Non-ambulant Duchenne Muscular Dystrophy Research Articles

Discriminatory Properties of the Quality-Adjusted Life Year Based Cost-Effectiveness Analyses for Patients With Disabilities: A Duchenne Muscular Dystrophy Case Study

ObjectivesQuality-adjusted life years (QALYs) have been challenged as a measure of benefit for people with disabilities, particularly for those in low-utility health states or with irreversible disability. This study examined the impact of a QALY-based assessment on the price for a hypothetical treatment for Duchenne muscular dystrophy (DMD), a progressive, genetic neuromuscular disease. MethodsA previously published, 5-state model, which analyzed treatments for early ambulatory (EA) DMD patients, was replicated, validated, and adapted to include early nonambulatory (ENA) DMD patients. The model was used to assess a QALY-based threshold price (maximum cost-effective price) for a hypothetical treatment for 13-year-old ENA and 5-year-old EA patients (initial health states with lower and higher utility, respectively). All inputs were replicated including willingness-to-pay thresholds of $50 000 to $200 000/QALY. ResultsIn contrast to EA patients, ENA patients had a 98% modeled decline in QALY-based threshold price at a willingness-to-pay of $150 000/QALY or higher, despite equal treatment benefit (delayed progression/death). At $100 000/QALY or lower, net nontreatment costs exceeded health benefits, implying any treatment for ENA patients would not be considered cost-effective, even at $0 price, including an indefinite pause in disease progression. ConclusionsFor certain severe, disabling conditions, traditional approaches are likely to conclude that treatments are not cost-effective at any price once a patient progresses to a disabled health state with low utility value. These findings elucidate theoretical/ethical concerns regarding potential discriminatory properties of traditional QALY assessments for people with disabilities, particularly those who have lost ambulation or have other physical limitations.

"If you cannot measure it, you cannot improve it". Outcome measures in Duchenne Muscular Dystrophy: current and future perspectives.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

Functional trajectories before and after loss of ambulation in Duchenne muscular dystrophy and implications for clinical trials.

This study examined functional trajectories of subjects during the transition phase between ambulatory and non-ambulatory Duchenne muscular dystrophy (DMD) to inform clinical trial designs for new therapeutics. Ambulatory, pulmonary, and upper limb function leading up to loss of ambulation (LoA) and non-ambulatory measures following LoA were quantified; time ordering of pulmonary and upper limb milestones relative to LoA were determined; and the 10-second time threshold for 10-meter walk/run (10MWR) as a marker of approaching LOA was explored. Included in this analysis were 51 subjects aged between 7 and 18 years who experienced LoA during follow-up in the PRO-DMD-01 natural history study. Mean age at LoA was 12.7 (7.1-18.6) years. Mean annual rates of decline in forced vital capacity (FVC) <80%-predicted and performance of upper limb (PUL) 1.2 total score were smaller before than after LoA, but not significantly (FVC %-predicted: 5.6% vs. 10.1%, p = 0.21; PUL 1.2 total score: 2.3 vs. 3.8 units, p = 0.20). More than half of patients experienced clinically significant deficits in FVC %-predicted and PUL 1.2 before experiencing LoA. Among subjects with baseline 10MWR >10 s, those with <1 year to LoA had similar mean ages but significantly worse mean ambulatory function at baseline compared to those with ≥1 year to LoA. Enriching DMD clinical trials for patients with declining pulmonary or upper limb function is achievable without restricting enrollment to non-ambulatory patients. The sequencing of LoA and initial deficits in pulmonary and upper limb function varied across patients and highlights the potential for composite outcomes or multi-outcome trial designs to assess disease-modifying therapies more comprehensively.

Decreased quality of life in Duchenne muscular disease patients related to functional neurological and cardiac impairment.

In this prospective study involving 37 Duchenne muscular dystrophy (DMD) patients aged 8-18 years and older, we examined the impact of neurological and cardiac factors on quality of life (QoL). Our findings revealed a negative correlation between upper limb movement and overall mobility, self-service, and usual activities. Ambulatory and non-ambulatory DMD patients showed significant differences in mobility-related parameters. Cardiac evaluations demonstrated associations between mitral annular plane systolic excursion (MAPSE) and mobility-related aspects. The PEDSQL 3.0 neuromuscular model questionnaire further highlighted age-related and movement-related correlations with QoL. The loss of ambulatory status and reduced upper limb movement were negatively associated with QoL, while upper limb movement positively correlated with septal MAPSE. However, no significant associations were found between MAPSE and anxiety/depression. These findings underscore the multifaceted impact of DMD on QoL and emphasize the importance of considering both neurological and cardiac factors in comprehensive patient care.

Pelvic obliquity, trunk control, and motor function: an exploratory study in a non-ambulatory Duchenne muscular dystrophy cohort.

The aim of this study was to investigate the relationship between pelvic obliquity and trunk control, spinal deformity, upper extremity functional performance, and motor function in patients with non-ambulatory Duchenne muscular dystrophy. This cross-sectional study included 21 patients with Duchenne muscular dystrophy aged 8-18 years. In the study, participants' upper extremity functional levels, pelvic obliquity degrees, spinal deformity, trunk control, upper extremity performance, and motor functions were evaluated using various tools such as the Brooke Upper Extremity Functional Scale, baseline scoliometer, spinal mouse, Trunk Control Measurement Scale, Upper Extremity Performance Scale, and Egen Klassifikation Scale Version 2, respectively. The study found a strong correlation between pelvic obliquity and frontal spine deformity (p<0.01), as well as moderate relationships between pelvic obliquity, motor function, wheelchair usage duration, and knee flexion contractures (p<0.05). The study found that pelvic obliquity may lead to spinal health deterioration and motor function limitations in non-ambulatory patients with Duchenne muscular dystrophy, especially those with lower extremity joint contractures and long-term wheelchair use.

Longitudinal Analysis of PUL 2.0 Domains in Ambulant and Non-Ambulant Duchenne Muscular Dystrophy Patients: How do they Change in Relation to Functional Ability?

The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.

High-Speed T2 -Corrected Multiecho Magnetic Resonance Spectroscopy for Quantitatively Detecting Skeletal Muscle Fatty Infiltration and Predicting the Loss of Ambulation in Patients With Duchenne Muscular Dystrophy.

High-speed T2 -corrected multiecho MRS (HISTO-MRS) is emerging as a quantitative modality for detecting muscle fat infiltration (MFF). However, the predictive value of HISTO-MRS for the loss of ambulation (LoA) in Duchenne muscular dystrophy (DMD) is unknown. To determine the feasibility of HISTO-MRS for assessing MFF in DMD and further identify the predictive value of HISTO-MRS for the LoA. Prospective. A total of 134 DMD boys (9.20 ± 2.43 years old) and 21 healthy boys (9.25 ± 2.10 years old). A 3 T, fast spin echo T1 -weighted imaging (T1 WI), two-point-Dixon gradient echo sequence (2-pt-Dixon) and HISTO-MRS. Subjective T1 WI fat grades by three radiologists, ROI analysis for MFF on 2pt-Dixon (Dixon MFF) and MFF on HISTO-MRS (HISTO MFF) by two radiologists. Clinical motor function: North Star Ambulatory Assessment, 10-m run/walk time, Gowers maneuver, and time to four-stairs climb and descend. Spearman rank correlation was used to assess the relation of fat filtration assessments and motor ability. Bland-Altman plots was performed to determine the agreement of HISTO MFF and Dixon MFF. Receiver operating characteristic (ROC) curves were analyzed to determine the discriminating ability of above MRI modalities for ambulatory and nonambulatory DMD. Logistic regression was used to identify the predictor of LoA. Variables with P < 0.05 in univariate logistic regression analysis were entered into the multivariate logistic regression model. HISTO MFF was significantly correlated with Dixon MFF. Bland-Altman plots show good agreement of HISTO MFF and Dixon MFF. ROC curves indicated that HISTO MFF show similar discrimination of LoA for DMD with Dixon MFF but better value than T1WI fat grades. Logistic regression showed that HISTO MFF was an independent predictor for LoA. HISTO-MRS is a potential quantitative method for assessing fat infiltration and shows predictive value for LoA in DMD patients. Stage 5.

Expert council resolution on the use of pathogenetic therapy with Ataluren in patients with non-ambulatory Duchenne muscular dystrophy

Прогрессирующая мышечная дистрофия Дюшенна (МДД) — это редкое хроническое прогрессирующее наследственное Х-сцепленное рецессивное заболевание, вызванное мутациями в гене DMD [1–9].

Natural history of circulating miRNAs in Duchenne disease: Association with muscle injury and metabolic parameters

This study aimed to evaluate whether the expression of circulating dystromiRs and a group of oxidative stress-related (OS-R) miRNAs is associated with muscle injury and circulating metabolic parameters in Duchenne muscular dystrophy (DMD) patients. Twenty-four DMD patients were included in this cross-sectional study. Clinical scales to evaluate muscle injury (Vignos, GMFCS, Brooke, and Medical Research Council), enzymatic muscle injury parameters (CPK, ALT, and AST), anthropometry, metabolic indicators, physical activity, serum dystromiRs (miR-1-3p, miR-133a-3p, and miR-206), and OS-R miRNAs (miR-21-5p, miR-31-5p, miR-128-3p, and miR-144-3p) levels were measured in ambulatory and non-ambulatory DMD patients. DystromiRs (except miR-1-3p) and miRNAs OS-R levels were lower (p-value <.05) in the non-ambulatory group than the ambulatory group. The expression of those miRNAs correlated with Vignos scale score (For instance, rho=-0.567, p-value <0.05 for miR-21-5p) and with other scales scores of muscle function and strength. CPK, AST, and ALT concentration correlated with expression of all miRNAs (For instance, rho=0.741, p-value <.05 between miR-206 level and AST concentration). MiR-21-5p level correlated with glucose concentration (rho=-0.369, p-value=.038), and the miR-1-3p level correlated with insulin concentration (rho=0.343, p-value=.05). Non-ambulatory DMD patients have lower circulating dystromiRs and OS-R miRNAs levels than ambulatory DMD patients. The progressive muscle injury is associated with a decrease in the expression of those miRNAs, evidencing DMD progress. These findings add new information about the natural history of DMD.

Non-ambulatory Duchenne muscular dystrophy: observations, interventions, and outcomes on a single case

Duchenne muscular dystrophy (DMD) is a X-linked recessive gene defect manifesting as a fatal, progressive neuromuscular disease. Treatment goals aim to inhibit disease progression, increase patients’ quality of life, and lengthen life expectancy. We report here a single case of non-ambulatory DMD.

The Black Box of Technological Outcome Measures: An Example in Duchenne Muscular Dystrophy.

Background:Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials.Objective:We assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation.Methods:Twenty-two non-ambulant DMD patients (range 8.6–24.1 years) and 14 healthy controls (HC; range 9.5–25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception.Results:Leap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (range p = 0.006 to <0.001). Reliability was low and the manufacturer’s hand model did not match the sensor’s depth images. ACTIVE differed between patients and HCs (p < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p = 0.030) with a standardized response mean (SRM) of –0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of –1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = –0.69).Conclusions:Only ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development.

Major Adverse Dystrophinopathy Event Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy

<h3>Purpose</h3> Accurate assessments of heart failure (HF) severity in Duchenne Muscular Dystrophy (DMD) is challenging due to overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy. We developed an ordinal scale of multiorgan clinical variables and events graded for severity that reflect cumulative disease burden-the <b>M</b>ajor <b>A</b>dverse <b>D</b>ystrophinopathy <b>E</b>vent <b>(MADE</b>) score. We hypothesized that a higher MADE score would be associated with increased mortality in DMD. We used the CINRG Duchenne Natural History Study (DNHS) dataset for MADE score validation. <h3>Methods</h3> DNHS variables were selected based on clinical relevance to prespecified MADE domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and serially. Ability of baseline MADE score to predict mortality that occurred during the DNHS was examined. <h3>Results</h3> DNHS enrolled 440 males, 12.6 ± 6.1 years old, followed for 3,559 study visits over 4.6 ± 2.8 years, with 45 deaths. MADE score increased with age and was higher in the nonambulatory cohort. Effect of Cardiac and Pulmonary domains on total Score over time doubled and tripled respectively for nonambulatory vs ambulatory cohorts (p<.001). Mean MADE score per visit was 19 ± 10 for those who died vs. 9.8 ± 9.3 in survivors p=0.03. A baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). A rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001<b>.</b> Figure <h3>Conclusion</h3> A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact HF in DMD. MADE score, independent of age, predicted DNHS mortality. MADE score can be used for serial HF assessment in nonambulatory DMD males and be optimized to serve as an endpoint for DMD clinical research.

Muscle-MRI and Functional Levels for the Evaluation of Upper Limbs in Duchenne Muscular Dystrophy: A Critical Review of the Literature.

Many qualitative and quantitative Magnetic Resonance Imaging (MRI) techniques have been applied to evaluate muscle fat degeneration in Duchenne muscular dystrophy (DMD) subjects, but only few studies have focused on the upper limbs. We reviewed the literature in order to evaluate the association between muscle MRI findings and motor function levels in the upper limbs of DMD patients. Ten studies with upper limb muscle MRI data were available. Four explored all upper limb segments, while six explored only the forearm. Functional assessments were performed in nine of the ten studies. All of the studies showed a significant correlation between muscle MRI changes and motor function levels in both ambulant and non-ambulant DMD patients.

Cessation of ambulation results in a dramatic loss of trabecular bone density in boys with Duchenne muscular dystrophy (DMD).

Glucocorticoids are currently used to improve muscle strength and prolong ambulation in boys with DMD although the effect on bone health is still unclear. The aim of this study was to compare bone strength in healthy children and boys with DMD and investigate the interaction between diminished muscle function, loss of ambulation and high dose oral steroids, over a two year time frame. Fifty children were studied, 14 healthy boys (HB), 13 boys with DMD who remained ambulant (DMD-RA) and 23 boys with DMD who lost ambulation (DMD-LA). All boys with DMD had taken oral glucocorticoids. Peripheral quantitative computed tomography was used to measure bone geometry, density, strength and muscle mass of the non-dominant tibia and radius. Measurements were made at baseline, 12 and 24months at the distal metaphysis and mid diaphysis sites. Differences between the three groups were evaluated using ANOVA and a repeated measures model. There were no significant differences in age between the groups: mean age was 9.4, 8.7 and 8.8years for HB, DMD-RA and DMD-LA, respectively. There was no significant difference in steroid exposure between the DMD groups. However, boys who lost ambulation had significantly lower muscle function at baseline (North Star Ambulatory Assessment DMD-RA 23.6 vs. DMD-LA 18.8; p<0.05). At baseline, healthy boys had significantly greater trabecular bone density at the distal radius /ulna (23%/27%) and distal tibia/fibula (30%/46%) than boys with DMD (p<0.05). They also had significantly larger diaphyseal tibiae/fibulae (74%/36%) and radii/ulnae (49%/31%) with thicker corticies and consequently greater bone strength. In contrast, boys with DMD had greater cortical density (4%). Over time, there were small significant differences in the rate of change of both muscle and bone parameters between healthy boys and boys with DMD. For both ambulant and non-ambulant boys with DMD the greatest changes in cortical bone were evident at the tibia. After two years boys with DMD had on average, 63% less bone strength than healthy boys. However, the most strikingly significant difference was in trabecular bone density for boys who became non-ambulant. By 2years non-ambulant DMD boys had 53% less trabecular bone density at distal tibia than their healthy age matched peers compared with boys who remained ambulant who had 27% less trabecular bone density. In conclusion, bone and muscle strength is reduced for all boys with DMD even while they remain ambulant. However, tibia trabecular bone density loss is significantly accelerated in DMD boys who lose independent ambulation compared to DMD boys who remain ambulant despite equivalent levels of corticosteroid exposure.

Longitudinal Motor Functional Outcomes and Magnetic Resonance Imaging Patterns of Muscle Involvement in Upper Limbs in Duchenne Muscular Dystrophy.

Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.

IMAGING: EP.336 Quantitative MRI, strength and function of the upper extremity flexor muscles in non-ambulant DMD patients: an 18 month follow-up analysis

Quantitative MRI (qMRI) of skeletal muscles is a promising method to objectively assess muscle involvement in Duchenne muscular dystrophy (DMD) and a potential outcome measure in clinical trials. qMRI data of the upper extremity (UE) muscles in non-ambulant DMD patients are limited. Therefore, we longitudinally assessed qMRI and UE functional outcome measures in this stage of the disease. 4-point Dixon MRI scans (3T) of the right upper arm, performance of the upper limb (PUL) version 2.0 and elbow flexion and grip strength were measured at baseline, 12 and 18 months follow-up.

Preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients.

BackgroundClinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non‐ambulant DMD patients, hand function is relatively preserved and crucial for daily‐life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non‐ambulant DMD patients.MethodsSeventeen non‐ambulant DMD patients (range 10.2–24.1 years) and 13 healthy controls (range 9.5–25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4‐point Dixon, and T2water was determined using multiecho spin‐echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non‐parametric tests.ResultsTotal volume was lower in patients compared with healthy controls (6.9 cm3, 5.3–9.0 cm3 vs. 13.0 cm3, 7.6–15.8 cm3, P = 0.010). CV was also lower in patients (6.3 cm3, 4.6–8.3 cm3 vs. 11.9 cm3, 6.9–14.6 cm3, P = 0.010). FF was slightly elevated (9.7%, 7.3–11.4% vs. 7.7%, 6.6–8.4%, P = 0.043), while T2water was higher (31.5 ms, 30.0–32.6 ms vs. 28.1 ms, 27.8–29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137–4.010 to 2.243 kg, 1.930–3.339 kg, and 29 points, 20–36 to 23 points, 17–30, both P < 0.001), while PROM did not (49 points, 36–57 to 44 points, 30–54, P = 0.041). All patients were able to play for 10 min at baseline or follow‐up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2water (rho = 0.57, rho = 0.51, and rho = −0.59).ConclusionsLow thenar FF, increased T2water, correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.

PMS61 Estimation of Health Utilities for NON-Ambulatory Duchenne Muscular Dystrophy (DMD) Patients and Their Caregivers

Duchenne muscular dystrophy (DMD) is a rare genetic disease in which muscle degeneration leads to loss of ambulation, assisted ventilation, and premature death. This study was designed to address evidence gaps regarding the health-related quality of life (HRQoL; utility) of non-ambulatory individuals with DMD and their caregivers. Health state (HS) vignettes were developed to describe five non-ambulatory DMD HS (1: forced vital capacity (FVC) ≥50%, no assisted ventilation, with hand to mouth function (HTMF); 2: same as 1 without HTMF; 3: FVC 30% - <50%; night-time assisted ventilation, with HTMF; 4: same as 3 without HTMF; 5: FVC <30%, full-time assisted ventilation, no HTMF). Five corresponding HS describing the caregivers HRQoL were also developed. Vignettes were developed via literature review, interviews with people with DMD, caregivers and healthcare professionals. Draft vignettes were revised following cognitive debriefing interviews. The final ten vignettes were valued by the UK general population using time trade-off (TTO) interviews with lead time trade-off for states considered worse than dead; visual analogue scale (VAS) ratings were also collected. The TTO was completed by 100 participants (age range: 19-74; mean age: 36; 54% Female; 81% white). Mean TTO values for the DMD HS ranged from 0.544 (HS1) to 0.075 (HS5). HTMF was valued as somewhat more detrimental to HRQoL than respiratory function, resulting in HS2 being valued lower (0.354) than HS3 (0.425). Caregiver mean utility values ranged from 0.639 (HS1) to 0.393 (HS5), decreasing in line with reduced respiratory function. For DMD and caregiver HS the mean VAS ratings followed the same patterns as the TTO values (45.50-20.17 and 51.59-32.80, respectively). The utility scores obtained in this study highlight the very substantial burden experienced by non-ambulatory individuals with DMD and their caregivers, and the benefit of treatments that can delay respiratory and HTMF decline.

Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy

HintergrundDie Muskeldystrophie Duchenne (DMD) ist die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.Ziel der Arbeit und Material und MethodenAuf der Grundlage aktueller Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main, Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt medikamentöse Therapien von Erwachsenen.Ergebnisse und DiskussionDer Verlust der Gehfähigkeit wird in Studien sehr unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den Patienten medikamentöse Therapien mit dem Ziel der Modifikation des Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen. Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um Expertenempfehlungen entsprechend der Evidenzklasse IV.

MUSCLE IMAGING – MRI: P.167 Last but not least: preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients

Hand function in Duchenne muscular dystrophy (DMD) is preserved relatively long, and is crucial for daily-life activities of non-ambulant patients such as operating a wheelchair. As a potential target for therapy, it is important to know to what extent intrinsic hand muscles are affected. We used quantitative MRI (qMRI) to study the relation between thenar muscle fat fraction (FF), total volume (TV), contractile volume (CV), T2 of muscle (T2water) and pinch strength. Seventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (HC; range 9.5-25.4 years) underwent qMRI of the right hand at 3T while positioned on their right side.