Darius M. Moshfeghi

Intravitreal injection of therapeutic agents.

Background: Intravitreal injection (IVI) with administration of various pharmacological agents is a mainstay of treatment in ophthalmology for endopthalmitis, viral retinitis, age-related macular degeneration, cystoid macular edema, diabetic retinopathy, uveitis, vascular occlusions, and retinal detachment. The indications and therapeutic agents are reviewed in this study. Methods: A search of the English, German, and Spanish language MEDLINE database was conducted. A total of 654 references spanning the period through early 2008 were individually evaluated. Results: The advantage of the IVI technique is the ability to maximize intraocular levels of medications and to avoid the toxicities associated with systemic treatment. Intravitreal injection has been used to deliver several types of pharmacological agents into the vitreous cavity: antiinfective and antiinflammatory medications, immunomodulators, anticancer agents, gas, antivascular endothelial growth factor, and several others. The goal of this review is to provide a detailed description of the properties of numerous therapeutic agents that can be delivered through IVI, potential complications of the technique, and recommendations to avoid side effects. Conclusion: The IVI technique is a valuable tool that can be tailored to the disease process of interest based on the pharmacological agent selected. This review provides the reader with a comprehensive summary of the IVI technique and its multitude of uses.

Incidence of Retinopathy of Prematurity in the United States: 1997 through 2005

PURPOSE To determine the incidence of retinopathy of prematurity (ROP) based on a national database and to identify baseline characteristics, demographic information, comorbidities, and surgical interventions. DESIGN Retrospective study based on the National Inpatient Sample from 1997 through 2005. METHODS The National Inpatient Sample was queried for all newborn infants with and without ROP. Multivariate logistic regression was used to predict risk factors for ROP. RESULTS Thirty-four million live births were recorded during the study period. The total ROP incidence was 0.17% overall and 15.58% for premature infants with length of stay of more than 28 days. Our results conclusively demonstrated the importance of low birth weight as a risk for ROP development in infants with length of stay of more than 28 days, as well as association with respiratory conditions, fetal hemorrhage, intraventricular hemorrhage, and blood transfer. An interesting finding was the protective effect conferred by hypoxia, necrotizing enterocolitis, and hemolytic disease of the newborn. Infants with ROP had a higher incidence of undergoing laser photocoagulation therapy, pars plana vitrectomy, and scleral buckle surgery. CONCLUSIONS The current study represents a large, retrospective analysis of newborns with ROP. The multivariate analysis emphasizes the role of birth weight in extended-stay infants, as well as respiratory conditions, fetal hemorrhage, intraventricular hemorrhage, and blood transfer.

Multiagent chemotherapy as neoadjuvant treatment for multifocal intraocular retinoblastoma.

PURPOSE To evaluate the efficacy of multiagent chemotherapy in the neoadjuvant treatment of retinoblastoma. DESIGN Noncomparative, prospective case series. PARTICIPANTS Twenty consecutive patients with multifocal intraocular retinoblastoma (4 unilateral, 16 bilateral [36 eyes]). INTERVENTION Eight cycles of chemotherapy with carboplatin and vincristine were administered at 3-week intervals over a 6-month period. Supplemental therapy was withheld until disease progression was documented. MAIN OUTCOME MEASURES Disease progression (defined as tumor growth, vitreous or subretinal seed progression, and new tumor formation), delay of external beam radiotherapy, and ocular survival. RESULTS Thirty-six eyes were treated. Eighteen eyes had Reese-Ellsworth group I-III tumors, and 16 eyes had Reese-Ellsworth group IV-V tumors at diagnosis. Two patients, who had unilateral disease at diagnosis, subsequently had tumors develop in the contralateral eye. Nineteen of 20 patients (95%) completed eight cycles of chemotherapy without disease progression. Three eyes of three different patients were successfully treated with chemotherapy alone. Thirty-three of 36 eyes (92%) progressed after completion of chemotherapy: 15 of the 18 eyes (83.3%) with Reese-Ellsworth group I-III and 16 of 16 eyes (100%) with Reese-Ellsworth group IV-V tumors. Seventeen eyes (52%) had growth of a tumor, whereas 14 eyes (42%) had progressive vitreous seeding, and 2 eyes (6%) had new tumors develop. Fifteen eyes (42%) required external beam radiotherapy. Twenty-nine of 36 (80.5%) eyes were salvaged. The median follow-up after chemotherapy was 19 months (range, 3-42 months). CONCLUSIONS Multiagent chemotherapy alone does not ensure a cure for multifocal intraocular retinoblastoma. Supplemental focal therapy is needed to control disease progression.

Expanded Spectrum of Congenital Ocular Findings in Microcephaly with Presumed Zika Infection.

PURPOSE To describe the ocular findings of 3 cases of suspected congenital Zika viral infection with microcephaly and maculopathy. DESIGN Retrospective, consecutive case series. PARTICIPANTS Three male infants born in northern Brazil whose mothers demonstrated a viral syndrome during the first trimester and who subsequently were born with microcephaly. METHODS Observational report of macular findings. MAIN OUTCOME MEASURES Continued observation. RESULTS Three male infants were born with microcephaly to mothers who had a viral syndrome during the first trimester of gestation in an area that subsequently has demonstrated epidemic Zika infection, a flavivirus related to Dengue. Ocular examination was performed. All 6 eyes demonstrated a pigmentary maculopathy ranging from mild to pronounced. In 4 eyes, well-delineated macular chorioretinal atrophy with a hyperpigmented ring developed. Three eyes demonstrated vascular tortuosity and 2 eyes demonstrated a pronounced early termination of the retinal vasculature on photographic evaluation. Two eyes demonstrated a washed out peripheral retina with a hypolucent spot. One eye had scattered subretinal hemorrhages external to the macula. Finally, 1 eye demonstrated peripheral pigmentary changes and clustered atrophic lesions resembling grouped congenital albinotic spots (polar bear tracks). CONCLUSIONS Zika virus has been linked to microcephaly in children of mothers with a viral syndrome during the first trimester of pregnancy. Ocular findings previously described a pigmentary retinopathy and atrophy that now can be expanded to include torpedo maculopathy, vascular changes, and hemorrhagic retinopathy. Ophthalmologic screening guidelines need to be defined to determine which children would benefit from newborn screening in affected regions.

Retinal and choroidal vascular occlusion after posterior sub-tenon triamcinolone injection

PURPOSE To report a case of retinal and choroidal vascular occlusion occurring as a complication after posterior sub-Tenon triamcinolone injection for treatment of uveitic cystoid macular edema. DESIGN Interventional case report. METHODS Retrospective study. A 32-year-old woman with uveitis and cystoid macular edema underwent a right posterior sub-Tenon injection of triamcinolone (40 mg/ml, 1 ml total) through a superotemporal approach after topical anesthesia. After the procedure, the patient experienced severe eye pain, orbital ecchymosis, and globe proptosis consistent with retrobulbar hemorrhage. RESULTS Dilated fundus examination of the right eye (OD) demonstrated multiple intraretinal hemorrhages with particulate white emboli occluding the retinal and choroidal vessels. Visual acuity was no light perception. Ocular massage and hypotensive therapy was initiated for an intraocular pressure of 50 mm Hg. Canthotomy and cantholysis were performed. A total of 39 months post-incident, her visual acuity improved to 20/100. CONCLUSION Posterior sub-Tenon triamcinolone injection can rarely result in retinal and choroidal occlusion. Immediate intervention may preserve limited visual acuity.

Photoacoustic ocular imaging

We developed a photoacoustic ocular imaging device and demonstrated its utility in imaging the deeper layers of the eye including the retina, choroid, and optic nerve. Using safe laser intensity, the photoacoustic system was able to visualize the blood distribution of an enucleated pigs eye and an eye of a living rabbit. Ultrasound images, which were simultaneously acquired, were overlaid on the photoacoustic images to visualize the eyes anatomy. Such a system may be used in the future for early detection and improved management of neovascular ocular diseases, including wet age-related macular degeneration and proliferative diabetic retinopathy.

Surveillance for potential adverse events associated with the use of intravitreal bevacizumab for retinal and choroidal vascular disease.

Purpose: To systematically study potential adverse events associated with the use of intraocular bevacizumab at a single medical center. Methods: Retrospective study of all consecutive patients receiving intraocular bevacizumab injections at the Stanford University Department of Ophthalmology between November 15, 2005 and July 14, 2006. Bevacizumab was given for exudative age-related macular degeneration, retinal vascular occlusion, diabetic macular edema, neovascular glaucoma, and five other indications. Results: We analyzed medical records of 186 subjects (203 eyes) who received a total of 578 injections of 1.25 mg of bevacizumab. The average follow-up was approximately 6 months. Five eyes with exudative age-related macular degeneration developed retinal pigment epithelial (RPE) tears, all with preexisting RPE detachments. These five eyes represented 2.9% of all age-related macular degeneration eyes treated and 7% of the age-related macular degeneration eyes with preexisting RPE detachments at initiation of treatment. Other adverse events were rare and included retinal ischemia, subretinal hemorrhage, vitreous hemorrhage, ocular irritation or pain, worsened hypertension, and headache. No death or thromboembolic events were observed. Conclusion: Intraocular bevacizumab appears to be well tolerated for the treatment of a variety of retinal and choroidal vascular diseases. RPE tears may occur when treating choroidal neovascularization, particularly in patients with preexisting RPE detachment.

Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy.

PURPOSE To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy. DESIGN Interventional case series. METHODS Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 microm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy. RESULTS Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen. CONCLUSIONS This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed.

Retinal pigment epithelium tears after intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration.

Background: Intravitreal bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) treatment of neovascular age-related macular degeneration (AMD) has become an important part of clinical retinal practice. We describe retinal pigment epithelium (RPE) tears that were noted after intravitreal injection of bevacizumab. Methods: In this multimember, retrospective case series, data on eyes that developed RPE tears after intravitreal bevacizumab injection were collected and analyzed. Previous treatments, type of lesion, time to tear, and preinjection and final visual acuities were all compared. The total numbers of bevacizumab injections were available from all four institutions and compiled to estimate the incidence rate. Results: Four retina centers administered a total of 1,455 intravitreal 1.25-mg bevacizumab injections for neovascular AMD during the 9-month study period. Twelve patients presented with RPE tears within 4 days to 8 weeks of injection (mean ± SD, 24.3 ± 15.2 days from injection to tear). In each case, the RPE tear was preceded by an RPE detachment, and all had a component of serous sub-RPE fluid. On the basis of our collective data, we estimate an incidence rate of ≈0.8%. Conclusions: RPE tears can occur after intravitreal injection of bevacizumab. The low incidence of this adverse event should not preclude anti–vascular endothelial growth factor therapy counseling for patients with neovascular AMD, but eyes with serous RPE detachments appear to be most vulnerable to this adverse event.

Retinopathy of Prematurity in the Time of Bevacizumab: Incorporating the BEAT-ROP Results into Clinical Practice

t z a 3 W t c 2 a h 2 o t o a Recently, the results of the Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) trial were published in the New England Journal of Medicine and careful review is important since the authors advocate for a change in the standard of care in the treatment of ROP. The BEAT-ROP trial design was a prospective, multicenter, randomized, unmasked Phase II trial of intravitreal bevacizumab (0.625 mg in 0.025 ml) vs. conventional diode laser photocoagulation. Eligible patients were 1500 g or less and 30 weeks gestational age or less with Stage 3 ROP in Zone I or Zone II posterior disease in both eyes. The primary outcome of the trial was modified from an absence of recurrence of Stage 3 ROP in Zone I or Zone II posterior by 54 weeks to recurrence of retinal neovascularization requiring retreatment by 54 weeks. Bevacizumab was injected 2.5 mm posterior to the limbus using a 31-gauge needle. Based upon a pre-study analysis of the predicted efficacy of bevacizumab, the trial targeted 50 patients with Zone I disease and 100 patients with Zone II posterior disease, with a 1:1 randomization of bevacizumab: diode laser photocoagulation. The authors elected to randomize based upon infants, not eyes, because of the threat of amblyopia induced by 1 eye receiving laser photocoagulation and potential exuberant inflammation and the other eye receiving an injection; each infant received the same therapy in both eyes. At the time of full enrollment, 150 patients had been enrolled, 67 in Zone I (33 bevacizumab, 34 laser), and 83 in Zone II posterior (42 bevacizumab, 41 laser). Of these, 143 were considered eligible for analysis, with 7 deaths before the 54 week primary outcome endpoint. There was 1 protocol violation, a patient who inadvertently received bevacizumab when they should have received laser photocoagulation, and they were included in the laser group by virtue of the intentto-treat analysis plan. The BEAT-ROP demonstrated a beneficial effect for bevacizumab vs. laser in the treatment of Zone I, Stage 3 ROP. In the bevacizumab group, recurrence of retinal neovascularization requiring treatment was 6% at 54 weeks vs. 42% in the laser group, for an odds ratio of 0.09 favoring bevacizumab (95% confidence interval of 0.02–0.43). No statistical difference was noted for Zone II posterior, Stage 3 ROP between bevacizumab and laser. Recurrence rates were 5% vs. 12%, bevacizumab and laser, respectively. Of the 7 deaths, 5 were in the bevacizumab group, 2 in the laser group, and this did not reach statistical significance. The authors offered the following conclusions: (1) bevacizumab is superior to laser for treatment of Zone I, Stage 3 ROP; (2) peripheral retinal vascularization continued as normal in the bevacizumab group, but not the laser group; and (3)“Bevacizumab is an inexpensive drug that can be rapidly administered at the bedside by any ophthalmologist.” g