Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones

Does visual cortex lactate increase following photic stimulation in migraine without aura patients? A functional 1H-MRS study

Proton magnetic resonance spectroscopy (1H-MRS) has been used in a number of studies to assess noninvasively the temporal changes of lactate (Lac) in the activated human brain. Migraine neurobiology involves lack of cortical habituation to repetitive stimuli and a mitochondrial component has been put forward. Our group has recently demonstrated a reduction in the high-energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) in the occipital lobe of migraine without aura (MwoA) patients, at least in a subgroup, in a phosphorus MRS (31P-MRS) study. In previous studies, basal Lac levels or photic stimulation (PS)-induced Lac levels were found to be increased in patients with migraine with aura (MwA) and migraine patients with visual symptoms and paraesthesia, paresia and/or dysphasia, respectively. The aim of this study was to perform functional 1H-MRS at 3 T in 20 MwoA patients and 20 control subjects. Repetitive visual stimulation was applied using MR-compatible goggles with 8 Hz checkerboard stimulation during 12 min. We did not observe any significant differences in signal integrals, ratios and absolute metabolite concentrations, including Lac, between MwoA patients and controls before PS. Lac also did not increase significantly during and following PS, both for MwoA patients and controls. Subtle Lac changes, smaller than the sensitivity threshold (i.e. estimated at 0.1–0.2 μmol/g at 3 T), cannot be detected by MRS. Our study does, however, argue against a significant switch to non-aerobic glucose metabolism during long-lasting PS of the visual cortex in MwoA patients

P.165 Clinical outcome study of dysferlinopathy: lower limb water T2 predicts functional decline in patients with dysferlinopathy

Water-T2 (T2H2O) mapping is used in muscular dystrophies to assess disease activity. It has been suggested as a surrogate outcome measure for clinical trials. However, the prognostic utility of T2H2O to identify changes in muscle function over time has not been described. A cohort of 18 patients (7 male) from two sites (Newcastle and Paris) with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study of dysferlinopathy. Imaging used 3.0 T MRI clinical scanners with acquisition parameters standardised across sites. A multi-spin-echo sequence, with 17 equidistant echoes at 9.5ms spacing, was used for T2H2O mapping. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over three years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration and baseline function. The T2H2O threshold which best predicted functional decline was determined. Higher T2H2O value correlated with greater functional decline in 21/35 muscles, and was never associated with slower decline (p0.6). Higher T2H2O values in adductor magnus, vastus intermedius, vastus lateralis and vastus medialis were the most sensitive, being associated with greater decline in timed tests. Patients with a higher than median T2H2O value (40.6 milliseconds (ms)) in these muscles deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy (NSAD) and lost an additional 86 metres on the six-minute walk than those with a lower T2H2O value (p<0.05). In dysferlinopathy, T2H2O did not correlate with current functional ability. However, T2H2O at baseline was higher in patients who worsened more rapidly on functional tests. With its capacity to predict progression, T2H2O mapping could be used to improve prognostication, patient selection and disease modelling for clinical trials

MRI vastus lateralis fat fraction predicts loss of ambulation in Duchenne muscular dystrophy

ObjectiveWe studied the potential of quantitative MRI (qMRI) as a surrogate endpoint in Duchennemuscular dystrophy by assessing the additive predictive value of vastus lateralis (VL) fat fraction(FF) to age on loss of ambulation (LoA).MethodsVL FFs were determined on longitudinal Dixon MRI scans from 2 natural history studies inLeiden University Medical Center (LUMC) and Cincinnati Children’s Hospital MedicalCenter (CCHMC). CCHMC included ambulant patients, while LUMC included a mixedambulant and nonambulant population. We fitted longitudinal VL FF values to a sigmoidalcurve using a mixed model with random slope to predict individual trajectories. The additivevalue of VL FF over age to predict LoA was calculated from a Cox model, yielding a hazard ratio.ResultsEighty-nine MRIs of 19 LUMC and 15 CCHMC patients were included. At similar age,6-minute walking test distances were smaller and VL FFs were correspondingly higher inLUMC compared to CCHMC patients. Hazard ratio of a percent-point increase in VL FF forthe time to LoA was 1.15 for LUMC (95% confidence interval [CI] 1.05–1.26; p = 0.003) and0.96 for CCHMC (95% CI 0.84–1.10; p = 0.569).ConclusionsThe hazard ratio of 1.15 corresponds to a 4.11-fold increase of the instantaneous risk of LoA inpatients with a 10% higher VL FF at any age. Although results should be confirmed in a largercohort with prospective determination of the clinical endpoint, this added predictive value ofVL FF to age on LoA supports the use of qMRI FF as an endpoint or stratification tool inclinical trials.Development and application of statistical models for medical scientific researc

FP.34 Clinical outcome study of dysferlinopathy: correlation between MRI fat fraction in lower limbs and clinical outcome assessments over a 3-year period

The Jain Foundation COS of dysferlinopathy is an international study in genetically confirmed dysferlinopathy patients, with the aim to identify relevant outcome measures to facilitate trial readiness. Due to its wide range of clinical phenotypes and rates of disease progression, an objective marker to quantify disease progression would be ideal. We assessed the application of quantitative magnetic resonance imaging (MRI) as a prognostic tool for these patients. Our aim is to establish whether there is a correlation between fat fraction (FF) in thigh and/or lower leg muscles and clinical outcome assessments (COA) when comparing baseline (BL) values and changes from BL to year 1 (Y1) and to year 3 (Y3). We selected 84 patients from COS1 who had a Dixon MRI of the lower limbs (LL) and at least one of the following COA: time to rise from floor (RFF), time to climb / descend 4 steps (4SC/4SD), time up and go (TUG), time to walk 10m (10MWT), 6 min walk test (6MWT) and North Star Assessment for limb girdle type muscular dystrophy (NSAD) score. Spearman correlation (rs) was performed using SPSS statistics, p value 0.05. We found a significant correlation at BL between LL FF values and all COA, with the highest rs between thigh FF and NSAD (-.675) and 6MWT (-.665). We didn't find any correlations between changes in FF between BL and Y1 and changes in COA during that same period, but we did observe a significant correlation with changes in TUG (.445) and 4SC (.41) between BL and Y3. We observed a significant correlation between changes in thigh FF between BL and Y3 and changes in TUG (.706), RFF (.607), 4SC (.545) and NSAD[HR1] (-.374). No correlations were found when analysing changes in lower legs FF and COA. Our results show that changes in FF of the thigh muscles over one year could predict functional changes at a later stage, in a three-year period, suggesting that MRI could be used to identify dysferlinopathy patients at risk of more severe disease progression in routine clinical care

Reduction of high-energy phosphates in the occipital lobe of migraine without aura patients : a P-31- and H-1-MRS study

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MRI and muscle imaging for idiopathic inflammatory myopathies

International audienceAlthough idiopathic inflammatory myopathies (IIM) are a heterogeneous group of diseases nearly all patients display muscle inflammation. Originally, muscle biopsy was considered as the gold standard for IIM diagnosis. The development of muscle imaging led to revisiting not only the IIM diagnosis strategy but also the patients' follow-up. Different techniques have been tested or are in development for IIM including positron emission tomography, ultrasound imaging, ultrasound shear wave elastography, though magnetic resonance imaging (MRI) remains the most widely used technique in routine. Whereas guidelines on muscle imaging in myositis are lacking here we reviewed the relevance of muscle imaging for both diagnosis and myositis patients' follow-up. We propose recommendations about when and how to perform MRI on myositis patients, and we describe new techniques that are under development

Higher MRI muscle fat fraction at similar age is associated with earlier loss of ambulation in Duchenne muscular dystrophy

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas