Christoph Mitsch

Antivascular Endothelial Growth Factors in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in adults aged over 50 years in developed countries. Until recently, argon laser photocoagulation and photo-dynamic therapy (PDT) were the only treatments available for the neovascular form of AMD. The introduction of new intravitreally injectable inhibitors of vascular endothelial growth factor (VEGF) revolutionized the management of the wet form. Pegaptanib was the first anti-VEGF agent to be approved by the US Food and Drug Administration (FDA) for use in neovascular AMD. The VISION study showed that patients receiving pegaptanib lost vision in a smaller rate than those treated with conventional care. Bevacizumab is a full-length recombinant humanized monoclonal antibody which binds to all isoforms of VEGF-A. It is licensed for the intravenous administration for the treatment of malignant solid tumors and is available for off-label use in the treatment of AMD-related CNV. Numerous retrospective studies have shown beneficial effects of bevacizumab in patients with neovascular AMD. Ranibizumab is a recombinant, humanized antibody antigen-binding fragment (Fab) that binds to all known active forms of VEGF-A. The US FDA approved ranibizumab for treatment of all subtypes of choroidal neovascularization secondary to AMD. VEGF trap is a pharmacologically engineered protein that binds VEGF with higher affinity than pegaptanib or ranibizumab and thus prevents VEGF binding to its cellular receptor offering a theoretically longer interval between necessary treatments. A number of studies have shown that OCT imaging allows identification of functionally relevant factors like subretinal fluid or retinal thickness, which are important for the establishment of optimized individual dosing regimen during anti-angiogenesis therapies.

Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography.

Purpose: To evaluate changes in the distribution and morphology of intraretinal microexudates and hard exudates (HEs) during intravitreal anti-vascular endothelial growth factor therapy in patients with persistent diabetic macular edema. Methods: Twenty-four patients with persistent diabetic macular edema after photocoagulation were investigated in this prospective cohort study. Each eye was assigned to a loading dose of three anti-vascular endothelial growth factor treatments at monthly intervals. Additional single treatments were performed if diabetic macular edema persisted or recurred. Intraretinal exudates were analyzed over 6 months using spectral domain optical coherence tomography (SD-OCT) and fundus photography. Results: Before treatment, microexudates were detected by SD-OCT as hyperreflective foci in 24 eyes, whereas HEs were seen in 22 eyes. During therapy, HE increased significantly in number and size. This was accompanied by accumulation of microexudates in the outer retina. Enlargement of hyperreflective structures in SD-OCT was accompanied by enlargement of HE at corresponding fundus locations. A rapid reduction in diabetic macular edema was seen in all patients, but to varying degrees. Patients with hemoglobin A1c levels <7% and serum cholesterol <200 mg/dL formed fewer HEs and featured more edema reduction and visual acuity gain. Conclusion: Diabetic macular edema reduction during intravitreal anti-vascular endothelial growth factor therapy was accompanied by dynamic rearrangement of intraretinal exudates at corresponding locations in fundus photography and SD-OCT. Intraretinal aggregates of microexudates detectable as hyperreflective foci by SD-OCT may compose and precede HE before they become clinically visible.

SAVE: a grading protocol for clinically significant diabetic macular oedema based on optical coherence tomography and fluorescein angiography

Aim To analyse a new grading protocol for clinically significant diabetic macular oedema (CSME) based on spectral domain optical coherence tomography (SD-OCT) and fluorescein angiography (FA). Methods 56 eyes of 40 patients with CSME were examined by Cirrus OCT (Carl Zeiss Meditec), Spectralis HRA and OCT (Heidelberg Engineering) on the same day. Three graders analysed images based on a newly developed grading protocol integrating all relevant information from OCT and FA. The protocol defined four categories: (1) subretinal fluid (category ‘S’); (2) the planimetrically measured oedematous area (category ‘A’); (3) vitreo-retinal interface abnormalities (category ‘V’); and (4) CSME aetiology (category ‘E’) defining the leakage source. Results The new grading protocol allowed for a detailed characterisation of each individual type of CSME. It defines four aetiological types of CSME and analyses four further categories important in diagnosis and during follow-up in clinical and study settings. Atrophic, a new type of CSME, was described and characteristic combinations of triggers of CSME were revealed. Inter-grader agreement, analysed using Fleiss’ κ values for Cirrus OCT and Spectralis OCT, respectively, was good for ‘S’ (0.9; 0.82), ‘A’ (1.0; 1.0) and ‘E’ (range 0.63–0.8; 0.57–0.77), and lower for ‘V’ (0.25; 0.42). Conclusions The ‘SAVE’ grading protocol of CSME integrates information from two imaging techniques, OCT and FA. Its clinical approach allows examiners to define and further categorise clinical characteristics to find tailored therapeutic strategies.

RETINAL MORPHOMETRY CHANGES MEASURED WITH SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER PAN-RETINAL PHOTOCOAGULATION IN PATIENTS WITH PROLIFERATIVE DIABETIC RETINOPATHY.

Purpose: To identify the effects of pan-retinal laser treatment on the integrity of neurosensory retinal layers. Methods: Patients were examined with fluorescence angiography after a standardized examination for diabetic retinopathy and a peripapillary ring scan with spectral domain optical coherence tomography. A single-session pan-retinal photocoagulation was performed using the PASCAL pattern scanning argon laser applying a minimum of 1,500 spots. Optical coherence tomography was evaluated more than 6 months. Results: Eighteen eyes of 12 consecutive patients with new onset, treatment-naive proliferative diabetic retinopathy secondary to diabetes Type 2 were treated and retinal optical coherence tomography morphology evaluated. Retinal nerve fiber layer thickness increased statistically significantly from baseline to week 1, when it reached its peak. The combined thickness of the outer plexiform and the inner nuclear layers and the combined thickness of the inner plexiform and the ganglion cell layers showed no relevant changes. The combined thickness of the retinal pigment epithelium and the photoreceptor cell layers decreased at month 1 followed by a steady increase in thickness, which remained below baseline values over time. Conclusion: Pan-retinal photocoagulation in proliferative diabetic retinopathy leads to a slowly reversible, marked biological response with statistically significant morphometric changes detected by spectral domain optical coherence tomography. Swelling of the retinal nerve fiber and outer nuclear layers induce an increase in peripapillary total retinal thickness. Simultaneously, the photoreceptor and retinal pigment epithelium layers decrease in thickness. These changes indicate diffuse retinal inflammation after pan-retinal laser therapy.

eHealth 2015 Special Issue: Impact of Electronic Health Records on the Completeness of Clinical Documentation Generated during Diabetic Retinopathy Consultations

Background: Two years ago, the Diabetic Retinopathy (DRP) and Traumatology clinic of the Department of Ophthalmology and Optometrics at the Medical University of Vienna, Austria switched from paper-based to electronic health records. A customized electronic health record system (EHR-S) was implemented. Objectives: To assess the completeness of information documented electronically compared with manually during patient visits. Methods: The Preferred Practice Pattern for Diabetic Retinopathy published by the American Academy of Ophthalmology was distilled into a list of medical features grouped into categories to be assessed and documented during the management of patients with DRP. The last seventy paper-based records and all electronic records generated since the switch were analyzed and graded for the presence of features on the list and the resulting scores compared. Results: In all categories, clinical documentation was more complete in the EHR group. Conclusions: In our setting, the implementation of an EHR-S showed a statistically significant positive impact on documentation completeness.

Early ultrasonographic tumor regression after linear accelerator stereotactic fractionated photon radiotherapy of choroidal melanoma as a predictor for metastatic spread

BACKGROUND AND PURPOSE During extended follow-up (of up to 15 years), approximately fifty percent of patients with choroidal melanoma will develop metastatic disease and eventually die. Thus, continuing research on prognostic factors, early detection and treatment is necessary. Height regression rates both after plaque brachytherapy and proton beam irradiation have been shown to have prognostic value. The purpose of this study was to analyze the influence of early tumor regression rate after treatment of choroidal melanoma with LINAC stereotactic fractionated radiotherapy (SFRT) as an independent risk factor for metastasis. MATERIAL AND METHODS 256 patients with choroidal melanoma treated with LINAC SFRT were included. Follow-up included standardized echography yielding apical height, smallest and largest basal linear diameter, tumor volume and mean reflectivity. The influence of baseline measurements and of a longitudinal, normalized area under the curve coefficient (NAC) of the latter marker on metastasis risk was assessed. RESULTS NAC for tumor thickness at months 3, 6, and 12 had a statistically significant (p < 0.001) non-linear effect on risk of metastasis. Additionally, ultrasonographic baseline tumor dimensions, but not internal reflectivity were found to be statistically significant risk factors for metastasis. CONCLUSIONS Our results demonstrate a non-linear influence of regression rate of choroidal melanoma as independent risk factor of metastatic disease after LINAC SFRT. These prove the clinical experience that, in comparison to rather slow regressions, very quick and very slow early tumor responses to LINAC SFRT are associated with a significantly higher metastasis risk.

Detailed analysis of retinal morphology in patients with diabetic macular edema (DME) randomized to ranibizumab or triamcinolone treatment — reply to the letter to the editor

We thank Dan and Mihai Călugăru for their letter and interest in our article [1]. In the study we presented, we included patients with visual impairment secondary to center involving diabetic macula edema (DME) (in our paper, we used this term to define central retinal subfield-thickness of more than 300 μm measured with spectral-domain OCT (see Methods section) . We used well-established inclusion criteria that are commonly used in DME trials: central retinal thickness (CRT) > 300 μm in spectral-domain optical coherence tomography (SD-OCT) and best-corrected visual acuity (BCVA) 20/ 25–20/400 Snellen equivalent. However, there was a significant difference in some morphologic details like area of fluorescein leakage, number of cotton-wool spots, and location of cystoid changes within the retina at baseline. These characteristics emphasize the high diversity of DME that cannot be reflected in CRT alone, as discussed in our article. We have evaluated these various characteristics and followed them over the course of a 1-year PRN treatment with ranibizumab or triamcinolone. As the efficacy of both treatment modalities was already shown in larger, multicenter studies, we merely focused on the morphologic details presented. In our study cohort, about half of the patients were treatment-naïve, which is also comparable with larger multicenter trials [2, 3]. As mentioned in our Methods section, any previous ocular treatment had been performed at least 3 months prior to study inclusion. This time-frame is also commonly used to exclude an interfering effect. The number of treatment-naïve patients and previously treated patients was wellbalanced between our two groups. Possibly, there might be a difference in treatment response of treatment naïve and recurrent DME, but this was not the aim of our study, and our sample size was too small to do a subgroup analysis. Elman and al. performed a similar subgroup analysis, but gain in visual acuity within the first year seemed to be similar in both previously treated and treatment-naïve eyes [2]. We agree with the Călugărus that DME is a chronic disease that needs prolonged intensive care. We do not claim that 1 year of PRN treatment is sufficient to cure DME. Cases of persistent edema are reflected in the data we presented, and details about persistent DME are added to Table 1. Hence, longer follow-up periods are commonly used to investigate the intensity of treatment needed [4, 5]. Macular ischemia is commonly found in patients with diabetic retinopathy. Although the area of FAZ increased within 1 year of treatment in our study cohort, these changes were not significant. We do not conclude that macular ischemia progresses under treatment. We thank the Călugărus for the suggestion of further variables that could have an effect on treatment response. Each suggested variable is addressed separately in Table 1. Missing variables that are not addressed in Table 1 were not evaluated. In our study, we concentrated on the evaluation of hallmark lesions in DR and their changes through 1 year of PRN treatment with ranibizumab or triamcinolone. To conclude, we would like to emphasize the high diversity of DME as presented in our study. In future, a detailed morphologic characterization of DME based on thorough image analyses might ease individualized treatment decisions. * Ursula Schmidt-Erfurth ursula.schmidt-erfurth@meduniwien.ac.at

Analysis of retinal layer thickness in diabetic macular oedema treated with ranibizumab or triamcinolone

To evaluate detailed changes in retinal layer thickness in spectral‐domain optical coherence tomography (SD‐OCT) images during a 1‐year follow‐up of patients treated for diabetic macula oedema (DME).

Optic nerve head morphology in primary open-angle glaucoma and nonarteritic anterior ischaemic optic neuropathy measured with spectral domain optical coherence tomography

Optic nerve head (ONH) parameters as well as circumpapillary retinal nerve fibre layer (RNFL) thickness values measured with two different spectral domain optical coherence tomography (SD‐OCT) machines (Spectralis® and Cirrus® OCT) have been compared between two patient groups, primary open‐angle glaucoma (POAG), nonarteritic anterior ischaemic optic neuropathy (NAION) and healthy controls. A comparison of the performance of the two OCT machines was made.