Jan C. van Meurs

Autologous retinal pigment epithelium and choroid translocation in patients with exudative age-related macular degeneration: short-term follow-up☆

Abstract Purpose To evaluate the feasibilty of translocating autologous retinal pigment epithelium cells and choroid after the removal of a subfoveal choroidal neovascular membrane in patients with exudative age-related macular degeneration. Design Interventional case series. Methods This was a prospective evaluation of six patients with a follow-up of 7 to 13 months. All patients had large (> 1 disk diameter) subfoveal choroidal membranes, five with subretinal hemorrhage. Preoperative visual acuity ranged from 20/400 to 20/200. After the extraction of the neovascular complex, an autologous peripheral full-thickness patch of retinal pigment epithelium, Bruch membrane, choriocapillary, and choroid was cut out from the midperiphery and repositioned under the macula. Functional tests included Early Treatment Diabetic Retinopathy Study vision testing, fixation testing on a optical coherence tomography monitor, fluorescein and indocyanine green angiography, and scanning laser ophthalmoscopy autofluorescence. Results The retinal pigment epithelium patch appeared flat and had a brown furry aspect in four patients. Fixation was on the patch in these four patients. Postoperative vision ranged from 20/200 to 20/64, with a 2-line increase in three patients. Revascularization was visible on fluorescein and indocyanide angiography in three patients examined in this manner. Normal retinal pigment epithelium autofluorescence was present over the patch in four patients. Conclusions The translocation of a full-thickness patch with autologous peripheral retinal pigment epithelium to the macula after choroidal neovascular membrane extraction was feasible and may result in a surviving and functioning graft for more than 1 year. Longer follow-up to evaluate its long-term benefit is necessary, as well as refinement of the surgery.

High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection

PURPOSE To determine the dexamethasone concentration in aqueous, vitreous, and serum of patients after a subconjunctival injection with dexamethasone disodium phosphate and to compare the effectiveness of a subconjunctival injection as a method of delivering dexamethasone into the vitreous with that of two previously tested routes: peribulbar injection and oral administration. METHODS In a prospective study, 50 phakic patients who underwent a pars plana vitrectomy received a single subconjunctival injection with 2.5 mg of dexamethasone disodium phosphate, aqueous solution (after topical anesthesia and a subconjunctival injection with lidocaine) at varied intervals before surgery. An aqueous and a vitreous sample were taken from each patient, and serum samples were collected at multiple time points from nine of 50 patients. Dexamethasone concentrations were measured by radioimmunoassay. RESULTS The estimated maximum dexamethasone concentration in the aqueous was 858 ng per ml at 2.5 hours after injection, and in the vitreous, 72.5 ng per ml at 3 hours. In serum, a mean maximum concentration of 32.4 ng per ml was measured at approximately 30 minutes after injection. CONCLUSIONS Subconjunctival injection of 2.5 mg of dexamethasone disodium phosphate resulted in an estimated vitreous dexamethasone peak concentration three and 12 times higher, respectively, than after a peribulbar injection of 5 mg of dexamethasone disodium phosphate and an oral dose of 7.5 mg of dexamethasone. Thus, a subconjunctival injection is the most effective method of delivering dexamethasone into both the anterior and posterior segments of the eye. Systemic drug absorption is considerable and is of the same order of magnitude as after peribulbar injection.

The angio-fibrotic switch of VEGF and CTGF in proliferative diabetic retinopathy.

Background In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. Methods/Principal Findings VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. Conclusions/Significance CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy.

Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate

PURPOSE To study the dexamethasone concentration in aqueous humor, vitreous, and serum of patients after repeated topical application of dexamethasone disodium phosphate. DESIGN Prospective nonrandomized comparative trial. PARTICIPANTS Twenty phakic patients scheduled for a first vitrectomy. METHODS All participants received dexamethasone disodium phosphate drops according to an application schedule intended to result in steady-state drug concentrations. Starting on the preoperative day, they received 1 drop of dexamethasone disodium phosphate (0.1%) every 1 hours until the time of vitrectomy (total, 10 or 11 drops). At night, ointment containing dexamethasone (0.3 mg/g) and gentamicin (5 mg/g) was administered once. From 7 AM on, the drop application schedule was resumed. At the start of the vitrectomy, samples were taken from the aqueous humor, vitreous, and blood. MAIN OUTCOME MEASURES The dexamethasone concentrations in the aqueous humor, vitreous, and serum measured by radioimmunoassay. RESULTS The mean dexamethasone concentrations in the aqueous humor, vitreous, and serum were 30.5 ng/ml (range, 7.1-57.7; standard deviation [SD] 15.0), 1.1 ng/ml (range, 0.0-1.6; SD 0.4), and 0.7 ng/ml (range, 0.0-1.2; SD 0.4), respectively. CONCLUSIONS Compared with previously tested administration routes (peribulbar or subconjunctival injection or oral administration), the penetration of dexamethasone into the vitreous after repeated drop application is negligible. Despite the frequent dosing schedule, the dexamethasone concentration in the aqueous humor is far lower than after a subconjunctival injection with dexamethasone disodium phosphate. Systemic uptake is low.

Dexamethasone Concentration in Vitreous and Serum After Oral Administration

PURPOSE To determine the dexamethasone concentration in vitreous and serum of patients after oral administration of dexamethasone and to compare the results with the concentrations in vitreous and serum found in a previous study with peribulbar injection of 5 mg dexamethasone disodiumphosphate. METHODS In a prospective study, 54 patients who were scheduled for vitrectomy received 7.5 mg dexamethasone orally at varied time intervals before surgery. A vitreous sample was taken from each patient and serum samples were collected at multiple time points from 32 out of 54 patients. Dexamethasone concentrations were measured by radioimmunoassay. RESULTS Dexamethasone concentrations in serum ranged from 2.5 to 98.1 ng/ml (median, 61.6 ng/ml) between 1 and 3 hours after oral administration of 7.5 mg dexamethasone. Serum concentrations after peribulbar injection of 5 mg dexamethasone disodiumphosphate (containing 3.75 mg dexamethasone) were lower by a factor of 1.5. Concentrations in vitreous ranged from 1.7 to 23.4 ng/ml (median, 5.2 ng/ml) between 4 and 10 hours after oral administration. After peribulbar injection of 5 mg dexamethasone disodiumphosphate, the intravitreal concentrations were 3.9 times higher. CONCLUSIONS An oral dose of 7.5 mg dexamethasone resulted in an intravitreal corticosteroid concentration with an anti-inflammatory potency that is clearly above physiological level. This concentration, however, is several times lower than is the intravitreal concentration after a peribulbar injection of 5 mg dexamethasone disodiumphosphate, although the two routes of administration resulted in nearly equal dexamethasone concentrations in serum. The higher intravitreal concentration after peribulbar injection is probably caused by diffusion from the serum and additional transscleral diffusion.

Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose

PURPOSE To determine dexamethasone concentrations in the subretinal fluid of patients after a peribulbar injection, a subconjunctival injection, or an oral dose of dexamethasone and to compare the results with those of previous similar studies of dexamethasone concentrations in the vitreous. DESIGN Prospective, nonrandomized, comparative trial. PARTICIPANTS One hundred forty-eight patients with a rhegmatogenous retinal detachment. METHODS Fifty patients received a peribulbar injection of 5 mg dexamethasone disodium phosphate, 49 received a subconjunctival injection of 2.5 mg dexamethasone disodium phosphate, and 49 received an oral dose of 7. 5 mg dexamethasone at various time intervals before surgery. At the time of surgery, a subretinal fluid sample was taken from each patient. MAIN OUTCOME MEASURES The dexamethasone concentration in the subretinal fluid measured by radioimmunoassay. RESULTS The estimated maximum dexamethasone concentrations in the subretinal fluid after the peribulbar injection, the subconjunctival injection, and the oral dose were, respectively, 82.2 ng/ml (standard error, 17. 6), 359 ng/ml (standard error, 80.2), and 12.3 ng/ml (standard error, 1.61). Corrected for dose, the maximum dexamethasone concentrations after subconjunctival injection and peribulbar injection were, respectively, 120 (95% confidence interval, 54/180) and 13 (95% confidence interval, 6.8/20) times greater than after oral administration. CONCLUSIONS A subconjunctival injection of dexamethasone disodium phosphate is more effective in delivering dexamethasone into the subretinal fluid of patients with a rhegmatogenous retinal detachment compared with peribulbar injection or oral administration. The subretinal dexamethasone concentrations were higher than concentrations measured in the vitreous in previous studies with a similar setup after all three delivery methods.

A Free Retinal Pigment Epithelium–Choroid Graft in Patients With Exudative Age-Related Macular Degeneration: Results up to 7 Years

PURPOSE To report and analyze long-term best-corrected visual acuity (BCVA) outcomes following a free autologous retinal pigment epithelium (RPE)-choroid graft translocation in patients with exudative age-related macular degeneration (AMD). DESIGN Prospective cohort study. METHODS SETTING Institutional. STUDY POPULATION One hundred and thirty consecutive patients (133 eyes) with AMD underwent RPE-choroid graft translocation between October 2001 and February 2006. All patients had a subfoveal choroidal neovascular membrane with or without hemorrhage and/or an RPE tear. All were either ineligible for or nonresponsive to photodynamic therapy, the standard treatment at the time of surgery. OBSERVATION PROCEDURES Data collection included preoperative and postoperative visual acuity measurements, fundus photography, fluorescein and indocyanine green angiography, and microperimetry. MAIN OUTCOME MEASURES Postoperative BCVA. RESULTS The mean preoperative BCVA was 20/250. Four years after surgery, 15% of the eyes had a BCVA of >20/200, and 5% had a BCVA of ≥20/40. One patient achieved a BCVA of 20/32, which was maintained at 7 years after surgery. Complications consisted of proliferative vitreoretinopathy (n = 13), recurrent neovascularization (n = 13), and hypotony (n = 2). CONCLUSIONS RPE-choroid graft transplantation may maintain macular function for up to 7 years after surgery, with relatively low complication and recurrence rates. Retinal sensitivity, BCVA data, and fixation on the graft suggest that the graft, rather than simply the removal of submacular hemorrhage and/or choroidal neovascular membrane, was responsible for the preservation of macular function. This surgery may be an alternative for patients with AMD who cannot undergo other standard treatment.

Randomized clinical trial of cryotherapy versus laser photocoagulation for retinopexy in conventional retinal detachment surgery

PURPOSE To investigate whether the method of retinopexy influences the visual recovery rate and the breakdown of the blood-ocular barrier after conventional retinal detachment surgery. METHODS Forty-eight patients (48 eyes) with primary rhegmatogenous retinal detachment entered into the study. All eyes were phakic, had an attached macula, and were scheduled for conventional scleral buckling surgery. Patients were randomly assigned to have either laser or cryotherapy for retinopexy. All visual acuity and flare measurements were performed by a masked observer. The interventional procedure was cryopexy at the time of scleral buckling surgery or postoperative (4 weeks) laser photocoagulation. Visual acuity testing with ETDRS chart and aqueous flare measurement with laser flare photometry were performed by a masked observer at standard intervals: preoperatively and 1 day, 7 days, 4 weeks, and 10 weeks postoperatively. Analysis of covariance by multiple linear regression was used for statistical evaluation. RESULTS Postoperative flare values from patients receiving cryotherapy were significantly higher at each measurement point in time (P < or =.001). The visual recovery was slower in the patients receiving cryotherapy (1 week, P =.003; 4 weeks, P =.03; 10 weeks, P =.081). CONCLUSION Laser flare photometry proved sufficiently sensitive to quantify an increase in aqueous flare after limited external retinal cryotherapy. Postoperative flare, as a measure of blood-ocular barrier breakdown, was significantly higher and visual recovery slower in the cryotherapy group. Visual acuity after 10 weeks was not significantly different between both groups.

Literature review of recombinant tissue plasminogen activator used for recent-onset submacular hemorrhage displacement in age-related macular degeneration.

Aims: To review and discuss the literature on recombinant tissue plasminogen activator (rtPA) for the treatment of a recent-onset submacular hemorrhage in patients with age-related macular degeneration. Methods: The administration technique of rtPA, the use of additional gas and vascular endothelial growth factor inhibitors (anti-VEGF), and the displacement rate of submacular hemorrhage and complications were noted from published reports, and a case series from the Rotterdam Eye Hospital (REH). Results: 38 studies with a total of 1,185 patients (1,176 eyes), and 28 patients from the REH were analyzed. Several methods for rtPA administration are available, which can be divided into two groups: submacular rtPA administration with vitrectomy; or intravitreal rtPA administration without vitrectomy. In both groups, the administration of gas and/or anti-VEGF agents could be additional. There appears to be no clear difference in complete displacement or complication rate between the more or the less invasive treatment groups. Conclusion: Although intravitreal injection of rtPA and gas only was reported to be as effective as subretinal rtPA with vitrectomy and gas, recent studies tend to use vitrectomy. These data underscore the need for a randomized controlled trial to choose the most effective and safe method of rtPA administration.Aims: To review and discuss the literature on recombinant tissue plasminogen activator (rtPA) for the treatment of a recent-onset submacular hemorrhage in patients with age-related macular degeneration. Methods: The administration technique of rtPA, the use of additional gas and vascular endothelial growth factor inhibitors (anti-VEGF), and the displacement rate of submacular hemorrhage and complications were noted from published reports, and a case series from the Rotterdam Eye Hospital (REH). Results: 38 studies with a total of 1,185 patients (1,176 eyes), and 28 patients from the REH were analyzed. Several methods for rtPA administration are available, which can be divided into two groups: submacular rtPA administration with vitrectomy; or intravitreal rtPA administration without vitrectomy. In both groups, the administration of gas and/or anti-VEGF agents could be additional. There appears to be no clear difference in complete displacement or complication rate between the more or the less invasive treatment groups. Conclusion: Although intravitreal injection of rtPA and gas only was reported to be as effective as subretinal rtPA with vitrectomy and gas, recent studies tend to use vitrectomy. These data underscore the need for a randomized controlled trial to choose the most effective and safe method of rtPA administration.

Collagen Distribution in the Human Vitreoretinal Interface

PURPOSE To evaluate the presence of collagen types I to VII, IX, XI, and XVIII at the posterior pole, the equator and the pre-equatorial area in human donor eyes, since collagens are important macromolecules that contribute to vitreoretinal adhesion at the vitreoretinal interface. METHODS Freshly isolated human retinectomy samples from the equator were used for reverse transcription-polymerase chain reaction to detect mRNA of the above-mentioned collagens. In addition, human donor eyes and equatorial retinectomy samples were embedded in paraffin, stained with antibodies against the collagens and evaluated by light microscopy (LM). RESULTS Retinectomy samples expressed mRNA of all tested collagen types. By LM, vitreous cortex was positive for collagen types II, V, IX, and XI. In all three regions within the donor eyes and in the retinectomy samples, the internal limiting membrane (ILM) showed types IV, VI, and XVIII; the retinal vasculature was positive for types I to VI and XVIII in most specimens; and the retinal layers showed condensed spots of type VII. In addition, type VII increased in density and in distribution over the retinal layers toward the posterior pole. CONCLUSIONS Staining patterns of collagen types I to V, IX, XI, and XVIII confirmed previous observations. Important new findings include the presence of type VI in the ILM and type VII in several layers of the retina. Both collagens can anchor matrix components, and type VI could be involved in vitreoretinal attachment. Furthermore, the presence of collagen mRNA in human retinectomy samples may be an indication of postnatal collagen production by retinal cells.