Dimitra Skondra

Characterization of Azurocidin as a Permeability Factor in the Retina: Involvement in VEGF-Induced and Early Diabetic Blood-Retinal Barrier Breakdown

PURPOSE Azurocidin, released by neutrophils during leukocyte-endothelial interaction, is a main cause of neutrophil-evoked vascular leakage. Its role in the retina, however, is unknown. METHODS Brown Norway rats received intravitreal injections of azurocidin and vehicle control. Blood-retinal barrier (BRB) breakdown was quantified using the Evans blue (EB) dye technique 1, 3, and 24 hours after intravitreal injection. To block azurocidin, aprotinin was injected intravenously before the intravitreal injections. To investigate whether azurocidin plays a role in vascular endothelial growth factor (VEGF)-induced BRB breakdown, rats were treated intravenously with aprotinin, followed by intravitreal injection of VEGF(164). BRB breakdown was quantified 24 hours later. To investigate whether azurocidin may mediate BRB breakdown in early diabetes, aprotinin or vehicle was injected intravenously each day for 2 weeks to streptozotocin-induced diabetic rats, and BRB breakdown was quantified. RESULTS Intravitreal injection of azurocidin (20 microg) induced a 6.8-fold increase in vascular permeability compared with control at 1-3 hours (P < 0.05), a 2.7-fold increase at 3 to 5 hours (P < 0.01), and a 1.7-fold increase at 24 hours (P < 0.05). Aprotinin inhibited azurocidin-induced BRB breakdown by more than 95% (P < 0.05). Furthermore, treatment with aprotinin significantly suppressed VEGF-induced BRB breakdown by 93% (P < 0.05) and BRB breakdown in early experimental diabetes by 40.6% (P < 0.05). CONCLUSIONS Azurocidin increases retinal vascular permeability and is effectively blocked by aprotinin. The inhibition of VEGF-induced and early diabetic BRB breakdown with aprotinin indicates that azurocidin may be an important mediator of leukocyte-dependent BRB breakdown secondary to VEGF. Azurocidin may become a new therapeutic target in the treatment of retinal vascular leakage, such as during diabetic retinopathy.

Proton Beam Irradiation Using a Light-Field Technique for the Treatment of Choroidal Hemangiomas

Background/Aims: To describe the clinical outcomes of patients with circumscribed and diffuse choroidal hemangiomas treated by proton beam irradiation using a nonsurgical light-field technique. Methods: A retrospective chart review was performed on a series of 19 patients (19 eyes) with choroidal hemangiomas treated with proton beam therapy between July 1988 and August 2005. Choroidal hemangiomas were treated with proton beam irradiation using a light-field technique and doses ranging from 15 to 30 cobalt Gray equivalents (CGE; CGE = proton Gy × relative biological effectiveness 1.1) in 4 fractions. Patients with at least 6 months’ follow-up were included in the study. Tumor regression, visual acuity, absorption of subretinal fluid, and treatment-associated complications were evaluated by clinical examination and ultrasonography. Results: Visual acuity improved or remained stable in 14 of 18 eyes (78%). Subretinal fluid was initially present in 16 of 19 eyes (84%), and completely resolved in all 16 eyes. Tumor height, as measured by B-scan ultrasonography, decreased in 18 of 19 eyes and remained stable in 1 of 19, as of the last examination. Complications of radiation developed in 9 of 19 eyes (47%) with the total applied dose ranging from 15 to 30 CGE for these 9 eyes. Conclusions: Proton beam irradiation using a light-field technique without surgical tumor localization is an effective treatment option in managing both circumscribed choroidal hemangiomas and diffuse hemangiomas associated with Sturge-Weber syndrome. A total proton dose as low as 15 CGE applied in 4 fractions appears to be sufficient to reduce tumor size, promote absorption of subretinal fluid, and improve or stabilize vision in most patients.

Role of OCT in the diagnosis and management of macular edema from uveitis

Uveitis is a potentially visually threatening disease accounting for 10% of vision loss in the developed world.1 The most common cause of vision loss in patients with uveitis has been shown to be macular edema (ME).1 The early detection and management of ME is critical to preserve vision in these patients. Optical coherence tomography (OCT) is a valuable tool in the management of many ocular diseases. The use of OCT has revolutionized the diagnosis and management of macular edema from a wide variety of ophthalmological diseases, including uveitis.2 In this review, we evaluate the role of OCT in the diagnosis and management of uveitic macular edema.

Visible-Light Optical Coherence Tomography Angiography for Monitoring Laser-Induced Choroidal Neovascularization in Mice.

Purpose This study sought to determine the earliest time-point at which evidence of choroidal neovascularization (CNV) could be detected with visible-light optical coherence tomography angiography (vis-OCTA) in a mouse model of laser-induced CNV. Methods Visible light-OCTA was used to study laser-induced CNV at different time-points after laser injury to monitor CNV development and measure CNV lesion size. Measurements obtained from vis-OCTA angiograms were compared with histopathologic measurements from isolectin-stained choroidal flatmounts. Results Choroidal neovascularization area measurements between the vis-OCTA system and isolectin-stained choroidal flatmounts were significantly different in area for days 2 to 4 postlaser injury, and were not significantly different in area for days 5, 7, and 14. Choroidal neovascularization area measurements taken from the stained flatmounts were larger than their vis-OCTA counterparts for all time-points. Both modalities showed a similar trend of CNV size increasing from the day of laser injury until a peak of day 7 postlaser injury and subsequently decreasing by day 14. Conclusions The earliest vis-OCTA can detect the presence of aberrant vessels in a mouse laser-induced CNV model is 5 days after laser injury. Visible light-OCTA was able to visualize the maximum of the CNV network 7 days postlaser injury, in accordance with choroidal flatmount immunostaining. Visible light-OCTA is a reliable tool in both detecting the presence of CNV development, as well as accurately determining the size of the lesion in a mouse laser-induced CNV model.

Near infrared autofluorescence imaging of retinal diseases.

Near infrared autofluorescence (excitation 787 nm, emission >800 nm) is a non-invasive imaging technology that provides information on the distribution of melanin within the retinal pigment epithelial cell/choroid complex. This review contains an introduction to near infrared autofluorescence imaging methods. Characteristics of near infrared imaging in a variety of retinal diseases, including age-related macular degeneration, choroidal nevus, retinal degenerations, retinal dystrophies, central serous chorioretinopathy, pseudoxanthoma elasticum and chloroquine retinopathy, are summarized.

ACUTE POSTERIOR MULTIFOCAL PLACOID PIGMENT EPITHELIOPATHY ON OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

Purpose: To investigate choroidal involvement in acute posterior multifocal placoid pigment epitheliopathy (APMPPE). Methods: A retrospective observational case series using multimodal imaging including optical coherence tomography (OCT) angiography. Results: Five patients with APMPPE were included. In most acute lesions, OCT angiography revealed outer retinal and retinal pigment epithelium (RPE) hyperreflective lesions with attenuated OCT signal in the underlying choroid, but careful examination allowed us to identify a single lesion with decreased choriocapillaris flow outside the signal attenuation. Optical coherence tomography angiography obtained after healing of lesions revealed areas of hypointense circular flow voids clustered in groups surrounded by either isointense or hyperintense signal background. Point-by-point evaluation revealed these flow voids did not correspond to areas of RPE thickening or focal pigmentary changes. Larger hypointense lesions were observed and did correlate with pigmentary changes. Conclusion: Our case series demonstrates choriocapillaris flow abnormalities in acute APMPPE extending beyond the OCT lesions, and distinct residual vascular abnormalities in healed APMPPE lesions on OCT angiography. Our findings support a primary ischemic insult to the photoreceptors and RPE, but choriocapillaris flow abnormalities could be secondary to (OCT invisible) retinal and RPE involvement. The lack of understanding of the etiology along with the inability to visualize most of the choroid in acute lesions precludes definite conclusions about the true pathogenesis of APMPPE.

Enhanced Depth Imaging Optical Coherence Tomography in Age-related Macular Degeneration

Imaging of the choroidal layer has been limited with the conventional commercial SD-OCTs. Enhanced depth imaging optical coherence tomography (EDI-OCT) is a modification of the standard spectral-domain OCT (SD-OCT) technique that enables better non-invasive imaging of the choroid. This review contains an introduction of EDI imaging technique and principles and summarizes the findings of EDI-OCT imaging in age-related macular degeneration.

Visual outcomes of surgery for stage 4 and 5 retinopathy of prematurity.

Retinopathy of prematurity (ROP) is a disease of abnormal retinal vascular development that occurs in premature and low–birth weight infants. Screening and treatment guidelines established by the CRYOROP and ETROP studies have reduced the rates of stage 4 and 5 ROP and resultant visual loss and are estimated to prevent 320 cases of blindness per year in the United States. Despite early treatment of highrisk disease, approximately 1 in 10 cases of ROP will progress to stage 4 or 5 retinal detachments needing surgical repair. This number is growing both in developed and developing countries because of advancements in neonatal care and improved survival of extremely premature infants (22 to 26 wk gestational age). In this review, we will discuss the most recent literature regarding visual and anatomic outcomes after surgery for stage 4 and 5 ROP. On the basis of results from the ETROP study, a total of 12% of eyes randomized in this study progressed to retinal detachments despite treatment. Several different surgical techniques have been used for the repair of retinal detachments associated with ROP including open-sky vitrectomy, scleral buckling, closed vitrectomy and lensectomy with or without scleral buckling, and, more recently, lens-sparing vitrectomy (LSV) without scleral buckling. Before the widespread use of vitrectomy, scleral buckle (SB) was the surgical treatment of choice for advanced stages of ROP with retinal detachment. Studies reported to date have shown a higher rate of anatomic success for LSV compared with scleral buckling in stage 4A

Traumatic chorioretinal rupture (Sclopetaria)

Chorioretinitis Plastica Sclopetaria was a term first coined by Goldzieher in 1901 to describe the characteristic fundus appearance after a direct choroidal and retinal trauma from a bullet wound in the orbital area. It is defined as a full-thickness break of the choroid and retina as the result of a high-velocity missile striking or passing adjacent to, but not penetrating, the globe. Other terms have been used in the past to describe this condition such as chorioretinitis proliferans, retinitis proliferans, traumatic proliferative chorioretinitis of lagrange, and acute retinal necrosis. All the above terms have in common the word chorioretinitis or retinitis consistent with Goldzieher’s theory that the white proliferative scar tissue sometimes seen in the late stage of this condition is a result of an exudative inflammatory process. At present, either the term traumatic chorioretinal rupture (TCR) or sclopetaria is more acceptable than chorioretinitis sclopetaria as it is clear that the chorioretinal rupture is a result of trauma and not of an inflammatory process. The etymology of the word sclopetaria is unclear. It may be derived from the old English verb ‘‘sclow,’’ which means to scratch, pull, or tear, thus describing the condition of scratching against the globe. Another possibility is that the term is derived from the Latin word ‘‘sclopetum’’ defined as a type of 14th century Italian handgun.

Characterizing Photoreceptor Changes In Acute Posterior Multifocal Placoid Pigment Epitheliopathy Using Adaptive Optics

Purpose: To characterize lesions of acute posterior multifocal placoid pigment epitheliopathy (APMPPE) by multimodal imaging including adaptive optics scanning laser ophthalmoscopy (AOSLO). Methods: We included patients with APMPPE at different stages of evolution of the placoid lesions. Color fundus photography, spectral domain optical coherence tomography, infrared reflectance, fundus autofluorescence, and AOSLO images were obtained and registered to correlate microstructural changes. Results: Eight eyes of four patients (two women) were included and analyzed by multimodal imaging. Photoreceptor reflectivity within APMPPE lesions was more heterogeneous than in adjacent healthy areas. Hyperpigmentation on color fundus photography appeared hyperreflective on infrared reflectance and on AOSLO. Irregularity of the interdigitation zone and the photoreceptor inner and outer segment junctions (IS/OS) on spectral domain optical coherence tomography was associated with photoreceptor hyporeflectivity on AOSLO. Interruption of the interdigitation zone or IS/OS was associated with loss of photoreceptor reflectivity on AOSLO. Conclusion: Irregularities in the reflectivity of the photoreceptor mosaic are visible on AOSLO even in inactive APMPPE lesions, where the photoreceptor bands on spectral domain optical coherence tomography have recovered. Adaptive optics scanning laser ophthalmoscopy combined with multimodal imaging has the potential to enhance our understanding of photoreceptor involvement in APMPPE.