A. Lappas

Macular translocation for surgical management of subfoveal choroidal neovascularizations in patients with AMD: first results

Abstract · Background: At present no satisfying treatment for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is available. Visual results after successful surgical removal of subfoveal CNV are disappointing. This has been explained by a primary dysfunction of the retinal pigment epithelium (RPE) in the macular region and the surgical trauma to the RPE in patients with AMD. Therefore, Machemer and Steinhorst developed a technique for macular translocation after surgical removal of subfoveal CNV. We report our first experiences with this technique in patients with subfoveal CNV secondary to AMD. · Methods: Seven patients aged between 71 and 83 years with subfoveal CNV were included in the study. Visual acuity of the fellow eyes was below 20/400. All patients underwent pars plana vitrectomy. Retinal detachment was produced by subretinal infusion of balanced salt solution and a 360° retinotomy at the base of the vitreous was performed. After removal of the CNV, retinal rotation and reattachment, the retina bordering the retinotomy was coagulated with endolaser photocoagulation. Silicone oil was used as temporary tamponade. · Results: In all patients the subfoveal CNV was removed and the macula was translocated by a 15°–45° rotation onto functional RPE. The mean duration of follow-up was 11±3 months. Initial visual acuity ranged from 20/80 to hand movements. Final visual acuity was 20/100 to 20/400. Initially all patients complained of tilted vision. During follow-up the rotation of the image regressed and was well tolerated by all patients. Complications included the development of retinal detachment in three patients after silicone oil removal, development of a macula pucker, and a significant increase of lens opacity in the phakic eyes. · Conclusion: In our series rapid improvement of visual function was observed in one patient only, even if the macula appeared ophthalmoscopically and angiographically normal. Vitreoretinal complications occurred frequently during follow-up.

Optical Coherence Tomography in Parkinsonian Syndromes

Background/Objective Parkinsons disease (PD) and the atypical parkinsonian syndromes multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) are movement disorders associated with degeneration of the central nervous system. Degeneration of the retina has not been systematically compared in these diseases. Methods This cross-sectional study used spectral-domain optical coherence tomography with manual segmentation to measure the peripapillar nerve fiber layer, the macular thickness, and the thickness of all retinal layers in foveal scans of 40 patients with PD, 19 with MSA, 10 with CBS, 15 with PSP, and 35 age- and sex-matched controls. Results The mean paramacular thickness and volume were reduced in PSP while the mean RNFL did not differ significantly between groups. In PSP patients, the complex of retinal ganglion cell- and inner plexiform layer and the outer nuclear layer was reduced. In PD, the inner nuclear layer was thicker than in controls, MSA and PSP. Using the ratio between the outer nuclear layer and the outer plexiform layer with a cut-off at 3.1 and the additional constraint that the inner nuclear layer be under 46 µm, we were able to differentiate PSP from PD in our patient sample with a sensitivity of 96% and a specificity of 70%. Conclusion Different parkinsonian syndromes are associated with distinct changes in retinal morphology. These findings may serve to facilitate the differential diagnosis of parkinsonian syndromes and give insight into the degenerative processes of patients with atypical parkinsonian syndromes.

One year follow up of macular translocation with 360 degree retinotomy in patients with age related macular degeneration

Aim: To evaluate the benefits of macular translocation with 360 degree retinotomy in patients with exudative age related macular degeneration (ARMD). Methods: A consecutive interventional case series was performed on patients who underwent macular translocation between June 1997 and January 2000 at the department of ophthalmology, University of Aachen, Germany. A retrospective pilot study was set up with a minimum follow up of 12 months in 39 consecutive patients with subfoveal choroidal neovascularisation secondary to ARMD. The surgical technique included pars plana vitrectomy, induction of retinal detachment, 360 degree retinotomy, removal of the choroidal neovascular membranes (CNVM), macular translocation, peripheral laser retinopexy, and silicone oil endotamponade. Results: 18 patients showed predominantly occult CNVM, six patients had predominantly classic CNVM, and 15 showed subretinal haemorrhage. At the 12 month follow up 13 patients (33%) showed an improvement in visual acuity of more than three lines (logMAR scale), 18 patients (46%) retained stable visual acuity with a change of equal or less than three lines (logMAR scale), and eight patients (21%) showed a decrease in visual acuity of more than three lines (logMAR scale). Recurrence of CNVM was observed in three (8%) eyes at 5–11 months postoperatively. Other complications included proliferative vitreoretinopathy with retinal detachment (n=10), peripheral epiretinal membranes (n=9), macular pucker (n=2), corneal decompensation (n=2), and hypotony (n=11). 18 patients (46%) complained about persistent diplopia. Conclusion: Macular translocation surgery is able to maintain or improve distant vision in the majority of patients with exudative ARMD. Proliferative vitreoretinopathy and diplopia are the two major complications. A prospective randomised controlled trial comparing macular translocation with observation for patients with the occult form of exudative ARMD may be justified.

Retinal pigment epithelium and endothelial cell interaction causes retinal pigment epithelial barrier dysfunction via a soluble VEGF-dependent mechanism

PURPOSE To investigate the effect of endothelial cells (EC) on the barrier function of the retinal pigment epithelium (RPE). METHODS Primary bovine RPE were grown in solo culture or in coculture with bovine EC. Culture media of RPE were varied to develop a monolayer with stable barrier properties determined by transepithelial electrical resistance (TER) and permeability to sodium fluorescein. The effect of EC on the barrier properties of RPE was tested in contacting and non-contacting cocultures of RPE and EC. The conditioned media of cocultures were analysed for soluble vascular endothelial growth factor (VEGF) by ELISA. A neutralizing antibody to VEGF(165) was added to cocultures of RPE and EC and the TER was measured. RESULTS RPE had maximal barrier properties (high TER, low permeability, positive staining for barrier proteins) at day 10 that persisted until day 20. Compared to solo RPE culture, cocultivation of RPE with EC reduced RPE barrier function significantly and led to a greater release of soluble VEGF into the conditioned media (p<0.05). Neutralizing VEGF with antibody led to partial recovery of barrier properties in the coculture conditions (p<0.03). CONCLUSIONS Coculture of RPE with EC reduces RPE barrier properties and the reduction is, in part, mediated by soluble VEGF. EC-RPE contact-induced disruption of barrier properties occurs in ocular pathologies such as choroidal neovascularization, where EC move through Bruchs membrane and contact the RPE, leading to further exacerbation of the already compromised blood-retinal barrier.

Iris pigment epithelial cell translocation in exudative age-related macular degeneration. A pilot study in patients.

Abstract Background: This prospective, non-controlled pilot study investigates the practicability of IPE translocation and functional outcome in ARMD patients. Removal of submacular choroidal neovascularization (CNV) in age-related macular degeneration (ARMD) is usually associated with RPE damage and poor visual prognosis. Homologous RPE transplants fail to preserve macular function, possibly due to immune rejection. Instead of homologous RPE, we suggest translocating autologous iris pigment epithelium (IPE), building on earlier evidence from animal and in vitro investigations that IPE can substitute RPE functions in the experimental animal. Immunological cell rejection is avoided. Methods: Four eyes with well- defined and eight eyes with ill- defined subfoveal CNV were submitted to operation and followed up for a minimum of 6 months. IPE cells were harvested from a peripheral iridectomy. A vitrectomy was performed. Submacular membranes were removed, and isolated IPE cells were injected into the subretinal space. Examinations included ETDRS visual acuity, fluorescein angiography, and SLO microperimetry. Results: All patients underwent successful surgical removal of CNV and subretinal IPE injection. Compared to preoperative visual acuity (20/400–20/100) no significant change was observed after 6 months (20/320–16/80). A change of more than two ETDRS chart lines was defined as significant. One eye with preoperative ill-defined CNV developed a recurrence, leading to reduced visual acuity. In all patients, postoperative fluorescence angiography revealed early hyperfluorescence (window defect) in the surgically denuded area. Central fixation was demonstrated in 50% of eyes. Conclusions: Preliminary data suggests that IPE translocation in submacular surgery for ARMD can preserve but not improve preoperative visual acuity over 6 months. Functional results are promising compared to submacular membrane extraction alone and RPE transplantation. Continued research on improvement of IPE translocation seems justified.

Comparison of tight junction permeability for albumin in iris pigment epithelium and retinal pigment epithelium in vitro.

Abstract• Background: The degenerative retinal diseases are one of the major causes of visual loss in the western world. Although heterologous RPE transplants rescue the photoreceptors in the dystrophic rat model, rejection remains a major limiting factor. Given the common embryonic origin, iris pigment epithelial (IPE) cells might be able to take over the functions of retinal pigment epithelial (RPE) cells, serving as an autologous graft for transplantation and thereby preventing rejection. One of the main functions of RPE cells is the generation of tight junctions which form the outer blood-retinal barrier. In this study we compared the tight junction permeabilities of IPE and RPE cells isolated from Long Evans rats by measuring their albumin clearances. • Methods: IPE and RPE cells were cultured on semipermeable filter supports with and without the addition of 0.02% ethylene diaminetetraacetic acid (EDTA). At selected intervals, the albumin clearances of the IPE and RPE cells were measured spectrophotometrically and compared. The morphology of the cells was compared using electron microscopy and fluorescent labeling. • Results: IPE and RPE cells both restricted the passage of albumin in vitro. After the modulation of tight junctions with 0.02% EDTA, the clearance increased in both types of cells in a similar fashion. The morphology of tight junctions was visualized with electron microscopy. • Conclusion: These results indicate that the functional barrier for macromolecules is similar in IPE and RPE cells in vitro. This raises the possibility that IPE cells would form tight junctions in the subretinal space, thereby substituting for the blood-retinal barrier normally formed by RPE cells.

Translocation of iris pigment epithelium in patients with exudative age-related macular degeneration: long-term results

PurposeTo report the practicability and efficacy of autologous iris pigment epithelium (IPE) translocation in exudative age-related macular degeneration (ARMD) over 1 year.MethodsThe consecutive interventional case series included 56 patients with exudative ARMD. During vitrectomy the submacular neovascular membrane (CNV) was removed and IPE cells, harvested from a peripheral iridectomy, were injected into the submacular space. Included were patients with subfoveal occult CNV (11 eyes), classic CNV (10 eyes), mixed CNV (17 eyes), CNV with a pigment epithelial detachment (13 eyes) or CNV with a hemorrhage (5 eyes). Outcome measures were visual acuity, foveal fixation, size of CNV and rate of recurrence based on fluorescence angiographic imaging.ResultsAll patients underwent successful surgical removal of the CNV with consecutive subretinal IPE injection. Visual acuity was better than 20/100 in 19 patients preoperatively and in 18 patients postoperatively. A visual acuity of 20/100 or less was found in 37 patients preoperatively and in 38 patients postoperatively. Mean preoperative visual acuity (1.0±0.3 logMAR units) did not change significantly after 1 year (1.0±0.3 logMAR units). Ten eyes (18%) developed a recurrence. Fixation within the surgically denuded area could be demonstrated in 25 eyes (45%).ConclusionsAutologous IPE translocation for ARMD over one year can preserve foveal function on a low level, but cannot improve visual acuity. IPE translocation is technically feasible with a low rate of complications. Continued research seems justified to improve functional outcome.

Constitutive Nuclear Factor-κB Activity Is Crucial for Human Retinoblastoma Cell Viability

Retinoblastoma (Rb) is the most common intraocular malignancy of childhood. Although systemic and intrathecal chemotherapy with local and cranial radiotherapy have improved overall survival, the prognosis for patients with central nervous system involvement is still poor. We investigated the role of the transcription factor nuclear factor (NF)-kappaB, which promotes cell survival in several other models, in the pathophysiology of Rb. The human Rb cell lines Y79 and WERI-Rb1 were treated with the cell permeable peptide SN50, that specifically inhibits the transcriptional activity of NF-kappaB by blocking its translocation into the nucleus. We found that NF-kappaB inhibition up-regulated Bax; down-regulated the anti-apoptotic proteins Bcl-2, A1, and cIAP-2; and induced loss of the mitochondrial transmembrane potential and caspase-independent, calpain-dependent apoptosis in Rb cells. Inhibition of the p38 kinase sensitized cells to SN50-induced cell death, whereas insulin-like growth factor-1 activated NF-kappaB and attenuated the proapoptotic effect of SN50. Finally, NF-kappaB inhibition sensitized Rb cells to doxorubicin. In conclusion, inhibition of NF-kappaB activity in Rb cells leads to loss of mitochondrial transmembrane potential and caspase-independent, calpain-dependent apoptosis. Therapeutic strategies targeting NF-kappaB could be beneficial in the clinical management of Rb, either alone or in combination with conventional chemotherapy.

Use of heavy silicone oil (Densiron-68®) in the treatment of persistent macular holes

Purpose:  In this retrospective case series, we studied the effect of ‘heavy’ silicone oil on persisting macular holes. Patients with macular holes that failed to close after conventional macular hole surgery were retreated with the longterm internal tamponade Densiron‐68®.

Clinical use of a new position-independent rebound tonometer.

Purpose:To compare intraocular pressure (IOP) measurements obtained by rebound tonometry (Icare PRO tonometer), applanation tonometry (Goldmann and Perkins tonometry), and dynamic contour tonometry in the upright and the supine positions, and to investigate the influence of axial length and central corneal thickness. Methods:Ninety-nine right eyes of 99 patients with glaucoma or suspect for glaucoma, admitted to our department between November 2010 and January 2011 to obtain an IOP profile including supine measurements, were included in our study. IOP measurements were obtained in an upright position using an Icare PRO rebound (RTPRO), a Goldmann applanation (GAT), and a Pascal dynamic contour tonometer (DCT). In the supine position, IOP measurements were taken using the RTPRO and a Perkins hand-held applanation tonometer (PAT). The means and SDs for all tonometers were compared. Agreement between the tonometers was calculated using the Bland-Altman method. Results:The mean IOPs obtained in the upright position were 17.7±8.0 mm Hg (RTPRO), 17.6±7.8 mm Hg (GAT), and 19.9±6.6 mm Hg (DCT). Correlation analysis of these data indicated a good correlation between IOP readings obtained using RTPRO and GAT (r=0.951; P<0.001), and RTPRO and DCT (r=0.897; P<0.001). Bland-Altman analysis revealed mean differences (bias) between RTPRO and GAT, and between RTPRO and DCT of 0.1 mm Hg and −1.8 mm Hg, with 95% limits of agreement of −3.6 to 3.8 mm Hg and −7.3 to 3.6 mm Hg, respectively. In the supine position, the mean IOPs were 19.2±6.4 mm Hg using the RTPRO and 19.6±6.2 mm Hg using the PAT. Conclusions:Measurements obtained with the RTPRO, either in the upright or in the supine position, show good correlation and agreement with those provided by applanation and dynamic contour tonometry. The study was registered with the DRKS (German Clinical Trials Register; http://www.germanctr.de; DRKS00000581).