Objective
To evaluate intravitreal injection of triamcinolone acetonide before laser panretinal photocoagulation (PRP) in the treatment of proliferative diabetic retinopathy.
Methods
This interventional case series included 9 patients with bilateral proliferative diabetic retinopathy. One eye received intravitreal triamcinolone before PRP (injected eye) and the other, PRP alone (control eye). The main outcome measures were the change in planimetric area of fluorescein leakage from retinal neovascularization and in central macular thickness on optical coherence tomography at 3, 6, 9, and 12 months. Secondary end points were change in vision, intraocular pressure, and cataract progression.
Results
All patients completed 9 months and 5 patients, 12 months of follow-up. Initial mean (SD) planimetric area of fluorescein leakage and central macular thickness were 7.22 (5.70) mm2 and 372.11 (91.88) μm in injected eyes and 9.08 (6.17) mm2 and 355.33 (115.23) μm in control eyes, respectively. At the 9- and 12-month intervals, the planimetric area of fluorescein leakage decreased by 86% and 88% in injected eyes and 33% and 50% in controls, respectively. Central macular thickness significantly decreased in injected eyes and increased in control eyes. Vision slightly improved in injected eyes and worsened in control eyes.
Conclusion
Intravitreal injection of triamcinolone before PRP may be useful in improving the effects of PRP in eyes with proliferative diabetic retinopathy by reducing neovascularization and macular thickening.
Proliferative diabetic retinopathy (PDR) is a leading cause of blindness. The Diabetic Retinopathy Study demonstrated that scatter laser panretinal photocoagulation (PRP) reduces the risk of severe visual loss by 50% or more in patients with high-risk PDR compared with no treatment.1 However, in patients with actively growing new vessels, long intervals between PRP sessions and the variable amount of time required for a favorable response may increase the incidence of complications due to the progression of PDR.2,3 In fact, neovascularization on and around the optic disc (NVD) and vitreous hemorrhage were found to be more frequently associated with severe visual loss despite PRP in the Diabetic Retinopathy Study and Early Treatment Diabetic Retinopathy Study (ETDRS), respectively.2,4 On the other hand, a single episode of PRP or shorter intervals between PRP episodes, although desirable in severe PDR and when the patient must travel long distances for treatment, are often associated with acute visual disturbances due to exudative choroidal, retinal detachment, and macular edema.5-8 Although the risks of visual acuity loss may be less if focal or grid laser of the edema precedes PRP, the delay of PRP is not always feasible owing to risks of vitreous hemorrhage or neovascular glaucoma.
The exact pathogenic mechanism for macular edema following PRP has not been determined. Recently, a series of studies suggested postlaser release of inflammatory factors, accumulation of leukocytes in the nonphotocoagulated posterior pole, and up-regulation of angiogenic growth factors, such as vascular endothelial growth factor, play a role in the pathogenesis of the edema.9-14
Recent studies have demonstrated the usefulness of intravitreal injection of triamcinolone acetonide in the reduction of inflammation,15-17 vascular permeability,18-20 fibrovascular proliferation,14,21,22 and macular thickening due to diffuse diabetic macular edema, at least in the short-term.23-26 The purpose of this prospective, controlled study was to evaluate the effectiveness of intravitreal triamcinolone injection plus PRP vs PRP alone on retinal neovascularization and macular thickening in patients with PDR.
Patients were included if they had bilateral PDR varying from mild proliferative PDR to high-risk PDR. To determine PDR severity, the same examiner (D.R.P.) graded the levels of retinopathy on the basis of slitlamp biomicroscopy and fluorescein angiography (FA). The patients could have clinically significant macular edema (CSME) on slitlamp contact lens biomicroscopy, as defined by the ETDRS.27 Glycated hemoglobin (HbA1c) levels had to be less than 9.5% and systolic and diastolic blood pressure, lower than 150 and 90 mm Hg, respectively. Patients with previous panretinal or focal or grid photocoagulation, signs of vitreomacular traction either on optical coherence tomography (OCT) or biomicroscopy, cataract extraction or lens implantation within the past 12 months, significant media opacities, and a history of glaucoma or ocular hypertension were excluded from the study. The tenets of the World Medical Association Declaration of Helsinki were followed. Each eligible patient was thoroughly informed about the study, both orally and in written form, and whoever agreed to participate signed a consent form.
Baseline data included age, sex, type and duration of diabetes mellitus, blood pressure measurements, and HbA1c levels. Patients also underwent a clinical examination including objective refraction, nonmasked Snellen best-corrected visual acuity (BCVA) testing, classification of lenticular status using the Lens Opacities Classification System III,28 applanation tonometry, fundus examination and photography, FA, and OCT.
To assess whether intravitreal injection of triamcinolone prior to PRP affected the outcome, one eye of each patient was selected at random and underwent intravitreal triamcinolone injection 10 to 15 days prior to initial PRP (injected eye), and the other eye was treated with PRP alone (control eye). If CSME was present at baseline, focal or grid laser therapy was performed only in control eyes at the first episode of PRP. Focal or grid laser treatment was also considered during follow-up in control eyes with treatable lesions on FA and either increased foveal thickening or persistent foveal thickening and decreased vision. The randomization sequence was generated from a number table.
Four milligrams of triamcinolone acetonide (Kenacort; Bristol-Myers Squibb, Sermoneta, Italy) in 0.1 mL were injected into the vitreous cavity (by the same surgeon, F.B.) with full asepsis under topical anesthesia. An eyelid speculum was used to stabilize the eyelids. The injection was performed 4 mm posterior to the limbus, through the inferior pars plana, with a 30-gauge needle. At the end of the injection, the surgeon verified central retina artery perfusion and the patient's light perception.
Scatter PRP was performed using a diode-pumped, solid-state, 561-nm, yellow laser (Lumenis Ltd, Yokneam, Israel) in 3 sessions approximately 1 week apart, in both injected and control eyes. In the first session, several rows of burns were positioned far from the posterior pole and extended for 360° with the quadraspheric fundus lens. In the second session, laser burns were applied closer to the posterior pole, leaving the remainder of the periphery for the third session, in which the Goldmann 3-mirror lens was used. The size of the spots on the retina was between 250 to 1000 μm, and the power and duration of the applications were adjusted so that a gray-white lesion was performed. The number of spots in each session was around 400 to 600, and the mean (SD) total number of burns after completion of the treatment was 1293 (257) in injected eyes and 1465 (587) in control eyes. The mean (SD) power of the spots in injected eyes was 319 (57) mW and slightly but significantly less than that measured in control eyes, which was 390 (67) mW (P = .008, bilateral Wilcoxon test for paired samples). Topical anesthesia was used in all cases, and all patients were treated by the same specialist (F.B.).
The main outcome measures were the change in retinal neovascularization defined as the change in the area of vitreous leakage from NVD and new vessels elsewhere in the late phase of FA and the change in central macular thickness (CMT) on OCT at 3, 6, 9, and 12 months from baseline. The leakage and CMT were also assessed 10 to 15 days after intravitreal triamcinolone administration in the injected eyes prior to initial PRP to evaluate the response to intravitreal triamcinolone administration alone.
The planimetric area of fluorescein leakage was measured on digital angiograms captured with the Topcon retinal camera (model 50IX; Topcon, Tokyo, Japan) with IMAGEnet 2.11 software. These angiograms consisted of 10 50° fields, fields 1 and 2 being centered on the macula and disc, respectively, and fields 3 to 10 imaging the superonasal, nasal, inferonasal, inferior, inferotemporal, temporal, superotemporal, and superior quadrants. All angiograms were taken following the same photographic plan. An injection of a 20% fluorescein solution (4-6 seconds) in a 5-mL syringe and a 20-gauge needle was performed at all visits by the same nurse. The digital images were imported into an Image Tools program (Topcon) and the planimetric area of fluorescein leakage was measured by tracing around the borders of the hyperfluorescence from NVD and new vessels elsewhere with the appropriate tool by the same masked examiner (P.M.).
Central macular thickness was defined as the average thickness of the central macular region 1000 μm in diameter, centered on the patient's foveola, and automatically measured by the Retinal Map analysis protocol (Humphrey Instruments Inc, Dublin, Calif). Optical coherence tomography was performed using the Fast Macular Thickness Mapping Protocol of the commercially available Stratus OCT (Carl Zeiss Meditec, Dublin) with version 2.0 software. Good reproducibility of this protocol has been recently demonstrated by our group.29 The normal mean (SD) value for CMT is 209 (22) μm. Increased CMT at baseline was established if CMT was greater than 250 μm.
Secondary end points were change in BCVA, intraocular pressure, and progression of cataract. Follow-up visits were performed 10 to 15 days after intravitreal injection of triamcinolone and at 3, 6, 9, and 12 months from baseline. Lens status evaluation was performed only at the 6- and 12-month follow-up visits.
For statistical analysis, paired series were compared, each treated eye being paired with the untreated eye of the same patient. Statistical analyses were performed using the bilateral Wilcoxon signed rank test for paired data. The null hypothesis was rejected for P values <.05. Analyses of visual acuity were performed by converting Snellen visual acuity measurements to log minimum angle of resolution (logMAR) equivalents. Results are presented in both logMAR units, which were used for analysis, and equivalent Snellen visual acuity notation.
Between January and September 2004, 9 patients (18 eyes) with mild to high-risk PDR were included in the study (8 men and 1 woman). In this preliminary report, we give the results for the 9 patients who had a follow-up of at least 9 months. Five of them were followed up for 12 months. The mean (SD) age of patients was 47.5 (2.3) years (range, 27-60 years). Three patients had type 1 diabetes and 6, type 2. The mean (SD) duration of diabetes was 15.8 (5.6) years (range, 8-24 years). All eyes were phakic. The clinical characteristics of the 18 enrolled eyes are presented in Table 1. Before intravitreal injection of triamcinolone, the mean (SD) HbA1c level was 8.2% (0.6%) (range, 7.2%-9%), and mean (SD) systolic and diastolic blood pressure were, respectively, 131.11 (8.2) mm Hg (range, 140-120 mm Hg) and 79.44 mm Hg (6.8) (range, 70-90 mm Hg). Fifteen eyes had CSME at the contact lens slitlamp examination.
Planimetric area of fluorescein leakage from new vessels and cmt
Table 2 summarizes the results for injected and control eyes. Mean (SD) planimetric areas of fluorescein leakage and CMTs of injected and control eyes at baseline and at 3, 6, 9, and 12 months after injection are given in Table 3. Ten to 15 days after injection, the mean (SD) planimetric area of fluorescein leakage and CMT of injected eyes were reduced by 52% to 3.09 (2.20) mm2 and by 31% to 244.56 (24.92) μm, respectively. In addition, FA showed a substantial regression of perivascular staining from large retinal vessels traversing areas of capillary nonperfusion in these eyes.
Relative decreases in planimetric area of fluorescein leakage at 3, 6, 9, and 12 months were 74%, 84%, 86%, and 88% in injected eyes and 19%, 22%, 33%, and 50% in control eyes, respectively (P = .01, .01, .02, and .04). One of the 9 injected eyes (patient 2) showed a complete regression of the leakage from new vessels at 3 months; 3 additional eyes (patients 1, 8, and 9), at 6 months; and 1 other eye, at 12 months (patient 3). Patient 1 is shown in the Figure. In the control group, only 1 eye showed a complete regression of leakage at 9 months (patient 9).
The CMT decreased by 31%, 28%, 24%, and 5% in injected eyes and increased by 12%, 17%, 7%, and 10% in control eyes at 3, 6, 9, and 12 months, respectively (P = .01, .01, .01, and .20).
For both injected and control eyes, mean (SD) LogMAR units and the equivalent Snellen BCVA at baseline and at 3, 6, 9, and 12 months are presented in Table 3. Injected eyes gained 1.2, 0.9, 0.7, and 0.2 Snellen lines and control eyes lost 1.7, 1.2, 1.7, and 2.8 Snellen lines during the same intervals, respectively (P = .01, .01, .03, .02, and .68).
The mean (SD) values for intraocular pressure in both groups are given in Table 3. In 4 of the 9 injected eyes, intraocular pressure exceeded 21 mm Hg at 3 months and in 1 case, at 6 and 9 months. However, in all cases it was controlled by topical medications. The maximal intraocular pressure was 34 mm Hg. No cataract progression or other injection-related complications were observed.
The preliminary results of this prospective study show efficacy of intravitreal injection of triamcinolone as adjunctive treatment to PRP on the regression of retinal new vessels and resolution of macular edema in patients with PDR. Both leakage due to retinal new vessels and macular thickening were significantly reduced in the combined treatment group, compared with control eyes. In addition, BCVA improved in injected eyes while it was slightly reduced in control eyes at 9 months.
Panretinal photocoagulation is the mainstay for the treatment of PDR, and its suppressive effect on retinal neovascularization has been well documented.1,3,5,30 However, substantial regression of new vessels may take weeks after completion of PRP, and in up to one third of cases, new vessels continue to grow despite initial PRP.5,30-32 In these cases, vitreous hemorrhage may induce visual loss and prevent complete laser. Moreover, macular edema may increase after PRP and cause transient or persistent visual loss.9-11
A growing number of studies are supporting the evidence of a corticosteroid action on reducing blood-retinal barrier breakdown and angiogenesis in diabetic retinopathy.33-35 Our group demonstrated that intravitreal injection of triamcinolone allowed PRP to be applied without worsening of macular edema and progression of retinopathy in a young patient with florid PDR.36 A similar beneficial response on leakage and macular thickening in eyes with PDR has been described by Brooks et al14 in a prospective study aimed to investigate the role of growth factors and chemokines before and after intravitreal injection of triamcinolone in the progression of diabetic retinopathy. Recently, Zacks and Johnson37 described the effectiveness of combined intravitreal injection of triamcinolone and PRP in preventing exacerbation of macular edema in patients with concomitant CSME and PDR.
To test the advantages of intravitreal injection of triamcinolone prior to PRP in patients with PDR, we used the paired eyes of patients with bilateral PDR to avoid possible bias due to systemic factors. The dose of the injected drug (4 mg) and the interval between injection and initial PRP were empirically chosen on the basis of the results of previous studies describing pharmacokinetics and pharmacodynamics of intravitreal triamcinolone.38,39 To determine the effect of intravitreal injection of triamcinolone on actively growing new vessels, we chose the change in vitreous leakage from retinal neovascularization as our primary outcome. The detection of NVD and new vessels elsewhere on FA allowed the use of a systematic morphometric approach to quantify and monitor the area of leaking new vessels over time. To determine the effect of intravitreal injection of triamcinolone on macular edema, we measured the change of retinal thickening with OCT.40,41
Both the regression of neovascularization and decrease of retinal thickening occurred in all injected eyes as soon as 10 to 15 days after intravitreal injection of triamcinolone prior to initial PRP. In particular, the regression of neovascularization continued up to 3, 6, and 9 months persisting through 12 months in the 5 eyes that reached the 12-month follow-up visit. In addition, in 4 of these eyes, all leakage completely disappeared at 6 months. A decrease in leakage from new vessels also occurred in control eyes throughout the entire follow-up period, but at a much slower rate. Mean CMT markedly decreased during the first 3 months and then stabilized in all injected eyes at 6 and 9 months, while it remained at higher than normal values at all visits in the control group. In 2 of the 5 injected eyes completing the 12-month follow-up visit, macular edema recurred. We also observed a significant difference between injected and control eyes with regard to the changes in visual acuity. After a marked increase for the first 3 months, visual acuity tended to stabilize at the end of the follow-up in injected eyes. In control eyes, visual acuity decreased during the first 3 months and remained lower than at the start of the study at 9 and 12 months.
Although the reduction in foveal thickness might have partly improved visual acuity in injected eyes, the entity of the improvement was not correlated with the amount of reduction in CMT, similar to the findings by Larsson et al.42 This suggests that other variables, such as the duration of the edema, may influence the functional response to intravitreal triamcinolone independently from its effect on the edema. Other explanations are additional actions of steroids, such as improving macular perfusion by reducing inflammation and leukostasis or by acting on retinal glial cells or photoreceptors.43
Similarly, in the control eyes, the progressive decrease in vision over time can be only partly explained by the increase in macular thickness. This may be owing to the relatively good initial visual acuity in eyes that “already” have a significant macular thickening prior to PRP, probably owing to a presumed short duration of the edema. In particular, 2 patients with severe thickening at baseline (528 and 463 μm) and relatively good vision were 27 and 30 years of age. The progressive decrease in vision might have occurred because of the persistence, rather than worsening, of the edema during the 9- to 12-month follow-up period. The presence of CSME at baseline in most of the eyes may have contributed to the decrease of visual acuity after PRP, similar to the outcome observed in a study by Shimura et al,8 where the decrease in visual acuity following PRP occurred only in the eyes with thicker macula at baseline.
No injection-related complication occurred. Intraocular pressure rose higher than 21 mm Hg in 4 of 9 injected eyes and was controlled by topical medication, and no cataract progression was observed.
The current study has several limitations, including a relatively small sample size, a relatively short duration of follow-up, and visual acuity measured on a Snellen as opposed to an ETDRS chart by a nonmasked examiner. However, the large difference in the quantitative morphologic outcomes between groups and the trend toward improvement in BCVA in injected eyes found at 9 months confirms our hypothesis that at least some eyes with PDR, such as those with preexisting macular edema or rapidly growing new vessels, may truly benefit from intravitreal injection of triamcinolone. Moreover, by increasing the chance of preserving a good initial visual acuity, intravitreal injection of triamcinolone prior to PRP may also improve the patient's compliance to treatment and follow-up visits.
In conclusion, intravitreal injection of triamcinolone seems a promising adjuvant treatment to PRP in that it may allow the achievement of a full, extensive PRP while minimizing the risk for exudative complications, progression of PDR, vitreous hemorrhage, and decreased vision, thus improving tolerance to PRP by patients. Although no serious complications of intravitreal injection of triamcinolone occurred in our series, further studies are needed to assess the efficacy and safety of intravitreal triamcinolone injection as adjunctive treatment to PRP in the treatment of PDR.
Correspondence: Francesco Bandello, MD, Department of Ophthalmology, University of Udine, Piazzale Santa Maria della Misericordia, 33100 Udine, Italy (francesco.bandello@uniud.it).
Submitted for Publication: May 23, 2005; final revision received July 28, 2005; accepted August 10, 2005.
Financial Disclosure: None.
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