Improving outcome measures in late onset Pompe disease: Modified Rasch-Built Pompe-Specific Activity scale.

BACKGROUND AND PURPOSE: The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries. METHODS: Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis. RESULTS: Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct. CONCLUSIONS: After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries.

Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study.

Background: Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties. Methods: The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry). Results: Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity. Conclusion: Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.

Smartphone-Based Assessment of Mobility and Manual Dexterity in Adult People with Spinal Muscular Atrophy.

Background: More responsive, reliable, and clinically valid endpoints of disability are essential to reduce size, duration, and burden of clinical trials in adult persons with spinal muscular atrophy (aPwSMA). Objective: The aim is to investigate the feasibility of smartphone-based assessments in aPwSMA and provide evidence on the reliability and construct validity of sensor-derived measures (SDMs) of mobility and manual dexterity collected remotely in aPwSMA. Methods: Data were collected from 59 aPwSMA (23 walkers, 20 sitters and 16 non-sitters) and 30 age-matched healthy controls (HC). SDMs were extracted from five smartphone-based tests capturing mobility and manual dexterity, which were administered in-clinic and remotely in daily life for four weeks. Reliability (Intraclass Correlation Coefficients, ICC) and construct validity (ability to discriminate between HC and aPwSMA and correlations with Revised Upper Limb Module, RULM and Hammersmith Functional Scale - Expanded HFMSE) were quantified for all SDMs. Results: The smartphone-based assessments proved feasible, with 92.1% average adherence in aPwSMA. The SDMs allowed to reliably assess both mobility and dexterity (ICC > 0.75 for 14/22 SDMs). Twenty-one out of 22 SDMs significantly discriminated between HC and aPwSMA. The highest correlations with the RULM were observed for SDMs from the manual dexterity tests in both non-sitters (Typing, ρ= 0.78) and sitters (Pinching, ρ= 0.75). In walkers, the highest correlation was between mobility tests and HFMSE (5 U-Turns, ρ= 0.79). Conclusions: This exploratory study provides preliminary evidence for the usability of smartphone-based assessments of mobility and manual dexterity in aPwSMA when deployed remotely in participants' daily life. Reliability and construct validity of SDMs remotely collected in real-life was demonstrated, which is a pre-requisite for their use in longitudinal trials. Additionally, three novel smartphone-based performance outcome assessments were successfully established for aPwSMA. Upon further validation of responsiveness to interventions, this technology holds potential to increase the efficiency of clinical trials in aPwSMA.

Start, switch and stop (triple-S) criteria for enzyme replacement therapy of late-onset Pompe disease: European Pompe Consortium recommendation update 2024.

BACKGROUND AND PURPOSE: Two novel enzyme replacement therapies (ERTs), studied in phase 3 trials in late-onset Pompe patients, reached marketing authorization by the European Medicines Agency in 2022 and 2023. The European Pompe Consortium (EPOC) updates and extends the scope of the 2017 recommendations for starting, switching and stopping ERT. METHODS: The European Pompe Consortium consists of 25 neuromuscular and metabolic experts from eight European countries. This update was performed after an in-person meeting, three rounds of discussion and voting to provide a consensus recommendation. RESULTS: The patient should be symptomatic, that is, should have skeletal muscle weakness or respiratory muscle involvement. Muscle magnetic resonance imaging findings showing substantial fat replacement can support the decision to start in a patient-by-patient scenario. Limited evidence supports switching ERT if there is no indication that skeletal muscle and/or respiratory function have stabilized or improved during standard ERT of 12 months or after severe infusion-associated reactions. Switching of ERT should be discussed on a patient-by-patient shared-decision basis. If there are severe, unmanageable infusion-associated reactions and no stabilization in skeletal muscle function during the first 2 years after starting or switching treatment, stopping ERT should be considered. After stopping ERT for inefficacy, restarting ERT can be considered. Six-monthly European Pompe Consortium muscle function assessments are recommended. CONCLUSIONS: The triple-S criteria on ERT start, switch and stop include muscle magnetic resonance imaging as a supportive finding and the potential option of home infusion therapy. Six-monthly long-term monitoring of muscle function is highly recommended to cover insights into the patient's trajectory under ERT.

Suitability of the Respicheck questionnaire and Epworth sleepiness scale for therapy monitoring in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is an autosomal dominant trinucleotide disorder that often leads to respiratory dysfunction resulting in hypoventilation symptoms, reduced quality of life and causing premature death if untreated. To early identify symptoms of hypoventilation, the Respicheck questionnaire was developed as a screening tool. Symptomatic therapies like inspiratory muscle training (IMT) are recommended to strengthen respiratory muscles and reduce or even prevent hypoventilation symptoms. Our study aimed to evaluate the Respicheck questionnaire's suitablility to monitor the efficacy of IMT. Patients with genetically confirmed DM1 were randomly assigned to either IMT - endurance or strength training, or control group. At baseline, end of study and four interim visits, pulmonary function tests, Respicheck questionnaire and Epworth sleepiness scale were assessed. While patients in training groups achieved a substantial improvement after nine months of regular IMT in pulmonary function tests, the Respicheck score did not improve likewise. Similarly, the ESS score did not change significantly in both training and control groups. Consequently, we conclude that either improvement of respiratory function is not necessarily associated with clinical improvement, or respiratory muscle weakness was not the only reason for hypoventilation syndrome, or both questionnaires are not sensitive enough to detect slight clinical changes.

Evaluation of myotonometry for myotonia, muscle stiffness and elasticity in neuromuscular disorders.

Neuromuscular disorders show extremely varied expressions of different symptoms and the involvement of muscles. Non-invasively, myotonia and muscle stiffness are challenging to measure objectively. Our study aims to test myotonia, elasticity, and stiffness in various neuromuscular diseases and to provide reference values for different neuromuscular disease groups using a novel handheld non-invasive myometer device MyotonPRO®. We conducted a monocentric blinded cross-sectional study in patients with a set of distinct neuromuscular diseases (NCT04411732, date of registration June 2, 2020). Fifty-two patients in five groups and 21 healthy subjects were enrolled. We evaluated motor function (6-min walk test, handheld dynamometry, Medical Research Council (MRC) Scale) and used ultrasound imaging to assess muscle tissue (Heckmatt scale). We measured muscle stiffness, frequency, decrement, creep, or relaxation using myotonometry with the device MyotonPRO®. Statistically, all values were calculated using the t test and Mann-Whitney U test. No differences were found in comparing the results of myotonometry between healthy and diseased probands. Furthermore, we did not find significant results in all five disease groups regarding myotonometry correlating with muscle strength or ultrasound imaging results. In summary, the myometer MyotonPRO® could not identify significant differences between healthy individuals and neuromuscular patients in our patient collective. Additionally, this device could not distinguish between the five different groups of disorders displaying increased stiffness or decreased muscle tone due to muscle atrophy. In contrast, classic standard muscle tests could clearly decipher healthy controls and neuromuscular patients.

Prediction of respiratory impairment in myotonic dystrophies using the 'Respiratory involvement symptom checklist' (Respicheck).

Chronic hypoventilation due to involvement of respiratory muscles is a frequent symptom in autosomal dominant inherited myotonic dystrophies, especially in type 1 (DM1), leading to a severely reduced quality of life, an early need for ventilatory support, or premature death. Thus, early knowledge of respiratory muscle weakness is essential to initiate further diagnostic and therapeutic measures. To get early, simple, and reliable information about respiratory impairment in DM patients, we performed a prospective controlled cohort study with DM1 and DM2 patients analysing the suitability of 'Respiratory involvement symptom checklist (Respicheck) as a clinically meaningful screening questionnaire for ventilatory impairment in patients with DM1 or DM2. Clinical assessments included a one-time pulmonary function test (spirometry and manometry) and the completion of the Respicheck. 172 participants were enrolled in this study (74 DM1, 72 DM2, 26 healthy controls). With a cut-off RespicheckCAT score of 4, the Respicheck can distinguish between patients with and without respiratory impairment with higher sensitivity and positive predictive value for DM1 than DM2 patients (DM1: sensitivity 77-87; positive predictive value 50-94%; DM2: sensitivity 67-80%; positive predictive value 14-38). In summary, our results confirm a clinically meaningful use of the Respicheck to detect respiratory impairments predominantly in DM1 patients.

Nociceptive pain in adult patients with 5q-spinal muscular atrophy type 3: a cross-sectional clinical study.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN gene, leading to progressive muscular weakness, atrophy and so far neglected musculoskeletal pain. This study is the first to characterize nociceptive pain in patients living with SMA type 3 by assessing whether muscle pain is associated with alterations in muscle strength, function, stiffness, frequency, decrement, relaxation, or creep. METHODS: We performed a cross-sectional pilot study on 20 SMA3 patients. We evaluated motor function and muscle strength (dynamometry, quick motor function test and 6-min-walk test), nociceptive pain (pressure algometer evaluating muscular pressure pain threshold (PPT)) and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, or creep (myotonometry with the MyotonPro®). For statistical analysis, we used t tests, Mann-Whitney U tests and linear regression. RESULTS: Significantly more women than men reported musculoskeletal pain (p = 0.003). A lower score in dynamometry was associated with lower scores in PPT in all extremities reflecting a higher sensitivity of these muscles to pressure. We did not find significant correlations between the PPT values and the MyotonPro values in the corresponding muscles. Assessments of PPT before and after the 6-min walk test did not show clinical meaningful changes. Besides nociceptive pain, fatigue was prevalent in 50% and pain in 55% of the patients. CONCLUSIONS: Muscle pain in SMA3 is associated with muscular weakness in the arms and legs, but not with changes in muscular stiffness, frequency, decrement, relaxation, or creep. This shows that muscle pain in SMA3 is mainly caused by changes in the dysbalanced musculoskeletal system due to muscle weakness.

Hypoventilation syndrome in neuromuscular disorders.

PURPOSE OF REVIEW: Hypoventilation syndrome in neuromuscular disorders (NMDs) is primarily due to respiratory muscle weakness and results in increased morbidity and mortality. This article highlights current aspects of neuromuscular hypoventilation syndrome, including pathophysiology, clinical symptoms, assessment, respiratory involvement in various NMD, and causal and symptomatic treatments with an emphasis on recent research and advances. RECENT FINDINGS AND SUMMARY: New therapeutic agents have been developed within the last years, proving a positive effect on respiratory system. Symptomatic therapies, including mechanical ventilation and cough assistance approaches, are important in NMD and respiratory muscle training may have benefit in strengthening respiratory muscles and should be offered patients with respiratory muscle weakness the same way as physiotherapy. Correct respiratory assessments and their correct interpretation are hallmarks for early diagnosis of hypoventilation syndrome and treatment.