Ilse Krebs

TRANSPLANTATION OF THE RPE IN AMD

The retinal pigment epithelium (RPE) maintains retinal function as the metabolic gatekeeper between photoreceptors (PRs) and the choriocapillaries. The RPE and Bruchs membrane (BM) suffer cumulative damage over lifetime, which is thought to induce age-related macular degeneration (AMD) in susceptible individuals. Unlike palliative pharmacologic treatments, replacement of the RPE has a curative potential for AMD. This article reviews mechanisms leading to RPE dysfunction in aging and AMD, laboratory studies on RPE transplantation, and surgical techniques used in AMD patients. Future strategies using ex vivo steps prior to transplantation, BM prosthetics, and stem cell applications are discussed. The functional peculiarity of the macular region, epigenetic phenomena leading to an age-related shift in protein expression, along with the accumulation of lipofuscin may affect the metabolism in the central RPE. Thickening of BM with age decreases its hydraulic conductivity. Drusen are deposits of extracellular material and formed in part by activation of the alternative complement pathway in individuals carrying a mutant allele of complement factor H. AMD likely represents an umbrella term for a disease entity with multifactorial etiology and manifestations. Presently, a slow progressing (dry) non-neovascular atrophic form and a rapidly blinding neovascular (wet) form are discerned. No therapy is currently available for the former, while RPE transplantation and promising (albeit non-causal) anti-angiogenic therapies are available for the latter. The potential of RPE transplantation was demonstrated in animal models. Rejection of allogeneic homologous transplants in patients focused further studies on autologous sources. In vitro studies elucidated cell adhesion and wound healing mechanisms on aged human BM. Currently, autologous RPE, harvested from the midperiphery, is being transplanted as a cell suspension or a patch of RPE and choroid in AMD patients. These techniques have been evaluated from several groups. Autologous RPE transplants may have the disadvantage of carrying the same genetic information that may have led to AMD manifestation. An intermittent culturing step would allow for in vitro therapy of the RPE, its rejuvenation and prosthesis of BM to improve the success RPE transplants. Recent advances in stem cell biology when combined with lessons learned from studies of RPE transplantation are intriguing future therapeutic modalities for AMD patients.

Transplantation of autologous retinal pigment epithelium in eyes with foveal neovascularization resulting from age-related macular degeneration: a pilot study

PURPOSE To describe the indications, surgical technique, and clinical results of 14 eyes in 13 patients with age-related macular degeneration and foveal choroidal neovascularization, in which subretinal surgery was combined with simultaneous transplantation of autologous retinal pigment epithelial cells. METHODS Between March 1999 and February 2000, in a prospective study, 14 eyes (13 patients) with age-related macular degeneration underwent subretinal surgery because of foveal choroidal neovascularization with simultaneous transplantation of retinal pigment epithelium harvested from the nasal subretinal area of the same eye. Preoperatively, 1 month postoperatively, 3 months postoperatively and at 3-month intervals thereafter, examinations were performed including best-corrected visual acuity, visual field, biomicroscopy of anterior and posterior segment, tonometry, fluorescein and indocyanine angiographies, autofluorescence, scotometry, and fixation tests. RESULTS Postoperatively, after median observation of 17 months (range, 12 to 24 months) best-corrected visual acuity was improved 2 or more lines in eight eyes (57.1%), remained the same (+/- 1 line) in five eyes (35%), and decreased by more than 2 lines in one eye (7.1%). Pairwise t test showed significant improvement after 1 month (P = .0031, P = .0062) as well as 1 year (P = .0066, P = .0105). Satisfactory reading vision between Jaeger 1 and 4 was achieved in three eyes (21.2%). No significant intraoperative or postoperative complications occurred in any eye. No recurrence of choroidal neovascularization was observed during the observation period. CONCLUSIONS In eyes with age-related macular degeneration and foveal choroidal neovascularization, autotransplantation of retinal pigment epithelium was performed in addition to conventional removal of the choroidal neovascularization without significant intraoperative or postoperative complications. Visual acuity improvement of 2 or more lines in 57% of the eyes was achieved. No recurrent choroidal neovascularization formation was observed during the observation period. The results of this pilot study suggest that autologous transplantation of retinal pigment epithelium combined with submacular surgery might be a reasonable treatment option for patients with foveal choroidal neovascularization secondary to age-related macular degeneration.

A randomised double-masked trial comparing the visual outcome after treatment with ranibizumab or bevacizumab in patients with neovascular age-related macular degeneration

Aim The current accepted standard treatment for neovascular age-related macular degeneration (AMD) consists of antivascular endothelial growth factor agents including ranibizumab and bevacizumab. The aim of the study was to examine whether bevacizumab is inferior to ranibizumab with respect to maintaining/improving visual acuity. Methods In this prospective randomised parallel group multicentre trial patients aged more than 50 years with treatment naive nAMD were included at 10 Austrian centres. Patients were randomised to treatment either with 0.5 mg ranibizumab or 1.25 mg bevacizumab. Both groups received three initial monthly injections and thereafter monthly evaluation of visual acuity and the activity of the lesion. Re-treatment was scheduled as needed. Outcome measures were early treatment of diabetic retinopathy visual acuity, retinal thickness, lesion size and safety evaluation. Results A total of 321 patients were recruited of which four had to be excluded due to different reasons. Of the 317 remaining patients 154 were randomised into the bevacizumab group and 163 into the ranibizumab group. At month 12, there was a mean increase of early treatment of diabetic retinopathy visual acuity of 4.9 letters in the bevacizumab and 4.1 letters in the ranibizumab group (p=0.78). Furthermore, there were no significant differences in the decrease of retinal thickness, change of lesion size and number of adverse events between the groups. Conclusions Bevacizumab was equivalent to ranibizumab for visual acuity at all time points over 1 year. There was no significant difference of decrease of retinal thickness or number of adverse events.

Vitreomacular Adhesion in Active and End-Stage Age-related Macular Degeneration

PURPOSE To evaluate vitreomacular relations in different stages of age-related macular degeneration (AMD) without the influence of genetics and environmental factors. DESIGN Retrospective, observational case series. METHODS This was a multicenter study consisting of 29 previously untreated subjects with active exudative (wet) AMD in one eye and active nonexudative (dry) AMD in the fellow eye who were compared with 10 previously untreated subjects with end-stage geographic atrophy in one eye and an end-stage fibrotic (disciform) scar in the fellow eye. All subjects were studied with ultrasonography to identify the presence of posterior vitreous detachment (PVD) and by optical coherence tomography to detect vitreomacular adhesion (VMA). RESULTS The incidence of PVD in eyes with nonexudative AMD was 20 (69%) of 29, compared with 6 (21%) of 29 with active exudative AMD (P = .002). VMA was present in 11 (38%) of 29 of eyes with exudative AMD and in only 3 (10%) of 29 eyes with nonexudative AMD (P = .008). The incidence of PVD in geographic atrophy was 7 (70%) of 10, compared with 4 (40%) of 10 with disciform scar (P = .44). VMA was present in 2 (20%) of 10 eyes with disciform scars and in 0 (0%) of 10 eyes with geographic atrophy (P = .48). CONCLUSIONS PVD may protect against exudative AMD, whereas VMA may promote exudative AMD. This phenomenon is not evident in end-stage disease because of an increased incidence of PVD and a decreased incidence of VMA in eyes with disciform scars. Genetic and environmental factors do not seem to influence these observations.

Non-responders to treatment with antagonists of vascular endothelial growth factor in age-related macular degeneration

Purpose Most of the publications on modern therapy of neovascular age-related macular degeneration focus on the effect of the treatment. The purpose of this study is to determine the frequency of non-responders to anti-vascular endothelial growth factor (anti-VEGF) treatment and find possible reasons for their failure to respond. Methods The records of patients treated until the end of 2008 the first time with either bevacizumab or ranibizumab were reviewed. Based on the availability of measurable results and according to prior publications showing the effect of the therapy, loss of three lines of distance acuity, increase of retinal thickness or lesion size were identified as indicators of non-responders. Two of these three signs had to be present. Results 334 eyes of 283 patients were included; 74.55% received bevacizumab and 25.45% received ranibizumab. Overall 14.37% of the eyes were identified as non-responders (14.06% in the bevacizumab group and 15.29% in the ranibizumab group). Baseline distance acuity and vitreo-retinal adhesions were significantly correlated with non-responders. Correlations with age, gender, lesion type, other morphologic features, and the kind of anti-VEGF agent failed to be significant. 10.4% of the non-responders showed a delayed but good response to anti-VEGF treatment. Conclusions About 15% did not sufficiently respond to anti-VEGF treatment. Vitreo-retinal adherences were the only ophthalmologic factor which could be identified to be significantly correlated with insufficient response.

Spectral domain optical coherence tomography for higher precision in the evaluation of vitreoretinal adhesions in exudative age-related macular degeneration

Aim The role of changes at the vitreoretinal interface and vitreomacular traction forces in pathogenesis, and the course of exudative age-related macular degeneration (AMD) need further exploration. This study examines the localisation of adhesion and the direction of traction lines in eyes with exudative AMD. Methods The cubes 512×128 of Cirrus optical coherence tomography (OCT) and volume scans of Spectralis OCT were reviewed in a consecutive series of patients presenting between December 2008 and March 2009 with vitreomacular adhesion in exudative AMD. Results 30 eyes of 25 patients with exudative AMD and vitreomacular adhesion were studied. 50% had type III lesions, 46.7% occult and 3.3% predominantly classic lesions. The localisation of the adhesion corresponded in 100% with the area of the neovascularisation (CNV), in 73.3% traction directed towards the CNV and in 83.3% towards the optic disc could be noted. Spectral domain OCT and 3D visualisation enabled clearer localisation of vitreomacular adhesion and definition of resulting traction lines. Conclusion There is a high prevalence of type III lesions within eyes with vitreomacular adhesions, and complete correspondence between the location of the adhesion and the CNV. There is also a high incidence of vitreopapillary adhesion in these cases, suggesting a possible role in pathogenesis.

Optical coherence tomography guided retreatment of photodynamic therapy.

Aim: To evaluate the results of a retreatment modality of photodynamic therapy (PDT) based on optical coherence tomography (OCT) and fluorescein angiography (FA). To quantify the effect of PDT with the help of measurement of the retinal thickness. Methods: Eyes with predominantly classic subfoveal choroidal neovascularisation (CNV) due to age related macular degeneration were included. PDT was performed every three months, when needed. OCT, FA, and measures of distance acuity were performed at baseline, after 6 weeks, 3 months, and from then on every 3 months. A control group of a consecutive series of eyes that had been retreated based only on FA results was installed. Results: Forty eyes of 38 patients were included. The average age was 73 years. The maximum retinal thickness decreased from 404 μm at baseline to 281.6 μm at month 12. Furthermore there was a significant decrease of retinal thickness in both subgroups. The number of retreatments was reduced, when activity was diagnosed using OCT and FA. (2.4 v 4.0). The distance acuity correlated significantly with the maximum retinal thickness (p = 0.0042). Conclusion: Information about the activity of a neovascular lesion can be obtained with the help of OCT. The retreatment modalities can be optimised by using OCT and FA and the number of retreatments can be reduced.

Repeatability and Reproducibility of Retinal Thickness Measurements by Optical Coherence Tomography in Age-Related Macular Degeneration

PURPOSE To evaluate the repeatability and reproducibility of retinal thickness measurements in exudative age-related macular degeneration (AMD) using Stratus optical coherence tomography (OCT) (Carl Zeiss Meditec, Inc., Dublin, CA). DESIGN Prospective, observational case series. PARTICIPANTS A total of 200 eyes of 200 subjects with exudative AMD. METHODS Macular thickness and fast macular thickness programs of Stratus OCT were performed twice by the same examiners or 2 different examiners. The sequence of examiners was randomized 1:1:1:1. The variability of 1-mm subfield central retinal thickness (CRT), center point thickness (CPT), and retinal volume (RV) was calculated. MAIN OUTCOME MEASURES Interobserver and intraobserver variability of retinal thickness measurements. RESULTS Ninety-nine patients/eyes were enrolled in study arm 1 (repeated by the same examiner), and 101 patients/eyes were enrolled in study arm 2 (repeated by different examiners). Values of CPT, CRT, and RV were well correlated (interclass correlation coefficient, 0.71-0.93) in both study arms, revealing better results for the macular thickness program than for the fast macular thickness program. Threshold algorithm line failures were significantly correlated to the absolute differences of 2 repeated measurements for CPT, CRT, and RV but not with manually corrected maximum retinal thickness (MRT). Maximum retinal thickness was significantly influenced by the examiner performing the measurement. Age, lesion composition, examiner performing OCT examination, and sequence of examination had no significant influence. CONCLUSIONS The repeatability and reproducibility of retinal thickness measurements were high, presenting better results for CRT and RV versus CPT, and for the macular thickness program versus the fast macular thickness program. The reliability of retinal thickness measurement was most frequently affected by algorithm line failures and fixation problems. A possible solution may be manually corrected measurement, such as MRT.

Quality of the threshold algorithm in age-related macular degeneration: Stratus versus Cirrus OCT.

PURPOSE Automatically generated measurements of the retinal volume or the central retinal thickness are based on correctly set threshold lines on the retinal surface and the retinal pigment epithelium. The purpose of this study was to compare the accuracy of threshold algorithm lines of Stratus optical coherence tomography (OCT) with those of Cirrus OCT. METHODS A consecutive series of patients at least 50 years of age with exudative age-related macular degeneration was included. Stratus OCT (retinal thickness program) and Cirrus OCT (macular cube 512 x 128) were performed by the same examiner, the sequence of the examinations was randomized. Two independent examiners evaluated the positioning of the threshold algorithm lines and performed a grading of the failures. Logistic regression analysis was applied for evaluation of the failure rate. RESULTS One hundred four patients were included. For the entire OCT examination (6 scans Stratus OCT, 128 scans Cirrus OCT) algorithm line failures were detected in 69.2% of the Stratus OCT and in 25% of the Cirrus OCT examinations, with the difference reaching statistical significance (P < 0.001). The median failure grade was 1 (0-6) for Stratus and 0 (0-5.15) for Cirrus OCT. Age, measurement sequence, and investigator did not influence the error rates. CONCLUSIONS With Cirrus OCT automatically performed and therefore objective measurements of central retinal thickness and retinal volume were provided correctly in 69.2% of the scans. Furthermore, this latest software version offers the possibility of manual correction of false positioned algorithm lines (ClinicalTrials.gov number, NCT00568191).

Quality and reproducibility of retinal thickness measurements in two spectral-domain optical coherence tomography machines.

PURPOSE To evaluate the accuracy and reproducibility of retinal thickness measurements in exudative age-related macular degeneration (AMD) by the Spectralis (Heidelberg Engineering, Heidelberg, Germany) and the Cirrus (Carl Zeiss Meditec, Dublin, CA) optical coherence tomography (OCT) systems. METHODS Eyes with exudative age-related macular degeneration were randomly assigned to one of eight groups, each different in the sequence of examiner and OCT system. The 512 × 128 cube program of the Cirrus and the 30° × 25° volume scan containing 32 lines of the Spectralis were performed twice. The correlation between the examinations was expressed by the interclass correlation coefficient (ICC). RESULTS Enrolled in the study were 112 patients and 112 eyes (mean age, 76.5 ± 7.9 years; range 51-89), with 14 patients in each group. The mean error scores per line were 0.53 and 0.52 in the Cirrus, significantly (P < 0.001) lower than in the Spectralis (0.83 and 0.98). For automatic central retinal thickness (CRT), the ICC for Cirrus (all examinations calculated) was 0.61 for groups 1 to 4 (the same examiner) and 0.65 for groups 5 to 8 (two different examiners); for Spectralis (13.4% not calculated) the ICC was 0.93 for groups 1 to 4 and 0.86 for groups 5 to 8. After error correction, the Cirrus ICC improved to 1.0 and 0.99 and the Spectralis ICC to 1.0 in both groups. CONCLUSIONS Considerable differences were found between the two systems, both of which incorporate the spectral-domain technology. Different positioning of segmentation lines, control of localization, density of included scan lines, and number of available maps explain the differences in segmentation quality and reproducibility. Manual correction of segmentation and centralization improves the reproducibility.