[National guidelines for treatment of diabetic retinopathy : Second edition of the national guidelines for treatment of diabetic retinopathy]. / Nationale Versorgungsleitlinie (NVL) Diabetische Retinopathie : 2. Auflage der NVL zur Therapie der diabetischen Retinopathie.

The updated German clinical practice guidelines (second edition) describe the consensus recommendations for prevention and treatment of retinal complications secondary to diabetes. According to the updated numbers on epidemiology a further increase of persons affected is expected. The prevalence of diabetic retinopathy is estimated to be 9-16 % in type 2 diabetes and 24-27 % in type 1 diabetes. A prolongation of the screening interval from 1 to 2 years is recommended for those patients with a lower risk of progression, when retinopathy has not already occurred and no increased systemic risk factors are present. Standardized documentation forms are the foundation for improved communication between the disciplines. If diabetic retinopathy is present, control examinations follow the stipulations of the ophthalmologist. The guidelines define scenarios when the use of optical coherence tomography (OCT) is necessary, e. g. diagnosis and follow-up of macular edema. Besides focal and panretinal laser therapy, the efficacy and risks of intravitreal operative pharmacotherapy are discussed. Focal laser coagulation is recommended for therapy of macular edema without foveal involvement and for macular edema with foveal involvement patients should be informed about the effective alternative forms of treatment. Panretinal laser coagulation is recommended for first line treatment of proliferative diabetic retinopathy and is optional for severe non-proliferative retinopathy.

Dicarbonyl Stress Mimics Diabetic Neurovascular Damage in the Retina.

The net effect of euglycemic treatment is grossly overestimated in diabetes mellitus and retinopathy, similar to what is observed in diabetic individuals, is found in the absence of chronic hyperglycemia. Explanations of this clinical paradox include the excess generation of reactive intermediates of metabolism. Excess formation or impaired detoxification of reactive intermediates can also result in multiple posttranslational modifications with a wide range of cellular dysfunctions. The multicellular neurovascular unit represents the response element of the retina which is crucial for the development of diabetic retinopathy. Current evidence suggests that increased reactive intermediates in the retina induce (micro-)glial activation, neurodegeneration and vasoregression similar to alterations found in the diabetic retina. Reactive metabolites can be lowered by metabolic signal blockade, by an activation of detoxification pathways and by quenching. The translation of these novel findings into treatment of patients with complications is important to reduce individual suffering and financial burden for societies.Quick Summary:Increased levels of reactive intermediates, independent of blood glucose levels, are linked to damage of the neurovascular unit of the diabetic retina.

Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 µmol/l liraglutide or 13 µmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.

Carnosine treatment in combination with ACE inhibition in diabetic rats.

In humans, we reported an association of a certain allele of carnosinase gene with reduced carnosinase activity and absence of nephropathy in diabetic patients. CN1 degrades histidine dipeptides such as carnosine and anserine. Further, we and others showed that treatment with carnosine improves renal function and wound healing in diabetic mice and rats. We now investigated the effects of carnosine treatment alone and in combination with ACE inhibition, a clinically established nephroprotective drug in diabetic nephropathy. Male Sprague-Dawley rats were injected i.v. with streptozotocin (STZ) to induce diabetes. After 4 weeks, rats were unilaterally nephrectomized and randomized for 24 weeks of treatment with carnosine, lisinopril or both. Renal CN1 protein concentrations were increased under diabetic conditions which correlated with decreased anserine levels. Carnosine treatment normalized CN1 abundance and reduced glucosuria, blood concentrations of glycosylated hemoglobin (HbA1c), carboxyl-methyl lysine (CML), N-acetylglucosamine (GlcNac; all p<0.05 vs. non-treated STZ rats), reduced cataract formation (p<0.05) and urinary albumin excretion (p<0.05), preserved podocyte number (p<0.05) and normalized the increased renal tissue CN1 protein concentration. Treatment with lisinopril had no effect on HbA1C, glucosuria, cataract formation and CN1 concentration, but reduced albumin excretion rate more effectively than carnosine treatment (p<0.05). Treatment with both carnosine and lisinopril combined the effects of single treatment, albeit without additive effect on podocyte number or albuminuria. Increased CN1 amount resulted in decreased anserine levels in the kidney. Both carnosine and lisinopril exert distinct beneficial effects in a standard model of diabetic nephropathy. Both drugs administered together combine the respective effects of single treatment, albeit without exerting additive nephroprotection.

Chronic hyperglycemia inhibits vasoregression in a transgenic model of retinal degeneration.

Vasoregression characterizes diabetic retinopathy in animal models and in humans. We have recently demonstrated that vasoregression is earlier initiated in a rat model of ciliopathy-induced retinal neurodegeneration (TGR rat). The aim was to assess the balance between vasoregressive effects of chronic hyperglycemia and photoreceptor degeneration on adult vascular remodelling. The retinas were analyzed at 4 and 9 months after streptozotocin-induced diabetes. Neurodegeneration was determined by quantitation of cell numbers and retinal layer thickness. Vasoregression was assessed by quantitative retinal morphometry in retinal digest preparations. Retinal VEGF levels were measured by ELISA. Glial activation, expression and location of HSP27 and phosphorylated HSP27 were evaluated by immunofluorescence staining. Unexpectedly, the numbers of acellular capillaries were reduced at both time points and led to fewer intraretinal microvascular abnormalities in late stage diabetic TGR. Concomitantly, inner nuclear layers (INLs) in diabetic TGR rats were protected from cell loss at both time points. Consequently, glial activation was reduced, but VEGF level was increased in diabetic TGR retinas. Expressions of HSP27 were upregulated in glia cells in the preserved INL of diabetic TGR. Chronic hyperglycemia preserves the microvasculature in the retinal model of neurodegeneration. Cell preservation in the retinal INL was associated with protective gene regulation. Together, these data indicate that diabetes can induce vasoprotection, in which retinal glia can play a particular role.

Healthy obese and post bariatric patients - metabolic and vascular patterns.

OBJECTIVE: Obesity and the metabolic syndrome (MetS) are associated with endothelial dysfunction (ED). An established method to determine ED is retinal vessel analysis. Obesity is associated with MetS, but obese patients not matching all criteria of the MetS and therefore defined as metabolically healthy obese subjects (MHOS) exist. Bariatric surgery may be an appropriate option to treat morbid obesity. The aim of this study was to compare MetS, MHOS and post bariatric patients in adipocytokine -patterns and ED. METHODS: Arterio-venous ratio (AVR) and vessel diameters from retinal photographs (IMEDOS™), parameters of MetS (IDF) and obesity-associated factors (hsCRP, TNF, Il-6, MCP-1, sICAM, sVCAM, IGF-BP3, RBP 4 and adiponectin) were assessed in 51 obese patients with MetS, 20 obese patients without MetS and 21 patients pre and post bariatric surgery. RESULTS: Bariatric surgery improved ED as reflected by AVR and venous diameters (p<0.05 for both). These improvements were associated with lower levels of fasting plasma glucose, insulin, HOMA-IR, LDL-C, triglycerides, cholesterol, hsCRP, sICAM, and higher levels of adiponectin and RBP4 (p<0.05 for each parameter). MHOS differed from MetS by neck circumference, fasting plasma glucose, HOMA-IR, triglycerides, HDL-C, sICAM, and adiponectin (p<0.05), but not by RRs, RRd, insulin, LDL-C, hsCRP, Il-6, TNF, MCP-1, sVCAM, RBP-4, IGF-BP3, and retinal ED. CONCLUSION: These data indicate that improved insulin-sensitivity and reduced inflammatory mediators characterize the metabolic outcome of postbariatric patients in comparison to MHOS. Thus, MHOS characterizes an intermediate state between MetS and postbariatric patients.

Crosstalk in the retinal neurovascular unit - lessons for the diabetic retina.

Diabetic retinopathy shares important features with neurodegenerative retinal diseases, including loss of ganglion cells and retinal thinning. The impact on vasoregression and subsequent ischemia-driven changes such as macular edema and proliferative retinopathy are not established. Studies using adult neurodegenerative animal models such as the transgenic TGR(CMV-PKD2(1/703)HA) rat imply early activation of the innate immunity system and the complement system as well as microglia playing a role in the damage of the retinal neurovascular unit.

Zebrafish: a model for understanding diabetic complications.

Diabetes mellitus causes several vascular complications in patients, such as macrovascular problems including myocardial infarction, peripheral artery diseases and stroke and microvascular problems including nephropathy and retinopathy. Likewise, diabetes mellitus is associated with other complications such as neuropathy and delayed wound healing. The zebrafish has been used for decades as a model organism for studies in developmental biology. In fact several common and important developmental mechanisms have been identified in zebrafish which are similar in mammals. The zebrafish has short generation intervals and zebrafish embryos are transparent and therefore provide unique imaging opportunities. In combination with genetic manipulations, including gene silencing protocols by using morpholinos, mutant or transgenic fish lines, the zebrafish has become one of the most important models in developmental biology. Over and above, zebrafish is also an established model organism for several pathophysiological conditions which are related to human diseases. For instance, zebrafish is used as an inflammation and regeneration model because of its ability to partially compensate for organ loss (e. g., heart and fins). It is also used for drug screening, in tumor biology, for systems biology, congenital and hereditary disease, and in infection [1].

Diabetic retinopathy in type 1 diabetes-a contemporary analysis of 8,784 patients.

AIMS/HYPOTHESIS: The aim of this study was to analyse the risk profile for diabetic retinopathy under real-life conditions in a large cohort of patients with type 1 diabetes. METHODS: Patients (n = 18,891) with childhood, adolescent or adult onset of type 1 diabetes from the prospective German Diabetes Documentation System survey were analysed. A total of 8,784 patients fulfilled the inclusion criterion, which was availability of retinopathy status. Retinopathy grading (any retinopathy, advanced retinopathy), treatment regimens and risk factors were prospectively recorded and tested as covariates by Kaplan-Meier analysis and logistic regression. RESULTS: Any retinopathy was present in 27.4% and advanced retinopathy (severe non-proliferative or proliferative diabetic retinopathy) in 8.0% of the cohort. After 40 years of diabetes, the cumulative proportion of patients with any retinopathy and advanced retinopathy was 84.1% and 50.2%, respectively. In multiple regression analysis, risk factors for any retinopathy were diabetes duration (OR 1.167 per year), HbA(1c) >7.0% (53 mmol/mol) (OR 2.225), smoking (OR 1.295) and male sex (OR 1.187) (p < 0.0001 for all). Young age at onset (5 vs 15 years at disease onset) was protective (0.410, p < 0.0001). No glycaemic threshold was detected for retinopathy protection. Risk factors for advanced retinopathy were duration (1.124 per year, p < 0.0001), male sex (1.323, p = 0.0020), HbA(1c) >7.0% (53 mmol/mol) (1.499, p < 0.0001), triacylglycerol >1.7 mmol/l (1.398, p = 0.0013) and blood pressure >140/90 mmHg (1.911, p < 0.0001). CONCLUSIONS/INTERPRETATION: The prevalence of retinopathy remains significant in type 1 diabetes. Any improvement of metabolic control and non-smoking is protective, while hypertension affects progression to severe levels under real-life conditions. These data reinforce the validity of multifactorial concepts for morbidity protection in type 1 diabetes.

[Diabetic retinopathy and maculopathy]. / Diabetische Retinopathie und Makulopathie.

Diabetic retinopathy is the most frequent microvascular complication in diabetes. Its early development indicates an increased cardiovascular risk. Since the early stages lack symptoms, yearly screening intervals are mandatory. Each retinopathy level determines evidence-based treatment with mutual interactive contributions from diabetology and ophthalmology. Intravitreal injection of inhibitors of the vascular endothelial growth factor may improve the so far only modestly successful therapy of diabetic macular edema.

Neuro-endocrine and neuropsychological outcome after aneurysmal subarachnoid hemorrhage (aSAH): a prospective cohort study.

OBJECTIVE: Neuropsychological sequelae are common after aneurysmal subarachnoid hemorrhage (aSAH) and may be associated with or caused by supposed hypothalamic-pituitary dysfunction. We evaluated the incidence of neuro-endocrine and neuropsychological deficits after aSAH and their interrelations in a standardized manner. METHODS: 26 patients (20 females) were prospectively screened for neuro-endocrine and neuropsychological deficits 3 and 6 months after aSAH. We measured GH, IGF-1, prolactin, LH, FSH, estradiol, TSH, fT4, total T3, testosterone, ACTH as well as cortisol before and after ACTH-stimulation. Neuropsychological analysis covered verbal comprehension, short term and working memory, visuospatial construction, figural memory, psychomotor speed, attention, and concentration. RESULTS: After 3 months central hypogonadism was observed in 2 patients accompanied by central hypothyroidism in 1 male subject. Central hypogonadism resolved spontaneously after 6 months in both. After 3 months, neuropsychological deficits were detected in 57% of the examined patients (44% attention deficits, 38% memory impairment, 12% psychomotor deficits). Neuropsychological deficits were still present in 53% after 6 months. CONCLUSION: We found a low prevalence of neuro-endocrine and a high prevalence of neuropsychological deficits in patients 3 and 6 months after aSAH. Thus, the absent co-incidence of central hormonal and psychological dysfunction leaves a causal association questionable.

SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases.

Pituitary carcinomas are rare and neurosurgically challenging lesions, as they commonly relapse after surgical removal. Their prognosis is dismal due to their limited response to radiotherapy and chemotherapy. In recent studies, temozolomide was administered in very few patients with partial effects. We report a patient with an ACTH-secreting pituitary carcinoma and widespread intracranial, spinal and systemic metastases despite repeated surgical treatment, bilateral adrenalectomy, medical treatment and radiotherapy. Additionally to chemotherapy with temozolomide, the patient received SOM230 as salvage therapy with an improvement of the patient's clinical status, and a reduction of ACTH levels. After 12 months of combination therapy a sustained tumor control was achieved and persisted upon monotherapy with SOM230 for more than 9 months thereafter. Thus, temozolomide in combination with SOM230 seems to be promising in patients with ACTH-secreting metastasized pituitary carcinoma.

Low-dose erythropoietin inhibits oxidative stress and early vascular changes in the experimental diabetic retina.

AIMS/HYPOTHESIS: Diabetic retinopathy is the result of increased oxidative and nitrosative stress induced by chronic hyperglycaemia, and affects the vasculature and the neuroglia. Erythropoietin is a neuroprotective and an endothelial survival factor. We assessed the effect of suberythropoietic epoetin delta doses on variables of oxidative stress in target tissues of diabetic complications and on pericyte loss in the diabetic retina. METHODS: We administered epoetin delta to streptozotocin-induced diabetic Wistar rats at doses of 384 IU/kg body weight once weekly or 128 IU/kg body weight three times a week. The treatment lasted for 3 months. Oxidative stress and formation of AGEs were assessed by immunoblotting, expression of Ang-2 (also known as Angpt2) by RT-PCR, activation of protein kinase B (AKT) and heat shock protein (HSP)-27 levels by immunofluorescence, and incipient retinal vascular changes by quantitative morphometry of retinal digest preparations. RESULTS: Diabetes increased variables of oxidative stress and nitrosative stress (N(epsilon)-carboxymethyl-lysine, nitrotyrosine and methylglyoxal-type AGEs) in retina, kidney and heart of diabetic rats. Epoetin delta reduced oxidative and nitrosative stress in all tissues, and AGEs in the retina. It also reduced increased retinal Ang-2 expression and pericyte loss, and ameliorated p-AKT and HSP-27 levels. CONCLUSIONS/INTERPRETATION: Epoetin delta has antioxidative properties in organs affected by diabetes and may prevent incipient microvascular damage in the diabetic retina.

Microvascular retinal changes in patients presenting with acute coronary syndromes.

BACKGROUND: Retinal microvascular changes predict cardiovascular morbidity and mortality independent of classical risk factors. However, it is unclear which retinal changes characterize patients with established coronary artery disease (CAD), and in particular, with acute coronary syndromes (ACS). The aim of the present preliminary study was to assess retinopathy in these patients. METHODS: 43 consecutive patients with ACS and 19 consecutive patients with stable CAD were investigated. Among the patient group with ACS, 20 patients presented with ST-Elevation Myocardial Infarction (STEMI) and 23 patients presented with Non-STEMI (NSTEMI). Standardized protocols were used and retinal fundus photography was taken within 48 h post-coronary angiography to assess retinopathy and general arteriolar narrowing as arterio-venous ratio (AVR). Clinical and laboratory cardiovascular risk factors were recorded. RESULTS: Despite comparable age and comparable frequency of diabetes and hypertension, patients with ACS had a much higher likelihood for retinal microaneurysms and dot bleedings than patients with stable CAD (17 (40%) vs. 1 (5%) patients, OR 11.77; 95%CI 1.43-96.59; p=0.006). Performing multivariate analysis, this association remains significant (OR 20.5, 95%CI 1.6-255, p=0.019). CAD patients presented more often with focal signs of arteriovenous nicking / focal vasoconstriction (10 (53%) vs. 9 (21%) patients, OR 4.2; 95%CI 1.31-13.4; p=0.018), however after multivariate analysis this association lost significance. The AVR was comparably low in both groups. CONCLUSION: Patients with ACS present more often with dot bleedings and microaneurysms. These findings provide preliminary evidence that retinal fundus examination may be useful to contribute to the risk profile of patients, enabling a more intensive survey and care.

Evaluation of urolithiasis: a link between stone formation and diabetes mellitus?

INTRODUCTION: The pathogenesis of calcium oxalate stone formation is not completely understood. Recently, an influence of vascular phenomena like arteriosclerosis on the crystallization process was hypothesized. Thus, stone formation should be more common in patients with diabetes mellitus (DM) who are at risk of developing angiopathy. The aim of the study was to determine the prevalence of urolithiasis (UL) in patients with DM and to identify specific risk factors. MATERIAL AND METHODS: 350 patients with DM were evaluated with respect to DM-related history, and a total of 179 patients was included (83 female, 96 male; age 23-84 years). All patients were interviewed to assess the history of stone formation. These data were compared to epidemiological data in Germany. RESULTS: The overall prevalence of UL in the diabetic group was 7.82% (vs. 4.73% in Germany, p = 0.0485; binominal test). The prevalence was significantly higher in patients with coronary heart disease (25%; p < 0.0001; Fisher's exact test). We could not demonstrate an increased prevalence of UL for patients with occlusive arterial disease or arterial hypertension as diabetic nephropathy was not a risk factor for developing urinary lithiasis (p = 0.7184, p = 1.000, p = 0.6266, respectively; Fisher's exact test). Thiazide medication lowered the prevalence of stone formation (p = 0.0399; Fisher's test). Calcium or magnesium supplementation did not influence stone formation significantly (p = 0.5279; p = 1.000; respectively; Fisher's test). CONCLUSIONS: In Germany, patients with DM are at higher risk of UL compared with patients without diabetes. We demonstrated a significantly higher prevalence of urinary stones in patients with coronary heart disease. These findings are consistent with the hypothesis that urinary stone formation has a vascular pathogenesis in part.

Clinical benefit of a short term dietary oatmeal intervention in patients with type 2 diabetes and severe insulin resistance: a pilot study.

AIMS/HYPOTHESIS: To evaluate the potential effectiveness of 'carbohydrate days' as a dietary intervention to overcome insulin resistance in type 2 diabetes. MATERIALS AND METHODS: Patients (n=14) with uncontrolled type 2 diabetes and insulin resistance as defined by a dosage of more than 1 IU/day (*)kg BW were consecutively enrolled in this prospective study. Primary outcomes were daily insulin requirement and mean blood glucose levels which were evaluated before, after, and 4 weeks after the intervention. RESULTS: All patients had a metabolic syndrome, 75% had microvascular and 57.1% macrovascular complications. Hospital setting and diabetes adapted diet alone led to improved glycemic control with a mean blood glucose 158+/-47 mg/dl. Intervention with two days of oatmeal diet further decreased mean blood glucose to 118+/-37 mg/dl (p<0.05). This was associated with a significant reduction of insulin dosage by 42.5% (before: 145+/-68.9 U/d, after 83+/-34.2 U/d, p<0.001) as well as a significant reduction (-26.4%, p<0.01) of serum leptin levels. After the four weeks outpatient period, insulin dosage remained significantly decreased (83+/-20.2 U/kg (*)d, p<0.01). Glycemic control was comparable (mean blood glucose141+/-20.78 mg/dl) to glucose levels within the hospital setting. Adiponectin levels increased significantly by 53.8% (p<0.05). CONCLUSIONS: In this uncontrolled pilot study, hospital admission and diabetes adapted diet followed by oatmeal intervention achieved a approximately 40% reduction of insulin dosage required to achieve controlled glucose levels. This effect was conserved after a 4 week outpatient phase with normal diet.

Identification of CML-modified proteins in hemofiltrate of diabetic patients by proteome analysis.

The posttranslational modification of extra- and intracellular proteins by non-enzymatic glycation results in the formation of advanced glycation end products (AGEs) in physiological systems and is associated with the loss of protein structure and function. Modification by N (epsilon)-carboxymethyl lysine (CML) correlates with the risk for retinopathy in diabetes mellitus and has been discussed as a marker for the prediction of mortality in hemodialysis patients. AGEing of proteins is particularly increased under hyperglycemia associated with different late complications of diabetes mellitus. Modification of proteins to form AGE residues is significantly more enhanced in patients suffering from chronic renal disease than in hyperglycemia and is associated with increased risk for cardiovascular complications and inflammation in patients with chronic renal insuffiency. In order to identify and define the protein "substrates" for non-enzymatic glycation we used a proteome approach combining two-dimensional gel electrophoresis and immunoblotting with Edman protein sequencing to identify specific CML-modified proteins in human hemofiltrate, which essentially resembles plasma with respect to protein composition. Albumin, Ig kappa chain, prostaglandin D2 synthase, lysozyme C, plasma retinol binding protein and beta-2-microglobulin were identified as the major CML-modified proteins. CML-modified fragments of these proteins were also found in hemofiltrate. All identified proteins have in common that they appeared in hemofiltrate predominantly in their CML-modified form(s). Further studies of the functional roles of proteins identified by this new experimental approach could lead to the development of diagnostic tools to follow the progression of diabetes and contribute to the understanding of the pathogenesis of AGE-related diseases.

Long-term treatment of central Cushing's syndrome with rosiglitazone.

CONTEXT: Central Cushing's syndrome is not always curable by surgery or radiation of the pituitary. Medical treatment is often not possible or effective. Some studies revealed beneficial effects of the PPARgamma (Peroxisome-Proliferator-Activator- Receptor-gamma)-agonist rosiglitazone (RG) in in vitro studies, animal models and short term clinical studies. OBJECTIVE: of this study was to observe the long-term effects of RG-treatment on cortisol- and ACTH -secretion, clinical outcomes and morphological changes of the pituitary in patients with persistent ACTH-overproduction despite previous operation and radiation. DESIGN, SETTING AND PATIENTS: 14 patients with persistent central ACTH -production were included and monitored over a period up to 12 months. RG was administered daily and increased to a maximum dosage of 24 mg daily, according to the response of ACTH and cortisol secretion. ACTH and cortisol were measured at least every 4 weeks during RG treatment. RESULTS: Patients were treated between 4 and 12 months with RG (mean 6.8 months). Compared to baseline, ACTH- and cortisol levels dropped significantly (p<0.01) after 12, 16, 20, 24 and 28 weeks but thereafter rose again during the study period, despite continuous RG- treatment and dose increase up to the maximum dosage. This was paralleled by reocurrence of clinical symptoms. MRI-scans were performed in 6 patients because of persisting visible adenoma, but showed no morphological changes. CONCLUSION: RG seems not to be a long-term treatment option for patients with persistent central ACTH-evcess. Though, in order to reduce perioperative complications, short term treatment of patients could be an alternative.