Abstract
Abstract
Purpose:
To evaluate functional and morphological changes of the macula after intravitreal injection of triamcinolone acetonide (IVTA) for macular edema with branch retinal vein occlusion (BRVO).
Methods:
Twenty patients with BRVO (mean age: 69.7±9.8 years; 14 women and 6 men) received IVTA. Macular function was documented by microperimetry and best-corrected visual acuity (BCVA) was determined. Retinal thickness and retinal volume were measured by optical coherence tomography, and mean retinal sensitivity was calculated for each of 9 macular subfields.
Results:
Mean BCVA significantly improved 6 months after IVTA. Mean retinal sensitivity, retinal thickness, and retinal volume significantly improved after 6 months in 4, 8, and 8 subfields, respectively. On multivariate analysis, improvement of retinal sensitivity was significantly correlated with the percent changes of both retinal thickness and retinal volume in 2 subfields [superior inner (the occlusion site) and temporal outer], although improvement of visual acuity was not significantly correlated with the percent change of macular edema in any of the 9 subfields.
Conclusions:
These findings suggest that IVTA can improve both functional and morphological changes due to macular edema in BRVO patients, and that morphological improvement after IVTA might be useful for assessing the functional prognosis of BRVO with macular edema.
Introduction
The visual prognosis is influenced by various factors, such as the duration of macular edema, age, initial visual acuity, history of coronary artery disease, and presence of retinal ischemia, in BRVO patients with macular edema.11–13 Because visual acuity only reflects foveal function, it may be an inadequate measure for evaluating the functional prognosis after treatment of macular edema in patients with BRVO. Instead, it may be more useful to evaluate the functional prognosis of BRVO patients by measuring the retinal sensitivity of both the fovea and the larger macular area with the MP-1. Kriechbaum et al. 14 reported that functional parameters (central visual acuity and visual fields) and a morphologic parameters (retinal thickness) were significantly correlated after treatment of RVO with intravitreal bevacizumab. Detection of correlations between functional improvement and treatment-induced changes of anatomic parameters will help to determine which parameters are the most relevant biomarkers. We recently reported that functional parameters such as BCVA and retinal sensitivity (measured by microperimetry) and morphologic parameters such as retinal thickness and volume (measured with a Stratus) were significantly associated. 10 However, it is unclear just how the changes of retinal thickness and volume influences the retinal sensitivity of BRVO patients with macular edema. Accordingly, we performed a prospective study to evaluate functional changes (BCVA and retinal sensitivity) and morphological changes (retinal thickness and volume) after intravitreal injection of triamcinolone acetonide (IVTA) in BRVO patients with macular edema.
Methods
Subjects
We prospectively studied 20 eyes of 20 patients with macular edema with BRVO who were treated with IVTA. Twenty consecutive patients (mean age: 69.7±9.8 years; 14 women and 6 men) were included in this prospective uncontrolled study conducted at the Department of Ophthalmology of Tokyo Women's Medical University between July 2008 and December 2010 (Table 1). Informed consent was obtained from each patient. This study was performed in accordance with the Helsinki Declaration of 1975 (1983 revision), and it was approved by the ethics committee of Tokyo Women's Medical University. Written informed consent was obtained from each patient. Each patient had unilateral BRVO and the duration of symptoms ranged from 3 months to 10 months (average, 4.4±1.9 months). 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. 15 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. 15 Fifteen of the 20 BRVO patients (75.0%) had hypertension. Twelve of the 20 BRVO patients (60.0%) had hyperlipidemia.
Data are shown as the number (%) or the mean±standard deviation.
BRVO, branch retinal vein occlusion; No., number of eyes; M, male; F, female.
The indications for treatment of macular edema with IVTA were: (1) clinically detectable diffuse macular edema or cystoid macular edema persisting for more than 3 months, (2) a foveal thickness >300 μm, and (3) BCVA worse than 120/200. Significant macular edema was defined as retinal thickening that covered at least 1 optic disc area and involved the fovea. 16 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 8 patients had inferior occlusion.
All patients received a comprehensive ophthalmologic examination, including measurement of BCVA and intraocular pressure (IOP), indirect ophthalmoscopy, and slit-lamp biomicroscopy with a contact lens before treatment and 6 months after treatment. In addition, retinal sensitivity was investigated by microperimetry, and retinal thickness and retinal volume were measured by optical coherence tomography (OCT).
Surgical procedure
Twenty patients received IVTA under local anesthesia. 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. 9 Recurrence of macular edema was observed in 2/20 eyes (10%), but the 2 patients did not want further treatment.
Fundus examination
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.), 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 previously reported.3–5 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. The average nonperfused area was 34±33 disc areas, with a range of 0 to 101 disc areas.
Measurement of BCVA
Each patient underwent measurement of BCVA with an SC-2000 System chart (Nidek). BCVA was measured in decimal units on a Landolt chart by the orthopticists. 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).
Optical coherence tomography
OCT was performed with an instrument from Zeiss-Humphrey Ophthalmic Systems (Zeiss Stratus OCT3; Carl Zeiss Meditec) 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 9 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. 10 The diameters of the central, inner, and outer circles were 1, 3, and 6 mm, respectively. In each region, measurement of retinal thickness and volume was automatically performed by computer software.
On OCT, serous retinal detachment was defined as typical subretinal fluid accumulation resulting in neurosensory retinal detachment with low or absent reflectivity anterior to a clearly distinguishable outer band irrespective of the coexistence of cystoid macular edema. The 20 BRVO patients included 6 patients with serous retinal detachment (mean age: 71.8±13.6 years; 4 women and 1 man) and 14 patients without it (mean age: 71.0±6.7 years; 9 women and 5 men).
Functional mapping by microperimetry
Microperimetry with the MP-1 (Nidek) 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. 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 9 subfields on the retinal map generated by OCT.
Retinal thickness, volume, and sensitivity data for the superior and inferior regions were exchanged in the patients with inferior BRVO, so that the superior region was always the region affected by occlusion and the inferior region was intact. Then the correlations between retinal thickness or volume and sensitivity data were analyzed in each of the 9 subfields.
Statistical analysis
All analyses were performed with SAS System 9.1 software (SAS Institute Inc.). Results are presented as the mean±SD or as frequencies. The paired t-test was employed to compare paired continuous variables before and after IVTA. To examine the relations between changes of retinal thickness or retinal volume and changes of visual acuity (log MAR), and the relations between changes of these retinal parameters and change of retinal sensitivity, Pearson's correlation coefficients were calculated and multiple linear regression analysis was done with 7 variables [age (years), gender, hypertension (present or absent), hyperlipidemia (present or absent), duration of BRVO (months), nonperfused retinal area (disc areas), and serous retinal detachment (present or absent)]. Two-tailed P-values of <0.05 were considered to indicate statistical significance.
Results
Functional outcome
Mean BCVA was logMAR 0.59±0.45 at the initial examination and it significantly improved to logMAR 0.35±0.39 by 6 months after IVTA (P<0.001). The mean retinal sensitivity of 4 subfields [fovea, superior inner (site of occlusion), nasal inner, and temporal inner] showed a significant improvement, 6 months after IVTA (Table 2).
Values are shown as the mean±standard deviation.
IVTA, intravitreal triamcinolone acetonide.
Mean IOP was 11.4±2.4 mmHg at the initial examination. IOP was >21 mmHg in 2/20 eyes (10%). These 2 patients were treated with a beta-blocker to reduce the IOP and the mean value was 11.7±2.4 after 6 months of treatment. During follow-up, no cataract progression, endophthalmitis, or injection-related complications were encountered.
Morphological changes
The initial mean retinal thickness of 8 subfields (except for the inferior outer subfield: nonocclusion site) significantly decreased 6 months after IVTA (Table 2). The initial mean retinal volume of 8 subfields (except for the inferior outer subfield) also significantly decreased 6 months after IVTA (Table 2).
Correlation of functional and morphologic changes
Improvement of BCVA was calculated by subtracting the value after IVTA from that before IVTA, and improvement of retinal sensitivity was calculated in the same way.
Improvement of macular edema (retinal thickness and volume) was evaluated by calculating the percent change of macular edema (%ΔME) as follows:
where MEpr and MEpo correspond to the retinal thickness and volume before IVTA and 6 months after IVTA, respectively.
To identify correlations between the different variables, a general linear model was applied. As a result, the improvement of visual acuity and the percent change of retinal thickness (%ΔME) were correlated in 4 subfields [fovea, superior inner (site of occlusion), nasal inner, and temporal inner], while the improvement of visual acuity and the percent change of retinal volume (%ΔME) were correlated in 3 subfields (fovea, superior inner, and temporal inner) (Table 3). In addition, the improvement of retinal sensitivity and the percent changes of both retinal thickness and volume (%ΔME) were correlated in 2 subfields (superior inner and nasal inner) (Table 4). Multivariate analysis revealed that the improvement of visual acuity was not significantly correlated with the percent change of macular edema (%ΔME) in any of the 9 subfields after adjustment for 7 variables (age, gender, hypertension, hyperlipidemia, duration of BRVO, nonperfused retinal area, and serous retinal detachment) (Table 3). In contrast, the improvement of retinal sensitivity was significantly correlated with the percent change of both retinal thickness and volume (%ΔME) in 2 subfields [superior inner (site of occlusion) and temporal outer] after adjustment for the same 7 variables (Table 4).
R, Standard partial regression coefficient.
R, Standard partial regression coefficient.
Discussion
In the present study, we found that the mean BCVA (logMAR) showed a significant improvement 6 months after IVTA, while the mean retinal sensitivity, retinal thickness, and retinal volume also significantly improved after 6 months in 4, 8, and 8 subfields, respectively. These findings suggested that morphological changes of the retina show a close relation with functional improvement. Therefore, we evaluated the association between the improvement of visual function and the percent change of each morphological parameter. As a result, we found that the improvement of BCVA was correlated with the percent change of retinal thickness and retinal volume in 4 and 3 subfields, respectively. This seems to be reasonable, because visual acuity reflects foveal function. Our findings suggested that visual acuity showed more improvement in BRVO patients with macular edema when the percent changes of morphological parameters were larger at the inner macula. However, assessment of visual acuity alone may not be sufficient to evaluate visual function in BRVO patients with macular edema because their edema usually involves the region beyond the fovea.
Unlike the improvement of BCVA, we found that improvement of retinal sensitivity was correlated with the percent changes of retinal thickness and volume in only 2 subfields [superior inner (the site of occlusion) and nasal inner]. Interestingly, on multivariate analysis, the improvement of retinal sensitivity was significantly correlated with the percent change of both retinal thickness and retinal volume in 2 subfields (superior inner and temporal outer), although the improvement of visual acuity was not significantly correlated with the percent change of macular edema in any of the 9 subfields. This suggests that the extent of morphological improvement in these 2 subfields may influence the retinal sensitivity of BRVO patients with macular edema, and that larger percent changes of morphological parameters in these 2 subfields are associated with greater improvement of macular function because improvement of retinal sensitivity in these 2 subfields (superior inner and nasal inner) was correlated with improvement in the foveal subfield [data not shown, standard partial regression coefficient (Rc)=0.60, P=0.005 and Rc=0.55, P=0.011, respectively]. Therefore, measuring OCT parameters in these 2 subfields might be useful for estimating macular sensitivity after IVTA. The temporal raphe is located in the temporal region of the retina 17 and its presence may have influenced our results. That is, pathological changes induced by BRVO (such as bleeding) may be more likely to affect the temporal region compared with other regions apart from the site of occlusion, because the nerve fibers of the temporal raphe penetrate the retinal layers so that retinal thickness and volume are easily influenced. Also, bleeding induced by BRVO might easily reach the temporal region along the retinal nerve fibers. We have previously reported that correlations for the nasal subfield were weaker than for other subfields, 10 and this might be because pathological changes induced by BRVO (such as bleeding) are less likely to affect the nasal region since it contains the papillomacular bundle with a high axon density. 18 Therefore, retinal thickness and volume could change more easily in the temporal raphe region compared with the nasal region. However, the reason why the improvement of retinal sensitivity and the percent changes of morphologic parameters were correlated in the temporal outer region remains unclear, so further investigation of the relation between improvement of macular function and changes of morphologic parameters in the temporal subfields after IVTA is needed.
To establish novel therapeutic strategies, evaluating the effects of treatment and retreatment is problematic and requires the establishment of appropriate guidelines that include both morphologic and functional parameters. Ideally, anatomical biomarkers should be correlated with functional changes during follow-up. As demonstrated in this study, the percent changes of morphological parameters (retinal thickness and retinal volume) and the improvement of retinal sensitivity were correlated in 2 subfields [superior inner (the site of occlusion) and temporal outer] according to multivariate analysis. Therefore, measurement of OCT parameters in these subfields may be recommended in addition to assessment of the fovea as part of routine clinical examination and the results could provide further insight into the pathophysiology of this retinal disease.
The present study had several limitations. One major drawback was the lack of a control group. Second, the patient population was small and this study investigated many parameters. However, there were no marked differences between the results of univariate and multivariate analyses (even if a variable was reduced by 1 from 7 variables and these analyses were performed, the statistical outcome did not show a great difference), indicating that the statistical model was appropriate. Third, the follow-up period was relatively short. Cataract progression may not have occurred simply because the follow-up period was too short in the present study. Longer follow-up might reveal cataract progression with an influence on macular function. Fourth, we could not evaluate the inner segment/outer segment ratio of the photoreceptor layer because we did not have access to spectral domain OCT. Fifth, a decrease of IOP may influence the prognosis of BRVO, but 2 patients who received beta-blockers for high IOP showed no differences of the functional changes after IVTA compared with the other patients (BCVA and retinal sensitivity in each of 9 subfields; all P>0.05). Finally, we did not separate superior and inferior occlusion. However, if the sites of bleeding were different in the superior and inferior regions, the decline of retinal function would be reversed. Also, we considered that correlations with functional-morphological parameters should be assessed by comparing regions with bleeding to those without bleeding. Therefore, to compare retinal functional-morphological changes between regions with and without bleeding, we converted inferior occlusion to superior occlusion by definition. As a result, the superior region was always the occluded region and the inferior region was the nonoccluded. We used 9 subfields rather than 3 to investigate the detailed differences of functional and morphologic changes after IVTA between the central and peripheral macular areas. Because of the above limitations, further investigations will be needed to clarify the relations among morphologic parameters and macular sensitivity in BRVO patients with macular edema.
In conclusion, IVTA can be effective for functional and morphological changes due to macular edema in patients with BRVO, and morphological improvement after IVTA might be useful for assessing the functional prognosis of these patients.
Footnotes
Author Disclosure Statement
No competing financial interests exist.
