|Year : 2017 | Volume
| Issue : 3 | Page : 149-153
Combined intravitreal bevacizumab and posterior sub-Tenon’s triamcinolone acetonide injections for persistent diabetic macular edema
Mona M Aly, Abd Elmagid M Tag Eldin
Department of Ophthalmology, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
|Date of Submission||04-Mar-2017|
|Date of Acceptance||16-May-2017|
|Date of Web Publication||17-Oct-2017|
Mona M Aly
Department of Ophthalmology, Faculty of Medicine, Al-Azhar University, Nasr City 11754, Cairo
Source of Support: None, Conflict of Interest: None
Purpose The aim of this study was to investigate the effect of posterior sub-Tenon’s triamcinolone acetonide injection (PSTI) in conjunction with intravitreal bevacizumab for the treatment of persistent diabetic macular edema (DME).
Patients and methods In a prospective, nonrandomized, interventional study, 30 eyes of phakic diabetic patients were diagnosed with persistent DME after being treated with at least two intravitreal bevacizumab injections. Eyes with a residual central macular thickness more than 300 µm were administered PSTI of 40 mg triamcinolone acetonide in conjunction with intravitreal bevacizumab. Best-corrected visual acuity, intraocular pressure, and foveal thickness were measured.
Results Significant improvements in the mean central macular thickness measurements were observed at the 1-month and 3-month follow-up visits. Best-corrected visual acuity improvement in eyes with extrafoveal hard exudates (83.3%) was significant at the follow-up intervals of 1 and 3 months, although it was insignificant in eyes with subfoveal hard exudates (16.7%).
Conclusion The combined use of intravitreal bevacizumab and PSTI of triamcinolone acetonide was effective in treating persistent DME.
Keywords: diabetic macular edema, intravitreal bevacizumab, optical coherence tomography, sub-Tenon’s injection, triamcinolone acetonide
|How to cite this article:|
Aly MM, Tag Eldin AM. Combined intravitreal bevacizumab and posterior sub-Tenon’s triamcinolone acetonide injections for persistent diabetic macular edema. Delta J Ophthalmol 2017;18:149-53
|How to cite this URL:|
Aly MM, Tag Eldin AM. Combined intravitreal bevacizumab and posterior sub-Tenon’s triamcinolone acetonide injections for persistent diabetic macular edema. Delta J Ophthalmol [serial online] 2017 [cited 2022 Jan 26];18:149-53. Available from: http://www.djo.eg.net/text.asp?2017/18/3/149/216920
| Introduction|| |
Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients . The Early Treatment of Diabetic Retinopathy Study has indicated that focal/grid laser photocoagulation for clinically significant macular edema effectively reduced the risk of moderate vision loss. Later studies showed that grid laser photocoagulation has limited efficacy and may cause decreased vision because of progressive macular scar and subretinal fibrosis . As macular laser photocoagulation has shown poor results, other treatment modalities including intravitreal triamcinolone acetonide (TA), pars plana vitrectomy, and antivascular endothelial growth factor (VEGF) therapy have been evaluated . The pathogenesis of DME has not been fully elucidated as it is caused by complex pathological processes with many contributing factors . VEGF is an important mediator of blood–retinal barrier breakdown, which leads to fluid leakage and development of macular edema , making it an important target for pharmaceutical intervention . Intravitreal anti-VEGF agents have revolutionized the treatment of DME by demonstrating visual improvement in multiple randomized clinical trials . As corticosteroids decrease the release of prostaglandins and inhibit the expression of the VEGF gene, therefore, these anti-inflammatory and anti-VEGF properties may be able to reduce breakdown of the blood–retina barrier . DME is a chronic disease with variable response and clinical manifestations during the entire life of the affected patients . Any form of intravitreal injection is associated with the potential risk of endophthalmitis, iatrogenic retinal tear, and detachment . It does not appear reasonable that a single treatment may be enough for the entire course of the disease . Different combined modalities of treatment aim to find a way of prolonging the beneficial effects of the pharmacological agents . Therefore, the management of DME is complex and often multiple treatment approaches are needed .
The purpose of this study was to assess the effect of using posterior sub-Tenon’s injection (PSTI) of TA combined with intravitreal injection of anti-VEGF ‘bevacizumab’ on the same operative session as a treatment option for persistent DME.
| Patients and methods|| |
This was a prospective, nonrandomized, interventional study. Thirty eyes of 17 patients of both sexes with persistent diffuse DME were included in the study. Eyes with persistent increase in central macular thickness (CMT) after repeated intravitreal injections of bevacizumab (≥2) at 1-month intervals were included. Eyes with a residual CMT more than 300 µm were offered PSTI of TA in conjunction with intravitreal bevacizumab injection.
Exclusion criteria were significant media opacity precluding retinal view, presence of traction on the macula evidenced by optical coherence tomography (OCT), previous ocular surgery, history of previous treatment by laser photocoagulation, intravitreal or PSTI of TA, glaucoma or ocular hypertension, history of uveitis episodes, any chorioretinal disease (other than diabetic retinopathy), ischemic maculopathy or diabetic papillopathy, and contraindications for bevacizumab or TA.
The systemic condition of all included patients was under control (whether their blood glucose level with oral hypoglycemic drugs or insulin, blood pressure, renal functions, or their general condition).
All patients were given a detailed explanation of the treatment and the potential risks and benefits. Informed consent was obtained before the interventions and the study was approved by the local ethics committee. Each patient received a complete ophthalmic examination at baseline and at every follow-up visit, which included best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurement using the Goldman applanation tonometry, and slit-lamp biomicroscopy with +90 diopter noncontact lens.
Fundus fluorescein angiography (using IMAGEnet 2000, Topcon TRC50IX; Topcon Corporation, Tokyo, Japan) was obtained at baseline for all patients and was repeated at follow-up visits if it was necessary for some patients. OCT was performed for all patients during preinjection and postinjections follow-up visits to determine the CMT using spectral domain OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Macular thickness map and six cardinal scans were performed with the same reference point for macular thickness map follow-up. The AutoRescan function of Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) allows the automatic repetition of follow-up scans for the individual patient. Once a baseline image was defined, the automatic re-scan function places the OCT scans at the exact same location during follow-up examinations.
The injections of bevacizumab (Avastin; Genentech Inc., San Francisco, California, USA) were administered under standard aseptic techniques in the ophthalmic surgical theater, including the use of a topical anesthetic, povidone–iodine scrubbing of the ocular surface, and a sterile speculum. Antibiotic eye drops were applied 1 day before the injection. A volume of 0.05 ml containing 1.25 mg of bevacizumab was injected into the vitreous cavity through the pars plana 3.5–4 mm posterior to the limbus in phakic eyes using a sterile 30 G needle in the inferotemporal quadrant. PSTI of TA (Kenacort A; Smith Kline Beecham, Cairo, Egypt) containing 40 mg of TA (1 ml) was injected with a 27 G needle attached to a tuberculin syringe. The superotemporal conjunctival fornix was penetrated with the needle. The needle was moved from side to side before injection to check whether the sclera was not engaged in the needle tip, and then the drug was injected. All patients were instructed to apply antibiotic (0.3% gatifloxacin) eye drops five times a day for 1 week.
All eyes underwent ophthalmic examination on days 1 and 7 following injections, evaluating injection-related complications (e.g. anterior chamber reaction or IOP rise, etc.). Follow-up was performed regularly by determining the BCVA, IOP measurement, and fundus biomicroscopy. OCT was performed to evaluate the prognosis of macular edema after the combined injection of bevacizumab and TA. Anatomical (CMT) and functional (BCVA) outcomes were evaluated monthly using spectral domain OCT and vision chart, respectively. The primary outcome measure was changes in CMT compared with baseline. Secondary outcome measures included changes in BCVA and IOP from baseline. The CMT, IOP, and visual acuities were compared before treatment and 1 and 3 months after treatment.
Statistical analyses were performed using SPSS software for Windows (version 15; SPSS Inc., Chicago, Illinois, USA). Preinjection and postinjection measurements at 1 month and 3 months for all variables were tested by the paired sample t-test. All values are expressed as mean±SD. P values less than 0.05 were accepted as significant.
| Results|| |
All treated patients suffered from type II diabetes and were in the stage of nonproliferative diabetic retinopathy with diffuse DME and had at least two previous injections of i.v. bevacizumab. Patients had a mean age of 56.3±8.3 years (range: 44–69 years); 47.1% were males and 52.9% were females. Twenty-five (83.3%) eyes had extrafoveal hard exudates and five (16.7%) eyes had subfoveal hard exudates as detected clinically and with OCT.
The preinjection mean CMT was 504.3±82.8 µm (range: 395–709 µm). After treatment, improvements in the mean CMT measurements were observed at 1 and 3 months. The postinjection mean CMT at 1 month was 210.2±17.9 µm (range: 190–245 µm) and was 238.8±24.2 µm (range: 200–278 µm) at 3 months ([Table 1] and [Figure 1]). The decrease in the mean CMT before treatment and 1 month and 3 months after treatment was statistically significant (P<0.05).
|Figure 1 Patients’ central macular thickness Pre- and Post-injection at 1 and 3 months. There was a significant decrease in the central macular thickness post-treatment|
Click here to view
The mean preinjection BCVA (expressed as decimal fraction) was 0.16±0.1. The mean postinjection BCVAs were 0.47±0.18 (range: 0.1–0.7) and 0.46±0.19 (range: 0.1–0.7) after 1 and 3 months, respectively. The mean postinjection BCVAs at 1 and 3 months in eyes with extrafoveal hard exudates (25/30 eyes) were 0.5±0.095 and 0.5±0.1, respectively ([Table 2]). BCVA improvement in eyes with extrafoveal hard exudates was statistically significant during follow-ups at 1 and 3 months (P<0.05). In eyes with subfoveal hard exudates (5/30 eyes), BCVA was stable with no improvement at 1 and 3 months after injection.
|Table 2 Best-corrected visual acuity before injection and 1 and 3 months after injection in eyes with extrafoveal hard exudates|
Click here to view
All patients had a within-normal IOP at baseline (15.0±2.7 mmHg). No cases with an IOP elevation exceeding 21 mmHg after posterior sub-Tenon’s TA injection were seen in all 30 eyes.
No ocular adverse events (such as endophthalmitis, traumatic cataract, retinal detachment, and globe rupture) were reported with the exception of mild subconjunctival hemorrhage at the injection site.
| Discussion|| |
Macular edema is the main cause of visual acuity loss in diabetic patients. It may occur at any stage of the retinal disorder and is the most common cause of sight reductions in these participants . Many factors are involved in the pathogenesis of DME; therefore, many alternatives may be suggested for these patients (pharmacologic or surgical) . Available therapies include macular laser photocoagulation, corticosteroids, and anti-VEGF drugs. However, single treatments are often not effective enough to control DME during the entire course of the disease, which can be very long. The multifactorial complex pathogenetic mechanisms require a comprehensive approach . The roles of oxidative stress, inflammatory mediators, and the upregulation of VEGF in DME have been elucidated . Anti-VEGF drugs decrease the concentration of free VEGF but do not change the concentrations of other proinflammatory molecules that also mediate vascular permeability. As corticosteroids downregulate a variety of damaging chemokines, they restore the integrity of the blood–retinal barrier, decrease DME, and improve vision. In addition, corticosteroids affect the production of hundreds of proteins that decrease the synthesis of VEGF . Thus, i.v. injections of corticosteroids and anti-VEGF drugs have been proposed in combination to treat DME . Combining corticosteroids with anti-VEGF drugs may produce the greatest possible suppression of vascular permeability by both direct VEGF blockade and by reducing the concentrations of other important proinflammatory and permeability-enhancing chemokines . Both bevacizumab and triamcinolone are the most cost-effective drugs, and therefore are widely used in DME .
However, the use of intravitreal triamcinolone injection had been linked to the development of cataracts, elevated IOP, sterile pseudoendophthalmitis, and infectious endophthalmitis . The PSTI of TA had a comparable effect with the intravitreal triamcinolone injection and showed a lower risk of elevated IOP . The underlying rationale for using sub-Tenon’s capsule injection of TA for DME is that, apart from its safety, it can penetrate the sclera and diffuse into the vitreous cavity . Bakri and Kaiser  evaluated the role of PSTI of TA in improving visual acuity in patients with refractory DME. They found significant improvement in visual acuity at 1 month, which was maintained till 12 months. Therefore, PSTI of TA may be a good alternative for the treatment of diffuse DME . Combined intravitreal bevacizumab and sub-Tenon’s TA injection could be one of the treatment options for improving visual acuity and reducing CMT in DME patients .
The outcome of the present study revealed that combined i.v. bevacizumab with PSTI-TA was effective for management of persistent DME in terms of decreasing CMT and improving BCVA. This combined treatment protocol decreased CMT effectively below 300 µm in all eyes (100%) and provided improvement of visual acuity in 25 (83.3%) eyes and stabilization in five (16.7%) eyes at the end of the 3-month follow-up. The mean CMT decreased from preinjection values of 504.3±82.8 µm to a mean CMT of 210.2±17.9 µm at 1 month and to 238.8±24.2 µm at 3 months. The improvements in the BCVAs were statistically significant between preinjection and postinjection measurements during the scheduled follow-up period. The preinjection BCVA in eyes with extrafoveal hard exudates (25/30) was 0.19±0.095, and the postinjection BCVAs were 0.5±0.095 and 0.5±0.1 at 1 and 3 months, respectively, which indicated significant improvement in BCVA after the suggested treatment protocol. The combined injection prevents further deterioration of BCVA in eyes with subfoveal hard exudates (5/30) during the 3-month follow-up period.
The concept of combined PSTI-TA and i.v. bevacizumab therapy for DME had been proposed in many previous studies. In their study of combined high-dose posterior sub-Tenon’s triamcinolone (∼75 mg), i.v. bevacizumab, and laser photocoagulation for refractory DME, Chan et al.  demonstrated that this triple therapy resulted in significant and sustained anatomical macular edema reduction, with the central foveal thickness still on a decreasing trend at 12 months. Kim et al.  reported that the combined therapy with i.v. bevacizumab injection and PSTI-TA (4.0 mg) produced better clinical outcomes, especially at 1 month after injection compared with single injections of each one of them.The improvement in the anatomical (CMT) and functional (BCVA) outcomes in the present study may be attributed to patients’ selection criteria including exclusion of ischemic DME cases and absent history of previous laser or ocular surgeries before enrollment.
It seems that adding steroids to intravitreal anti-VEGF agents may intensify and/or consolidate either effect of both agents . Ahmadieh et al.  compared i.v. bevacizumab with or without i.v. TA in DME and found that the addition of TA induced earlier visual improvement.
Because of localization of the drug near the macula, PSTIs are effective in the treatment of DME. The main advantage of posterior sub-Tenon’s steroid injection is a prolonged effect due to a maximal local concentration of the drug that causes minimal systemic side effects .
None of the patients, in the present study, developed cataract or rise in IOP that necessitated antiglaucoma drugs during the 3-month follow-up period.
Limitations of the current study include the relatively small number of enrolled patients and the short follow-up time. Therefore, further, long-term studies on a larger number of patients are required to confirm the long-term efficacy and safety of this combined treatment as a treatment option for persistent DME after previous i.v. bevacizumab injections.
| Conclusion|| |
The results of the present study show that adding PSTI-TA to i.v. bevacizumab has a role in the treatment of persistent DME after previous i.v. bevacizumab monotherapy. The combined use of i.v. bevacizumab and PSTI-TA was effective for the treatment of persistent DME.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Al Rashaed S, Arevalo JF. Combined therapy for diabetic macular edema. Middle East Afr J Ophthalmol 2013; 20:315–320.
Aksoy S, Yilmaz G, Akkoyun I, Yazici AC. Comparison of intravitreal bevacizumab and triamcinolone acetonide therapies for diffuse diabetic macular edema. Int J Ophthalmol 2015; 8:550–555.
Tas M, Oner V, Alakus MF, Turkcu FM, Iscan Y, Yuksel K. Single injection of triamcinolone versus three repeated injections of bevacizumab for treatment of diabetic macular edema. Int Ophthalmol 2013; 33:375–380.
Zhang X, Zeng H, Bao S, Wang N, Gillies MC. Diabetic macular edema: new concepts in pathophysiology and treatment. Cell Biosci 2014; 4:27.
Stefanini FR, Badaró E, Falabella P, Koss M, Farah ME, Maia M. Anti-VEGF for the management of diabetic macular edema. J Immunol Res 2014; 2014:632307.
Messenger WB, Beardsley RM, Flaxel CJ. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. Drug Des Devel Ther 2013; 7: 425–434.
Kulkarni AD, Ip MS. Diabetic macular edema: therapeutic options. Diabetes Ther 2012; 3:1–14.
Chan CK, Lai TY, Mohamed S, Lee VY, Liu DT, Li CL et al.
Combined high-dose sub-tenon triamcinolone, intravitreal bevacizumab, and laser photocoagulation for refractory diabetic macular edema: a pilot study. Retina 2012; 32:672–678.
Cellini M, Pazzaglia A, Zamparini E, Leonetti P, Campos EC. Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema. BMC Ophthalmol 2008; 8:5.
Faghihi H, Roohipoor R, Mohammadi SF, Hojat-Jalali K, Mirshahi A, Lashay A et al.
Intravitreal bevacizumab versus combined bevacizumab-triamcinolone versus macular laser photocoagulation in diabetic macular edema. Eur J Ophthalmol 2008; 18: 941–948.
Zur D, Loewenstein A. Combination therapy for diabetic macular edema. J Ophthalmol 2012; 2012:484612.
Cellini M, Balducci N, Strobbe E, Campos EC. Subtenon injection of natural leukocyte interferon α-2a in diabetic macular edema: a case report. BMC Ophthalmol 2013; 13:63.
Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW. A 12-month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema after multiple anti-VEGF injections to assess the efficacy of the dexamethasone-delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina 2015; 35:1604–1614.
Kriechbaum K, Prager S, Mylonas G, Scholda C, Rainer G, Funk M et al.
Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: one-year results. Eye (Lond) 2014; 28:9–15.
Kim MW, Moon H, Yang SJ, Joe SG. Effect of posterior subtenon triamcinolone acetonide injection on diabetic macular edema refractory to intravitreal bevacizumab injection. Korean J Ophthalmol 2016; 30:25–31.
Choi YJ, Oh IK, Oh JR, Huh K. Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema. Korean J Ophthalmol 2006; 20:205–209.
Lee SJ, Kim ES, Geroski DH, McCarey BE, Edelhauser HF. Pharmacokinetics of intraocular drug delivery of Oregon Green 488-labeled triamcinolone by subtenon injection using ocular fluorophotometry in rabbit eyes. Invest Ophthalmol Vis Sci 2008; 49:4506–4514.
Bakri SJ, Kaiser PK. Posterior subtenon triamcinolone acetonide for refractory diabetic macular edema. Am J Ophthalmol 2005; 139:290–294.
Kim HD, Kang KD, Choi KS, Rhee MR, Lee SJ. Combined therapy with intravitreal bevacizumab and posterior subtenon triamcinolone acetonide injection in diabetic macular oedema. Acta Ophthalmol 2014; 92:e589–e590.
Ahmadieh H, Ramezani A, Shoeibi N, Bijanzadeh B, Tabatabaei A, Azarmina M et al.
Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema: a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2008; 246:483–489.
Javadzadeh A. The effect of posterior subtenon methylprednisolone acetate in the refractory diabetic macular edema: a prospective nonrandomized interventional case series. BMC Ophthalmol 2006; 6:15.
[Table 1], [Table 2]