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Intravitreal triamcinolone injection for diabetic macular edema: a clinical and fluorescein angiograhic case series
Intravitreal triamcinolone injection for diabetic macular edema: a clinical and .fluorescein angiographic case series Sophie J. Bakri, MD; Paul M. Beer, MD ABSTRACT • RESUME Background: A significant number of eyes with diabetic macular edema remain refractory to treatment despite numerous attempts at photocoagulation. Triamcinolone acetonide, a minimally water soluble steroid injected in suspension form, has been reported to be a well-tolerated agent for intravitreal injection, prompting a decrease in diabetic macular edema on optical coherence tomography. We report our experience with this treatment in 19 eyes with persistent diabetic macular edema. Methods: We reviewed the charts of 16 patients ( 19 eyes) from a clinical practice with diabetic macular edema persistent after focal or grid laser photocoagulation. All eyes had received 4 mg of triamcinolone, injected into the vitreous cavity 3.5 mm posterior to the limbus. Fluorescein angiography was performed before and about 2 weeks after the injection. Snellen visual acuity and intraocular pressure (as determined with Goldmann applanation tonometry) were also measured before and after the injection. Results: Fluorescein angiography showed marked improvement of macular edema in 4 eyes (21.0%), mild improvement in I0 eyes (52.6%) and no change in 5 eyes (26.3%); no patient had worsening of macular edema. Visual acuity improved by at least I line in 13 eyes (68.4%), by 2 or more lines in 5 eyes (26.3%), by 3 or more lines in 2 eyes (I 0.5%) and by 4 lines in I eye (5.3%); visual acuity remained unchanged in 5 eyes (26.3%) and deteriorated by I line in I eye (5.3%). Intraocular pressure elevation of I0 mm Hg or greater occurred in two eyes (I 0.5%) and was successfully treated with topical administration of 0.15% brimonidine. The triamcinolone was well tolerated, and there were no other ocular complications.
Interpretation: lntravitreal injection of triamcinolone has potential in the treatment of diabetic macular edema and warrants investigation in a randomized prospective clinical trial.
Contexte : Un nombre important d'yeux ayant un redeme maculaire diabetique demeurent refractaires au traitement malgre les nombreuses tentatives de photocoagulation. L'on a rapporte que l'acetonide de triamcinolone, stero"ide a peine soluble dans l'eau, injecte en suspension, etait un agent bien tolere pour injection intravitreenne, declenchant une reduction de l'redeme maculaire diabetique a Ia
From the Lions Eye Institute, Albany Medical College, Albany, NY Originally received Mar. 10, 2003 Accepted for publication Sept 8, 2004
Intravitreal triamcinolone-Bakri et al
Correspondence to: Dr. Paul M. Beer, Lions Eye Institute, Albany Medical College, Albany, NY 12208, USA; fax: (518) 262-2551 This article has been peer-reviewed.
Can} Ophtha/mo/2004;39:755-60
755
Intravitreal triamcinolone-Bak ri et al
tomographie en coherence optique. Nous rendons compte de notre experience avec le traitement de 19 yeux ayant un redeme maculaire diabetique persistant. Methodes : No us avons passe en revue les dossiers de 16 patients ( 19 yeux) d'une clinique, dont l'redeme maculaire diabetique persistait apres une photocoagulation au laser, focale ou en damier. Les yeux ont tous re~u une injection de 4 mg de triamcinolone dans Ia cavite vitree a 3,5 mm derriere le limbe. Une angiographie a Ia fluoresceine a ete pratiquee avant !'injection et environ deux semaines apres. L'on a aussi mesure l'acuite visuelle selon l'echelle de Snellen et Ia pression intraoculaire (avec le tonometre a aplanation de Goldmann) avant et apres !'injection. Resultats : L'angiographie a Ia fluoresceine a fait voir une reduction remarquable de l'redeme maculaire dans 4 yeux (21 ,0 %), une faible reduction dans I0 yeux (52,6 %) et aucun changement dans 5 yeux (26,3 %); l'redeme ne s'est aggrave chez aucun patient. L'acuite visuelle s'est amelioree d'au moins I ligne dans 13 yeux (68,4 %), de 2 Iignes ou plus dans 5 yeux (26,3 %), de 3 lignes ou plus dans 2 yeux (I 0,5 %) et de 4 lignes dans I reil (5,3 %); l'acuite visuelle n'a pas change dans 5 yeux (26,3 %) et s'est deterioree de I ligne dans I reil (5,3 %). La pression intraoculaire a monte de I0 mm Hg ou plus dans deux yeux (I 0,5 %) et le traitement a reussi avec une administration topique de brimonidine a 0, IS %. Le triamcinolone a ete bien tolere et il n'y a pas eu d'autres complications oculaires.
Interpretation : L'injection intravitreenne de triamcinolone offre un patentiel pour le traitement de l'mdeme maculaire diabetique et justifie !'investigation par d'eventuels essais cliniques randomises.
M
acular edema is the most common cause of visual loss among patients with diabetic retinopathy. Treatment of clinically significant macular edema consists of focal or grid laser photocoagulation, based on the results of the Early Treatment Diabetic Retinopathy Study (ETDRS) Research Group. 1- 3 After photocoagulation, a period of 1 to 4 months is required for maximal resorption of fluid, and if macular edema persists clinically, repeat photocoagulation is recommended if "treatable lesions" persist. Treatable lesions are defined as persistent leaking microaneurysms 500 11 from the centre of the macula or, if the vision is less than 20/40 and there is no perifoveal capillary dropout, 300 11 from the centre of the macula. 2 Grid laser photocoagulation can also be performed in areas of diffuse leakage 500 11 from the centre of the macula, but only if these areas have received no previous photocoagulation. However, retreatment of areas previously treated by grid laser photocoagulation may result in confluence of laser scars and is therefore not recommended. 4 A significant number of eyes remain refractory to treatment despite numerous attempts at photocoagulation. In addition, laser photocoagulation inevitably destroys retinal tissue. Sequelae of chronic macular edema include permanent retinal damage and loss of visual acuity secondary to cystic degeneration, lamel-
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lar hole formation, epiretinal membrane formation and atrophy of the outer retinal layers. Pars plana vitrectomy has been advocated to relieve any tractional component contributing to macular edema, 5•6 but it is an invasive technique that may carry significant complications.7 Triamcinolone acetonide, a minimally water soluble steroid injected in suspension form, has been reported to be a well-tolerated agent for intravitreal injection in diabetic macular edema, prompting a decrease in macular thickness on optical coherence tomography (OCT). 8•9 It has also been found to be beneficial in uveitis, 10•11 macular edema secondary to ocular injury or retinal vascular disease 12 and intraocular proliferations, such as proliferative vitreoretinopathy13 and choroidal neovascularization from agerelated macular degeneration. 14.1 5 Antcliff and colleagues10 showed anatomic resolution by OCT in five of six patients treated with intravitreal injection of triamcinolone for long-standing cystoid macular edema secondary to uveitis. Triamcinolone's hydrophobicity accounts for its lengthy duration of action, and therapeutic levels may be present for 3 months. In a previous study, we found that after a single 4-mg intravitreal injection, triamcinolone persisted in the vitreous for a mean of 93 days in nonvitrectomized eyes and for 18.7 days in a
Intravitreal triamcinolo ne-Bakri et al
vitrectomized eye. 16 Triamcinolone crystals were identified on ·scleral depression for as long as 101 days in one patient. The intravitreal injection, which is done in a routine office setting, is simple to perform and well tolerated by the patient. It requires minimal topical and subconjunctival anesthesia, instillation of antibiotic drops and sterile technique. In this pilot study, we report the clinical and fluorescein angiographic outcome of treatment of diabetic macular edema with a single intravitreal injection of triamcinolone. METHODS
We performed a retrospective chart review to identify patients who had had an intravitreal injection of triamcinolone acetonide (Kenalog-40 Injection, Westwood-Squibb, Montreal) for the treatment of diabetic macular edema persistent after laser photocoagulation treatment. We defined "persistence" as macular edema and retinal thickening for more than 4 months, a history of one or more focal laser treatments and the absence of "treatable" focal lesions. "Treatable" lesions consisted of persistent leaking aneurysms 500 fl from the centre of the macula (or 300 fl from the centre if the vision was less than 20/40 2 and there was no perifoveal capillary dropout). Patients were excluded if they had previous posterior sub-Tenon's triamcinolone injections or if they had had the triamcinolone injection during pars plana vitrectomy for macular edema. Under aseptic technique and subconjunctival anesthesia, 4 mg of triamcinolone acetonide in 0.1 mL had been injected into the vitreous cavity 3.5 mm posterior to the limbus. The eye was premedicated with one drop of ofloxacin, and the patient was instructed to instil ofloxacin onto the treated eye four times a day for 3 days after the procedure. Anterior chamber paracentesis was done to lower the intraocular pressure (lOP) after the injection in some patients. Change in macular edema was assessed by comparing fluorescein angiograms obtained before and about 2 weeks after the injection. The change was graded as mild improvement, marked improvement, no change or worsening of macular edema. Best-corrected Snellen visual acuity and lOP (measured by means of Goldmann applanation tonometry) were also recorded before and after the injection. Visual acuity was measured by a certified ophthalmic technician using the same projection chart each time.
For visual acuity after the injection, the time to reach best-corrected acuity was documented. We also noted whether the patient had a past history of glaucoma, cataract extraction or pars plana vitrectomy. RESULTS
Nineteen eyes of 16 patients were eligible for inclusion. There were 11 women and 5 men ranging in age from 47 to 83 years (median 72 years, mean 71 years). The length of follow-up ranged from 5 to 20 weeks (median 14.4 weeks, mean 14 weeks). The outcome for the 19 eyes is shown in Table 1. Four eyes (21.0%) showed marked improvement of macular edema, 10 (52.6%) showed mild improvement, and 5 (26.3%) showed no change; no patient had worsening of the macular edema. In 13 eyes (68.4%) the best-corrected visual acuity improved by at least 1 line, and in 5 eyes (26.3%) it improved by 2 or more lines. Two eyes (10.5%) had a significant improvement of 3 or more lines, and one eye (5.3%) had an improvement of 4lines. There was no change in visual acuity in five eyes (26.3% ), and in one eye (5.3%) the visual acuity deteriorated by 1line. A rise in lOP of 5 mm Hg or greater was noted in seven eyes (36.8% ), and of 10 mm Hg or greater in two eyes (10.5% ); the pressure returned to normal with topical administration of 0.15% brimonidine. Of the three eyes with a past history of glaucoma, one had no change in lOP, one had an lOP rise of 6 mm Hg, and one had an lOP rise of 15 mm Hg. Of the four eyes with a past history of vitrectomy, two showed mild improvement of macular edema, and two showed no change. Of the nine phakic eyes, two had marked improvement of macular edema, six had mild improvement, and one had no change. Of the 10 pseudophakic eyes, 2 had marked improvement, 4 had mild improvement, and 4 had no change. None of the patients experienced pain during the intravitreal triamcinolone injection, and there were no ocular complications except for transient ocular hypertension. Despite the opaque nature of the steroid, no patient complained of floaters after the injection. The material was found to settle in the inferior vitreous and was out of the visual axis by the first day following the injection. Several patients had a small amount of subconjunctival blood related to the subconjunctival lidocaine injection or scleral penetration. One patient reported blepharoptosis on the same side as the steroid injection, which occurred the day
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Table 1-0utcome of treatment of persistent diabetic macular edema with a single intravitreal injection of triamcinolone acetonide Change in Fluorescein Age, yr/ Eye no.
Visual acuity
Snellen
Intraocular
visual
Time of
Length of
pressure
Lens
angiographic
Before
After
acuity, no.
acuity
follow-up,
change,
response
injection
injection
of lines
change, wk
wk
mm Hg
sex
PPV
status
I
47/F
No
Phakic
Marked
20/40
20/30
+I
I
19
2
69/F
No
Phakic
None
20/400
20/100
+2
I
16
0
3
68/F
No·
IOL
Mild
20/200
20/100
+I
I
8
+9
4
78/F
Yes
IOL
None
20/80
20/80
0
18
+I
5
79/F
No
IOL
Mild
CF 0.6 m
CF 0.6 m
0
6
74/F
Yes
IOL
Mild
20/200
20/100
-
0
5
-I +6
+I
8
17
7
68/F
No
Phakic
Mild
20/50
20/30
+2
8
12
0
8
68/F
No
Phakic
Mild
20/30
20/25
+I
6
12
+6
9
73/M
No
Phakic
Mild
20/80
20/50
+3
4
19
+13
10
75/M
No
IOL
Marked
20/80
20/60
+2
10
10
-I
II
75/M
No
IOL
Marked
20/60
20/50
+I
13
13
+6
12
70/F
Yes
Phakic
Mild
20/400
20/400
0
-
20
+2
13
70/F
No
Phakic
Mild
CF 0.6 m
CF 0.6 m
0
-
15
+7
14
74/F
No
IOL
Mild
20/70
20/60
+I
2
13
0
15
72/F
No
Phakic
Mild
20/80
20/100
-I
I
14
+2
16
72/F
Yes
IOL
None
201100
20/70
+2
18
18
0
17
75/M
No
IOL
None
20/80
20/70
+I
3
12
+15
18
83/F
No
IOL
None
20/400
20/100
+2
6
19
+I
19
55/M
No
Phakic
Marked
20/70
20/30
+4
14
14
+2
Note: PPV = pars plana vitrectomy, IOL = intraocular lens, CF = counting fingers. *Eyes 6, 16 and 17 had a past history of glaucoma.
following the injection. In one patient, triamcinolone migrated into the inferior anterior chamber after paracentesis and was seen there for 2 months, but this caused no problems. There was no obvious evidence of increased cataract progression. INTERPRETATION
Fourteen of 19 eyes in this series demonstrated some angiographic resolution of diabetic macular edema that had been persistent after prior treatment by photocoagulation, and five eyes showed marked resolution. However, Snellen visual acuity improved by 1 or more lines in only 13 eyes. Although fluorescein angiography is an objective method of assessing resolution of macular edema, it is more likely than OCT to have a subjective component to its interpretation. In our study, the person who measured visual acuity was not the same person who read the angiograms, and the angiogram reader was masked as
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to the visual acuity of the patient. Owing to the chronic nature of macular edema in these eyes, there may have been irreversible retinal damage and concurrent macular ischemia, limiting further visual acuity improvement despite anatomic resolution of the edema. In addition, since visual acuity measurements may vary from one visit to the next - even in healthy eyes but particularly in diabetic patients - a 1-line improvement may not represent a significant change. Longer-term results and meticulous methodology would be needed to assess a true modest improvement in visual acuity. Of note, one eye had marked resolution of macular edema and a 4-line improvement in visual acuity. Laser photocoagulation inevitably destroys retinal tissue, and coalescence of chorioretinal laser scars in the macula may occur over time, especially with higher laser energies. In a clinicopathological correlation of focal photocoagulation treatment in a diabetic patient treated as part of the ETDRS, fibrous subreti-
Intravitreal triamcinolone-Bakri et al
nal and subpigment epithelial membranes extended up to 900 11 from the burn centresY Because of the risk of membrane formation, these findings call for caution when treating close to the fovea. Other complications include choroidal neovascularization from inadvertent rupture of Bruch's membrane. The goal of f()callaser in the ETDRS was to preserve visual acuity over the long term, and the definition of clinically significant macular edema did not include a visual acuity level. Accordingly, some patients with clinically significant macular edema and 20/20 or better vision qualify for focal treatment. The ETDRS Research Group concluded that for eyes with less extensive retinal thickening and less thickening at the centre of the macula, an initial period of close observation may be preferable to immediate treatment. 3 This is particularly the case when most of the leakage to be treated lies close to the centre of the macula, increasing the risk of damage to the macula from direct treatment or subsequent migration of treatment scars. These patients may represent a subgroup who could be treated with intravitreal injection of triamcinolone, thus deferring focal laser photocoagulation and its potential complications. Our series consisted of patients whose macular edema failed to resolve despite treatment according to the ETDRS protocol. In a study in rabbits, McCuen and associates 18 found no adverse effect of intravitreal injection of pure triamcinolone on electroretinography or on light or electron microscopy. Hida and coworkers 19 investigated the toxicity of the vehicles used in commercial steroid preparations and found no adverse effect on the retina or lens from the vehicle in Kenalog. In our series, no patient had significant ocular complications20 •21 except for transient ocular hypertension. In two eyes the rise in lOP was significant but was reversed with topical administration of 0.15% brimonidine. The pressure spikes occurred at various times, as early as 1 week after injection. The lOP must be monitored carefully during the follow-up of patients who receive an intravitreal triamcinolone injection. 22 There was no obvious indication of increased cataract progression in our series, but this was not specifically assessed owing to the retrospective nature of the study. In one patient triamcinolone was seen in the inferior anterior chamber for 2 months after the injection, forming a pseudohypopyon, 23 but caused no problems. We do not know whether the eyelid ptosis in an elderly patient with coexisting dehiscence of the levator aponeurosis was related to the intravitreal tri-
amcinolone or to the use of an eyelid speculum. Singh and coworkers 24 reported incidence rates of ptosis after cataract surgery of 44% when an eyelid speculum was used and 23% when no speculum was used; they concluded that the cause of the ptosis was multifactorial. This is a pilot study and has limitations imposed by those of a retrospective study, including lack of protocol refraction and the somewhat subjective nature of fluorescein angiogram interpretation. In conclusion, intravitreal injection of triamcinolone is a promising adjunct in the treatment of diabetic macular edema. It may be useful as an alternative primary treatment to focal laser photocoagulation, especially in eyes in which leakage occurs predominantly in the centre of the fovea, which are particularly likely to undergo damage from direct laser treatment and subsequent migration of subretinal scars. It may also be used in conjunction with focal laser photocoagulation when the response to photocoagulation alone is deemed to be unsatisfactory. Our angiographic results may support the role of intravitreal triamcinolone injection earlier in the course of diabetic macular edema, before irreversible retinal changes occur. However, intravitreal triamcinolone lasts for about 3 months, 16 and recurrence of macular edema is common, necessitating repeat injections. Owing to the retrospective nature of our study, we cannot draw conclusions regarding the longterm risks or benefits of this procedure. A randomized clinical trial is needed in this regard. REFERENCES
1. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmoll985;l03(l2):l796-806. 2. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1987;94(7):761-74. 3. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1995; 113(9):1144-55. 4. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmoll99l;l09(11):l549-5l. 5. Lewis H, Abrams GW, Blumenkranz MS, Campo RV.
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Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology 1992;99(5):753-9. Massin P, Duguid G, Erginay A, Haouchine B, Gaudric A. Optical coherence tomography for evaluating diabetic macular edema before and after vitrectomy. Am J Ophthalmol2003;135(2):169-77. Yamamoto T, Hitani K, Tsukahara I, Yamamoto S, Kawasaki R, Yamashita H, et al. Early postoperative retinal thickness changes and complications after vitrectomy for diabetic macular edema. Am J Ophthalmol 2003;135(1):14-9. Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002; 109(5):920-7. Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology 2004;111(2):218-24; discussion 224-5. Antcliff RJ, Spalton DJ, Stanford MR, Graham EM, ffytche TJ, Marshall J. Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology 2001;108(4):765-72. Young S, Larkin G, Branley M, Lightman S. Safety and efficacy of intravitreal triamcinolone for cystoid macular oedema in uveitis. Clin Exp Ophthalmol2001;29(1):2-6. Park CH, Jaffe GJ, Fekrat S. Intravitreal triamcinolone acetonide in eyes with cystoid macular edema associated with central retinal vein occlusion. Am J Ophthalmol 2003;136(3):419-25. Jonas JB, Hayler JK, Panda-Jonas S. Intravitreal injection of crystalline cortisone as adjunctive treatment of proliferative vitreoretinopathy. Br J Ophthalmol 2000;84(9): 1064-7. Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal triamcinolone acetonide in exudative age-related macular degeneration. Retina 2000;20(3):244-50. Challa JK, Gillies MC, Penfold PL, Gyory JF, Hunyor
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16.
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AB, Billson FA. Exudative macular degeneration and intravitreal triamcinolone: 18 month follow up. Aust N Z J Ophthalmol1998;26(4):277-81. Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3rd, Miller M. Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 2003;110(4):681-6. Wallow IH, Bindley CD. Focal photocoagulation of diabetic macular edema. A clinicopathologic case report. Retina 1988;8(4):261-9. McCuen BW 2nd, Bessler M, Tano Y, Chandler D, Machemer R. The lack of toxicity of intravitreally administered triamcinolone acetonide. Am J Ophthalmol 1981;91(6):785-8. Hida T, Chandler D, Arena JE, Machemer R. Experimental and clinical observations of the intraocular toxicity of commercial corticosteroid preparations. Am J Ophthalmol 1986; 101(2): 190-5. Moshfeghi DM, Kaiser PK, Scott IU, Sears JE, Benz M, Sinesterra JP, et al. Acute endophthalrnitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol2003;136(5):791-6. Moshfeghi DM, Kaiser PK, Bakri SJ, Scott IU, Sears JE, Benz M, et al. Sterile endophthalrnitis following intravitreal triamcinolone acetonide injection. Ophthalmic Surg Lasers Imaging (in press). Bakri SJ, Beer PM. The effect of intravitreal triamcinolone acetonide on intraocular pressure. Ophthalmic Surg Lasers Imaging 2003;34(5):386-90. Sharma MC, Lai WW, Shapiro MJ. Pseudohypopyon following intravitreal triamcinolone acetonide injection. Cornea 2004;23(4):398-9. Singh SK, Sekhar GC, Gupta S. Etiology of ptosis after cataract surgery. J Cataract Refract Surg 1997;23(9): 1409-13.
Key words: injections, intravitreal; triamcinolone acetonide; diabetes mellitus; macula lutea; intraocular pressure; fluorescein angiography; visual acuity
Interpretation: lntravitreal injection of triamcinolone has potential in the treatment of diabetic macular edema and warrants investigation in a randomized prospective clinical trial.
Contexte : Un nombre important d'yeux ayant un redeme maculaire diabetique demeurent refractaires au traitement malgre les nombreuses tentatives de photocoagulation. L'on a rapporte que l'acetonide de triamcinolone, stero"ide a peine soluble dans l'eau, injecte en suspension, etait un agent bien tolere pour injection intravitreenne, declenchant une reduction de l'redeme maculaire diabetique a Ia
From the Lions Eye Institute, Albany Medical College, Albany, NY Originally received Mar. 10, 2003 Accepted for publication Sept 8, 2004
Intravitreal triamcinolone-Bakri et al
Correspondence to: Dr. Paul M. Beer, Lions Eye Institute, Albany Medical College, Albany, NY 12208, USA; fax: (518) 262-2551 This article has been peer-reviewed.
Can} Ophtha/mo/2004;39:755-60
755
Intravitreal triamcinolone-Bak ri et al
tomographie en coherence optique. Nous rendons compte de notre experience avec le traitement de 19 yeux ayant un redeme maculaire diabetique persistant. Methodes : No us avons passe en revue les dossiers de 16 patients ( 19 yeux) d'une clinique, dont l'redeme maculaire diabetique persistait apres une photocoagulation au laser, focale ou en damier. Les yeux ont tous re~u une injection de 4 mg de triamcinolone dans Ia cavite vitree a 3,5 mm derriere le limbe. Une angiographie a Ia fluoresceine a ete pratiquee avant !'injection et environ deux semaines apres. L'on a aussi mesure l'acuite visuelle selon l'echelle de Snellen et Ia pression intraoculaire (avec le tonometre a aplanation de Goldmann) avant et apres !'injection. Resultats : L'angiographie a Ia fluoresceine a fait voir une reduction remarquable de l'redeme maculaire dans 4 yeux (21 ,0 %), une faible reduction dans I0 yeux (52,6 %) et aucun changement dans 5 yeux (26,3 %); l'redeme ne s'est aggrave chez aucun patient. L'acuite visuelle s'est amelioree d'au moins I ligne dans 13 yeux (68,4 %), de 2 Iignes ou plus dans 5 yeux (26,3 %), de 3 lignes ou plus dans 2 yeux (I 0,5 %) et de 4 lignes dans I reil (5,3 %); l'acuite visuelle n'a pas change dans 5 yeux (26,3 %) et s'est deterioree de I ligne dans I reil (5,3 %). La pression intraoculaire a monte de I0 mm Hg ou plus dans deux yeux (I 0,5 %) et le traitement a reussi avec une administration topique de brimonidine a 0, IS %. Le triamcinolone a ete bien tolere et il n'y a pas eu d'autres complications oculaires.
Interpretation : L'injection intravitreenne de triamcinolone offre un patentiel pour le traitement de l'mdeme maculaire diabetique et justifie !'investigation par d'eventuels essais cliniques randomises.
M
acular edema is the most common cause of visual loss among patients with diabetic retinopathy. Treatment of clinically significant macular edema consists of focal or grid laser photocoagulation, based on the results of the Early Treatment Diabetic Retinopathy Study (ETDRS) Research Group. 1- 3 After photocoagulation, a period of 1 to 4 months is required for maximal resorption of fluid, and if macular edema persists clinically, repeat photocoagulation is recommended if "treatable lesions" persist. Treatable lesions are defined as persistent leaking microaneurysms 500 11 from the centre of the macula or, if the vision is less than 20/40 and there is no perifoveal capillary dropout, 300 11 from the centre of the macula. 2 Grid laser photocoagulation can also be performed in areas of diffuse leakage 500 11 from the centre of the macula, but only if these areas have received no previous photocoagulation. However, retreatment of areas previously treated by grid laser photocoagulation may result in confluence of laser scars and is therefore not recommended. 4 A significant number of eyes remain refractory to treatment despite numerous attempts at photocoagulation. In addition, laser photocoagulation inevitably destroys retinal tissue. Sequelae of chronic macular edema include permanent retinal damage and loss of visual acuity secondary to cystic degeneration, lamel-
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lar hole formation, epiretinal membrane formation and atrophy of the outer retinal layers. Pars plana vitrectomy has been advocated to relieve any tractional component contributing to macular edema, 5•6 but it is an invasive technique that may carry significant complications.7 Triamcinolone acetonide, a minimally water soluble steroid injected in suspension form, has been reported to be a well-tolerated agent for intravitreal injection in diabetic macular edema, prompting a decrease in macular thickness on optical coherence tomography (OCT). 8•9 It has also been found to be beneficial in uveitis, 10•11 macular edema secondary to ocular injury or retinal vascular disease 12 and intraocular proliferations, such as proliferative vitreoretinopathy13 and choroidal neovascularization from agerelated macular degeneration. 14.1 5 Antcliff and colleagues10 showed anatomic resolution by OCT in five of six patients treated with intravitreal injection of triamcinolone for long-standing cystoid macular edema secondary to uveitis. Triamcinolone's hydrophobicity accounts for its lengthy duration of action, and therapeutic levels may be present for 3 months. In a previous study, we found that after a single 4-mg intravitreal injection, triamcinolone persisted in the vitreous for a mean of 93 days in nonvitrectomized eyes and for 18.7 days in a
Intravitreal triamcinolo ne-Bakri et al
vitrectomized eye. 16 Triamcinolone crystals were identified on ·scleral depression for as long as 101 days in one patient. The intravitreal injection, which is done in a routine office setting, is simple to perform and well tolerated by the patient. It requires minimal topical and subconjunctival anesthesia, instillation of antibiotic drops and sterile technique. In this pilot study, we report the clinical and fluorescein angiographic outcome of treatment of diabetic macular edema with a single intravitreal injection of triamcinolone. METHODS
We performed a retrospective chart review to identify patients who had had an intravitreal injection of triamcinolone acetonide (Kenalog-40 Injection, Westwood-Squibb, Montreal) for the treatment of diabetic macular edema persistent after laser photocoagulation treatment. We defined "persistence" as macular edema and retinal thickening for more than 4 months, a history of one or more focal laser treatments and the absence of "treatable" focal lesions. "Treatable" lesions consisted of persistent leaking aneurysms 500 fl from the centre of the macula (or 300 fl from the centre if the vision was less than 20/40 2 and there was no perifoveal capillary dropout). Patients were excluded if they had previous posterior sub-Tenon's triamcinolone injections or if they had had the triamcinolone injection during pars plana vitrectomy for macular edema. Under aseptic technique and subconjunctival anesthesia, 4 mg of triamcinolone acetonide in 0.1 mL had been injected into the vitreous cavity 3.5 mm posterior to the limbus. The eye was premedicated with one drop of ofloxacin, and the patient was instructed to instil ofloxacin onto the treated eye four times a day for 3 days after the procedure. Anterior chamber paracentesis was done to lower the intraocular pressure (lOP) after the injection in some patients. Change in macular edema was assessed by comparing fluorescein angiograms obtained before and about 2 weeks after the injection. The change was graded as mild improvement, marked improvement, no change or worsening of macular edema. Best-corrected Snellen visual acuity and lOP (measured by means of Goldmann applanation tonometry) were also recorded before and after the injection. Visual acuity was measured by a certified ophthalmic technician using the same projection chart each time.
For visual acuity after the injection, the time to reach best-corrected acuity was documented. We also noted whether the patient had a past history of glaucoma, cataract extraction or pars plana vitrectomy. RESULTS
Nineteen eyes of 16 patients were eligible for inclusion. There were 11 women and 5 men ranging in age from 47 to 83 years (median 72 years, mean 71 years). The length of follow-up ranged from 5 to 20 weeks (median 14.4 weeks, mean 14 weeks). The outcome for the 19 eyes is shown in Table 1. Four eyes (21.0%) showed marked improvement of macular edema, 10 (52.6%) showed mild improvement, and 5 (26.3%) showed no change; no patient had worsening of the macular edema. In 13 eyes (68.4%) the best-corrected visual acuity improved by at least 1 line, and in 5 eyes (26.3%) it improved by 2 or more lines. Two eyes (10.5%) had a significant improvement of 3 or more lines, and one eye (5.3%) had an improvement of 4lines. There was no change in visual acuity in five eyes (26.3% ), and in one eye (5.3%) the visual acuity deteriorated by 1line. A rise in lOP of 5 mm Hg or greater was noted in seven eyes (36.8% ), and of 10 mm Hg or greater in two eyes (10.5% ); the pressure returned to normal with topical administration of 0.15% brimonidine. Of the three eyes with a past history of glaucoma, one had no change in lOP, one had an lOP rise of 6 mm Hg, and one had an lOP rise of 15 mm Hg. Of the four eyes with a past history of vitrectomy, two showed mild improvement of macular edema, and two showed no change. Of the nine phakic eyes, two had marked improvement of macular edema, six had mild improvement, and one had no change. Of the 10 pseudophakic eyes, 2 had marked improvement, 4 had mild improvement, and 4 had no change. None of the patients experienced pain during the intravitreal triamcinolone injection, and there were no ocular complications except for transient ocular hypertension. Despite the opaque nature of the steroid, no patient complained of floaters after the injection. The material was found to settle in the inferior vitreous and was out of the visual axis by the first day following the injection. Several patients had a small amount of subconjunctival blood related to the subconjunctival lidocaine injection or scleral penetration. One patient reported blepharoptosis on the same side as the steroid injection, which occurred the day
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Table 1-0utcome of treatment of persistent diabetic macular edema with a single intravitreal injection of triamcinolone acetonide Change in Fluorescein Age, yr/ Eye no.
Visual acuity
Snellen
Intraocular
visual
Time of
Length of
pressure
Lens
angiographic
Before
After
acuity, no.
acuity
follow-up,
change,
response
injection
injection
of lines
change, wk
wk
mm Hg
sex
PPV
status
I
47/F
No
Phakic
Marked
20/40
20/30
+I
I
19
2
69/F
No
Phakic
None
20/400
20/100
+2
I
16
0
3
68/F
No·
IOL
Mild
20/200
20/100
+I
I
8
+9
4
78/F
Yes
IOL
None
20/80
20/80
0
18
+I
5
79/F
No
IOL
Mild
CF 0.6 m
CF 0.6 m
0
6
74/F
Yes
IOL
Mild
20/200
20/100
-
0
5
-I +6
+I
8
17
7
68/F
No
Phakic
Mild
20/50
20/30
+2
8
12
0
8
68/F
No
Phakic
Mild
20/30
20/25
+I
6
12
+6
9
73/M
No
Phakic
Mild
20/80
20/50
+3
4
19
+13
10
75/M
No
IOL
Marked
20/80
20/60
+2
10
10
-I
II
75/M
No
IOL
Marked
20/60
20/50
+I
13
13
+6
12
70/F
Yes
Phakic
Mild
20/400
20/400
0
-
20
+2
13
70/F
No
Phakic
Mild
CF 0.6 m
CF 0.6 m
0
-
15
+7
14
74/F
No
IOL
Mild
20/70
20/60
+I
2
13
0
15
72/F
No
Phakic
Mild
20/80
20/100
-I
I
14
+2
16
72/F
Yes
IOL
None
201100
20/70
+2
18
18
0
17
75/M
No
IOL
None
20/80
20/70
+I
3
12
+15
18
83/F
No
IOL
None
20/400
20/100
+2
6
19
+I
19
55/M
No
Phakic
Marked
20/70
20/30
+4
14
14
+2
Note: PPV = pars plana vitrectomy, IOL = intraocular lens, CF = counting fingers. *Eyes 6, 16 and 17 had a past history of glaucoma.
following the injection. In one patient, triamcinolone migrated into the inferior anterior chamber after paracentesis and was seen there for 2 months, but this caused no problems. There was no obvious evidence of increased cataract progression. INTERPRETATION
Fourteen of 19 eyes in this series demonstrated some angiographic resolution of diabetic macular edema that had been persistent after prior treatment by photocoagulation, and five eyes showed marked resolution. However, Snellen visual acuity improved by 1 or more lines in only 13 eyes. Although fluorescein angiography is an objective method of assessing resolution of macular edema, it is more likely than OCT to have a subjective component to its interpretation. In our study, the person who measured visual acuity was not the same person who read the angiograms, and the angiogram reader was masked as
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to the visual acuity of the patient. Owing to the chronic nature of macular edema in these eyes, there may have been irreversible retinal damage and concurrent macular ischemia, limiting further visual acuity improvement despite anatomic resolution of the edema. In addition, since visual acuity measurements may vary from one visit to the next - even in healthy eyes but particularly in diabetic patients - a 1-line improvement may not represent a significant change. Longer-term results and meticulous methodology would be needed to assess a true modest improvement in visual acuity. Of note, one eye had marked resolution of macular edema and a 4-line improvement in visual acuity. Laser photocoagulation inevitably destroys retinal tissue, and coalescence of chorioretinal laser scars in the macula may occur over time, especially with higher laser energies. In a clinicopathological correlation of focal photocoagulation treatment in a diabetic patient treated as part of the ETDRS, fibrous subreti-
Intravitreal triamcinolone-Bakri et al
nal and subpigment epithelial membranes extended up to 900 11 from the burn centresY Because of the risk of membrane formation, these findings call for caution when treating close to the fovea. Other complications include choroidal neovascularization from inadvertent rupture of Bruch's membrane. The goal of f()callaser in the ETDRS was to preserve visual acuity over the long term, and the definition of clinically significant macular edema did not include a visual acuity level. Accordingly, some patients with clinically significant macular edema and 20/20 or better vision qualify for focal treatment. The ETDRS Research Group concluded that for eyes with less extensive retinal thickening and less thickening at the centre of the macula, an initial period of close observation may be preferable to immediate treatment. 3 This is particularly the case when most of the leakage to be treated lies close to the centre of the macula, increasing the risk of damage to the macula from direct treatment or subsequent migration of treatment scars. These patients may represent a subgroup who could be treated with intravitreal injection of triamcinolone, thus deferring focal laser photocoagulation and its potential complications. Our series consisted of patients whose macular edema failed to resolve despite treatment according to the ETDRS protocol. In a study in rabbits, McCuen and associates 18 found no adverse effect of intravitreal injection of pure triamcinolone on electroretinography or on light or electron microscopy. Hida and coworkers 19 investigated the toxicity of the vehicles used in commercial steroid preparations and found no adverse effect on the retina or lens from the vehicle in Kenalog. In our series, no patient had significant ocular complications20 •21 except for transient ocular hypertension. In two eyes the rise in lOP was significant but was reversed with topical administration of 0.15% brimonidine. The pressure spikes occurred at various times, as early as 1 week after injection. The lOP must be monitored carefully during the follow-up of patients who receive an intravitreal triamcinolone injection. 22 There was no obvious indication of increased cataract progression in our series, but this was not specifically assessed owing to the retrospective nature of the study. In one patient triamcinolone was seen in the inferior anterior chamber for 2 months after the injection, forming a pseudohypopyon, 23 but caused no problems. We do not know whether the eyelid ptosis in an elderly patient with coexisting dehiscence of the levator aponeurosis was related to the intravitreal tri-
amcinolone or to the use of an eyelid speculum. Singh and coworkers 24 reported incidence rates of ptosis after cataract surgery of 44% when an eyelid speculum was used and 23% when no speculum was used; they concluded that the cause of the ptosis was multifactorial. This is a pilot study and has limitations imposed by those of a retrospective study, including lack of protocol refraction and the somewhat subjective nature of fluorescein angiogram interpretation. In conclusion, intravitreal injection of triamcinolone is a promising adjunct in the treatment of diabetic macular edema. It may be useful as an alternative primary treatment to focal laser photocoagulation, especially in eyes in which leakage occurs predominantly in the centre of the fovea, which are particularly likely to undergo damage from direct laser treatment and subsequent migration of subretinal scars. It may also be used in conjunction with focal laser photocoagulation when the response to photocoagulation alone is deemed to be unsatisfactory. Our angiographic results may support the role of intravitreal triamcinolone injection earlier in the course of diabetic macular edema, before irreversible retinal changes occur. However, intravitreal triamcinolone lasts for about 3 months, 16 and recurrence of macular edema is common, necessitating repeat injections. Owing to the retrospective nature of our study, we cannot draw conclusions regarding the longterm risks or benefits of this procedure. A randomized clinical trial is needed in this regard. REFERENCES
1. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 1. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmoll985;l03(l2):l796-806. 2. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1987;94(7):761-74. 3. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol 1995; 113(9):1144-55. 4. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmoll99l;l09(11):l549-5l. 5. Lewis H, Abrams GW, Blumenkranz MS, Campo RV.
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Key words: injections, intravitreal; triamcinolone acetonide; diabetes mellitus; macula lutea; intraocular pressure; fluorescein angiography; visual acuity