Intravitreal triamcinolone for diffuse diabetic macular oedema

Short abstract

How to improve the long term efficacy?

The treatment of diffuse diabetic macular oedema (DMO) has significantly improved in recent years: intravitreal triamcinolone acetonide (IVTA) has been shown to improve visual acuity (VA)¹,² and reduce central macular thickness (CMT) more effectively than laser treatment.³ IVTA is associated with a low incidence of surgical complications but with some side effects (increase in intraocular pressure, cataract development).

Since diabetes is a chronic disease, the long term efficacy of the treatment is fundamental. Unfortunately, recurrence of DMO after IVTA injection is a common finding; after a rapid decrease in CMT and a phase of stability, a relapse can occur after 3–6 months with the more common dosage of 4 mg³,⁴,⁵,⁶,⁷ and after 7–9 months with a higher dosage (20 mg).⁸ Recurrence can be treated with re‐injection of IVTA (up to three to four re‐injections have been reported),⁵ but unlimited repetition of IVTA injection cannot be offered to our patients, because it implies additional surgical risks and complications.

In the paper published in this issue of the BJO (p 1137), Chan and associates report the outcome after repeated injections of IVTA in patients with diffuse DMO who were good responders at the first injection.⁹ They report that, in spite of a significant reduction in macular thickness, the improvement in VA was smaller and not significant.

This raises the question of the utility of re‐injection, and emphasises the necessity of stable retinal conditions after triamcinolone treatment.

Several aspects of the efficacy of this treatment need to be clarified. The recurrence of DMO is related to the disappearance of triamcinolone from the vitreous: a mean elimination half life of 18.6 days has been found, and it was estimated that 4 mg of triamcinolone would last in the vitreous for 3 months.¹⁰ Re‐injection (at 5–6 months) has been reported in 30–40% of eyes treated with 4 mg IVTA.³,⁴,⁵,⁶,⁷ But the criteria used for re‐injection have been different in different studies: usually a VA decrease,⁵ sometimes to baseline values,¹¹ and increase of the retinal thickness (CMT >300 μm).⁴ In a prospective study, re‐injection was performed when a patient lost 50% of the VA improvement obtained with the first injection.³ The retrospective studies included cases with different systemic and ocular conditions, while in the prospective study, patients with hypertension, nephropathy, and poor diabetes control were excluded.³,⁶ Further studies of the efficacy of treatment with IVTA should evaluate the time course of the effect of IVTA, define the criteria for re‐injection, and take these possible confounding factors into account.

The condition of the retina is a key factor in the outcome of DMO: three kinds of alteration of macular structure in diabetic retinopathy detected by optical coherence tomography have been described: sponge‐like swelling, retinal oedema with cystoid spaces and retinal oedema with subfoveal fluid accumulation.¹² IVTA has been reported to be effective for diffuse DMO,¹,² cystoid DMO,³ and DMO associated with serous macular detachment,⁷ and improvement of VA after re‐injection has also been reported in the three conditions.

A long list of questions about the IVTA indicates a need of further investigation

However, a reduction in the efficacy of repeated injection has been found: Jonas and associates¹¹ reported in 22 eyes that received a second injection after a mean of 10 (SD 3) months (range 4–19 months), a VA increase from 0.98 to 0.67 logMAR after the first injection, and a significant increase from 1.09 to 0.90 logMAR at the second injection, with substantially decreased final VA. No data were given about cataract progression, which could have influenced the results. The effects of both injections lasted about 6–8 months, without signs of tachyphylaxis. These results are consistent with the findings of Chan and associates that re‐injection of IVTA does not improve VA.

Oedema in the outer retinal layers¹³ and long standing oedema are more disruptive, leading to irreversible damage to photoreceptors. Recurrence of DMO could also increase the formation of cystoid spaces. All these factors could reduce the efficacy of IVTA and explain the lack of correlation found between CMT reduction and VA improvement.¹⁴ In one study of cystoid macular oedema, IVTA re‐injection was performed when 50% of VA improvement had been lost.³ To postpone the treatment until VA returned to baseline values could lead to irreversible damage to the macular structure.

Then, some aspects of IVTA treatment could also be improved: the definition of the macular condition and the timing for more effective treatment; the triamcinolone dosage (now only 4 mg and 20 mg are used); and the role of concomitant laser (medical?) treatment. In one study, in eyes with no previous laser treatment, macular laser grid photocoagulation was performed 3 months after IVTA, in order to reduce the energy used in the laser treatment.³ Because of the small sample and short follow up (6–9 months), no net advantage was seen for IVTA or combined treatment. Recently, macular laser grid photocoagulation performed 3 weeks after IVTA was reported to improve VA and to reduce CMT at 3 months and 6 months, compared with IVTA.¹⁵ However, a broader series and longer follow up are needed determine the optimal combined treatment. Also, in previously laser treated eyes the efficacy of adjuvant laser treatment should be evaluated.

Additional laser treatment could be necessary in some patients or in eyes at risk because of systemic or ocular conditions.

Stabilisation of the retinal conditions should also be obtained in patients who will undergo cataract surgery, or who require peripheral laser treatment: timing and modalities of such treatments also need to be evaluated.

This long list of questions about the IVTA indicates a need of further investigation. In the meantime the use of IVTA is spreading in centres treating DMO, although it is used off‐label. Under the sponsorship of the National Eye Institute (NEI), several studies are in the recruiting phase in the United States.

Development of slow release devices could also improve the long term efficacy of therapy with triamcinolone.