Sander R. Dubovy

A Variable-dosing Regimen with Intravitreal Ranibizumab for Neovascular Age-related Macular Degeneration: Year 2 of the PrONTO Study

PURPOSE To assess the long-term efficacy of a variable-dosing regimen with ranibizumab in the Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study, patients were followed for 2 years. DESIGN A 2-year prospective, uncontrolled, variable-dosing regimen with intravitreal ranibizumab based on OCT. METHODS In this open-label, prospective, single-center, uncontrolled clinical study, AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 microm as measured by OCT were enrolled to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg) [Lucentis; Genentech Inc, South San Francisco, California, USA]. During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion was fulfilled such as an increase in OCT-CRT of at least 100 microm or a loss of 5 letters or more. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT. RESULTS Forty patients were enrolled and 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (P < .001) and the OCT-CRT decreased by 212 microm (P < .001). VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months. CONCLUSIONS The PrONTO Study using an OCT-guided variable-dosing regimen with intravitreal ranibizumab resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.

Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration.

Purpose: To evaluate the safety and efficacy of intravitreal bevacizumab (Avastin, Genentech Inc.) for the treatment of neovascular age-related macular degeneration (ARMD). Methods: A retrospective review was performed on consented patients with neovascular ARMD receiving intravitreal bevacizumab therapy. All patients received intravitreal bevacizumab at baseline with additional monthly injections given at the discretion of the treating physician. At each visit, a routine Snellen visual acuity assessment was performed followed by an ophthalmic examination and optical coherence tomography (OCT) imaging. Results: Fifty–three eyes of 50 patients received an intravitreal bevacizumab injection between May and August 2005. Including the month 3 visit, the average number of injections was 2.3 out of a maximum of 4 injections. No serious drug-related ocular or systemic adverse events were identified. Improvements in visual acuity and central retinal thickness measurements were evident by week 1 and continued through month 3. At month 3, the mean visual acuity improved from 20/160 to 20/125 (P<0.001) and the mean central retinal thickness decreased by 99.6 &mgr;m (P<0.001). Conclusion: Off-label intravitreal bevacizumab therapy for neovascular ARMD was well tolerated over 3 months with improvements in visual acuity and OCT central retinal thickness measurements. While the long-term safety and efficacy of intravitreal bevacizumab remain unknown, these short-term results suggest that intravitreal bevacizumab may be the most cost effective therapy for the treatment of neovascular ARMD.

Endophthalmitis after intravitreal anti-vascular endothelial growth factor antagonists: A six-year experience at a university referral center

Purpose: To assess the rate of infectious endophthalmitis and to describe the clinical and microbiological features of eyes that develop clinically suspected endophthalmitis after an intravitreal injection of vascular endothelial growth factor antagonists. Methods: The medical records of patients undergoing intravitreal injections of anti-vascular endothelial growth factor agents from January 1, 2005, through December 31, 2010, at a single university referral center and associated satellite clinics were retrospectively analyzed to determine the rate of infectious endophthalmitis after intravitreal anti-vascular endothelial growth factor injections. Results: Twelve cases (11 patients) of clinically suspected endophthalmitis were identified after a total of 60,322 injections (0.02%; 95% confidence interval, 0.0114%-0.0348%). Of the 12 cases, 11 presented within 3 days of the injection. Of the 7 culture-positive cases, 5 were because of Streptococcus species. In 4 of the 5 Streptococcus cases, final visual acuity was hand motions or worse. The rate of clinically suspected endophthalmitis was 0.018% after bevacizumab and 0.027% after ranibizumab injections. Conclusion: A very low rate of endophthalmitis after intravitreal injections of anti-vascular endothelial growth factor agents was observed. Patients typically presented within 3 days of injection. Streptococcus species was the most common bacteria isolated, and it was generally associated with poor visual outcomes.

Corneal Ectasia After Excimer Laser Keratorefractive Surgery : Histopathology, Ultrastructure, and Pathophysiology

PURPOSE To evaluate the histopathology and ultrastructure of corneas developing ectasia after LASIK or photorefractive keratectomy (PRK). DESIGN Retrospective case series. PARTICIPANTS Thirteen specimens from 12 patients undergoing corneal transplantation for progressive ectasia after LASIK (12 specimens) or PRK (1 specimen) were obtained for histopathologic and ultrastructural evaluation. METHODS All 13 ectatic corneas were submitted in formalin for light microscopy. Nine specimens were bisected, and the second half was placed in 2.5% glutaraldehyde for transmission electron microscopy (TEM). MAIN OUTCOME MEASURES Corneal histopathology, ultrastructure, and pathophysiology. RESULTS Light microscopy of the post-LASIK specimens showed corneal epithelial hypoplasia and occasional foci of epithelial hyperplasia, Bowmans layer breaks, a normal stromal thickness of the LASIK flap, a normal thickness of the hypocellular primitive stromal scar, a thinned residual stromal bed (RSB), and larger than normal artifacteous interlamellar clefts in the RSB of the ectatic region. The post-PRK specimen showed similar findings with the addition of a thinned hypercellular fibrotic stromal scar. TEM showed thinning of the collagen lamellae and loss of lamellar number in the RSB of post-LASIK ectasia corneas or throughout the entire corneal stromal bed in the post-PRK ectasia cornea, with the posterior aspect of the corneal stroma being most affected. CONCLUSIONS Histopathologic and ultrastructural studies suggest that interlamellar and interfibrillar biomechanical slippage occurs when the cornea becomes ectatic after LASIK or PRK in the postoperative stress-bearing regions of the corneal stroma. This 2-phase chronic biomechanical failure process is similar to that seen in keratoconus. Composite sciences classify this chronic biomechanical failure process as interfiber fracture. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any materials discussed in this article.

Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma.

Purpose: The purpose of this study is to report the complication profile and safety evaluation of supraselective intra-arterial melphalan chemotherapy in children undergoing treatment with advanced retinoblastoma. Methods: Twelve eyes of 10 children with advanced retinoblastoma (Reese-Ellsworth Group Vb or International Classification Group D) were treated with supraselective intra-ophthalmic artery infusion of melphalan. Eleven eyes of nine children had previously failed traditional management with systemic chemotherapy and laser ablation and underwent intra-ophthalmic artery infusion of melphalan as an alternative to enucleation. Serial ophthalmic examinations, retinal photography, and ultrasonographic imaging were used to evaluate treatment regime. Results: Ophthalmic artery cannulation was successfully performed in 12 eyes of 10 patients (total 16 times). Striking regression of tumor, subretinal and vitreous seeds were seen early in each case. No severe systemic side effects occurred. Grade III neutropenia was seen in one patient. No transfusions were required. Three patients developed a vitreous hemorrhage obscuring tumor visualization. One patient developed periocular edema associated with inferior rectus muscle inflammation per orbital MRI. This same patient had scattered intraretinal hemorrhages and peripapillary cotton wool spots consistent with a Purtscher’s-like retinopathy that resolved spontaneously. At the 6-month follow-up examination, nine eyes had no evidence of tumor progression, whereas three eyes were enucleated for tumor progression. In each enucleated case, viable tumor was identified on histopathologic examination. Conclusions: Ophthalmic intra-arterial infusion with melphalan is an excellent globe-conserving treatment option in advanced retinoblastoma cases with minimal systemic side effects. Local toxicities include microemboli to the retina and choroid (1/12, 8%), vitreous hemorrhage (3/12, 25%), and myositis (1/12, 8%). Enucleation remained a definitive treatment for tumor progression in 3 of 12 eyes in this small case series with limited follow-up. Further studies are necessary to establish the role of supraselective intra-arterial melphalan chemotherapy for children with retinoblastoma.

Mycobacterium interface keratitis after laser in situ keratomileusis

PURPOSE To report the clinical course, management, and outcome of infectious interface keratitis caused by mycobacterium species after laser in situ keratomileusis (LASIK). DESIGN A small noncomparative interventional case series. PARTICIPANTS Five eyes in four patients who underwent LASIK in different locations around the world and had culture-positive mycobacterium keratitis develop. INTERVENTION The LASIK flap was lifted or amputated, samples were submitted for Ziehl-Neelsen acid-fast stain and Lowenstein-Jensens agar cultures for diagnosis; topical treatment with fortified clarithromycin and amikacin was administered until clinical resolution. MAIN OUTCOME MEASURES Time periods from onset to diagnosis and from diagnosis to clinical resolution, and the final visual acuity. RESULTS Onset of symptoms of infection occurred after a mean of 20 days (range, 11 days-6 weeks) after LASIK or an enhancement procedure. Definitive diagnosis was obtained after a mean period of 4.5 weeks (range, 12 days-8 weeks) from onset. Keratitis resolved within 8.4 weeks (range, 1-18 weeks) of treatment with fortified clarithromycin and amikacin. Corticosteroids were found to worsen and prolong the course of disease. In four of five eyes the LASIK flap was amputated. CONCLUSIONS Mycobacterial keratitis is a potentially vision-threatening complication after LASIK, characterized by a long latent period, delayed diagnosis, and a protracted course even under intensive specific antibiotic therapy. Inclusion of specific culture media and staining protocols for mycobacteria, along with aggressive treatment on diagnosis, including lifting or amputating the LASIK flap, culturing, topical fortified clarithromycin and amikacin, while avoiding corticosteroids, may significantly improve resolution of the infection and potentially improve the visual outcome.

Ultra-high resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia and pterygia.

OBJECTIVE To assess the use of an ultra-high-resolution (UHR) optical coherence tomography (OCT) as an adjuvant diagnostic tool in distinguishing ocular surface squamous neoplasia (OSSN) and pterygia. DESIGN Prospective case series. PARTICIPANTS Thirty-four eyes of 34 patients with conjunctival lesions clinically suspicious for OSSN or pterygia. METHODS All patients were photographed and then imaged with a custom-built UHR OCT device. Subsequently, each patient underwent excisional or incisional biopsy with histopathologic diagnosis. MAIN OUTCOME MEASURES Comparison of preoperative UHR OCT images and the corresponding histopathologic specimen; comparison of epithelial thickness between the 2 groups as measured by UHR OCT. RESULTS Preoperative UHR OCT images of OSSN demonstrated similarities to the histopathologic specimens. Both optical and pathologic specimens showed a thickened layer of epithelium, often with an abrupt transition from normal to neoplastic tissue. Likewise, preoperative UHR OCT images of patients with pterygia were well correlated with the histopathologic specimens. As opposed to OSSN, both UHR OCT and pathologic images of pterygia demonstrated a normal thin epithelium, with underlying thickening of the subepithelial mucosal layers. Differences in the measured epithelial thickness on UHR OCT between OSSN and pterygia were statistically significant, with an average epithelial thickness of 346 μm (standard deviation [SD], 167) in OSSN patients and 101 μm (SD, 22) in pterygium patients (P<0.001). By receiver operating characteristic curve, the sensitivity and specificity of UHR OCT for differentiating between OSSN and pterygia was found to be 94% and 100%, respectively, using a cutoff value of 142 μm. CONCLUSIONS Ultra-high-resolution OCT may show promise as a noninvasive diagnostic tool to evaluate ocular surface lesions. In addition to a statistically significant difference in epithelial thickness, a significant degree of morphologic correlation with the histopathologic results demonstrates its potential in evaluating ocular surface squamous neoplasia and pterygia.

Topographic Thickness of Bowman's Layer Determined by Ultra-High Resolution Spectral Domain–Optical Coherence Tomography

PURPOSE To characterize the thickness profile of the corneal epithelium and the Bowmans layer across the horizontal meridian. METHODS Forty-four eyes of 22 healthy subjects were investigated in this study. Ultra-high resolution anterior segment spectral domain-optical coherence tomography (SD-OCT) was used to assess the topographic thickness of the epithelium and the Bowmans layer across the cornea. Thicknesses at five locations, including the center, midperiphery, and periphery close to the limbus, on both the nasal and the temporal sides along the horizontal meridian, were analyzed. RESULTS Mean epithelial thickness at the central cornea was 52.5 ± 2.4 μm. It increased gradually from the center to the periphery (P < 0.001). There was no significant difference between the nasal side and the temporal side for epithelial thickness. The central Bowmans layer thickness was 17.7 ± 1.6 μm, and it remained constant from the center to the midperiphery (P > 0.05). However, thicknesses at the nasal and temporal periphery, 20.0 ± 1.9 μm and 19.8 ± 2.2 μm, respectively, were significantly greater than the central and midperipheral thicknesses (P < 0.001). Nasal and temporal thicknesses were similar on either side of the center. CONCLUSIONS The epithelium and the Bowmans layer were not evenly distributed across the horizontal meridian of the cornea. SD-OCT provided useful information about topographic thickness of the different corneal layers in vivo.

Efficacy of various drugs in the prevention of posterior capsule opacification: Experimental study of rabbit eyes

Purpose: To assess the efficacy of various drugs in the prevention of posterior capsule opacification (PCO) in a closed capsular bag technique. Setting: Ophthalmic Biophysics Center, Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida, USA. Methods: Lens material was removed using phacoaspiration or phacoemulsification through a microcapsulorhexis according to the hardness of the crystalline lens correlated with the weight and age of the rabbits. A mixture of an ophthalmic viscosurgical device (sodium hyaluronate 1.4% [SHA]) and a drug was injected into the empty capsular bag, allowed to remain inside for 3 minutes, and removed. The capsular bag was rinsed with balanced salt solution (BSS®) and refilled with SHA. In a group of rabbits, the capsulorhexis was sealed with a minicapsulorhexis valve (MCV). Rabbits were treated with 1 of the following: SHA (control), BSS, mitomycin‐C (MMC, 0.2 mg/mL), ethylenediaminetetraacetic acid (EDTA) (10 mM and 15 mM), 5‐fluorouracil (5‐FU, 33 mg/mL), acetic acid (3%, 0.3%, and 0.003%), and distilled water. Results: Upon completion of the study, the control and treated eyes had PCO and new lens material (not residual). Anterior capsule proliferation was observed in eyes treated with 5‐FU. The order of PCO appearance (earliest to latest) was as follows: 15 mM EDTA, SHA, MMC, acetic acid 0.3%, acetic acid 3%, BSS, distilled water (small animals; no MCV), acetic acid 0.003%, 5‐FU, 10 mM EDTA, and distilled water (large animals; MCV). The earliest appearance was day 1 postoperatively and the latest, day 47. Conclusions: Distilled water and 10 mM EDTA treatments were the most efficient in retarding the appearance of PCO.

Predictors of Ocular Surface Squamous Neoplasia Recurrence after Excisional Surgery

PURPOSE To identify predictors of ocular surface squamous neoplasm (OSSN) recurrence after operative resection. DESIGN Retrospective case series. PARTICIPANTS Three hundred eighty-nine consecutive patients who underwent excisional biopsy for OSSN lesions at the Bascom Palmer Eye Institute from January 1, 2001, to September 20, 2010. METHODS Review of pathology records and patient charts. MAIN OUTCOME MEASURES Identification of factors predictive of OSSN recurrence. RESULTS Of 389 excised OSSN lesions, 44 recurred during follow-up. The 1-year recurrence rate was 10% and the 5-year recurrence rate was 21%, with a mean time to recurrence in those with a recurrence of 2.5 years (standard deviation, 3.4). Using the American Joint Committee on Cancer (AJCC) clinical staging system, T3 and T2 lesions portended a higher risk of recurrence compared with T1 (T2/T1 hazard ratio [HR], 2.05 [P = 0.04]; T3/T1 HR, 2.31 [P = 0.07]). In addition, a location characteristic that increased the risk of tumor recurrence was tarsal involvement (AJCC T3 stage lesion; HR, 4.12; P = 0.007). Nasal location was associated with a decreased risk of tumor recurrence (HR, 0.41; P = 0.008). Pathologic characteristics significantly associated with tumor recurrence were the presence of positive margins (HR, 2.73; P = 0.008) and higher grade lesions (carcinoma in situ and squamous cell carcinoma versus dysplasia; HR, 2.55; P = 0.02). Treatment with adjuvant cryotherapy significantly decreased the risk of tumor recurrence (HR, 0.51; P = 0.03). In those patients with positive margins, the use of postoperative topical interferon therapy lowered the recurrence rate to a level similar to that of patients with negative margins. CONCLUSIONS Certain patient and tumor factors are associated with a higher risk of OSSN recurrence after operative excision, such as tarsal tumor location and positive surgical margins. Postoperative adjuvant therapy should be considered in patients with high-risk OSSN characteristics.