Do Early Relapses Predict the Risk of Long-Term Relapsing Disease in an Adult and Paediatric Cohort with MOGAD?

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can be monophasic or relapsing, with early relapse being a feature. However, the relevance of early relapse on longer-term relapse risk is unknown. Here, we investigate whether early relapses increase longer-term relapse risk in patients with MOGAD. METHODS: A retrospective analysis of 289 adult- and pediatric-onset patients with MOGAD followed for at least 2 years in 6 specialized referral centers. "Early relapses" were defined as attacks within the first 12 months from onset, with "very early relapses" defined within 30 to 90 days from onset and "delayed early relapses" defined within 90 to 365 days. "Long-term relapses" were defined as relapses beyond 12 months. Cox regression modeling and Kaplan-Meier survival analysis were used to estimate the long-term relapse risk and rate. RESULTS: Sixty-seven patients (23.2%) had early relapses with a median number of 1 event. Univariate analysis revealed an elevated risk for long-term relapses if any "early relapses" were present (hazard ratio [HR] = 2.11, p < 0.001), whether occurring during the first 3 months (HR = 2.70, p < 0.001) or the remaining 9 months (HR = 1.88, p = 0.001), with similar results yielded in the multivariate analysis. In children with onset below aged 12 years, only delayed early relapses were associated with an increased risk of long-term relapses (HR = 2.64, p = 0.026). INTERPRETATION: The presence of very early relapses and delayed early relapses within 12 months of onset in patients with MOGAD increases the risk of long-term relapsing disease, whereas a relapse within 90 days appears not to indicate a chronic inflammatory process in young pediatric-onset disease. ANN NEUROL 2023;94:508-517.

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

The impact of smoking cessation on multiple sclerosis disease progression.

The negative impact of smoking in multiple sclerosis is well established; however, there is much less evidence as to whether smoking cessation is beneficial to progression in multiple sclerosis. Adults with multiple sclerosis registered on the United Kingdom Multiple Sclerosis Register (2011-20) formed this retrospective and prospective cohort study. Primary outcomes were changes in three patient-reported outcomes: normalized Multiple Sclerosis Physical Impact Scale (MSIS-29-Phys), normalized Multiple Sclerosis Walking Scale (MSWS-12) and the Hospital Anxiety and Depression Scale (HADS). Time to event outcomes were clinically significant increases in the patient-reported outcomes. The study included 7983 participants; 4130 (51.7%) of these had ever smoked, of whom 1315 (16.5%) were current smokers and 2815/4130 (68.2%) were former smokers. For all patient-reported outcomes, current smokers at the time of completing their first questionnaire had higher patient-reported outcomes scores indicating higher disability compared to those who had never smoked (∼10 points difference in MSIS-29-Phys and MSWS-12; 1.5-1.8 points for HADS-Anxiety and HADS-Depression). There was no improvement in patient-reported outcomes scores with increasing time since quitting in former smokers. Nine hundred and twenty-three participants formed the prospective parallel group, which demonstrated that MSIS-29-Phys [median (IQR) 5.03 (3.71, 6.34)], MSWS-12 [median (IQR) 5.28 (3.62, 6.94)] and HADS-Depression [median (IQR) 0.71 (0.47, 0.96)] scores worsened over a period of 4 years, whereas HADS-Anxiety remained stable. Smoking status was significant at Year 4; current smokers had higher MSIS-29-Phys and HADS-Anxiety scores [median (IQR) 3.05 (0.22, 5.88) and 1.14 (0.52, 1.76), respectively] while former smokers had a lower MSIS-29-Phys score of -2.91 (-5.03, -0.79). A total of 4642 participants comprised the time to event analysis. Still smoking was associated with a shorter time to worsening event in all patient-reported outcomes (MSIS-29-Phys: n = 4436, P = 0.0013; MSWS-12: n = 3902, P = 0.0061; HADS-Anxiety: n = 4511, P = 0.0017; HADS-Depression: n = 4511, P < 0.0001). Worsening in motor disability (MSIS-29-Phys and MSWS-12) was independent of baseline HADS-Anxiety and HADS-Depression scores. There was no statistically significant difference in the rate of worsening between never and former smokers. When smokers quit, there is a slowing in the rate of motor disability deterioration so that it matches the rate of motor decline in those who have never smoked. This suggests that smoking cessation is beneficial for people with multiple sclerosis.

Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax): Evaluation of Measurement Performance.

BACKGROUND: Clinical trials of primary axillary hyperhidrosis (AHH) require rigorous measurement of AHH severity from the patient’s perspective. Previously, we reported conceptualization and item content development for the Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) scale. OBJECTIVE: To evaluate the psychometric performance and estimate clinically meaningful change scores for the HDSM-Ax in a Phase IIb clinical study of sofpironium bromide gel for AHH. METHOD: HDSM-Ax measurement performance was analyzed in trial response data using two psychometric paradigms: Classical Test and Rasch Measurement Theories (CTT; RMT). HDSM-Ax meaningful change scores were estimated from anchor-based methods using two global summary questions of hyperhidrosis severity and the Hyperhidrosis Disease Severity Score (HDSS). RESULTS: HDSM-Ax satisfied CTT and RMT criteria as a fit-for-purpose outcome measure in AHH clinical trials. Within-person anchor-based analyses indicated a 1-point change in HDSM-Ax severity score (range, 0–4) represents a clinically meaningful change in AHH severity. CONCLUSION: HDSM-Ax is a well-defined and reliable measure of AHH severity. A 1-point change in HDSM-Ax score is clinically meaningful. J Drugs Dermatol.20(4):410-418. doi:10.36849/JDD.5569.

International consensus on quality standards for brain health-focused care in multiple sclerosis.

BACKGROUND: Time matters in multiple sclerosis (MS). Irreversible neural damage and cell loss occur from disease onset. The MS community has endorsed a management strategy of prompt diagnosis, timely intervention and regular proactive monitoring of treatment effectiveness and disease activity to improve outcomes in people with MS. OBJECTIVES: We sought to develop internationally applicable quality standards for timely, brain health-focused MS care. METHODS: A panel of MS specialist neurologists participated in an iterative, online, modified Delphi process to define 'core', 'achievable' and 'aspirational' time frames reflecting minimum, good and high care standards, respectively. A multidisciplinary Reviewing Group (MS nurses, people with MS, allied healthcare professionals) provided insights ensuring recommendations reflected perspectives from multiple stakeholders. RESULTS: Twenty-one MS neurologists from 19 countries reached consensus on most core (25/27), achievable (25/27) and aspirational (22/27) time frames at the end of five rounds. Agreed standards cover six aspects of the care pathway: symptom onset, referral and diagnosis, treatment decisions, lifestyle, disease monitoring and managing new symptoms. CONCLUSION: These quality standards for core, achievable and aspirational care provide MS teams with a three-level framework for service evaluation, benchmarking and improvement. They have the potential to produce a profound change in the care of people with MS.

The Hyperhidrosis Disease Severity Measure-Axillary: Conceptualization and Development of Item Content.

INTRODUCTION: Patients with primary axillary hyperhidrosis (AHH) suffer from a variety of symptoms. Improved patient-reported outcome (PRO) measures are needed to better assess and categorize the severity of AHH symptoms experienced by patients because the widely used Hyperhidrosis Disease Severity Scale (HDSS) is a single-item measure that cannot capture the broad scope of disease impact. METHODS: The Hyperhidrosis Disease Severity Measure-Axillary (HDSM-Ax) was developed for determining the severity of excessive sweating in patients with primary focal AHH based on face-to-face concept elicitation interviews with 58 AHH patients, a literature review, and expert clinical input. Two waves of face-to-face cognitive interviews (n=26 and n=27) were conducted to evaluate HDSM-Ax clarity and relevance. Additional interviews (n=5) were conducted to confirm content. Adding Rasch Measurement Theory (RMT) analyses allowed for an iterative streamlined approach to documenting content validity and other cross-sectional measurement properties of the new HDSM-Ax measurement. RESULTS: The 11-item HDSM-Ax PRO scale (0-4 scale per item; 0-44 total scale) represents an AHH symptom range of 0 (no sweating) to 44 (worst possible sweating). Content validity of the HDSM-Ax was documented by showing that chronologically-grouped interviews demonstrated saturation in AHH symptom severity concepts. Cognitive debriefing interviews provided evidence that item content is complete, comprehensible, meaningful, and relevant. RMT-based exploration indicated that targeting of the HDSM-Ax was adequate, suggesting good matching between items and persons; item fit was adequate, suggesting a clinically cohesive scale; and items appeared to be stable between subgroups, thereby supporting a summary score. CONCLUSIONS: The HDSM-Ax is a well-developed measure of AHH severity based on patient-reported signs and symptoms. It is a superior measure to the HDSS and can be used in clinical research and clinical practice to quantify changes in symptom severity in response to treatment. J Drugs Dermatol. 2018;17(7):707-714.

Measuring treatment satisfaction in MS: Is the Treatment Satisfaction Questionnaire for Medication fit for purpose?

BACKGROUND: The Treatment Satisfaction Questionnaire for Medication (TSQM) was designed to assess patient treatment satisfaction in chronic diseases. Its performance has not been examined in multiple sclerosis (MS). The 14 items of the TSQM cover four domains: Effectiveness, Side Effects, Convenience, and Global Satisfaction. OBJECTIVE: To evaluate performance of the TSQM in patients with relapsing MS, using data collected from the TENERE study (NCT00883337), in which 324 patients received oral teriflunomide or subcutaneous interferon beta-1a for ⩾48 weeks. METHODS: Five measurement properties were examined using traditional psychometric methods: data completeness, scale-to-sample targeting, scaling assumptions, reliability (including test-retest), and construct validity (internal: item-level scaling success, confirmatory factor analysis, and exploratory factor analysis; external: convergence, discrimination, and group differences). RESULTS: There were few (<2%) missing item data; domain scores could be computed for all patients. Score distributions were skewed toward higher satisfaction; two domains had marked ceiling effects. Scaling assumptions were supported. Internal consistency reliability was high (Cronbach's α > 0.90). Internal validity tests supported item groupings. Correlations supported convergent and discriminant construct validity; hypothesis testing supported group differences validity. CONCLUSION: This investigation found the TSQM to be a useful tool, exhibiting good psychometric measurement properties in patients with relapsing MS in the TENERE study.

Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

Measuring arm function early after stroke: is the DASH good enough?

OBJECTIVE: Despite a growing call to use patient-reported outcomes in clinical research, few are available for measuring upper limb function post-stroke. We examined the Disabilities of the Arm, Shoulder and Hand (DASH) to evaluate its measurement performance in acute stroke. In doing so, we compared results from traditional and modern psychometric methods. METHODS: 172 people with acute stroke completed the DASH. Those with upper limb impairments completed the DASH again at 6 weeks (n=99). Data (n=271) were analysed using two psychometric paradigms: traditional psychometric (Classical Test Theory, CTT) analyses examined data completeness, scaling assumptions, targeting, reliability and responsiveness; Rasch Measurement Theory (RMT) analyses examined scale-to-sample targeting, scale performance and person measurement. RESULTS: CTT analyses implied the DASH was psychometrically robust in this sample. Data completeness was high, criteria for scaling assumptions were satisfied (item-total correlations 0.55-0.95), targeting was good, internal consistency reliability was high (Cronbach's α=0.99) and responsiveness was clinically moderate (effect size=0.51). However, RMT analyses identified important limitations: scale-to-sample targeting was suboptimal, 4 items had disordered response category thresholds, 16 items exhibited misfit, 3 pairs of items had high residual correlations (>0.60) and 84 person fit residuals exceeded the recommended range. CONCLUSIONS: RMT methods identified limitations missed by CTT and indicate areas for improvement of the DASH as an upper limb measure for acute stroke. Findings, similar to those identified in multiple sclerosis, highlight the need for scales to have strong conceptual underpinnings, with their development and modification guided by sophisticated psychometric methods.

Lending a hand: can DASH items help ABILHAND improve manual ability measurement in multiple sclerosis?

BACKGROUND: Our examination in multiple sclerosis (MS) of the ABILHAND, a patient-reported outcome (PRO) instrument measuring manual ability, identified limited measurement range and precision. These deficiencies could lead to type II errors in clinical trials. OBJECTIVES: This paper aims to determine if ABILHAND's measurement performance in MS can be improved by adding relevant items from the Disabilities of the Arm, Shoulder and Hand scale (DASH). METHODS: The 23-item ABILHAND and 30-item DASH were administered to 461 people with MS. Data from the ABILHAND were combined with 16 DASH items to create a 39-item scale (AD-39). Using Rasch Measurement Theory methods, we compared the psychometric properties of AD-39 with ABILHAND. RESULTS: Data were analysed from 300 people. AD-39 performed robustly as a measure and had greater measurement range, lower floor and ceiling effects, and higher reliability (person separation index 0.97) than ABILHAND. Surprisingly, AD-39 appeared no better than ABILHAND at detecting group differences in self-reported hand function. CONCLUSION: Despite improving some psychometric properties, adding 16 DASH items to the ABILHAND did not improve its measurement performance to the degree expected. Our explanations for this anomaly emphasise the importance of evidence-based, conceptually driven scale modifications guided by hypothesis testing psychometric methods.

Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient's health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment's benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment's intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient's typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.

Is NICE guidance for identifying lumbar nerve root compression misguided?

PURPOSE: To determine the extent to which the clinical manifestations of a cohort of people undergoing surgery for lumbosacral nerve root compression satisfy those described in The National Institute for Health and Care Excellence (NICE) guidance. METHOD: We studied consecutive admissions for lumbar nerve root decompression surgery at two neurosurgical units. Pre-operatively, each person's clinical manifestations were documented and compared with NICE's description. Post-operatively, at three time points (within 48 h, 3 months, 12 months), each person rated their symptoms as either better, the same, or worse. RESULTS: Pre-operatively, one person (0.8%), from 123 admissions, under 20 different consultant neurosurgeons, had manifestations consistent with NICE's clinical description of lumbar nerve root compression. Post-operatively, self-reported benefit associated with surgery appeared high, at all three time points (78-91%), supporting the diagnosis of symptomatic nerve root compression and the value of surgery. CONCLUSIONS: In this small sample, from two units, NICE's description of the clinical manifestations of lumbar nerve root compression did not describe 99% of people having surgery for it. Using NICE's definition to triage people with low back pain could result in prolonged symptoms and delayed treatment. Diagnosing lumbar nerve root compression is complex. NICE's guidance requires examination.

Reconciling lesions, relapses and smouldering associated worsening: A unifying model for multiple sclerosis pathogenesis.

The failure of relapses and white matter lesions to properly explain long-term disability and progression in multiple sclerosis is compounded by its artificial separation into relapsing remitting, secondary progressive, and primary progressive pigeonholes. The well-known epidemiological disconnection between relapses and long-term disability progression has been rediscovered as "progression independent of relapse activity", i.e. smouldering multiple sclerosis. This smouldering associated worsening proceeds despite early and prolonged use of disease modification therapies, even those that are highly effective at preventing relapses and new/enhancing white matter lesions on MRI. We recognise that smouldering associated worsening and relapse/lesion associated worsening coexist, to varying extents. The extent of cortical demyelination has been shown to correlate significantly with the severity of diffuse injury in normal appearing white matter (post mortem histopathologically (r = 0.55; P = 0.001), and in vivo with MRI (r = -0.6874; P = 0.0006)) and does so independently of white matter lesion burden. Axon loss in the normal appearing white matter explains disability in multiple sclerosis better than focal white matter lesions do. Smouldering associated worsening typically manifests as a length-dependent central axonopathy. We propose a unifying model for multiple sclerosis pathogenesis, wherein accumulation of cortical lesion burden predisposes associated normal appearing white matter to diffuse injury, whilst also intensifying damage within white matter lesions. Our novel two-hit hypothesis implicates cortical disease as a culprit for smouldering multiple sclerosis, abetted by active focal inflammation in the white matter (and vice versa). Substantiation of the two-hit hypothesis would advance the importance of specific therapeutic intervention for (and monitoring of) cortical/meningeal inflammation in people with multiple sclerosis.

A study of referral bias in NMOSD and MOGAD cohorts.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare disorders often seen in highly specialized services or tertiary centres. We aimed to assess if cohort characteristics depend on the origin of the referral catchment areas serviced by our centre (i.e. local, regional or national). METHODS: Retrospective cohort study using a national referral service database including local (Oxfordshire), regional (Oxfordshire and neighbouring counties), and national patients. We included patients with the diagnosis of NMOSD, seronegative NMOSD or MOGAD, followed at the Oxford Neuromyelitis Optica Service. RESULTS: We included 720 patients (331 with MOGAD, 333 with aquaporin-4 antibody (AQP4)-NMOSD, and 56 with seronegative NMOSD. The distribution of diagnoses was similar across referral cohorts. There were no significant differences in the proportion of pediatric onset patients, sex, or onset phenotype; more White AQP4-NMOSD patients were present in the local than in the national cohort (81 % vs 52 %). Despite no differences in follow-up time, more relapsing MOGAD disease was present in the national than in the local cohort (42.9 % vs. 24 %, p = 0.029). CONCLUSION: This is the first study assessing the impact of potential referral bias in cohorts of NMOSD or MOGAD. The racial difference in the AQP4-NMOSD cohorts likely reflects the variation in the population demographics rather than a referral bias. The over representation of relapsing MOGAD patients in the national cohort probably is a true referral bias and highlights the need to analyze incident cohorts when describing disease course and prognosis. It seems reasonable therefore to compare MOGAD and NMOSD patients seen withing specialised centres to general neurology services, provided both use similar antibody assays.

Evaluating change in mobility in people with multiple sclerosis: relative responsiveness of four clinical measures.

BACKGROUND AND OBJECTIVES: Determining responsiveness of measures across different samples and settings is important for selecting measures of mobility and understanding multiple sclerosis (MS) study results. Currently such information is limited. METHODS: This exploratory study examined the relative responsiveness of four mobility measures (walking velocity, 6-minute walk distance, Rivermead Mobility Index and MS Walking Scale) in a community sample (n = 70), after three annual assessments. Distribution based estimates and anchor-based methods (comparison against transition questions) determined responsiveness. A head-to-head comparison was made. RESULTS: While variations in individuals occurred, the group mean change scores for all measures was small, suggesting that there was minimal deterioration in the total sample. Consistent with this, total sample Effect Size (ES) was negligible to small (ES -0.32 to +0.03) for all measures. Differentiation between sub-groups, defined by the participants' perception of change in mobility over the past year (transition questions), showed that some instruments could detect clinically significant changes (small sample sizes limited this interpretation). Correlation analyses between change scores demonstrated that these measures captured related, but different information (r < 0.364). CONCLUSIONS: The measures were broadly comparable in detecting mobility changes in this community sample. These correlations highlight that in selection of measures, one should also consider the discrete mobility dimension that the intervention intends to impact.

Achieving valid patient-reported outcomes measurement: a lesson from fatigue in multiple sclerosis.

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.

Interspinous spacers for lumbar foraminal stenosis: formal trials are justified.

PURPOSE: To determine whether preliminary evidence supports X-STOP implants as an effective treatment for lumbar radiculopathy secondary to foraminal stenosis, and if larger formal trials are warranted. METHODS: Participants had a clinical diagnosis of lumbar radiculopathy supported by MRI findings of foraminal stenosis and relevant nerve root compression. Self-reported disability and pain were measured pre-operation, early and late post-operation using the widely used Oswestry Disablity Index (ODI) and the bodily pain scale of the Medical Outcomes Study 36-item Short Form Health Survey (SF-36BP). The statistical significance (paired samples t test; Wilcoxon signed ranks test), and clinical significance (Cohen's effect size; Standardised response means) of change scores was determined. RESULTS: Fifteen people had X-STOP implants. Data pre- early- and late post-operation were available for ten. Self-reported disability and pain improved substantially by the early post operative measurement. Mean change scores (ODI = 29; SF-36BP = -45), significant at the p < 0.05 but not significant at the p < 0.001, were very large and effect sizes exceeded notably criteria for large clinical improvements (>0.80). Improvements were maintained at 2-3 years. Both scales had floor and ceiling effects implying changes may be underestimated. There were no surgical complications. CONCLUSIONS: In this small study, X-STOP appeared safe and effective. It is less invasive than other established surgical procedures, but does not jeopardise other options in the event of failure. Large scale clinical trials are justified but floor and ceiling effects suggest that the ODI and SF-36 may not be the best choice of outcome measures for those studies.