Heart Transplantation in Systemic Sclerosis: New Impulses for Conventional Scleroderma Transplantation Regimen and Scleroderma Diagnostic Monitoring: 2 Case Reports.

BACKGROUND: Although low (but increasing) rates of lung/lung-heart transplantations of scleroderma (systemic sclerosis [SSc]) patients have been reported, exclusive heart transplantation is a rare approach for treatment of heart failure due to SSc. CASES: We report on 2 cases of SSc patients receiving a heart transplantation (HTx) due to severe and progressive right heart failure without pulmonary artery hypertension. One patient received a hepatitis C virus (HCV)-positive donor heart and recovered excellently from viral transmission after administration of a direct-acting antiviral (DAA) regimen. This is the first published case of an SSc patient who underwent HTx using an HCV-positive donor heart. The clinical course of both patients was monitored by different serum SSc biomarkers. Only xylosyltransferase activity proved to be a promising biomarker for disease stage determination and therapeutic monitoring, precisely reflecting fibrotic remodeling and successful organ recovery. CONCLUSIONS: Successful implementation of the 2 cases described here demonstrates that HTx is a safe and effective therapeutic option for defined SSc sub-patient groups despite the progressive character of the underlying disease. In the future, xylosyltransferase activity might be conducive to simplify the identification of patients with low systemic involvement but a strong indication for single heart transplantation. Finally, we demonstrate that treatment of HCV viral transmission from HCV-positive donor to organ recipient using DAA gives us new opportunities to consider HCV-positive donor organs for HTx and might reveal new possibilities to ease the lack of donor organs.

[History of the anatomical and clinical autopsy]. / Geschichte der anatomischen und klinischen Obduktion.

The history of the autopsy is naturally also a part of the history of anatomy and pathology and spans over about 2300 years. The first documented autopsies were conducted in about 300 B.C. Thereafter, due to the prohibition of dissections due to religious, social, or hygienic reasons, a long period of stagnation took place. With the onset of the Renaissance in the 15th and 16th century, interest in the ancient sciences such as anatomy began to rise and consequently an increasing number of dissections for anatomical studies were conducted. Nevertheless, it took nearly 200 years until clinical symptoms and/or causes of disease and death were correlated with anatomical findings. In the second half of the 19th century, the clinical autopsy based on the combination of macroscopic and microscopic findings became more and more important as a precondition for the systematic description of diseases. Based on autopsy findings and together with several new techniques, modern pathology could be established at the beginning of the 20th century as a source of scientific knowledge for the clinical medicine and as a theoretical discipline of its own.

[Hereditary Macular Dystrophies]. / Hereditäre Makuladystrophien.

Hereditary macular dystrophies are part of the group of inherited retinopathies caused by mutations of specific genes. Challenging features are their rarity, enormous clinical and genetic heterogeneity, unspecific visual disturbances, and often only mild initial fundus changes. The onset of macular dystrophies may occur at any age. They manifest in the macular region, whereas fundus changes can reach the mid periphery as well. In some cases, macular dystrophy can progress into generalised retinal dystrophy, depending on the severity of the causative mutations. Funduscopy alone is often insufficient for diagnosis. However, correct diagnosis is essential for the patient for counseling, low vision aids, support, and therapeutic options. Retinal imaging, with fundus autofluorescence, near-infrared autofluorescence and optical coherence tomography, is very important, as it can show typical changes not visible on funduscopy. In cases where morphological changes are absent, retinal dysfunction must be detected by electrophysiological testing. There has been technical progress in molecular genetic testing in recent years. With the development of modern sequencing, an analysis for all known genes of hereditary retinal dystrophies has been established. The genetic defect can now be identified in more cases than before. However, a correct initial clinical diagnosis is still required for successful genetic analysis. The importance of a genetically confirmed diagnosis is increasing, as this is needed for patients who could have the chance in the near future to participate in therapeutic trials.

[Surprise in abrasion diagnostics]. / Überraschung in der Abradatdiagnostik.

Typical localizations of gynecological squamous cell carcinomas are the cervix, vulva and vagina and are therefore not uncommonly diagnosed in curettages. A differentiation from reactive hyperplastic alterations with a possible invasiveness in samples taken from the surface of the special type of well-differentiated verrucous squamous cell carcinoma can be difficult. This pitfall of such a tumor is presented in the case described here with corresponding diagnostic difficulties.

[Inherited retinal or optic nerve disorders ­ five steps to diagnosis]. / Erbliche Netzhaut- und Sehbahnerkrankungen ­ 5 Schritte zur Diagnose.

An early diagnosis of inherited retinal or optic nerve disorders is often delayed due to unspecific clinical signs, multiple clinical manifestations and striking genetic heterogeneity of the underlying molecular defects. This study represents a retrospective analysis of findings in 4,021 patients with inherited retinal or optic nerve disorders seen between 1986 and 2014 (1,171 with follow-up). In addition to the basic ophthalmological examination, electrophysiological tests (ERG, n = 2,088, since 1986; EOG, n = 381, since 1986; VEP n = 595, since 1986; mfERG, n = 819, since 1998) and non-invasive retinal imaging (fundus autofluorescence (FAF, n = 1,784, since 2002), near-infrared autofluorescence (NIA, n = 1,091, since 2006), spectral domain OCT (SD-OCT, n = 848, since 2008) and three-wavelengths multicolour spectral reflection imaging (MC, n = 366, since 2013) were performed at least once. Molecular DNA testing was done in 383 patients between 2006 and 2014. Based on these data an efficient diagnostic strategy is suggested: 1) inclusion of inherited retinal and optic nerve disorders into the differential diagnosis of visual loss or visual field defects with undefined causes; 2) non-invasive retinal imaging; 3) electrophysiological tests; 4) DNA testing to confirm the initial clinical diagnosis; 5) examination in specialised centres, therapy and follow-up. In recent years, the spectrum of diagnostic techniques has continuously expanded. Importantly, non-invasive retinal imaging has become the primary diagnostic tool and DNA testing based on state-of-the-art high throughput techniques increases the identification of associated gene mutations. In conclusion, a structured process in the diagnostic procedure of inherited retinal and optic nerve disorders greatly reduces a diagnostic delay, enables an earlier counselling and therapy and avoids further unnecessary diagnostic tests.

[Resistance to medicinal tumor therapy. Current status]. / Resistenzen gegenüber medikamentöser Tumortherapie. Aktueller Status.

In the past multiple mechanisms could be identified that are involved in anticancer drug resistance; however, diagnostic assays for prediction of therapy response to classical cytostatic drugs did not enter routine clinical diagnostics. Only when new targeted drugs, e.g. tyrosine kinase inhibitors or therapeutic antibodies, were introduced in oncology were diagnostics for prediction of therapy response routinely preformed. First and foremost this was the result of the development of highly standardized techniques, i.e. exact mutation analysis in functional relevant codons of genes encoding signal proteins of cancer-related signal transduction pathways targeted by the new drugs. Due to increasing costs of health systems, in the future predictive diagnostics will probably become more and more important. Therefore, it will be necessary to develop improved diagnostic assays for prediction of individual therapy response.

[Evidence-based diagnostic approach to inherited retinal dystrophies 2009]. / Evidenzbasierte Diagnostik hereditärer Netzhautdystrophien 2009.

BACKGROUND: Hereditary retinal dystrophies comprise a heterogeneous group of inherited retinal disorders with variable clinical presentation and multiple associated genes. Clinical diagnosis and differential diagnosis are difficult. The purpose of the current paper is to provide guidelines for an effective diagnostic approach. METHODS: A literature search was carried out and our own data on clinical (n = 3200) and molecular genetic (n = 4050) diagnosis of patients with retinal dystrophies were evaluated. RESULTS: For an early diagnosis it is of importance to include inherited retinal dystrophies in the differential diagnosis of unexplained visual disturbances. The most important clinical test is the full-field electroretinogram (ERG), which allows detection or exclusion of generalised retinal dystrophies. If the full-field ERG is normal, a multifocal ERG will distinguish macular dystrophies. Fundus autofluorescence, near-infrared autofluorescence and high resolution optical coherence tomography improve the early diagnosis because morphological alterations can be detected prior to their ophthalmoscopic visibility. In addition, these non-invasive imaging techniques reveal new phenomena which are important for the differential diagnosis and follow-up of retinal dystrophies as well as for an improved understanding of their pathogenesis. Routine molecular genetic diagnosis is available for an increasing number of retinal dystrophies. A succinct clinical diagnosis is a prerequisite to allow selection of the gene(s) to be analysed. If genetic testing is indicated, a human geneticist should be involved for counselling of the patient and possibly further family members and initiation of the necessary steps for DNA testing. CONCLUSION: The combination of electrophysiological testing, retinal imaging and molecular genetic analysis allows a differentiated diagnosis of inherited retinal dystrophies and an individual counselling of patients. If inherited retinal dystrophies are suspected, a detailed examination in a retinal centre specialised on inherited retinal dystrophies is recommended.

Spectral domain optical coherence tomography detects early stages of chloroquine retinopathy similar to multifocal electroretinography, fundus autofluorescence and near-infrared autofluorescence.

AIMS: To compare spectral domain optical coherence tomography (sdOCT) with melanin-related near-infrared fundus autofluorescence (NIA, excitation 787 nm, emission >800 nm), lipofuscin-related fundus autofluorescence (FAF, excitation 488 nm, emission >500 nm) and multifocal electroretinography (mfERG) in patients with long-term chloroquin (CQ) treatment. METHODS: Eight patients with 5.5-22 years of CQ treatment underwent clinical examination, mfERG recording, FAF and NIA imaging using a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2) and sdOCT imaging (Spectralis OCT Heidelberg Retina Angiograph). RESULTS: In three patients, all test results were normal after 5.5-16 years of CQ treatment. Five patients presented with variably progressed CQ retinopathy (10-22 years of treatment) and abnormalities in all tests. In the mildest case, pericentral reduction in mfERG amplitudes corresponded to increased pericentral FAF, reduced pericentral NIA and pericentral interruption of the photoreceptor inner/outer segment junction in the sdOCT. In all sdOCT scans, the outer nuclear layer thickness was reduced. More severe cases showed preserved subfoveal photoreceptors and function with marked changes in all examinations towards the periphery. The most severe case presented with additional loss of subfoveal photoreceptors. CONCLUSION: MfERG, FAF, NIA and sdOCT detect early stages of CQ retinopathy. Loss of outer nuclear layer thickness might be the earliest indicator of CQ retinopathy.

[Clinical findings and diagnostics of cone dystrophy]. / Klinik und Diagnostik der Zapfen-Dystrophien.

BACKGROUND: Cone dystrophies present with highly variable clinical findings and often limited retinal changes, which may lead to misdiagnosis. The purpose of the present review of the clinical presentation and diagnosis of cone dystrophies is to provide guidelines for improved patient care. METHODS: A literature search and evaluation of the clinical findings were carried out in 450 patients with cone dystrophy examined between 1986 and 2008. RESULTS: Characteristic signs are loss of visual acuity, photophobia and central scotoma. The diagnosis of cone dystrophy is determined by a full-field electroretinogram (ERG). Fundus and near-infrared autofluorescence as well as optical coherence tomography allow detection of retinal structural abnormalities even when findings from ophthalmoscopy are normal. CONCLUSION: The diagnosis of cone dystrophy is difficult due to unspecific subjective symptoms and absence of characteristic ophthalmoscopic findings. The differential diagnosis of unexplained visual loss should include cone dystrophy and requires either a full-field or multifocal ERG.

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa.

AIMS: To compare melanin-related near-infrared fundus autofluorescence (FAF; NIA, excitation 787 nm, emission >800 nm) with lipofuscin-related FAF (excitation 488 nm, emission >500 nm) in retinitis pigmentosa (RP). METHODS: Thirty-three consecutive RP patients with different modes of inheritance were diagnosed clinically, with full-field ERG, and if possible with molecular genetic methods. FAF and NIA imaging were performed with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2). RESULTS: Rings of increased FAF were present within an area of preserved retinal pigment epithelium (RPE) at the posterior pole (31/33). Rings of increased NIA were located in the same region as rings of increased FAF. In contrast to FAF, NIA showed a precipitous decline of NIA peripheral to the ring. In larger areas of preserved NIA (11/31), pericentral and foveal NIA were of similar intensity with an area of lower NIA in between. In smaller areas of preserved NIA (20/31), NIA was homogeneous from the perifovea to the fovea. In one patient without a ring of increased FAF, NIA distribution was normal. In the remaining patient with severely advanced RP, no residual RPE as well as no FAF and NIA were detectable. CONCLUSION: Characteristic features for FAF and NIA alterations in a heterogeneous group of RP patients indicate a common pathway of RPE degeneration. Patterns of NIA and FAF indicate different pathophysiologic processes involving melanin and lipofuscin. Combined NIA and FAF imaging will provide further insight into the pathogenesis of RP and non-invasive monitoring of future therapeutic interventions.