Discriminating neurogenic from myopathic disease via measurement of muscle anisotropy

Skeletal muscle is electrically anisotropic, with a tendency for applied electrical current to flow more readily along muscle fibers than across them. In this study, we assessed a method for non‐invasive measurement of anisotropy to determine its potential to serve as a new technique for distinguishing neurogenic from myopathic disease. Measurements were made on the biceps brachii and tibialis anterior muscles in 15 normal subjects and 12 patients with neuromuscular disease (6 with amyotrophic lateral sclerosis and 6 with various myopathies) using 50 kHZ applied current. Consistent multi‐angle anisotropic patterns were found for reactance and phase in both muscles in normal subjects. Normalized anisotropy differences for each subject were defined, and group average values identified. The amyotrophic lateral sclerosis (ALS) patients demonstrated increased and distorted anisotropy patterns, whereas myopathic patients demonstrated normal or reduced anisotropy. These results suggest that non‐invasive measurement of muscle anisotropy has potential for diagnosis of neuromuscular diseases. © 2008 Wiley Periodicals, Inc. Muscle Nerve, 2009     

Non‐invasive assessment of muscle stiffness in patients with duchenne muscular dystrophy

ABSTRACT: Introduction: Assessment of muscle mechanical properties may provide clinically valuable information for follow‐up of patients with Duchenne muscular dystrophy (DMD) through the course of their disease. In this study we aimed to assess the effect of DMD on stiffness of relaxed muscles using elastography (supersonic shear imaging). Methods: Fourteen DMD patients and 13 control subjects were studied. Six muscles were measured at 2 muscle lengths (shortened and stretched): gastrocnemius medialis (GM); tibialis anterior (TA); vastus lateralis (VL); biceps brachii (BB); triceps brachii (TB); and abductor digiti minimi (ADM). Results: Stiffness was significantly higher in DMD patients compared with controls for all the muscles (main effect for population, P < 0.033 in all cases), except for ADM. The effect size was small (d = 0.33 for ADM at both muscle lengths) to large (d = 0.86 for BB/stretched). Conclusions: Supersonic shear imaging is a sensitive non‐invasive technique to assess the increase in muscle stiffness associated with DMD. Muscle Nerve 51 : 284–286, 2015     

Diagnostic value of in situ muscle fiber conduction velocity measurements in myopathies

In situ studies on muscle fiber conduction velocity (MFCV) were performed in 54 patients with histologically and biochemically defined myopathies. MFCV was measured over a 10 cm segment of the rectus femoris muscle by intramuscular stimulation and recording. Muscle disorders included muscular dystrophies, myotonic dystrophy, inflammatory myopathies, metabolic myopathies, endocrine myopathies, and congenital myopathies with structural abnormalities. Ten healthy volunteers served as controls. MFCV was significantly reduced in all patients except those with a defect in glycolysis and those that had recovered from acute myositis. MFCV did not vary with either sex, age or the duration of the disease. This shows that MFCV slowing is an unspecific finding in most myopathies. However, in some patients with normal needle electromyography, MFCV provided additional information in diagnosing muscle disease.     

Magnetic resonance imaging pattern recognition in sporadic inclusion‐body myositis

Introduction: In sporadic inclusion‐body myositis (IBM), additional tools are needed to confirm the diagnosis, particularly in clinically atypical or pathologically unproven patients. The aims of this study were to define the pattern of muscle MRI in IBM and to assess its accuracy in differentiating IBM from other myopathies that overlap with it clinically or pathologically. Methods: Blind assessment was done on the scans of 17 definite IBM, 2 possible IBM, and 118 patients with other myopathies. Results: The diagnostic accuracy to detect definite IBM was 95% for the typical pattern (with 100% specificity) and 97% for both typical and consistent patterns (with 97% specificity). Conclusions: Muscle MRI is an accurate tool for diagnostic work‐up of suspected IBM patients and may be particularly helpful in patients with early disease or who lack the classical IBM pathology. Muscle Nerve 52 : 956–962, 2015     

Inflammatory myopathies: Part 1

The inflammatory myopathies have diverse clinical and pathological features and multiple etiologies. Some are confined to a single muscle or group of muscles (e.g., orbital myositis and localized nodular myositis) while others are diffuse. Infective forms may be due to viral, bacterial, fungal, protozoal, or parasitic organisms. Viruses may cause acute self-limited forms of myositis and have been isolated from muscle in some cases of acute rhabdomyolysis and inclusion body myositis. They have also been implicated in some cases of congenital myopathy and in polymyositis and dermatomyositis, but there is no evidence of viral invasion of muscle in these conditions. In polymyositis and dermatomyositis there are derangements in humoral and cellular immune function, and recent evidence suggests an underlying disturbance of immunoregulation. The roles of genetic factors, drugs, and Toxoplasma infection have been under scrutiny. There is increasing recognition of immunological and pathological differences in polymyositis and juvenile and adult dermatomyositis, and in cases with associated connective tissue diseases, suggesting different underlying pathogenetic mechanisms. Inclusion body myositis, eosinophilic myositis, and granulomatous myositis can be separated from the other idiopathic inflammatory myopathies because of distinctive clinical and pathological features and this may also reflect different mechanisms of muscle injury. Recent developments in the treatment of the idiopathic inflammatory myopathies include the use of plasmapheresis and total-body irradiation in cases that are resistant to corticosteroids and immunosuppressive drugs.     

Inflammatory myopathies: evaluation and management

The inflammatory myopathies, including dermatomyositis, inclusion body myositis, and polymyositis, are poorly understood autoimmune diseases affecting skeletal muscle. Dermatomyositis is a disease mainly of skin and muscle, but may affect lung and other tissues. Proximal or generalized weakness or skin rash are the typical presenting features. Inclusion body myositis has a specific clinical pattern of weakness that generally distinguishes it from other inflammatory myopathies, with prominent involvement of wrist and finger flexors, and quadriceps. Polymyositis generally presents with proximal or generalized weakness. Typical dermatomyositis muscle pathology is quite distinct, with perivascular inflammatory cells that include plasmacytoid dendritic cells, and abnormal capillaries and perimysial perifascicular myofibers. Both inclusion body myositis and polymyositis usually have infiltration into muscle of large numbers of inflammatory cells, typically surrounding and displacing, and sometimes invading, myofibers. Inclusion body myositis is refractory to corticosteroids and to several immunomodulating therapies that have been used. Dermatomyositis and polymyositis are treated with corticosteroids and a variety of agents. Osteoporosis and opportunistic infections pose a significant risk during treatment of patients. This review discusses the clinical manifestations, pathology, and treatment approaches for the inflammatory myopathies.     

Take two: Utility of the repeat skeletal muscle biopsy

Introduction: The utility of repeat muscle biopsy has not been adequately evaluated. Methods: A retrospective review was undertaken of 144 repeat muscle biopsies performed from 1980 to 2017. Repeat biopsy was considered clinically relevant if it provided a new diagnosis, changed the existing diagnosis, or led to treatment changes or further investigations. Results: Repeat biopsy was abnormal in 118 cases, different from the initial biopsy in 67 cases, and specific in 40 cases. Factors with a significant effect on clinical relevance of the repeat biopsy (P < 0.05) were an abnormal, specific, or inflammatory initial biopsy, proximal muscle weakness, absence of myalgia, and a repeat biopsy that is different, specific, or consistent with polymyositis or inclusion body myositis. Conclusions: Utility of repeat biopsy was limited to weak patients whose initial biopsy showed inflammatory myositis. Ongoing advances in the diagnosis of immune inflammatory myopathies have led to evolution of the role of repeat biopsy. Muscle Nerve, 2019     

Distribution of glucocorticoid receptor alpha and beta subtypes in the idiopathic inflammatory myopathies

In contrast with dermatomyositis and polymyositis, inclusion body myositis is unresponsive to glucocorticoid treatment. Glucocorticoid action is mediated through an active glucocorticoid receptor-alpha and negatively regulated by another glucocorticoid receptor isoform. In several autoimmune diseases glucocorticoid receptor-beta up-regulation is involved in glucocorticoid resistance. We studied glucocorticoid receptor distribution in normal and inflammatory myopathy muscle and investigated whether differences in glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein expression are involved in the differential glucocorticoid sensitivity in inclusion body myositis versus polymyositis. Multistep immunofluorescence and Western blotting on fractionated cytoplasmic or nuclear muscle samples were used. Glucocorticoid receptor-alpha was the predominant receptor subtype in muscle and occurred abundantly in myonuclei of control and diseased muscle alike. Glucocorticoid receptor-beta was constitutively expressed on a subset of endothelial cells. No differences between dermatomyositis and the other idiopathic inflammatory myopathies were observed. Increased nuclear glucocorticoid receptor that has dissociated from heat shock protein 90 was found in glucocorticoid treated subjects. Glucocorticoid receptor-alpha and -beta isoform levels were unaltered in muscle tissues from control subjects that had received glucocorticoid treatment prior to biopsy. No differences in relative glucocorticoid receptor-alpha and glucocorticoid receptor-beta protein expression were seen in inclusion body myositis versus polymyositis specimens. Our study indicates that the different glucocorticoid sensitivity in the idiopathic inflammatory myopathies is not related to up- or down-regulation of a given glucocorticoid receptor isoform at the protein level.     

Late‐onset Becker muscular dystrophy: Refining the clinical features and electrophysiological findings

Introduction: The aim of this study was to characterize a unique distribution of muscle involvement in sporadic Becker muscle dystrophy (BMD). Methods: Retrospective chart review, clinical examination, electrophysiological studies, cardiac testing, and genetic testing were performed in 5 patients. Results: Predominant weakness and atrophy of biceps brachii, hip adduction, and quadriceps muscles was noted along with calf and extensor forearm hypertrophy. Finger flexor muscles were severely weak in 3 of 5 patients, a feature that could lead to a misdiagnosis of inclusion body myositis. Creatinine kinase was only mildly elevated in most patients. Electromyography was abnormal in all patients. Muscle biopsy in 1 patient demonstrated normal immunostaining for dystrophin. Conclusions: We found a unique and uniform distribution of muscle involvement in 5 sporadic cases of BMD. Recognizing these features is important for differentiating it from other myopathies that may have similar features and avoids unnecessary invasive procedures such as muscle biopsy. Muscle Nerve 52 : 885–887, 2015     

Review: An update on inflammatory and autoimmune myopathies

The review provides an update on the diagnosis of the main subtypes of inflammatory myopathies including dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM) and sporadic inclusion body myositis (sIBM). The fundamental aspects on muscle pathology and the unique pathomechanisms of each subset are outlined and the diagnostic dilemmas concerning the distinction of PM from sIBM and NAM are addressed. Dermatomyositis is a complement-mediated microangiopathy leading to destruction of capillaries, hypoperfusion and inflammatory cell stress on the perifascicular regions. NAM, is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmuity with macrophages as the final effector cells causing fibre injury. In PM and sIBM cytotoxic CD8-positive T cells clonally expand in situ and invade major histocompatibility-I-expressing muscle fibres. The pathology of sporadic inclusion body myositis is complex because, in addition to the inflammatory mechanisms, there are degenerative features characterized by vacuolization and the accumulation of stressor and amyloid-related misfolded proteins. Inducible pro-inflammatory molecules, such as interleukin 1-β, may enhance the accumulation of stressor proteins. The principles for more effective treatment strategies are discussed.     

Inflammatory myopathies

The inflammatory myopathies are a heterogeneous group of disorders with recent evidence demonstrating differences in clinical features, pathologic changes, pathogenesis, and response to therapy. The inflammatory myopathies generally produce predominantly proximal, symmetric muscle weakness and wasting. Additional criteria for diagnosis include elevated serum muscle enzymes, myopathic features on EMG, and muscle biopsy abnormalities, including muscle fiber necrosis, degeneration, and inflammatory infiltrates. Inclusion body myositis is distinctive in that distal weakness is most commonly equal to or greater than proximal weakness and muscle biopsy reveals rimmed, cytoplasmic vacuoles, eosinophilic inclusions in the cytoplasm, and nucleus and abnormal filamentous structures. Autoimmune mechanisms seem likely to be involved in the pathogenesis of these disorders and viral infection may be etiologically involved in some of these diseases. The differences in the site of immune-mediated damages suggest an angiography in dermatomyositis while direct muscle fiber involvement is more likely in polymyositis and inclusion body myositis. Therapy of these disorders is similar although some, particularly inclusion body myositis, may be particularly resistant to therapy. Prednisone is currently recommended as the first treatment with azathioprine or methotrexate added after 3 months if steroids are ineffective.     

Single muscle fiber contractile properties in adults with muscular dystrophy treated with MYO‐029

Myostatin inhibitors are being investigated as treatments for myopathies. We assessed single muscle fiber contractile properties before and after 6 months of study drug in 6 patients with facioscapulohumeral, Becker, and limb‐girdle muscular dystrophy. Five of the patients received MYO‐029, a myostatin inhibitor, and 1 received placebo. The chemically skinned single muscle fiber preparation was used to measure single fiber force, specific force, maximum unloaded shortening velocity, power, and specific power in type I and IIa fibers from each subject. In 4 of 5 patients who received MYO‐029, improvement was seen in single muscle fiber contractile properties; thus, there may be a beneficial effect of myostatin inhibition on muscle physiology at the cellular level. No improvement was seen in the patient who received placebo. This finding may be clinically relevant in spite of the fact that quantitative muscle strength measurements in our patients did not improve. Further studies of myostatin inhibition as a treatment for muscular dystrophy are warranted, and single muscle fiber contractile studies are a useful assay for muscle function at the cellular level. Muscle Nerve 39: 3–9, 2009     

Antibody Therapies in Autoimmune Inflammatory Myopathies: Promising Treatment Options

Inflammatory myopathies, including polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), necrotizing myopathy (NM), antisynthetase syndrome (ASS) and overlap myositis (OM), in short myositis, are rare diseases. All forms of myositis have progressive muscle weakness in common, with each subtype characterized by different autoantibody profiles, histological findings and extramuscular manifestations. Due to better understanding of the pathogenesis of the muscle inflammation in myositis, new molecular pathways for targeted therapy have been discovered. Current therapies aim at different components of the innate or the adaptive immune response. Additionally, non-inflammatory mechanisms in myositis have come into focus as possible treatment targets. The use of therapeutical antibodies in myositis has been examined in various clinical studies, several of them randomized controlled ones: Depletion of B-cells by rituximab has been established as treatment of refractory myositis. IVIG, an antibody therapy in the wider sense, has now been licensed for DM following a recent positive clinical trial. Negative study results were reported in randomized trials with infliximab, sifalimumab and bimagrumab. Studies on basiliximab and eculizumab are currently underway, and are expected to yield results in a couple of years. Despite some promising results of clinical studies with antibody therapy in myositis, further research is crucial to optimize the treatment for this debilitating disease and to find treatment alternatives for treatment-refractory patients.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01220-z.     

The role of skeletal muscle biopsy in the diagnosis of neuromuscular disorders

Muscle biopsy is required to provide a definitive diagnosis in many neuromuscular disorders. Biopsy findings may indicate whether the pathological process is of neurogenic or myopathic origin. The muscle biopsy may give important information on the course of the disease (acute or chronic) and on the disease stage and progression. The interpretation of muscle biopsy, including histochemical and ultrastructural analysis, is a key factor in the diagnosis of muscular dystrophies, glycogenoses, inflammatory myopathies and congenital myopathies. An assessment of muscle biopsy on electron microscopy enables a definite diagnosis of oculopharyngeal muscular dystrophy, mitochondrial myopathy or inclusion body myositis. This paper presents an overview of general indications for muscle biopsy, biopsy procedures, as well as transportation and preparation of muscle tissue for final microscopic analysis. The interpretation of specific microscopic findings and a brief discussion on the clinical usefulness of muscle biopsy in the era of molecular diagnosis are also presented.     

Appropriate window width for the “clustering index method” in the tibialis anterior muscle

We previously reported a new quantitative analysis of single‐channel surface electromyography (EMG), the “clustering index method” (CI method), in the tibialis anterior muscle, which achieved sufficiently good sensitivity to detect neurogenic or myogenic abnormalities. The window width is a fundamental parameter of the CI method, and was arbitrarily set at 15 ms in that study. In this study, we searched for the most appropriate window width using expanded patient data. The data from our previous study were reanalyzed, and new patients were enrolled. Window width in the CI method was changed from 5 to 27.5 ms with a step of 2.5 ms. For each window width, Z‐score values of individual subjects were calculated and the diagnostic yield was investigated. We enrolled 67 controls, 29 subjects with neurogenic disorders, and 39 with myogenic disorders. When the window width was set at 22.5 ms, the highest sensitivity was achieved both for neurogenic (97%) and myogenic (72%) disorders, with a specificity of 97%. Seven of 10 patients with inclusion body myositis were also abnormal. Reliable results were obtained by collecting 15 epochs per subject. There are two conflicting effects that appear to be best balanced at a window width of 22.5 ms: a wider width decreases the chance that a motor unit potential (MUP) is divided into two adjacent windows, and a narrower width reduces the possibility that an MUP firing at a low‐frequency is counted twice by the differential sequences. CI is promising as a non‐invasive method to diagnose neuromuscular disorders.     

Mechanomyographic determination of post-activation potentiation in myopathies.

OBJECTIVE: There is a need to provide an index of muscle contractility in evaluating myopathies especially in the clinical setting. This study was conducted to investigate if the mechanomyogram post-activation potentiation (MMG-PAP) can be used as an index of muscle contractile force potentiation (force-PAP), if it differs between normal and myopathic muscles, and if it can reflect abnormalities in muscle fiber anatomy. METHODS: The correlation between MMG-PAP and force-PAP was evaluated in 12 normal subjects after maximum voluntary contraction (MVC) of the biceps brachii muscle. The same method was then applied to study MMG-PAP in 16 patients with myopathies, 16 disease and 25 normal controls. Mean fiber diameters and the proportions of type 1 and 2 fibers in biopsied biceps brachii muscle were determined and compared with MMG-PAP values. RESULTS: There was a significant positive correlation between force-PAP (197 +/- 148%) and MMG-PAP (135 +/- 68%) immediately after MVC (P < 0.05). The mean MMG-PAP in myopathies (66 +/- 53%) was significantly lower than those of the disease (128 +/- 34%; P < 0.005) and normal controls (120 +/- 56%; P < 0.005). Patients with non-dystrophic myopathies, including those with myositis, had significantly lower MMG-PAP values (38 +/- 20%; P < 0.005) than those with muscular dystrophy (148 +/- 23%). MMG-PAP did not clearly correlate with either type 2 fiber atrophy or type 2 fiber disproportion based on muscle biopsy analysis of myopathic patients. CONCLUSIONS: This study shows that MMG-PAP can be used as an index of muscle contractility and that it is significantly lower in non-dystrophic myopathies compared to normal subjects. MMG-PAP does not seem to reflect abnormal muscle fiber anatomy. SIGNIFICANCE: MMG-PAP may become a valuable non-invasive tool in augmenting routine clinical electrophysiologic studies especially in evaluating muscle contractility in myopathies.     

Upregulation of MHC class I in transgenic mice results in reduced force‐generating capacity in slow‐twitch muscle

Expression of major histocompatibility complex (MHC) class I in skeletal muscle fibers is an early and consistent finding in inflammatory myopathies. To test if MHC class I has a primary role in muscle impairment, we used transgenic mice with inducible overexpression of MHC class I in their skeletal muscle cells. Contractile function was studied in isolated extensor digitorum longus (EDL, fast‐twitch) and soleus (slow‐twitch) muscles. We found that EDL was smaller, whereas soleus muscle was slightly larger. Both muscles generated less absolute force in myopathic compared with control mice; however, when force was expressed per cross‐sectional area, only soleus muscle generated less force. Inflammation was markedly increased, but no changes were found in the activities of key mitochondrial and glycogenolytic enzymes in myopathic mice. The induction of MHC class I results in muscle atrophy and an intrinsic decrease in force‐generation capacity. These observations may have important implications for our understanding of the pathophysiological processes of muscle weakness seen in inflammatory myopathies. Muscle Nerve, 2008     

Microsporidial polymyositis in human immunodeficiency virus−infected patients,a rare life‐threatening opportunistic infection: Clinical suspicion,diagnosis, and management in resource‐limited settings

Introduction: Microsporidial myositis is a rare opportunistic infection that has been reported in HIV‐infected and HIV‐uninfected immunocompromised patients. Methods: In this study we present a retrospective analysis of 5 cases of microsporidial myositis in HIV‐infected patients, including the clinical, laboratory, and histologic features, and a review of the literature. Results: Five young men with HIV infection [median CD4 count of 20 cells (range 14?144)/mm³] who presented with signs and symptoms suggestive of myositis underwent EMG‐NCV and muscle biopsy, which revealed signs compatible with microsporidial myositis. Early and aggressive treatment led to improvement in 3 patients. Two of the 5 patients died due to a delay in diagnosis, because the spores were mistaken for Candida without confirmatory stains or a high index of suspicion. Conclusions: Myositis in HIV‐infected patients with low CD4 counts should be evaluated using muscle biopsy. A high index of suspicion is required for early diagnosis of microsporidial myositis in HIV‐infected patients. Early diagnosis and immediate, aggressive treatment are the keys to favorable outcomes in these patients. Muscle Nerve 51 :775–780, 2015