THE LATEST PUBLISHED RESEARCH

Effects of Vitrectomy on PO(2) Levels in the Vitreous Cavity
London researchers investigated the effects of vitrectomy on PO(2) in the vitreous cavity in central retinal vein occlusion (CRVO) in this prospective, controlled, interventional pilot study. Included were six patients with ischemic CRVO in one eye (undergoing vitrectomy for radial optic neurotomy [RON]) and six with either macula hole or membrane. Mean age was 65 years.

The researchers inserted an oxygen probe before removal of the vireous (pre-virectomy) and after removal of vireous (post-vitrectomy) and took measurements in the patients with CRVO before they performed RON. Additionally, they took oxygenation recordings (PO[2]) in the mid-vitreous cavity and the preretinal vitreous.

In controls, pre-vitrectomy, the mean PO(2) adjacent to the retina (15.0 mmHg S.D. 5.7) was significantly less than mid-cavity (33.7 mmHg S.D. 12.8). Similarly in CRVO, the pre-vitrectomy pre-retinal PO(2) (8.1 mmHg S.D. 3.5) was significantly less than mid-cavity (19.8 mmHg S.D. 7.3) and the mean PO(2) was significantly less in the eyes with CRVO than in control eyes. Post-vitrectomy, the PO(2) was significantly greater than pre-vitrectomy at both recording sites in the controls mid-cavity (61.5 mmHg S. D. 13.9), pre-retinal (75.8 mmHg S. D. 9.1) and CRVO eyes mid-cavity (53.7 mmHg S.D. 17.9) and pre-retinal (59.8 mmHg S.D. 5.8).

PO(2) is reduced in the vitreous cavity in CRVO, the researchers found. They concluded that vitrectomy may be a method of increasing oxygen availability to the retina.

Source: Williamson TH, Grewal J, Gupta B, et al. Measurement of PO(2) during vitrectomy for central retinal vein occlusion, a pilot study. Graefes Arch Clin Exp Ophthalmol 2009; Apr 5 [Epub ahead of print]. DOI: 10.1007/s00417-009-1072-z.

Benefits of Intravitreal Pegaptanib Sodium for Macular Edema Related to CRVO
In this dose-ranging, double-masked, multi-center, phase 2 trial, investigators assessed the safety and efficacy of intravitreous pegaptanib sodium for the treatment of macular edema following central retinal vein occlusion (CRVO). Included in the trial were subjects with CRVO for 6 months duration or less, randomly assigned (1:1:1) to receive pegaptanib sodium or sham injections every 6 weeks for 24 weeks (0.3 mg and 1 mg, n=33; sham, n=32). The main outcome measure was visual acuity at week 30.

In the primary analysis at week 30, 12 of 33 (36%) subjects treated with 0.3 mg of pegaptanib sodium and 13 of 33 (39%) treated with 1 mg gained 15 or more letters from baseline vs. 9 of 32 (28%) sham-treated subjects (p=.48 for 0.3 mg and p=.35 for 1 mg of pegaptanib sodium vs. sham). The investigators observed that in secondary analyses, subjected treated with pegaptanib sodium were less likely to lose 15 or more letters (9% and 6%; 0.3-mg and 1-mg pegaptanib sodium groups, respectively) compared with sham-treated eyes (31%; p=.03 for 0.3 mg and p=.01 for 1 mg of pegaptanib sodium vs. sham) and showed greater improvement in mean visual acuity (+7.1 and +9.9, respectively, vs. -3.2 letters with sham; p=.09 for 0.3 mg and p=.02 for 1 mg of pegaptanib sodium vs. sham). By week 1, the mean central retinal thickness decreased in the 0.3-mg and 1-mg pegaptanib sodium groups by 269 µm and 210 µm, respectively, vs. 5 µm with sham (p<.001).

Based on the results of this 30-week study, the investigators noted that intravitreous pegaptanib sodium appears to provide visual and anatomical benefits in the treatment of macular edema following CRVO.

Source: Wroblewski JJ, Wells JA III, Adamis AP, et al; for the Pegaptanib in Central Retinal Vein Occlusion Study Group. Pegaptanib sodium for macular edema secondary to central retinal vein occlusion. Arch Ophthalmol 2009;127(4):374-380.

Pharmacologic Modulations of Hemoglobin by RPE
In this study, researchers sought to demonstrate the production of hemoglobin by human retinal pigment epithelium (RPE). They found that malfunction of RPE-hemoglobin production may underlie the pathophysiology of ocular diseases characterized by subfoveal hypoxia and VEGF upregulation, such as AMD and diabetic retinopathy.

Proteomic analysis using 10 donor eyes identified hemoglobin as a major constituent of soluble human RPE proteome. To confirm the results, the researchers used Western blot analysis, RT-PCR and immunocytochemistry and investigated the presence of erythrocyte-specific proteins within primary human RPE cytosol to rule out phagocytosis as the source of hemoglobin. In addition, they used ELISA to determine the rate of hemoglobin secretion from human RPE cells and studied globin mRNA expression of human RPE in comparison with a human erythroblast cell line and a spontaneously transformed human RPE cell line (ARPE-19).

Hemoglobin is a regular constituent of soluble human RPE proteome. According to the study researchers, RT-PCR and Western blot analysis confirmed the presence of hemoglobin in human RPE. No other erythrocyte-specific proteins were detected within human RPE cytosol. Moreover, hemoglobin expression persisted up to seven passages in vitro and human RPE globin expression exceeded that in human erythroblast and ARPE-19 cells. Immunohistochemistry revealed the presence of hemoglobin within RPE and Bruch's membrane. The hemoglobin release rate was calculated to be 1.9 ± 1.2 attomoles per cell per hour.

The researchers concluded that pharmacologic modulations of local hemoglobin production in RPE cells will create new opportunities to interfere with the course of these diseases.

Source: Tezel TH, Geng L, Lato EW, et al. Synthesis and secretion of hemoglobin by retinal pigment epithelium. Invest Ophthalmol Vis Sci 2009;50:1911-1919. DOI:10.1167/iovs.07-1372.

Choriocapillaris and RPE Changes in AMD
To examine the relationships between choriocapillaris (CC) and retinal pigment epithelial (RPE) changes in AMD, investigators quantified morphological changes in the RPE/choriocapillaris complex in dry and wet forms of AMD and compared the results with aged control eyes without maculopathy.

They analyzed postmortem choroids from 3 aged control subjects, 5 geographic atrophy (GA) subjects and 3 wet AMD subjects using a semi-quantitative computer-assisted morphometric technique developed to measure percent RPE and CC areas in choroidal whole mounts incubated for alkaline phosphatase activity. The tissues were subsequently embedded in methacrylate and sectioned to examine structural changes.

The investigators noted a linear relationship between the loss of RPE and CC in GA and found a 50% reduction in vascular area in regions of complete RPE atrophy. They also found extreme constriction of remaining viable capillaries in areas devoid of RPE. Adjacent to active choroidal neovascularization (CNV) in wet AMD, CC dropout was evident in the absence of RPE atrophy, resulting in a 50% decrease in vascular area. Lumenal diameters of the remaining capillaries in wet AMD eyes were similar to controls.

The primary insult in GA appears to be at the level of the RPE, according to investigators, and there is an intimate relationship between RPE atrophy and secondary CC degeneration. CC degeneration occurs in the presence of viable RPE in wet AMD. The RPE in regions of vascular dropout are presumably hypoxic, which may result in an increase in VEGF production by the RPE and stimulation of CNV.

Source: McLeod DS, Grebe R, Bhutto I, et al. Relationship between RPE and choriocapillaris in age-related macular degeneration. Invest Ophthalmol Vis Sci 2009; Apr 8 [Epub ahead of print]. DOI: 10.1167/iovs.09-3639.

Changes in Retinal Function in Patients with Neovascular AMD
In this retrospective, 24-week follow-up study, the authors set out to assess functional and structural changes in patients with neovascular age-related macular degeneration (AMD) treated with intravitreal ranibizumab 0.5 mg. They evaluated 18 patients with neovascular AMD who had been treated with three injections of ranibizumab 0.5 mg, 1 month apart and retreated according to predefined criteria.

At baseline, all patients were subjected to visual acuity measurement, fluorescein angiography, microperimetry and optical coherence tomography (OCT) stratus. Visual acuity, microperimetry and OCT evaluations were repeated 28 ± 2 days after each injection.

The authors found that mean retinal sensitivity significantly improved from 3.89 ± 3.0 dB at baseline to 6.61 ± 3.4 dB at 24 weeks (p=0.044). Mean visual acuity also significantly improved, from 48.67 ± 8.58 to 60.72 ± 16.09 (p=0.026); visual acuity improved in 44.4% of patients ≥ 15 letters (24.5 ± 8.0 letters), and in 38.9% of patients improved <15 letters (6.14 ± 3.7 letters), while 16.7% of patients lost <15 letters (7.3 ± 2.1 letters). They observed an improvement of fixation stability from baseline in 33.3% of patients and noted that central macular thickness significantly decreased from 310.5 ± 85.7 µm to 217.3 ± 46.8 µm at 24 weeks (p<0.001).

Based on their findings, the study authors concluded that although visual acuity and retinal thickness changes seemed to be almost maximum at 4 weeks after intravtireal ranibizumab 0.5 mg, retinal sensitivity as measured by microperimetry showed a trend of progressive improvement up to 24 weeks, which they say suggests that microperimetry may give additional information about macular function not given by visual acuity alone.

Source: Parravano M, Oddone F, Tedeschi M, et al. Retinal functional changes measured by microperimetry in neovascular age-related macular degeneration patients treated with ranibizumab. Retina 2009; 29(3):329-334.

Intravitreal Bevacizumab for the Treatment of CNV Associated with AMD
This prospective, randomized, comparative clinical trial compared the safety and efficacy of intravitreal injections of 1.25 mg and 2.5 mg bevacizumab for the treatment of choroidal neovascularization (CNV) associated with AMD.

A total of 86 patients with active CNV associated with AMD were studied and baseline best-corrected visual acuity in the study eye was from 20/40 to 20/2000. Patients were randomly assigned to receive intravitreal injections of 2.5 (39 patients) or 1.25 mg (47 patients) of intravitreal bevacizumab and best-corrected visual acuity measurement and clinical ocular examination were performed at 1 week, 1 month and then monthly for 5 months. In addition, fluorescein angiography and optical coherence tomography were performed at 1 month and 3 months after each injection.

The mean change in best-corrected visual acuity was -0.06 ± 0.3 logMAR in 1.25 mg and -0.07 ± 0.34 in 2.5 mg groups in 3 months (p=0.9) and -0.06 ± 0.27 logMAR in 1.25 mg and -0.09 ± 0.28 in 2.5 mg groups in 5 months (p=0.6). There was no significant difference in visual acuity between the two groups at any time point during the study. The mean change in foveal thickness was -49 ± 36 µm in the 1.25 mg and -65 ± 31 µm in the 2.5 mg group (p=0.6). In the 2.5 mg group, three cases of vitreous reaction and one case of massive subretinal hemorrhage were observed.

It was determined that intravitreal injection of 2.5 mg bevacizumab has the same efficacy as 1.25 mg, but may be associated with a higher rate of adverse events.

Source: Modarres M, Naseripour M, Falavarjani KG, et al. Intravitreal injection of 2.5 mg versus 1.25 mg bevacizumab (Avastin) for treatment of CNV associated with AMD. Retina 2009;29(3):319-324.

OCT-Guided Retreatment with Intravitreal Ranibizumab for Neovascular AMD
The Prospective Optical coherence tomography (OCT) imaging of patients with Neovascular age-related macular degeneration (AMD) Treated with intraOcular Ranibizumab (PrONTO) Study is a 2-year, prospective, uncontrolled study that used a variable-dosing regimen to assess the long-term efficacy of such a regimen with ranibizumab.

This open-label, prospective, single-center, uncontrolled clinical study enrolled AMD patients with neovascularization involving the central fovea and a central retinal thickness (CRT) of at least 300 µm as measured by OCT to receive 3 consecutive monthly intravitreal injections of ranibizumab (0.5 mg). During the first year, retreatment with ranibizumab was performed at each monthly visit if any criterion (e.g., an increase in OCT-CRT of at least 100 µm or a loss of 5 letters or more) was fulfilled. During the second year, the retreatment criteria were amended to include retreatment if any qualitative increase in the amount of fluid was detected using OCT.

Out of the 40 patients, enrolled 37 completed the 2-year study. At month 24, the mean visual acuity (VA) improved by 11.1 letters (p<.001) and the OCT-CRT decreased by 212 µm (p<.001). Furthermore, VA improved by 15 letters or more in 43% of patients. These VA and OCT outcomes were achieved with an average of 9.9 injections over 24 months.

Using an OCT-guided variable-dosing regimen with intravitreal ranibizumab, the PrONTO Study resulted in VA outcomes comparable with the outcomes from the phase III clinical studies, but fewer intravitreal injections were required.

Source: Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO study. Am J Ophthalmol 2009; Apr 20 [Epub ahead of print]. DOI: 10.1016/j.ajo.2009.01.024.

Use of Immunosuppression to Treat Autoimmune Retinopathy
To report the results of treating autoimmune retinopathy (AIR) with immunosuppression therapy, a retrospective review of 30 consecutive patients with AIR followed for 3 to 89 months (median, 17 months) who were treated with immunosuppression (systemic or local) was conducted. Subgroups consisted of cancer-associated retinopathy (CAR), nonparaneoplastic AIR (npAIR) and npAIR with cystoid macular edema (npAIR/CME). Outcome measures used were improvement of Snellen visual acuity by at least 2 lines, expansion of the visual field area by more than 25% and resolution of CME. The results of this review challenge the commonly held belief that AIR is untreatable.

Of 30 patients, 21 (70%) showed improvement overall. Broken down by subgroup, all 6 CAR patients, 7 of the 13 npAIR (54%) patients and 8 of the 11 (73%) npAIR/CME patients showed improvement. Furthermore, 5 of 21 (24%) patients had improvement in visual acuity, 15 of 21 (71%) had expansion of visual field area and 6 of 11 (55%) had resolution of CME. And out of the 30 total patients, 26 exhibited diffuse retinal atrophy without pigment deposits. An autoimmune family history was common in all of the groups: npAIR, 69% (9 of 13); npAIR/CME, 64% (7 of 11); and CAR, 50% (3 of 6).

Long-term treatment with immunosuppression resulted in clinical improvement in all subgroups of AIR. The most responsive subgroup was CAR; the least was npAIR.

Source: Ferreyra HA, Jayasundera T, Khan NW, et al. Management of autoimmune retinopathies with immunosuppression. Arch Ophthalmol 2009;127(4):390-397.