The Natural History and Neuroprotection in Parkinson Plus Syndromes (NNIPPS) study was a large phase III randomized placebo-controlled trial of riluzole in Progressive Supranuclear Palsy (PSP, n = ...362) and Multiple System Atrophy (MSA, n = 398). To assess disease severity and progression, we constructed and validated a new clinical rating scale as an ancillary study.
Patients were assessed at entry and 6-montly for up to 3 years. Evaluation of the scale's psychometric properties included reliability (n = 116), validity (n = 760), and responsiveness (n = 642). Among the 85 items of the initial scale, factor analysis revealed 83 items contributing to 15 clinically relevant dimensions, including Activity of daily Living/Mobility, Axial bradykinesia, Limb bradykinesia, Rigidity, Oculomotor, Cerebellar, Bulbar/Pseudo-bulbar, Mental, Orthostatic, Urinary, Limb dystonia, Axial dystonia, Pyramidal, Myoclonus and Tremor. All but the Pyramidal dimension demonstrated good internal consistency (Cronbach α ≥ 0.70). Inter-rater reliability was high for the total score (Intra-class coefficient = 0.94) and 9 dimensions (Intra-class coefficient = 0.80-0.93), and moderate (Intra-class coefficient = 0.54-0.77) for 6. Correlations of the total score with other clinical measures of severity were good (rho ≥ 0.70). The total score was significantly and linearly related to survival (p<0.0001). Responsiveness expressed as the Standardized Response Mean was high for the total score slope of change (SRM = 1.10), though higher in PSP (SRM = 1.25) than in MSA (SRM = 1.0), indicating a more rapid progression of PSP. The slope of change was constant with increasing disease severity demonstrating good linearity of the scale throughout disease stages. Although MSA and PSP differed quantitatively on the total score at entry and on rate of progression, the relative contribution of clinical dimensions to overall severity and progression was similar.
The NNIPPS-PPS has suitable validity, is reliable and sensitive, and therefore is appropriate for use in clinical studies with PSP or MSA.
ClinicalTrials.gov NCT00211224.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
An improper balance of regulatory/effector T (Treg/Teff) cells is central to the development of autoimmune diseases, including type 1 diabetes. We previously showed that low-dose interleukin 2 (IL2) ...induced Treg cell expansion and activation and clinical improvement in patients with hepatitis-C-virus-induced vasculitis. We aimed to establish which low doses of IL2 would be safe and induce Treg cells in patients with type 1 diabetes, considering that: (1) type 1 diabetes might be linked to alteration of the IL2/IL2R activation pathway; (2) activation of pathogenic Teff cells by IL2 could exacerbate disease; and (3) the safety of low-dose IL2 is not known in type 1 diabetes.
This was a single-centre phase 1/2 study. 24 adult patients (18-55 years) with established insulin-dependent type 1 diabetes and at least one diabetes-related autoantibody were enrolled and randomly assigned (in a 1:1:1:1 ratio, by computer-generated randomisation list, with block size four) to placebo or IL2 at 0.33 MIU/day, 1 MIU/day, or 3 MIU/day for a 5-day course and were followed up for 60 days. All investigators and participants were masked to assignment. The primary outcome was change in Treg cells, measured by flow cytometry, and expressed as a percentage of CD4+ T cells, from day 1 to day 60. This trial is registered with ClinicalTrials.gov, number NCT01353833.
Six patients were assigned to each group between June 1, 2011, and Feb 3, 2012. IL2 was well tolerated at all doses, with no serious adverse events. However, there was a dose-response association for non-serious adverse events during the treatment phase (days 1-6); one patient in the placebo group, three patients in the 0.33 MIU group, five patients in the 1 MIU group, and six patients in the 3 MIU group had non-serious adverse events. The most common adverse events in the treatment phase were injection-site reaction (no patients with placebo vs three patients with 0.33 MIU and 1 MIU vs two patients with 3 MIU) and influenza-like syndrome (no patients with placebo vs one patient with 0.33 MIU and 1 MIU vs four patients with 3 MIU). After the treatment phase, adverse events did not differ between groups. IL2 did not induce deleterious changes in glucose-metabolism variables. IL2 induced a dose-dependent increase in the proportion of Treg cells, significant at all doses compared with placebo (placebo mean increase 0.5% SD 0.4; 0.33 MIU 2.8% 1.2, p=0.0039; 1 MIU 3.9% 1.8, p=0.0039; 3 MIU 4.8% 1.9 p=0.0039).
We have defined a well-tolerated and immunologically effective dose range of IL2 for application to type 1 diabetes therapy and prevention, which could be relevant to other disorders in which a Treg cell increase would be desirable.
ABSTRACT
Introduction: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). ...Methods: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. Muscle Nerve 49:422–430, 2014
Objective
Limb‐girdle muscular dystophy 2A (LGMD2A, OMIM) is a slowly progressive myopathy caused by the deficiency in calpain 3, a calcium‐dependent cysteine protease of the skeletal muscle.
Methods
...In this study, we carried out an observational study of clinical manifestations and disease progression in genetically confirmed LGMD2A patients for up to 4 years. A total of 85 patients, aged 14–65 years, were recruited in three centers located in metropolitan France, the Basque country, and the Reunion Island. They were followed up every 6 months for 2 years and a subgroup was assessed annually thereafter for two more years. Data collected for all patients included clinical history, blood parameters, muscle strength assessed by manual muscle testing (MMT) and quantitative muscle testing, functional scores, and pulmonary and cardiac functions. In addition, CT scans of the lower limbs were performed in a subgroup of patients.
Results
Our study confirms the clinical description of a slowly progressive disorder with onset in the first or second decade of life with some degree of variability related to gender and mutation type. The null mutations lead to a more severe phenotype while compound heterozygote patients are the least affected. Muscle weakness is remarkably symmetrical and predominant in the axial muscles of the trunk and proximal muscles of the lower limb. There was a high correlation between the weakness at individual muscle level as assessed by MMT and the loss of density in CT scan analysis.
Interpretation
All the generated data will help to determine the endpoints for further clinical studies.
Abstract Objective To assess the ability of the Motor Function Measure (MFM) to detect changes in the progression of spinal muscular atrophy (SMA). Design Observational, retrospective, multicenter ...cohort study. Setting Seventeen departments of pediatric physical medicine. Participants Volunteer patients with SMA (N=112) aged 5.7 to 59 years with no treatment other than physical therapy and nutritional or respiratory assistance. Interventions Not applicable. Main Outcome Measures The distributions of the MFM scores (total score and 3 subscores) were analyzed per SMA subtype. The relationships between scores and age were studied. The slopes of score changes (reflecting MFM responsiveness) were estimated in patients with at least 6 months' follow-up and 2 MFMs. Hypothetical sample sizes for specific effect sizes in clinical trial scenarios are given. Results In 12 patients with SMA type 2 and 19 with SMA type 3 (mean ± SD follow-up, 25.8±19mo), there was a moderate inverse relationship between age and the MFM total score. Patients with less than 6 months' follow-up showed little score changes. Patients with longer follow-ups showed a slow deterioration (−0.9 points/y for type 2 and −0.6 points/y for type 3). Substantial responsiveness was obtained with the MFM Dimension 2 subscore (proximal and axial motricity) in patients with SMA type 2 (standardized response mean SRM=1.29), and with the MFM Dimension 1 subscore (standing and transfers) in patients with SMA type 3 aged 10 to 15 years (SRM=.94). Conclusions If further confirmed by larger studies, these preliminary results on the relative responsiveness of the MFM in SMA will foster its use in monitoring disease progression in patients who participate in clinical trials.
Abstract Objective To validate a useful version of the Motor Function Measure (MFM) in children with neuromuscular diseases aged <7 years old. Design Two prospective cohort studies that documented ...the MFM completion of children aged between 2 and 7 years old. Setting French-speaking rehabilitation departments from France, Belgium, and Switzerland. Participants Healthy children (n=194) and children with a neuromuscular disease (n=88). Interventions Patients were rated by the MFM either once or twice by trained medical professionals, with a delay between the 2 MFMs ranging between 8 and 30 days. Main Outcome Measure Intra- and interrater reliability of the MFM. Results The subtests making up the MFM-32, a scale monitoring severity and progression of motor function in patients with a neuromuscular disease in 3 functional domains, were carried out in healthy children aged 2 to 7 years. Twenty items of the MFM-32 were successfully completed by these children and were used to constitute the MFM-20. Principal component analysis of the MFM-20 confirmed the 3 functional domains. Inter- and intrarater reliability of the 3 subscores and total score were high (intraclass correlation coefficient >.90), and discriminant validity was good. Conclusions The MFM-20 can be used as an outcome measure for assessment of motor function in young children with neuromuscular disease.
Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood.
We conducted a joint analysis of 5,523,934 imputed SNPs in two ...newly-genotyped progressive supranuclear palsy cohorts, primarily derived from two clinical trials (Allon davunetide and NNIPPS riluzole trials in PSP) and a previously published genome-wide association study (GWAS), in total comprising 1646 cases and 10,662 controls of European ancestry.
We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10
, including replication of 3 loci from previous studies and 2 novel loci at 6p21.1 and 12p12.1 (near RUNX2 and SLCO1A2, respectively). At the 17q21.31 locus, stepwise regression analysis confirmed the presence of multiple independent loci (localized near MAPT and KANSL1). An additional 4 loci were highly suggestive of association (P < 1 × 10
). We analyzed the genetic correlation with multiple neurodegenerative diseases, and found that PSP had shared polygenic heritability with Parkinson's disease and amyotrophic lateral sclerosis.
In total, we identified 6 additional significant or suggestive SNP associations with PSP, and discovered genetic overlap with other neurodegenerative diseases. These findings clarify the pathogenesis and genetic architecture of PSP.
Abstract Hogrel J-Y, Payan CA, Ollivier G, Tanant V, Attarian S, Couillandre A, Dupeyron A, Lacomblez L, Doppler V, Meininger V, Tranchant C, Pouget J, Desnuelle C. Development of a French isometric ...strength normative database for adults using quantitative muscle testing. Objective To establish a normative database for isometric strength measured by quantitative muscle testing (QMT) for a French adult population. Design Measurement of maximal voluntary isometric contraction. Setting Four clinical centers involved in neuromuscular disorders. Participants A total of 315 healthy adults (147 men, 168 women) ages 20 to 80 years. Interventions Not applicable. Main Outcome Measure Isometric torque values of 14 muscle functions (13 bilaterally and neck). Results This study led to the development of a French isometric strength normative database for adults measured by QMT. For each muscle function, predictive regression models using age, sex, and weight are proposed. Some methodologic issues concerning strength measurement are discussed. Conclusions This database can be used to compute relative deficits in muscle strength for 27 muscle functions and also to estimate composite scores for follow-up of patients either during the natural history of their disease or during a therapeutic trial.
Abstract Vuillerot C, Payan C, Girardot F, Fermanian J, Iwaz J, Bérard C, Ecochard R, the MFM Study Group. Responsiveness of the Motor Function Measure in neuromuscular diseases. Objectives To study ...the responsiveness (sensitivity to change) of the Motor Function Measure (MFM) in detecting change in neuromuscular disease patients with the intent of using this measure in future clinical trials. Design Prospective cohort observational study. Setting Inpatient and outpatient facilities for follow-up and treatment of neuromuscular diseases. Participants Patients (N=152) with various neuromuscular diseases aged 6 to 60 years. Interventions Not applicable. Main Outcome Measure(s) We used the MFM total score and its 3 subscores on 2 measurements grossly 1 year apart. The physicians and the patients (or proxy) were asked to provide their perceived change in functional status since the first MFM. These changes were expressed in 3 outcomes: deterioration, stability, or improvement. Results The overall 12-month-standardized mean change of the total score mean ± SD annual total score change was −2.4±5.5 points ( P <.001), with patients with Duchenne muscular dystrophy (DMD) presenting the most significant change (−5.8±6.3, P <.001). The change in patients reporting deterioration (34%) was significantly larger than that of those reporting stability (47%) or improvement (10%) (−4.4±6.4 vs −2.0±5.6 and +0.9±4.4 points, respectively, P <.01). The 12-month-standardized total score changes were significantly greater in physician-rated deteriorated (49%) versus stable patients (51%), with mean differences in scores being −5.3±7.6 and −1.2±5.3, respectively ( P <.001). Conclusions The MFM showed a good responsiveness, especially in patients with DMD and agreements with patients' and physicians' perceived change. Confirming this responsiveness requires larger age groups of patients with DMD and other neuromuscular diseases as well as disease-specific interexamination delays.
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