Whole‐body magnetic resonance imaging evaluation of facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary disorder that causes progressive muscle wasting. Increasing knowledge of the pathophysiology of FSHD has stimulated interest in developing biomarkers of disease severity. Methods: Two groups of MRI scans were analyzed: whole‐body scans from 13 subjects with FSHD; and upper and lower extremity scans from 34 subjects with FSHD who participated in the MYO‐029 clinical trial. Muscles were scored for fat infiltration and edema‐like changes. Fat infiltration scores were compared with muscle strength and function. Results: The analysis revealed a distinctive pattern of both frequent muscle involvement and frequent sparing in FSHD. Averaged fat infiltration scores for muscle groups in the legs correlated with quantitative muscle strength and 10‐meter walk times. Conclusions: Advances in MRI technology allow for acquisition of rapid, high‐quality, whole‐body imaging in diffuse muscle disease. This technique offers a promising disease biomarker in FSHD and other muscle diseases. Muscle Nerve 52: 512–520, 2015     

MRI change metrics of facioscapulohumeral muscular dystrophy: Stir and T1

Introduction: MRI evaluation in facioscapulohumeral muscular dystrophy (FSHD) demonstrates fatty replacement and inflammation/edema in muscle. Our previous work demonstrated short T1 inversion recovery (STIR)‐hyperintense (STIR+) signal in muscle 2 years before fatty replacement. We evaluated leg muscle STIR changes and fatty replacement within 14 months. Methods: FSHD subjects received 2 MRI scans of thigh and calf over a 6.9‐ to 13.8‐month interval. Quality of life measures were collected. One Radiologist rated muscle changes on a semi‐quantitative scale. Results: Fifteen subjects completed longitudinal imaging. Four STIR + muscles and 3 STIR‐normal (STIR?) muscles were rated as progressing to fatty tissue over the study period. Discussion: STIR + muscles with confluent regions of fat at baseline increased more in fat, while STIR? muscles had increases in septal‐fat over the study period. These changes may reflect two phases of FSHD, demonstrating MRI sensitivity is weighted toward gross pathological phases of the disease. Muscle Nerve 57 : 905–912, 2018     

The magnetic resonance imaging spectrum of facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is associated with a repeat contraction in the D4Z4 gene locus on chromosome 4q35. We used a one‐step quantitative magnetic resonance imaging (MRI) method to evaluate muscle, edema, and fat in patients spanning the range of severity. Methods: Fifteen patients with FSHD were compared with 10 healthy subjects using non‐negative linear least‐squares fitting of 32‐echo relaxation data (T2). The results were compared with a biexponential approach for characterizing muscle/fat ratio and T2 relaxation measurements from fat‐suppressed inversion recovery. Results: Increased T2 signal consistent with edema was common in FSHD subjects, a pattern not present in healthy controls. A varied pattern of edema and fatty replacement in muscles was shown. Conclusions: As a discrete biomarker, edema may be useful for following the clinical course of FSHD. Future work toward optimizing measurement is discussed. Muscle Nerve, 2012     

Quantitative ultrasound of the tongue and submental muscles in children and young adults

Introduction: The purpose of this study was to assess the feasibility of quantitative muscle ultrasound (QMUS) to visualize oral muscles and to establish normative data for muscle thickness and echo intensity of submental and tongue muscles in healthy children and young adults. The data were compared with those of 5 patients with Duchenne muscular dystrophy (DMD). Methods: Ultrasound images from the suprahyoid region and from the surface of the tongue were made in 53 healthy subjects aged 5 to 30 years. Results: All measurements were feasible in all subjects and patients with good reproducibility except for the mylohyoid muscle. Muscle thickness depended on height, and echo intensity depended on weight. Our findings suggest gradual involvement of oral muscles in DMD. Conclusions: QMUS in oral muscles is feasible in healthy children, adults and patients with DMD. These data show that it is possible to differentiate between healthy persons and patients with DMD. Muscle Nerve 46:31–37, 2012     

Quantitative muscle ultrasonography in the follow‐up of juvenile dermatomyositis

Introduction: We explored the use of quantitative muscle ultrasonography (QMUS) for follow‐up of juvenile dermatomyositis (JDM). Methods: Seven JDM patients were evaluated at diagnosis and 1, 3, 6, 12, and 24 months using the Childhood Myositis Assessment Scale (CMAS) and QMUS. Muscle thickness (MT) and quantitative muscle echo intensity (EI) were assessed with QMUS in 4 muscles. Results: Six patients experienced a monocyclic course. At diagnosis EI was slightly increased, and MT was relatively normal. After start of treatment MT first decreased and EI increased, with normalization of EI within 6–12 months (n = 4). One patient had higher EIs at diagnosis and slower normalization, indicating fibrosis, despite early normalization of CMAS. One patient experienced a chronic course, with high EIs and atrophy during follow‐up. Conclusions: QMUS can provide additional information for follow‐up of JDM regarding disease severity and residual muscle damage, particularly after normalization of CMAS. Muscle Nerve 52: 540–546, 2015     

Muscle pathology grade for facioscapulohumeral muscular dystrophy biopsies

Introduction: As we move toward planning for clinical trials in facioscapulohumeral muscular dystrophy (FSHD), a better understanding of the clinical relationship with morphological changes in FSHD muscle biopsies will be important for stratifying patients and understanding post‐therapeutic changes in muscle. Methods: We performed a prospective cross‐sectional study of quadriceps muscle biopsies in 74 genetically confirmed FSHD participants (64 with FSHD type 1 and 10 with FSHD type 2). We compared a 12‐point muscle pathology grade to genetic mutation, disease severity score, and quantitative myometry. Results: Pathology grade had moderate correlations with genetic mutation (rho = –0.45, P < 0.001), clinical severity score (rho = 0.53, P < 0.001), disease duration (rho = 0.31, P = 0.03), and quantitative myometry (rho = –0.47, P < 0.001). We found no difference in the frequency of inflammation between FSHD types 1 and 2. Conclusions: The pathology grade of quadriceps muscle may be a useful marker of disease activity in FSHD, and it may have a role in stratification for future clinical trials. Muscle Nerve 52: 521–526, 2015     

Longitudinal features of stir bright signal in FSHD1

Introduction: Magnetic resonance imaging of muscle shows short tau‐inversion recovery (STIR) brightness in autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1) suggestive of active inflammation/injury. We measured the longitudinal stability/progression of this potential disease biomarker. Methods: Nine subjects underwent calf MRI imaging over 2 years. Two radiologists evaluated qualitative muscle changes. Results: In 3/9 subjects, calf muscles demonstrated moderate/severe STIR hyperintensity at Time 1 that had progressed to fatty replacement 2 years later (Time 2). In the remaining subjects, moderate/severe muscle STIR abnormalities, when present, were consistent between exams. Mild STIR+ elevations had roughly similar patterns between exams. Conclusions: Moderate/severe STIR hyperintensities often foreshadow fatty replacement over a 2‐year interval. Whether longer time courses are required to observe muscle degeneration and fatty replacement in some subjects remains to be explored. Muscle Nerve 49 : 257–260, 2014     

Multivoxel proton magnetic resonance spectroscopy in facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary disorder that causes progressive muscle wasting. This study evaluates the use of proton magnetic resonance spectroscopy (¹H MRS) as a biomarker of muscle strength and function in FSHD. Methods: Thirty‐six individuals with FSHD and 15 healthy controls underwent multivoxel ¹H MRS of a cross‐section of the mid‐thigh. Concentrations of creatine, intramyocellular and extramyocellular lipids, and trimethylamine (TMA)‐containing compounds in skeletal muscle were calculated. Metabolite concentrations for individuals with FSHD were compared with those of controls. The relationship between metabolite concentrations and muscle strength was also examined. Results: The TMA/creatine (Cr) ratio in individuals with FSHD was reduced compared with controls. The TMA/Cr ratio in the hamstrings also showed a moderate linear correlation with muscle strength. Discussion: ¹H MRS offers a potential method of detecting early muscle pathology in FSHD prior to the development of fat infiltration. Muscle Nerve 57 : 958–963, 2018     

Longitudinal 2‐point dixon muscle magnetic resonance imaging in becker muscular dystrophy

Introduction: Quantitative MRI techniques detect disease progression in myopathies more sensitively than muscle function measures or conventional MRI. To date, only conventional MRI data using visual rating scales are available for measurement of disease progression in Becker muscular dystrophy (BMD). Methods: In 3 patients with BMD (mean age 36.8 years), the mean fat fraction (MFF) of the thigh muscles was assessed by MRI at baseline and at 1‐year follow‐up using a 2‐point Dixon approach (2PD). The motor function measurement scale (MFM) was used for clinical assessment. Results: The mean MFF of all muscles at baseline was 61.6% (SD 7.6). It increased by 3.7% to 65.3% (SD 4.7) at follow‐up. The severity of muscle involvement varied between various muscle groups. Conclusions: As in other myopathies, 2PD can quantify fatty muscle degeneration in BMD and can detect disease progression in a small sample size and at relatively short imaging intervals. Muscle Nerve 51 : 918–921, 2015     

Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy

The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD).Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired from seven FSHD patients and healthy volunteers. Signal decay in the multiecho MR images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue and used to calculate the degree of fatty infiltration in eight muscles in the lower leg.Considerable differences in fatty infiltration between different muscles were observed in FSHD patients, suggesting that this could be used as a biomarker for disease progression. TIRM imaging indicated an inflammatory component of the disease previously only observed in muscle biopsies. Typically, muscle involvement was non-uniform even within one muscle, indicating that MRI can be used as a valuable tool to study pathophysiology and therapy evaluation in FSHD.     

MRI as outcome measure in facioscapulohumeral muscular dystrophy: 1-year follow-up of 45 patients

There is no effective treatment available for facioscapulohumeral muscular dystrophy type 1 (FSHD1), but emerging therapies are under way that call for a better understanding of natural history in this condition. In this prospective, longitudinal study, we used quantitative MRI to assess yearly disease progression in patients with FSHD1. Ambulatory patients with confirmed diagnosis of FSHD1 (25/20 men/women, age 20–75 years, FSHD score: 0–12) were tested with 359–560-day interval between tests. Using the MRI Dixon technique, muscle fat replacement was evaluated in paraspinal, thigh, and calf muscles. Changes were compared with those in FSHD score, muscle strength (hand-held dynamometry), 6-minute-walk-distance, 14-step-stair-test, and 5-time-sit-to-stand-test. Composite absolute fat fraction of all assessed muscles increased by 0.036 (CI 0.026–0.046, P < 0.001), with increases in all measured muscle groups. The clinical severity FSHD score worsened (10%, P < 0.05), muscle strength decreased over the hip (8%), neck (8%), and back (17%) (P < 0.05), but other strength measures, 6-minute-walk-distance, 5-times-sit-to-stand-test, and 14-step-stair-test were unchanged. Changes in muscle strength, FSHD score, and fat fraction did not correlate. This first study to systemically monitor quantitative fat replacement longitudinally in FSHD1 shows that MRI provides an objective measure of disease progression, often before changes can be appreciated in strength and functional tests. The study indicates that quantitative MRI can be a helpful end-point in follow-up and therapeutic trials of patients with FSHD1.     

Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1‐year follow‐up study

Introduction: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD). Methods: Thirty‐two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year. Results: There were no significant changes in the EIM variables. Although 50‐kHZ reactance correlated the strongest with clinical measures at baseline, the 50–211‐kHZ phase ratio demonstrated lower within‐subject 12‐month variability, potentially offering sample size savings for FSHD clinical trial planning. Discussion: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58 : 213–218, 2018     

An instrumented timed up and go in facioscapulohumeral muscular dystrophy

Introduction: Instrumenting timed functional motor tasks may reveal a continuum of motor disability that predicts future motor dysfunction. Methods: We performed a prospective study of the instrumented timed up and go (iTUG) test in genetically confirmed facioscapulohumeral muscular dystrophy (FSHD) participants using a commercially available system of wireless motion sensors. Patients returned within 2 weeks to determine test–retest reliability. Gait parameters in FSHD participants were compared with a normative database, FSHD clinical severity score, manual muscle testing, and patient‐reported functional disability. Results: Gait parameters in FSHD participants were significantly (P < 0.05) altered compared with normative values, and reliability was excellent (intraclass correlation coefficient 0.84–0.99). Stride velocity and trunk sagittal range of motion had moderate to strong correlations to other FSHD disease measures. Discussion: The iTUG was reliable, abnormal in FSHD, and could distinguish between participants with differing disease severities. Instrumenting timed functional tasks may prove to be useful in FSHD clinical trials. Muscle Nerve 57 : 503–506, 2018     

Pattern of skeletal muscle involvement in primary dysferlinopathies: a whole‐body 3.0‐T magnetic resonance imaging study

Objectives and methods – Mutations in the gene encoding dysferlin cause limb girdle muscular dystrophy type 2B (LGMD2B), distal Miyoshi myopathy (MM), and a rare form of distal anterior compartment myopathy. To study the correlations between clinical manifestations and muscle imaging changes we conducted a 3.0‐T magnetic resonance imaging (MRI) study in six German patients with primary dysferlinopathies defined by absence of dysferlin expression in muscle (MM, n = 3; LGMD2B, n = 2; hyperCKemia without clinical symptoms, n = 1). Results – Patients with manifest myopathy had widespread muscular pathology. In analogy to previous imaging studies, we confirmed an involvement of the anterior and posterior thigh compartments and a predominant involvement of posterior lower legs. However, our whole‐body MRI study further provided evidence of signal alterations in the glutei, erector spinae and shoulder girdle muscles. Correlation of clinical findings with imaging demonstrated the potential of MRI to detect subclinical muscle pathology. Conclusions – Whole‐body 3.0‐T MRI is a non‐invasive method to demonstrate various degrees of skeletal muscle alterations and disease progression in muscular dystrophies. Furthermore, whole‐body high‐field MRI may serve as a helpful diagnostic tool in differentiating primary dysferlinopathies from other forms of LGMD and distal myopathies.     

Restrictive lung involvement in facioscapulohumeral muscular dystrophy

Introduction: Few studies have evaluated the frequency or predisposing factors for respiratory involvement in facioscapulohumeral muscular dystrophy type 1 (FSHD1) and type 2 (FSHD2). Methods: We performed a prospective cross‐sectional observational study of 61 genetically confirmed FSHD participants (53 FSHD1 and 8 FSHD2). Participants underwent bedside pulmonary function testing in sitting and supine positions, a standard clinical history and physical assessment, and manual muscle testing. Results: Restrictive respiratory involvement was suggested in 9.8% (95% confidence interval 2.4–17.3): 7.5% FSHD1 and 25.0% FSHD2 (P = 0.17). Participants with testing suggestive of restrictive lung involvement (n = 6) were more severely affected (P = 0.005), had weaker hip flexion (P = 0.0007), and were more likely to use a wheelchair (P = 0.01). Conclusions: Restrictive respiratory involvement should be considered in all moderate to severely affected FSHD patients with proximal lower extremity weakness. The higher frequency of restrictive lung disease in FSHD2 seen here requires confirmation in a larger cohort of FSHD2 patients. Muscle Nerve 50 : 739–743, 2014     

LAMA2‐related myopathy: Frequency among congenital and limb‐girdle muscular dystrophies

Introduction: Muscular dystrophy caused by LAMA2‐gene mutations is an autosomal recessive disease typically presenting as a severe, early‐onset congenital muscular dystrophy (CMD). However, milder cases with a limb‐girdle type muscular dystrophy (LGMD) have been described. Methods: In this study, we assessed the frequency and phenotypic spectrum of LAMA2‐related muscular dystrophy in CMD (n = 18) and LGMD2 (n = 128) cohorts identified in the last 15 years in eastern Denmark. The medical history, brain‐MRI, muscle pathology, muscle laminin‐α2 expression, and genetic analyses were assessed. Results: Molecular genetics revealed 2 pathogenic LAMA2 mutations in 5 of 18 CMD and 3 of 128 LGMD patients, corresponding to a LAMA2‐mutation frequency of 28% in the CMD and 2.3% in the LGMD cohorts, respectively. Conclusions: This study demonstrates a wide clinical spectrum of LAMA2‐related muscular dystrophy and its prevalence in an LGMD2 cohort, which indicates that LAMA2 muscular dystrophy should be included in the LGMD2 nomenclature. Muscle Nerve 52: 547–553, 2015     

Reachable workspace reflects dynamometer‐measured upper extremity strength in facioscapulohumeral muscular dystrophy

Introduction: It is not known whether a reduction in reachable workspace closely reflects loss of upper extremity strength in facioscapulohumeral muscular dystrophy (FSHD). In this study we aimed to determine the relationship between reachable workspace and quantitative upper extremity strength measures. Methods: Maximal voluntary isometric contraction (MVIC) testing of bilateral elbow flexion and shoulder abduction by hand‐held dynamometry was performed on 26 FSHD and 27 control subjects. In addition, Kinect sensor‐based 3D reachable workspace relative surface areas (RSAs) were obtained. Loading (500‐g weight) effects on reachable workspace were also evaluated. Results: Quantitative upper extremity strength (MVIC of elbow flexion and shoulder abduction) correlated with Kinect‐acquired reachable workspace RSA (R = 0.477 for FSHD, P = 0.0003; R = 0.675 for the combined study cohort, P < 0.0001). Progressive reduction in RSA reflected worsening MVIC measures. Loading impacted the moderately weak individuals the most with additional reductions in RSA. Conclusions: Reachable workspace outcome measure is reflective of upper extremity strength impairment in FSHD. Muscle Nerve 52 : 948–955, 2015     

Facioscapulohumeral muscular dystrophy functional composite outcome measure

Introduction: We developed an evaluator‐administered functional facioscapulohumeral muscular dystrophy composite outcome measure (FSHD‐COM) comprising patient‐identified areas of functional burden for future clinical trials. Methods: We performed a prospective observational study of 41 patients with FSHD at 2 sites. The FSHD‐COM includes functional assessment of the legs, shoulders and arms, trunk, hands, and balance/mobility. We determined the test‐retest reliability and convergent validity compared to established FSHD disease metrics. Results: The FSHD‐COM demonstrated excellent test‐retest reliability (intraclass correlation coefficient [ICC] 0.96; subscale ICC range, 0.90–0.94). Cross‐sectional associations between the FSHD‐COM and disease duration, clinical severity, and strength were moderate to strong (Pearson correlation coefficient range |0.51–0.92|). Discussion: The FSHD‐COM is a disease‐relevant, functional composite outcome measure suitable for future FSHD clinical trials that shows excellent test‐retest reliability and cross‐sectional associations to disease measures. Future directions include determining multisite reliability, sensitivity to change, and the minimal clinically important change in the FSHD‐COM. Muscle Nerve 58 : 72–78, 2018     

Magnetic resonance imaging in duchenne muscular dystrophy: Longitudinal assessment of natural history over 18 months

Introduction: In Duchenne muscular dystrophy (DMD), fat replacement of muscle may be a useful endpoint in trials of therapy, although progression in different muscle groups is uneven. In this study we assessed the progression of fat replacement with T₁‐weighted imaging over 2 9‐month periods. Methods: Eight ambulant, corticosteroid‐treated boys with DMD were imaged at 3 Tesla at 3 time‐points (baseline and 9 and 18 months) with T₁‐weighted imaging to measure fat replacement. Results: The greatest increase in fat content was measured in the biceps femoris long head, vastus lateralis, and rectus femoris, whereas the biceps femoris short head and gluteus maximus progressed more slowly. None of the lower leg muscles studied changed significantly. Conclusions: MRI can measure specific changes in fat replacement of muscle over time, demonstrating the variability in rates of natural progression between muscle groups and identifying those muscles suitable for use as biomarkers in clinical trials. Muscle Nerve 48 : 586–588, 2013     

Risk of functional impairment in Facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies. Nevertheless, little is known about the risk of developing functional impairment. Here we determine the 6‐year risk of functional impairment in FSHD. Methods: A retrospective cohort of 313 genetically confirmed, clinically affected FSHD participants in a United States registry between January 2002 and June 2011. Our main outcome was wheelchair (WC) use. Results: The 6‐year risk of WC use was 24.0% (95% confidence interval 18.6–29.3). The distribution of WC risk was bimodal, with a peak in the second decade associated with large D4Z4 contractions, followed by an age‐related increase in risk. Other functional categories showed moderate risk. Prevalence of hearing aid use and difficulty pronouncing words was increased in large D4Z4 contractions. Conclusions: The 6‐year risk of functional impairment in FSHD is moderate, and early WC use is associated with large D4Z4 contractions. Muscle Nerve 49:520–527, 2014