteld Vellinga,
David Miller, Alan Thompson
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ABSTRACT: Rates of progression vary widely in primary progressive multiple sclerosis. This multicenter study aimed to identify predictors of progression over 10 years. A total of 101 patients who had been imaged at baseline and 2 years were scored on the expanded disability status scale after 10 years. Ordinal logistic regression identified the following independent variables that predicted progression: male sex, shorter disease duration, and slower timed walk test at baseline (best overall predictor), and deterioration in expanded disability status scale score and reduction in brain volume over 2 years. These predictors of long-term disability provide some insight into disease progression.
Annals of Neurology 07/2008; 63(6):790-3. · 11.09 Impact Factor
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Zhaleh Khaleeli MRCP,
Olga Ciccarelli PhD,
Francesco Manfredonia MD,
Frederik Barkhof PhD,
Bruno Brochet MD,
Mara Cercignani PhD,
Vincent Dousset MD,
Massimo Filippi MD,
Xavier Montalban MD,
Chris Polman MD, [......],
Vincent Dousset,
Massimo Filippi,
Xavier Montalban,
Chris Polman,
Marco Rovaris,
Alex Rovira,
Jaume Sastre‐Garriga,
Machteld Vellinga,
David Miller, Alan Thompson
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ABSTRACT: Rates of progression vary widely in primary progressive multiple sclerosis. This multicenter study aimed to identify predictors of progression over 10 years. A total of 101 patients who had been imaged at baseline and 2 years were scored on the expanded disability status scale after 10 years. Ordinal logistic regression identified the following independent variables that predicted progression: male sex, shorter disease duration, and slower timed walk test at baseline (best overall predictor), and deterioration in expanded disability status scale score and reduction in brain volume over 2 years. These predictors of long-term disability provide some insight into disease progression. Ann Neurol 2008
Annals of Neurology 05/2008; 63(6):790 - 793. · 11.09 Impact Factor
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Maria A Rocca,
Federica Agosta,
Maria P Sormani,
Kryshani Fernando,
Mar Tintorè,
Tijmen Korteweg,
Paola Tortorella,
David H Miller, Alan Thompson,
Alex Rovira,
Xavier Montalban,
Chris Polman,
Frederik Barkhof,
Massimo Filippi
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ABSTRACT: To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS.
Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM).
During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00-2.77) as an independent predictor of evolution to definite MS.
Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.
Journal of Neurology 05/2008; 255(5):683-91. · 3.47 Impact Factor
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Waqar Rashid,
Andreas Hadjiprocopis,
Gerard Davies,
Collette Griffin,
Declan Chard,
Michaela Tiberio,
Dan Altmann,
Claudia Wheeler-Kingshott,
Dan Tozer, Alan Thompson,
David H Miller
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ABSTRACT: Diffusion tensor imaging (DTI) parameters such as mean diffusivity (MD) and fractional anisotropy (FA) assess aspects of structural integrity within tissue. In relapsing-remitting (RR) multiple sclerosis (MS), abnormalities in normal appearing brain tissue (NABT) have been shown cross-sectionally. The evolution of these abnormalities over time is unclear. We present a longitudinal study investigating early RR MS subjects. The aims were to determine DTI changes over two years and assess the potential of DTI as a longitudinal quantitative marker at this stage of MS. Fifteen controls and 28 patients with RR MS (median disease duration 1.9 years; median EDSS 1.5) had DTI yearly for two years. NABT and whole brain tissue (NABT plus lesions) FA and MD histograms analysed. At baseline, differences in FA were noted between patients and controls (mean [p = 0.042] and peak height [p = 0.008]), while at two years differences in MD were observed (mean [p = 0.008] and peak location [p = 0.024]). However there were no significant DTI differences in longitudinal rates of change between patients and cohorts. In conclusion, although subtle NABT abnormalities were detected in early RR MS, the absence of longitudinal change suggests a limited role for global DTI assessment of NABT in following the early disease course.
Journal of Neurology 04/2008; 255(3):390-7. · 3.47 Impact Factor
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Marco Rovaris,
Elda Judica,
Jaume Sastre-Garriga,
Alex Rovira,
Maria Pia Sormani,
Beatrice Benedetti,
Tijmen Korteweg,
Nicola De Stefano,
Zhaleh Khaleeli,
Xavier Montalban,
Frederik Barkhof,
David H Miller,
Chris Polman, Alan J Thompson,
Massimo Filippi
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ABSTRACT: Although the mechanisms underlying the accumulation of disability in primary progressive (PP) multiple sclerosis (MS) are still unclear, a major role seems to be played by 'occult' tissue damage. We investigated whether conventional and magnetization transfer (MT) MRI may provide complementary information for the assessment of PPMS severity. Conventional and MT MRI scans from 226 PPMS patients and 84 healthy controls were collected for centralized analysis. The expanded disability status scale (EDSS) score was rated at the time of MRI acquisition. T2 lesion volume, normalized brain volume (NBV) and cervical cord cross-sectional area (CSA) were measured. Magnetization transfer ratio (MTR) histograms from whole brain tissue, normal-appearing white matter and grey matter (NAGM) were also obtained. Mean NBV, CSA and MTR histogram-derived metrics showed significant inter-centre heterogeneity. After correcting for the acquisition centre, pooled average MTR and histogram peak height values were different between PPMS patients and controls for all tissue classes (P-values between 0.03 and 0.0001). More severe brain and cord atrophy and MT MRI-detectable NAGM damage were found in patients who required walking aids than in those who did not (P-values: 0.03, 0.001 and 0.016). A composite score of NBV, CSA, whole brain and NAGM MTR histogram peak height z-scores was correlated with patients' EDSS (r = 0.37, P 0.001). Magnetization transfer MRI might provide information complementary to that given by conventional MRI when assessing PPMS severity. Sequence-related variability of measurements makes the standardization of MT MRI acquisition essential for the design of multicentre studies.
Multiple Sclerosis 02/2008; 14(4):455-64. · 4.26 Impact Factor
