[Expert recommendations for magnetic resonance imaging of muscle disorders]. / Expertenempfehlung zur Magnetresonanztomographie bei Muskelerkrankungen.

BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.

[Expert recommendations for magnetic resonance imaging of muscle disorders]. / Expertenempfehlung zur Magnetresonanztomographie bei Muskelerkrankungen.

BACKGROUND: Magnetic resonance (MRI) imaging of the skeletal muscles (muscle MRI for short) is increasingly being used in clinical routine for diagnosis and longitudinal assessment of muscle disorders. However, cross-centre standards for measurement protocol and radiological assessment are still lacking. OBJECTIVES: The aim of this expert recommendation is to present standards for the application and interpretation of muscle MRI in hereditary and inflammatory muscle disorders. METHODS: This work was developed in collaboration between neurologists, neuroradiologists, radiologists, neuropaediatricians, neuroscientists and MR physicists from different university hospitals in Germany. The recommendations are based on expert knowledge and a focused literature search. RESULTS: The indications for muscle MRI are explained, including the detection and monitoring of structural tissue changes and oedema in the muscle, as well as the identification of a suitable biopsy site. Recommendations for the examination procedure and selection of appropriate MRI sequences are given. Finally, steps for a structured radiological assessment are presented. CONCLUSIONS: The present work provides concrete recommendations for the indication, implementation and interpretation of muscle MRI in muscle disorders. Furthermore, it provides a possible basis for the standardisation of the measurement protocols at all clinical centres in Germany.

Quantitative, Dynamic 18F-FDG PET/CT in Monitoring of Smoldering Myeloma: A Case Report.

We report on a 52-year-old patient with an initial diagnosis of smoldering myeloma (SMM), who was monitored by means of dynamic and static positron emission tomography/computed tomography (PET/CT) with the radiotracer 18F-fluorodeoxyglucose (18F-FDG). Baseline PET/CT revealed no pathological signs. Six months later, a transition to symptomatic, multiple myeloma (MM) was diagnosed. The transition was not accompanied by focal, hypermetabolic lesions on PET/CT. However, a diffusely increased 18F-FDG uptake in the bone marrow, accompanied by a marked increase of semi-quantitative (standardized uptake value, SUV) and quantitative, pharmacokinetic 18F-FDG parameters, was demonstrated. After successful treatment, including tandem autologous transplantation, the diffuse uptake in the bone marrow as well as the semi-quantitative and quantitative parameters showed a marked remission. This response was also confirmed by the clinical follow-up of the patient. These findings suggest that in MM a diffuse 18F-FDG uptake in the bone marrow may indeed reflect an actual bone marrow infiltration by plasma cells. Moreover, SUV values and kinetic parameters, not only from myeloma lesions but also from random bone marrow samples, may be used for MM monitoring. This could be particularly helpful in the follow-up of myeloma patients negative for 18F-FDG-avid focal lesions.

Camptocormia as the presenting symptom in sporadic late onset nemaline myopathy: a case report.

BACKGROUND: Camptocormia has been reported in a plethora of diseases comprising disorders of the central nervous system, the peripheral nervous system, and the neuromuscular junction as well as hereditary and acquired myopathies. In sporadic late onset nemaline myopathy concomitant axial myopathy is common, but reports about camptocormia as the only presenting symptom in this condition are very rare. Notably, sporadic late onset nemaline myopathy is a potentially treatable condition in particular when associated with monoclonal gammopathy of unknown significance, HIV or rheumatological disorders. CASE PRESENTATION: We report the case of a 62-year-old female patient, who presented with slowly progressive camptocormia. Comprehensive work-up including neurological work-up, laboratory tests, MR-imaging, muscle biopsy and genetic testing led to the diagnosis of sporadic late onset nemaline myopathy. CONCLUSIONS: Our case report highlights that sporadic late onset nemaline myopathy has to be considered in patients presenting with isolated camptocormia and comprehensive work-up of camptocormia is mandatory to ascertain the individual diagnosis, especially in consideration of treatable conditions.

Myositis and neuromuscular side-effects induced by immune checkpoint inhibitors.

AIM: To characterise clinical presentation, laboratory and histopathologic characteristics and assess the treatment and outcome of neuromuscular side-effects of checkpoint therapy. METHODS: The side-effect registry and the institutional database from ten skin cancer centres were queried for reports on myositis and neuromuscular side-effects induced by checkpoint inhibitors. In total, 38 patients treated with ipilimumab, tremelimumab, nivolumab and pembrolizumab for metastatic skin cancer were evaluated and characterised. RESULTS: Myositis was the most frequent neuromuscular adverse event. In 32% of cases, myositis was complicated by concomitant myocarditis. Furthermore, cases of isolated myocarditis, myasthenia gravis, polymyalgia rheumatica, radiculoneuropathy and asymptomatic creatine kinase elevation were reported. The onset of side-effects ranged from the first week of treatment to 115 weeks after the start of therapy. Most of the cases were severe (49% grade III-IV Common Terminology Criteria for Adverse Events), and there were two fatalities (5%) due to myositis and myositis with concomitant myocarditis. Only half of the cases (50%) completely resolved, whereas the rest was either ongoing or had sequelae. Steroids were given in 80% of the resolved cases and in 40% of the unresolved cases. CONCLUSION: Immune-mediated neuromuscular side-effects of checkpoint inhibitors greatly vary in presentation and differ from their idiopathic counterparts. These side-effects can be life threatening and may result in permanent sequelae. Occurrence of these side-effects must be taken into consideration for patient information, especially when considering adjuvant immunotherapy with anti-programmed cell-death protein 1 (PD-1) antibodies and monitoring, which should include regular surveillance of creatine kinase.

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding.

RYR1 mutations, the most common cause of non-dystrophic neuromuscular disorders, are associated with the malignant hyperthermia susceptibility (MHS) trait as well as congenital myopathies with widely variable clinical and histopathological manifestations. Recently, bleeding anomalies have been reported in association with certain RYR1 mutations. Here we report a preterm infant born at 32 weeks gestation with arthrogryposis multiplex congenita due to compound heterozygous, previously MHS-associated RYR1 mutations, with additional signs of prenatal hemorrhage. The patient presented at birth with multiple joint contractures, scoliosis, severe thoracic rigidity and respiratory failure. He continued to depend on mechanical ventilation and tube feeding. Muscle histopathology showed a marked myopathic pattern with eccentric cores. Interestingly, the patient had additional unusual prenatal intraventricular hemorrhage, resulting in post-hemorrhagic hydrocephalus as well as epidural hemorrhage affecting the spinal cord. This report adds to the phenotypic variability associated with RYR1 mutations, and highlights possible bleeding complications in affected individuals.

Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients. PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.

VCP and PSMF1: Antagonistic regulators of proteasome activity.

Protein turnover and quality control by the proteasome is of paramount importance for cell homeostasis. Dysfunction of the proteasome is associated with aging processes and human diseases such as neurodegeneration, cardiomyopathy, and cancer. The regulation, i.e. activation and inhibition of this fundamentally important protein degradation system, is still widely unexplored. We demonstrate here that the evolutionarily highly conserved type II triple-A ATPase VCP and the proteasome inhibitor PSMF1/PI31 interact directly, and antagonistically regulate proteasomal activity. Our data provide novel insights into the regulation of proteasomal activity.