Lessons for future clinical trials in adults with Becker muscular dystrophy: Disease progression detected by muscle magnetic resonance imaging, clinical and patient-reported outcome measures.

BACKGROUND AND PURPOSE: Because Becker muscular dystrophy (BMD) is a heterogeneous disease and only few studies have evaluated adult patients, it is currently still unclear which outcome measures should be used in future clinical trials. METHODS: Muscle magnetic resonance imaging, patient-reported outcome measures and a wide range of clinical outcome measures, including motor function, muscle strength and timed-function tests, were evaluated in 21 adults with BMD at baseline and at 9 and 18 months of follow-up. RESULTS: Proton density fat fraction increased significantly in 10/17 thigh muscles after 9 months, and in all thigh and lower leg muscles after 18 months. The 32-item Motor Function Measurement (MFM-32) scale (-1.3%, p = 0.017), North Star Ambulatory Assessment (-1.3 points, p = 0.010) and patient-reported activity limitations scale (-0.3 logits, p = 0.018) deteriorated significantly after 9 months. The 6-min walk distance (-28.7 m, p = 0.042), 10-m walking test (-0.1 m/s, p = 0.032), time to climb four stairs test (-0.03 m/s, p = 0.028) and Biodex peak torque measurements of quadriceps (-4.6 N m, p = 0.014) and hamstrings (-5.0 N m, p = 0.019) additionally deteriorated significantly after 18 months. At this timepoint, domain 1 of the MFM-32 was the only clinical outcome measure with a large sensitivity to change (standardized response mean 1.15). DISCUSSION: It is concluded that proton density fat fraction imaging of entire thigh muscles is a sensitive outcome measure to track progressive muscle fat replacement in patients with BMD, already after 9 months of follow-up. Finally, significant changes are reported in a wide range of clinical and patient-reported outcome measures, of which the MFM-32 appeared to be the most sensitive to change in adults with BMD.

Neuromuscular hyperexcitability syndromes.

PURPOSE OF REVIEW: To provide an update on recent developments regarding acquired, antibody-mediated, neuromuscular hyperexcitability syndromes, including Isaac's and Morvan's syndromes, cramp-fasciculation syndrome and rippling muscle disease, and their genetic differential diagnoses. RECENT FINDINGS: Antibodies in auto-immune peripheral nerve hyperexcitability syndromes (PNHS) are directed against CASPR2 and LGI1, proteins of the voltage-gated potassium channel (VGKC) complex. We discuss the significance of 'double-negative' VGKC antibodies in PNHS and the rationale for ceasing VGKC antibody testing (but testing CASPR2 and LGI1 antibodies instead) in clinical practice. Recent case reports also expand the possible clinical phenotypes related to CASPR2/LGI1 antibodies, but the interpretation of these findings is complicated by the frequent association of antibody-mediated neuromuscular hyperexcitability syndromes with other auto-immune disorders (e.g. myasthenia gravis).Finally, a hereditary origin of neuromuscular hyperexcitability should always be considered, even in non-VGKC-related genes, as evidenced by the recently discovered high frequency of HINT1 mutations in people of Slavic origin. SUMMARY: This review provides an update on recent clinical, immunological and genetic developments in neuromuscular hyperexcitability syndromes. We also provide a guide for the clinician for diagnosing and managing these disorders in clinical practice, with a special focus on the main differential diagnoses.

Malignant hyperthermia: still an issue for neuromuscular diseases?

PURPOSE OF REVIEW: We will give an overview of neuromuscular disorders that can be linked with malignant hyperthermia or malignant hyperthermia-like reactions, and suggest an appropriate approach to interpret the risks. RECENT FINDINGS: An increasing number of neuromuscular phenotypes have been linked to malignant hyperthermia susceptibility (MHS). This is for an important part due to the highly variable phenotype associated with mutations in the ryanodine receptor 1 gene (RYR1), the gene most frequently associated with MHS. A RYR1-mutation or a clinical RYR1-phenotype does not automatically translate in MHS, but precautions should be taken nonetheless. In addition, several other genes and phenotypes are now considered to be associated with MHS. In contrast, several neuromuscular diseases that were long thought to be linked to MHS are now known to cause malignant hyperthermia-like reactions instead of malignant hyperthermia. This is highly relevant as not only the given preoperative advice differs, but also acute treatment. SUMMARY: This review provides a summary of current evidence linking certain neuromuscular diseases to malignant hyperthermia or malignant hyperthermia-like reactions. We provide a guide for the clinician, to determine which patients are at risk of malignant hyperthermia or malignant hyperthermia-like reactions perioperatively, and to ensure adequate treatment in case such a severe acute complication occurs.

Test-retest reliability and follow-up of muscle magnetic resonance elastography in adults with and without muscle diseases.

BACKGROUND: We investigated the potential of magnetic resonance elastography (MRE) stiffness measurements in skeletal muscles as an outcome measure, by determining its test-retest reliability, as well as its sensitivity to change in a longitudinal follow-up study. METHODS: We assessed test-retest reliability of muscle MRE in 20 subjects with (n = 5) and without (n = 15) muscle diseases and compared this to Dixon proton density fat fraction (PDFF) and volume measurements. Next, we measured MRE muscle stiffness in 21 adults with Becker muscular dystrophy (BMD) and 21 age-matched healthy controls at baseline, and after 9 and 18 months. We compared two different methods of analysing MRE data in this study: 'Method A' used the stiffness maps generated by the Philips MRE software, and 'Method B' applied a custom-made procedure based on wavelength measurements on the MRE images. RESULTS: Intraclass correlation coefficients (ICC) of muscle stiffness ranged from good (0.83 for left vastus medialis, P < 0.001) to poor (0.19 for right rectus femoris, P = 0.212) for the examined thigh muscles with Method A, but we did not find a significant test-retest reliability with Method B (P > 0.050 for all). The ICC of muscle PDFF and volume measurements was excellent (>0.90; P < 0.001) for all muscles. At baseline, the average stiffness of all thigh muscles was significantly lower in adults with BMD than in controls for both Method A (-0.2 kPa, P = 0.025) and Method B (-0.6 kPa, P < 0.001). Regardless of which method was used, there was no significant difference in the evolution of muscle stiffness in patients and controls over 18 months. CONCLUSIONS: Test-retest reliability of muscle MRE using a simple 2D technique was suboptimal, and did not reliably measure muscle stiffness changes in adults with BMD as compared with controls over 18 months. While the results provide motivation for testing more advanced 3D MRE methods, we conclude that the simple 2D MRE implementation used in this study is not suitable as an outcome measure for characterizing thigh muscle in clinical trials.

Automated MRI quantification of volumetric per-muscle fat fractions in the proximal leg of patients with muscular dystrophies.

Muscular dystrophies (MD) are a class of rare genetic diseases resulting in progressive muscle weakness affecting specific muscle groups, depending on the type of disease. Disease progression is characterized by the gradual replacement of muscle tissue by fat, which can be assessed with fat-sensitive magnetic resonance imaging (MRI) and objectively evaluated by quantifying the fat fraction percentage (FF%) per muscle. Volumetric quantification of fat replacement over the full 3D extent of each muscle is more precise and potentially more sensitive than 2D quantification in few selected slices only, but it requires an accurate 3D segmentation of each muscle individually, which is time consuming when this has to be performed manually for a large number of muscles. A reliable, largely automated approach for 3D muscle segmentation is thus needed to facilitate the adoption of fat fraction quantification as a measure of MD disease progression in clinical routine practice, but this is challenging due to the variable appearance of the images and the ambiguity in the discrimination of the contours of adjacent muscles, especially when the normal image contrast is affected and diminished by the fat replacement. To deal with these challenges, we used deep learning to train AI-models to segment the muscles in the proximal leg from knee to hip in Dixon MRI images of healthy subjects as well as patients with MD. We demonstrate state-of-the-art segmentation results of all 18 muscles individually in terms of overlap (Dice score, DSC) with the manual ground truth delineation for images of cases with low fat infiltration (mean overall FF%: 11.3%; mean DSC: 95.3% per image, 84.4-97.3% per muscle) as well as with medium and high fat infiltration (mean overall FF%: 44.3%; mean DSC: 89.0% per image, 70.8-94.5% per muscle). In addition, we demonstrate that the segmentation performance is largely invariant to the field of view of the MRI scan, is generalizable to patients with different types of MD and that the manual delineation effort to create the training set can be drastically reduced without significant loss of segmentation quality by delineating only a subset of the slices.

Histopathological correlations and fat replacement imaging patterns in recessive limb-girdle muscular dystrophy type 12.

BACKGROUND: Despite the widespread use of proton density fat fraction (PDFF) measurements with magnetic resonance imaging (MRI) to track disease progression in muscle disorders, it is still unclear how these findings relate to histopathological changes in muscle biopsies of patients with limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12). Furthermore, although it is known that LGMDR12 leads to a selective muscle involvement distinct from other muscular dystrophies, the spatial distribution of fat replacement within these muscles is unknown. METHODS: We included 27 adult patients with LGMDR12 and 27 age-matched and sex-matched healthy controls and acquired 6-point Dixon images of the thighs and T1 and short tau inversion recovery (STIR) MR images of the whole body. In 16 patients and 15 controls, we performed three muscle biopsies, one in the semimembranosus, vastus lateralis, and rectus femoris muscles, which are severely, intermediately, and mildly affected in LGMDR12, respectively. We correlated the PDFF to the fat percentage measured on biopsies of the corresponding muscles, as well as to the Rochester histopathology grading scale. RESULTS: In patients, we demonstrated a strong correlation of PDFF on MRI and muscle biopsy fat percentage for the semimembranosus (r = 0.85, P < 0.001) and vastus lateralis (r = 0.68, P = 0.005). We found similar results for the correlation between PDFF and the Rochester histopathology grading scale. Out of the five patients with inflammatory changes on muscle biopsy, three showed STIR hyperintensities in the corresponding muscle on MRI. By modelling the PDFF on MRI for 18 thigh muscles from origin to insertion, we observed a significantly inhomogeneous proximo-distal distribution of fat replacement in all thigh muscles of patients with LGMDR12 (P < 0.001), and different patterns of fat replacement within each of the muscles. CONCLUSIONS: We showed a strong correlation of fat fraction on MRI and fat percentage on muscle biopsy for diseased muscles and validated the use of Dixon fat fraction imaging as an outcome measure in LGMDR12. The inhomogeneous fat replacement within thigh muscles on imaging underlines the risk of analysing only samples of muscles instead of the entire muscles, which has important implications for clinical trials.

Biochemical and clinical biomarkers in adult SMA 3-4 patients treated with nusinersen for 22 months.

OBJECTIVE: To investigate biomarkers of disease progression in cerebrospinal fluid (CSF) and serum in adult patients with spinal muscular atrophy (SMA). Furthermore, we assess the clinical response to nusinersen treatment in adults with SMA over a longer follow-up period than the previously reported 6-14 months. METHODS: We included 16 adults with SMA type 3-4 for nusinersen treatment over 22 months in this prospective study. We evaluated chitotriosidase-1 (CHIT1) and chitinase-3-like protein 1 (YKL-40) as neuroinflammatory biomarkers in CSF, and neurofilament light chain (NfL) and heavy chain (pNfH) as neurodegenerative markers in CSF and serum at baseline, month 6, 14 and 22, together with a wide range of clinical outcome measures. RESULTS: Levels of CHIT1 increased significantly (p = 0.048) throughout the 22-month treatment period and pNfH decreased significantly (p = 0.022) in CSF, but both did not correlate with clinical outcome measures. YKL-40 correlated strongly with neurofilaments in CSF (rho = 0.76) and decreased significantly (p = 0.037) in patients with improvements in the revised upper limb module (RULM). Finally, patients showed significant improvements in hand grip strength, hand motor function, medical research council (MRC) sum score, and peak expiratory flow (PEF) after 22 months of treatment. INTERPRETATION: YKL-40 in CSF correlated with clinical improvements during nusinersen treatment. In contrast, CHIT1 and pNfH in CSF changed significantly during treatment but did not correlate with clinical outcomes. Finally, we demonstrated a sustained clinical effect of nusinersen treatment in adults after 22 months.

Prospective Natural History Study in 24 Adult Patients With LGMDR12 Over 2 Years of Follow-up: Quantitative MRI and Clinical Outcome Measures.

BACKGROUND AND OBJECTIVES: Limb-girdle muscular dystrophy autosomal recessive type 12 (LGMDR12) is a rare hereditary muscular dystrophy for which outcome measures are currently lacking. We evaluated quantitative MRI and clinical outcome measures to track disease progression to determine which tests could be useful in future clinical trials to evaluate potential therapies. METHODS: We prospectively measured the following outcome measures in all participants at baseline and after 1 and 2 years: 6-minute walk distance (6MWD), 10-meter walk test (10MWT), the Medical Research Council (MRC) sum scores, Biodex isometric dynamometry, serum creatine kinase, and 6-point Dixon MRI of the thighs. RESULTS: We included 24 genetically confirmed, adult patients with LGMDR12 and 24 age-matched and sex-matched healthy controls. Patients with intermediate-stage thigh muscle fat replacement at baseline (proton density fat fraction [PDFF] 20%-70%) already showed an increase in PDFF in 8 of the 14 evaluated thigh muscles after 1 year. The standardized response mean demonstrated a high responsiveness to change in PDFF for 6 individual muscles over 2 years in this group. However, in patients with early-stage (<20%) or end-stage (>70%) muscle fat replacement, PDFF did not increase significantly over 2 years of follow-up. Biodex isometric dynamometry showed a significant decrease in muscle strength in all patients in the right and left hamstrings (-6.2 Nm, p < 0.002 and -4.6 Nm, p < 0.009, respectively) and right quadriceps muscles (-9 Nm, p = 0.044) after 1 year of follow-up, whereas the 6MWD, 10MWT, and MRC sum scores were not able to detect a significant decrease in muscle function/strength even after 2 years. There was a moderately strong correlation between total thigh PDFF and clinical outcome measures at baseline. DISCUSSION: Thigh muscle PDFF imaging is a sensitive outcome measure to track progressive muscle fat replacement in selected patients with LGMDR12 even after 1 year of follow-up and correlates with clinical outcome measures. Biodex isometric dynamometry can reliably capture the loss of muscle strength over the course of 1 year in patients with LGMDR12 and should be included as an outcome measure in future clinical trials as well.

Respiratory decline in adult patients with Becker muscular dystrophy: A longitudinal study.

Becker muscular dystrophy (BMD) is a rare hereditary neuromuscular disease, caused by a genetic defect in the Duchenne Muscular Dystrophy (DMD) gene. We studied the natural history of respiratory function and its affecting factors in 23 adult BMD patients. These important data are needed for (future) clinical trials in BMD but are largely lacking. Patients had a median age of 51 years (28-78y) and median follow-up duration of 14 years (2-25y). We analysed 190 pulmonary function measurements with a median interval of one year (1-17y) and measured a 1.00% decline of Forced Vital Capacity percent predicted (FVC%pred) per year (p = 0.004). Loss of ambulation significantly increased the annual rate of FVC decline and was dependent of patient's body mass index (BMI; p = 0.015), with increases in BMI correlating with an even more rapid deterioration of FVC. A decline in Medical Research Council (MRC) sum score was significantly correlated with a decline in FVC (p = 0.003). We conclude that adult BMD patients experience a significant but mild respiratory decline. However, this decline is significantly more rapid and clinically relevant after loss of ambulation, which warrants a more vigilant follow-up of respiratory function in this subgroup.

Nusinersen treatment significantly improves hand grip strength, hand motor function and MRC sum scores in adult patients with spinal muscular atrophy types 3 and 4.

BACKGROUND: Nusinersen recently became available as the first treatment for Spinal Muscular Atrophy (SMA) and data on its effectiveness and safety in adult SMA patients are still scarce. METHODS: We evaluated the effectiveness and safety of nusinersen treatment during 14 months in 16 adult patients with SMA types 3 and 4 in a prospective study, and retrospectively detailed the natural history of 48 adult SMA patients types 2, 3 and 4. RESULTS: Hand grip strength (p = 0.03), hand motor function (p = 0.04) as assessed by a sub-score of the Revised Upper Limb Module (RULM) and the Medical Research Council (MRC) sum score (p = 0.04) improved significantly at month 14. Importantly, the MRC sum score had declined significantly (p < 0.01) prior to start of treatment in these patients. A minimal clinically important difference (MCID) in the Hammersmith Functional Motor Scale Expanded (HFMSE) and RULM scores was achieved in 31% and 50% of the patients, respectively, but the mean changes from baseline failed to reach significance. Forced Vital Capacity (FVC) transiently increased at month 6 (p = 0.01), whereas the Peak Expiratory Flow (PEF) did not. The Activity Limitations scale declined significantly prior to start of treatment (p < 0.01) and showed an improvement with nusinersen which was not significant. The safety evaluation did not reveal serious adverse events and no signs of nephrotoxicity or antisense oligonucleotide (ASO)-mediated inflammation. CONCLUSIONS: We conclude that hand grip strength and hand motor function, as well as MRC sum scores improved significantly in nusinersen-treated adult patients with SMA types 3 and 4.