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Incidence of Visual Impairment in Type 1 Diabetes Mellitus

To examine the 25-year cumulative incidence of visual impairment (VI) and its relation to various risk factors, the authors of this population-based study included 955 insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in a baseline (1980-1982) and at least 1 of 4 follow-up (4-, 10-, 14- and 25-year) examinations or who died before the first follow-up examination (n=64).

Using the main outcome measure of incidence of VI, the authors measured best-corrected visual acuity (VA) using a modification of the Early Treatment Diabetic Retinopathy Study protocol. They defined visual impairment and severe VI as best-corrected VA in the better eye of 20/40 or worse and 20/200 or worse, respectively.

The authors reported that the 25-year cumulative incidences of any VI and severe VI (accounting for competing risk of death) were 13% and 3%, respectively. Multivariate models showed increased risk of VI was associated (hazard ratio, 95% confidence interval and p value) with more severe baseline retinopathy (1.14 per 1-step increase in retinopathy level; 1.03-1.27; p=0.01), presence of cataract (2.49 versus absence; 1.53-4.04; p<0.001), higher glycosylated hemoglobin (1.28 per 1%; 1.16-1.42; p<0.001), presence of hypertension (1.72 versus absence; 1.05-2.83; p=0.03) and currently smoking (vs. never smoked, 1.63; 1.01-2.61; p=0.04), but not proteinuria.

These data show that the 25-year cumulative incidence of VI is related to modifiable risk factors and, therefore, that VI may be reduced by better glycemic and blood pressure control and avoidance of smoking, the authors concluded.

Source: Klein R, Lee KE, Gangnon RE, Klein BE. The 25-year incidence of visual impairment in type 1 diabetes mellitus: the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Ophthalmology 2010;117(1):63-70.

In Vivo Retinal Morphology in DME

This prospective clinical trial analyzed immediate in vivo intraretinal morphologic changes secondary to standardized grid photocoagulation using spectral domain optical coherence tomography (SD OCT).

Participating in this trial were 13 consecutive patients with treatment-naïve, clinically significant diabetic macular edema (DME). Optical coherence tomography (OCT) examinations based on an eye-tracking system, infrared fundus imaging, color fundus photography and biomicroscopy were performed before and 1 day after standardized grid photocoagulation. At baseline, a standardized visual acuity assessment (Early Treatment Diabetic Retinopathy Study protocol) and fluorescein angiography were performed. Morphologic changes secondary to grid laser treatment were the main outcomes measured.

Immediate morphologic alterations of only the outer retinal layers, that is, the retinal pigment epithelium (RPE), the photoreceptor layer (PRL) and the outer nuclear layer (ONL) were observed one day after laser therapy. The shape of the laser-induced lesions did not show a sagittal alteration pattern throughout all 3 of the layers, however, but rather seemed to follow an oblique pathway throughout the ONL, changing direction at the level of the external limiting membrane and proceeding sagittally through the PRL and RPE. Additionally, biometric changes, such as a decrease in central retinal thickness combined with local thickening at the lesion site, especially in the PRL were induced by these morphologic changes.

In conclusion, SD OCT provides new insight into the immediate morphologic changes after laser treatment using the laser system and standardized grid photocoagulation induces characteristic homogenous alteration in the neurosensoric retinal layers. Biometric changes, indicating an immediate effect, were observed within 1 day after treatment.

Source: Bolz M, Kriechbaum K, Simader C, et al; for the Diabetic Retinopathy Research Group Vienna. In vivo retinal morphology after grid laser treatment in diabetic macular edema. Ophthalmology 2009; Jan 4 [Epub ahead of print]. DOI: 10.1016/j.ophtha.2009.07.035.

Imaging the Retina in Vivo Following Scatter Photocoagulation

The purpose of this Austrian prospective, interventional study was to image the ultrastructural morphology of retinal laser effects and their healing response in vivo using spectral domain optical coherence tomography (SD-OCT). It involved 10 patients undergoing panretinal photocoagulation (PRP) for proliferative diabetic retinopathy.

PRP was performed using a semiautomated patterned scanning laser system providing a raster of effects with homogenous intensity. Retinal morphology and localization of effects owing to laser-tissue interaction were imaged at 1 day, 1 week and at monthly intervals for 6 months. Additionally, the characteristic, specific structural changes during the healing process were followed over time using an SD-OCT device allowing for high-resolution raster scanning of the entire lesion pattern with identification of identical retinal sites (tracking modality). Retinal morphology and localization of effects of photocoagulation on SD-OCT images were the main outcome measures.

The photocoagulation effects were sharply delineated from the surrounding unaffected retina at day 1 and all spots seemed to be identical in size and location. The area of tissue destruction was confined to the outer retinal layers, extending from the outer nuclear layer (ONL) to the retinal pigment epithelium (RPE). It was noted that at 1 week, images showed a progressive loss of the affected outer retinal layers, namely the ONL and the outer plexiform layer. Concomitant distortion of the inner nuclear and plexiform layers generated a pattern of “archways” between adjacent laser spots. Also, the photoreceptor layers (PRL) seemed to be eliminated in the photocoagulated area, particularly at the borders of each lesion and the lesion center contained a condensed RPE and PRL segment. Furthermore, the ONL recovered partially, but the PRL inner and outer segments remained absent. During the long-term follow up, RPE cells migrated to the center of the lesion, forming a hyperplastic scar.

The characteristic morphology of retinal photocoagulation effects in vivo and over time was identified for the first time in human eyes using SD-OCT. A well-defined, reproducible area of destruction confined to the outer retinal layers was demonstrated by OCT imaging and healing proceeded as the condensation of the RPE and PRL in the lesion center.

Source: Kriechbaum K, Bolz M, Deak GG, et al. High-resolution imaging of the human retina in vivo after scatter photocoagulation treatment using a semiautomated laser system. Ophthalmology 2009; Dec 24 [Epub ahead of print]. DOI: 10.1016/j.ophtha.2009.07.031.

Retinal Photography for Grading Diabetic Retinopathy Severity

Investigators assessed agreement between between monoscopic and stereoscopic photography for research classification of diabetic retinopathy (DR) severity level in this study.

They compared monoscopic digital (MD) images with stereo digital (SD) and film (SF) photographs from a 152-eye cohort with full spectrum Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels for agreement on severity level, DR presence with ascending severity threshold, presence of DR index lesions and repeatability of grading.

The investigators noted substantial agreement classifying ETDRS DR severity levels between MD and SF images (=0.65, w [linear weighted] = 0.87), between MD versus SD (=0.66, w =0.87) and SD versus SF (= 0.62 and w= 0.86). Marginal homogeneity analyses found no significant difference between MD and SF (p=0.53 with Bhapkar test) and Kappa agreement between MD and SF ranged from 0.80 to 0.94 for presence/absence of eight ascending DR severity thresholds. MD repeatability between readers was equal to or better than SD or SF, the investigators reported. Severity threshold grading repeatability between readers was similar using MD or SF images. Kappa agreement between MD and SF for identifying diabetic retinopathy lesions ranged from moderate to almost perfect. Finally, Kappa comparisons showed that performance of grading new vessels on the disc from MD was slightly lower than that from SF.

The study investigators concluded that monoscopic photography can equal the reliability of stereo photography for full ETDRS DR severity scale grading.

Source: Li HK, Hubbard LD, Danis RP, et a. Monoscopic vs. stereoscopic retinal photography for grading diabetic retinopathy severity. Invest Ophthalmol Vis Sci 2010; Jan 6 [Epub ahead of print] DOI: 10.1167/iovs.09-4886.

Predicting Risk of Diabetic Retinopathy Using Common Sequence Variation in the VEGFA Gene

In South Australia, researchers conducted a study to determine whether common sequence variation in the vascular endothelial growth factor (VEGF)A gene plays a role in the development of diabetic retinopathy (DR).

They recruited 554 subjects with diabetes mellitus (DM) including 190 type 1 DM (T1DM) and 364 type 2 DM (T2DM). The study group consisted of 235 participants without DR, 158 with nonproliferative DR (NPDR), 132 with proliferative DR (PDR) and 93 with clinically significant macular edema (CSME). The researchers defined blinding DR as severe NPDR, PDR or CSME and they genotyped VEGFA tag single-nucleotide polymorphisms (SNPs) in all subjects and tested them for association with blinding DR.

The researchers associated multiple tag SNPs in the VEGFA with blinding DR. After controlling for sex, HbA1c and duration of disease, in T1DM, the AA genotype of rs699946 (p=0.007, odds ratio [OR], 4.1; 95% confidence interval [CI], 1.5-11.4) and the GG genotype of rs833068 (p=0.017, OR, 3.1; 95% CI, 1.3-7.2) were most significantly associated. In T2DM, the C allele of rs3025021 (p=0.002; OR, 3.8; 95% CI, 1.5-10.0) and the G allele of rs10434 (p=0.002; OR, 2.6; 95% CI, 1.3-5.3) were most significantly associated with blinding DR. Furthermore, haplotype analyses suggested an important role for the haplotype TCCGCG in blinding DR (p=0.0004).

According to the study researchers, sequence variation in the VEGFA gene is associated with risk of developing blinding DR in T1DM and T2DM. Identifying specific genetic markers will allow for refined screening algorithms and earlier intervention in patients at highest risk.

Source: Abhary S, Burdon KP, Gupta A, et al. Common sequence variation in the VEGFA gene predicts risk of diabetic retinopathy. Invest Ophthalmol Vis Sci 2009;50(12):5552-5558.

Response of VEGF Gene Variation to PDT in AMD

The authors of this Finnish study evaluated the role of vascular endothelial growth factor (VEGF) gene polymorphisms in exudative age-related macular degeneration (AMD). They found that the VEGF gene polymorphic single nucleotide polymorphisms (SNPs) at rs699947 and rs2146323 are strong determinants of the anatomic outcome after PDT, but the SNPs studied were not associated with the presence of exudative AMD or with the choroidal neovascularization (CNV) lesion side or configuration.

Patients with recent exudative AMD (n=162) and age-matched subjects without AMD (n=85) participated in this retrospective, comparative case series that employed fluorescein angiography (FA), clinical examination and single nucleotide polymorphism (SNP) genotyping. The authors analyzed the frequencies of 3 VEGF gene SNPs, 1 at the promoter site (rs699947, A→C) and 2 intronic SNPs (rs2146323, A → C and rs3025033, A → G), in relation to the risk of AMD, to choroidal neovascular (CNV) lesion size and configuration and to the anatomic response to photodynamic therapy (PDT). As for main outcome measures, these SNPs were chosen to cover all the haploblocks of the VEGF gene. The 86 patients who had undergone PDT were classified as either PDT responders or PDT nonresponders based on the outcome of PDT after the last treatment session. For PDT responders, the treating physician had deemed the lesion to be clinically dry and without leakage from CNV in FA at a visit scheduled at least 12 weeks after the last PDT treatment. The PDT sessions had been discontinued by the treating retina specialist for the PDT nonresponders because of an apparently poor response and a still exudative lesion after several PDT sessions.

The presence of exudative AMD or lesion size or configuration was not associated with the SNPs studied here, the authors reported. They also noted that the frequencies of the rs699947 were significantly different in PDT nonresponders and PDT responders. The AA, AC and CC genotypes were 14%, 39% and 46%, respectively, in PDT nonresponders, compared with 40%, 48% and 12%, respectively, in the PDT responders (p=0.0008). The corresponding frequencies for the rs2146323 AA, AC and CC genotypes were 4%, 32% and 64%, respectively, in nonresponders and 24%, 38% and 38%, respectively, in responders (p=0.0369). The genotypes of the rs3025033 SNP were distributed evenly between the responders and nonresponders.

Source: Immonen I, Seitsonen S, Tommila P, et al. Vascular endothelial growth factor gene variation and the response to photodynamic therapy in age-related macular degeneration. Ophthalmology 2010;117(1):103-108.

Recombinant Tissue Plasminogen Activator and Bevacizumab for Neovascular AMD

In this consecutive interventional case series, investigators in Germany evaluated the efficacy and safety of pars plana vitrectomy (ppV) with subretinal coapplication of recombinant tissue plasminogen activator (rtPA) and bevacizumab, and fluid-gas exchange for neovascular age-related macular degeneration (AMD) with submacular hemorrhage (SMH).

Included were 12 patients with neovascular AMD with SMH with a maximum history of 14 days. According to the investigators, all patients underwent ppV with subretinal coapplication of rtPA and bevacizumab and fluid-gas (20% SF6) exchange. Phakic patients underwent concomitant cataract surgery and additional injections of bevacizumab were applied intravitreally 4 and 8 weeks postop.

Complete displacement of SMH from the fovea was achieved in 9 of 12 patients and the mean best-corrected visual acuity (BCVA) improved significantly from preop logMAR 1.9 (range 3.0 to 0.7) to logMAR 1.2 (range 3.0 to 0.3) at 4 weeks postop (p=0.01) and to logMAR 0.9 (range 1.6 to 0.2) at 12 weeks postop (p=0.006). The investigators reported that the mean improvement of BCVA 4 weeks postop as compared with preop was logMAR 0.7 (range -0.2 to 2.3), whereas the mean improvement of BCVA 12 weeks postop as compared with preop was logMAR 0.96 (range -0.3 to 2.8). Overall, at 12 weeks postop, BCVA had improved in 10 patients, remained unchanged in one patient and worsened in one patient.

The investigators concluded that ppV with subretinal coapplication of rtPA and bevacizumab, and fluid-gas exchange effectively displaces SMH and improves visual acuity in most patients.

Source: Treumer F, Klatt C, Roider J, Hillenkamp J. Subretinal coapplication of recombinant tissue plasminogen activator and bevacizumab for neovascular age-related macular degeneration with submacular haemorrhage. Br J Ophthalmol 2010:94(1):48-53.

Feasibility of Surgery for CNV and Autologous Choroidal RPE Patch Transplantation

This Italian study evaluated the feasibility of transplanting a full-thickness patch of choroids, choriocapillaries, Bruch's membrane and RPE (RPE-choroid FTAP) from the peripheral to the subfoveal area of the same eye, after performing a 180° peripheral retinotomy and removing subfoveal choroidal neovascularization (CNV). Surgical complications, anatomical outcome and patch perfusion during follow up were also studied.

All patients in this retrospective case series suffered from advanced subfoveal CNV and were non-responders to standard care. Included were 13 eyes of 13 consecutive patients with a follow up of 4 to 20 months. After a complete vitrectomy, a 180° peripheral temporal retinotomy and the removal of subfoveal neovascularization, a FTAP of choroids, choriocapillaris, Bruch's membrane and the RPE were isolated from the midperiphery of the uveal bed, transpositioned under the fovea and covered with the retina. Patients received a complete ophthalmic examination, fluorescein angiography (FA), indocyanin green angiography (ICGA) and optical coherence tomography (OCT) during follow up.

An FTAP was harvested in every eye and transplanted under the fovea. No intraoperative complications occurred and the FTAP was recocnizable at FA, ICGA and OCT at each time point, up to 20 months postoperatively. Additionally, perfusion of the choroidal bed were observed into the FTAP during follow up from one week after surgery.

It was concluded that the creation of an FTAP through a 180° peripheral retinotomy is feasible and safe and that the FTAP is vital and perfused. Further studies are recommended to collect additional data.

Source: Cereda MG, Parolini B, Bellesini E, Pertile G. Surgery for CNV and autologous choroidal RPE patch transplantation: exposing the submacular space. Greafes Arch Clin Exp Ophthalmol 2010;248(1):37-47.

Angiographic Characteristics of BRVO and HRVO

To study the peripheral angiographic features of branch retinal vein occlusions (BRVOs) and hemicentral retinal vein occlusions (HRVO) and explore associations with macular edema and neovascularization, researchers included 78 outpatients in this retrospective observational case series.

They searched an imaging database of angiograms performed at a single academic institution for patients with a diagnosis of BRVO or HRVO and graded images for the presence of untreated nonperfusion, late peripheral vascular leakage (LPVL), neovascularization, macular edema and prior laser treatment. The researchers also reviewed optical coherence tomography images for all patients to confirm the presence of macular thickening and to exclude eyes with vitreomacular traction. Main outcome measures were angiographic evidence of nonperfusion, neovascularization, macular edema, LPVL and prior laser treatment.

The study researchers analyzed angiograms from 80 eyes of 78 patients with a diagnosis of BRVO (86%) or HRVO (14%) and observed angiographic macular edema (80%), untreated nonperfusion (82%), neovascularization (21%) and LPVL (58%). They reported that untreated nonperfusion at any location was significantly associated with macular edema (p=0.043) and that untreated nonperfusion anterior to the globe equator was significantly associated with macular edema (p=0.007). Furthermore, untreated nonperfusion was significantly associated with the presence of neovascularization (p=0.033). Late peripheral vascular leakage was not associated with other angiographic or clinical findings studied.

In conclusion, ultra wide-field angiography provides visualization of peripheral retinal pathology in BRVO and HRVO patients, which may be useful in their evaluation and treatment. According to the researchers, their findings support the hypothesis that areas of untreated retinal nonperfusion may be the source of production of biochemical mediators that promote neovascularization and macular edema.

Source: Prasad PS, Oliver SC, Coffee RE, et al. Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. Ophthalmology 2010; Jan 4 [Epub ahead of print]. DOI: 10.1016/j.ophtha.2009.09.019.

Link Between Retinal Vascular Caliber and Blood Levels of Homocysteine, Folate and Vitamin B12

To assess the association of total serum levels of homocysteine (tHcy), folate and vitamin B12 with retinal vascular caliber in older adults, researchers conducted this cross-sectional, population-based study and found that retinal vascular caliber is associated with tHcy in men but not in women.

They examined 1,772 of 2,334 Blue Mountains Eye Study participants. They took fundus photographs and also measured and summarized retinal arteriolar and venular caliber using computer-assisted techniques. The researchers determined serum folate and vitamin B12 levels and tHcy from venous blood samples. To assess whether serum levels of tHcy, folate and vitamin B12 were associated with retinal arteriolar and venular caliber, they used linear regression models adjusting for age, gender, mean arterial blood pressure, smoking and diabetes.

What they found was that arteriolar and venular caliber was not associated with tHcy in the total population. Further analysis demonstrated a significant serum homocysteine-gender interaction (p=.04). The researchers also noted a significant inverse association between tHcy and arteriolar caliber in men only (p=.03), with a threshold detected at a level of 17 µmol/l. Above this threshold, increasing tHcy was linearly associated with narrower arteriolar caliber (0.86 µm reduction per 1.0 µmol/l increase in tHcy) in men, but the researchers observed no significant association below this threshold. They also found no significant associations between serum folate or vitamin B12 levels and either retinal vessel caliber.

The study researchers believe that their finding may reflect the stronger association between blood pressure and tHcy in men than in women.

Source: Gopinath B, Wang JJ, Flood VM, et al. The associations between blood levels of homocysteine, folate, vitamin B12, and retinal vascular caliber. Am J Ophthalmology 2009;148(6):902-909.

Analyzing Retinal Thickness with Regard to Race, Gender and Age

Scientists sought to detect differences in retinal thickness among patients of different race, gender and age using optical coherence tomography (OCT) in this multicenter, university-based cross-sectional study. They enrolled 126 patients with no history of ocular disease (78 diabetics without retinopathy and 48 nondiabetics) and performed OCT. They made statistical comparisons of center point foveal thickness and mean foveal thickness using generalized estimating equations adjusting for diabetic status, race, age and gender.

The study population consisted of 36% male subjects, 39% Caucasian, 33% African-American and 28% Hispanic. The scientists noted that mean foveal thickness was 191.6 ± 2.7 µm and 194.5 ± 2.7 µm for diabetics and nondiabetics, respectively (p=.49). They reported that the mean foveal thickness in male subjects was significantly larger than in female (201.8 ± 2.7 µm and 186.9 ± 2.6 µm, respectively; p<.001). Moreover, mean foveal thickness was 200.2 ± 2.7 µm for Caucasian, 181.0 ± 3.7 µm for African-American and 194.7 ± 3.9 µm for Hispanic subjects. According to the scientists, mean foveal thickness was significantly less for African-American than Caucasian (p<.0001) or Hispanic subjects (p=.005) and center point foveal thickness and mean foveal thickness showed a significant increase with age.

They determined that there are statistically significant differences in retinal thickness between subjects of different race, gender and age. When compared to Caucasian and Hispanic subjects, African-American race is a predictor of decreased mean foveal thickness; and male sex (regardless of race) is a significant predictor of increased mean foveal thickness. The scientists also observed that mean foveal thickness is similar among diabetics and nondiabetics when data are controlled for age, race and sex. These results suggest that studies comparing OCT measurements should carefully control for age-based, race-based and gender-based variations in retinal thickness.

Source: Kashani AH, Zimmer-Galer IE, Shah SM, et al. Retinal thickness analysis by race, gender, and age using Stratus OCT. Am J Ophthalmol 2009;Dec 30 [Epub ahead of print] DOI: 10.1016/j.ajo.2009.09.025.

Displaced Retina Following Vitrectomy for Rhegmatogenous Retinal Detachment

Japanese investigators studied unintentional displacement of the retina after standard vitrectomy for rhegmatogenous retinal detachment (RRD) in this prospective interventional case series that involved 43 eyes of 43 consecutive patients with cystic RRD involving one or more quadrants. All 43 eyes underwent successful standard vitrectomy with 20% sulfur hexafluoride gas injection. The investigators performed neither scleral buckling nor retinotomy.

They subsequently recorded fundus autofluorescence (FAF) to detect displacement of the retina at 10 days and 1, 3 and 6 months postop and they also recorded fluorescein angiography using standard techniques for patients with abnormal FAF findings. They measured cyclotorsion and vertical deviation postop. The proportion of eyes with postoperative retinal displacement detected by FAF imaging was the main outcome measure.

The investigators recorded a mean age of 60 years for these 43 patients, with a range of 39 to 77 years. Of the 43 eyes, retinal detachment involved 1 quadrant in 2 eyes, 2 quadrants in 31 eyes, 3 quadrants in 8 eyes and 4 quadrants in 2 eyes. After complete reattachment of the retina, FAF photography demonstrated hyperfluorescent lines superiorly parallel to retinal vessels within the vascular arcade in 27 of the 43 eyes (62.8%). Fluorescein angiography did not demonstrate any abnormalities corresponding to the linear autofluorescence, the investigators reported. This autofluorescence was hypothesized to originate from increased metabolic activity of the retinal pigment epithelium that had been preoperatively located under the major retinal vessels and was postoperatively exposed to light because of downward displacement of the retina. The investigators in this study observed 1 to 5 degrees of extorsion in 16 of the 27 eyes (59.3%), and 1 to 4 degrees of vertical deviation in 13 eyes (48.1%). None of the 27 patients had diplopia or slant. The extent of retinal detachment (p=0.019) and the macular status (on or off) (p=0.016) were significantly associated with postoperative displacement of the retina.

In eyes with RRD treated with standard vitrectomy and gas injection, the retina may move downward after the surgery. According to the investigators, if the extent of retinal detachment is large, or macular detachment is present, unintentional postoperative retinal translocation may easily occur.

Source: Shirgami C, Shiraga F, Yamaji H, et al. Unintentional displacement of the retina after standard vitrectomy for rhegmatogenous retinal detachment. Ophthalmology 2010;117(1):86-92.