Cross-sectional study of patients with VCP multisystem proteinopathy 1 using dual-energy x-ray absorptiometry.

INTRODUCTION/AIMS: VCP multisystem proteinopathy 1 (MSP1), encompassing inclusion body myopathy (IBM), Paget's disease of bone (PDB) and frontotemporal dementia (FTD) (IBMPFD), features progressive muscle weakness, fatty infiltration, and disorganized bone structure in Pagetic bones. The aim of this study is to utilize dual-energy x-ray absorptiometry (DXA) parameters to examine it as a biomarker of muscle and bone disease in MSP1. METHODS: DXA scans were obtained in 28 patients to assess body composition parameters (bone mineral density [BMD], T-score, total fat, and lean mass) across different groups: total VCP disease (n = 19), including myopathy without Paget's ("myopathy"; n = 12) and myopathy with Paget's ("Paget"; n = 7), and unaffected first-degree relatives serving as controls (n = 6). RESULTS: In the VCP disease group, significant declines in left hip BMD and Z-scores were noted versus the control group (p ≤ .03). The VCP disease group showed decreased whole body lean mass % (p = .04), and increased total body fat % (p = .04) compared to controls. Subgroup comparisons indicated osteopenia in 33.3% and osteoporosis in 8.3% of the myopathy group, with 14.3% exhibiting osteopenia in the Paget group. Moreover, the Paget group displayed higher lumbar L1-L4 T-score values than the myopathy group. DISCUSSION: In MSP1, DXA revealed reduced bone and lean mass, and increased fat mass. These DXA insights could aid in monitoring disease progression of muscle loss and secondary osteopenia/osteoporosis in MSP1, providing value both clinically and in clinical research.

Imaging With PET/CT of Diffuse CD8 T-Cell Infiltration of Skeletal Muscle in Patients With Inclusion Body Myositis.

BACKGROUND AND OBJECTIVES: Inclusion body myositis (IBM) is a progressive autoimmune skeletal muscle disease in which cytotoxic CD8+ T cells infiltrate muscle and destroy myofibers. IBM has required a muscle biopsy for diagnosis. Here, we administered to patients with IBM a novel investigational PET tracer 89Zr-Df-crefmirlimab for in vivo imaging of whole body skeletal muscle CD8 T cells. This technology has not previously been applied to patients with autoimmune disease. METHODS: Four patients with IBM received 89Zr-Df-crefmirlimab followed by PET/CT imaging 24 hours later, and the results were compared with similar imaging of age-matched patients with cancer. Mean standardized uptake value (SUVmean) was measured for reference tissues using spherical regions of interest (ROIs). RESULTS: 89Zr-Df-crefmirlimab was safe and well-tolerated. PET imaging demonstrated diffusely increased uptake qualitatively and quantitatively in IBM limb musculature. Quantitation of 89Zr-Df-crefmirlimab intensity in ROIs demonstrated particularly increased CD8 T-cell infiltration in patients with IBM compared with patients with cancer in quadriceps (SUVmean 0.55 vs 0.20, p < 0.0001), biceps brachii (0.62 vs 0.26, p < 0.0001), triceps (0.61 vs 0.25, p = 0.0005), and forearm finger flexors (0.71 vs 0.23, p = 0.008). DISCUSSION: 89Zr-Df-crefmirlimab uptake in muscles of patients with IBM was present at an intensity greater than the comparator population. The ability to visualize whole body in vivo cytotoxic T-cell tissue infiltration in the autoimmune disease IBM may hold utility as a biomarker for diagnosis, disease activity, and therapeutic development and potentially be applicable to other diseases with cytotoxic T-cell autoimmunity.

Correlation of muscle ultrasound with clinical and pathological findings in idiopathic inflammatory myopathies.

INTRODUCTION/AIMS: In idiopathic inflammatory myopathies (IIMs), the change in muscle echogenicity and its histopathological basis are not well understood. We quantitatively measured muscle echogenicity in patients with IIMs and evaluated its correlation with disease activity and histopathological findings. METHODS: This study involved patients with IIMs who underwent both ultrasonography (US) and muscle biopsy, as well as age- and sex-matched rheumatoid arthritis patients as inflammatory disease controls. On US, axial images of the right biceps brachii and vastus medialis were obtained. Standardized histopathological scoring was used to quantitatively measure each pathological domain. RESULTS: Forty-two patients (17 with inclusion body myositis [IBM] and 25 with IIMs other than IBM) and 25 controls were included. The muscle echo intensity (EI) of patients with IIMs was significantly higher than that of controls. Muscle EI showed significant correlations with creatine kinase (r = 0.66, p < .001) and muscle strength (r = -0.73, p < .0001) in patients with non-IBM IIMs. In patients with IBM, moderate correlation was found between muscle EI and quadriceps muscle strength (r = -0.53, p = .028). Histopathologically, the number of infiltrating CD3+ inflammatory cells correlated with muscle EI in the non-IBM group (r = 0.56, p = .017), but not in the IBM group. DISCUSSION: Muscle EI may be useful as a surrogate marker of muscle inflammation in non-IBM IIM. Increased muscle EI may be difficult to interpret in patients with long-standing IBM, which has advanced and complex histopathology.

Role of MRI in idiopathic inflammatory myopathies: a review article.

Idiopathic inflammatory myopathies are a rare heterogeneous group of chronic, autoimmune conditions characterized by the slow, progressive weakness of the skeletal muscles and inflammatory infiltrates in the muscle tissue. The predominant role of magnetic resonance imaging (MRI) in myositis imaging is to assess disease activity and to identify the target site for biopsy. Its role in phenotyping the disease is less explored. The aim of the present review was to examine the role of MRI in differentiating between the common inflammatory myopathies, i.e. dermatomyositis, polymyositis, and sporadic inclusion body myositis, and to describe the specific spectrum of MRI findings in various inflammatory myopathies.

Correlation Between Quantitative MRI and Muscle Histopathology in Muscle Biopsies from Healthy Controls and Patients with IBM, FSHD and OPMD.

BACKGROUND: Muscle MRI is increasingly used as a diagnostic and research tool in muscle disorders. However, the correlation between MRI abnormalities and histopathological severity is largely unknown. OBJECTIVE: To investigate correlations between muscle MRI abnormalities and histopathological severity in healthy controls and patients with muscle disease. METHODS: We performed quantitative MRI and histopathological analysis in 35 patients with inclusion body myositis, facioscapulohumeral muscular dystrophy or oculopharyngeal muscular dystrophy and 12 healthy controls. Participants contributed needle biopsies of the vastus lateralis and/or tibialis anterior, yielding 77 muscle biopsies with matched T1, T2 and TIRM MRI imaging. Muscle biopsies were evaluated with a semi-quantitative histopathology severity grading scale (range 0-12) and an inflammation severity grading scale (range 0-3). RESULTS: In muscle disease, histopathology sum scores ranged from 0 to 11 and correlated significantly with fat percentage as measured on MRI (Spearman's rho = 0.594, p < 0.001). Muscle edema on muscle MRI was associated with increased amounts of inflammation (p < 0.001). Mild abnormalities occured in 95% of control biopsies and were more pronounced in tibialis anterior (median sum score of 1±1 in vastus lateralis and 2±1 in tibialis anterior (p = 0.048)). CONCLUSION: In muscle disease, fatty infiltration on MRI correlates moderately with muscle histopathology. Histopathological abnormalities can occur prior to the onset of fatty infiltration. In middle-aged controls, almost all biopsies showed some histopathological abnormalities. The findings from this study may facilitate the choice for appropriate imaging sequences as outcome measures in therapeutic trials.

Sporadic inclusion body myositis: a rare hazardous entity with important imaging findings.

Inclusion body myositis is a rare acquired muscle disease that predominantly affects individuals older than 45 years of age and that has been classified as an idiopathic inflammatory myopathy. However, it has a distinct course being characterized by a slowly progressive weakness and resistance to immunosuppressive therapy. This diagnosis is usually based on a typical clinical presentation, elevated serum skeletal muscle enzymes, electromyographic findings and muscle biopsy. Magnetic Resonance Imaging (MRI) can aid in the diagnosis by directing muscle biopsy sites through accurate localization of muscle involvement, which avoids the high false-negative rate of blind muscle biopsies. MRI can also depict the nature and extent of muscle abnormalities with high signal intensity seen in the active phase and refractory treated patients on fluid-sensitive images. Recently, there has been important progress in the understanding of IBM. These advances may lead to improved diagnosis and the discovery of effective drug treatments for this debilitating entity with usually poor prognosis and high levels of disability.

Differential Diagnoses of Inclusion Body Myositis.

Inclusion body myositis is a slowly progressive myopathy, characteristically affecting quadriceps and long finger flexors. Atypical presentations do occur, however, and there is overlap with other myopathies, including inflammatory and hereditary etiologies. This article discusses atypical cases and differential diagnoses and considers the role of imaging and histopathology in differentiating inclusion body myositis.

Association between muscle strength, histopathology, and magnetic resonance imaging in sporadic inclusion body myositis.

OBJECTIVES: Inclusion body myositis is characterized by inflammatory and degenerative changes, but the temporal relation of these events is unknown. MATERIALS AND METHODS: In nineteen patients with inclusion body myositis, muscle strength was correlated with inflammatory and degenerative findings on magnetic resonance imaging (MRI) and in muscle biopsies in three different muscles (tibialis anterior, vastus lateralis, and biceps brachii). Muscle strength, measured with a handheld dynamometer, was described as percentage of muscle strength in age- and sex-matched normal individuals. The muscles were categorized as the strongest, the intermediate, and the weakest muscle in each individual. T1-weighted sequences on MRI were used to evaluate the degree of fatty infiltration and muscle atrophy and STIR sequences to evaluate edematous changes. RESULTS: The vastus lateralis, which in general was the weakest muscle, was significantly more atrophic compared to the other two muscles and also demonstrated most edema. The biceps brachii had in most cases an intermediate degree of weakness and atrophy but the most pronounced inflammatory cell infiltration on biopsy. Cytochrome c oxidase-negative muscle fibers were significantly more prevalent in the vastus lateralis and biceps brachii muscles than in the tibialis anterior and thus correlated with muscular atrophy, indicating that this is a secondary change. Inflammatory changes as assessed by MRI and muscle biopsy were seen in all muscles irrespective of atrophy and thus appear to be prevalent at all stages of the disease. CONCLUSIONS: Our study could not provide an answer to the question which comes first, the inflammation or the degenerative changes.

[Inclusion Body Myopathy, Paget's Disease, and Fronto-temporal Dementia: a VCP-related Multi-systemic Proteinopathy]. / Einschlusskörpermyopathie, Paget-Krankheit und frontotemporale Demenz: eine VCP-bedingte, multisystemische Proteinopathie.

Mutations of the human VCP gene, which encodes the V: alosin C: ontaining P: rotein (synonyms: p97, TER ATPase), are associated with various multi-systemic protein aggregation diseases. We report on a patient with progressive myopathy and incipient cognitive deficits. A diagnostic muscle biopsy revealed an inclusion body myopathy with protein aggregates. Magnetic resonance imaging and F18-positron-emission-tomography disclosed a fronto-temporal atrophy and glucose hypometabolism of the frontal and temporal lobes, respectively. Based on the clinical findings, a genetic analysis was performed which revealed a heterozygous c.277C>T (p.Arg93Cys) mutation of the VCP gene, thus confirming the diagnosis of IBMPFD (I: nclusion B: ody M: yopathie with P: aget Disease of the Bones and F: ronto-temporal D: ementia).

Muscle Shear Wave Elastography in Inclusion Body Myositis: Feasibility, Reliability and Relationships with Muscle Impairments.

Degenerative muscle changes may be associated with changes in muscle mechanical properties. Shear wave elastography (SWE) allows direct quantification of muscle shear modulus (MSM). The aim of this study was to evaluate the feasibility and reliability of SWE in the severely disordered muscle as observed in inclusion body myositis. To explore the clinical relevance of SWE, potential relationships between MSM values and level muscle impairments (weakness and ultrasound-derived muscle thickness and echo intensity) were investigated. SWE was performed in the biceps brachii at 100°, 90°, 70° and 10° elbow flexion in 34 patients with inclusion body myositis. MSM was assessed before and after five passive stretch-shortening cycles at 4°/s from 70° to 10° elbow angle and after three maximal voluntary contractions to evaluate potential effects of muscle pre-conditioning. Intra-class correlation coefficients and standard errors of measurements were >0.83 and <1.74 kPa and >0.64 and <1.89 kPa for within- and between-day values, respectively. No significant effect of passive loading-unloading and maximal voluntary contractions was found (all p values >0.18). MSM correlated to predicted muscle strength (all Spearman correlation coefficients (ρ) > 0.36; all p values < 0.05). A significant correlation was found between muscle echo intensity and muscle shear modulus at 70° only (ρ = 0.38, p <0.05). No correlation was found between muscle thickness and MSM (all ρ values > 0.23 and all p values > 0.25, respectively). Within- and between-day reliability of muscle SWE was satisfactory and moderate, respectively. SWE shows promise for assessing changes in mechanical properties of the severely disordered muscle. Further investigations are required to clarify these findings and to refine their clinical value.

Sporadic Inclusion Body Myositis: MRI Findings and Correlation With Clinical and Functional Parameters.

OBJECTIVE: The purpose of this prospective study is to assess MRI findings in patients with sporadic inclusion body myositis (IBM) and correlate them with clinical and functional parameters. SUBJECTS AND METHODS: This study included 12 patients with biopsy-proven sporadic IBM. All patients underwent MRI of the bilateral upper and lower extremities. The images were scored for muscle atrophy, fatty infiltration, and edema pattern. Clinical data included onset and duration of disease. Muscle strength was measured using the Medical Research Council (MRC) scale, and functional status was assessed using the Modified Rankin Scale. Correlation between MRI and different clinical and functional parameters was calculated using the Spearman rank test and Pearson correlation. RESULTS: All patients showed MRI abnormalities, which were more severe within the lower limbs and the distal segments. The most prevalent MRI finding was fat infiltration. There was a statistically significant correlation between disease duration and number of muscles infiltrated by fat (r = 0.65; p = 0.04). The number of muscles with fat infiltration correlated with the sum of the scores of MRC (r = -0.60; p = 0.04) and with the Modified Rankin Scale (r = 0.48; p = 0.03). CONCLUSION: Our findings suggest that most patients with biopsy-proven sporadic IBM present with a typical pattern of muscle involvement at MRI, more extensively in the lower extremities. Moreover, MRI findings strongly correlated with clinical and functional parameters, because both the extent and severity of muscle involvement assessed by MRI and clinical and functional parameters are associated with the early onset of the disease and its duration.

A Case of Asymptomatic Inclusion Body Myositis.

OBJECTIVES: To present a case of asymptomatic inclusion body myositis. METHODS: The authors report a case of a 67-year-old man who presented with idiopathic hyperCKemia. Physical examination including a complete neurological evaluation was unremarkable. Systemic causes of hyperCKemia, including medication side effects, metabolic and endocrine disorders, and connective tissue disorders, were ruled out with various indicated tests. RESULTS: Two and a half years after initial consultation, the patient reported left knee pain. Magnetic resonance imaging of the left knee showed edema in the mid and distal aspect of the vastus medialis and vastus lateralis muscles. A biopsy of the left quadriceps muscles was diagnostic of inclusion body myositis. He remained asymptomatic for the ensuing 2.5 years. CONCLUSIONS: Asymptomatic hyperCKemia should be investigated and followed closely for definitive diagnosis and possible treatable causes.

Preoperative and intraoperative ultrasound aids removal of migrating plant material causing iliopsoas myositis via ventral midline laparotomy: a study of 22 dogs.

BACKGROUND: Migrating plant material is often suspected clinically to be the underlying cause of iliopsoas myositis in the dog, but cannot always be found pre- or intraoperatively. In most cases, recurrence of clinical signs is related to failure to remove the plant material. Preoperative ultrasonography can be useful to visualize migrating plant material and to determine anatomical landmarks that can assist in planning a surgical approach. The purpose of the present study was to report the role of intraoperative (intra-abdominal) ultrasonography for visualizing and removing the plant material from iliopsoas abscesses using a ventral midline laparotomy approach. RESULTS: A retrospective case series of 22 dogs with iliopsoas muscle abnormalities and suspected plant material was reported. Preoperative visualization and subsequent retrieval of the plant material was performed during a single hospitalization. In all 22 dogs, the plant material (including complete grass awns, grass awn fragments and a bramble twig) was successfully removed via ventral midline laparotomy in which intraoperative ultrasonography was used to direct the grasping forceps tips to the foreign body and guide its removal. In 11 of these 22 dogs, the plant material was not completely removed during prior surgery performed by the referring veterinarians without pre- or intraoperative ultrasonography. Clinical signs resolved in all dogs and all dogs resumed normal activity after successful surgical removal of the plant material. CONCLUSION: Intraoperative ultrasonography is a safe and readily available tool that improves success of surgical removal of plant material within the iliopsoas abscesses via ventral midline laparotomy. Moreover, ultrasonographic findings of unusual plant material can be useful in planning and guiding surgical removal, by providing information about the size and shape of the foreign body.

Diagnostic criteria for inclusion body myositis.

Inclusion body myositis (IBM) was first identified as a specific disorder about 40 years ago and is now recognized to be the most frequently presenting primary myopathy in middle age and beyond. Initial characterization was based on the observation of specific pathological features distinguishing it from polymyositis. It was soon appreciated that there were also distinguishing clinical features. The earliest diagnostic criteria were heavily biased towards pathological features, but over time revised criteria have given increasing importance to certain clinical features. Until the specific cause of IBM is determined, and the basic pathogenetic mechanisms are better understood, there can be no diagnostic gold-standard against which to compare the sensitivity and specificity of any proposed diagnostic criteria, but such criteria are essential to ensure that patients entering clinical, epidemiological, genetic, pathological or therapeutic studies represent a homogeneous population. It is likely that any currently accepted diagnostic criteria will, once a gold-standard is eventually established, be shown to have 'missed' patients with atypical features, but that has to be accepted to make certain that current studies are not contaminated by patients who do not have IBM. In other words, in everyday clinical practice there will be the occasional patient who an experienced myologist strongly suspects has IBM, but does not meet current criteria - the criteria lack sensitivity. But if the criteria are so broad as to include all such atypical cases, they would be likely to include patients who do not in fact have IBM - they would lack specificity. The sensitivity and specificity of existing criteria have been reviewed recently, in so far as it is possible to do so, and found to have high specificity but variable sensitivity.

Inclusion body myositis masquerading as cardiac dyspnea.

Dyspnea in the elderly can be due to a wide array of pathologies. We discuss a case of an elderly gentleman with an extensive cardiovascular history presenting with acute worsening of chronic dyspnea. Because of persistent respiratory distress unresponsive to standard therapy for congestive heart failure, chronotropic insufficiency, and pulmonary hypertension, further evaluation was undertaken which revealed that diaphragmatic weakness was the etiology of his respiratory failure. EMG and muscle biopsy confirmed the diagnosis of inclusion body myositis (IBM).

Radiological features of Paget disease of bone associated with VCP myopathy.

OBJECTIVE: Mutations in the Valosin-containing protein (VCP) gene cause a unique disorder characterized by classic Paget disease of bone (PDB), inclusion body myopathy, and frontotemporal dementia (IBMPFD). Our objective was to analyze the radiographic features of PDB associated with VCP mutations since there is a dearth of literature on the PDB component of VCP disease. MATERIALS AND METHODS: Radiographic bone surveys were examined in 23 individuals with VCP mutation and compared with their unaffected relatives. Laboratory testing relevant for VCP disease was performed in all individuals. RESULTS: Of the 17 affected individuals with clinical manifestations of VCP disease, 16 of whom had myopathy, radiographic analysis revealed classic PDB in 11 individuals (65%). The mean age of diagnosis for myopathy was 43.8 years and for PDB was 38.1 years of age. Radiological evidence of PDB was seen in one individual (16%) amongst six clinically asymptomatic VCP mutation carriers. Alkaline phosphatase was a useful marker for diagnosing PDB in VCP disease. CONCLUSIONS: Radiographic findings of classic PDB are seen in 52% of individuals carrying VCP mutations at a significantly younger age than conventional PDB. Screening for PDB is warranted in at-risk individuals because of the benefit of early treatment with the new powerful bisphosphonates that hold the potential for prevention of disease.

Left ventricular hypertrabeculation/noncompaction in hereditary inclusion body myopathy.

Left ventricular hypertrabeculation (LVHT) also known as noncompaction has not been reported in association with hereditary inclusion body myopathy (IBM). In a 62 year old Caucasian male, with a history of muscle stiffness, myalgias, recurrent hyper-creatin-kinase(CK)-aemia, muscle cramps particularly during cold, polyarthralgias, a family history positive for muscle cramping and muscle disease, normal clinical neurologic examination, and myogenic needle EMG, muscle biopsy was indicative of hereditary IBM. Cardiologic investigations revealed arterial hypertension, left anterior hemiblock, slight myocardial thickening, and surprisingly lone LVHT. LVHT was not associated with arrhythmias, systolic dysfunction, or cardioembolic events, No neurological or cardiac therapy was necessary. During a follow-up of 18 months neither the neurological nor the cardiologic abnormalities progressed. LVHT may also occur in patients with IBM. Patients with hereditary IBM should be investigated for cardiac involvement, which may manifest not only as myocardial damage but also as impulse propagation abnormalities.