Tamer H. Mahmoud

Effect of Anti–Vascular Endothelial Growth Factor Therapy on Choroidal Thickness in Diabetic Macular Edema

PURPOSE To determine the effect of anti-vascular endothelial growth factor (VEGF) therapy on choroidal thickness in eyes with diabetic macular edema (DME). DESIGN A retrospective, cohort analysis of 59 eyes from 59 patients with DME without prior anti-VEGF therapy. METHODS Choroidal thickness was measured using semiautomated segmentation of enhanced depth imaging optical coherence tomography images at 0.5-mm intervals from 2.5 mm nasal to 2.5 mm temporal to the fovea. Changes in choroidal thickness with and without anti-VEGF treatment over 6 months were compared. Best-corrected visual acuity and central foveal thickness were analyzed to evaluate the association of choroidal thickness with functional and anatomic outcomes. RESULTS Of the 59 eyes with DME, 26 eyes were observed without treatment, whereas 33 underwent intravitreal anti-VEGF therapy (mean number of injections, 2.73) over 6 months. In untreated eyes, there was no significant change in best-corrected visual acuity (P = .098), central foveal thickness (P = .472), or choroidal thickness at all measurements along the macula (P = .057 at the fovea). In eyes treated with anti-VEGF injections, choroidal thickness decreased significantly at the fovea (246.6 to 224.8 μm; P < .001) and at 0.5 mm nasal (240.9 to 221.9 μm; P = .002) and 0.5 mm temporal (249.3 to 224.8 μm; P = .011) to the fovea. The decrease in subfoveal choroidal thickness after anti-VEGF treatment was not associated with the cumulative number of anti-VEGF injections (R(2) = 0.031; P = .327) or to changes in best-corrected visual acuity (R(2) = 0.017; P = .470) or central foveal thickness (R(2) = 0.040; P = .263). CONCLUSIONS Central choroidal thickness decreases after anti-VEGF therapy for DME after 6 months, but may not be associated with functional or anatomic outcomes in eyes with DME.

Dispase facilitates posterior vitreous detachment during vitrectomy in young pigs.

Purpose To evaluate the role of intravitreal dispase in conjunction with pars plana vitrectomy to facilitate the creation of a posterior vitreous detachment (PVD) in young pig eyes. Methods Twenty-four eyes of 24 animals were randomized to receive an intravitreal injection of dispase (50 &mgr;g/0.05 mL) or phosphate buffered saline (PBS) immediately after core vitrectomy and before attempted creation of a posterior cortical vitreous detachment. Following a 15-minute waiting period, surgical creation of a posterior vitreous separation was attempted by aspiration of the posterior vitreous immediately adjacent to the optic disk. Eyes were evaluated postoperatively by clinical examination (1, 4, and 8 weeks) and electroretinography (4 and 8 weeks), after which they were enucleated for light, scanning, and transmission electron microscopy. Results Based on intraoperative findings and postoperative scanning electron microscopy, eyes receiving intravitreal dispase exhibited a higher incidence of PVD compared to eyes receiving PBS (P = 0.029). Electroretinographic responses recorded at postoperative weeks 4 and 8 were similar in both dispase and PBS eyes compared to the unoperated fellow eyes. Clinical examinations, including indirect ophthalmoscopy, were indistinguishable between the PBS eyes and 11 of 12 eyes in the dispase group. Light and transmission electron microscopy demonstrated no differences in the retina between the dispase eyes and the PBS operated controls. Conclusion Dispase is a useful adjunct in facilitating surgical creation of a PVD in young pig eyes.

Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: A comprehensive analysis of premarketing and postmarketing experiences

Purpose: After the recent approval of ocriplasmin by the Food and Drug Administration, postmarketing safety concerns have been raised by the vitreoretinal community. The American Society of Retina Specialists Therapeutic Surveillance Committee was commissioned to monitor postmarketing drug-related and device-related adverse events. The purpose of this report is to analyze the postmarketing safety experience in the context of available premarketing safety data. Methods: Periodic aggregate safety reports consisting of premarketing, or clinical trial, data (n = 999 injections) and postmarketing reports through July 16, 2013 (n = 4,387 injections), were retrospectively analyzed by the TSC. The aggregate data were analyzed to classify adverse events, and the postmarketing safety data for each event type were compared with the premarketing data. Results: Eight categories of adverse events were identified. Acute reduction in visual acuity attributable to either worsening of macular pathology or development of subretinal fluid, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the premarketing and postmarketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the postmarketing experience. Rates of postmarketing reports were lower than in the premarketing data. Adverse events were generally transient, and characteristics of these adverse events were generally similar between the premarketing and postmarketing experience. Conclusion: Postmarket analyses are limited by significant underreporting, and in the case of ocriplasmin as a first in-class drug, they may not have captured safety events that have only more recently been identified. Nonetheless, postmarket analyses can identify the scope of potential safety events based on real-world experiences. Ocriplasmin administration should be guided by an appropriate and informed risk-benefit discussion with the patient. Ongoing active postmarket surveillance by all practitioners will continue to be critical to better understand this safety profile.

Anticoagulation and clinically significant postoperative vitreous hemorrhage in diabetic vitrectomy.

Purpose: The purpose of this study was to provide further information about the risks of perioperative hemorrhage in diabetic vitrectomy in patients on anticoagulation. This may help us to better understand more about the fine balance between the risks of stopping anticoagulation versus continuation for intraocular surgery. Methods: A retrospective, comparative cohort study of all patients undergoing a diabetic pars plana vitrectomy by a single surgeon over a 30-month period at a single institution was conducted. Results: Ninety-seven eyes were included for analysis. Twenty-seven eyes remained on anticoagulation during the surgery. There were no perioperative complications related to the anticoagulation. Surgical intervention resulted in a significant increase in visual acuity in both groups. There was no difference in the incidence of postoperative vitreous hemorrhage or surgical reoperation between the two groups. Patients on anticoagulation had significantly worse postoperative vision compared with those not on anticoagulation (best-corrected visual acuity of 20/230 vs. 20/100, P = 0.03). Conclusion: Patients undergoing diabetic vitrectomy, who are on anticoagulation or antiplatelet agents, do not exhibit a higher risk of intraoperative or postoperative vitreous hemorrhage. Anticoagulants and antiplatelets may be safely continued perioperatively to avoid complications secondary to their systemic disease.

Aflibercept-Related Sterile Inflammation

All injections were performed with standard techniques based on survey responses. Povidone-iodine 5% was applied before injection in all cases. Thirteen of 15 eyes were administered topical anesthesia, and 2 eyes were given subconjunctival lidocaine. All eyes were injected with the Becton Dickinson (Franklin Lakes, NJ) 1-ml Luer-Lok syringe included in the aflibercept packaging. The majority of eyes were injected in the superotemporal quadrant (12 of 15 eyes) and with a 32-G needle (13 of 15 eyes), while the remainder were injected in the inferotemporal quadrant (3 of 15 eyes) and with a 30-G needle (2 of 15 eyes). These differences likely represent individual practice pattern differences and are not an implication of these techniques. Five physicians practicing in the Northeast, the Southeast, and the Southern United States reported cases of sterile inflammation. Three physicians practiced in the same retina group, and 9 of 15 cases (60%) were reported by a single retina specialist in this practice, consistent with a clustering pattern previously reported with other intravitreal therapies. 2 All cases were attributed to 5 separate drug lots, with 3 lots accounting for 13 of 15 cases. All but 1 patient experienced symptoms within 3 days. Visual acuity generally recovered to baseline levels with nearly identical mean visual acuities at baseline (0.4 logarithm of the minimum angle of resolution) and after resolution (0.32 logarithm of the minimum angle of resolution) and a mean time to resolution of 30 days. No patient lost 1 Snellen line of visual acuity. In contrast with previous reports associating sterile inflammation from other intravitreal therapies with painless loss of vision, 3 9 of these 15 aflibercept-related cases (60%) presented with pain. Redness was noted only in eyes presenting with pain and in 6 of these 9 painful cases. It is possible that aflibercept-related sterile inflammation may be associated with higher rates of pain than previously reported. Alternatively, this difference may reflect differences in the treatment cohorts. Distinguishing between infectious and sterile endophthalmitis was at the discretion of the treating physician. Although all reported cases were culture negative, some of the cases treated with intravitreal antibiotics may have represented culture-negative infectious endophthalmitis, which is associated with increased pain, and not true sterile inflammation. However, 5 of 9 cases associated with pain were treated with vitreous tap and intravitreal antibiotic injection, and the remaining 4 cases were treated with topical steroids only, suggesting that potential misclassification of these symptoms is not fully responsible for this difference. It is likely that patients presenting with more pain were biased toward an initial diagnosis of infectious endophthalmitis (treated with tap/antibiotic injection) compared with those patients managed with topical steroids alone. Small sample size, clinical variation, and the limitations of voluntary reporting preclude definitive conclusions. Subgroup analysis did not detect any variables significantly affecting visual outcome or number of days to resolution (Tables 4 and 5; available at http://www.aaojournal.org). This letter serves as a descriptive case series to better understand the clinical characteristics of a cluster of aflibercept-related sterile inflammation. The manufacturer reports that approximately 30 000 injections had been administered during the reporting period, corresponding with a sterile inflammation rate of approximately 0.05%. Although there may certainly be additional, nonreported cases resulting in a higher actual rate, this frequency lies within the range documented by pivotal, prospective trials with aflibercept and other intravitreal agents and by retrospective analyses (Tables 6 and 7; available at http://www.aaojournal.org). The manufacturer continued to closely observe without public recalls or testing, and use of aflibercept has continued without persistent reports of unexpected rates of complications. The American Society of Retina Specialists Therapeutic Surveillance Subcommittee strongly urges practitioners to actively participate in postmarket surveillance of drug- and device-associated adverse events.

Lensectomy and vitrectomy decrease the rate of photoreceptor loss in rhodopsin P347L transgenic pigs

BackgroundPhotoreceptor degeneration in retinitis pigmentosa (RP) runs an inevitable, gradually progressive course. A wide variety of growth factors of different origins have been shown to slow the rate of degeneration in some rodent models of RP. Recently, lens-derived neurotrophic factors have been shown to rescue degenerating ganglion cells in crush models of the optic nerve. Our objective was to evaluate the potential rescue effect of lensectomy and vitrectomy (L&V) on photoreceptor degeneration in a large-animal model, the rhodopsin P347L transgenic pig.MethodsWe operated on one eye of each of 49 3-week-old pigs—15 vitrectomies and 34 L&V, 6 of which received steroids. Retinal paraffin sections were prepared for all eyes, in addition to immunohistochemistry in four eyes, 8 weeks after L&V.ResultsAt eight weeks after L&V, operated eyes showed significantly more nuclei in the outer nuclear layer (ONL) than the unoperated fellow eyes. The better preservation of the ONL persisted but was less prominent by 20 weeks after surgery. Steroid treatment did not markedly reduce the better preservation of the ONL seen at 8, 10, and 12 weeks after surgery. The significant difference in cell count between operated and unoperated eyes in the L&V group at 8 weeks was due to the difference in the number of rods, not the cones.ConclusionLensectomy and vitrectomy delay photoreceptor degeneration in rhodopsin P347L transgenic pigs. Lens-related rescue effect is a probable reason for the delayed degeneration.

Autologous Neurosensory Retinal Free Flap for Closure of Refractory Myopic Macular Holes

Macular holes (MHs) in highly myopic patients often develop at a younger age and may be associated with foveoschisis and a posterior retinal detachment (RD), which portend a poorer prognosis. Although recent anatomical success following primary pars plana vitrectomy (PPV) and internal limiting membrane (ILM) peel with gas tamponade have improved to 60% to 100%, closure rates are significantly lower if associated with foveoschisis or RD, the MH may attain a flat-open configuration even following retinal reattachment, and reopening rates are higher.1,2 Early treatment reports described perifoveolar laser photocoagulation to form chorioretinal adhesions resulting in permanent photoreceptor loss.3 Several procedures are now available for primary repair of myopic MH and MH RD including PPV with ILM peel and gas or silicone oil tamponade, inverted ILM flaps,4,5 episcleral posterior buckling, adjuvant blood components,6 suprachoroidal buckling, and scleral shortening techniques.7 However, options for patients whose MHs fail to close despite initial PPV and ILM peel are limited. Techniques described recently include temporal scleral imbrication,8 autologous ILM flap,5 addition of autologous blood to the autologous ILM flap,9 and autologous anterior or posterior lens capsule flap as a scaffold to plug the MH.10 We describe a new technique involving the use of an autologous neurosensory retinal free flap for closure of refractory myopic MHs with associated foveoschisis and/or RD. This technique involves harvesting an autologous neurosensory retinal free flap and positioning it over the refractory MH to provide a scaffold and plug for hole closure. Surgical Technique A woman in her 50s, with −15-diopter myopia, had undergone a PPV with ILM peel for MH 6 months prior that was complicated by a refractory MH and the development of RD postoperatively. She subsequently underwent a scleral buckle and PPV for RD repair with silicone oil endotamponade. Silicone oil was removed 3 months postoperatively and she had a persistent 1100-μm MH (Figure, inset) with corrected visual acuity of 20/200. The fellow eye had myopic foveoschisis without an MH. Surgery was undertaken using peribulbar anesthesia with 23-gauge vitrectomy (Constellation; Alcon). There was poor staining using indocyanine green in the staphyloma but an adequate peel was confirmed by the ILM remnant in the macula. Additional ILM for use as an autologous flap could not be harvested. As she was pseudophakic with an open posterior capsule following a Yag capsulotomy, no lens capsule could be harvested. A neurosensory retina harvest site was selected superior to the superotemporal arcade. Endolaser barricade was applied in a circular manner around a 2–disc diameter area of retina followed by endodiathermy to blood vessels at the site edges. Using a bimanual approach under chandelier illumination, the edge of the graft was held using forceps and cut using vertical scissors. A 2–disc diameter fullthickness neurosensory retinal free flap was obtained and gently moved toward the MH. Diathermy marks at the edges and pattern of retinal vessels served as anatomical markers to maintain correct orientation of the retinal free flap. Perfluoro-n-octane heavy liquid (PFC) (Perfluoron; Alcon) was instilled over the retinal flap. Flap edges were gently flattened and it was stretched to lay flat and cover the entirety of the hole (Video). Direct PFC–silicone oil (1000 centistokes) exchange was performed. Using active aspiration, a few Video at jamaophthalmology.com

Bacterial Contamination of Needles Used for Intravitreal Injections: A Prospective, Multicenter Study

Purpose: To determine the incidence of bacterial contamination of needles used for intravitreal injections. Methods: Patients undergoing intravitreal injections were enrolled prospectively. No pre-injection antibiotics were administered. Following povidone–iodine irrigation, conjunctival cultures were taken and the injection was performed. The needle was cultured. A dry control needle was exposed to the surgical field and cultured. Results: No patients developed endophthalmitis. Eighteen injection needles (18%) yielded positive bacterial growth. The most commonly encountered organisms were Propionibacterium acnes (n = 8) and Staphylococcus epidermidis (n = 6). Four control needles showed positive growth, in 2 cases with the same organism as a matching positive used needle. The difference between contamination rates of used and control needles was significant (p = .002, McNemar’s test). Conclusions: Bacterial contaminants are present on a substantial proportion of needles. Since the needle contacts both the ocular surface and the vitreous, it is possible that inoculation of the vitreous cavity occurs in such cases.

Postmarketing Analysis of Aflibercept-Related Sterile Intraocular Inflammation

IMPORTANCE Aflibercept-related sterile inflammation, an event that is poorly understood, has been the subject of ongoing postmarketing reports. OBJECTIVE To analyze cases of aflibercept-related sterile inflammation reported to the American Society of Retina Specialists (ASRS) Therapeutic Surveillance Committee (TSC), an independent task force formed to monitor drug- and device-related safety events. DESIGN, SETTING, AND PARTICIPANTS A retrospective review of 56 cases in 55 patients was performed of all cases of sterile inflammation after aflibercept injection that were voluntarily reported by 12 practices throughout the United States to the ASRS TSC from December 1, 2011, through February 12, 2014. MAIN OUTCOMES AND MEASURES Cases of aflibercept-related sterile inflammation were analyzed for baseline and demographic information, presenting symptoms and findings, visual acuity changes, injection technique, and management details. RESULTS Among 56 reported cases of sterile inflammation, mean time to onset was 3.5 days (median, 2 days; range, 0-30 days). Most cases consisted of initial loss of vision and intraocular inflammation without prominent redness, severe pain, or hypopyon. Thirty-seven cases (66%) were treated with topical corticosteroids and/or observation alone. Mean time to resolution was 28.6 days (median, 28 days; range, 4-84 days). Although final vision was overall unchanged, some patients developed permanent vision loss, which may have resulted from inflammation and/or progression of the underlying disease. Age older than 80 years was associated with worse visual outcomes. No difference in visual outcome was detected in patients with sterile inflammation undergoing topical therapy alone vs invasive procedures (vitreous biopsy and/or intravitreal antibiotic administration and/or vitrectomy). CONCLUSIONS AND RELEVANCE With the largest number of reported cases of aflibercept-related sterile inflammation to our knowledge, this analysis suggests typical findings and an often favorable prognosis of this event. Analysis of real-world, postmarketing data has limitations, and these findings should be considered as hypothesis-generating assessments rather than a definitive reflection of this event or its typical course. Distinguishing sterile inflammation and infectious endophthalmitis at the time of presentation may often be difficult, and cautious evaluation and management of these patients are warranted. The ASRS TSC encourages active postmarketing surveillance by all physicians.

Subretinal Pneumatic Displacement of Subretinal Hemorrhage

Massive submacular hemorrhage can cause disastrous visual complications. Prompt displacement away from the fovea is desirable in some patients. We describe a novel surgical technique involving subretinal air as a therapeutic adjuvant for massive submacular hemorrhage displacement.