Is the Effect of Intravitreal Triamcinolone Acetonide on Diabetic Macular Edema Dose-Dependent?

Abstract

Purpose:

To determine whether the effect of intravitreal triamcinolone acetonide in diffuse diabetic macular edema is dose-dependent regarding the velocity and duration of macular edema reduction, visual acuity improvement, and induction of predictable complications.

Methods:

This clinical prospective study included 32 consecutive patients (32 eyes) with diffuse diabetic macular edema. All patients had visual acuity, fluorescein angiogram, and optical coherence tomography performed at the initial visit (baseline). Single triamcinolone acetonide injection was applied intravitreally in different high doses using sterile technique followed by timolol-maleate 0.5%/acetazolamide fixed combination eyedrops twice a day for 6 consecutive months. Macular edema, intraocular pressure, and best-corrected distance visual acuity were reviewed after 5 days and 1, 3, and 6 months.

Results:

Intraocular pressure did not change significantly during 6 months and was maintained within normal levels in all patients using prescribed antiglaucoma therapy. Best-corrected distance visual acuity and macular edema were better than preoperatively even 6 months after treatment while the highest improvement was recorded 1 month after treatment. There was a slight correlation of macular edema reduction and triamcinolone dose, especially in central 1-mm diameter zone 6 months post triamcinolone acetonide intravitreal injection, but it was not statistically significant.

Conclusions:

Triamcinolone intravitreal injection is a relatively safe, inexpensive, and effective method used for diabetic macular edema reduction but its effect is not proven to be dose-dependent, at least in 10-32 mg dose range. Macular edema reduction rate correlated significantly with preoperative edema.

Keywords

Diabetic retinopathy Intraocular pressure Intravitreal injections Macular edema Triamcinolone acetonide

Introduction

Diabetic macular edema (DME) is one of the most common causes of vision loss in patients with diabetes (1). It can be either focal or diffuse in distribution. Focal DME is often associated with circinate rings of hard exudates (lipoprotein deposits) around leaking microaneurysms. Diffuse DME represents more extensive breakdown of the blood-retinal barrier, with leakage from both microaneurysms and retinal capillaries. Systemic arterial hypertension may also contribute to accumulation of fluid in DME according to Starling and LaPlace laws (1). Diagnostic methods used in DME detection consist of funduscopy, preferably on slit-lamp with narrow beam, and ancillary examinations. Fluorescein angiography is utilized to detect disruption of the blood—retinal barrier in order to determine the presence and extent of macular edema. The most commonly used technique in objective measurement of DME extent is optical coherence tomography (OCT), which is useful in the diagnostics and follow-up of DME. Mean normal retinal thickness depends on the OCT device used and the central circular 1 mm diameter measures 182 ± 42 μm on OCT Copernicus, Optopol (2). Central macular volume is calculated using central macular thickness value. Macular edema usually affects macular function, which can be tested using visual acuity (VA) and contrast sensitivity tests. Regarding treatment options for DME, stepwise approach is optimal. In chronic and persistent cases of DME, the use of pharmaceutical agents and surgical management are described in the literature. Nonsteroidal anti-inflammatory drugs, carbonic anhydrase inhibitors, and steroids are widely used, and lately anti—vascular endothelial growth factor (VEGF) treatment has also been introduced as a DME treatment option (3, 4). In persistent cases of DME, surgical methods like laser photocoagulation and vitrectomy should be considered (5-8). Steroids inhibit the production of prostaglandins, but at a higher level in the biochemical pathway, by inhibiting the enzyme phospholipase A2, which catalyzes the conversion of membrane lipids to arachidonic acid. By this process, steroids inhibit the formation of both prostaglandins and leukotrienes (9). Corticosteroids may be administered topically, by periocular injection, orally, intravitreally, and parenterally. In treatment of DME, intravitreal injection of triamcinolone acetonide (IVTA) or anti-VEGF agents have become standard treatments that provide a time-limited effect on edema regression and necessitate repeated injections. Miyamoto et al showed that intravitreal triamcinolone acetonide (TA) reduces macular edema as early as 1 hour after injection (10). Some authors suggested a dose-dependent effect of TA on duration and extent of DME regression in patients with diffuse diabetic macular edema who received intravitreal TA (11-13). Regarding refractory diabetic macular edema, intravitreal triamcinolone was shown to effectively reduce foveal thickness and improve visual acuity in the short term, but with extended follow-up, the number of recurrences and steroid-related complications increase (14). The most common complications of intraocular triamcinolone are elevated intraocular pressure (iatrogenic glaucoma) and cataract formation (15). Risks of intraocular injection like endophthalmitis, retinal detachment, and hemorrhages should also be taken into consideration. Triamcinolone acetonide intravitreal injection was shown to improve VA and reduce central macular thickness (CMT) more than macular laser grid photocoagulation within the first 6 months so intravitreal TA injection could be used as primary treatment in patients with cystoid macular edema (6, 8). Corticosteroid-based intravitreal implants have been developed to provide a sustained release and longer lasting drug in order to make repetition of the intravitreal injections less frequent.

Methods

This clinical prospective study included 32 eyes (32 patients) with diffuse DME. A total of 22 men and 10 women aged 63 ± 9 years (range 40-77 years) were enrolled in the study. The patients were randomly treated with 10 mg to 32 mg of TA intravitreally, 17 ± 6 mg on average (Fig. 1). Assessment of DME was based on ophthalmoscopic examination, fluorescein angiography, and OCT of the macular region. Visual acuity was determined using Snellen visual acuity chart. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry (GAT). The CMT and central macular volume in 1-, 3-, and 6-mm diameter zone were measured using spectral-domain OCT (SOCT Copernicus, Optopol). None of the eyes received any intravitreal injection or underwent retinal laser photocoagulation or surgical treatment before inclusion into the study. Patients with other macular disorders were excluded from the study. Prior to intravitreal injection, 40 mg/1 mL TA suspension was triple filtered respecting aseptic conditions using 0.2-μm filter unit and thus concentrated to 40 mg/0.4 mL. Topical anesthesia was achieved using 0.5% tetracaine hydrochloride eyedrops. Povidone iodine 10% solution was instilled and left for 3 minutes in conjunctival sac. Anterior chamber paracentesis at temporal side was performed to lower IOP. Filtered and concentrated TA was slowly injected transsclera into the vitreous on pars plana using a 30-G × 12.7 mm needle, until digitally examined normal corneal rigidity (IOP) was reached. Thus, patients received random doses of IVTA. After the injection of TA, patients were given tobramycin solution eyedrops and ointment for 5 days and a fixed combination of dorzolamide hydrochloride-timolol maleate ophthalmic solution twice a day for 6 months as a prophylactic treatment for ocular infection and IOP raise, respectively. Follow-up consisted of best-corrected distance visual acuity (BCDVA) examination, CMT, and central macular volume (1, 3, and 6 mm zone) measurements at 1, 3, and 6 months postoperatively. The GAT and clinical examinations were performed at days 1 and 5 and then 1, 3, and 6 months post IVTA. All measurements were performed by the same experienced examiner. During follow-up, if ocular surgery or other ocular treatment of diabetic retinopathy had been performed, the patients were regarded as dropped at follow-up. Descriptive statistical methods were used to present the data. Group differences and correlations were analyzed using paired-samples Student t test and Pearson correlations, respectively (p<0.05 was considered significant). Analyses were conducted in SPSS Statistics 17.0.

Fig. 1

The distribution of patients according to intravitreal triamcinolone acetonide (IVTA) dose.

Results

The distribution of patients according to received dose of TA is shown in Figure 1.

The CMT in 1-mm diameter zone was lower than preoperative 1, 3, and 6 months after IVTA. The best effect regarding CMT was 1 month after IVTA, with gradual thickening of macula 3 and 6 months post IVTA (Tab. I, Fig. 2). Postoperative CMT (1, 3, and 6 months after IVTA [Tab. II]) significantly correlated with preoperative CMT.

Table I

PREOPERATIVE AND POSTOPERATIVE BEST-CORRECTED DISTANCE VISUAL ACUITY ON SNELLEN CHART, CENTRAL MACULAR THICKNESS, CENTRAL MACULAR VOLUME, AND INTRAOCULAR PRESSURE VALUES (N = 32)

	Preoperative	1^st day postoperatively	5^th day postoperatively	1 month postoperatively	3 months postoperatively	6 months postoperatively
BCDVA	0.30 ± 0.04 (0.01-0.90)			0.38 ± 0.05 (0.02-1.00)	0.39 ± 0.06 (0.02-1.00)	0.32 ± 0.06 (0.01-1.00)
CMT in central 1-mm diameter zone (μm)	495 ± 31 (181-942)			318 ± 21 (147-634)	353 ± 23 (174-672)	398 ± 32 (196-828)
CMV in central 1-mm diameter zone (mm³)	0.39 ± 0.02 (0.14-0.74)			0.25 ± 0.02 (0.12-0.50)	0.28 ± 0.02 (0.14-0.53)	0.31 ± 0.03 (0.15-0.65)
CMV in central 3-mm diameter zone (mm³)	3.26 ± 0.16 (1.73-5.57)			2.37 ± 0.10 (1.64-4.03)	2.56 ± 0.12 (1.76-4.55)	2.77 ± 0.17 (1.66-4.95)
CMV in central 6-mm diameter zone (mm³)	10.73 ± 0.40 (6.65-16.06)			8.69 ± 0.26 (6.21-13.10)	8.86 ± 0.34 (6.40-14.77)	9.49 ± 0.48 (5.94-14.98)
IOP (mm Hg)	16.1 ± 0.56 (11.0-25.0)	14.2 ± 0.6 (7.0-19.0; 22.0^a)	14.1 ± 0.5 (10.0-16.0)	16.8 ± 0.6 (13.0-21.0; 24.0^a)	16.6 ± 1.2 (9.0-21.0; 43.0^a)	15.4 ± 0.5 (9.0-19.0; 21.0^a)

BCDVA = best-corrected distance visual acuity; CMT = central macular thickness; CMV = central macular volume; IOP = intraocular pressure.

Data are listed as average ± standard equation of mean (minimum and maximum levels).

IOP in a patient not using prescribed antiglaucoma eyedrops.

Table II

PAIRED-SAMPLES CORRELATIONS OF CENTRAL MACULAR THICKNESS PREOPERATIVELY WITH CENTRAL MACULAR THICKNESS 1, 3, AND 6 MONTHS AFTER INTRAVITREAL TRIAMCINOLONE ACETONIDE INJECTION IN CENTRAL 1-MM DIAMETER ZONE (N = 32)

Paired samples	N	Pearson correlation	Significance level
Preoperative CMT and CMT 1 month post IVTA	32	0.366	0.039^a
Preoperative CMT and CMT 3 months post IVTA	32	0.417	0.018^a
Preoperative CMT and CMT 6 months post IVTA	32	0.476	0.006^a

CMT = central macular thickness; IVTA = intravitreal triamcinolone acetonide.

p<0.05.

Fig. 2

Central macular thickness (CMT) in central 1-mm diameter macular zone prior to and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) injection. Results are graphically shown as average ± standard equation of mean.

The central macular volume was reduced in 1, 3, and 6 mm diameter of central macular zone 1, 3, and 6 months post IVTA compared to pretreatment values with the greatest reduction of central macular volume 1 month after IVTA treatment (Tab. I, Figs. 3-5).

Fig. 3

Central macular volume (CMV) in central 1-mm macular zone prior to and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) injection. Results are graphically shown as average ± standard equation of mean.

Fig. 4

Central macular volume (CMV) in central 3-mm macular zone prior to and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) injection. Results are graphically shown as average ± standard equation of mean.

Fig. 5

Central macular volume (CMV) in central 6-mm macular zone prior to and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) injection. Results are graphically shown as average ± standard equation of mean.

The BCDVA improved slightly 1 month (0.38 ± 0.30) and even more 3 months (0.39 ± 0.29) after IVTA treatment, but decreased at 6 months (0.32 ± 0.30) post IVTA, reaching a level slightly above the pretreatment values (0.30 ± 0.04) (Tab. I, Fig. 6).

Fig. 6

Best-corrected distance visual acuity (BCDVA) on Snellen chart prior to and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) treatment. Results are graphically shown as average ± standard equation of mean.

The IOP levels generally maintained below 22 mm Hg during follow-up period in all patients (eyes) with antiglaucoma eyedrops. Minor IOP fluctuation was observed. The lowest values were at 1 and 5 days post IVTA application and the highest at 1 and 3 months after IVTA application (Tab. I, Fig. 7). Higher IOP levels were measured in some patients who did not use recommended antiglaucoma eyedrops (Tab. I) and shortly after their reintroduction the IOP reduced to normal levels.

Fig. 7

Intraocular pressure (IOP) values prior to and 1 day (d), 5 d, and 1, 3, and 6 months (m) after intravitreal triamcinolone acetonide (IVTA) injection. Results are graphically shown as average ± standard equation of mean.

Low degree of negative correlation was observed between initial BCDVA and CMT in central 1-mm diameter zone 1, 3, and 6 months after IVTA application. We found low degree of negative correlation between initial CMT in central 1-mm diameter zone and CMT in the same zone 1, 3, and 6 months after IVTA (Tab. II). High degree of negative correlation was observed between initial and 1, 3, and 6 months post IVTA central macular volume in 1-, 3-, and 6-mm diameter central zone (Tab. III). There was positive correlation of TA dose with CMT (macular edema) reduction after 1, 3, and 6 months post IVTA, but it was not statistically significant (p = 0.63, p = 0.43, and p = 0.07, respectively). No correlation of TA dose with IOP levels during the follow-up period was observed. Statistically insignificant positive correlations of IVTA dose with the BCDVA improvement, macular edema reduction, and the duration of macular edema reduction were found, although there was borderline correlation of TA dose and CMT and central macular volume reduction rate in central 1-mm diameter zone 6 months after IVTA compared to initial levels (p = 0.068 and p = 0.064, respectively). Slight transient sectorial subconjunctival hemorrhage at the injection site was the only side effect to the administered therapy we noted in our study, concerning all the other possible injection-related or late complications that might be related to intravitreal therapy.

Table III

PAIRED-SAMPLES CORRELATIONS OF PREOPERATIVE CENTRAL MACULAR VOLUME WITH CENTRAL MACULAR VOLUME 1, 3, AND 6 MONTHS AFTER INTRAVITREAL TRIAMCINOLONE ACETONIDE INJECTION IN CENTRAL 1-, 3-, AND 6-MM DIAMETER ZONE (N = 32)

	Paired samples	N	Pearson correlation	Significance level
CMV (1-mm diameter zone)	Preoperative CMV and 1 month post IVTA CMV	32	0.373	0.036^a
	Preoperative CMV and 3 months post IVTA CMV	32	0.431	0.014^a
	Preoperative CMV and 6 months post IVTA CMV	32	0.472	0.006^a
CMV (3-mm diameter zone)	Preoperative CMV and 1 month post IVTA CMV	32	0.415	0.018^a
	Preoperative CMV and 3 months post IVTA CMV	32	0.312	0.082^a
	Preoperative CMV and 6 months post IVTA CMV	32	0.499	0.004^a
CMV (6-mm diameter zone)	Preoperative CMV and 1 month post IVTA CMV	32	0.527	0.002^a
	Preoperative CMV and 3 months post IVTA CMV	32	0.501	0.004^a
	Preoperative CMV and 6 months post IVTA CMV	32	0.476	0.008^a

CMV = central macular volume; IVTA = intravitreal triamcinolone acetonide.

p<0.05.

Discussion

Intravitreal injection of TA, one of the treatment options for DME, was shown to effectively reduce foveal thickness and improve visual acuity in the short term, but with extended follow-up, a number of recurrences and steroid-related complications, like increased IOP, may occur. After intravitreal triamcinolone injection, IOP elevation may occur as early as 1 day until as late as 12 weeks in 20%-65% of patients (16). Jonas et al found that 41% of eyes developed a maximal IOP higher than 21 mm Hg after high-dose (20-25 mg) IVTA (17). Increased IOP after IVTA can damage retinal nerves and small retinal and choroidal vessels, especially in diabetic patients, who are more prone to vascular damage (16, 18). Although paracentesis carries a potential risk of infection and lens damage, we used paracentesis to create extra volume and avoid ocular damage by possible IOP rise because we injected higher than usual IVTA doses. Lin et al recommend paracentesis before IVTA to avoid immediate post IVTA IOP rise and drug reflux (19). Chang and Chung suggested that routine anterior chamber paracentesis is inappropriate due to the brief immediate postoperative IOP elevation after IVTA, which normalizes within 15 minutes after IVTA (18). In all our patients, IOP maintained mainly within normal levels during 6 months of follow-up, which is surely due to antiglaucoma medications prescribed routinely immediately after IVTA (Fig. 7).

The mean elimination half-life of TA was 18.6 days in nonvitrectomized patients after a single IVTA (20). Diabetic Retinopathy Clinical Research showed that 4 mg of TA intravitreally has better effect on DME regression and visual acuity improvement compared to 1 mg of TA (12). Comparing single 4 mg and 20 mg of IVTA in DME, Jonas stated that the duration of a therapeutic effect of TA is dose-dependent, regarding visual acuity improvement and edema reduction (13). In a case study of 27 eyes, Spandau et al stated that maximal increase in visual acuity and duration of the IVTA therapeutic effect, but not increase in IOP, significantly correlated with the dosage of TA in the 2 to 13 mg dose range (21). Jonas et al used high TA doses (20-25 mg) in patients with DME and gained maximal average increase in BCDVA of 0.11 on Snellen chart 4 months after IVTA and maintained better than baseline levels (0.15 on Snellen chart) for 10 months after IVTA (17). Having better baseline visual acuity than the patients of Jonas et al (17) and being treated with lower average TA doses (10-32 mg, average 17 ± 6 mg) (Fig. 1), our patients gained maximal average increase in BCDVA of 0.09 on Snellen chart 3 months after IVTA and BCDVA better than baseline (0.30 on Snellen chart) for at least 6 months after IVTA (Tab. I, Fig. 6), which is comparable to Jonas et al (17). We found positive correlations of TA dose (10-32 mg) with BCDVA improvement, duration, and level of macular edema reduction, but they were not statistically significant.

In conclusion, IVTA is an effective transient treatment option for diffuse DME, regarding edema regression and visual acuity improvement. Greater initial volume of DME implies greater edema reduction after IVTA application. In our study, the effect of IVTA on BCDVA, macular edema reduction, or duration of edema reduction measured by CMT and central macular volume is not dose-dependent, at least not in 10-32 mg TA dose range during 6 months of follow-up. So it seems there is no need to use doses higher than 10 mg of IVTA and thus the need for paracentesis decreases. The IOP values measured during 6 months post IVTA were within the normal range in all patients receiving additional prophylactic antiglaucoma therapy, so we would recommend this regimen for all patients being treated with high-dose IVTA. Central macular volume in central 6-mm diameter zone showed better correlation with pretreatment central macular volume values compared to CMT and central macular volume in central 1 mm and 3 mm zone during 6 months post IVTA application and could be of more value than CMT in follow-up of edema regression in diffuse DME after IVTA (Tab. III).

Footnotes

Acknowledgement

The authors thank Miroslava Kičić, Martina Medved, and Marina Vrhovec, University Hospital Sveti Duh, Zagreb, Croatia.

Financial Support: No financial support was received for this submission.

Conflict of Interest Statement: None of the authors has conflict of interest with this submission.

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