[Myofasciitis under nivolumab treatment]. / Myofasziitis unter Nivolumab-Therapie.

We report the case of a 73-year-old female patient with malignant melanoma who developed rapidly progressive dermatosclerosis of the arms and legs as well as myalgia and flexion contractures during treatment with the immune checkpoint inhibitor nivolumab. The diagnosis of a myofasciitis was confirmed by imaging and biopsy. Following consultation with the treating dermato-oncologists nivolumab treatment was paused and treatment with methotrexate and prednisolone was initiated. Immune checkpoint inhibitors can induce a variety of immune-mediated side effects and can also imitate symptoms of rheumatological diseases. The occurrence of myofasciitis under immune checkpoint inhibition has been reported in the literature only in a few cases. Further oncological and rheumatological treatment management should be carried out in close interdisciplinary coordination.

A spontaneous missense mutation in the chromodomain helicase DNA-binding protein 8 (CHD8) gene: a novel association with congenital myasthenic syndrome.

AIMS: Congenital myasthenic syndromes (CMS) are characterized by muscle weakness, ptosis and episodic apnoea. Mutations affect integral protein components of the neuromuscular junction (NMJ). Here we searched for the genetic basis of CMS in female monozygotic twins. METHODS: We employed whole-exome sequencing for mutation detection and Sanger sequencing for segregation analysis. Immunohistology was done with antibodies against CHD8, rapsyn, ß-catenin (ßCAT) and golgin on fi-bro-blasts, human and mouse muscle. We recorded superresolution images of the NMJ using 3D-structured illumination microscopy. RESULTS: We discovered a spontaneous missense mutation in CHD8 [chr14:g.21,884,051G>A, GRCh37.p11 | c.1732C>T, NM_00117062 | p.(R578C)], the gene encoding chromodomain helicase DNA-binding protein 8. This is the first missense mutation affecting Duplin, the short 110 kDa isoform of CHD8. It is known that CHD8/Duplin negatively regulates ßCAT signalling in the WNT pathway and plays a role in chromatin remodelling. Inactivating CHD8 mutations are associated with autism spectrum disorder and intellectual disability in combination with facial dysmorphism, overgrowth and macrocephalus. No muscle-specific phenotype has been reported to date. Co-immunostaining with rapsyn on human and mouse muscle revealed a strong presence of CHD8 at the NMJ being located towards the sarcoplasmic side of the rapsyn cluster, where it co-localizes with ßCAT. CONCLUSION: We hypothesize CHD8 to have a role in the maintenance of the structural integrity and function of the NMJ. Both patients benefited from treatment with 3,4-diaminopyridine, a reversible blocker of voltage-gated potassium channels at the nerve terminal that prolongs the action potential and increases acetylcholine release.

An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease.

AIMS: Pompe disease is caused by pathogenic mutations in the alpha 1,4-glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype-phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability. METHODS: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology-score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule-associated protein 1A/1B-light chain 3, p62 and Bcl2-associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies. RESULTS: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology-score. High morphology-scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology-score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine-kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.-32-13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type. CONCLUSIONS: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.

Practical implementation of robust MR-thermometry during clinical MR-guided microwave ablations in the liver at 1.5 T.

Practical non-invasive equipment modifications and effective acquisition methods to achieve robust and reliable real-time MR thermometry for monitoring of clinical hepatic microwave ablations were implemented. These included selection of the microwave generator location (inside versus outside the MR scan room), the number of radiofrequency chokes added to the microwave generator's coaxial lines, and the use of copper wool to maximize their electrical grounding. Signal-to-noise ratio (SNR) of MR thermometry images of a small fluid-filled phantom acquired during activation of microwave antenna were used to evaluate image quality as a function of each modification. SNR measurements corresponding to both locations of the microwave generator were comparable and so it was located outside the MR scan room. For this location, addition of one RF choke on the power and four chokes on the sensor coaxial lines was found to be optimal, corresponding to a 68% increase in SNR. Furthermore, image quality strongly depended on the proper electrical grounding of the power and sensor lines. SNR ratio (relative to SNR of baseline images) during activation of microwave generator was found to be 0.49 ±â€¯0.28 without adequate grounding, and 0.88 ±â€¯0.08 with adequate grounding (p = 0.002, Student's t-test). These SNR measurements were sufficiently sensitive to detect issues related to equipment performance and hence formed part of the quality assurance testing performed prior to each clinical treatment. Incorporating these non-invasive approaches resulted in significant improvements to image quality and, importantly while maintaining the clinical integrity of the microwave system which is of paramount importance in a highly regulated healthcare environment.

[Peripheral nerve involvement in rheumatic diseases]. / Periphere Nervenbeteiligung bei rheumatischen Erkrankungen.

Peripheral neuropathies are probably an under-diagnosed complication of many rheumatic diseases. In some cases they take a mild clinical course, in others they cause severe impairment of patients' quality of life. A precise diagnosis and etiological classification are of major importance for successful treatment and prognosis of peripheral neuropathies. A detailed patient history and physical examination are the foundation of every diagnostic approach. Electrophysiological studies are obligatory when peripheral neuropathy is suspected, whereas nerve or nerve-muscle biopsies are indicated only in selected cases. Therapeutic approaches are often complicated by a lack of evidence. They correspond to frequently tested immunosuppressive treatment of the underlying disease, such as glucocorticoids, cyclophosphamide, mycophenolate mofetil and intravenous immunoglobulins and are based on the symptomatic pain treatment of other neuropathies. As first-line treatment gabapentin, pregabalin, duloxetine, venlafaxine and tricyclic antidepressants are frequently used.

Diagnostic potential of sarcoplasmic myxovirus resistance protein A expression in subsets of dermatomyositis.

AIMS: To elucidate the diagnostic value of sarcoplasmic expression of myxovirus resistance protein A (MxA) for dermatomyositis (DM) specifically analysing different DM subforms, and to test the superiority of MxA to other markers. METHODS: Immunohistochemistry for MxA and retinoic acid-inducible gene I (RIG-I) was performed on skeletal muscle samples and compared with the item presence of perifascicular atrophy (PFA) in 57 DM patients with anti-Mi-2 (n = 6), -transcription intermediary factor 1 gamma (n = 10), -nuclear matrix protein 2 (n = 13), -melanoma differentiation-associated gene 5 (MDA5) (n = 10) or -small ubiquitin-like modifier activating enzyme (n = 1) autoantibodies and with no detectable autoantibody (n = 17). Among the patients, nine suffered from cancer and 22 were juvenile-onset type. Disease controls included antisynthetase syndrome (ASS)-associated myositis (n = 30), immune-mediated necrotizing myopathy (n = 9) and inclusion body myositis (n = 5). RESULTS: Sarcoplasmic MxA expression featured 77% sensitivity and 100% specificity for overall DM patients, while RIG-I staining and PFA reached respectively 14% and 59% sensitivity and 100% and 86% specificity. In any subset of DM, sarcoplasmic MxA expression showed higher sensitivity than RIG-I and PFA. Some anti-MDA5 antibody-positive DM samples distinctively showed a scattered staining pattern of MxA. No ASS samples had sarcoplasmic MxA expression even though six patients had DM skin rash. CONCLUSIONS: Sarcoplasmic MxA expression is more sensitive than PFA and RIG-I expression for a pathological diagnosis of DM, regardless of the autoantibody-related subgroup. In light of its high sensitivity and specificity, it may be considered a pathological hallmark of DM per se. Also, lack of MxA expression in ASS supports the idea that ASS is a distinct entity from DM.

Integrated classification of inflammatory myopathies.

Inflammatory myopathies comprise a multitude of diverse diseases, most often occurring in complex clinical settings. To ensure accurate diagnosis, multidisciplinary expertise is required. Here, we propose a comprehensive myositis classification that incorporates clinical, morphological and molecular data as well as autoantibody profile. This review focuses on recent advances in myositis research, in particular, the correlation between autoantibodies and morphological or clinical phenotypes that can be used as the basis for an 'integrated' classification system.

Immune-mediated necrotizing myopathy.

BACKGROUND: Immune-mediated necrotizing myopathy (IMNM) is a newly identified subgroup of idiopathic inflammatory myopathies. It is defined as a rare and severe disease, with symmetrical and proximal muscle weakness and a characteristic histology. An autoimmune aspect of IMNM is suggested by its association with autoantibodies directed against signal recognition particle (SRP) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in the majority of patients. Statin use is strongly associated with anti-HMGCR-positive IMNM. The pathophysiological mechanisms of this disease are still poorly understood, and as a result, no therapeutic strategy has been validated to date. OBJECTIVE: The aim of this article is to provide an overview of the current knowledge about epidemiology, clinical features, and pathophysiology of IMNM, as well as treatment strategies. RESULTS AND CONCLUSION: IMNM is a subject of widespread interest, with quick and meaningful advances being made. In recent years, huge progress has been made in terms of diagnosis and patient management. However, the understanding of pathophysiological mechanisms and treatment strategies still requires further investigation.

The most fulminant course of the Marburg variant of multiple sclerosis-autopsy findings.

Multiple sclerosis (MS) is usually a chronic and disabling inflammatory disease. Marburg's type of MS is characterized by rapid progression and severe disease course that leads to death within one year after the onset of clinical signs. We describe a fulminant clinical presentation of this malignant subtype of MS and discuss the neuropathological hallmarks as well as differential diagnoses of other fulminant demyelinating diseases. To the best of our knowledge, this is the most fulminant course of this MS variant reported in the literature.

T1/ST2 promotes T helper 2 cell activation and polyfunctionality in bronchopulmonary mycosis.

Interleukin (IL)-33 enhances T helper (Th)2 immunity via its receptor T1/ST2. Infection with the yeast-like pathogen Cryptococcus neoformans is usually controlled by a Th1-mediated immune response. The mechanisms responsible for nonprotective Th2 immunity leading to allergic inflammation in pulmonary cryptococcosis are still not fully understood. Using a murine pulmonary model of C. neoformans infection, we report that T1/ST2 expression correlates with the intensity of Th2 activation, as demonstrated by the expression of CD25 and CD44 and downregulation of CD62L. Antigen-specific T1/ST2(+) Th cells are the primary source of the Th2 cytokines IL-5 and IL-13 as compared with wild-type T1/ST2(-) Th cells or Th cells from T1/ST2(-/-) mice. In addition, T1/ST2(+) Th cells almost exclusively contain bi- and trifunctional Th2 cytokine-producing Th cells compared with T1/ST2(-) Th cells or Th cells from T1/ST2(-/-) mice. Finally, T1/ST2-driven Th2 development resulted in defective pulmonary fungal control. These data demonstrate that T1/ST2 directs Th2 cell activation and polyfunctionality in allergic bronchopulmonary mycosis.

Review: immune-mediated necrotizing myopathies--a heterogeneous group of diseases with specific myopathological features.

Immune-mediated necrotizing myopathies (IMNMs) are now well recognized among the so-called idiopathic inflammatory myopathies (IIMs), which also comprise dermatomyositis (DM), polymyositis (PM), sporadic inclusion body myositis (sIBM) and non-specific myositis. All of these conditions are defined on the basis of distinct clinical symptoms, in combination with results derived from muscle biopsy and additional data, such as measurement of the serum creatine kinase (CK) level as well as myositis-associated and myositis-specific autoantibodies, electromyography (EMG) and modern imaging techniques. Importantly, diagnosis of one of the above mentioned myositis forms implies a specific clinical syndrome or a distinct disease. However, there is considerable clinical heterogeneity, and overlap requiring further diagnostic precision. Classification and subclassification of IIMs are highly debated and the subjects of intense research, especially as clinical trials with anti-inflammatory agents should follow universally defined and accepted criteria. This review focuses on the description of the spectrum of immune-mediated necrotizing myopathies with an emphasis on their myopathological features.

Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis.

T helper (Th)1 and Th2 cells play decisive roles in the regulation of resistance vs. susceptibility to pulmonary cryptococcosis. To study the function of interleukin (IL)-4 receptor (IL-4R) on Th cells in pulmonary cryptococcosis, we infected mice specifically lacking IL-4Rα on CD4(+) T cells (Lck(Cre)IL-4Rα(-/lox) mice) and IL-4Rα(-/lox) controls. Lck(Cre)IL-4Rα(-/lox) mice developed enhanced resistance accompanied by reduced pulmonary allergic inflammation and diminished production of the Th2 cytokines IL-4, IL-5, and IL-13 as compared with IL-4Rα(-/lox) mice. Polyfunctional antigen-specific Th2 cells producing simultaneously two or three Th2 cytokines were reduced in infected Lck(Cre)IL-4Rα(-/lox) mice, pointing to a critical role of polyfunctional Th2 cells for disease progression. Reduced Th2 polyfunctionality was associated with fewer pulmonary alternatively activated macrophages. This work is the first direct evidence for a critical contribution of the IL-4R on Th cells to Th2-dependent susceptibility during allergic bronchopulmonary mycosis. Moreover, the data demonstrate that the quality of the Th2 response has an impact on type 2 inflammation. The analysis of polyfunctional Th2 cells may be useful for monitoring the course of the disease.

[Amyloidoses in neuropathology]. / Amyloidosen in der Neuropathologie.

Amyloidoses play an important role in neuropathology, both in autopsies and biopsy specimens. Cerebral amyloidoses are typically characterized by the deposition of beta-amyloid and mostly affect patients >60 years. The cardinal symptom of cerebral amyloid angiopathy (CAA) is spontaneous intracerebral hemorrhage, whereas the clinical presentation of Alzheimer's disease is dementia. Rare familial forms of amyloidoses may affect young patients and need thorough neuropathological assessment, similar to the relatively infrequent prion diseases. Amyloidoses within neuromuscular tissues mainly occur in the setting of systemic amyloid diseases. Detailed evaluation including thorough characterisation of amyloid is essential for ensuring the neuropathological diagnosis.

Treatment strategies of space-occupying intradural metastases of the cauda equina of nonneurogenic origin.

BACKGROUND: Compressive intradural metastases of the cauda equina are a rare site of metastatic spread in systemic cancer. So far, only few reports have been published with conflicting statements concerning a surgical versus nonsurgical approach. METHOD: Five patients with symptomatic space-occupying intradural metastases of the cauda equina were analyzed retrospectively, focusing on the influence of surgical intervention on pain relief, neurological outcome and thus the patients' quality of life. FINDINGS: At the time of diagnosis, all patients were in an advanced metastatic state. Surgical resection was the primary treatment in four patients and radiotherapy in one. Despite infiltration of the cauda rootlets, gross total tumour resection could be achieved in two of the four patients treated surgically. Functional outcome was beneficial in these patients with marked and immediate relief of pain and improvement of motor function even following incomplete tumour resection. CONCLUSIONS: Surgical treatment of compressive intradural metastases of the cauda equina seems to be feasible with low operative risk and with the potential benefit of an immediate relief of pain and improvement in motor function and thus an increase in quality of life.

Development of a method for the determination of citrinin in barley, rye and wheat by solid phase extraction on aminopropyl columns and HPLC-FLD.

A method for the determination of the mycotoxin citrinin (CT) in rye, wheat and barley is described. The proposed method is based on ethyl acetate extraction, solid phase clean-up (SPE) on aminopropyl columns and reversed phase high performance liquid chromatography with fluorescence detection (RP-HPLC-FLD). The limits of detection and quantification of CT amounted to 0.6-0.9 µg/kg and 1.7- 3.3 µg/kg with mean recovery rates in the range of 77-92% (RSD 4.8-5.5%). This method can also be used for the determination of CT in red-fermented rice.

Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3.

OBJECTIVE: We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3. MATERIALS AND METHODS: Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease. RESULTS: NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes. CONCLUSIONS: Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.