Inclusion‐body myositis presenting with facial diplegia

Introduction: The hallmark clinical presentation of inclusion‐body myositis (IBM) is slowly progressive weakness that characteristically affects the quadriceps and finger and wrist finger flexor muscles. Facial weakness can also occur, but it is typically mild and not a prominent finding. Methods: We describe the clinical features, laboratory investigations, and muscle biopsy findings in a 58‐year old man who presented with a 6‐year history of marked progressive symmetrical facial weakness. Examination also showed shoulder abduction and hip extensor weakness. Results: The patient's serum creatine kinase level was 655 U/L, and electromyography showed fibrillation potentials and myopathic motor unit potentials. A biopsy specimen of the left biceps muscle was pathognomonic for IBM. Conclusions: This patient did not have a typical presentation for IBM but rather fulfilled the pathological criteria for IBM. To our knowledge, facial diplegia has not been reported previously as a presenting manifestation of IBM. Muscle Nerve 49 : 287–289, 2014     

Sporadic inclusion body myositis presenting with severe camptocormia

Sporadic inclusion body myositis (sIBM) is a slowly progressive idiopathic inflammatory myopathy. The characteristic early quadriceps and finger flexor muscle weakness often leads to the diagnosis of sIBM, especially when all canonical pathological features of sIBM are not present on muscle biopsy. Weakness of the paraspinal muscles, resulting in head drop and/or camptocormia, is a rare clinical finding along the course of sIBM, and even more rare as the presenting feature. We describe two patients with sIBM manifesting with camptocormia as the sole clinical manifestation for several years prior to the diagnosis by muscle biopsy. This observation emphasizes the role of sIBM in the etiology of camptocormia and the need to consider this common myopathy as a cause of weakness, despite the lack of classic quadriceps and finger flexor muscle weakness years after the onset of the paraspinal muscle weakness.     

Genetics of inclusion-body myositis

Sporadic inclusion-body myositis (sIBM) is the most common acquired muscle disease in Caucasians over the age of 50 years. Pathologically it is marked by inflammatory, degenerative, and mitochondrial changes that interact in a yet-unknown way to cause progressive muscle degeneration and weakness. The cause of the disease is unknown, but it is thought to involve a complex interplay between environmental factors, genetic susceptibility, and aging. The strongest evidence for genetic susceptibility comes from studies of the major histocompatibility complex (MHC), where different combinations of alleles have been associated with sIBM in different ethnic groups. The rare occurrence of familial cases of inclusion-body myositis (fIBM) adds additional evidence for genetic susceptibility. Other candidate genes such as those encoding some of the proteins accumulating in muscle fibers have been investigated, with negative results. The increased understanding of related disorders, the hereditary inclusion-body myopathies (hIBM), may also provide clues to the underlying pathogenesis of sIBM, but to date there is no indication that the genes responsible for these conditions are involved in sIBM. This review summarizes current understanding of the contribution of genetic susceptibility factors to the development of sIBM.     

Camptocormia as presenting manifestation of a spectrum of myopathic disorders

Introduction: Camptocormia is the involuntary flexion of the thoracolumbar spine leading to an abnormal posture. Methods: We retrospectively identified patients with myopathy who manifested with camptocormia and were seen in our neuromuscular clinic. The diagnosis of myopathy was based on myopathic electromyographic changes, often accompanied by 1 or more of the following: elevated creatine kinase (CK); myopathic histopathological findings; and genetic confirmation. Results: Fifty‐two patients were identified; 35 had symptoms limited to camptocormia, but were found to have additional weakness of facial (8 patients), neck (11 patients), and limb muscles (17 patients). CK values were normal or mildly to moderately elevated. MRI/CT of the spine showed paraspinal muscle atrophy and fat replacement. Facioscapulohumeral muscular dystrophy and sporadic inclusion body myositis were the most commonly identified myopathies in this cohort. Conclusions: Despite the difficulty in characterizing the myopathy in patients with camptocormia, a definitive diagnosis was possible in 54% of cases. The pattern of associated extra‐axial weakness may provide clues to the diagnosis. Muscle Nerve 52 : 1008–1012, 2015     

Inclusion body myositis: Clinical and pathological boundaries

Inclusion body myositis, polymyositis, and dermatomyositis are three distinct categories of inflammatory myopathy. Some authorities commented on the selective early weakness of the volar forearm muscles, quadriceps, and ankle dorsiflexors in inclusion body myositis. The most important feature distinguishing inclusion body myositis from the other two inflammatory myopathies is the lack of responsiveness to immunosuppressive treatment. Although most patients with inclusion body myosities have characteristic muscle biopsy findings, some cannot be distinguished histologically early from polymyositis. Presdicting responsiveness to mmunosuppressive medications, independent of muscle histology, would be valuable to clinicians. We retrospectively reviewed the pattern of weakness and other clinical features of 46 patients newly diagnosed with either inclusion body myositis, polymyositis, or dermatomyosities. Asymmetrical muscle weakness with prominent wrist flexor, finger flexor, and knee extensor involvement was specific for inclusion body myositis and unresponsive polymyositis. Male sex, lower creatine kinase levels, slower rate of progression, and peripheral neuropathy were also more common in inclusion body myositis and unresponsive polymyositis than in responsive polymyositis and dermatomyositis patients. Repeat muscle biopsy in 2 patients in teh unresponsive polymyositis group demonstrated histological features of inclusion body myositis. We suspect that patients with clinical features of inclusion body myositis but lacking histological confirmation may nonetheless have inclusion body myositis. Our study supports the recently proposed criteria for defintie and possible inclusion body myositis.     

A novel case of inclusion body myositis and myasthenia gravis

The co-existence of myasthenia gravis and other inflammatory myopathies has been reported in the literature before, but no clinical cases involving inclusion body myositis have been reported. We report a case of a 67-year-old patient who presented with dysphagia, exhibiting the typical electrophysiological features of postsynaptic neuromuscular junction defect with positive muscle acetylcholine receptor antibodies, consistent with the diagnosis of myasthenia gravis. Nevertheless, response to acetylcholinesterase inhibitors and immunomodulatory treatment was unexpectedly poor. As the disease progressed, the patient developed asymmetric muscle weakness, initially affecting mainly the quadriceps and the finger flexors. Muscle MRI imaging supported the presence of an inflammatory myopathy and muscle biopsy confirmed the diagnosis of inclusion body myositis. Thus, our patient represents the first reported overlap case of myasthenia gravis and inclusion body myositis.     

Inflammatory myopathy with cytochrome oxidase negative muscle fibers: Methotrexate treatment

Inflammatory myopathy with cytochrome oxidase negative muscle fibers (IM/COX−) is characterized by slowly progressive weakness, most prominent in the quadriceps, muscle fibers with reduced COX staining and mitochondrial DNA mutations, and a poor response to corticosteroid treatment. We reviewed records of quantitative measurements of muscle strength in 7 IM/COX− patients to evaluate the outcomes after treatment with oral, once weekly, methotrexate for an average of 15 months. We compared the results to 6 patients with IM/COX− who received no long-term immunosuppression, and to 4 with inclusion body myositis (IBM) who received methotrexate during the same period. Methotrexate treatment of IM/COX− was followed by improved muscle strength in 5 of 7 patients, averaging 17 ± 5%. In contrast, there was no improvement in the strength of 6 untreated IM/COX− patients (−6 ± 4%; P = 0.003), or 4 methotrexate-treated IBM patients (1 ± 2%; P = 0.03). We conclude that, despite clinical similarities to inclusion body myositis, which is usually refractory to immunosuppressive therapy, strength in IM/COX− appears to improve with methotrexate treatment. Biopsy studies of inflammatory myopathies with evaluation of muscle for mitochondrial changes and vacuoles can help to direct the choice of appropriate immunomodulating treatments. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21: 1724–1728, 1998     

The unfolding spectrum of inherited distal myopathies

Distal myopathies are a group of rare muscle diseases characterized by distal weakness at onset. Although acquired myopathies can occasionally present with distal weakness, the majority of distal myopathies have a genetic etiology. Their age of onset varies from early-childhood to late-adulthood while the predominant muscle weakness can affect calf, ankle dorsiflexor, or distal upper limb muscles. A spectrum of muscle pathological changes, varying from nonspecific myopathic changes to rimmed vacuoles to myofibrillar pathology to nuclei centralization, have been noted. Likewise, the underlying molecular defect is heterogeneous. In addition, there is emerging evidence that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders, be manifestation of multisystem proteinopathies or the result of the altered interplay between different genes. In this review, we provide an overview on the clinical, electrophysiological, pathological, and molecular aspects of distal myopathies, focusing on the most recent developments in the field. Muscle Nerve 59 :283–294, 2019     

Novel p.Asp27Glu ACTA1 variant features congenital myopathy with finger flexor weakness,cardiomyopathy, and cardiac conduction defects

Pathogenic variants in the skeletal muscle α-actin 1 gene (ACTA1) cause a spectrum of myopathies with clinical and myopathological diversity. Clinical presentations occur from the prenatal period to adulthood, commonly with proximal-predominant weakness and rarely preferential distal weakness. Myopathological findings are wide-ranging, with nemaline rods being most frequent. Associated cardiomyopathy is rare and conduction defects are not reported. We describe a family with congenital myopathy with prominent finger flexor weakness and cardiomyopathy with cardiac conduction defects. The proband, a 48-year-old Caucasian male, his 73-year-old mother, 41-year-old sister, and 19-year-old nephew presented with prominent finger flexor weakness on a background of neonatal hypotonia and delayed motor milestones. All had progressive cardiomyopathy with systolic dysfunction and/or left ventricular dilation. The proband and sister had intraventricular conduction delay and left anterior fascicular block, respectively. The mother had atrial fibrillation. Muscle biopsy in the proband and sister demonstrated congenital fiber-type disproportion and rare nemaline rods in the proband. A novel dominant variant in ACTA1 (c.81C>A, p.Asp27Glu) segregated within the family. This family expands the genotypic and phenotypic spectrum of ACTA1-related myopathy, highlighting preferential finger flexor involvement with cardiomyopathy and conduction disease. We emphasize early and ongoing cardiac surveillance in ACTA1-related myopathy.     

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     

Cytochrome c oxidase deficiencies in the muscle of patients with inflammatory myopathies

We studied mitochondrial function in inflammatory myopathies, using cytochrome c oxidase (COX) reaction on muscle biopsy samples from 30 patients (15 with dermatomyositis, 12 with polymyositis, and 3 with inclusion body myositis) and 30 age-matched controls. We also performed immunocytochemistry for COX II and COX IV subunits in 7 of these patients who had COX deficiency. COX-deficient fibers were a constant finding in patients or controls older than 65 years and the percentage of COX-deficient fibers correlated with age in both patients and controls. Focal COX deficiency was found in 24 patients (13 of 15 with dermatomyositis, 8 of 12 with polymyositis, and 3 of 3 with inclusion body myositis) and 18 controls. The percentages of COX-deficient fibers were higher in patients with inflammatory myopathies (range: 0–4.7%; mean: 1.2%) than in age-matched controls (range: 0–1.9%; mean: 0.4%) (P < 0.01). In the subgroup of patients under age 65, COX-deficient fibers were more frequent in dermatomyositis than in polymyositis (mean: 0.8% vs 0.2%, P = 0.02). In patients with dermatomyositis, capillary loss correlated positively with COX deficiency (P < 0.02). Immunocytochemistry for COX II and IV showed that 82% of COX-negative fibers were COX II-negative and 26% were COX IV-negative, suggesting that proteins encoded by mitochondrial DNA are predominantly, but not exclusively, involved in COX deficiency. We conclude that mitochondrial dysfunction and COX deficiency can occur in inflammatory myopathies. Such a mitochondrial dysfunction is not solely related to the aging process. We suggest that muscle ischemia contributes to mitochondrial dysfunction in dermatomyositis. Received: 16 October 1995 / Revised, accepted: 10 November 1995     

CBA/J mice infected with Trypanosoma cruzi: an experimental model for inflammatory myopathies

Idiopathic inflammatory myopathies are inflammatory disorders of unknown origin, characterized by muscle weakness. The aim of our study was to establish and characterize an animal model for chronic inflammatory myopathy which would permit investigations of the role of T-cells in chronic myositis as well as of the mechanisms for muscle weakness in chronic inflammatory muscle disorders. CBA/J mice were infected with the protozoan parasite Trypanosoma cruzi. Immunohistochemistry was used to characterize the distribution and composition of inflammatory infiltrates, and demonstrated a chronic focal inflammation comprised mainly of T-cells and macrophages in infected mice. The inflammatory infiltrates were predominantly found in the endomysium and, to a lesser extent, in perivascular areas. CD8(+) T-cells were found to have invaded nonnecrotic muscle fibers. Degenerating muscle fibers were also found, as well as an increased number of central muscle nuclei. The murine model described in this article may be useful in studying certain aspects of idiopathic inflammatory myopathies such as the role of T-cells in chronic muscle inflammation and chronic myocytotoxicity.     

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.     

Trouble at the junction: When myopathy and myasthenia overlap

Although myopathies and neuromuscular junction disorders are typically distinct, their coexistence has been reported in several inherited and acquired conditions. Affected individuals have variable clinical phenotypes but typically display both a decrement on repetitive nerve stimulation and myopathic findings on muscle biopsy. Inherited causes include myopathies related to mutations in BIN1, DES, DNM2, GMPPB, MTM1, or PLEC and congenital myasthenic syndromes due to mutations in ALG2, ALG14, COL13A1, DOK7, DPAGT1, or GFPT1. Additionally, a decrement due to muscle fiber inexcitability is observed in certain myotonic disorders. The identification of a defect of neuromuscular transmission in an inherited myopathy may assist in establishing a molecular diagnosis and in selecting patients who would benefit from pharmacological correction of this defect. Acquired cases meanwhile stem from the co-occurrence of myasthenia gravis or Lambert-Eaton myasthenic syndrome with an immune-mediated myopathy, which may be due to paraneoplastic disorders or exposure to immune checkpoint inhibitors.     

Nuclear membrane proteins are present within rimmed vacuoles in inclusion-body myositis

The rimmed vacuoles within muscle in inclusion-body myositis (IBM) are structures of uncertain origin. Two hypotheses have been proposed for their formation: that they develop as a consequence of abnormal lysosomal function or in association with the breakdown of myonuclei. We tested the latter hypothesis by studying muscle samples from 14 patients with IBM and 18 controls using immunohistochemistry for nuclear membrane proteins, examining semithin sections, and performing electron microscopy. We found that in IBM muscle vacuoles were immunoreactive for the inner nuclear membrane proteins emerin and lamin A/C. Myonuclei with fragmented or focally absent nuclear membranes were present in immunohistochemical and electron microscopy studies. The association of nuclear membrane proteins with rimmed vacuoles confirms the hypotheses that rimmed vacuoles in IBM form in association with myonuclear pathology and that IBM differs from other inflammatory myopathies in that abnormalities of myonuclei are more prominent.     

Frequency and phenotype of patients carrying TPM2 and TPM3 gene mutations in a cohort of 94 patients with congenital myopathy

Congenital myopathies are difficult to classify correctly through molecular testing due to the size and heterogeneity of the genes involved. Therefore, the prevalence of the various genetic causes of congenital myopathies is largely unknown. In our cohort of 94 patients with congenital myopathy, two related female patients and two sporadic, male patients were found to carry mutations in the tropomyosin 2 (TPM2) and tropomyosin 3 (TPM3) genes, respectively. This indicates a low (4.3%) frequency of TPM2 and TPM3 mutations as a cause of congenital myopathy. Compared to previously described patients carrying the same mutations as found in our study (c.503G > A, and c.502C > T in TPM3, and c.415_417delGAG in TPM2), clinical presentation and muscle morphological findings differed in our patients. Differences included variation in distribution of muscle weakness, presence of scoliosis and ptosis, physical performance and joint contractures. The variation in clinical profiles emphasizes the phenotypic heterogeneity. However, common features were also present, such as onset of symptoms in infancy or childhood, musculoskeletal deformities and normal or low plasma levels of creatine kinase.One patient had nemaline myopathy and fiber size disproportion, while three patients had congenital fiber type disproportion (CFTD) on muscle biopsies. TPM2-related CFTD has only been described in two cases, indicating that mutations in TPM2 are rare causes of CFTD.     

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.     

Acute mitochondrial myopathy with respiratory insufficiency and motor axonal polyneuropathy

Background: Mitochondrial myopathies (MMs) are mainly presented with chronic muscle weakness and accompanied with other syndromes. MM with acute respiratory insufficiency is rare. Aims: To reveal the clinical, pathological and molecular characteristics of a life-threatening MM. Methods: Muscle biopsy and enzyme staining were performed in skeletal muscles. Mitochondrial DNA (mtDNA) sequencing was analyzed and heteroplasmy were quantified by pyrosequencing. Results: All three patients had tachycardia, acute lactic acidosis, dyspnea and sudden severe muscle weakness. Two patients had calf edema and abdominal pain, and one had a heart attack. Electromyography in two patients showed dramatically decreased axonal amplitudes of motor nerves. Muscle biopsies showed ragged red fibers and dramatic mitochondrial abnormality. A mtDNA m.3243A>G mutation was identified in Patient 1 (mutation load: 29% in blood and 73% in muscle) and Patient 3 (79% in blood and 89% in muscle). A mtDNA m.8344A>G mutation was found in Patient 2 (mutation load 80.4% in blood). Conclusion: MM characterized by lactic acidosis, respiratory failure and acute motor axonal neuropathy is life threatening.