This study was approved by the Institutional Ethics Committee of Tokyo Women’s Medical University and adhered to the tenets of the Declaration of Helsinki. Written informed consent was obtained from each patient. IVTA was performed as part of standard care because it has been reported that macular edema and visual acuity can be improved in BRVO patients by this procedure . At our hospital, the treatment options for macular edema associated with BRVO include follow-up, intravitreal anti-VEGF therapy, IVTA, laser photocoagulation, and pars plana vitrectomy. This study enrolled the patients in whom IVTA was selected as the management option for CME, including SRD. We prospectively studied 21 eyes of 21 consecutive patients (mean age: 69.4 ± 9.6 years; 14 women and 7 men) who had BRVO with macular edema and were treated with IVTA. This prospective uncontrolled study was conducted at the Department of Ophthalmology of Tokyo Women’s Medical University between August 2008 and March 2011. Patients were diagnosed as having hypertension if the systolic blood pressure was ≥140 mm Hg and diastolic blood pressure was >90 mm Hg, or if the systolic pressure was ≥140 mm Hg at one examination and the diastolic pressure was ≥90 mm Hg on a different day, or if the patient was already taking antihypertensive medication . A diagnosis of hyperlipidemia was based on a total cholesterol≥240 mg/dL, triglycerides≥160 mg/dL, low-density lipoprotein cholesterol≥130 mg/dL, or use of cholesterol-lowering medication .
The inclusion criteria were eyes with a foveal thickness greater than 300 μm and a visual acuity equal to or less than 20/30. The exclusion criteria were (1) previous ocular surgery, (2) diabetes mellitus with diabetic retinopathy, (3) previous macular laser photocoagulation, (4) previous intravitreal injection of anti-VEGF agents or triamcinolone acetonide, (5) a history of ocular inflammation, (6) marked retinal hemorrhage (including macular bleeding involving the intrafoveal or subfoveal spaces), (7) coexisting ocular disease (i.e., epiretinal membrane or glaucoma), and (8) retreatment during the 6-month follow-up period. Twelve patients had superior vein occlusion and 9 patients had inferior occlusion.
All patients had undergone a comprehensive ophthalmologic examination, including best-corrected visual acuity measurement, intraocular pressure determination, indirect ophthalmoscopy, and slit-lamp biomicroscopy with a contact lens before and at 3, and 6 months after treatment. In addition, retinal sensitivity was investigated by microperimetry, and retinal thickness was measured by OCT.
In the current study, 21 patients received IVTA under local anaesthesia. For intravitreal therapy, the most common dosage of triamcinolone acetonide was 4.0 mg in a volume of 0.1 ml. Injection of triamcinolone into the vitreous fluid was done via the pars plana at 3–4 mm posterior to the limbus. All injections were performed with a sterile technique, and prophylactic topical antibiotics were applied for 1 week after injection. All patients were followed up for at least 6 months postoperatively. Recurrence of macular edema was defined as an increase (by >100 μm compared with the value at 3 months after initial IVTA) of foveal thickness when the thickness had once decreased to <300 μm at 3 months after initial IVTA . Recurrence of macular edema was observed in 3/21 eyes (14%), but the 3 patients did not want further treatment.
As baseline screening, patients underwent ophthalmoscopy and biomicroscopic examination using a slit-lamp with a fundus contact lens. They also underwent standard fundus color photography and fluorescein angiography, which was performed with a Topcon TRC-50EX fundus camera, an image-net system (Tokyo Optical Co. Ltd., Japan), and a preset lens with a slit-lamp.
A masked grader independently assessed ischemic retinal vascular occlusion on the fluorescein angiograms by measuring the ischemic area of the retina with the public domain Scion Image program, as reported previously [6–8]. On digital photographs of the fundus, the optic disc was outlined with a cursor and then its area was measured, as was also done for the nonperfused area of the retina. Then the nonperfused area was divided by the disc area to calculate the severity of retinal ischemia.
Measurement of BCVA
Each patient underwent measurement of best-corrected visual acuity (BCVA) with an SC-2000 System chart (Nidek, Gamagori, Japan). BCVA was measured in decimal units on a Landolt chart by the orthoptists. The chart brightness was set at 80–320 cd/m2, and chart contrast was more than 74%. The results were converted to the logarithm of the minimum angle of resolution scale (log MAR).
Measurement of optical coherence tomography
OCT was performed with an instrument from Zeiss-Humphrey Ophthalmic Systems (Zeiss Stratus OCT3, Carl Zeiss Meditec, Dublin, CA, USA) to measure the foveal thickness. At each visit, all patients underwent Stratus OCT examination in the vertical cross-section with the instrument centered on the fovea and in the fast macular thickness mode. On these views, retinal thickness was defined as the distance between the inner surface of the neurosensory retina and the retinal pigment epithelium. Foveal thickness was calculated as the average retinal thickness within a circle of 500-μm radius centered on the fovea. A retinal thickness map and retinal volume map were obtained by scanning 6×6 mm (20°×20°) areas of the macular region, which was divided into the following nine subfields: 1) fovea, 2) superior inner macula, 3) nasal inner macula, 4) inferior inner macula, 5) temporal inner macula, 6) superior outer macula, 7) nasal outer macula, 8) inferior outer macula, and 9) temporal outer macula . The diameters of the central, inner, and outer circles were 1, 3, and 6 mm, respectively. In each region, measurement of retinal thickness was automatically performed by computer software.
In this study, we exchanged the superior and inferior regions to separate the regions into those with occlusion and those without it. As a result, the superior region was always the occluded region and the inferior region was always non-occluded. We then analyzed the occluded and non-occluded regions separately. For the occluded region, the mean macular thickness was determined across four subfields (fovea, superior inner, nasal inner, and temporal inner) covering the central 3×3 mm (10°×10°), as well as across seven subfields (fovea, superior inner, nasal inner, temporal inner, superior outer, nasal outer, and temporal outer) covering the central 6×6 mm (20°×20°). For the non-occluded region, the mean macular thickness was determined in one subfield (inferior inner) covering the central 3×3 mm (10°×10°), as well as across two subfields (inferior inner and inferior outer) covering the central 6×6 mm (20°×20°). The mean macular thickness was also determined in one subfield (fovea) covering the central 1×1 mm (4°×4°).
SRD was defined as being present if OCT revealed typical accumulation of subretinal fluid resulting in neurosensory retinal detachment with low or absent reflectivity anterior to a clearly distinguishable outer band, irrespective of the coexistence of CME . CME was defined as present if OCT revealed hyporeflective intraretinal cavities. All 11 patients with SRD had both SRD and CME. Therefore, we classified the subjects into a CME without SRD group (SRD (−) group) and a CME with SRD group (SRD (+) group).
Functional mapping by microperimetry
Microperimetry with the MP-1 (Nidek, Gamagori, Japan) is performed using an infrared fundus camera with a liquid crystal display controlled by special software. The MP-1 software contains an automatic tracking system for fundus movements; this evaluates every acquired frame for shifts in the x and y directions of the fundus with respect to a reference frame obtained by an infrared camera at the beginning of the examination. Each patient underwent fundus-monitored microperimetry with the MP-1 system (Nidek, Gamagori, Japan). Its software performs automatic tracking of fundus movements and evaluates every frame acquired for fundus shift in the x and y directions relative to a reference frame obtained with an infrared camera at the beginning of the examination. Microperimetry settings were identical for all examinations: Goldmann III stimuli were presented in random order according to a 4-2-1 double staircase strategy. The stimulus intensity ranged from 0 to 20 decibels (dB) (0 dB corresponded to the strongest signal intensity of 127 cd/m2) in 1-dB steps, and the duration of each stimulus was 200 ms. The fixation target was varied in size according to the patient's visual acuity. Retinal sensitivity maps were obtained by using the macula 20 degrees program of the MP-1. During the examination, background illumination was set at 1.27 cd/m2. Mean retinal sensitivity was calculated from the sensitivity for each of nine subfields on the retinal map generated by OCT. We analyzed data for the occluded and non-occluded regions separately. For the occluded region, we determined the mean macular sensitivity at 23 sites in the central 10° field (four subfields: fovea, superior inner, nasal inner, and temporal inner) and at 44 sites in the central 20° field (seven subfields: fovea, superior inner, nasal inner, temporal inner, superior outer, nasal outer, and temporal outer). For the non-occluded region, we determined the mean macular sensitivity at 6 sites in the central 10° field (inferior inner subfield) and at 13 sites in the central 20° field (inferior inner and inferior outer subfields). The mean macular sensitivity was also determined at five sites in the central 4° field.
All analyses were performed with SAS System 9.1 software (SAS Institute Inc., Cary, North Carolina, USA). Results are presented as the mean ± SD or as the frequency. One-way or two-way repeated measures ANOVA was used to evaluate changes in visual acuity, macular sensitivity, and macular thickness. To examine differences in the changes of parameters over time, trend profiles were determined by repeated measures analysis. Two-tailed P values of less than 0.05 were considered to indicate statistical significance.