Editor’s comment: From time to time, treatments for diabetes and its complications are promulgated, which seem to have sufficient nonrandomized clinical data to support their consideration for use in our patients. Rather than wait for randomized clinical trials to be published (and in some cases, this is unlikely to occur), descriptions of these treatments, their effectiveness, and their side effects will be published in Diabetes Care as a Commentary. In many situations, these therapeutic approaches would only be considered after more conventional therapy has been ineffective. Intraocular injections of glucocorticoids for macular edema fit these criteria.

Diabetic retinopathy is a major cause of visual impairment in the U.S. (13). Diabetic macular edema is a manifestation of diabetic retinopathy that produces loss of central vision and is commonly diagnosed by ophthalmologists. The Wisconsin Epidemiologic Study of Diabetic Retinopathy estimated that after 15 years of known diabetes, the prevalence of diabetic macular edema is ∼20% in patients with type 1 diabetes, 25% in patients with type 2 diabetes who are taking insulin, and 14% in patients with type 2 diabetes who do not take insulin (1).

Diabetic macular edema, because of the frequency with which it is seen, is a condition that has considerable public health importance. Currently, the only demonstrated means to reduce the risk of vision loss from diabetic macular edema are intensive glycemic control, as demonstrated by the Diabetes Control and Complications Trial (DCCT) (4) and the U.K. Prospective Diabetes Study (5), and laser photocoagulation, as demonstrated by the Early Treatment Diabetic Retinopathy Study (ETDRS) (6).

In the DCCT, intensive glucose control reduced the risk of onset of diabetic macular edema by 23% compared with conventional treatment. Long-term follow-up of patients in the DCCT show a sustained effect of intensive glucose control, with a 58% risk reduction in the development of diabetic macular edema for the DCCT patients followed in the Epidemiology of Diabetes Interventions and Complications Study (7).

In the ETDRS, laser photocoagulation of eyes with diabetic macular edema reduced the risk of moderate visual loss by ∼50% (from 24 to 12%, 3 years after initiation of treatment) (6). These results show that for some patients, laser photocoagulation is effective but that 12% of treated eyes developed moderate visual loss in spite of treatment. Furthermore, ∼40% of treated eyes that had retinal edema involving the center of the macula at baseline still had edema involving the center at 12 months, as did 25% of treated eyes at 36 months (8).

The frequency of an unsatisfactory outcome following laser photocoagulation in some eyes with diabetic macular edema has prompted interest in other treatments. One such treatment is a procedure to remove the vitreous humor from the eye (vitrectomy surgery) (911). These studies suggest that vitreomacular traction, or the vitreous itself, may play a role in increased retinal vascular permeability. Removal of the vitreous or relief of mechanical traction with vitrectomy may, in some patients, be followed by substantial resolution of macular edema and corresponding visual rehabilitation. However, this treatment may be applicable only to a specific subset of eyes with diabetic macular edema. It also requires a significant and complex surgical intervention. Other treatments such as pharmacologic therapy with oral protein kinase C inhibitors and intravitreal injection of antibodies targeted at vascular endothelial growth factor (VEGF) are under investigation. Recently, delivery of corticosteroids via the vitreous cavity to treat diabetic macular edema has generated significant interest. The delivery route may be via either a sustained release, surgically placed intravitreal implant or via injection of corticosteroid, using a 27- or 30-gauge needle, directly into the vitreous cavity of the eye (intravitreal injection). The remainder of this commentary will discuss intravitreal injection of corticosteroid for diabetic macular edema.

The rationale for the use of corticosteroids to treat diabetic macular edema follows from the observation (12) that the increase in retinal capillary permeability that results in diabetic macular edema may be caused by a breakdown of the blood retina barrier mediated in part by VEGF, a 45-kDa glycoprotein. Antonetti et al. (13) demonstrated that VEGF may regulate vessel permeability by increasing the phosphorylation of tight junction proteins such as occludin and zonula occluden 1. This model provides, at the molecular level, a potential mechanism for VEGF-mediated vascular permeability in the eye. Similarly, in human nonocular disease states such as ascites, VEGF has been characterized as a potent vascular permeability factor (14).

Pharmacologic attenuation of the effects of VEGF is the rationale for the use of corticosteroids in the treatment of macular edema associated with diabetic retinopathy. Corticosteroids, a class of substances with anti-inflammatory properties, have been demonstrated to inhibit the expression of the VEGF gene (15). In a study by Nauck et al. (15), the platelet-derived growth factor-induced expression of the VEGF gene in cultures of human aortic vascular smooth muscle cells was inhibited by corticosteroids in a dose-dependent manner. A separate study by Nauck et al. (16) demonstrated that corticosteroids downregulate the induction of VEGF by the proinflammatory mediator platelet-derived growth factor and platelet-activating factor, in a time- and dose-dependent manner.

Intravitreal injection has been proposed as a way to efficiently deliver corticosteroid to the posterior portion of the eye, in close proximity to the retina. Triamcinolone acetonide is the corticosteroid currently used by ophthalmologists in the clinical setting because it is a readily available pharmacologic agent (Kenalog 40; Bristol-Myers-Squibb, Princeton, NJ).Currently, the typical dose of triamcinolone acetonide used to treat eyes with diabetic macular edema is 4 mg in a volume of 0.1 ml (17).

Triamcinolone acetonide has traditionally been used as a periocular injection for the treatment of macular edema secondary to inflammation or following intraocular surgery (typically cataract surgery) (18,19). To achieve a higher intraocular concentration of corticosteroid to treat retinal disease, the intravitreal injection of triamcinolone acetonide was first proposed in the 1970s, in an animal model, as a pharmacological adjunct to prevent the formation of proliferative scar tissue (proliferative vitreoretinopathy) in order to improve outcomes following retinal detachment surgery (20). Since then, pure triamcinolone acetonide and the vehicle in Kenalog have been shown to have an acceptable safety profile in animal studies (21,22). Subsequent to the demonstration of the safety profile of intravitreal Kenalog in animal models, intravitreal triamcinolone in the form of Kenalog has been used clinically in a variety of retinal diseases, such as age-related macular degeneration (2325).

Intravitreal triamcinolone acetonide was first proposed, in 1999, as a treatment for diabetic macular edema because of the safety profile demonstrated in animal models, prior clinical experience with other retinal diseases, and the rationale of attenuating the VEGF-mediated retinal capillary permeability that is presumed to contribute to diabetic macular edema. The use of intravitreal triamcinolone acetonide is now widespread among ophthalmologists who specialize in the treatment of retinal disease. The treatment has become common as a result of initial anecdotal experiences showing great promise in patients with diabetic macular edema as well as other ophthalmologic disorders, such as retinal vascular occlusion and certain inflammatory disorders. Some patients experience rapid and dramatic resolution of macular edema and improvement in visual acuity (26). Furthermore, the treatment is inexpensive and readily available, using commercially available Kenalog. The treatment is also easy to administer. It is typically performed in the outpatient setting using only topical anesthesia, and a small-bore needle (e.g., 27 or 30 gauge) is used to deliver the medication into the vitreous cavity of the eye via the pars plana portion of the globe. However, despite the extensive use of intravitreal corticosteroids, published data are limited. There have been no published controlled trials of intravitreal corticosteroids for diabetic macular edema. Two nonrandomized and noncontrolled case series have been published (Table 1).

Martidis et al. (17) reported results using intravitreal triamcinolone acetonide injection in 16 eyes with macular edema due to diabetic retinopathy. All 16 eyes had persistent macular edema after having received multiple sessions of laser photocoagulation. Using a diagnostic technique named optical coherence tomography, it was demonstrated that the mean thickness of the central macula decreased from 540 μm before injection (at baseline) to 242 μm after injection (the normal average thickness of the central macula is ∼175 μm). Visual acuity improved by 2.4, 2.4, and 1.3 lines (from the baseline value) at the 1-, 3-, and 6-month follow-up intervals, respectively.

Jonas et al. (27) described the results of intravitreal triamcinolone acetonide injection in 26 eyes with macular edema due to diabetic retinopathy. All 26 eyes had visual acuity loss due to diabetic macular edema for at least 1 year. The mean follow-up time was 6.6 months. For the 21 patients in whom both the preinjection and postinjection fluorescein angiogram was available, evaluation showed decreased fluorescein leakage following intravitreal injection in all patients. Visual acuity improved from a mean of 20/165 at baseline to a mean of 20/105 at the end of follow-up. In comparison, 16 patients followed in a control group who received laser photocoagulation showed no improvement in visual acuity.

The results of such published studies as well as myriad anecdotal reports have generated intense interest in the use of this treatment. The technique was originally utilized only in patients who were refractory to prior laser photocoagulation treatment. As the technique has become more familiar to ophthalmologists, it is increasingly being utilized as a first-line therapy for some patients with diabetic macular edema. However, the enthusiasm for the use of intravitreal steroids is often tempered by the adverse effect profile seen in these published series and in anecdotal reports. These adverse events are related to both the injection itself and the potential toxicity of corticosteroids. Injection-related events include bacterial infection of the eye (endophthalmitis), vitreous hemorrhage, and retinal detachment. The potential toxicity of corticosteroids includes the development of cataracts and glaucoma. Furthermore, the treatment effect typically wanes, and patients who are initially successfully treated may require repeated injections. With each repeat injection, the patient is again subjected to the risks of the injection procedure and the risk of a steroid-related cataract and/or glaucoma increases.

Another unresolved issue with the use of this technique is that commercially available Kenalog is formulated specifically for intrabursal and intramuscular use and not for intravitreal use, necessitating “off-label” use of Kenalog by the ophthalmology community. There have been several anecdotal reports of inflammatory reactions, possibly to one of the excipients in the Kenalog formulation, following intravitreal injection of Kenalog. These sterile inflammatory reactions are often difficult to distinguish from a postinjection bacterial infection of the eye. Ultimately, the manufacture of a formulation for intravitreal use (i.e., preservative free, endotoxin free, and sterile) may alleviate some of the current concerns about the use of the Kenalog formulation.

One final unresolved issue concerning the use of intravitreal Kenalog is that the optimal dose to maximize efficacy and minimize side effects is not known. The commonly used dose of 4 mg/0.1 ml is principally being used because of convenience. At a shelf dosage of 40 mg/ml, Kenalog is easily aliquoted to a 4 mg/0.1 ml dose. A volume of 0.1 ml is readily tolerated when injected into the vitreous cavity. Other than the convenience of this dose, there are no data that support the use of 4 mg over any other alternative dose.

As a result of the potential for improvement in visual acuity in an ocular condition that does not often have good treatment options and for serious sight-threatening complications as described above, there is currently a need for a randomized trial to better define the efficacy and safety profile of this treatment. The Diabetic Retinopathy Clinical Research Network (www.drcr.net) is a National Eye Institute-sponsored research infrastructure dedicated to multicenter clinical research of diabetic retinopathy, macular edema, and associated disorders. One of the initial studies performed by this research network will be the study of intravitreal triamcinolone for the treatment of diabetic macular edema. This study is expected to begin the recruitment of patients in 2004 and will hopefully provide ophthalmologists answers in terms of the risk-to-benefit ratio of this new treatment for diabetic macular edema.

Table 1—

Efficacy of intravitreal steroids (published clinical studies)

StudyNo. eyes treatedDiseaseAnatomical improvementMean baseline visual acuityMean visual acuity at end pointMean follow-up (months)
Martidis et al. (1716 DME 11 of 16 eyes (69%)* 20/200 20/80 
Jonas et al. (2726 DME 21 of 21 eyes had less leakage (FA) 20/165 20/105 6.6 
StudyNo. eyes treatedDiseaseAnatomical improvementMean baseline visual acuityMean visual acuity at end pointMean follow-up (months)
Martidis et al. (1716 DME 11 of 16 eyes (69%)* 20/200 20/80 
Jonas et al. (2726 DME 21 of 21 eyes had less leakage (FA) 20/165 20/105 6.6 
*

Anatomical improvement documented by the technique of optical coherence tomography (a diagnostic technique that can measure the thickness of the retina).

DME, diabetic macular edema; FA, fluorescein angiography.

1
Klein R, Klein B, Moss S, Davis M, DeMets D: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. IV. Diabetic macular edema.
Ophthalmology
91
:
1464
–1474,
1984
2
Moss S, Klein R, Klein B: Ten-year incidence of visual loss in a diabetic population.
Ophthalmology
101
:
1061
–1070,
1994
3
Moss S, Klein R, Klein B: The 14-year incidence of visual loss in a diabetic population.
Ophthalmology
105
:
998
–1003,
1998
4
Diabetes Control and Complication Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med
329
:
977
–986,
1993
5
UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes: UKPDS 33.
Lancet
352
:
837
–853,
1998
6
Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema: ETDRS report number 1.
Arch Ophthalmol
103
:
1796
–1806,
1985
7
Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy.
N Engl J Med
342
:
381
–389,
2000
8
Early Treatment Diabetic Retinopathy Study Research Group: Early photocoagulation for diabetic retinopathy: ETDRS report number 9.
Ophthalmology
98
:
766
–785,
1991
9
Lewis H, Abrams G, Blumenkranz M, Campo R: Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction.
Ophthalmology
1992
:
753
–759,
1992
10
Harbour J, Smiddy W, Flynn HJ, Rubsamen P: Vitrectomy for diabetic macular edema associated with a thickened and taut posterior hyaloid membrane.
Am J Ophthalmol
121
:
405
–413,
1996
11
Tachi N, Ogina N: Vitrectomy for diffuse macular edema in cases of diabetic retinopathy.
Am J Ophthalmol
122
:
258
–260,
1996
12
Aiello LP, Bursell SE, Clermont A, Duh E, Ishii H, Takagi C, Mori F, Ciulla TA, Ways K, Jirousek M, Smith LE, King GL: Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective β-isoform-selective inhibitor.
Diabetes
46
:
1473
–1480,
1997
13
Antonetti D, Barber A, Hollinger L, Wolpert E, Gardner T: Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden.
J Bio Chem
274
:
23463
–23467,
1999
14
Senger D, Galli S, Dvorak A, Peruzzi C, Harvey V, Dvorak H: Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid.
Science
219
:
983
–985,
1983
15
Nauck M, Karakiulakis G, Perruchoud A, Papakonstantinou E, Roth M: Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells.
Euro J Pharmacol
341
:
309
–315,
1998
16
Nauck M, Roth M, Tamm M, Eickelberg O, Wieland H, Stulz P, Perruchoud AP: Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids.
Am J Resp Cell Mol Biol
16
:
398
–406,
1997
17
Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, Baumal C: Intravitreal triamcinolone for refractory diabetic macular edema.
Ophthalmology
109
:
920
–927,
2002
18
Yoshikawa K, Kotake S, Ichiishi A, Sasamoto Y, Kosaka S, Matsuda H: Posterior sub-Tenon injections of repository cortisteroids in uveitis patients with cystoid macular edema.
Jap J Ophthalmol
39
:
71
–76,
1995
19
Thach A, Dugel P, Flindall R, Sipperley J, Sneed S: A comparison of retrobulbar versus sub-Tenon’s corticosteroid therapy for cystoid macular edema refractory to typical medications.
Ophthalmology
104
:
2003
–2008,
1997
20
Machemer R, Sugita G, Tano Y: Treatment of intraocular proliferations with intravitreal steroids.
Tr Am Ophth Soc
77
:
177
–178,
1979
21
Hida T, Chandler D, Arena J, Machemer R: Experimental and clinical observations of the intraocular toxicity of commercial corticosteroid preparations.
Am J Ophthalmol
101
:
190
–195,
1986
22
McCuen B, Bressler N, Tano Y, Chandler D, Machemer R: The lack of toxicity of intravitreally administered triamcinolone acetonide.
Am J Ophthalmol
91
:
785
–788,
1981
23
Penfold P, Gyory J, Hunyor A, Billson F: Exudative macular degeneration and intravitreal triamcinplone: a pilot study.
Aust N Z J Ophthalmol
23
:
293
–298,
1995
24
Challa J, Gillies M, Penfold P, Gyory J, Hunyor A: Exudative macular degeneration and intravitreal tramcinolone: 18 month follow up.
Aust N Z J Ophthalmol
26
:
277
–281,
1998
25
Danis R, Ciulla T, Pratt L, Anliker W: Intravitreal triamcinolone acetonide in exudative age-related macular degeneration.
Retina
20
:
244
–250,
2000
26
Jonas J, Sofker A: Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema.
Am J Ophthalmol
132
:
425
–427,
2001
27
Jonas J, Kreissig I, Sofker A, Degenring R: Intravitreal injection of triamcinolone for diffuse diabetic macular edema.
Arch Ophthalmol
121
:
57
–61,
2003

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.