Ron A. Adelman

Inverted Internal Limiting Membrane Flap Technique for Large Macular Holes

PURPOSE Large macular holes usually have an increased risk of surgical failure. Up to 44% of large macular holes remain open after 1 surgery. Another 19% to 39% of macular holes are flat-open after surgery. Flat-open macular holes are associated with limited visual acuity. This article presents a modification of the standard macular hole surgery to improve functional and anatomic outcomes in patients with large macular holes. DESIGN A prospective, randomized clinical trial. PARTICIPANTS Patients with macular holes larger than 400 μm were included. In group 1, 51 eyes of 40 patients underwent standard 3-port pars plana vitrectomy with air. In group 2, 50 eyes of 46 patients underwent a modification of the standard technique, called the inverted internal limiting membrane (ILM) flap technique. METHODS In the inverted ILM flap technique, instead of completely removing the ILM after trypan blue staining, a remnant attached to the margins of the macular hole was left in place. This ILM remnant was then inverted upside-down to cover the macular hole. Fluid-air exchange was then performed. Spectral optical coherence tomography and clinical examination were performed before surgery and postoperatively at 1 week and 1, 3, 6, and 12 months. MAIN OUTCOME MEASURES Visual acuity and postoperative macular hole closure. RESULTS Preoperative mean visual acuity was 0.12 in group 1 and 0.078 in group 2. Macular hole closure was observed in 88% of patients in group 1 and in 98% of patients in group 2. A flat-hole roof with bare retinal pigment epithelium (flat-open) was observed in 19% of patients in group 1 and 2% of patients in group 2. Mean (or median) postoperative visual acuity 12 months after surgery was 0.17 (range, 0.1-0.6) in group 1 and 0.28 (range, 0.02-0.8) in group 2 (P = 0.001). CONCLUSIONS The inverted ILM flap technique prevents the postoperative flat-open appearance of a macular hole and improves both the functional and anatomic outcomes of vitrectomy for macular holes with a diameter greater than 400 μm. Spectral optical coherence tomography after vitrectomy with the inverted ILM flap technique suggests improved foveal anatomy compared with the standard surgery.

Persistent Ocular Hypertension Following Intravitreal Bevacizumab and Ranibizumab Injections

PURPOSE To study ocular hypertension (OHT) following intravitreal injections of bevacizumab and/or ranibizumab in patients with age-related macular degeneration (AMD). METHODS Retrospective case series. Patients with AMD who were treated at a tertiary referral center with intravitreal bevacizumab and/or ranibizumab injections from January 1, 2006 to December 31, 2008 were studied. The development of OHT following these injections was investigated. RESULTS Four out of 116 patients with AMD (3.45%) developed sustained elevated intraocular pressure (IOP) after multiple intravitreal injections of bevacizumab 1.5 mg/0.06 mL and/or ranibizumab 0.5 mg/0.05 mL. An analysis of 4 cases revealed: None of the patients had a previous diagnosis or family history of glaucoma/OHT. Two patients had both bevacizumab and ranibizumab injections. Two patients developed OHT after recent intravitreal ranibizumab and 2 patients after recent intravitreal bevacizumab injection. Two patients were pseudophakic with a history of YAG capsulotomy. The range of preinjection IOP was 8-15 mmHg (mean, 13 mmHg). The range of postinjection IOP was 28-36 mmHg (mean, 31.75 mmHg). The range of IOP increase was 17-21 mmHg (mean, 18.75 mmHg). Mean number of pan-anti-VEGF injections prior to OHT was 13.3 (range, 3-19). A disrupted posterior capsule might predispose patients to the development of OHT. CONCLUSIONS Persistent OHT may occur after intravitreal anti-VEGF injection in patients with no previous diagnosis of glaucoma or OHT. OHT may persist across several visits and patients may require IOP-lowering therapy. Sustained elevation in IOP usually occurs after multiple injections.

Trends in the indications for penetrating keratoplasty, 1980-2001.

Purpose: To study the leading indications and changing trends for penetrating keratoplasty (PK) over the past 3 decades. Methods: This is a retrospective review of 696 cases of PK. The indications for PKs performed at the Duke University Eye Center during the years 1980-1981, 1990- 1991, and 2000-2001 were tabulated to determine trends over the past 3 decades. The main outcome measures were indications for PK. Results: During this study, 696 PKs were performed. The leading indications for PK and their respective frequencies during 1980-1981, 1990-1991, and 2000-2001 were failed grafts (10.8%, 19.0%, 27.0%, respectively), pseudophakic bullous keratopathy (PBK)/aphakic bullous keratopathy (ABK) (19.4%, 20.6%, 16.7%, respectively), Fuchs dystrophy (15.6%, 13.0%, 23.8%, respectively), keratoconus (13.4%, 8.2%, 11.8%, respectively), and corneal scar (7.0%, 8.9%, 10.7%, respectively). The number of PKs for failed grafts and Fuchs dystrophy increased over time. Conclusions: In this study, failed graft has gradually become the leading indication for PK, whereas most other studies have reported PBK as the leading indication. Unlike many other studies, Fuchs dystrophy was a common indication for PK.

Strategy for the Management of Uncomplicated Retinal Detachments: The European Vitreo-Retinal Society Retinal Detachment Study Report 1

OBJECTIVE To study success and failure in the treatment of uncomplicated rhegmatogenous retinal detachments (RRDs). DESIGN Nonrandomized, multicenter retrospective study. PARTICIPANTS One hundred seventy-six surgeons from 48 countries spanning 5 continents provided information on the primary procedures for 7678 cases of RRDs including 4179 patients with uncomplicated RRDs. METHODS Reported data included specific clinical findings, the method of repair, and the outcome after intervention. MAIN OUTCOME MEASURES Final failure of retinal detachment repair (level 1 failure rate), remaining silicone oil at the studys conclusion (level 2 failure rate), and need for additional procedures to repair the detachment (level 3 failure rate). RESULTS Four thousand one hundred seventy-nine uncomplicated cases of RRD were included. Combining phakic, pseudophakic, and aphakic groups, those treated with scleral buckle alone (n = 1341) had a significantly lower final failure rate than those treated with vitrectomy, with or without a supplemental buckle (n = 2723; P = 0.04). In phakic patients, final failure rate was lower in the scleral buckle group compared with those who had vitrectomy, with or without a supplemental buckle (P = 0.028). In pseudophakic patients, the failure rate of the initial procedure was lower in the vitrectomy group compared with the scleral buckle group (P = 3×10(-8)). There was no statistically significant difference in failure rate between segmental (n = 721) and encircling (n = 351) buckles (P = 0.5). Those who underwent vitrectomy with a supplemental scleral buckle (n = 488) had an increased failure rate compared with those who underwent vitrectomy alone (n = 2235; P = 0.048). Pneumatic retinopexy was found to be comparable with scleral buckle when a retinal hole was present (P = 0.65), but not in cases with a flap tear (P = 0.034). CONCLUSIONS In the treatment of uncomplicated phakic retinal detachments, repair using scleral buckle may be a good option. There was no significant difference between segmental versus 360-degree buckle. For pseudophakic uncomplicated retinal detachments, the surgeon should balance the risks and benefits of vitrectomy versus scleral buckle and keep in mind that the single-surgery reattachment rate may be higher with vitrectomy. However, if a vitrectomy is to be performed, these data suggest that a supplemental buckle is not helpful. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Acute syphilitic posterior placoid chorioretinitis: report of a case series and comprehensive review of the literature.

Purpose: To describe the clinical and angiographic features of a series of patients with acute syphilitic posterior placoid chorioretinitis (ASPPC) in the context of previously published cases. Methods: A retrospective, noncomparative, multicenter chart review was performed on 16 patients with active ASPPC. Positive serologic tests supported the diagnosis in all patients. Color and red-free photographs as well as fluorescein angiography were obtained in each case. Indocyanine green angiography, optical coherence tomography, and fundus autofluorescence were performed on selected patients. A total of 44 previously published cases of ASPPC were identified using both a Medline Search and references listed in articles identified. Results: Ocular involvement was bilateral in 9 of our 16 patients (56.3%). The mean and median ages at presentation were 40 and 38 years, respectively (range 28–57 years). Nine patients (56.3%) were human immunodeficiency virus positive, with most recent CD4 cell counts ranging from 160 cells/&mgr;L to 450 cells/&mgr;L and a median CD4 cell count of 250 cells/&mgr;L. Seven of 16 patients (43.8%) had a history of mucocutaneous manifestations of secondary syphilis, whereas 4 (25.0%) had evidence of neurosyphilis. Anterior chamber and/or vitreous inflammation was evident in 13 patients (81.3%). Fifteen of 16 patients had positive venereal disease research laboratory or rapid plasma regain titers, and 13 of 13 tested patients had a positive serum fluorescent treponemal antibody absorption. The initial vision in the 25 affected eyes ranged from 20/20 to counting fingers, with a median of 20/80. In all patients, posterior segment examination in the involved eyes revealed a large, yellowish, placoid, outer retinal lesion. Fluorescein angiography showed progressive hyperfluorescence in the area of the lesion, often with scattered focal hypofluorescence, or leopard spotting. Inflammation subsided, the yellowish lesions resolved, and vision improved shortly after antibiotic therapy in 20 of 25 affected eyes. Visual acuity at last visit ranged from 20/20 to 20/150, with a median final vision of 20/25. A review of the literature revealed 44 previously reported cases of ASPPC. Shared demographic, clinical, and angiographic features were summarized. Conclusion: Acute syphilitic posterior placoid chorioretinitis is an uncommon but clinically and angiographically distinct manifestation of ocular syphilis. All patients with characteristic clinical and angiographic findings of ASPPC should be tested for both neurosyphilis and human immunodeficiency virus coinfection. Vision recovery typically followed completion of appropriate antibiotic therapy.

Claudin-19 and the Barrier Properties of the Human Retinal Pigment Epithelium

PURPOSE The retinal pigment epithelium (RPE) separates photoreceptors from choroidal capillaries, but in age-related macular degeneration (AMD) capillaries breach the RPE barrier. Little is known about human RPE tight junctions or the effects of serum on the retinal side of the RPE. METHODS Cultured human fetal RPE (hfRPE) was assessed by the transepithelial electrical resistance (TER) and the transepithelial diffusion of methylated polyethylene glycol (mPEG). Claudins and occludin were monitored by quantitative RT-PCR, immunoblotting, and immunofluorescence. RESULTS Similar to freshly isolated hfRPE, claudin-19 mRNA was 25 times more abundant than claudin-3. Other detectable claudin mRNAs were found in even lesser amounts, as little as 3000 times less abundant than claudin-19. Claudin-1 and claudin-10b were detected only in subpopulations of cells, whereas others were undetectable. Knockdown of claudin-19 by small interfering RNA (siRNA) eliminated the TER. siRNAs for other claudins had minimal effects. Serum affected tight junctions only when presented to the retinal side of the RPE. The TER increased 2 times, and the conductance of K(+) relative to Na(+) decreased without affecting the permeability of mPEG. These effects correlated with increased steady-state levels of occludin. CONCLUSIONS Fetal human RPE is a claudin-19-dominant epithelium that has regional variations in claudin-expression. Apical serum decreases RPE permeability, which might be a defense mechanism that would retard the spread of edema due to AMD.

TEMPORAL INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE VERSUS CLASSIC INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE: A Comparative Study.

Purpose: To determine if reducing the area of internal limiting membrane (ILM) peeling in the inverted ILM flap technique results in satisfactory outcomes for the repair of large Stage IV idiopathic macular holes. Methods: Prospective comparative interventional study of 87 consecutive eyes. Participants were randomized into two treatment groups. In Group A, the classic inverted ILM flap technique was performed. In Group B, a modification of this procedure, the temporal inverted ILM flap technique, was performed. In the modified inverted ILM flap technique, peeling of the ILM was restricted to the temporal side of the fovea only—the macular hole was then covered with the temporal ILM flap. Results: There was no significant difference in initial and final visual acuities between Groups A and B. In both groups, defects in photoreceptors and the external limiting membrane decreased with time. Successive postoperative examinations revealed an increasing number of patients with the dissociated optic nerve fiber layer appearance, although this was less frequent in Group B (modified ILM flap) than in Group A. Conclusion: The study results indicate that the temporal inverted ILM flap technique is as effective as the classic inverted ILM flap technique for the repair of large Stage IV macular holes.

Minimal Effects of VEGF and Anti-VEGF Drugs on the Permeability or Selectivity of RPE Tight Junctions

PURPOSE Bevacizumab and ranibizumab are currently used to treat age-related macular degeneration by neutralizing vascular endothelial growth factor (VEGF). In this study, the potential side effects on the outer blood-retinal barrier were examined. METHODS Human fetal RPE (hfRPE) cells were used because they are highly differentiated in culture. The claudin composition of RPE tight junctions was determined by RT-PCR, immunoblot analysis, and immunofluorescence. ELISA assays monitored the secretion and trafficking of VEGF and a fluid-phase marker, methylpolyethylene glycol (mPEG). Tight junction functions were assessed by the conductance of K(+) and Na(+) (derived from the transepithelial electrical resistance, TER) and the flux of NaCl and mPEG. RESULTS Claudin-3, claudin-10, and claudin-19 were detected in RPE tight junctions. VEGF was secreted in equal amounts across the apical and basolateral membranes, but the apical membrane was more active in endocytosing and degrading VEGF. Exogenous VEGF and mPEG crossed the RPE monolayer by transcytosis, predominantly in the apical-to-basal direction. RPE tight junctions were selective for K(+), but did not discriminate between Na(+) and Cl(-). VEGF, bevacizumab, and ranibizumab had minimal effects on TER, permeation of mPEG, and selectivity for K(+), Na(+), and Cl(-). They had minimal effects on the expression and distribution of the claudins. CONCLUSIONS RPE has mechanisms for maintaining low concentrations of VEGF in the subretinal space that include endocytosis and degradation and fluid-phase transcytosis in the apical-to-basal direction. RPE tight junctions are selective for K(+) over Na(+) and Cl(-). Permeability and selectivity of the junctions are not affected by VEGF, bevacizumab, or ranibizumab.

Strategy for the Management of Complex Retinal Detachments

OBJECTIVE To study the outcome of the treatment of complex rhegmatogenous retinal detachments (RRDs). DESIGN Nonrandomized, multicenter, retrospective study. PARTICIPANTS One hundred seventy-six surgeons from 48 countries spanning 5 continents reported primary procedures for 7678 RRDs. METHODS Reported data included clinical manifestations, the method of repair, and the outcome. MAIN OUTCOME MEASURES Failure of retinal detachment repair (level 1 failure rate), remaining silicone oil at the studys conclusion (level 2 failure rate), and need for additional procedures to repair the detachments (level 3 failure rate). RESULTS The main categories of complex retinal detachments evaluated in this investigation were: (1) grade B proliferative vitreoretinopathy (PVR; n = 917), (2) grade C-1 PVR (n = 637), (3) choroidal detachment or significant hypotony (n = 578), (4) large or giant retinal tears (n = 1167), and (5) macular holes (n = 153). In grade B PVR, the level 1 failure rate was higher when treated with a scleral buckle alone versus vitrectomy (P = 0.0017). In grade C-1 PVR, there was no statistically significant difference in the level 1 failure rate between those treated with vitrectomy, with or without scleral buckle, and those treated with scleral buckle alone (P = 0.7). Vitrectomy with a supplemental buckle had an increased failure rate compared with those who did not receive a buckle (P = 0.007). There was no statistically significant difference in level 1 failure rate between tamponade with gas versus silicone oil in patients with grade B or C-1 PVR. Cases with choroidal detachment or hypotony treated with vitrectomy had a significantly lower failure rate versus treatment with scleral buckle alone (P = 0.0015). Large or giant retinal tears treated with vitrectomy also had a significantly lower failure rate versus treatment with scleral buckle (P = 7×10(-8)). CONCLUSIONS In patients with retinal detachment, when choroidal detachment, hypotony, a large tear, or a giant tear is present, vitrectomy is the procedure of choice. In retinal detachments with PVR, tamponade with either gas or silicone oil can be considered. If a vitrectomy is to be performed, these data suggest that a supplemental buckle may not be helpful. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Phenotype and genotype correlations in two Best families

OBJECTIVE To evaluate mutations in the Best mascular dystrophy (VMD2) gene in two families with Best disease and to describe the phenotype-genotype correlations of genetically determined affected and unaffected individuals. DESIGN Family genetic study. PARTICIPANTS Two families with Best disease were identified, and family members were evaluated by ophthalmologic examination or fundus photography to assess their phenotype. All affected patients and some of the unaffected family members had a blood sample drawn, and the DNA was analyzed for mutations in the VMD2 gene. MAIN OUTCOME MEASURES Twenty-one subjects in the two pedigrees with Best disease were studied. One amino acid-changing mutation in the VMD2 gene was found to segregate independently in each family (P297S or E300D, respectively). RESULTS Eleven individuals had some evidence of maculopathy, including retinal pigment epithelial changes, drusen, pigment epithelial irregularities, or cicatricial changes. Ten of these 11 patients (91%) with maculopathy had a mutation in the VMD2 gene, of whom 8 were clinically diagnosed as having Best disease and 2 were diagnosed as having possible Best maculopathy. The one patient without a mutation in the VMD2 gene had age-related macular degeneration (AMD). Ten family members did not have evidence of maculopathy, of whom 6 had no mutation in the VMD2 gene. Four family members (2 in each pedigree) had mutations in the VMD2 gene, abnormal electro-oculogram (EOG) results, but normal maculae at age 40 or older. Of the 7 individuals with no mutation in the VMD2 gene, 6 were phenotypically normal and the other had late-onset visual loss resulting from AMD. CONCLUSIONS All family members with maculopathy consistent with Best disease (n = 10) had an amino acid-changing mutation in the VMD2 gene. Four individuals who did not have maculopathy, but did have an abnormal EOG, also had mutations in the VMD2 gene. The presence of a VMD2 mutation is associated with abnormal retinal function, which can occur in the absence of phenotypic manifestation of macular disease.