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Correspondence to:
S A Vernon
Department of Ophthalmology, Queens Medical Centre, University Hospital, Nottingham NG7 2UH, UK; stephen.vernon@qmc.nhs.uk
Which dosage should we use?
Keywords: diabetic retinopathy; corticosteroids; macular oedema; intravitreal drug delivery
It is less than 4 years ago since publication of the first report on the use of crystalline cortisone in the form of triamcinolone acetonide to treat recalcitrant macular oedema in patients with diabetes.1 This report of a single eye was rapidly followed by a case series from the same author (Jonas),2 who has remained faithful to a dosage regimen of 20 mg in a number of publications documenting the efficacy and side effects of this novel form of therapy.3–8 In parallel with Jonas, Martidis and co-workers in the United States9 reported on the use of a 4 mg dosage in a similar clinical scenario. Since then there have been many reports, including early results from a randomised controlled trial (RCT), utilising this somewhat lower dosage.10–15 All studies have thus far indicated a significant improvement in macular function and/or structure following injection, at least in the short term.
Why have different dosage regimens been employed? Triamcinolone acetonide is conveniently and affordably available in concentrations of 40 mg/ml in a sterile preparation (Kenolog, or Volon A or Kenacort depending on country, Bristol-Myers-Squibb) used commonly in other specialties such as orthopaedics. As 0.1 ml is the maximum volume most eyes can tolerate when injected into the vitreous cavity without causing inevitable central retinal artery occlusion, the maximum dosage of unadulterated triamcinolone one can give at any one time without resorting to paracentesis is clearly 4 mg. Jonas concentrates the triamcinolone crystals using a filter and then injects (after a routine paracentesis) 0.2 ml of a suspension of triamcinolone and Ringer’s solution (0.4 ml in the comparative dosage study in this issue of the BJO (p 999)).
In the aforementioned study, a small RCT comparing the efficacy of three dosages of triamcinolone (assayed to be 2 mg, 5 mg, and 13 mg of injected triamcinolone), Spandau and colleagues from Jonas’s team make a case for the use of the higher dosage in diabetic macular oedema (13 mg was found to be the equivalent of a 20 mg stated dose in Jonas’s previous studies). This was based upon a significantly improved outcome in terms of maximum distance visual acuity in the 13 mg group compared with the 2 mg group (but notably not the 5 mg group—a dosage closest to that probably injected in all other series), and a finding of a significant dose/duration effect correlation when all three doses were considered. There are a number of unanswered questions posed by the study such as the duration of oedema before treatment and the numbers in each group who had received laser treatment. It would also be tempting to discount this small study after viewing the data points on the figures where it can be seen that one or two eyes in the 13 mg group appear to be having a disproportionate influence on the results. The results, however, appeal somewhat intuitively, and merit further consideration.
Whether vitrectomy or intravitreal triamcinolone, perhaps combined with cataract surgery, proves to be optimal for an individual patient/eye will require much more research
Examination of the literature, comparing Jonas’s results with those of others, fails to create a clearcut difference in outcome between dosage regimens for many reasons. These include differing entry criteria (with or without previous macular laser, duration of oedema, levels of acuity at baseline), methods of acuity measurement (EDTRS chart versus Snellen chart), the presence or lack of supporting evidence of efficacy such as optical coherence tomography (OCT), and methods of comparison (randomised trial versus non-randomised case or case-control series). However, a common feature of all series extending to 6 months or longer is a rapid improvement phase, followed by a plateau phase and then regression, at least in some eyes.
Martidis et al,9 using 4 mg, reported that three of the eight eyes at 6 months required re-injection for recurrence of oedema with loss of vision. In the study by Massin et al11 (4 mg), the difference in macular thickness (which correlates well with visual improvement) measured by OCT at 6 months compared with baseline had become non-significant owing to recurrence of oedema in five of the 12 injected eyes. In addition, at no stage was there a significant difference between the acuity in treated and the control (untreated) eyes. However, Sutter et al (RCT with 4 mg versus subconjuctival placebo),10 at 3 months, showed a significant visual improvement in treated eyes with 24% improving by 10 or more EDTRS letters. In the study by Ciardella et al,12 8/30 (27%) of eyes had received at least one re-injection (again 4 mg) because of recurrence of oedema at a median time of 6 months between the first and second injection. Audren et al,16 used pharmacokinetic-pharmacodynamic modelling of OCT readings, estimated the mean maximum duration of effect of a 4 mg injection to be 140 days. In Jonas’s largest series to date, in which triamcinolone was the only treatment for diabetic macular oedema, a dosage of 20 mg (probably 13 mg active triamcinlone) resulted in an improvement of at least two Snellen lines in 68% of the 97 treated eyes with a mean increase of 2.6 lines at best.4 There was no tendency to regress over the first 4 months following injection but by 6 months the effect of injection on acuity had become insignificant in a group analysis, a finding similar to our own series13 utilising a 4 mg injection.
The lack of any comparative data on lens morphology and density and macular thickness in Spandau’s study is unfortunate as acuity some months after injection may be compromised by cataract formation.17 Comparative data on all aspects of visual function, including the much neglected reading ability13,18 and complication rates, in particular cataract and glaucoma, will only be answered by further prospective RCTs, which should begin to utilise subjective patient generated outcome measures relating visual improvement to time of perceived benefit.
The use of intravitreal triamcinolone has given new hope to many patients with chronic diabetic macular oedema often permitting them to read again, even if only for a few months.13,18 Whether vitrectomy19 or intravitreal triamcinolone, perhaps combined with cataract surgery,20 proves to be optimal for an individual patient/eye will require much more research. The National Eye Institute in the United States has funded studies examining the efficacy of intraocular steroids in diabetic retinopathy and retinal vein occlusion.21 Those practising elsewhere should take into account the results from Professor Jonas’s team when formulating their protocols for similar research.
REFERENCES
Jonas JB, Sofker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425–7.
Jonas JB, Kreissig I, Sofker A, et al. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol 2003;121:57–61.
Jonas JB, Harder B, Kamppeter BA. Inter-eye difference in diabetic macular edema after unilateral intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 2004;138:970–7.
Jonas JB, Akkoyun I, Kreissig I, et al. Diffuse diabetic macular oedema treated by intravitreal triamcinolone acetonide: a comparative, non-randomised study. Br J Ophthalmol 2005;89:321–6.
Jonas JB, Kreissig I, Degenring RF, et al. Repeated intravitreal injection of triamcinolone acetonide for diffuse diabetic macular oedema. Br J Ophthalmol 2005;89:122.
Jonas JB, Degenring R, Kreissig I, et al. Safety of intravitreal high-dose reinjections of triamcinolone acetonide. Am J Ophthalmol 2004;138:1054–5.
Jonas JB, Degenring RF, Kamppeter BA, et al. Duration of the effect of intraviteal triamcinolone acetonide as treatment for diffuse diabetic macular edema. Am J Ophthalmol 2004;138:158–60.
Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87:24–7.
Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920–7.
Sutter FKP, Simpson JM, Gillies MC. Intravitreal traimcinolone for diabetic macular edema that persists after laser treatment. Ophthalmology 2004;111:2044–9.
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Gillies MC, Simpson JM, Billson FA, et al. Saftey of an intravitreal injection of triamcinolone—results from a randomised clinical trial. Arch Ophthalmol 2004;122:336–40.
Islam MS, Negi A, Vernon SA. Improved visual acuity and macular thickness 1 week after intravitreal triamcinolone for diabetic macular oedema. Eye. 2004 .
Yamamoto T, Akabane N, Takeuchi S. Vitrectomy for diabetic macular edema: the role of posterior vitreous detachment and epimacular membrane. Am J Ophthalmol 2001;132:369–77.
Lam DSC, Chan CKM, Mohamed S, et al. Phacoemulsification with intravitreal triamcinolone in patients with cataract and coexisting diabetic macular oedema: a six-month prospective pilot study. Eye. 2004 .
Flynn HW, Scott IU. Intravitreal triamcinolone acetonide for macular edema associated with diabetic retinopathy and venous occlusive disease. Arch Ophthalmol 2005;123:258–9.