Clemens Lange

Resolving the clinical acuity categories “hand motion” and “counting fingers” using the Freiburg Visual Acuity Test (FrACT)

PurposeThe Freiburg Visual Acuity Test (FrACT) has been suggested as a promising test for quantifying the visual acuity (VA) of patients with very low vision, a condition often classified using the semi-quantitative clinical scale “counting fingers” (CF), “hand motion” (HM), “light perception” (LP) and “no light perception”. The present study was designed to assess FrACT performance in a sizable number of CF, HM, and LP patients in order to generate a setting for future clinical studies in the low vision range.MethodsWe examined a total of 41 patients (LP, nu2009=u200911; CF, nu2009=u200915; HM, nu2009=u200915) with various eye diseases (e.g., diabetic retinopathy, ARMD), covering the clinical VA scale from LP to CF. The FrACT optotypes were presented at a distance of 50xa0cm on a 17-inch LCD monitor with four random orientations. After training, two FrACT measurements (test and retest) were taken, each comprising 30 trials.ResultsFrACT measures reproducibly the VA of CF and HM patients. In CF patients, FrACT resulted in a mean logMARu2009=u20091.98u2009±u20090.24 (corresponding to a decimal VA of 0.010), for HM in a mean logMARu2009=u20092.28u2009±u20090.15 (corresponding to a decimal VA of 0.0052). In all LP patients the FrACT values were close to what would be obtained by random guessing. The mean test–retest 95% confidence interval was 0.21 logMAR for CF patients and 0.31 logMAR for HM respectively. Test-retest variability declined from 24 to 30 trials, showing that at least 30 trials are necessary.ConclusionFrACT can reproducibly quantify VA in the CF and HM range. We observed a floor effect for LP, and it was not quantifiable further. Quantitative VA measures are thus obtainable in the very low-vision range using FrACT.

Intraocular Oxygen Distribution in Advanced Proliferative Diabetic Retinopathy

PURPOSEnTo determine the preretinal distribution of oxygen in advanced proliferative diabetic retinopathy, and to investigate the relationship between intraocular oxygen tensions and vitreous cytokine concentrations.nnnDESIGNnComparative cross-sectional study.nnnMETHODSnOxygen levels were measured at sites in the vitreous and at the inner retinal surface using an optical oxygen sensor in 14 control subjects and in 14 subjects with advanced proliferative diabetic retinopathy who had developed tractional retinal detachments despite previous panretinal photocoagulation. The vitreous and plasma concentrations of 42 cytokines were measured using multiplex cytokine arrays and their correlation with intraocular oxygen tension was investigated.nnnRESULTSnThe mean oxygen tension in the mid-vitreous in diabetic retinopathy was 46% lower than that in control subjects (P = .017). However, the mean preretinal oxygen tension at the posterior pole in diabetic retinopathy was 37% higher than in controls (P = .039). We measured significant alterations in the vitreous concentrations of 9 cytokines-eotaxin, Flt-3 ligand, growth-related oncogene (GRO), interleukin (IL)-6, IL-8, IL-9, IFN-inducible protein-10 (IP-10), macrophage-derived cytokine (MDC), and vascular endothelial growth factor (VEGF)-in advanced proliferative diabetic retinopathy, and found that oxygen tension at the posterior pole was directly correlated with vitreous VEGF concentration.nnnCONCLUSIONnWe identified significant intraocular oxygen gradients in proliferative diabetic retinopathy. Our findings are consistent with the hypothesis that VEGF induces the development of neovascular complexes in the posterior retina that are richly perfused but nonetheless fail to redress hypoxia in the mid-vitreous. Upregulation of vitreous VEGF may be a consequence of retinal hypoxia at unidentified sites or of chronic inflammatory processes in advanced proliferative diabetic retinopathy.

Kinetics of retinal vaso-obliteration and neovascularisation in the oxygen-induced retinopathy (OIR) mouse model

PurposeTo evaluate the kinetics of peripheral vascularisation, central vessel regression and neovascularisation in the OIR mouse model in order to: i) generate standard kinetics for further studies in this model, and ii) define optimal time points to investigate cellular mechanisms of retinal vascular plasticity.MethodsFrom postnatal day 7 (P7) until P12, newborn mice were kept at 75% oxygen. The animals were sacrificed on different time points, during and after O2 exposure. After intracardial perfusion with FITC–dextran, retinal flatmounts were prepared, and the size of the retinal vascular network, the size of the central avascular area, and the number of blood vessel tufts and clusters were determined. In addition to the fluorescein stain for perfused capillaries, endothelial cells were stained with isolectin.ResultsUpon O2 exposure, there is a rapid depletion of capillaries starting adjacent to the large central arteries. These avascular stripes fuse to form an avascular central area which amounts to 37% of the whole retinal surface after 2xa0days of hyperoxia. The peripheral capillary network remains intact throughout the incubation period, even though the pace of its centrifugal spreading is decelerated compared to room air controls. Already during O2 exposure, revascularisation of the central avascular area is initiated by peripheral vessels sprouting in a centripetal direction. Revascularisation is accelerated after the return to room air, and is completed at P25. Maximal pathological neovascularisation can be found at P17, at the border between the avascular and vascular retina.ConclusionHyperoxia leads to a rapid development of a central avascular area of the retina, with its maximum during not at the end of the hyperoxic phase. Central capillary loss and peripheral vascularisation take place simultaneously, indicating different cellular control mechanisms for different areas of the retina. These standard kinetics for peripheral vascularisation and central vessel regression will: 1) help to compare the effects of angio-modulation, and 2) serve as normal baseline for the characterization of knock-out mice strains with regard to gene-specific vascular changes in the OIR-model.

Five-year visual acuity outcomes and injection patterns in patients with pro-re-nata treatments for AMD, DME, RVO and myopic CNV

Background Anti vascular endothelial growth factor (VEGF) therapy is an established treatment for various retinal diseases. Long-term data on injection frequencies and visual acuity (VA), however, are still rare. Methods Five-year analysis of real-life VA developments and injection patterns from 2072 patients (2577 eyes; 33u2005187 injections) with chronically active disease undergoing pro-re-nata treatment for age-related macular degeneration (AMD), diabetic macular oedema (DME), retinal vein occlusion (RVO) and myopic choroidal neovascularisation (CNV). Results Maximum mean VA gain in year 1 was+5.2 letters in AMD, +6.2 in DME, +10 in RVO and+7.2 in myopic CNV. Over 5u2005years, however, VA in patients with AMD declined. By year 5, 34% of patients with AMD had experienced VA loss of >15 letters, 56% had remained stable and 10% had gained >15 letters. Long-term VA developments in DME and RVO were more favourable with 81% of DME and 79% of patients with RVO gaining or maintaining vision at 5u2005years. In AMD, median injection frequency was six in year 1 and between four and five in consecutive years. In DME and RVO, median injection frequency was six in year 1 but lower compared with AMD in consecutive years. Injection frequency in DME was weakly associated with patient age (rs=0.1; p=0.03). Conclusions In AMD, the initial VA gain was not maintained long term despite higher injection numbers compared with DME, RVO and myopic CNV. The presented real-world data provide a peer-group-based estimate of VA developments and injection frequencies for counselling patients undergoing long-term anti-VEGF therapy.

Therapeutic interference with EphrinB2 signalling inhibits oxygen-induced angioproliferative retinopathy.

Acta Ophthalmol. 2011: 89: 82–90

Clinical experience with eplerenone to treat chronic central serous chorioretinopathy

PurposeChronic central serous chorioretinopathy (CSC) is a vision-threatening eye disease for which there is still no approved treatment. Recent studies suggest that the corticosteroid pathway in the choroid is implicated in CSC pathogenesis, and that therapy with the aldosterone antagonist eplerenone improves clinical outcomes. However, there is still little clinical data to support this hypothesis. We performed a retrospective chart review to further investigate the clinical value of eplerenone treatment in patients with chronic CSC and to identify possible response predictors.MethodsTwenty-four patients with chronic CSC resistant to conventional therapy over at least 4xa0months were included in this retrospective study. Patients were initially treated with 25xa0mg/day of eplerenone administered orally for 1 week, followed by a sustained daily dose of 50xa0mg. The primary outcome measure was percentage of eyes achieving complete resolution of subretinal fluid (SRF), recorded by spectral domain optical coherence tomography (SD-OCT). Secondary outcomes included changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA). Baseline SD-OCT images were also evaluated as possible predictors of treatment response.ResultsTwenty-nine percent of patients experienced complete resolution of SRF after a median of 106xa0days of treatment, while 33xa0% of patients showed a transient initial decrease in SRF, and 25xa0% failed to respond to treatment. Treatment had to be stopped in 13xa0% of patients because of adverse effects of the eplerenone treatment. In the study population, CMT decreased from 342 to 275xa0μm after treatment, which was associated with a modest improvement in mean BCVA from 0.35 to 0.3 logMar. The integrity of the ellipsoid zone and the retinal pigment epithelium (RPE) at baseline were associated with a tendency towards a favourable visual outcome.ConclusionThis study confirms the proposed clinical value of eplerenone for treating patients with therapy-resistant CSC. However, patients presenting widespread RPE changes are less likely to benefit from eplerenone treatment, which may argue for an earlier intervention. Larger studies are needed to characterise patient subgroups that may benefit the most from eplerenone treatment.

Enhanced TKTL1 Expression in Malignant Tumors of the Ocular Adnexa Predicts Clinical Outcome

PURPOSEnMalignant tumors metabolize glucose to lactate even in the presence of oxygen via the pentose-phosphate pathway. The metabolic switch from oxidative glycolysis to nonoxidative fermentation in tumors has been associated with overexpression of the transketolase-like-1-gene (TKTL1), which encodes an essential and rate-limiting enzyme in the nonoxidative part of the pentose-phosphate pathway. This study investigates the role of TKTL1 in ocular adnexal tumors and analyzes how its expression correlates with the clinical outcomes against the background of tumor thickness and mitotic rate.nnnDESIGNnComparative case studies.nnnPARTICIPANTSnWe included 89 subjects with malignant tumors of the ocular adnexa (44 squamous cell carcinomas, 26 lymphomas, 19 malignant melanomas) who had been treated at the University Eye Hospital Freiburg from 1994 to 2008. Sixteen subjects with conjunctival nevi, 19 with conjunctival papilloma, and 2 with conjunctival-reactive lymphoid hyperplasia were included as controls.nnnMETHODSnTKTL1 expression was assessed by reverse transcriptase-polymerase chain reaction and immunohistochemistry and semiquantitatively analyzed using an established immunoreactive score (IRS). The tumor recurrence rate, metastasis occurrence, and survival time of each patient were assessed retrospectively and correlated with the TKTL IRS using Kaplan-Meier and Cox regression analyses.nnnMAIN OUTCOME MEASURESnTKTL1 expression, mitotic rate within the tumor mass, and tumor thickness and its association with clinical outcome.nnnRESULTSnWe identified increased TKTL1 protein levels in malignant conjunctival tumors compared with control samples and detected an average IRS of 1.78 (standard deviation [SD], ± 0.46) for melanomas, 1.3 for lymphomas (SD, ± 0.79), and 1.22 for squamous cell carcinomas (SD, ± 0. 97) compared with 0.86 for conjunctival nevi (SD, ± 0.57) and 0.5 for conjunctival papilloma (SD, ± 0.83). Multifactorial survival analysis showed that TKTL1 overexpression correlated with the patient outcomes in malignant tumors (P = 0.045). In the squamous cell carcinomas, tumor thickness and mitotic rate correlated more strongly with prognosis compared with TKTL1 overexpression (P = 0.0061, P = 0.015, and P = 0.061, respectively).nnnCONCLUSIONSnTKTL1 is dysregulated in malignant tumors of the ocular adnexa, and enhanced expression seems to predict clinical outcome, especially the tumor recurrence rate.

Corneal endothelial loss after crosslinking with riboflavin and ultraviolet-A.

Keratoconus is a progressive, non-inflammatory degenerative ectasia of the cornea characterized by paraxial stromal thinning, irregular astigmatism and progressive loss of visual acuity. Current treatment options focus on the correction of the associated refractive error by means of glasses for mild keratoconus, or rigid contact lenses for moderate keratoconus. As the corneal ectasia progresses, contact lenses can no longer be fitted, and 20 % of patients require corneal transplantation [1]. Corneal collagen crosslinking by a combined topical riboflavin and UVA treatment has been proposed to stabilize and prevent progression of corneal ectasia in keratoconus [2]. This technique is still undergoing both clinical evaluation and risk assessment worldwide. In this case report, we present a patient with irreversible corneal endothelial damage and significant visual deterioration following corneal crosslinking.

Franceschetti hereditary recurrent corneal erosion.

PURPOSEnTo describe new affected individuals of Franceschettis original pedigree of hereditary recurrent erosion and to classify a unique entity called Franceschetti corneal dystrophy.nnnDESIGNnObservational case series.nnnMETHODSnSlit-lamp examination of 10 affected individuals was conducted. Biomicroscopic examinations were supplemented by peripheral corneal biopsy in 1 affected patient with corneal haze. Tissue was processed for light and electron microscopy and immunohistochemistry was performed. DNA analysis was carried out in 12 affected and 3 nonaffected family members.nnnRESULTSnAll affected individuals suffered from severe ocular pain in the first decade of life, attributable to recurrent corneal erosions. Six adult patients developed bilateral diffuse subepithelial opacifications in the central and paracentral cornea. The remaining 4 affected individuals had clear corneas in the pain-free stage of the disorder. Histologic and immunohistochemical examination of the peripheral cornea in a single patient showed a subepithelial, avascular pannus. There was negative staining with Congo red. DNA analysis excluded mutations in the transforming growth factor beta-induced (TGFBI) gene and in the tumor-associated calcium signal transducer 2 (TACSTD2) gene.nnnCONCLUSIONnWe have extended the pedigree of Franceschetti corneal dystrophy and elaborated its natural history on the basis of clinical examinations. A distinctive feature is the appearance of subepithelial opacities in adult life, accompanied by a decreased frequency of recurrent erosion attacks. Its clinical features appear to distinguish it from most other forms of dominantly inherited recurrent corneal erosion reported in the literature.

CNTF Attenuates Vasoproliferative Changes Through Upregulation of SOCS3 in a Mouse-Model of Oxygen-Induced Retinopathy

Purpose Retinal vascular disease represents a major cause for vision loss in the Western world. Recent research has shown that neuronal and vascular damage are closely related in retinal disease. Ciliary neurotrophic factor (CNTF) is a well-studied neurotrophic factor that is currently being tested in clinical trials for the treatment of retinal degenerative diseases and macular telangiectasia. However, little is known about its effect on retinal vasculature. In this study, we investigate the effects of CNTF in retinal neovascular disease using the mouse model of oxygen-induced retinopathy (OIR). Methods Newborn pups were exposed to 75% oxygen from postnatal day (P)7 to P12 and subsequently returned to room air. Ciliary neurotrophic factor was injected intravitreally at OIR P12 and the vaso-obliterated and neovascular areas were quantified at OIR P17. Immunohistochemistry, RNA, and protein analysis were used to identify CNTF-responsive cells. In vitro experiments were performed to analyze the effect of CNTF on endothelial and astroglial cells. Results In the OIR model, CNTF facilitated capillary regrowth and attenuated preretinal neovascularization in a dose-dependent manner. The protective effect of CNTF was mediated via activation of the JAK/STAT3/SOCS3 signaling pathway. Immunohistochemical studies identified endothelial cells among others as CNTF-responsive cells in the retina. In vitro studies confirmed the anti-angiogenic effect of CNTF on endothelial cell sprouting. Conclusions This study provides evidence for a therapeutic potential of CNTF beyond degenerative retinal disease. Vasoproliferative retinopathies may benefit from a CNTF-dependent and SOCS3-mediated angiomodulatory effect.