Cord Huchzermeyer

Strain-rate imaging during dobutamine stress echocardiography provides objective evidence of inducible ischemia.

Background—Interpretation of dobutamine stress echocardiography (DSE) is subjective and strongly dependent on the skills of the reader. Strain-rate imaging (SRI) by tissue Doppler may objectively analyze regional myocardial function. This study investigated SRI markers of stress-induced ischemia and analyzed their applicability in a clinical setting. Methods and Results—DSE was performed in 44 patients with known or suspected coronary artery disease. Simultaneous perfusion scintigraphy served as a “gold standard” to define regional ischemia. All patients underwent coronary angiography. Segmental strain and strain rate were analyzed at all stress levels by measuring amplitude and timing of deformation and visual curved M-mode analysis. Results were compared with conventional stress echo reading. In nonischemic segments, peak systolic strain rate increased significantly with dobutamine stress (−1.6±0.6 s−1 versus −3.4±1.4 s−1, P <0.01), whereas strain during ejection time changed only minimally (−17±6% versus −16±9%, P <0.05). During DSE, 47 myocardial segments in 19 patients developed scintigraphy-proven ischemia. Strain-rate increase (−1.6±0.8 s−1 versus −2.0±1.1 s−1, P <0.05) and strain (−16±7% versus −10±8%, P <0.05) were significantly reduced (both P <0.01 compared with nonischemic). Postsystolic shortening (PSS) was found in all ischemic segments. The ratio of PSS to maximal segmental deformation was the best quantitative parameter to identify stress-induced ischemia. Compared with conventional readings, SRI curved M-mode assessment improved sensitivity/specificity from 81%/82% to 86%/90%. Conclusions—During DSE, SRI quantitatively and qualitatively differentiates ischemic and nonischemic regional myocardial response to dobutamine stress. The ratio of PSS to maximal strain may be used as an objective marker of ischemia during DSE.

Levels of Aqueous Humor Trace Elements in Patients with Non-Exsudative Age-related Macular Degeneration: A Case-control Study

Trace elements might play a role in the complex multifactorial pathogenesis of age-related macular degeneration (AMD). The aim of this study was to measure alterations of trace elements levels in aqueous humor of patients with non-exsudative (dry) AMD. For this pilot study, aqueous humor samples were collected from patients undergoing cataract surgery. 12 patients with dry AMD (age 77.9±6.62, female 8, male 4) and 11 patients without AMD (age 66.6±16.7, female 7, male 4) were included. Aqueous levels of cadmium, cobalt, copper, iron, manganese, selenium, and zinc were measured by use of Flow-Injection-Inductively-Coupled-Plasma-Mass-Spectrometry (FI-ICP-MS), quality controlled with certified standards. Patients with AMD had significantly higher aqueous humor levels of cadmium (median: 0.70 µmol/L, IQR: 0.40–0.84 vs. 0.06 µmol/L; IQR: 0.01–.018; p = 0.002), cobalt (median: 3.1 µmol/L, IQR: 2.62–3.15 vs. 1.17 µmol/L; IQR: 0.95–1.27; p<0.001), iron (median: 311 µmol/L, IQR: 289–329 vs. 129 µmol/L; IQR: 111–145; p<0.001) and zinc (median: 23.1 µmol/L, IQR: 12.9–32.6 vs. 5.1 µmol/L; IQR: 4.4–9.4; p = 0.020) when compared with patients without AMD. Copper levels were significantly reduced in patients with AMD (median: 16.2 µmol/L, IQR: 11.4–31.3 vs. 49.9 µmol/L; IQR: 32.0–.142.0; p = 0.022) when compared to those without. No significant differences were observed in aqueous humor levels of manganese and selenium between patients with and without AMD. After an adjustment for multiple testing, cadmium, cobalt, copper and iron remained a significant factor in GLM models (adjusted for age and gender of the patients) for AMD. Alterations of trace element levels support the hypothesis that cadmium, cobalt, iron, and copper are involved in the pathogenesis of AMD.

Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort—Impact of Selected Deep Intronic Variants and Common SNPs

Purpose Stargardt disease (STGD1) is an autosomal recessive retinopathy, caused by mutations in the retina-specific ATP-binding cassette transporter (ABCA4) gene. To establish the mutational spectrum and to assess effects of selected deep intronic and common genetic variants on disease, we performed a comprehensive sequence analysis in a large cohort of German STGD1 patients. Methods DNA samples of 335 STGD1 patients were analyzed for ABCA4 mutations in its 50 coding exons and adjacent intronic sequences by resequencing array technology or next generation sequencing (NGS). Parts of intron 30 and 36 were screened by Sanger chain-terminating dideoxynucleotide sequencing. An in vitro splicing assay was used to test selected variants for their splicing behavior. By logistic regression analysis we assessed the association of common ABCA4 alleles while a multivariate logistic regression model calculated a genetic risk score (GRS). Results Our analysis identified 148 pathogenic or likely pathogenic mutations, of which 48 constitute so far unpublished ABCA4-associated disease alleles. Four rare deep intronic variants were found once in 472 alleles analyzed. In addition, we identified six risk-modulating common variants. Genetic risk score estimates suggest that defined common ABCA4 variants influence disease risk in carriers of a single pathogenic ABCA4 allele. Conclusions Our study adds to the mutational spectrum of the ABCA4 gene. Moreover, in our cohort, deep intronic variants in intron 30 and 36 likely play no or only a minor role in disease pathology. Of note, our findings demonstrate a possible modifying effect of common sequence variants on ABCA4-associated disease.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial—study protocol

Introduction Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. Methods and analysis Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. Ethics and dissemination TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Trial registration number NCT01962571.

Macular pigment optical density measured by heterochromatic modulation photometry

Purpose To psychophysically determine macular pigment optical density (MPOD) employing the heterochromatic modulation photometry (HMP) paradigm by estimating 460 nm absorption at central and peripheral retinal locations. Methods For the HMP measurements, two lights (B: 460 nm and R: 660 nm) were presented in a test field and were modulated in counterphase at medium or high frequencies. The contrasts of the two lights were varied in tandem to determine flicker detection thresholds. Detection thresholds were measured for different R:B modulation ratios. The modulation ratio with minimal sensitivity (maximal threshold) is the point of equiluminance. Measurements were performed in 25 normal subjects (11 male, 14 female; age: 30±11 years, mean ± sd) using an eight channel LED stimulator with Maxwellian view optics. The results were compared with those from two published techniques – one based on heterochromatic flicker photometry (Macular Densitometer) and the other on fundus reflectometry (MPR). Results We were able to estimate MPOD with HMP using a modified theoretical model that was fitted to the HMP data. The resultant MPODHMP values correlated significantly with the MPODMPR values and with the MPODHFP values obtained at 0.25° and 0.5° retinal eccentricity. Conclusions HMP is a flicker-based method with measurements taken at a constant mean chromaticity and luminance. The data can be well fit by a model that allows all data points to contribute to the photometric equality estimate. Therefore, we think that HMP may be a useful method for MPOD measurements, in basic and clinical vision experiments.

Successful remission induction with a combination therapy of rituximab, cyclophosphamide, and steroids in a patient with refractory optic neuritis in Wegener’s granulomatosis

A 56-year old patient with a history of limited Wegeners granulomatosis presented with signs and symptoms of optic neuritis. Radiologic signs of orbital inflammation were absent. Testing of visual acuity and visual field allowed close monitoring of disease activity. Thus, rapid improvement of visual function was achieved with high-dose steroids. Despite maintenance therapy with cyclophosphamide recurrence occurred repeatedly as soon as tapering of steroids was begun. After remission induction with rituximab, the patient retained good visual function under maintenance therapy with azathioprine and low-dose corticosteroids. Optic neuritis in Wegeners granulomatosis without signs of orbital involvement is rare and most likely caused by occlusive vasculitis of the vasa nervorum. In this patient with optic neuritis refractory to conventional therapy, rituximab in combination with cyclophosphamide and corticosteroids was well tolerated and successfully used for remission induction, followed by maintenance therapy with azathioprine and low dose corticosteroids.

Short-term fluctuation of intraocular pressure is higher in patients with pseudoexfoliation syndrome despite similar mean intraocular pressure: a retrospective case–control study

PurposeHigher levels of short-term fluctuation of intraocular pressure (IOP) are characteristic of pseudoexfoliation syndrome (PEX). However, it is not known whether they are just a side effect of the higher mean intraocular pressure (IOP) or an independent feature. The purpose of this study was to compare short-term fluctuation of IOP between eyes with PEX and control eyes that were matched as closely as possible for mean IOP.MethodsIn this retrospective case–control study, all patients with confirmed PEX were identified from the database of the Erlangen Glaucoma Registry. From the same database, matched control eyes with similar treatment, age, glaucoma stage, and mean IOP were identified. For each patient, data from multiple extended diurnal IOP profiles were available.ResultsSeventy-eight eyes were included in the study (39 with PEX and 39 matched control eyes). Although a very close match was achieved, a small but statistically significant difference in mean IOP was still present, but this did not seem to explain the differences in IOP fluctuation levels. Eyes with PEX had significantly higher short-term IOP fluctuations (SD of IOP and range of IOP).ConclusionsThe higher levels of short-term fluctuation in IOP appear to be an independent feature of PEX and not merely a secondary effect of the higher mean IOP. We suggest that this may have practical implications, even if IOP fluctuation levels should not prove to be an independent risk factor for development/progression of glaucoma, because more frequent measurements are needed in these patients to obtain good estimates of mean IOP and changes in IOP under treatment.

Perifoveal S-cone and rod-driven temporal contrast sensitivities at different retinal illuminances

We evaluated a technique for measuring temporal contrast sensitivities to sine-wave modulation driven by S-cones and rods in the perifovea using triple silent substitution. Isolating stimuli for S-cones and rods were created using an eight-channel, four-primary LED stimulator that has been validated before. Sensitivities were measured at 10 different temporal frequencies between 1 and 28 Hz in three normal observers at 14 different retinal illuminances between 0.07 and 587 photopic troland (phot Td) and at three different retinal illuminances over the same range in one S-cone monochromat. The technique was further validated by measuring bleaching adaptation in two normal subjects, demonstrating sufficient isolation in rods. Good isolation was apparent from the differences in the temporal contrast sensitivity functions and the sensitivity-versus-retinal illuminance functions between S-cones and rods, and also from the results in the S-cone monochromats and the delayed recovery of rod sensitivities after bleaching. The results will help to determine optimal stimulus conditions in future studies. The results in the S-cone monochromat demonstrate the potential clinical value of our protocol.

Evaluation of central corneal thickness after cataract surgery, penetrating keratoplasty and long-term soft contact lens wear

PURPOSE The aim of this study was to compare central corneal thickness (CCT) between corneas of normal healthy eyes (cNHE), corneas of eyes that had undergone cataract surgery by clear corneal phacoemulsification with implantation of an intracapsular intraocular lens (cIOL), corneal grafts after penetrating keratoplasty (gPK) and corneas of long-term soft contact lens wearers (cCL). METHODS The study design was a consecutive cross-sectional trial. CCT was measured using rotating Scheimpflug camera (Pentacam, software version 1.16r04) in 80 cNHE, 79 cIOL, 46 gPK and 78 cCL. Analysis of variance (one-way ANOVA) was performed to compare differences of mean values between these four groups. Pearsons or Spearmans correlation coefficient (r) was determined between CCT value and age, follow up time after penetrating keratoplasty (timePK) or contact lens wearing time (timeCL). RESULTS Means of CCT measurements were comparable between cNHE (mean CCT±standard deviation, 554±36μm), cIOL (551±40μm) and gPK (534±52μm) as determined by one-way ANOVA. Mean CCT values in cCL (537±37μm) were statistically significantly lower in comparison to cNHE (p=0.026, 95% CI=1.43-31.44). There was no linear correlation between age and CCT values of cNHE and cIOL (p=0.841, r=-0.031 and p=0.931, r=0.011, respectively). No linear relationship was determined between CCT values of cCL and timeCL (p=0.315, r=-0.125). CCT values of gPK did not correlate with timePK (p=0.738, r=0.054). CONCLUSIONS The data reported here indicate that in the same statistical model among CCT values of cNHE, cIOL and gPK only long-term soft contact lenses (CL) wearer have significantly lower CCT measurements.

Histological and Biochemical Findings in Membranous Cataract

Background: In this report we present a patient with unilateral membranous cataract and describe the histological and biochemical findings accompanying this rare condition. Methods: The patient underwent an uneventful cataract extraction. Aqueous humor (20 µl) was aspirated from the anterior chamber intraoperatively and processed for fibroblast growth factor (FGF) and epidermal growth factor (EGF) using an immunoassay method (ELISA). The lens material was subjected to histological examination. Results: The patient had increased levels of FGF and EGF in the aqueous humor, as measured by ELISA. Histological examination of the lens material showed a marked fibrous metaplasia and thickening of the anterior lens capsule, while the lens epithelial cells were transformed to active myofibroblasts which generated a fibrous matrix of collagen lamellae. Unfortunately, visual function was not restored postoperatively due to underlying amblyopia. Conclusions: Our histological and biochemical findings suggest that FGF and EGF may play a key role in the formation of membranous cataract, and therefore their impact on lens physiology should be further investigated.