Initial Muscle Biopsy Research Articles

EP.19Anti-HMGCR positive necrotizing myopathy presenting in childhood

A 12-year-old girl, previously healthy, was hospitalized because of progressive proximal weakness for a few months. CK was 17000U/L. There were only minor skin changes, but an initial muscle biopsy was reported to have changes possibly compatible with dermatomyositis. Treatment was started with prednisolone and methotrexate, without adequate improvement. A biopsy two years later did not exclude the diagnosis of a muscular dystrophy. The fast development of weakness did not however really fit clinically. A neuromuscular gene panel analysis (328 genes) did not reveal the etiology, and ANA- and ANCA tests were negative. She gradually became weaker. At the age of 15,5y, she could not walk any longer, her upper extremities were weak, and she could not shift position in bed. She also had pain in her legs, and breathing and swallowing were affected. She was still on prednisolone, but methotrexate had been stopped. A new biopsy showed more extensive, chronic myopathic changes and acute changes, with fibers in different stages of necrosis. CK was 2600 U/L. MRI of total body disclosed generalized edema and patchy infiltration of fat in all visible muscles, combined with muscle atrophy. It was then suggested to test for HMGCR antibodies which were positive. The patient was started on IVIG infusions in addition to previous therapy and restarted methotrexate. She improved gradually. After one year she could walk with assistance, swallowing was normal, and respiration was much improved. HMGCR associated necrotizing autoimmune myopathy (NAM) may well occur without statin exposure. However, the disease is rare in childhood. A muscle biopsy with scattered necrotic fibers without inflammatory infiltrate should raise the suspicion of the disease. Because it is treatment responsive, HMGCR associated NAM is an important differential diagnosis also in children when the clinical picture, imaging and laboratory findings are in the borderline between a myositis and a muscular dystrophy.

The Correlation of Muscle Biopsy Scores with the Clinical Variables in Idiopathic Inflammatory Myopathies.

Objectives: To compare the muscle pathology findings among subgroups of idiopathic inflammatory myopathies (IIM) patients, and to determine the correlations of muscle biopsy scores with muscle power and creatine kinase (CK).Methods:The medical records of IIM patients consisting of the demographic data, clinical parameters and laboratory conducted were retrospectively reviewed. Their initial muscle biopsies were reviewed, and four domains were scored: inflammation, vascular, muscle, and connective tissue.Results: Ninety-five IIM patients (28 patients with idiopathic polymyositis (PM) 9 idiopathic dermatomyositis (DM), 5 DM associated with malignancy, and 53 PM/DM associated with connective tissue disease) with median (IQR: Q1, Q3) disease duration of 1.2 (0.5, 3.1) months were included. No significant differences in initial muscle pathology findings and muscle pathology score among the subgroups were found. Muscle degeneration and endomysial fibrosis scores were negatively correlated with muscle power (r=-0.23 and-0.24, respectively, p<0.05) and positively correlated with CK (r=0.27 and 0.39, respectively, p<0.01). No significant correlation was detected either inflammation or vasculitis scores with muscle power and CK levels.Conclusion:In this study, muscle biopsy cannot be used to differentiate among subgroups of IIM patients. In addition, we found only modest correlation of muscle biopsy scores with muscle power and CK. Further study is necessary to confirm our findings.

P2.42 Clinical and imaging features of inclusion body myositis

Objective: Sporadic inclusion body myositis (sIBM) is the most common myopathy presenting over the age of 50 years. The diagnosis of sIBM is frequently delayed being initial errors common, as a consequent of the variation of clinical phenotype at presentation and frequent false negative results of initial muscle biopsy because of lack of rimmed vacuoles. For better diagnosis, we evaluate the clinical and radiological characteristics of Japanese patients with sIBM. Patients and methods: Thirteen patients (11 male and 2 female, being mean age of onset and diagnosis 58±8 years old and 65±8 years old, respectively) with sIBM based on muscle biopsy in the Department of Neurology, the University of Tsukuba Hospital over a 33-year period from 1976 to 2009 were included in this study.

Timing of the initial muscle biopsy does not affect the measured muscle protein fractional synthesis rate during basal, postabsorptive conditions

The muscle protein fractional synthesis rate (FSR) is determined by monitoring the incorporation of an amino acid tracer into muscle protein during a constant-rate intravenous tracer infusion. Commonly two sequential muscle biopsies are obtained some time after starting the tracer infusion. However, other protocols, including those with an initial biopsy before starting the tracer infusion to measure the background enrichment and those with only a single biopsy after several hours of tracer infusion have been used. To assess the validity of these approaches, we compared the muscle protein FSR obtained by calculating the difference in [ring-(2)H(5)]phenylalanine and [5,5,5-(2)H(3)]leucine incorporation into muscle protein at approximately 3.5 h after starting the tracer infusion and 1) at 60 min; 2) before starting the tracer infusion (background enrichment); 3) a population average muscle protein background enrichment; and 4) by measuring the tracer incorporation into muscle protein at approximately 3.5 h assuming essentially no background enrichment. Irrespective of the tracer used, the muscle protein FSR calculated from the difference in the muscle protein labeling several hours after starting the tracer infusion and either the labeling at 60 min or the background enrichment were not different (e.g., 0.049 +/- 0.007%/h vs. 0.049 +/- 0.007%/h, respectively, with [(2)H(5)]phenylalanine; P = 0.99). However, omitting the initial biopsy and assuming no background enrichment yielded average FSR values that were approximately 15% (with [(2)H(5)]phenylalanine) to 80% (with [(2)H(3)]leucine) greater (P < or = 0.059); using a population average background enrichment reduced the difference to approximately 3% (P = 0.76) and 22% (P = 0.52) with [(2)H(5)]phenylalanine and [(2)H(3)]leucine, respectively. We conclude that during basal, postabsorptive conditions, valid muscle protein FSR values can be obtained irrespective of the timing of the initial biopsy so long as the protein labeling in two sequential biopsies is measured whereas the single biopsy approach should be avoided.

Lymphoma‐Associated Polymyositis in Dogs

Lymphoma‐Associated Polymyositis in Dogs

Progressive myofiber loss with extensive fibro-fatty replacement in a child with mitochondrial DNA depletion syndrome and novel thymidine kinase 2 gene mutations

The mitochondrial DNA depletion syndromes (MDS) are autosomal recessive disorders with a decreased mitochondrial DNA copy number. Mutations in thymidine kinase 2 ( TK2) have been responsible for the myopathic form of MDS. We describe a child with congenital muscle weakness who had a progressive mitochondrial myopathy associated with extensive fibro-fatty replacement of myofibers resembling muscular dystrophy. MDS was suspected based upon findings in the initial muscle biopsy. Sequence analysis of the TK2 gene revealed two novel heterozygous mutations: the frame shift mutation, c.255_c.258delAGAA, and the heterozygous missense mutation, c.515G>A, (p.R172Q). This report extends the phenotype and genotype of TK2 defects.

Predictability of the clinical course of juvenile dermatomyositis based on initial muscle biopsy: A retrospective study of 72 patients

Except when the diagnosis of juvenile dermatomyositis (DM) is in doubt, a case has not been made for routine muscle biopsy (MB). We sought to determine whether MB findings prior to systemic therapy have prognostic value. We reviewed the hospital records and slides prepared from the initial open MB of 72 patients treated at one center between 1977 and 2002 and followed for a minimum of 2 years. None of the patients had received a course of systemic corticosteroid therapy at the time of MB. Our approach to MB evaluation was based on recent discussions with muscle pathology experts to develop criteria for assessing inflammation, vasculopathy, myofiber atrophy, regeneration, acute and chronic myopathic change, and stromal changes. Using simple and multivariate logistic regression, we tested each MB parameter for ability to predict outcome using 2 published classification systems. Extensive active myopathic changes (excluding regeneration) and central nuclei without basophilia predicted chronic juvenile DM. Severe arteropathic change, positive arterial direct immunofluorescence, obvious foci of severe capillary loss/endomysial fibrosis, and muscle infarcts predicted chronic juvenile DM, particularly with ulceration. Other MB parameters, regardless of severity, were not significant predictors of chronic juvenile DM versus limited disease. A scoring system for evaluating pretreatment MB in juvenile DM that focuses on extent of necrotizing myopathy, severity of vasculopathy, and features of established chronicity such as central nucleation of nonbasophilic myofibers may provide a basis for stratification of therapeutic regimens according to risk for chronic disease. The validity of our findings should be prospectively tested.

Clinicopathological and molecular biological studies in a patient with neurolymphomatosis

We describe a patient with a clinical disorder that resembled vasculitic neuropathy in which peripheral nerves were successively affected over several months, but without systemic involvement. An initial muscle biopsy near the involved nerves showed signs of nonspecific inflammation around the muscle and nerve fibers. Immunosuppressive treatment resulted in a dramatic reduction in pain, but relapses of the disease eventually occurred, and the patient died 22 months after onset of the first symptoms. Pathologically, a malignant non-Hodgkin's B-cell lymphoma, restricted to the intra- and extradural peripheral nervous system, was found. The demonstration by Southern blotting of immunoglobulin heavy chain gene rearrangement confirmed the monoclonal nature of the lymphomatous cells. In situ hybridization tests for Epstein-Barr and herpes virus subtypes were negative. Our case underlines i) how difficult diagnosis can be despite extensive investigations, ii) the usefulness of immunosuppressive treatment in the early stage of the disease, iii) the importance of immunostaining and genome analysis for distinguishing between different types of human neurolymphomatosis, and iv) the fact that the initial inflammatory process in the muscle biopsy may be interpreted either as a paraneoplastic effect of the lymphoma or as a viral inflammatory neuromyopathy that triggers the development of the malignant lymphoma.

The therapeutic dilemma of inclusion body myositis

Inclusion body1 myositis (IBM) has unique clinical, histologic, and therapeutic features that distinguish it from other inflammatory myopathies, particularly polymyositis and dermatomyositis. [1-3] Although similar but noninflammatory familial forms are recognized, this editorial is concerned with only the sporadic form of the disease. IBM patients develop slowly progressive weakness, usually after the age of 50. The slow evolution of the disease is one of the primary reasons for the delay in diagnosis, which averages approximately 6 years from the onset of symptoms. [1] Men are much more commonly affected than women. The clinical hallmark of IBM is early weakness and atrophy of the quadriceps, wrist and finger flexors, and ankle dorsiflexors. Severe weakness in these muscle groups is so characteristic of IBM, that even if the classic histologic findings are not present on muscle biopsy, a presumptive diagnosis of possible IBM should be considered. [1,2] Classic light microscopy features are endomysial inflammation with invasion of non-necrotic muscle fibers, eosinophilic cytoplasmic inclusions, and rimmed vacuoles within the muscle fibers that contain amyloid deposits. [4] Electron microscopy reveals an accumulation of cytoplasmic and intranuclear 15- to 21-nm tubofilaments. The inflammatory response consists of macrophages and CD8 sup + cytotoxic/suppressor T lymphocytes and is often the most prominent initial histologic finding. [5] The other pathologic features may not be identified on the initial muscle biopsy, often necessitating second or third biopsy for confirmation. Despite the inflammatory response …

Mitochondrial myopathy simulating spinal muscular atrophy

A patient with a severe progressive neuromuscular disorder resembling spinal muscular atrophy is reported. The initial muscle biopsy was consistent with a denervating process. DNA analysis did not reveal deletions in exons 7 and 8 of the survival motor neuron gene. Histology, histochemistry, and biochemistry of a second muscle biopsy suggested mitochondrial myopathy accompanying the denervating features. Immunohistochemistry using anti-DNA antibodies revealed only nuclear staining in skeletal muscle, suggesting mitochondrial DNA depletion. In patients with clinical features of spinal muscular atrophy and no deletions in the survival motor neuron gene, mitochondrial DNA depletion should be considered.

Sarcoid myopathy and mitochondrial respiratory chain defects: clinicopathological, biochemical and molecular biological analyses

We report on a 33-yr-old female patient with myalgia, CK values up to 3500 Ul −1 and proximal weakness. An initial muscle biopsy showed myositis. One year later an enlarged lymph node was investigated and sarcoidosis diagnosed. In a second muscle biopsy inflammatory cells and morphological characteristics of mitochondrial myopathy were found. Biochemical analyses indicated a 50% reduction in complex II activity of the respiratory chain. Due to failure in clinical improvement a third muscle biopsy was performed in 1990 where only 19% of normal complex II activity was present. Southern blot analysis of the mitochondrial genome was normal. Thus for the first time we describe a patient with sarcoid myopathy and a complex II deficiency. Our interpretation is that a pre-existing complex II defect became clinically relevant because of additional sarcoid myopathy.

Transient Cytoplasmic Bodies in Muscle of Three Infants with Werdnig-Hoffmann Disease

We present three instances in which cytoplasmic bodies in muscle fibers were associated with Werdnig-Hoffmann disease. The children presented within the first 6 weeks of life with clinical symptoms and laboratory studies indicative of infantile spinomuscular atrophy (ISMA). Initial muscle biopsies in each case revealed signs of muscle immaturity and cytoplasmic bodies but lacked features of denervation. Follow-up biopsies in 2 cases revealed changes typical of ISMA, but cytoplasmic bodies were no longer present. A follow-up biopsy was not available in the third child who also had a clinical course consistent with ISMA. We discuss the pathogenesis of cytoplasmic bodies and their significance in association with Werdnig-Hoffmann disease.

Congenital muscular dystrophy: A clinicopathologic report of 24 cases

Congenital muscular dystrophy (muscular dystrophy presenting from birth) with a wide spectrum of clinical severity is reported in 24 patients. Progression of symptoms was evident, leading to significant motor handicap in all patients and death in eight cases. Muscle enzyme studies did not always correlate with the severity of the disease. In six cases, initial muscle biopsy showed only minimal, nonspecific abnormalities; however, characteristic dystrophic changes were evident on repeat biopsies. Histochemical and electron microscopic studies did not show consistent changes, except type I predominance in a few cases. Evidently the condition is rarely, if ever, benign and the clinical course cannot be predicted from the initial presentation or early pathologic findings. Clinical, laboratory and pathologic characteristics are outlined for the diagnosis of this disorder.

Muscle biopsy in polymyositis and dermatomyositis: a clinicopathological study.

The initial muscle biopsies of 30 patients with active polymyositis or dermatomyositis have been assessed histologically and morphometrically. Only 1 patient (3.3%) had a normal biopsy, while 3 had a normal electromyograph and 8 had a normal serum CPK level. No significant morphological differences were found between the various diagnostic subgroups. Sequential biopsies of 11 of these patients treated either with corticosteroids only or with intensive immunosuppression were studied. With response to treatment atrophy factors, variability coefficients, internal nuclei count, and the various histological changes improved in the whole group of patients. However, there was no consistent correlation between any of the morphological features or between these and clinical parameters in individual patients. The percentage of fibres with internal nuclei in the initial biopsy was lower (P < 0.001) in patients responding to up to 60 mg prednisolone per day than in those who eventually required cytotoxic drugs in addition.