Ординатура / Офтальмология / Английские материалы / Diabetic Retinopathy_Lang_2007

from 26.5 12.1 to 21.75 11.3 mm Hg. This suggests that IVTA, mostly in combination with a retinal ablative procedure, may be an additional option in the treatment of neovascular glaucoma.

Progressive ocular hypotony or prephthisical ocular hypotony can be a complication of ciliary destructive procedures as surgical treatment for neovascular glaucoma due to proliferative diabetic retinopathy. In an attempt to use a side effect of steroids as desired effect, triamcinolone acetonide was injected intravitreally into 3 eyes with longstanding prephthisical ocular hypotony [49, 50]. In all 3 patients, intraocular pressure and visual acuity increased after the injection, associated with a stabilization of the eyes. It suggests that in some eyes with long-standing prephthisical ocular hypotony, intravitreal injection of triamcinolone acetonide can be beneficial to increase intraocular pressure and stabilize the eye.

Cataract is one of the most common ophthalmologic diseases in the elderly population. Therefore, it is common that cataract is present in eyes additionally showing other age-related disorders, such as diabetic retinopathy. Since these diseases may be treatable by intraocular injections of triamcinolone acetonide, and because intraocular triamcinolone acetonide by itself may further increase a preexisting lens opacification, it may be useful to combine an intravitreal injection of triamcinolone acetonide with cataract surgery. Taking into account that one has just recently started to clinically evaluate intravitreal injections of triamcinolone acetonide, and in view of the already known complications and side effects of intraocular triamcinolone acetonide, any additional procedure may further increase the frequency and enlarge the spectrum of complications of the new therapy. However, in a recent clinical investigation, frequencies of postoperative infectious endophthalmitis, wound leakage or other corneal wound healing problems, persisting corneal endothelial decompensation, rhegmatogenous retinal detachment, marked postoperative pain, or a clinically significant decentration of the intraocular lens did not vary between a study group of 60 eyes undergoing cataract surgery with implantation of a posterior chamber lens and an additional intravitreal injection of about 20 mg triamcinolone acetonide and a control group of 290 eyes consecutively receiving IVTA without additional intraocular cataract surgery [51]. It was concluded that for a mean follow-up of about 9 months, the frequency and the amount of complications of an intravitreal injection of triamcinolone acetonide, such as increased intraocular pressure, do not markedly differ whether the injection is combined with a standard cataract surgery or not. A similar conclusion was drawn in a study by Lam et al. [19] on 19 eyes of 15 consecutive diabetic patients with cataract and diabetic macular edema, in which phacoemulsification with concurrent intravitreal injection of 4 mg triamcinolone acetonide appeared to be a safe option for managing diabetics with cataract and diabetic macular edema.

Since steroids applied in a high dosage may lead to several changes, such as alterations in collagenous structures and the immunologic status, intraocular surgery performed after an intravitreal application of triamcinolone acetonide may have an unusual spectrum of complications. Addressing this question, a case series study included 22 patients presenting with cataract which had progressed after a single or repeated intravitreal injection of about 20 mg of triamcinolone acetonide for the treatment of exudative age-related macular degeneration or diffuse diabetic macular edema [52]. During routine phacoemulsification surgery, an intraoperative dialysis of the lens zonules with vitreous prolapse occurred in 1 eye (4.5%). During the postoperative follow-up, an optically significant decentration of the intraocular lens or infectious endophthalmitis was not encountered in any patient. It was concluded that cataract surgery after single or repeated intravitreal injections of about 20 mg triamcinolone acetonide may not harbor a markedly elevated frequency or a markedly changed profile of complications of standard cataract surgery.

In patients with dense cataract and iris neovascularization due to proliferative diabetic retinopathy, the lens opacification prevents a transpupillary laser coagulation of the retina. However, an intraocular intervention such as cataract surgery will lead to a marked postoperative inflammation if iris neovascularization is additionally present. In that clinical situation, cataract surgery has been combined with an intravitreal injection of triamcinolone acetonide [53]. In the postoperative period, visual acuity increased, and without additional retinal ablative treatments, iris neovascularization markedly regressed within the first 5 weeks after surgery. The study suggested that IVTA can be a useful adjunctive treatment tool in eyes with iris neovascularization undergoing cataract surgery, and that IVTA may have an antiangiogenic effect.

The use of IVTA is associated with several complications. One of the two most common side effects of IVTA was the steroid-induced elevation of intraocular pressure [54–56]. A recent prospective clinical interventional comparative nonrandomized study included 260 consecutive patients (293 eyes) receiving an intravitreal injection of 20–25 mg triamcinolone acetonide as treatment for diffuse diabetic macular edema, exudative age-related macular degeneration, retinal vein occlusions, uveitis and cystoid macular edema [56]. Intraocular pressure readings higher than 21, 30, 35 and 40 mm Hg were measured in 94 (36.2%), 22 (8.5%), 11 (4.2%) and 4 (1.5%) patients, respectively. Triamcinolone-induced elevation of intraocular pressure could be treated by antiglaucomatous medication in all but 3 eyes (1.0%), for which filtering surgery became necessary. About 40% of the patients developed a secondary ocular hypertension, starting about 1 week after the injection in few eyes and occurring about 1–2 months after the intravitreal injection of 20–25 mg triamcinolone acetonide in most eyes, developing an ocular hypertension. Using this

dosage, the increase in intraocular pressure lasted about 7–9 months after which the intraocular pressure measurements return to the normal range without any further antiglaucomatous medication taken. Younger age was a significant factor contributing to the triamcinolone acetonide-induced increase in intraocular pressure. Diagnosis of diabetes mellitus or presence of a clinically significant diffuse diabetic macular edema did not influence the reaction of intraocular pressure after the injection. It agrees with previous randomized clinical trials in which diabetes mellitus was not a major risk factor for glaucoma [56]. Therefore, from a clinical point of view, diagnosis of diabetes mellitus may not be contradictory against IVTA. This fits with another aforementioned study, in which patients after IVTA did not show any, or only traces of, triamcinolone acetonide in the serum [43].

Those patients who received a second injection of 20–25 mg triamcinolone acetonide showed a similar reaction of intraocular pressure to that after the first injection [56]. This result suggests that if after a first injection intraocular pressure remained in the normal range, intraocular pressure may also remain in the normal range after a second injection. In a similar manner, if intraocular pressure increased after the first injection, a similar rise in intraocular pressure can be expected after a second injection. So far, there are no reports on a permanent rise in intraocular pressure after an intravitreal injection of triamcinolone acetonide.

Comparing studies using different dosages of triamcinolone acetonide for intravitreal injection suggests that the higher the dosage, the longer the duration of the steroid-induced ocular hypertension [7, 10, 16, 17, 20, 21, 26, 27, 34, 35, 58]. The figures of the frequency of secondary ocular hypertension may not be directly correlated with the dosage injected. In the study performed by Smithen et al. [58] with the intravitreal use of 4 mg triamcinolone acetonide, a pressure elevation defined as a pressure of 24 mm Hg or higher during the follow-up was found in 36 (40.4%) out of 89 patients at a mean of 101 83 days after the injection. Out of nonglaucomatous patients with a baseline intraocular pressure of 15 mm Hg or above, 60.0% experienced a pressure elevation, compared with only 22.7% of those with baseline pressures below 15 mm Hg. In glaucoma patients, 6 of 12 (50%) experienced a pressure elevation, and this elevation was not correlated with baseline pressure. Thirty-two patients (36.0%) received repeated injections, and there was no difference in the incidence of procedure elevation in patients receiving multiple injections versus those receiving a single injection. Pressure elevation was controlled with topical medications in all patients. Using a dosage of 8 mg triamcinolone acetonide, Ozkiris and Erkilic [59] detected a transient elevation of intraocular pressure above 21 mm Hg in 20.8% of eyes. The average intraocular pressure rose by 28.5, 38.2, 16.7 and 4.2% from baseline at 1, 3, 6 and 9 months, respectively.

If further studies confirm the assumption that the frequency of secondary ocular hypertension after an intravitreal injection of triamcinolone acetonide does not markedly depend on the dosage used, one may assume that relatively low triamcinolone acetonide dosages are already so high that all steroid receptors are occupied. One has to take into account that the eye makes out about 0.01% of the body volume. Assuming an equal distribution of triamcinolone acetonide throughout the body, an intravitreal injection of 4 mg is equal to a intragluteal injection of 40 g, and an intravitreal injection of 25 mg triamcinolone acetonide is equal to a quarter of a kilogram injected intragluteally.

Another complication of IVTA is the postinjection infectious endophthalmitis. In recent studies on patients receiving an intravitreal injection of triamcinolone acetonide, the frequency of postinjection infectious endophthalmitis ranged between 0/700 and 8/992 (0.87%) [60–64]. The risk of an infectious endophthalmitis may partially depend on the setting of the injection itself. The studies suggest that if the injection is performed under sterile conditions, the risk may be less. Histologically, eyes with IVTA and infectious endophthalmitis show a marked destruction of the whole globe and a morphallaxia-like morphology [65]. It may go along with the clinical observation that patients with infectious endophthalmitis after IVTA usually have almost no pain. With respect to susceptibility to infectious endophthalmitis, a recent experimental study showed that rabbit eyes with IVTA have a significantly higher rate of apparent intraocular infection than rabbits without IVTA [66]. Concerning the multiple use of triamcinolone acetonide-containing bottles, another investigation [67] showed that even after 24 h of exposure to the benzyl alcohol preservative, four of five challenge organisms demonstrated moderate growth in the bottle so that the use of multiple-dose containers of triamcinolone for intravitreal injections may be discouraged.

A ‘sterile endophthalmitis’ has been described to occur after an intravitreal injection of triamcinolone acetonide [63, 64, 68]. It has been inconclusive so far whether the solvent agent of triamcinolone acetonide is the cause for the sterile intraocular inflammation after the injection, and whether the solvent agent should be removed. The disadvantage of removal of the solvent agent is that the dosage gets inaccurate [69, 70]. Bakri et al. [71] reported on the use of a commercially available preservative-free solution of triamcinolone acetonide, and Hernaez-Ortega and Soto-Pedre [72] described the use of density gradient centrifugation to remove the preservative.

Postinjection pseudo-endophthalmitis is present if triamcinolone acetonide crystals are washed from the vitreous cavity into the anterior chamber and settle down in the inferior anterior chamber angle mimicking a hypopyon [73–76]. The diagnostic problem is the differentiation between a painless hypopyon caused by postinjection infectious endophthalmitis and a pseudo-hypopyon due

to triamcinolone acetonide crystals. So far, there have been no reports showing a corneal endothelial damage or a damage to the trabecular meshwork by the crystals.

A postinjection, steroid-induced cataract is one of the most frequent complications or side effects of IVTA. In a recent study on 144 phakic eyes which consecutively received an intravitreal injection of about 20 mg triamcinolone acetonide for diffuse diabetic macular edema, exudative age-related macular degeneration and branch retinal vein occlusion, cataract surgery was performed in 20 eyes (13.9%) 17.4 9.1 months (median 12.7 months, range 8.0–35.5) after the intravitreal injection [77]. Out of the 20 eyes undergoing cataract surgery, 19 eyes (95%) had received one intravitreal injection, and 1 eye (5%) had received two previous injections. It was concluded that in the elderly population of patients with exudative age-related macular degeneration, diffuse diabetic macular edema or branch retinal vein occlusion, intravitreal high-dosage injection of triamcinolone acetonide leads to clinically significant cataract with eventual cataract surgery in about 15–20% of eyes within about 1 year after the intravitreal injection.

In an analysis of longitudinal data from a randomized, double-masked, placebo-controlled trial of intravitreal triamcinolone for age-related macular degeneration, Gillies et al. [78] compared 57 phakic eyes in the treatment group with 4 mg triamcinolone acetonide versus 54 phakic eyes in the control group. They found that progression of posterior subcapsular cataract by 2 or more grades in the treatment group was significantly higher among 16 intraocular pressure responders (51% after 2 years) than among 37 nonresponders (3%; p 0.0001). There was no significant progression of posterior subcapsular cataract in the placebo group or the opposite eye of the treatment group. Progression of cortical cataracts was also significantly higher among responders than among nonresponders (15 vs. 3%; p 0.015). The progression of nuclear cataracts (13 vs. 3%) was not significantly different between intraocular pressure responders and nonresponders (p 0.3). The authors concluded that although steroid-related cataracts were unlikely to develop in eyes that do not experience an elevation of intraocular pressure after intravitreal triamcinolone, those eyes that do experience an elevation also have a very high risk of rapidly experiencing posterior subcapsular lens opacification. They postulated that the strong association suggests a similar mechanism responsible for the development of steroid-induced posterior subcapsular cataract and for the elevation of intraocular pressure.

Direct toxic effects of triamcinolone acetonide on the retina and optic nerve have not been observed yet, independently of the dosage used. Correspondingly, a recent safety and efficacy study of an intravitreal fluocinolone acetonide-sustained delivery device as treatment for cystoid macular

edema in patients with uveitis and other clinical and experimental studies have not shown a toxic effect of intraocular steroids [39, 41]. The same was found by Hida et al. [79]. However, a recent study performed by Yeung et al. [80] reported a possible cytotoxic effect of triamcinolone acetonide. Yeung et al. [80] cultured a retinal pigment epithelium cell line (ARPE19) and added corticosteroids (0.01–1 mg/ml) or vehicle (benzyl alcohol, 0.025%), diluted in culture medium. Subsequently, the culture medium containing corticosteroid or vehicle was refreshed daily. After 1, 3 and 5 days, the proliferated amount of cells with and without corticosteroid treatment was determined. They found that triamcinolone acetonide caused a significant reduction in cell numbers throughout the whole range of concentrations when cells were exposed for more than 1 day. Compared with dexamethasone and hydrocortisone, triamcinolone acetonide showed a higher relative toxicity. The vehicle alone had no effect. In a similar study, Yeung et al. [81] compared the cytotoxic effect of triamcinolone acetonide on human retinal pigment epithelium (cell line ARPE19) and human glial cells over a range of concentrations and durations of exposure. They found that triamcinolone acetonide caused a significant reduction in the retinal pigment epithelium cell line ARPE19 that had been exposed to the substance for more than 1 day. Significant reductions in the number of glial cells were observed as early as day 1. The glial cells appeared to be more susceptible to triamcinolone acetonide. The vehicle of triamcinolone acetonide had no effect.

In conclusion, the intravitreal injection of triamcinolone acetonide may possibly open new avenues for the treatment of intraocular edematous and neovascular diseases [82]. However, as for any new therapy, one has to be very careful since long-term experience has not been available yet. There are many open issues still to be addressed. What may be the best dosage for which disease and for which clinical situation? Is the proliferation of retinal pigment epithelium cells in high concentrations of triamcinolone acetonide decreased and, paradoxically, increased in low concentrations [83]? What is the best mode of application of triamcinolone acetonide? Is the sub-Tenon application, the subconjunctival application or the retrobulbar application better than the intravitreal injection? Are there other complications than those already described in clinical studies or after accidental injection of triamcinolone acetonide into the vitreous cavity? Is it necessary to remove the solvent agent prior to the intraocular injection, and how should the solvent agent be removed? The most fascinating point is that the intravitreal injection of triamcinolone acetonide together with previous clinical experiences on the use of intravitreal antibiotics and virustatic drugs makes one infer that retinal diseases may become locally treatable diseases. Unbelievably high intraocular concentrations of drugs become achievable, and systemic side effects may mostly be avoided.

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Dr. Jost B. Jonas Universitäts-Augenklinik Theodor-Kutzer-Ufer 1–3 DE–68167 Mannheim (Germany)

Tel. 49 621 383 2652, Fax 49 621 383 3803 E-Mail Jost.Jonas@augen.ma.uni-heidelberg.de