Jonathan E. Sears

Macular traction detachment and diabetic macular edema associated with posterior hyaloidal traction

PURPOSE To review the clinical, photographic, fluorescein angiographic, and optical coherence tomographic findings in patients with the diabetic macular traction and edema (DMTE) associated with posterior hyaloidal traction (PHT). METHODS We performed a prospective review of nine eyes of nine patients with diabetic macular edema (DME) and PHT on clinical examination. The patients had a comprehensive ophthalmic history and examination, color photographs, fluorescein angiography, and optical coherence tomography (OCT). RESULTS All patients had diabetic retinopathy and DME. Of the nine eyes, eight patients had previous focal or grid photocoagulation. All nine eyes had a thickened, taut, glistening posterior hyaloid on clinical biomicroscopic examination with no posterior vitreous separation. Fluorescein angiography was performed on seven eyes, and all had early hyperfluorescence with deep, diffuse, late leakage in the macular area consistent with DMTE associated with PHT. Optical coherence tomography scans of the macular region revealed retinal thickening in all eyes with a mean retinal thickness of 556.9 +/- 114.7 microns. In addition, eight of the nine eyes had a shallow macular traction detachment associated with PHT. CONCLUSION Eyes with DME associated with PHT may have a shallow, subclinical, macular detachment. Optical coherence tomography may be useful in evaluating patients with DME to see if a macular detachment is present.

Carboxyethylpyrrole oxidative protein modifications stimulate neovascularization: Implications for age-related macular degeneration.

Choroidal neovascularization (CNV), the advanced stage of age-related macular degeneration (AMD), accounts for >80% of vision loss in AMD. Carboxyethylpyrrole (CEP) protein modifications, uniquely generated from oxidation of docosahexaenoate-containing lipids, are more abundant in Bruch’s membrane from AMD eyes. We tested the hypothesis that CEP protein adducts stimulate angiogenesis and possibly contribute to CNV in AMD. Human serum albumin (HSA) or acetyl-Gly-Lys-O-methyl ester (dipeptide) were chemically modified to yield CEP-modified HSA (CEP-HSA) or CEP-dipeptide. The in vivo angiogenic properties of CEP-HSA and CEP-dipeptide were demonstrated by using the chick chorioallantoic membrane and rat corneal micropocket assays. Low picomole amounts of CEP-HSA and CEP-dipeptide stimulated neovascularization. Monoclonal anti-CEP antibody neutralized limbal vessel growth stimulated by CEP-HSA, whereas anti-VEGF antibody was found to only partially neutralize vessel growth. Subretinal injections of CEP-modified mouse serum albumin exacerbated laser-induced CNV in mice. In vitro treatments of human retinal pigment epithelial cells with CEP-dipeptide or CEP-HSA did not induce increased VEGF secretion. Overall, these results suggest that CEP-induced angiogenesis utilizes VEGF-independent pathways and that anti-CEP therapeutic modalities might be of value in limiting CNV in AMD.

Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome

Objective To evaluate the anatomical and visual outcomes of patients treated with ocriplasmin for the treatment of symptomatic vitreomacular adhesion (sVMA), including vitreomacular traction syndrome and macular holes. Design Retrospective, interventional, single centre, case series. Participants Patients with sVMA. Intervention Patients were treated with a single intravitreal injection of 0.125 mg ocriplasmin (Jetrea, Thrombogenics Inc, USA, Alcon/Novartis EU) with the reconstitution technique recommended by the manufacturer. Main outcome measures The primary study endpoint was the resolution of sVMA by spectral domain optical coherence tomography (SDOCT) at day 28. Secondary outcome measures included time to vitreous release, visual acuity (VA), changes in the optical coherence tomography (OCT) thickness and structure and macular hole closure rate. Results 17 patients were included in the study and resolution of vitreomacular adhesion (VMA) was verified by SDOCT in eight patients by day 28 (overall response rate of 47.1%, 8/17 eyes) with most patients experiencing VMA release by 7 days (41.2%, 7/17 eyes). Those who did not have VMA resolution showed no statistically significant change in VMA diameter as measured by horizontal and vertical 5-line raster scans at final follow-up (p=0.82 and p=0.75, respectively). The mean baseline Snellen VA was 20/49 and at final follow-up was 20/46 (p=0.59). The average central subfield thickness was 371 microns prior to treatment and 324 microns at final follow-up (range 191–767 microns, p=0.25). Patients meeting three of four positive predictors criteria (eg, no epiretinal membrane (ERM) at baseline, VMA diameter ≤1500 µm and phakic lens status) showed a response rate of 50.0% (seven of 14 patients); those meeting all four criteria (eg, younger than 65, no ERM at baseline, VMA diameter ≤1500 µm and phakic lens status) showed a response rate of 75.0% (three of four eyes). Transient outer segment ellipsoid zone loss was documented in seven patients and subretinal fluid presence following injection was noted in five patients. Four of the five patients with macular holes at baseline experienced resolution of their macular hole after injection. Conclusions This is the first study to quantify the extent of outer retinal changes seen in patients receiving ocriplasmin. Our initial experience with ocriplasmin shows a significant anatomical effect and is accompanied by transient changes in the outer retinal structures visualised by SDOCT.

A Change in Oxygen Supplementation Can Decrease the Incidence of Retinopathy of Prematurity

PURPOSE To determine the incidence of retinopathy of prematurity (ROP) over a 2-year period before and after a change in the practice of oxygen supplementation. DESIGN Nonrandomized, retrospective study. PARTICIPANTS All infants in a single Level III neonatal intensive care unit between the years of 2005 and 2007. METHODS A prospective database recorded the gestational age, birth weight, stage and zone of ROP, threshold disease, treatment, final outcome and date of examination, maternal and infant demographics, and neonatal intensive care unit course. Year 1 (August 1, 2005 to July 31, 2006) includes a patient cohort who received the standard oxygen supplementation protocol, which has oxygen targets of 95% to 100% saturation. Year 2 (August 1, 2006 to July 31, 2007) includes a patient cohort who has strictly monitored oxygen targets of <34 weeks corrected gestational age oxygen limits of 80% to 95% and target 85% to 92% oxygen saturation and >34 weeks corrected gestational age limits of 85% to 100% and target 92% to 97% saturation. MAIN OUTCOME MEASURE Incidence of ROP in year 1 before a change in oxygen protocol compared with the incidence of ROP in year 2 after a change in the oxygen protocol. RESULTS A total of 114 children in year 1 and 108 children in year 2 were identified as having been born or transferred to the Fairview Nursery. Ninety-eight infants were examined before and 92 infants were examined after the change in oxygen standards, comprising 190 consecutive patients examined between September 2005 and October 2007. ROP was present in 35% of infants in group 1 before the change in oxygen protocol compared with 13% after the change in oxygen standards (P=0.001); stage 3 decreased from 11% to 2% (P=0.021); threshold disease decreased from 7% to 1% (P=0.066). Stage 0 (immature vessels, no ROP) incidence increased (pre/post-oxygen change 30%/51% stage 0, P=0.001). There were statistically significant differences in mode of delivery (P=0.007), sepsis <3 days of life (P=0.01), and oxygen at discharge (P=0.003). CONCLUSIONS Lower oxygen targets at early gestational age and higher oxygen targets at older gestational age decrease the severity and incidence of ROP while inducing normal retinal development.

Prolyl hydroxylase inhibition during hyperoxia prevents oxygen-induced retinopathy

Oxygen-induced retinopathy (OIR) in the mouse, like the analogous human disease retinopathy of prematurity, is an ischemic retinopathy dependent on oxygen-induced vascular obliteration. We tested the hypothesis that chemically overriding the oxygen-induced downregulation of hypoxia-inducible factor (HIF) activity would prevent vascular obliteration and subsequent pathologic neovascularization in the OIR model. Because the degradation of HIF-1α is regulated by prolyl hydroxylases, we examined the effect of systemic administration of a prolyl hydroxylase inhibitor, dimethyloxalylglycine, in the OIR model. Our results determine that stabilizing HIF activity in the early phase of OIR prevents the oxygen-induced central vessel loss and subsequent vascular tortuosity and tufting that is characteristic of OIR. Overall, these findings imply that simulating hypoxia chemically by stabilizing HIF activity during the causative ischemia phase (hyperoxia) of retinopathy of prematurity may be of therapeutic value in preventing progression to the proliferative stage of the disease.

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.

Photodynamic therapy of circumscribed choroidal haemangioma

Aim: To evaluate efficacy of verteporfin ocular photodynamic therapy (PDT) in treatment of 10 patients with a symptomatic circumscribed choroidal haemangioma. Design: Prospective non-randomised, interventional case series and critical review of previously published studies. Methods: 10 consecutive patients (seven primary, two failed transpupillary thermotherapy (TTT), and one failed external beam radiotherapy) with symptomatic circumscribed choroidal haemangioma were treated using verteporfin 6 mg/m2 given as an intravenous infusion over 10 minutes. Diode laser (690 nm) with an intensity of 600 mW/cm2 for 83 seconds (50 J/cm2) was applied 5 minutes after completion of infusion. Single or multiple partially overlapping spots were applied based on the tumour basal dimensions. Periodic follow up with ophthalmoscopy, ultrasonography, and angiographic studies was performed. Results: All 10 patients showed evidence of regression with flattening of tumour, resolution of subretinal fluid, and reduction of choroidal vasculature on angiograms. The visual acuity either improved or remained stable in eight (80%) patients. Visual loss due to delayed choroidal atrophy was seen in two patients. Conclusions: Although verteporfin PDT is an effective treatment for management of symptomatic circumscribed choroidal haemangioma, delayed treatment related effects can lead to visual loss.

VESGEN 2D: automated, user-interactive software for quantification and mapping of angiogenic and lymphangiogenic trees and networks.

Quantification of microvascular remodeling as a meaningful discovery tool requires mapping and measurement of site‐specific changes within vascular trees and networks. Vessel density and other critical vascular parameters are often modulated by molecular regulators as determined by local vascular architecture. For example, enlargement of vessel diameter by vascular endothelial growth factor (VEGF) is restricted to specific generations of vessel branching (Parsons‐Wingerter et al., Microvascular Research72: 91, 2006). The averaging of vessel diameter over many successively smaller generations is therefore not particularly useful. The newly automated, user‐interactive software VESsel GENeration Analysis (VESGEN) quantifies major vessel parameters within two‐dimensional (2D) vascular trees, networks, and tree‐network composites. This report reviews application of VESGEN 2D to angiogenic and lymphangiogenic tissues that includes the human and murine retina, embryonic coronary vessels, and avian chorioallantoic membrane. Software output includes colorized image maps with quantification of local vessel diameter, fractal dimension, tortuosity, and avascular spacing. The density of parameters such as vessel area, length, number, and branch point are quantified according to site‐specific generational branching within vascular trees. The sole user input requirement is a binary (black/white) vascular image. Future applications of VESGEN will include analysis of 3D vascular architecture and bioinformatic dimensions such as blood flow and receptor localization. Branching analysis by VESGEN has demonstrated that numerous regulators including VEGF165, basic fibroblast growth factor, transforming growth factor β‐1, angiostatin and the clinical steroid triamcinolone acetonide induce ‘fingerprint’ or ‘signature’ changes in vascular patterning that provide unique readouts of dominant molecular signaling. Anat Rec, 292:320–332, 2009.

Management of subretinal macular haemorrhage by direct administration of tissue plasminogen activator

Background/aims: Recent studies on the treatment of acute subretinal macular haemorrhage have shown that the volume of the clot and the time to evacuation have strong prognostic factors for visual outcome. A novel technique for surgical evacuation of these lesions involves direct injection of tissue plasminogen activator (t-PA) into the haematoma using pars plana vitrectomy. The aim of this study was to evaluate the clinical outcomes of this recently described procedure. Methods: 17 consecutive patients with subretinal macular haemorrhages caused by age related macular degeneration were enrolled. Patient demographics, acuities, and fluorescein angiograms were obtained for all evaluations. All patients underwent complete three port pars plana vitrectomy to enable direct cannulation of the subretinal space and injection of 48 μg of t-PA, partial fluid-air exchange, 1 hour face up supine positioning postoperatively, followed by upright positioning overnight. Results: 88% of patients within the study had stabilisation or improvement of visual acuity. Nine patients had total clearing of the macular haemorrhage and eight patients had subtotal clearing. Two patients had recurrence of the haemorrhage after the procedure and one patient underwent repair for retinal detachment. Occult lesions demonstrated similar outcomes to classic or predominately classic lesions. Nine patients required no therapy after the study to treat subfoveal neovascularisation. Conclusions: This study represents one of the largest case series to date showing that direct injection of subretinal t-PA with air-fluid exchange only and no intraoperative clot lysis period can have favourable results.

Verteporfin photodynamic therapy of six eyes with retinal capillary haemangioma

Acta Ophthalmol. 2010: 88: e334–e340