Cystoid macular edema, part 2: the history of its prophylaxis and treatment. (See Part 1 here.)
Treatments of CME evolved with the improved understanding of disease pathogenesis. In 1964, H. Wyatt Laws in Montreal reported a retrospective series of 203 patients with “macular degenerative changes,” including eight patients with “postoperative cataract with macular edema” that were treated with oral peripheral vasodilators (nicotinic acid, nicotinyl alcohol, tolazoline, or nylidrin) for at least one year. Laws reported that among the eight patients with what we would now call CME, “seven out of eight improved dramatically and achieved corrected visual acuities of 20/35 or better” (1). This series was published before the 1966 description of the fluorescein angiographic characteristics of CME by J. Donald Gass and Edward Norton (2,3), and thus reported only visual acuity data.
In 1968, John Gehring in Boston reported 18 eyes of 17 patients with “edema of the macula following cataract extraction,” in which “fifteen eyes showed cystoid changes, and three did not.” Gehring cited Gass and Norton’s second paper on fluorescein angiography of CME but did not report this technique in this series. He treated 17 patients with oral prednisone (20 to 40 mg per day) and defined a “cure” as recovery of visual acuity to 20/30 with absence of visible CME using direct ophthalmoscopy with a corneal contact lens. Thirteen patients (76 percent) achieved this outcome, with an average treatment duration of 5.5 weeks (4).
Also in 1968, H. Christian Zweng and colleagues in Northern California reported 81 eyes of 76 patients with various macular diseases, including 17 eyes with postoperative CME not responsive to at least three weeks of oral prednisone, imaged with fluorescein angiography and treated with pulsed ruby photocoagulation. Of these 17 eyes with CME, 5 (29 percent) showed improved visual acuity, 9 (53 percent) remained stable, and 3 (18 percent) worsened (5).
Despite these apparently promising results, subsequent investigators expressed doubt that any treatment was effective. In 1969, Gass and Norton reported on 66 eyes of 48 patients with postoperative CME, concluding: “systemic steroid therapy probably does not [significantly affect] the duration of the macular edema … Probably it is safe to observe these patients for a period of 12 months to allow time for spontaneous resolution of macular edema” (6). Similarly, in 1974 Douglas Jacobson and Angelos Dellaporta at Stanford reviewed their institution’s fluorescein angiography results and concluded: “no medical or surgical therapy has been demonstrated to improve the rate of natural, spontaneous resolution,” and also recommended observation for at least 12 months before attempting any therapy (7).
Starting in the late 1970s, nonsteroidal anti-inflammatory drugs (NSAIDs) began to show benefit. In 1977, Kensaku Miyake in Nagoya, Japan reported a prospective series of 119 intracapsular cataract extractions, of which 30 eyes were treated with topical indomethacin 1 percent in sesame oil solution starting the evening before surgery and continuing three times daily for 40 days following surgery, in addition to standard antibiotic and steroid treatment. Fluorescein angiography was performed weekly from the third through the seventh postoperative weeks. Fluorescein “pooling” (what we would now call leakage) was reported in 77 percent of control eyes but only 33 percent of eyes treated with indomethacin, which was statistically significant (8).
In 1982, Manus Kraff and colleagues in Chicago reported a prospective double-masked trial of 500 patients randomized to receive topical indomethacin or placebo before planned extracapsular cataract extraction or phacoemulsification; treatment was initiated prior to surgery and continued for nine months postoperatively. All patients also received topical steroids. Of these 500 patients, 390 were imaged with fluorescein angiography between 2.5 and 5 months post surgery. Angiographic macular edema was significantly more common among placebo-treated patients versus indomethacin-treated patients (18.5 percent vs. 9.6 percent) although postoperative visual acuity was not significantly different (9). There were many clinical trials of various topical NSAIDs in the 1990s, including ketorolac (10), flurbiprofen (11), diclofenac (12), and others.
Starting in the early 2000s, both OCT (for diagnosis) and intravitreal medications were investigated. In 2003, two groups – Nathanael Benhamou and colleagues in Paris (13) and Murat Karacorlu and colleagues in Istanbul (14) – reported benefits following the use of intravitreal triamcinolone acetonide using OCT. In 2006, John Mason and colleagues in Birmingham, Alabama reported effectiveness following intravitreal bevacizumab using OCT (15).
At this time, the optimal strategy for the prophylaxis and treatment of CME remains unknown. Combination use of topical steroids and NSAIDS is common, but there is relatively little evidence from randomized clinical trials to support this approach (16).
References
- H Laws, “Peripheral vasodilators in the treatment of macular degenerative changes in the eye,” Can Med Assoc J, 91, 325–30 (1964).
- JD Gass, EW Norton, “Fluorescein studies of patients with macular edema and papilledema following cataract extraction,” Trans Am Ophthalmol Soc, 64, 232–249 (1966).
- JD Gass, EW Norton, “Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopic and angiographic study,” Arch Ophthalmol, 76(5), 646–661 (1966).
- JR Gehring, “Macular edema following cataract extraction,” Arch Ophthalmol, 80(0), 626–31 (1968).
- HC Zweng et al., “Laser photocoagulation of macular lesions,” Trans Am Ophthalmol Otolaryngol, 72, 377 (1968).
- M Gass, EW Norton, “Follow-up study of cystoid macular edema following cataract extraction,” Trans Am Ophthalmol Soc, 73, 665–82 (1969).
- DR Jacobson, A Dellaporta, “Natural history of cystoid macular edema after cataract extraction,” Am J Ophthalmol, 77, 445–7 (1974).
- K Miyake, “Prevention of cystoid macular edema after lens extraction by topical indomethacin (I). A preliminary report,” Albrecht Von Graefes Arch Klin Exp Ophthalmol, 203, 81–8 (1977).
- M Kraff et al., “Prophylaxis of pseudophakic cystoid macular edema with topical indomethacin,” Ophthalmology, 89, 885 (1982).
- AJ Flach et al., “Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study,” Ophthalmology, 97, 1253–8 (1990).
- L Solomon, “Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I,” J Cataract Refract Surg, 21, 73–81 (1995).
- L Rossetti et al., “Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery,” J Cataract Refract Surg, 22 Suppl, 794–9 (1996).
- N Benhamou et al., “Intravitreal triamcinolone for refractory pseudophakic macular edema,” Am J Ophthalmol, 135(2), 246–9 (2003).
- M Karacorlu et al., “Intravitreal triamcinolone acetonide for the treatment of chronic pseudophakic cystoid macular edema,” Acta Ophthalmol Scand, 81, 648–52 (2003).
- JO Mason III et al.,, “Intravitreal bevacizumab (Avastin) for refractory pseudophakic cystoid macular edema,” Retina, 26, 356–7 (2006).
- KJ Taubenslag et al., “Anti-inflammatory pharmacotherapy for the prevention of cystoid macular edema after cataract surgery,” Am J Ophthalmol, 232, 1–8 (2021).
