Erhard Godehardt

Relevance of anti-Mullerian hormone measurement in a routine IVF program

BACKGROUND Diminished ovarian reserve has become a major cause of infertility. Anti-Mullerian hormone (AMH) seems to be a promising candidate to assess ovarian reserve and predict the response to controlled ovarian hyperstimulation (COH). This prospective study was conducted to evaluate the relevance of AMH in a routine IVF program. METHODS Three hundred and sixteen patients were prospectively enrolled to enter their first IVF/ICSI-cycle. Age, FSH-, inhibin B- and AMH-levels and their predictive values for ovarian response and clinical pregnancy rate were compared by discriminant analyses. RESULTS A total of 132 oocyte retrievals were performed. A calculated cut-off level < or =1.26 ng/ml AMH alone detected poor responders (< or =4 oocytes) with a sensitivity of 97%, and there was a 98% correct prediction of normal response in COH if levels were above this threshold. With levels <0.5 ng/ml, a correct prediction of very poor response (< or =2 oocytes) was possible in 88% of cases. Levels of AMH > or =0.5 ng/ml were not significantly correlated with clinical pregnancy rates. CONCLUSIONS AMH is a predictor of ovarian response and suitable for screening. Levels < or =1.26 ng/ml are highly predictive of reduced ovarian reserve and should be confirmed by a second line antral follicle count. Measurement of AMH supports clinical decisions, but alone it is not a suitable predictor of IVF success.

The risk of ischemic spinal cord injury in patients undergoing graft replacement for thoracoabdominal aortic aneurysms

PURPOSE We developed a monitoring system to detect spinal cord ischemia during aortic cross-clamping (AXC). This system was used to prospectively determine in which patients ischemia occurs, in which patients reimplantation of intercostal arteries is unnecessary or mandatory, and when reperfusion of intercostal arteries (ICAs) is urgent. METHODS Two hundred sixty patients underwent thoracoabdominal aortic aneurysm (TAA) repair with simple AXC. In 167 patients, two electrocatheters were placed before the onset of anaesthesia at level L1/L2 (stimulation) and level T5/T6 (recording) within the epidural space. During surgery, spinal cord function was monitored by recording spinal somatosensory evoked potentials (sSSEP). According to the extent of aortic replacement, most patients were expected to have a high risk of paraplegia. RESULTS In group A (59 patients), sSSEP remained normal throughout surgery, and in 54 of these patients ICAs were not reattached outside the proximal aortic anastomosis. In the other five patients ICAs were reimplanted separately because of possible anatomic relation to spinal cord blood supply. No patient in group A had postoperative neurologic deficit. In group B (54 patients) sSSEP remained normal until 15 minutes after AXC but were impaired thereafter. Nineteen patients had early reimplantation of ICAs. Of the 19, three had paraparesis and two had paraplegia. Neurologic deficit developed in the patients without early reimplantation of ICAs. In four patients separate reimplantation of ICAs was performed late in the procedure because of incomplete sSSEP recovery. Subsequently, the sSSEP returned to normal and only one of the four patients had mild paraparesis. The total rate of neurologic deficits in this group was 13% (paraplegia, 3.5%; paraparesis, 9.5%). All 54 patients in group C showed rapid loss of sSSEP within 15 minutes of AXC. In 28 patients ICAs were reimplanted only within the proximal anastomosis. Twenty-one of these patients showed prompt signal recovery after blood-flow release into the reimplanted ICAs, and none had neurologic deficit. Seven patients had no or very late and incomplete sSSEP recovery. Of the seven, three had paraplegia and four had paraparesis. In 26 patients ICAs were reimplanted separately to the proximal anastomosis. This was done early during the procedure in 17 patients, of whom 13 had full recovery of sSSEP and normal neurologic status. Four patients had incomplete or no recurrence of sSSEP, followed by paraplegia in one and paraparesis in three. In nine patients ICAs were reimplanted after the aortic replacement had been completed because of sSSEP recovery was not satisfactory. In all patients in this subgroup sSSEP returned to normal. Six patients had a normal neurologic status and three had mild paraparesis. The total neurologic complication rate in group C was 26% (paraplegia, 7.5%; paraparesis, 18.5%). CONCLUSION The risk of ischemic spinal cord injury during replacement for TAA can be assessed continuously by monitoring the sSSEP directly from the spinal cord. Patients without sSSEP changes during aortic reconstruction do not require ICA reattachment and will not have neurologic deficit. Patients who lose sSSEP after AXC are at risk for paraplegia. Patients with impairment or loss of sSSEP >15 minutes after AXC have some collateral vessels, and must have ICAs reimplanted only if sSSEP do not return within normal recovery time after blood-flow release into the proximal anastomosis. Loss of sSSEP within 15 minutes of AXC shows poor collateralization and mandates early restoration of spinal cord blood supply. If the surgeon can achieve the return of sSSEP to normal by subsequent separate reimplantation of ICAS, paraplegia will not occur and paraparesis will be rare and mild. Spinal cord monitoring is a valuable guide to detect whether the spinal cord is at risk and to take measures against par

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study

OBJECTIVE To produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO). DESIGN Retrospective cohort analysis. SETTING Fifteen academic reproductive centers. PATIENT(S) A total of 3,871 infertile women. INTERVENTION(S) Blood sampling for AMH level. MAIN OUTCOME MEASURE(S) Serum AMH levels and correlation between age and different percentiles of AMH. RESULT(S) Age-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age. CONCLUSION(S) Age-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

The influence of glaucoma history on graft survival after penetrating keratoplasty

Abstract• Background: It was the purpose of this retrospective study to evaluate the effect of a preoperative history of glaucoma on graft survival after penetrating keratoplasty. • Patients and methods: Six hundred and forty-six penetrating keratoplasties with generally good prognosis were analyzed retrospectively. Indications for surgery were corneal dystrophy, degeneration and scarring. Only first keratoplasties in corneas without severe vascularization or acute inflammation were included. Surface disorders, a history of herpes or Acanthamoeba keratitis were further exclusion criteria. Keratoplasties were performed only if glaucoma seemed to be controlled preoperatively. Graft survival ratios were calculated according to Kaplan and Meier, and statistical significance was evaluated by means of the log-rank test. • Results: With a glaucoma history the estimated 3-year graft survival rate was 71%, in contrast to 89% without such a history. This difference was statistically significant (P <0.001). There was no difference between the groups with respect to immune reactions. With a glaucoma history, postoperative episodes of glaucoma decompensation were responsible for half of the graft failures. • Conclusions: A preoperative history of glaucoma affects graft prognosis negatively, presumably through a negative influence of postoperatively elevated intraocular pressure on a vulnerable graft endothelium, and not by an increase in immune reactions. Therefore, keratoplasties in eyes with glaucoma are high-risk procedures and glaucoma has to be monitored more efficiently pre- and postoperatively.

The effects of cidofovir 1% with and without cyclosporin a 1% as a topical treatment of acute adenoviral keratoconjunctivitis: a controlled clinical pilot study

OBJECTIVE To evaluate the efficacy of cidofovir 1% eyedrops with and without cyclosporin A 1% eyedrops as a treatment of acute adenoviral keratoconjunctivitis (AKC). DESIGN Randomized, controlled trial. PARTICIPANTS Thirty-four patients with acute adenoviral keratoconjunctivitis of recent onset. METHODS Patients were divided into 4 treatment groups: 1) cidofovir four times daily, 2) cidofovir 10 times daily, 3) cidofovir four times daily and cyclosporin A four times daily, and 4) sodium chloride four times daily (control). The diagnosis was confirmed by adenoviral polymerase chain reaction from conjunctival swabs. Duration of treatment was 21 days. MAIN OUTCOME MEASURES Severity of conjunctival injection, conjunctival chemosis, punctate epithelial keratitis during the course of treatment, and presence and severity of corneal subepithelial infiltrates were evaluated by a clinical score. Duration until subjective improvement of symptoms was recorded. RESULTS The frequency of severe corneal opacities was lower with cidofovir (P = 0.048). Cidofovir was toxic locally to the skin of the eyelids and the conjunctiva in a dose-dependent manner. Symptoms of local toxicity were clinically similar to the signs of the initial viral inflammation. They first appeared 8 to 12 days after beginning of treatment and completely subsided 7 to 28 days after discontinuation of cidofovir. The outcome measures of local inflammation did not differ between the four treatment groups. Cyclosporin A did not alter the course of the infection. CONCLUSIONS Cidofovir lowers the frequency of severe corneal opacities, but its clinical use 4 to 10 times daily at a 1% concentration is limited by local toxicity. Further clinical studies to find an efficacious yet tolerable dosage regimen of cidofovir, possibly using an improved pharmaceutical preparation, are required.

Mycophenolate mofetil versus cyclosporin A in high risk keratoplasty patients: a prospectively randomised clinical trial

BACKGROUND/AIMS The requirement for an effective, minimally toxic immunosuppressive agent remains a major obstacle to performing high risk corneal transplantation. Although therapy with cyclosporin A (CSA) allows superior graft survival, its use is limited because of a wide range of side effects. Mycophenolate mofetil (MMF) has been shown to be a safe and effective immunosuppressive agent following renal transplantation. This prospective, randomised clinical trial was carried out to investigate the efficacy and safety of MMF in preventing corneal allograft rejection. METHODS Recipients of corneal transplants who were at high risk for graft failure were randomly assigned to either CSA or MMF immunosuppressive therapy. CSA was given in doses to achieve whole blood trough levels of 120–150 ng/ml. MMF was given in a daily dose of 2 g. Both therapy groups additionally received oral corticosteroids (fluocortolone 1 mg/kg) which were tapered and discontinued within the first 3 postoperative weeks. Patients were monitored closely for evidence of corneal graft rejection and adverse side effects. Drug efficacy was measured, primarily, by the number of patients who experienced at least one episode of clinical graft rejection. Safety analysis focused on reported adverse side effects and laboratory measurements. RESULTS 41 patients were enrolled in the study. There was no statistically significant difference between the two groups. 20 patients received CSA and 21 patients received MMF. Two patients in each group showed evidence of acute graft rejection which could be treated effectively by corticosteroids. All corneal grafts remained clear throughout the follow up. CONCLUSIONS In this study it was shown that MMF is just as effective as CSA in preventing acute rejection following high risk corneal transplantation. Mycophenolate mofetil represents a promising alternative therapeutic option in patients who are at high risk for corneal graft failure.

Prospective Randomized Trial Comparing Magnetic Resonance Imaging (MRI)-guided In-bore Biopsy to MRI-ultrasound Fusion and Transrectal Ultrasound-guided Prostate Biopsy in Patients with Prior Negative Biopsies

BACKGROUND A significant proportion of prostate cancers (PCas) are missed by conventional transrectal ultrasound-guided biopsy (TRUS-GB). It remains unclear whether the combined approach using targeted magnetic resonance imaging (MRI)-ultrasound fusion-guided biopsy (FUS-GB) and systematic TRUS-GB is superior to targeted MRI-guided in-bore biopsy (IB-GB) for PCa detection. OBJECTIVE To compare PCa detection between IB-GB alone and FUS-GB + TRUS-GB in patients with at least one negative TRUS-GB and prostate-specific antigen ≥4 ng/ml. DESIGN, SETTING, AND PARTICIPANTS Patients were prospectively randomized after multiparametric prostate MRI to IB-GB (arm A) or FUS-GB + TRUS-GB (arm B) from November 2011 to July 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The study was powered at 80% to demonstrate an overall PCa detection rate of ≥60% in arm B compared to 40% in arm A. Secondary endpoints were the distribution of highest Gleason scores, the rate of detection of significant PCa (Gleason ≥7), the number of biopsy cores to detect one (significant) PCa, the positivity rate for biopsy cores, and tumor involvement per biopsy core. RESULTS AND LIMITATIONS The study was halted after interim analysis because the primary endpoint was not met. The trial enrolled 267 patients, of whom 210 were analyzed (106 randomized to arm A and 104 to arm B). PCa detection was 37% in arm A and 39% in arm B (95% confidence interval for difference, -16% to 11%; p=0.7). Detection rates for significant PCa (29% vs 32%; p=0.7) and the highest percentage tumor involvement per biopsy core (48% vs 42%; p=0.4) were similar between the arms. The mean number of cores was 5.6 versus 17 (p<0.001). A limitation is the limited number of patients because of early cessation of accrual. CONCLUSIONS This trial failed to identify an important improvement in detection rate for the combined biopsy approach over MRI-targeted biopsy alone. A prospective comparison between MRI-targeted biopsy alone and systematic TRUS-GB is justified. PATIENT SUMMARY Our randomized study showed similar prostate cancer detection rates between targeted prostate biopsy guided by magnetic resonance imaging and the combination of targeted biopsy and systematic transrectal ultrasound-guided prostate biopsy. An important improvement in detection rates using the combined biopsy approach can be excluded.

Prospective randomized trial of operative vs interventional treatment for renal artery ostial occlusive disease (RAOOD)

INTRODUCTION AND OBJECTIVES Patients with either renovascular hypertension (RVH) and/or renal insufficiency (RI) due to renal artery ostial occlusive disease (RAOOD) can successfully undergo an open surgical reconstruction procedure (OSRP), but since the publication of Blum et al(1) percutaneous balloon stent angioplasty (PTRA + stent) leaving a small part of the stent within the aorta has become very popular. However, balloon dilatation and stenting does not remove the atherosclerotic plaque, which is often heavily calcified but leads to disruption of the plaque causing myointimal hyperplasia and recurrent stenosis. Therefore, a comparison of the two treatment modalities concerning complications and durability in a prospective randomized design was felt to bring more insight to the discussion. METHODS From 1998 to 2004, we performed OSRP in 330 patients with RVH and/or RI for various locations of RAOOD. During this time period, 50 patients (female 18, male 32, mean age 64.4 years) with RAOOD of at least 70% stenosis (DSA and duplex criteria) in one or both renal arteries, who did not require other aorto/mesenteric/iliac reconstructive procedures agreed and were randomized to either OSRP (n = 25 patients, 49 arteries) or PTRA + stent (n = 25 patients, 28 arteries). Two patients crossed over to surgical treatment. Patients were followed on a regular basis for 4 years and longer. Endpoints were re-occurrence of RAOOD and impairment of either kidney function or RVH. RESULTS We approached 77 arteries. There was no early mortality in either group, but directly procedure-related morbidity was 13% in the interventional group and 4% in the surgical group. Four-year follow-up mortality was 18% in the interventional group and 25% in the surgical group. Both groups showed significant improvement of RVH (P < .001 in each group) as well as improvement or stabilization in patients with insufficient renal function. Freedom from recurrent RAOOD (>70%) was achieved in 90.1% of the surgical group and 79.9% of the interventional group. CONCLUSION Both treatment modalities showed good early results concerning RVH, kidney function, and renal perfusion. Despite a higher number of bilateral renal artery reconstructions in patients undergoing OSRP, which was probably due to the preferred technique of transaortic endarterectomy eliminating the plaque originating in the aorta and usually extending into both renal arteries, mortality was not higher and procedure-related morbidity was even lower compared to PTRA + stent. These findings and also longer durability of OSRP imply that surgical reconstruction remains the gold standard for patients with RAOOD before PTRA + stent may be considered.

Systemische Cyclosporin-A-Prophylaxe nach Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor

Ziel: In dieser retrospektiven Studie sollte die Effektivität eines systemischen Cyclosporin-A (CsA)-Einsatzes nach Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktorüberprüft werden.Patienten und Methode: Zwischen November 1986 und Juni 1994 wurden 1121 perforierende Keratoplastiken, davon 646 Normalrisiko- und 475 Hochrisikokeratoplastiken, durchgeführt. Nur bei 130 dieser 475 Hochrisikokeratoplastiken stellte ein erhöhtes Risiko für Immunreaktionen den einzigen erhöhten Risikofaktor dar. Bei 26 dieser 130 Keratoplastiken wurde systemisches CsA eingesetzt.Ergebnisse: Mit systemischem CsA war in der Hochrisikogruppe Keratoplastik mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor innerhalb der Nachbeobachtungszeit von bis zu 66 Monaten keine dauerhafte Transplantateintrübung zu verzeichnen (100% klare Transplantate). Ohne CsA lag der Anteil klarer Transplantate nach Kaplan-Meier 3 Jahre postoperativ in dieser Hochrisikogruppe bei nur 71,7% im Vergleich zu 86,0% bei Normalrisikokeratoplastiken. Die Unterschiede zwischen diesen 3 Gruppen waren statistisch signifikant. Mit systemischem CsA wurden in der Hochrisikogruppe Keratoplastik mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor zwar mehr Immunreaktionen beobachtet als ohne diese Prophylaxe oder als bei Normalrisikokeratoplastiken. Das Verhältnis akuter und chronischer Immunreaktionen war mit CsA aber statistisch signifikant zugunsten der günstigen chronischen Verläufe verschoben.Schlußfolgerungen: Systemisches CsA verbessert die Ergebnisse von Keratoplastiken mit erhöhtem Risiko für Immunreaktionen als einzigem erhöhten Risikofaktor deutlich. Es werden zwar immer noch recht viele Immunreaktionen beobachtet, das Verhältnis akuter und chronischer Immunreaktionen ist aber deutlich zugunsten der gut zu beeinflussenden chronischen Verläufe verschoben.Background: In this retrospective study our aim was to evaluate the effectiveness of systemic cyclosporin A (CsA) after keratoplasties with an elevated risk for immune reactions as the only elevated risk factor. Patients and methods: Between November 1986 and June 1994, 1121 penetrating keratoplasties, 646 normal-risk and 475 high-risk keratoplasties were performed. In 130 out of the 475 high-risk keratoplasties an elevated risk for immune reactions was the only elevated risk factor. Twenty-six of these 130 high-risk keratoplasties were treated with systemic CsA. Results: In the high-risk group keratoplasties with an elevated risk for immune reactions as the only elevated risk factor no permanent graft failure occurred with CsA (100% clear grafts). Without CsA the percentage of clear grafts in this high risk group was only 71.7% according to Kaplan Meier 3 years postoperatively in contrast to 86.0% in normal-risk keratoplasties. The differences between these three groups were statistically significant. In the high-risk group keratoplasties with an elevated risk for immune reactions as the only elevated risk factor more immune reactions occured than without CsA or than in normal-risk keratoplasties. However, these immune reactions were mostly of the benign chronic types. Conclusions: Systemic CsA considerably improves graft prognosis after high-risk keratoplasties with an elevated risk for immune reactions as the only elevated risk factor. With CsA application we observed a significant shift from acute to chronic immune reactions, which respond much better to topical steroids.

Influence of membrane differential filtration on the natural course of age-related macular degeneration: a randomized trial.

Purpose: Membrane differential filtration is able to optimize rheologic parameters by eliminating high molecular weight proteins and lipoproteins from the blood. Following the hypothesis that these changes result in an improvement of the microcirculation, the authors tested the efficacy of membrane differential filtration in improving visual function in patients with age‐related macular degeneration (ARMD). Methods: Forty patients (40 eyes) were randomized into two groups. The treatment group was treated five times over a period of 21 weeks. In both groups, 9/20 of the eyes showed subfoveolar subretinal neovascularization. The main parameter of the study was visual acuity (VA). Electroretinogram (ERG), electrooculogram, and macular visual evoked potentials were also recorded. Plasma and whole blood viscosity and erythrocyte aggregation were measured. Results: The 20 patients treated repeatedly over a period of 21 weeks showed a mean improvement of 0.63 lines (SD 1.8) of VA on Early Treatment Diabetic Retinopathy Study charts. The control group showed a deterioration of 0.94 lines (SD 1.7) compared to VA at baseline examination. The amplitude of the ERG photopic a‐wave and the flicker ERG was significantly increased. The rheologic parameters were lowered in all treated patients. Conclusion: Repetitive treatment with membrane differential filtration is able to improve visual acuity of patients with ARMD and the natural course of this disease. Several questions arise from the results of this study. Further research will show if it is possible to optimize the selection of patients for subgroups with predictive responses through morphologic and functional tests and how to create an optimized and individual treatment strategy determined by the quality, intensity, and frequency of treatment sessions.