Efficacy and safety of mexiletine in non-dystrophic myotonias: A randomised, double-blind, placebo-controlled, cross-over study.

The MYOMEX study was a multicentre, randomised, double-blind, placebo-controlled, cross-over study aimed to compare the effects of mexiletine vs. placebo in patients with myotonia congenita (MC) and paramyotonia congenita (PC). The primary endpoint was the self-reported score of stiffness severity on a 100 mm visual analogic scale (VAS). Mexiletine treatment started at 200 mg/day and was up-titrated by 200 mg increment each three days to reach a maximum dose of 600 mg/day for total treatment duration of 18 days for each cross-over period. The modified intent-to-treat population included 25 patients (13 with MC and 12 with PC; mean age, 43.0 years; male, 68.0%). The median VAS score for mexiletine was 71.0 at baseline and decreased to 16.0 at the end of the treatment while the score did not change for placebo (81.0 at baseline vs. 78.0 at end of treatment). A mixed effects linear model analysis on ranked absolute changes showed a significant effect of treatment (p < 0.001). The overall score of the Individualized Neuromuscular Quality of Life questionnaire (INQoL) was significantly improved (p < 0.001). No clinically significant adverse events were reported. In conclusion, mexiletine improved stiffness and quality of life in patients with nondystrophic myotonia and was well tolerated.

Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2.

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.

Automated Categorization of Parkinsonian Syndromes Using Magnetic Resonance Imaging in a Clinical Setting.

BACKGROUND: Machine learning algorithms using magnetic resonance imaging (MRI) data can accurately discriminate parkinsonian syndromes. Validation in patients recruited in routine clinical practice is missing. OBJECTIVE: The aim of this study was to assess the accuracy of a machine learning algorithm trained on a research cohort and tested on an independent clinical replication cohort for the categorization of parkinsonian syndromes. METHODS: Three hundred twenty-two subjects, including 94 healthy control subjects, 119 patients with Parkinson's disease (PD), 51 patients with progressive supranuclear palsy (PSP) with Richardson's syndrome, 35 with multiple system atrophy (MSA) of the parkinsonian variant (MSA-P), and 23 with MSA of the cerebellar variant (MSA-C), were recruited. They were divided into a training cohort (n = 179) scanned in a research environment and a replication cohort (n = 143) examined in clinical practice on different MRI systems. Volumes and diffusion tensor imaging (DTI) metrics in 13 brain regions were used as input for a supervised machine learning algorithm. To harmonize data across scanners and reduce scanner-dependent effects, we tested two types of normalizations using patient data or healthy control data. RESULTS: In the replication cohort, high accuracies were achieved using volumetry in the classification of PD-PSP, PD-MSA-C, PSP-MSA-C, and PD-atypical parkinsonism (balanced accuracies: 0.840-0.983, area under the receiver operating characteristic curves: 0.907-0.995). Performances were lower for the classification of PD-MSA-P, MSA-C-MSA-P (balanced accuracies: 0.765-0.784, area under the receiver operating characteristic curve: 0.839-0.871) and PD-PSP-MSA (balanced accuracies: 0.773). Performance using DTI was improved when normalizing by controls, but remained lower than that using volumetry alone or combined with DTI. CONCLUSIONS: A machine learning approach based on volumetry enabled accurate classification of subjects with early-stage parkinsonism, examined on different MRI systems, as part of their clinical assessment. © 2020 International Parkinson and Movement Disorder Society.

Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflammatory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), we evaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects. METHODS: We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlled study. Eligibility criteria included age < 75 years, disease duration < 5 years, riluzole treatment > 3 months, and a slow vital capacity ≥ 70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, or placebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Treg percentage of CD4+ T cells (%Tregs) following a first cycle. Secondary laboratory outcomes included: %Treg and Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL) concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slow vital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759. FINDINGS: All randomised patients (12 per group), recruited from October 2015 to December 2015, were alive at the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverse event was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 doses compared to placebo, including injection site reactions and flu-like symptoms. Primary outcome analysis showed a significant increase (p < 0·0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6·2% [2·2]; 1 MIU: +3·9% [1·2]) as compared to placebo (mean [SD]: -0·49% [1·3]). Effect sizes (ES) were large in treated groups: 2 MIU ES=3·7 (IC95%: 2·3-4·9) and 1 MIU ES=3·5 (IC95%: 2·1-4·6). Secondary outcomes showed a significant increase in %Tregs following repeated cycles (p < 0·0001) as compared to placebo, and a dose-dependent decrease in plasma CCL2 (p = 0·0049). There were no significant differences amongst the three groups on plasma NFL levels. INTERPRETATION: Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results warrant further investigation into their eventual therapeutic impact on slowing ALS disease progression. FUNDING: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pour la Recherche sur la SLA (ARSLA).

Genome-wide survey of copy number variants finds MAPT duplications in progressive supranuclear palsy.

BACKGROUND: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. METHODS: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. RESULTS: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. CONCLUSIONS: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.

Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases.

BACKGROUND: Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease for which the genetic contribution is incompletely understood. METHODS: 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. RESULTS: We identified 5 associated loci at a genome-wide significance threshold P < 5 × 10- 8, 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- 6). 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. CONCLUSIONS: 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.

Corticosteroids in Duchenne muscular dystrophy: impact on the motor function measure sensitivity to change and implications for clinical trials.

AIM: To monitor the evolution of the motor function of ambulatory patients with Duchenne muscular dystrophy (DMD) treated by corticosteroids for 2 years in comparison with untreated patients. METHOD: This observational, multicentre cohort study explores the evolution of the motor function measure (MFM) over a 24-month period for 29 ambulant corticosteroids-treated and 45 ambulant untreated patients with DMD. RESULTS: Significant differences were found between mean MFM scores in corticosteroids-treated and untreated groups for domain 1 of the MFM (standing position and transfers; D1), domain 2 of the MFM (axial and proximal motor function; D2), and domain 3 of the MFM (distal motor function; D3). Subscores were between 0 months and 6 months, and 0 months and 24 months. For the D1 subscore specifically, there was a significant increase in the corticosteroids-treated group (mean±standard deviation [SD] slope of change=12.6±15.5%/y), while a decrease was observed in the untreated group (-17.8±17.7%/y) between 0 months and 6 months (p<0.001). Sensitivity to change as assessed by standardized response means was high between 12 months and 24 months for D1 of both corticosteroids-treated and untreated groups (1.0 and 1.2 respectively), and low for D2 and D3 of both treated and untreated groups. INTERPRETATION: Patients with DMD treated by corticosteroids present a different course of the disease as assessed by MFM, confirming the sensitivity to change of the MFM in this population. WHAT THIS PAPER ADDS: Corticosteroids have a quantitative impact on muscle strength 6 to 24 months after starting treatment. Motor function measure is a valid outcome measure in Duchenne muscular dystrophy patients under corticosteroid treatment.

Outcome of gastrostomy in parkinsonism: A retrospective study.

OBJECTIVE: To investigate the indications and the outcomes of gastrostomy tube insertion in patients with parkinsonian syndromes. METHODS: Consecutive patients with Parkinson's disease or atypical parkinsonism, seen in two French tertiary referral movement disorders centers, that received gastrostomy tube insertion (GTI) for feeding between 2008 and 2014 were included in this retrospective study. Data regarding clinical status, indications and outcomes were retrieved from medical files. The main outcome measure was survival duration following gastrostomy insertion according to Kaplan-Meier estimate. Cox analysis was also performed to identify factors associated with survival. Finally, we described short term and long term adverse effects occurring during the follow-up period. RESULTS: We identified 33 patients with Parkinsonism that received GTI during the study period. One patient was excluded from the analysis because of missing data. Among 32 patients, 7 (22%) had Parkinson's disease and 25 (78%) had atypical parkinsonism. The median survival following the procedure was 186 days (CI 95% [62-309]). In Cox model analysis, total dependency was the only factor negatively associated with survival (HR 0.1; 95% CI [0.02-0.4], p = 0.001). Pneumonia was the most frequent adverse event. CONCLUSION: In this sample of patients with parkinsonian syndromes, survival after GTI was short particularly in totally dependent subjects. Aspiration pneumonia was not prevented by GTI. A larger prospective study is warranted to assess the potential benefits of gastrostomy, in order to identify the most appropriate indications and timing for the procedure.

Natural history of LGMD2A for delineating outcome measures in clinical trials.

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.

Wrist flexion and extension torques measured by highly sensitive dynamometer in healthy subjects from 5 to 80 years.

BACKGROUND: Wrist movements become impaired with disease progression in various neuromuscular disorders. With the development of new therapies, thorough measurement of muscle strength is crucial to document natural disease progression and to assess treatment efficacy. We developed a new dynamometer enabling wrist flexion and extension torque measurement with high sensitivity. The aims of the present study were to collect norms for healthy children and adults, to compute predictive equations, to assess the reliability of the measurements and to test the feasibility of using the device in patients with a neuromuscular disease. METHODS: The peak isometric torque of wrist flexion and extension was measured with the MyoWrist dynamometer in 345 healthy subjects aged between 5 and 80 years old and in 9 patients with limb girdle muscle dystrophy type 2 C (LGMD2C) aged between 16 and 38 years old. RESULTS: Predictive equations are proposed for the wrist flexion and extension strength in children and adults. Intra-rater and inter-rater reliability was good with ICCs higher than 0.9 for both wrist flexion and extension. However, retest values were significantly higher by 4% than test results. The dynamometer was applied with no difficulty to patients with LGMD2C and was sensitive enough to detect strength as weak as 0.82 N.m. From our models, we quantified the mean strength of wrist extension in LGMD2C patients to 39 ± 17% of their predicted values. CONCLUSIONS: The MyoWrist dynamometer provides reliable and sensitive measurement of both wrist flexion and extension torques. However, a training session is recommended before starting a study as a small but significant learning effect was observed. Strength deficit can be quantified from predictive equations that were computed from norms of healthy children and adults.

English cross-cultural translation and validation of the neuromuscular score: a system for motor function classification in patients with neuromuscular diseases.

OBJECTIVE: To develop and validate an English version of the Neuromuscular (NM)-Score, a classification for patients with NM diseases in each of the 3 motor function domains: D1, standing and transfers; D2, axial and proximal motor function; and D3, distal motor function. DESIGN: Validation survey. SETTING: Patients seen at a medical research center between June and September 2013. PARTICIPANTS: Consecutive patients (N=42) aged 5 to 19 years with a confirmed or suspected diagnosis of congenital muscular dystrophy. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: An English version of the NM-Score was developed by a 9-person expert panel that assessed its content validity and semantic equivalence. Its concurrent validity was tested against criterion standards (Brooke Scale, Motor Function Measure [MFM], activity limitations for patients with upper and/or lower limb impairments [ACTIVLIM], Jebsen Test, and myometry measurements). Informant agreement between patient/caregiver (P/C)-reported and medical doctor (MD)-reported NM scores was measured by weighted kappa. RESULTS: Significant correlation coefficients were found between NM scores and criterion standards. The highest correlations were found between NM-score D1 and MFM score D1 (ρ=-.944, P<.0001), ACTIVLIM (ρ=-.895, P<.0001), and hip abduction strength by myometry (ρ=-.811, P<.0001). Informant agreement between P/C-reported and MD-reported NM scores was high for D1 (κ=.801; 95% confidence interval [CI], .701-.914) but moderate for D2 (κ=.592; 95% CI, .412-.773) and D3 (κ=.485; 95% CI, .290-.680). Correlation coefficients between the NM scores and the criterion standards did not significantly differ between P/C-reported and MD-reported NM scores. CONCLUSIONS: Patients and physicians completed the English NM-Score easily and accurately. The English version is a reliable and valid instrument that can be used in clinical practice and research to describe the functional abilities of patients with NM diseases.

Rasch analysis of clinical outcome measures in spinal muscular atrophy.

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.

Motor function measure: validation of a short form for young children with neuromuscular diseases.

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.

Ankle dorsi- and plantar-flexion torques measured by dynamometry in healthy subjects from 5 to 80 years.

BACKGROUND: Ankle strength is often impaired in some of the most common neuromuscular disorders. Consequently, strength generated around this joint is important to assess, because it has a great impact on balance and gait. The objectives of this study were to establish normative data and predictive equations for both ankle dorsi- and plantar-flexion strength from a population of healthy subjects (children and adults), to assess the reliability of the measurements and to study the feasibility of using a novel dynamometer on a group of patients with a neuromuscular disorder. METHODS: Measurements of maximal isometric torque for dorsi- and plantar-flexion were performed on 345 healthy subjects from 5 to 80 years of age. The feasibility of the method was tested on nine patients diagnosed with type 2A limb girdle muscular dystrophy. RESULTS: The results documented normal strength values depending on gender and age on ankle dorsi- and plantar-flexion. The reliability of the technique was good with no evaluator effect and a small learning effect. The dynamometer was found suitable in the group of patients, even very weak. CONCLUSIONS: The device developed was both reliable and accurate in assessing both ankle dorsi-flexion and plantar-flexion torque measurements from weak patients and children to strong healthy adults. Norms and predictive equations are provided for these two muscle functions.

Responsiveness of the motor function measure in patients with spinal muscular atrophy.

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.

Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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.

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.

Intensive versus subcutaneous insulin in patients with hyperacute stroke: results from the randomized INSULINFARCT trial.

BACKGROUND AND PURPOSE: Intensive insulin therapy (IIT) has not yet proven its efficacy on stroke prognosis or in the reduction of MRI infarct growth. The INSULINFARCT study aims at determining in patients with hyperacute stroke whether IIT, with a better control of poststroke hyperglycemia, would reduce subsequent MRI infarct growth than usual care with subcutaneous insulin. METHODS: One hundred eighty patients with MRI-proven ischemic stroke and with National Institutes of Health Stroke Scale from 5 to 25 at admission (<6 hours) were randomized to receive IIT or usual subcutaneous insulin for 24 hours. Admission hyperglycemia was not required for recruitment. Control MRI and 3-month follow-up (with functional outcome and serious adverse events) were planned. The primary objective was to detect a difference in the proportion of patients with mean capillary glucose test <7 mmol/L during 24 hours. The secondary objective was to investigate whether IIT would reduce infarct growth. The analysis was planned in intention-to-treat. Patients with >3 missing capillary glucose test were excluded (n=4). RESULTS: The proportion of patients with mean capillary glucose test <7 mmol/L in the first 24 hours was higher in the IIT group (95.4% [83 of 87] versus 67.4% [60 of 89]; P<0.0001). The infarct growth was lower in the subcutaneous insulin group (median, 10.8 cm(3); 95% CI, 6.5-22.4 versus 27.9 cm(3); 14.6-40.7; 60% of increase; P=0.04). The 3-month functional outcome (45.6% [41 of 90] versus 45.6% [41 of 90]), death (15.6% [14 of 90] versus 10% [9 of 90]), and serious adverse events (38.9% [35 of 90] versus 35.6% [32 of 90]) were similar in the subcutaneous insulin and IIT group. CONCLUSIONS: The IIT regimen improved glucose control in the first 24 hours of stroke but was associated with larger infarct growths. IIT cannot be recommended in hyperacute ischemic stroke. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique Identifier: NCT00472381.

The economic costs of progressive supranuclear palsy and multiple system atrophy in France, Germany and the United Kingdom.

Progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) are progressive disabling neurological conditions usually fatal within 10 years of onset. Little is known about the economic costs of these conditions. This paper reports service use and costs from France, Germany and the UK and identifies patient characteristics that are associated with cost. 767 patients were recruited, and 760 included in the study, from 44 centres as part of the NNIPPS trial. Service use during the previous six months was measured at entry to the study and costs calculated. Mean six-month costs were calculated for 742 patients. Data on patient sociodemographic and clinical characteristics were recorded and used in regression models to identify predictors of service costs and unpaid care costs (i.e., care from family and friends). The mean six-month service costs of PSP were €24,491 in France, €30,643 in Germany and €25,655 in the UK. The costs for MSA were €28,924, €25,645 and €19,103 respectively. Unpaid care accounted for 68-76%. Formal and unpaid costs were significantly higher the more severe the illness, as indicated by the Parkinson's Plus Symptom scale. There was a significant inverse relationship between service and unpaid care costs.