Intravitreous treatment of severe ocular von Hippel-Lindau disease using a combination of the VEGF inhibitor, ranibizumab and PDGF inhibitor, E10030: Results from a phase 1/2 clinical trial.

BACKGROUND: Treatment options for severe ocular von Hippel-Lindau (VHL) disease are limited. This trial evaluated preliminary safety and potential efficacy of combination intravitreous injection with ranibizumab, a vascular endothelial growth factor (VEGF) inhibitor, and E10030, a PDGF inhibitor, for eyes with VHL disease-associated retinal hemangioblastoma (RH) not amenable or responsive to thermal laser photocoagulation. METHODS: This was a prospective, single-arm, open-label phase 1/2 study, comprised of three adults with VHL-associated RH and vision loss. Intravitreous injections of ranibizumab (0.5 mg) and E10030 (1.5 mg) were given unilaterally every 4 weeks in the study eye through 16 weeks, then every 8 weeks through 48 weeks. Supplementary standard care therapies were allowed without restriction after 40 weeks. The primary outcome was the ocular and systemic adverse effect profile at 52 weeks. Secondary outcomes included changes in best-corrected visual acuity (BCVA), RH size, exudation, epiretinal proliferation and retinal traction, and need for ablative treatment of RH or ocular surgery at week 52. RESULTS: Three participants each received nine injections prior to week 52 and were followed for 104 weeks. One participant manifested mild episodic ocular hypertension in the study eye. Change in BCVA in the study eye at week 52 for the three participants was -5, -12 and +2 letters. No reduction in RH size was measured at 52 weeks. Variable mild improvements in exudation in two participants at week 16 were not sustained through week 52. CONCLUSIONS: Combination intravitreous injection with ranibizumab and E10030 demonstrated a reasonable preliminary safety profile, but limited treatment effect.

Deep Learning Automated Detection of Reticular Pseudodrusen from Fundus Autofluorescence Images or Color Fundus Photographs in AREDS2.

PURPOSE: To develop deep learning models for detecting reticular pseudodrusen (RPD) using fundus autofluorescence (FAF) images or, alternatively, color fundus photographs (CFP) in the context of age-related macular degeneration (AMD). DESIGN: Application of deep learning models to the Age-Related Eye Disease Study 2 (AREDS2) dataset. PARTICIPANTS: FAF and CFP images (n = 11 535) from 2450 AREDS2 participants. Gold standard labels from reading center grading of the FAF images were transferred to the corresponding CFP images. METHODS: A deep learning model was trained to detect RPD in eyes with intermediate to late AMD using FAF images (FAF model). Using label transfer from FAF to CFP images, a deep learning model was trained to detect RPD from CFP (CFP model). Performance was compared with 4 ophthalmologists using a random subset from the full test set. MAIN OUTCOME MEASURES: Area under the receiver operating characteristic curve (AUC), κ value, accuracy, and F1 score. RESULTS: The FAF model had an AUC of 0.939 (95% confidence interval [CI], 0.927-0.950), a κ value of 0.718 (95% CI, 0.685-0.751), and accuracy of 0.899 (95% CI, 0.887-0.911). The CFP model showed equivalent values of 0.832 (95% CI, 0.812-0.851), 0.470 (95% CI, 0.426-0.511), and 0.809 (95% CI, 0.793-0.825), respectively. The FAF model demonstrated superior performance to 4 ophthalmologists, showing a higher κ value of 0.789 (95% CI, 0.675-0.875) versus a range of 0.367 to 0.756 and higher accuracy of 0.937 (95% CI, 0.907-0.963) versus a range of 0.696 to 0.933. The CFP model demonstrated substantially superior performance to 4 ophthalmologists, showing a higher κ value of 0.471 (95% CI, 0.330-0.606) versus a range of 0.105 to 0.180 and higher accuracy of 0.844 (95% CI, 0.798-0.886) versus a range of 0.717 to 0.814. CONCLUSIONS: Deep learning-enabled automated detection of RPD presence from FAF images achieved a high level of accuracy, equal or superior to that of ophthalmologists. Automated RPD detection using CFP achieved a lower accuracy that still surpassed that of ophthalmologists. Deep learning models can assist, and even augment, the detection of this clinically important AMD-associated lesion.

Outcomes after Intravitreal Bevacizumab versus Laser Photocoagulation for Retinopathy of Prematurity: A 5-Year Retrospective Analysis.

PURPOSE: To determine the relative effectiveness, major complications, and refractive errors associated with intravitreal bevacizumab (IVB) versus panretinal photocoagulation (PRP) to treat type 1 retinopathy of prematurity (ROP). DESIGN: Retrospective case series. PARTICIPANTS: Consecutive infants with type 1 ROP who received either IVB or PRP and had at least 6 months of follow-up. METHODS: The data from infants treated with either IVB or PRP for type 1 ROP between 2008 and 2012 were recorded from 2 medical centers in Atlanta, Georgia. MAIN OUTCOME MEASURES: Recurrence rate, complication rate, and refractive error. RESULTS: A total of 54 eyes (28 patients) with type 1 ROP were evaluated: 22 eyes (11 patients) received IVB, and 32 eyes (17 patients) received PRP. Among the 22 eyes treated with IVB, 16 eyes had zone I ROP and 6 eyes had posterior zone II ROP. The number of zone I and II ROP eyes treated with PRP were 5 and 27, respectively. Mean gestational age, birth weight, postmenstrual age at initial treatment, and follow-up period for the infants receiving IVB were 24.2 weeks, 668.1 g, 35.1 weeks, and 21.7 weeks, respectively, and for the infants receiving PRP, these were 24.8 weeks, 701.4 g, 36.1 weeks, and 34.5 weeks, respectively. Retinopathy of prematurity recurred in 3 (14%) of 22 IVB-treated eyes and in 1 (3%) of 32 PRP-treated eyes. Neither retinal detachment nor macular ectopia developed in any of the IVB-treated eyes. In PRP-treated eyes, retinal detachment developed in only 1 eye and macular ectopia developed in 5 eyes. Mean spherical equivalent and postgestational age at the last refraction for IVB-treated eyes were -2.4 diopters (D) and 22.4 months, respectively, and for PRP-treated eyes, these were -5.3 D and 37.1 months, respectively. Mean spherical equivalent for zone I ROP eyes treated with IVB and PRP were -3.7 D and -10.1 D, respectively, and for zone II ROP eyes, these were 0.6 D and -4.7 D, respectively. CONCLUSIONS: Both IVB and PRP are effective treatment options for type 1 ROP with low complication rates. IVB was associated with less myopia than PRP, although longer follow-up was available for PRP.

Circadian rhythm of contrast sensitivity is regulated by a dopamine-neuronal PAS-domain protein 2-adenylyl cyclase 1 signaling pathway in retinal ganglion cells.

Spatial variation in light intensity, called spatial contrast, comprises much of the visual information perceived by mammals, and the relative ability to detect contrast is referred to as contrast sensitivity (Purves et al., 2012). Recently, retinal dopamine D4 receptors (D4Rs) have been implicated in modulating contrast sensitivity (Jackson et al., 2012); however, the cellular and molecular mechanisms have not been elucidated. Our study demonstrates a circadian rhythm of contrast sensitivity that peaks during the daytime, and that its regulation involves interactions of D4Rs, the clock gene Npas2, and the clock-controlled gene adenylyl cyclase 1 (Adcy1) in a subset of retinal ganglion cells (RGCs). Targeted disruption of the gene encoding D4Rs reduces the amplitude of the contrast sensitivity rhythm by reducing daytime sensitivity and abolishes the rhythmic expression of Npas2 and Adcy1 mRNA in the ganglion cell layer (GCL) of the retina. Npas2(-/-) and Adcy1(-/-) mice show strikingly similar reductions in the contrast sensitivity rhythm to that in mice lacking D4Rs. Moreover, Adcy1 transcript rhythms were abolished in the GCL of Npas2(-/-) mice. Luciferase reporter assays demonstrated that the Adcy1 promoter is selectively activated by neuronal PAS-domain protein 2 (NPAS2)/BMAL1. Our results indicate that the contrast sensitivity rhythm is modulated by D4Rs via a signaling pathway that involves NPAS2-mediated circadian regulation of Adcy1. Hence, we have identified a circadian clock mechanism in a subset of RGCs that modulates an important aspect of retinal physiology and visual processing.

Technical brief: a comparison of two methods of euthanasia on retinal dopamine levels.

PURPOSE: Mice are commonly used in biomedical research, and euthanasia is an important part of mouse husbandry. Approved, humane methods of euthanasia are designed to minimize the potential for pain or discomfort, but may also influence the measurement of experimental variables. METHODS: We compared the effects of two approved methods of mouse euthanasia on the levels of retinal dopamine. We examined the level of retinal dopamine, a commonly studied neuromodulator, following euthanasia by carbon dioxide (CO2)-induced asphyxiation or by cervical dislocation. RESULTS: We found that the level of retinal dopamine in mice euthanized through CO2 overdose substantially differed from that in mice euthanized through cervical dislocation. CONCLUSIONS: The use of CO2 as a method of euthanasia could result in an experimental artifact that could compromise results when studying labile biologic processes.

Melatonin: an underappreciated player in retinal physiology and pathophysiology.

In the vertebrate retina, melatonin is synthesized by the photoreceptors with high levels of melatonin at night and lower levels during the day. Melatonin exerts its influence by interacting with a family of G-protein-coupled receptors that are negatively coupled with adenylyl cyclase. Melatonin receptors belonging to the subtypes MT(1) and MT(2) have been identified in the mammalian retina. MT(1) and MT(2) receptors are found in all layers of the neural retina and in the retinal pigmented epithelium. Melatonin in the eye is believed to be involved in the modulation of many important retinal functions; it can modulate the electroretinogram (ERG), and administration of exogenous melatonin increases light-induced photoreceptor degeneration. Melatonin may also have protective effects on retinal pigment epithelial cells, photoreceptors and ganglion cells. A series of studies have implicated melatonin in the pathogenesis of age-related macular degeneration, and melatonin administration may represent a useful approach to prevent and treat glaucoma. Melatonin is used by millions of people around the world to retard aging, improve sleep performance, mitigate jet lag symptoms, and treat depression. Administration of exogenous melatonin at night may also be beneficial for ocular health, but additional investigation is needed to establish its potential.

TATTOO-ASSOCIATED CASES OF POSTERIOR SEGMENT UVEITIS WITH VOGT-KOYANAGI-HARADA DISEASE-LIKE FEATURES.

PURPOSE: To present two patients with treatment-naïve posterior segment uveitis with Vogt-Koyanagi-Harada-like features associated with tattoo-related inflammatory skin changes. METHODS: Retrospective report of two cases. RESULTS: Using clinical history and multimodal imaging, a diagnosis of posterior segment uveitis with Vogt-Koyanagi-Harada-like features was made in association with tattoo skin changes in both patients. CONCLUSION: Physicians should be aware that tattoo-associated posterior segment uveitis with Vogt-Koyanagi-Harada-like features can occur.

Dopamine D4 receptor activation controls circadian timing of the adenylyl cyclase 1/cyclic AMP signaling system in mouse retina.

In the mammalian retina, dopamine binding to the dopamine D4 receptor (D4R) affects a light-sensitive pool of cyclic AMP by negatively coupling to the type 1 adenylyl cyclase (AC1). AC1 is the primary enzyme controlling cyclic AMP production in dark-adapted photoreceptors. A previous study demonstrated that expression of the gene encoding AC1, Adcy1, is downregulated in mice lacking Drd4, the gene encoding the D4R. The present investigation provides evidence that D4R activation entrains the circadian rhythm of Adcy1 mRNA expression. Diurnal and circadian rhythms of Drd4 and Adcy1 mRNA levels were observed in wild-type mouse retina. Also, rhythms in the Ca²âº-stimulated AC activity and cyclic AMP levels were observed. However, these rhythmic activities were damped or undetectable in mice lacking the D4R. Pharmacologically activating the D4R 4 h before its normal stimulation at light onset in the morning advances the phase of the Adcy1 mRNA expression pattern. These data demonstrate that stimulating the D4R is essential in maintaining the normal rhythmic production of AC1 from transcript to enzyme activity. Thus, dopamine/D4R signaling is a novel zeitgeber that entrains the rhythm of Adcy1 expression and, consequently, modulates the rhythmic synthesis of cyclic AMP in mouse retina.

Progression of Geographic Atrophy with Subsequent Exudative Neovascular Disease in Age-Related Macular Degeneration: AREDS2 Report 24.

PURPOSE: To examine whether the rate of geographic atrophy (GA) enlargement is influenced by subsequent exudative neovascular age-related macular degeneration (nAMD) and hence, to explore indirectly whether nonexudative nAMD may slow GA enlargement. DESIGN: Post hoc analysis of a controlled clinical trial cohort. PARTICIPANTS: Age-Related Eye Disease Study 2 participants 50 to 85 years of age. METHODS: Baseline and annual stereoscopic color fundus photographs were evaluated for (1) GA presence and area and (2) exudative nAMD presence. Two cohorts were constructed: eyes with GA at study baseline (prevalent cohort) and eyes in which GA developed during follow-up (incident cohort). Mixed-model regression of the square root of GA area was performed according to the presence or absence of subsequent exudative nAMD. MAIN OUTCOME MEASURES: Change over time in square root of GA area. RESULTS: Of the 757 eyes in the incident GA cohort, over a mean follow-up of 2.3 years (standard deviation [SD], 1.2 years), 73 eyes (9.6%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was significantly slower (0.20 mm/year; 95% confidence interval [CI], 0.12-0.28 mm/year) compared with the other 684 eyes in which subsequent exudative nAMD did not develop (0.29 mm/year; 95% CI, 0.27-0.30 mm/year; P = 0.037). Of the 456 eyes in the prevalent GA cohort, over a mean follow-up of 4.1 years (SD, 1.4 years), 63 eyes (13.8%) demonstrated subsequent exudative nAMD. Geographic atrophy enlargement in these eyes was similar (0.31 mm/year; 95% CI, 0.24-0.37 mm/year) compared with the other 393 eyes in which subsequent exudative nAMD did not develop (0.28 mm/year; 95% CI, 0.26-0.29 mm/year; P = 0.37). CONCLUSIONS: In eyes with recent GA, GA enlargement before the development of exudative nAMD seems slowed. This association was not observed in eyes with more long-standing GA, which have larger lesion sizes. Hence, perilesional nonexudative choroidal neovascular tissue (presumably present before the development of clinically apparent exudation) may slow enlargement of smaller GA lesions through improved perfusion. This hypothesis warrants further evaluation in prospective studies.

Spontaneous dissection of the superior mesenteric artery.

We describe a case of spontaneous dissection and thrombosis of the superior mesenteric artery in a 54-year-old man who presented with new onset of hypertension and epigastric pain. Initial unsuccessful treatment with catheter-directed thrombolysis was followed by surgical intervention. In cases in which an extensive intimectomy is performed, early institution of antiplatelet therapy or anticoagulation may be necessary to preserve vessel patency due to the presence of a prothrombotic surface and compromised outflow.

Estimated volume growth characteristics of renal tumors undergoing active surveillance.

INTRODUCTION: The detection rate of incidental renal masses is increasing. Historically these masses have been treated with extirpative surgery. Hence, there is little information on the growth rate, metastatic potential, and natural history of renal tumors. Through active surveillance, we study the natural history of renal masses and determine their growth rate and risk for metastasis. MATERIALS AND METHODS: From 1997 to 2007, active surveillance was offered to select patients with renal masses with no evidence of metastasis. Based on imaging studies from the initial diagnosis to the last follow up, tumor growth rates were determined. RESULTS: Forty-six patients were studied for a total of 58 masses. Mean age of patients at diagnosis was 64.3 years. Mean Charlson comorbidity score was 5.2 (median 5, range 2-13). Mean follow up period was 22 months (median 17, range 5-121). Mean initial tumor volume was 6.6 cm3 (median 2.7, range 0.03-43.2). Mean growth rate was 1.9 cm3/yr (median 0.1, range -3.8-27.9), and 6.8% had a volume doubling time of less than 1 year. No patient developed radiographic evidence of metastasis or died during follow up. Thirteen patients (15 masses) went onto operative intervention at a mean follow up of 19 months (median 18, range 4-36); 10/15 (67%) revealed renal cell carcinoma and 5/15 (33%) were benign. CONCLUSIONS: In our cohort, negligible growth rates are observed in the vast majority of renal masses undergoing active surveillance, and thus, a carefully selected patient population may be safely managed with active surveillance with serial imaging.

Concurrent vascular flow defects at the deep capillary plexus and choriocapillaris layers in acute macular neuroretinopathy on multimodal imaging: A case series.

PURPOSE: To describe multimodal imaging findings with focus on retinal and choroidal vascular features in acute macular neuroretinopathy (AMN). OBSERVATIONS: Three eyes from 3 patients (1 man, 2 women) with average age of 31 were included in this retrospective case series at a single institution. Each case showed petaloid hyporeflective areas on infrared images (IR) with variable levels of outer retinal defects on spectral domain optical coherence tomography (OCT). En face OCT angiography (OCT-A) images showed quantifiable reduction in vessel density at levels of the deep capillary plexus (DCP) and choriocapillaris (CC) layers. In 2 of the cases with near-infrared autofluorescence imaging (NIRAF), there were subtle areas of hypoautofluorescence corresponding in location to the lesions seen on IR. In one case, fluorescein angiography (FA) showed a small area of retinal vascular leakage in the area of the IR lesion, and in other 2 cases, there were paracentral areas of hypofluorescence in the area of the IR lesions. En face structural OCT image at the retinal pigment epithelium (RPE) level in each case showed no evidence of projection artifact from the retina. CONCLUSIONS AND IMPORTANCE: The pathogenesis of AMN is suspected to involve a vasogenic insult. However, the precise localization of the vascular insult has been controversial and unclear. Our findings demonstrate that concurrent vascular flow defects in both DCP and CC could be possible in AMN and suggest that an inflammatory and vascular etiology in concert could underlie the pathogenesis of AMN.

Two cases of severe Purtscher-like retinopathy demonstrating recurrence and progression to neovascularization and vitreous hemorrhage.

PURPOSE: To report the clinical course of two cases with Purtscher-like retinopathy (PLR), associated with peritoneal dialysis (PD), demonstrating disease recurrence and progression to neovascularization and vitreous hemorrhage. OBSERVATIONS: Case 1 (45-year old woman) experienced acute bilateral vision loss. Medical history included hypertension, end-stage renal failure (ESRF), PD, and obstructive sleep apnea. Visual acuity (VA) was 20/100 OD, 20/80 OS. Fundus findings were pathognomonic for PLR and included white streaks within arterioles. Nine months later, repeat imaging demonstrated disease recurrence and progression, including increased ischemia and new retinal neovascularization. The patient was managed with pan-retinal photocoagulation, sleep apnea treatment, and oral corticosteroids. Four months later, VA remained stable without additional progression.Case 2 (74-year old woman) experienced acute bilateral vision loss. Medical history included hypertension, ESRF, and PD, complicated by peritonitis. VA was 20/25 OD, 20/32 OS. Fundus findings were pathognomonic for PLR and included white streaks within arterioles. Three months later, further acute vision loss occurred, coinciding with recurrent peritonitis. Repeat imaging revealed disease recurrence and progression, including severely increased retinal ischemia. The PD catether was removed and the patient converted to hemodialysis. Bilateral vitreous hemorrhage later complicated the course. CONCLUSIONS AND IMPORTANCE: PLR can occur in association with PD, particularly in acute peritonitis. Contrary to classical descriptions, PLR may take a chronic and progressive course, with increasing ischemia and progression to neovascularization or vitreous hemorrhage. Increased surveillance for complications is recommended and treatment of neovascularization may be required.

Anterior chamber fibrinoid syndrome after cataract extraction in a patient on ibrutinib for B-cell chronic lymphocytic leukemia: a case report and review of the literature.

BACKGROUND: Ibrutinib is a tyrosine kinase inhibitor commonly used in patients with chronic lymphocytic leukemia. Based on the published literature, it has a very sound ophthalmologic safety profile. In the following, we describe a case of anterior chamber fibrinoid syndrome in a patient on ibrutinib for B-cell chronic lymphocytic leukemia after uncomplicated cataract extraction. CASE PRESENTATION: A 75-year-old white man with B-cell chronic lymphocytic leukemia on ibrutinib therapy and without significant past ocular history presented 1 day after uncomplicated phacoemulsification with in-the-bag intraocular lens implantation with multiple, discrete, pigmented cords in the anterior chamber. His vision was 20/100 and intraocular pressure was 43 mmHg. There was no hypopyon, hyphema, or cellular reaction. The dilated fundus examination was unremarkable. He was diagnosed as having fibrinoid syndrome and started on topical prednisolone, brimonidine, timolol-dorzolamide, and orally administered acetazolamide. Within 2 weeks, the fibrin cords disappeared completely, vision improved to 20/30, and the intraocular pressure normalized off all medications. CONCLUSIONS: The precise etiology of fibrinoid syndrome remains unclear. This is the first case of fibrinoid syndrome in a patient on ibrutinib, which is known to cross the blood-brain barrier and induce intraocular changes. It is important to differentiate this syndrome from toxic anterior segment syndrome and endophthalmitis, and to initiate appropriate treatment. The fibrin bands tend to be exquisitely sensitive to topical steroids and to resolve within a few weeks without sequelae.

Subretinal Bone Formation in a Patient with Giant Cell Tumor of the Sphenoid.

BACKGROUND/AIMS: To report a case of subretinal bone formation after the treatment with denosumab for a giant cell tumor of the sphenoid, which had recurred after surgical resection. METHODS: The clinical history and fundus findings including imaging, histologic and immunohistochemical features of the primary tumor and subretinal lesion were reviewed. RESULTS: A 14-year-old boy was evaluated for a suprasellar mass. Resection of the lesion showed giant cell tumor of bone (GCT). An MRI study at the 1-month follow-up appointment showed tumor progression, and denosumab was initiated. Two months after the initial presentation, the patient developed a worsening scotoma of the right eye. Dilated fundus examination showed a yellow-tan-colored subretinal mass temporal to the fovea. The subretinal lesion was removed and showed lamellar bone with associated fibrocellular tissue. CONCLUSION: Denosumab therapy for GCT of the sphenoid may be associated with subretinal bone formation.

Global rural diabetes prevalence: a systematic review and meta-analysis covering 1990-2012.

AIM: To investigate diabetes prevalence in rural areas globally and how it has changed over time in high-income countries (HIC) and low-middle income countries (LMIC). METHODS: We systematically searched four electronic databases (MEDLINE, EMBASE, Cochrane Library, and CINAHL) for studies reporting rural prevalence of diabetes between January 1990 and January 2012. We used random effect meta-analysis to estimate pooled prevalence and metaregression to identify factors that may be associated with our estimates. FINDINGS: We included 109 population-based surveys involving 1,100,746 individuals. Pooled global rural prevalence of diabetes was 6.8% (95% confidence intervals: 6.1-7.6) with no gender difference. Considering five-year increments between 1985 and 2011, when studies were conducted, global rural prevalence was 5.7% (3.5-7.9) during 1985-1989 and 8.7% (6.8-10.7) during 2005-2011. In LMICs, rural diabetes prevalence was 1.8% (1.0-2.6) during 1985-1989 and 7.5% (5.6-9.5) during 2005-2011. In HICs, rural diabetes prevalence was 8.2% (6.0-10.4) during 1985-1989 and 14.3% (8.7-20) in the most recent period. CONCLUSION: Diabetes prevalence has increased in all rural areas globally but relative growth was faster in LMIC than HIC rural areas. These data suggest a need to expand diabetes surveillance to rural areas using standardized measures, as well as the need to devise and deploy appropriate prevention and control interventions.