Prophylactic Ranibizumab to Prevent Neovascular Age-Related Macular Degeneration in Vulnerable Fellow Eyes: A Randomized Clinical Trial.

PURPOSE: To determine whether prophylactic ranibizumab prevents the development of neovascular age-related macular degeneration (nAMD) in eyes with intermediate age-related macular degeneration (AMD) for patients with preexisting nAMD in their contralateral eye. DESIGN: Multicenter randomized clinical trial. PARTICIPANTS: Adults aged 50 years and older with intermediate AMD (multiple intermediate drusen [≥63 µm and <125 µm] or ≥1 large drusen [≥125 µm] and pigmentary changes) in the study eye and nAMD in the contralateral eye. INTERVENTION: Intravitreal ranibizumab injection (0.5 mg) or sham injection every 3 months for 24 months. MAIN OUTCOME MEASURES: Conversion to nAMD over 24 months (primary). Change in best-corrected visual acuity from baseline to 24 months (secondary). RESULTS: Among 108 enrolled participants (54 [50%] in each group), all except 2 were non-Hispanic Whites, 61 participants (56%) were female, and the mean age was 78 years. The mean baseline visual acuity was 77.7 letters (Snellen equivalent 20/32). Conversion to nAMD over 24 months occurred among 7 of 54 eyes (13%) in both groups (ranibizumab vs. sham hazard ratio = 0.91 [95% confidence interval (CI), 0.32-2.59]; P = 0.86). At 24 months, the cumulative incidence of nAMD adjusted for loss to follow-up was 14% (95% CI, 4%-23%) in the ranibizumab group and 15% (95% CI, 4%-25%) in the sham group. At 24 months, the mean change in visual acuity from baseline was -2.1 letters (standard deviation, 5.4 letters) with ranibizumab and -1.4 letters (standard deviation, 7.7 letters) with sham (adjusted difference = -0.8 letters [95% CI, -3.7 to 2.2 letters]; P = 0.62). The proportion of eyes that lost at least 10 letters of visual acuity from baseline at 24 months was 2 of 39 (5%) with ranibizumab and 4 of 40 (10%) with sham. There were no serious ocular adverse events in either group. CONCLUSIONS: Quarterly dosing of 0.5 mg ranibizumab in eyes with intermediate AMD did not reduce the incidence of nAMD compared with sham injections; however, the study was likely underpowered given the 95% CI, and a clinically meaningful effect cannot be excluded. There also was no effect on visual acuity at 24 months. Other strategies to reduce neovascular conversion in these vulnerable eyes are needed.

Late-onset Etanercept-associated Ocular Sarcoidosis with Profound Vision Loss.

INTRODUCTION: Etanercept is a tumor necrosis factor-alpha-blocking immunosuppressive agent and carries the risk of paradoxical induction of sarcoidosis. We present a case of a 75-year-old woman with rheumatoid arthritis treated with etanercept who developed etanercept-associated ocular sarcoidosis after 4 years of therapy. CASE REPORT: The patient presented to clinic with visual acuity of light perception in the right eye and hand motions in the left eye. Examination revealed optic disc edema in both eyes with serous retinal detachment in the right eye. Work-up revealed an elevated serum angiotensin-converting enzyme level, and computed tomographic scan of the chest revealed innumerable bilateral peribronchial pulmonary nodules with calcifications. A diagnosis of presumed ocular sarcoidosis was made. Etanercept was stopped, and the patient was treated with oral prednisone and subcutaneous methotrexate, with clinical and visual recovery. CONCLUSIONS: Etanercept-associated sarcoidosis can occur at any time after initiating therapy and should be considered in patients on etanercept with ocular inflammation.

Treat and extend regimen with aflibercept for chronic central retinal vein occlusions: 2 year results of the NEWTON study.

BACKGROUND: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) could continue to extend the macular edema free interval in patients on a treat and extend (TAE) with non-ischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) in the second year. METHODS: Twenty patients with macular edema secondary to non-ischemic CRVOs previously treated with ranibizumab or bevacizumab were prospectively treated with intravitreal aflibercept injection (IAI) using a TAE dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. In the second year of the study, patients who have recurrences of macular edema could be re-challenged with a longer treatment interval under the following criterion: absence of any macular edema on three consecutive visits with the same treatment interval. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range 7-90) and averaged an anti-VEGF treatment every 42 days (range 28-60 days). The macular edema free interval increased from 38 to 75 days when switched to aflibercept (p = 0.000003) at month 24. There was an average increase of 37 days (median 34 days; range 0-91 days) in the macular edema free interval with aflibercept. At the month 24 visit, 50% (8/16) went > 12 weeks with a macular edema free interval between IAI. There was an improvement in vision (+ 8 ETDRS letters, p = 0.006) and decreased retinal thickness (158 µm, p = 0.00003) with aflibercept treatment at month 24. CONCLUSIONS: The 2-year results of the NEWTON study demonstrated the sustained benefits of a TAE dosing regimen with aflibercept in patients with chronic CRVOs. The visual acuity gains and anatomic improvements observed at year one were maintained through month 24 with less visits and treatments. This may help minimize the treatment burden in patients with recurrent macular edema secondary to non-ischemic CRVO.Trial Registration ClinicalTrials.gov, NCT01870427, Registered June 6, 2013, https://clinicaltrials.gov/ct2/show/NCT01870427?cond=NEWTON&rank=1.Presented at the RETICON 2017: The Retina Congress with Live Surgery, Chennai, India-April 2017.

Aflibercept for Previously Treated Macular Edema Associated with Central Retinal Vein Occlusions: 1-Year Results of the NEWTON Study.

PURPOSE: To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, NY) can extend the macular edema-free interval in patients with nonischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech, South San Francisco, CA). DESIGN: Prospective, single-arm, interventional study. PARTICIPANTS: Twenty patients with chronic nonischemic CRVOs. METHODS: Patients with nonischemic CRVOs previously treated with ranibizumab or bevacizumab were switched to aflibercept. The inclusion criteria included treatment for ≥6 months with ≥3 initial loading doses and evidence of recurrence of edema when treatment with either ranibizumab or bevacizumab extended beyond 4 weeks. Intravitreal aflibercept was administered with a treat-and-extend dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. MAIN OUTCOME MEASURES: Macular edema-free interval at week 52. RESULTS: Twenty patients had an average duration of a CRVO for 22 months (range, 7-90 months) and averaged an anti-vascular endothelial growth factor (anti-VEGF) treatment every 42 days (range, 28-60 days). These patients received a mean of 15 treatments (range, 5-47 treatments) of ranibizumab or bevacizumab for macular edema secondary to nonischemic CRVO. Among the 17 patients who completed 1 year of follow-up, 94% had a greater macular edema-free interval with aflibercept treatment. The macular edema-free interval increased from 5.4 weeks to 9.1 weeks when treatment was switched to aflibercept (P = 0.000003). There was an average increase of 26 days (range, 0-63 days) in the macular edema free interval with aflibercept. There was an improvement in vision (+6 Early Treatment Diabetic Retinopathy Study letters, P = 0.02) and decreased retinal thickness (152 µm, P = 0.0002) with aflibercept treatment. CONCLUSIONS: In patients previously treated with ranibizumab or bevacizumab for macular edema due to nonischemic CRVO, aflibercept increased the macular edema free interval. This may help minimize the treatment burden in patients with recurrent macular edema secondary to nonischemic CRVO.

THE ASSOCIATION OF EPIRETINAL MEMBRANE WITH MACULAR HOLE FORMATION AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR.

PURPOSE: To describe the clinical and optical coherence tomography findings associated with the development of full-thickness macular holes after rhegmatogenous retinal detachment (RRD) repair. METHODS: Retrospective, interventional case series. All patients who developed full-thickness macular holes after successful RRD repair from 3 clinical practices were reviewed. All cases of combined/simultaneous full-thickness macular hole and RRD were excluded. The main outcome measure was the presence of an epiretinal membrane at time of diagnosis of macular hole. RESULTS: Twenty-five full-thickness macular holes were diagnosed after successful retinal detachment repair. Surgical approach to RRD repair included pneumatic retinopexy (6, 24%), scleral buckle alone (5, 20%), pars plana vitrectomy only (8, 32%), and combined scleral buckle and pars plana vitrectomy (6, 24%). The preceding RRD involved the macula in 19 patients (76%) before the formation of the macular hole. The median time to full-thickness macular hole diagnosis after RRD repair was 63 days (range, 4-4,080 days). An epiretinal membrane was present in all 25 (100%) macular holes. Two macular holes (8%) spontaneously closed, whereas the other 23 (92%) were successfully closed with a single surgical procedure. Mean visual acuity improved by approximately 5 lines to 20/72 (range, 20/20 to counting fingers at 1 foot) from 20/240 (range, 20/30 to hand motions) after macular hole repair (P < 0.0001). CONCLUSION: Full-thickness macular hole formation can occur after all types of RRD repair and is associated with an epiretinal membrane. The epiretinal membrane may play a role in the pathogenesis of secondary macular hole formation after RRD repair.

PROSPECTIVE EVALUATION OF A SUSTAINED-RELEASE DEXAMETHASONE INTRAVITREAL IMPLANT FOR CYSTOID MACULAR EDEMA IN QUIESCENT UVEITIS.

PURPOSE: To investigate dexamethasone intravitreal implant (DEX implant; OZURDEX, Allergan, Inc) in the treatment of uveitic cystoid macular edema that had persisted in the absence of intraocular inflammation. METHODS: In this prospective interventional case series, 10 patients with uveitic cystoid macular edema and quiescent uveitis were treated with dexamethasone intravitreal implant at baseline and evaluated monthly for one year. Patients were retreated whenever cystoid macular edema recurred. The primary outcome measure was best-corrected visual acuity (BCVA) at day 90. RESULTS: At day 90, mean improvement from baseline BCVA was 14.4 letters (P = 0.0003), 70% of patients had a ≥10 letter BCVA improvement, 50% of patients had a ≥15 letter BCVA improvement, and the mean decrease from baseline central subfield retinal thickness was 140 µm (P = 0.008). Improvements were maintained through day 360 with retreatment as needed. At day 360, mean improvement in BCVA was 16.5 letters (P = 0.006) and the mean decrease in central subfield retinal thickness was 158 µm (P = 0.002). One patient experienced intraocular pressure >25 mmHg (managed with topical medication). Two phakic patients (2/8; 25%) had worsening of lens opacity requiring cataract extraction. CONCLUSION: Dexamethasone intravitreal implant may be an effective treatment for patients with persistent cystoid macular edema in quiescent uveitis.

Influence of Glycosylated Hemoglobin on the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the RIDE/RISE Trials.

PURPOSE: To investigate the influence of glycosylated hemoglobin (HbA1c) on treatment outcomes in patients with diabetic macular edema (DME) receiving intravitreal ranibizumab. DESIGN: Post hoc analysis of 2 identical phase III clinical trials assessing the efficacy and safety of intravitreal ranibizumab in DME over 36 months (RIDE: NCT00473382/RISE: NCT00473330). PARTICIPANTS: A total of 483 adults with vision loss from DME treated with ranibizumab were included in this analysis from RIDE/RISE. Participants received monthly intravitreal ranibizumab (0.3 or 0.5 mg). MAIN OUTCOME MEASURES: Differences in visual and anatomic outcomes, and diabetic retinopathy (DR) severity score, between subgroups of patients with baseline HbA1c ≤7% versus HbA1c >7% at 36 months. RESULTS: There were 195 patients in RIDE/RISE who were treated with ranibizumab with a baseline HbA1c ≤7% and 288 patients with a baseline HbA1c >7% included in this analysis. The mean improvement in visual acuity (VA) at 36 months was +13 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in patients with baseline HbA1c ≤7% compared with +11 ETDRS letters in the patients with a baseline HbA1c >7% (P = 0.17). After adjustment for baseline central foveal thickness (CFT) and duration of diabetes, the mean CFT reduction was -268 µm in patients with a baseline HbA1c ≤7% and -269 µm in patients with a baseline HbA1c >7% (P = 0.98; 95% confidence interval, -22.93 to 23.54). The proportion of patients with a ≥2-step improvement in DR severity score was 38% in patients with baseline HbA1c ≤7% compared with 41% in the patients with a baseline HbA1c >7% (P = 0.53). There was no correlation of baseline HbA1c with any visual or anatomic parameter. CONCLUSIONS: The improvement in VA, anatomic reduction of macular edema, and improvement in DR severity score with ranibizumab treatment seem to be independent of baseline HbA1c.

Endogenous Serratia marcescens endophthalmitis.

PURPOSE: The purpose of this study was to describe a rare case of endogenous endophthalmitis associated with dental disease secondary to Serratia marcescens in an HIV-negative individual. METHODS: Retrospective case report. RESULTS: A 50-year-old white man with a history of intravenous drug use presented with pain and decreased vision in his right eye. Slit-lamp examination showed a hazy cornea, hypopyon with fibrin in the anterior chamber, and elevated intraocular pressure. B-scan ultrasound showed vitritis and choroidal thickening. Computed tomography showed gingival inflammation and lucencies of several teeth. Blood and urine cultures were negative, and HIV testing was negative. Echocardiography was negative for vegetations. Intravitreal culture revealed S. marcescens. Despite intravitreal and systemic antibiotics, the patient's clinical situation rapidly deteriorated, and the eye was eviscerated. The patient underwent dental extraction and was subsequently discharged in stable condition. CONCLUSION: The first case of endogenous endophthalmitis secondary to S. marcescens in an otherwise healthy, HIV-negative, intravenous drug user in association with severe dental disease is reported. Serratia may be found in oral biofilm, and this mechanism should be considered in cases where other etiologies have been ruled out.

Safety of pars plana vitrectomy in eyes with plaque-irradiated posterior uveal melanoma.

OBJECTIVE: To determine the long-term safety of pars plana vitrectomy (PPV) in eyes with plaque-irradiated posterior uveal melanoma. METHODS: In this retrospective case series, patients with plaque-irradiated posterior uveal melanoma subsequently underwent PPV for vitreous hemorrhage. The main outcome measures are the rates of intraocular melanoma dissemination, extrascleral extension of melanoma, local melanoma recurrence, and systemic melanoma metastasis after PPV. RESULTS: Forty-seven eyes of 47 patients underwent PPV for vitreous hemorrhage after iodine 125-labeled plaque radiotherapy for choroidal melanoma. The mean interval between the onset of vitreous hemorrhage and PPV was 13 (median, 10; range, 0-52) months. The mean time from PPV to last follow-up was 5 (range, 0.5-16) years. There were no cases of intraocular melanoma dissemination or extrascleral extension of melanoma. One patient (2%) developed local choroidal melanoma recurrence (2 years after PPV and 5 years after initial plaque radiotherapy) and was successfully managed with transpupillary thermotherapy. Systemic melanoma metastasis occurred in 4 patients (9%) during a mean interval of 5 years after plaque radiotherapy. During follow-up, 43 patients (91%) were alive without systemic metastasis and 4 patients (9%) were alive with metastasis. CONCLUSION: Management of vitreous hemorrhage by PPV in eyes with previously irradiated uveal melanoma appears to be safe and without increased risk for intraocular, local, orbital, or systemic dissemination of the tumor.

Optic neuropathy after vitrectomy for retinal detachment: clinical features and analysis of risk factors.

PURPOSE: To describe the clinical characteristics of and risk factors for the development of optic neuropathy after pars plana vitrectomy (PPV) for macula-sparing primary rhegmatogenous retinal detachment (RRD) repair. DESIGN: Retrospective case-control study. PARTICIPANTS: Seven patients who underwent PPV for macula-sparing primary RRD with subsequent development of optic neuropathy and 42 age- and gender-matched control patients undergoing PPV for macula-sparing primary RRD. METHODS: Retrospective chart review of medical and surgical records. MAIN OUTCOME MEASURES: Clinical features of patients who developed optic neuropathy after PPV for macula-sparing RRD and analysis of potential risk factors (age, gender, medical history, surgical technique, intraoperative ocular perfusion pressure [OPP], and operative time). RESULTS: At last follow-up, all 7 patients with optic neuropathy had visual acuity less than 20/200, relative afferent pupillary defects, optic nerve pallor, and visual field defects. A total of 5 of 7 patients (71%) demonstrated intraoperative reduced OPP with associated systemic hypotension compared with 7 of 42 patients (17%) in the control cohort (P = 0.01). CONCLUSIONS: Optic neuropathy after PPV for macula-sparing primary RRD is a rare but potentially devastating complication. Although the cause is often unclear, reduced ocular perfusion due to intraoperative systemic hypotension may be a contributing risk factor in some eyes.

Influence of flap thickness on visual and refractive outcomes after laser in situ keratomileusis performed with a mechanical keratome.

PURPOSE: To study the effect of flap thickness on visual acuity and refractive outcomes after laser in situ keratomileusis (LASIK) using 2 blade types with a mechanical microkeratome. SETTING: Emory Vision, Atlanta, Georgia, USA. METHODS: This retrospective analysis was of LASIK cases performed between January 2005 and June 2006 using an Amadeus I microkeratome and an ML7090 CLB blade (blade A) or a Surepass blade (blade B). Outcomes analyzed included flap thickness, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), manifest refraction spherical equivalent (MRSE), the enhancement rate, and surgical complications 3 months postoperatively. RESULTS: Two hundred sixty-three eyes of 153 patients were analyzed; blade A was used in 158 eyes and blade B, in 105 eyes. The mean flap thickness was significantly thinner with blade A than with blade B (107 microm +/- 12 [SD] versus 130 +/- 20 microm) (P<.0001). There was no overall correlation with either blade between flap thickness and UDVA, CDVA, or MRSE (all r<0.2). At 3 months, there was no statistically significant difference in UDVA, CDVA, or MRSE between the 2 blade groups at 3 months (all P > .10), and there was no difference in the complication rates. CONCLUSION: Flap thickness did not affect visual or refractive outcomes with a mechanical microkeratome with either blade type.

Peripheral retinal findings in highly myopic children < or =10 years of age.

PURPOSE: The purpose of this study was to characterize the peripheral retinal findings in highly myopic young children without other known risk factors for retinal detachment. METHODS: A retrospective review of all cases of children < or =10 years of age with high myopia (>6.00 diopters) who were evaluated for presumed risk of retinal detachment by either an examination under anesthesia or office examination by a single retina specialist from January 2001 through December 2008. Patients with regressed retinopathy of prematurity, retinal detachment in the fellow eye, or known Stickler syndrome were excluded. RESULTS: Fifty-four eyes of 30 patients with high myopia were examined. Twenty-six eyes of 14 patients were examined under anesthesia because of the examiner's inability to adequately visualize the peripheral retina during an office examination. Mean age at examination was 6 +/- 3 (range, 1-10) years. Mean spherical equivalent refractive error was -13.88 +/- 3.79 (range, -6.00 to -25.00) diopters. Peripheral retinal findings were identified in 33% of eyes, the most common being lattice degeneration (20%), white without pressure (11%), and retinal holes with subretinal fluid (4%). CONCLUSION: Approximately one third of highly myopic children in our study showed peripheral retinal findings. If the peripheral retina is not adequately visualized during an office evaluation, examination under anesthesia should be considered.

Recurrence of acute lymphocytic leukemia diagnosed by subretinal biopsy.

PURPOSE: To report a case of leukemia relapse in the subretinal space that was diagnosed by transvitreal subretinal biopsy. METHODS: Case report and literature review. RESULTS: A 5-year-old girl with prior history of acute lymphocytic leukemia who was in clinical remission was examined for a unilateral subretinal mass. Her systemic evaluation was negative for recurrence of the acute lymphocytic leukemia. Pars plana vitrectomy with a subretinal biopsy showed leukemic cells confirmed by flow cytometric immunophenotyping. The patient subsequently underwent bone marrow transplantation with regression of the subretinal mass. CONCLUSION: Leukemia relapse may occur in the subretinal space. A relapse may be successfully diagnosed with a subretinal biopsy through a pars plana vitrectomy.

Quantitative optical coherence tomography findings in various subtypes of neovascular age-related macular degeneration.

PURPOSE: To compare the volume of various spaces visible on optical coherence tomography (OCT) images in different angiographic lesion subtypes of neovascular age-related macular degeneration (AMD). METHODS: Sixty-six cases of previously untreated, active subfoveal choroidal neovascularization (CNV) associated with AMD were retrospectively collected. CNV lesions were classified as occult with no classic CNV, minimally classic CNV, predominantly classic CNV, or CNV lesions with associated retinal angiomatous proliferation (RAP). Corresponding OCT image sets were analyzed by trained graders using previously validated custom software that allows manual placement of boundaries on OCT B-scans. Spaces delineated by these boundaries included the neurosensory retina, subretinal fluid, subretinal tissue, and pigment epithelial detachments (PEDs). Volume measurements were calculated by the software and compared among groups. RESULTS: Minimally and predominantly classic CNV membranes demonstrated subretinal tissue on OCT in all cases and appeared to show a significantly greater volume of subretinal tissue than did the occult membranes. Subretinal fluid was present in all the predominantly classic cases. A PED was visible in all the occult CNV cases in our study, demonstrating less retinal thickening and significantly greater PED volumes than minimally and predominantly classic CNV lesions. Lesions associated with RAP showed the highest percentage of cystoid spaces. CONCLUSIONS: OCT and angiography provide complementary information regarding CNV lesions. Quantitative analysis of OCT images allows for an improved understanding of the anatomic characteristics of angiographically defined CNV lesion subtypes.

Should transcranial magnetic stimulation research in children be considered minimal risk?

OBJECTIVE: Transcranial magnetic stimulation (TMS) is a neurophysiologic technique with research applications. Institutional Review Boards (IRBs) must carefully consider potential risks and possible benefits in research involving children. The purpose of this study is to provide concise information for investigators and IRBs about the safety of single and paired pulse TMS research in children. METHODS: This paper has 4 sections: (I) Regulations governing research in children are reviewed and applied to the use of TMS. (II) Energy imparted by TMS is assessed in terms of theoretical biological risks to human subjects. (III) Through MEDLINE review, the empirical evidence of risk from TMS is assessed. Reported adverse events, including issues related to risk of seizures and of hearing loss, are summarized. (IV) Safety data are presented from a study of TMS in children with Tourette Syndrome. RESULTS: No published or empirical evidence was found to suggest that single or paired pulse TMS is associated with more than minimal risk in children. CONCLUSIONS: IRBs may consider well-designed studies using single and paired pulse TMS protocols similar to those described in this study as bearing minimal risk to children. SIGNIFICANCE: This manuscript may be useful as a reference to IRBs and TMS investigators.

Association of cortical disinhibition with tic, ADHD, and OCD severity in Tourette syndrome.

Hyperkinetic disorders may involve excess excitatory output from thalamus to cerebral cortex. Case-control, neurophysiological studies in persons with Tourette Syndrome (TS), Attention Deficit Hyperactivity Disorder (ADHD), and Obsessive-Compulsive Disorder (OCD) support this model. To compare the strength of association between motor cortex inhibition and tic, ADHD, and OCD severity in TS, we used transcranial magnetic stimulation to measure motor cortex inhibition in 36 children and adults with TS. Current symptom severity was assessed with standard clinical rating scales and compared with neurophysiological measures using correlational and multivariate regression analyses. Severity of ADHD symptoms and motor tics were associated significantly and independently with short interval intracortical inhibition (SICI) (r(2) = 0.50; F[2,27] = 13.7; P < 0.001), particularly in subjects not taking neuroleptics (r(2) = 0.68; F[2,17] = 17.8; P < 0.0001). The correlation of cortical disinhibition was greater with ADHD symptoms severity (r = 0.53; P = 0.003) than with tic severity (r = 0.42; P = 0.02), suggesting that in TS, the association between SICI and ADHD symptoms may be more consistent or direct than the association between SICI and tics.