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     

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     

Reduced alpha‐synuclein in cerebrospinal fluid in synucleinopathies: Evidence from a meta‐analysis

Alpha‐synuclein plays a key role in the pathology of synucleinopathies including Parkinson's disease (PD) and multiple system atrophy (MSA). However, whether alpha‐synuclein level in cerebrospinal fluid (CSF) could distinguish synucleinopathies from progressive supranuclear palsy (PSP) is still a contentious issue. A comprehensive literature search yielded nine eligible studies. We expressed the between‐group difference of the concentration of alpha‐synuclein in CSF as the standardized mean difference. The proportion of variation attributable to heterogeneity was computed and expressed as I². Nine studies involved 537 controls, 843 PD, 130 MSA, and 98 PSP patients. The overall effect of PD on alpha‐synuclein in CSF was significantly different from normal control or disease control (standardized mean difference = –0.67, P < 0.00001). These studies were heterogeneous (I² = 40%). Alpha‐synuclein in CSF in MSA was significantly reduced relative to controls with heterogeneous studies (standardized mean difference = –0.75, P < 0.0001; I² = 62%). In contrast, no significant difference of alpha‐synuclein in CSF was observed between PSP and controls with heterogeneous studies (standardized mean difference = –0.28, P = 0.13; I² = 53%). Alpha‐synuclein in CSF was significantly reduced in synucleinopathies compared with PSP (“PD vs. PSP”: standardized mean difference = –0.38, P = 0.001; “MSA vs. PSP”: standardized mean difference = –0.66, P < 0.00001). The included studies were homogeneous (I² = 0%). Our study showed that alpha‐synuclein levels in CSF in synucleinopathies was significantly lower than in PSP. This finding provides insights into the pathophysiological difference between synucleinopathies and PSP as well as possibility of development of a tool for differential diagnosis between MSA and PSP using enzyme‐linked immunosorbent assay (ELISA) and similar methods. © 2014 International Parkinson and Movement Disorder Society     

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.     

Evidence for anticipation and association of deletion size with severity in facioscapulohumerd muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by marked inter and intrafamilial heterogeneity in its clinical expression. The contribution of genetic factors to this variability is not well characterized. We examined the relationship of phenotype to genotype in a clinically and genetically well-defined FSHD population. Quantitative isometric myometry (QMT) scores, normalized for age, gender, and height, were used to quantify disease severity. We found a significant (r = 0.92, p < 0.004) correlation between disease severity and the size of the 4q35-associated deletion. In addition, when relative disease severity of parent-offspring pairs was compared, the offspring were found to be significantly more severely affected (p = 0.01 1). This generational effect suggests the presence of anticipation in FSHD and raises the possibility of an underlying dynamic mutation.     

Cardiac sympathetic denervation correlates with clinical and pathologic stages of Parkinson's disease

Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH‐immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH‐immunoreactive fibers correlated with the PD stage (r = ?0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = ?0.61, P < 0.001), and disease duration (r = ?0.63, P < 0.001). Immunohistochemistry for α‐synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of α‐synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and α‐synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity. © 2008 Movement Disorder Society.     

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     

Sonography in carpal tunnel syndrome with normal nerve conduction studies

Introduction: Electrical impedance myography (EIM) is a non‐invasive, painless, objective technique to quantify muscle pathology. Methods: We measured EIM in 8 arm and leg muscles in 61 boys with Duchenne muscular dystrophy (DMD) and 31 healthy boys, ages 3–12 years, at 5 centers. We determined the reliability of EIM and compared results in boys with DMD to controls and to 6‐minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), timed functional tests (TFTs), and strength (hand‐held dynamometry). Results: EIM was well tolerated and had good inter‐ and intrarater reliability (intraclass correlation coefficient 0.81–0.96). The averaged EIM phase value from all muscles was higher (P < 0.001) in controls (10.45 ± 2.29) than boys with DMD (7.31 ± 2.23), and correlated (P ≤ 0.001) with 6MWD (r = 0.55), NSAA (r = 0.66), TFTs (r = –0.56), and strength (r = 0.44). Conclusion: EIM is a reliable and valid measure of disease severity in DMD. Longitudinal studies comparing EIM with other assessments over time in DMD are warranted. Muscle Nerve 52: 592–597, 2015     

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     

Specific muscle strength is reduced in facioscapulohumeral dystrophy: An MRI based musculoskeletal analysis

The aim was to test whether strength per unit of muscle area (specific muscle strength) is affected in facioscapulohumeral dystrophy (FSHD) patients, as compared to healthy controls. Ten patients and ten healthy volunteers underwent an MRI examination and maximum voluntary isometric contraction measurements (MVICs) of the quadriceps muscles. Contractile muscle volume, as obtained from the MR images, was combined with the MVICs to calculate the physiological cross-sectional area (PCSA) and muscle strength using a musculoskeletal model. Subsequently, specific strength was calculated for each subject as muscle strength divided by total PCSA. FSHD patients had a reduced quadriceps muscle strength (median(1st quartile–3rd quartile): 2011 (905.4–2775) N vs. 5510 (4727–8321) N, p <0.001) and total PCSA (83.6 (62.3–124.8) cm² vs. 140.1(97.1–189.9) cm², p = 0.015) compared to healthy controls. Furthermore, the specific strength of the quadriceps was significantly lower in patients compared to healthy controls (20.9 (14.7–24.0) N/cm² vs. 41.9 (38.3–49.0) N/cm², p <0.001). Thus, even when correcting for atrophy and fatty infiltration, patients with FSHD generated less force per unit area of residual muscle tissue than healthy controls. Possible explanations include impaired force propagation due to fatty infiltration, reduced intrinsic force-generating capacity of the muscle fibers, or mitochondrial abnormalities leading to impaired energy metabolism.     

Quantitative muscle ultrasound versus quantitative magnetic resonance imaging in facioscapulohumeral dystrophy

Introduction: Ultrasound and magnetic resonance imaging (MRI) are non‐invasive methods that can be performed repeatedly and without discomfort. In the assessment of neuromuscular disorders it is unknown if they provide complementary information. In this study we tested this for patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: We performed quantitative muscle ultrasound (QMUS) and quantitative MRI (QMRI) of the legs in 5 men with FSHD. Results: The correlation between QMUS‐determined z‐scores and QMRI‐determined muscle fraction and T1 signal intensity (SI) was very high. QMUS had a wider dynamic range than QMRI, whereas QMRI could detect inhomogeneous distribution of pathology over the length of the muscles. Conclusions: Both QMUS and QMRI are well suited for imaging muscular dystrophy. The wider dynamic range of QMUS can be advantageous in the follow‐up of advanced disease stages, whereas QMRI seems preferable in pathologies such as FSHD that affect deep muscle layers and show inhomogeneous abnormality distributions. Muscle Nerve 50: 968–975, 2014     

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     

Muscle proteins during 60‐day bedrest in women: Impact of exercise or nutrition

Almost no data exist regarding skeletal muscle responses to real or simulated spaceflight in women. We determined the impact of 60‐day bedrest (BR, n = 8), 60‐day bedrest with exercise‐training (BRE, n = 8), and 60‐day bedrest with a leucine‐enriched, high‐protein diet (BRN, n = 8) on muscle protein composition. Vastus lateralis and soleus muscle biopsies were analyzed for global protein fractions (mixed, sarcoplasmic, myofibrillar) and force‐specific proteins (myosin, actin, collagen). Concentrations (micrograms per milligram muscle wet weight) of these proteins were maintained (P > 0.05) in BR, despite large changes in quadriceps (?21%) and triceps surae (?29%) volume. Neither countermeasure influenced muscle protein content in either muscle (P > 0.05), despite exacerbation (BRN) or prevention (BRE) of atrophy. Pre‐bedrest comparisons showed less myofibrillar protein in the soleus (?16%, P < 0.05), primarily due to less myosin (?12%, P < 0.05) and more collagen (234%, P < 0.05) than the vastus lateralis. Muscle protein composition is tightly regulated in lower limb muscles of women, despite the most extreme weightlessness‐induced atrophy reported in humans. In contrast, men who underwent prolonged unloading were unable to proportionally regulate atrophy of the soleus. These findings have implications for astronauts and clinical conditions of sarcopenia regarding the maintenance of muscle function and prevention of frailty. Muscle Nerve, 2008     

Skeletal muscle fiber characteristics and oxidative capacity in hemiparetic stroke survivors

Introduction: Skeletal muscle is changed after stroke, but conflicting data exist concerning muscle morphology and oxidative enzyme capacity. Methods: In 36 chronic stroke patients bilateral rectus femoris muscle biopsies were analyzed, and fiber type proportions and cross‐sectional areas were determined by ATPase histochemistry. Enzymatic concentrations of citrate synthase (CS) and 3‐Hydroxyacyl‐coenzymeA‐dehydrogenase (HAD) were determined using freeze‐dried muscle tissue. Findings were correlated with clinical outcomes. Results: In the paretic muscles the mean fiber area was smaller (P = 0.0004), and a lower proportion of type 1 fibers (P = 0.0016) and a higher proportion of type 2X fibers (P = 0.0002) were observed. The paretic muscle had lower CS (P = 0.013) and HAD concentrations (P = 0.037). Mean fiber area correlated with muscle strength (r = 0.43; P = 0.041), and CS concentration correlated with aerobic capacity (r = 0.47; P = 0.01). Conclusions: In stroke survivors there is a phenotypic shift toward more fatigable muscle fibers with reduced oxidative enzymatic capacity that relates to clinical outcomes. Muscle Nerve 53 : 748–754, 2016     

Randomized,placebo‐controlled trial of incobotulinumtoxina for upper‐limb post‐stroke spasticity

Introduction: Efficacy and safety of incobotulinumtoxinA in post‐stroke upper‐limb spasticity were studied. Methods: Subjects randomized 2:1 to incobotulinumtoxinA (fixed dose 400 U) or placebo, with fixed doses for the primary target clinical pattern (PTCP; flexed elbow, 200 U; flexed wrist, 150 U; clenched fist, 100 U). Doses for non‐primary patterns were flexible within predefined ranges. Results: At week 4, incobotulinumtoxinA led to larger improvements in PTCP Ashworth scale (AS) scores than placebo [least‐squares mean change ± standard error: –0.9 ± 0.06 (n = 171) vs. –0.5 ± 0.08 (n = 88); P < 0.001], and more subjects were PTCP AS responders (≥1‐point improvement) with incobotulinumtoxinA (69.6%) than with placebo (37.5%; P < 0.001). Investigator's Global Impression of Change confirmed superiority of incobotulinumtoxinA vs. placebo (P = 0.003). IncobotulinumtoxinA was associated with functional improvements, as demonstrated in responder rates for Disability Assessment Scale principal target at week 4 (P = 0.007). Adverse events were mainly mild/moderate, and were reported by 22.4% (incobotulinumtoxinA) and 16.8% (placebo) of subjects. Conclusions: IncobotulinumtoxinA significantly improved upper‐limb spasticity and associated disability, and was well‐tolerated. Muscle Nerve 53: 415–421, 2016     

Bioenergetics and intermuscular fat in chronic obstructive pulmonary disease‐associated quadriceps weakness

Introduction: Chronic obstructive pulmonary disease (COPD) is associated with metabolic abnormalities in muscles of the lower limbs, but it is not known whether these abnormalities are generalized or limited to specific muscle groups, nor is there an easy way of predicting their presence. Methods: Metabolism in the quadriceps and biceps of 14 COPD patients and controls was assessed during sustained contraction using 31‐phosphorus magnetic resonance spectroscopy (³¹P MRS). T1 MRI was used to measure quadriceps intermuscular adipose tissue (IMAT). Results: COPD patients had prolonged quadriceps phosphocreatine time (patients: 38.8 ± 12.7 s; controls: 25.2 ± 10.6 s; P = 0.006) and a lower pH (patents: 6.88 ± 0.1; controls: 6.99 ± 0.06; P = 0.002). Biceps measures were not significantly different. IMAT was associated with a nadir pH <7.0 (area under the curve = 0.84). Conclusions: Anaerobic metabolism during contraction was characteristic of quadriceps, but not biceps, muscles of patients with COPD and was associated with increased IMAT. Because IMAT can be assessed quickly by conventional MRI, it may be a useful approach for identifying patients with abnormal muscle bioenergetics. Muscle Nerve 51 : 214–221, 2015     

Effect of gender and obesity on electrical current thresholds

Introduction: In this study we investigated the influence of gender and obesity on electrical current thresholds in an attempt to optimize the application of skeletal muscle electrical stimulation (ES) in clinical practice. Methods: Thirty‐two obese and 35 age‐matched, non‐obese men and women received graded ES to the quadriceps muscle for sensory (detection) and motor (contraction) threshold assessment. Concomitant pain and tolerance to ES were recorded. Results: Sensory threshold was lower in women than in men (P < 0.001), both obese and non‐obese. Sensory and motor thresholds were higher in obese than in non‐obese subjects (P < 0.05), and body mass index was a strong predictor of motor excitability (r² = 0.56–0.61). Current tolerance to motor stimulation was reduced in obese individuals, particularly in women, whereas pain was not influenced by gender or obesity. Conclusions: We suggest that both gender and obesity factors should be carefully considered in the design of rational ES treatments. Muscle Nerve, 2011     

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     

Quantification method affects estimates of voluntary quadriceps activation

The aim of this study was to investigate the effect of quantification method on estimates of voluntary quadriceps muscle activation. Twenty‐two people with no history of serious lower extremity injuries underwent voluntary quadriceps activation testing at 60° of knee flexion. Estimates of quadriceps activation were derived with: (1) a formula based on the interpolated twitch technique (ITT); (2) the central activation ratio (CAR); and (3) a modified central activation ratio. Predictive equations were developed that describe the relationships between the three methods. Significant differences (P < 0.001) were observed between the estimates of voluntary quadriceps muscle activation obtained using the three methods (ITT percent activation = 93.0 ± 6.4%, CAR = 95.9 ± 3.8%, modified CAR = 98.5 ± 4.1%). Excellent correlation (r = 0.995) was observed between ITT‐based percent activation and the CAR method. The associations between these methods and the modified CAR approach were weaker. Quantification method affects activation estimates. The equations developed will assist scientists in accurately comparing the results of studies that use different methods of quantifying activation. Muscle Nerve, 2010