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Prophylaxis and Treatment of Irvine-Gass Syndrome

Serge Bourgault, MD; Karolina Chmielewska, MD; Eric Tourville, MD, FRCSC

ABSTRACT

Irvine-Gass syndrome (IGS) is a known and relatively frequent problem after a cataract surgery. No guide- lines nor randomized trial has established the best treatment for this problem and many surgeons deal with it at their best knowledge. We reviewed the current literature on the subject to come up with a proposition as to how and when to start treating or preventing macular edema. We analysed the evidence regarding the use of NSAIDs, corticosteroids, topically or locally, oral acetazolamide, anti-VEGF injections and vitrectomy. We conclude that prophylaxis treatment should be reserved for high risk patients and that curative treatment should start with topical NSAIDs before adding or changing to another option, as topical NSAIDs seem to have a positive outcome on IGS.

INTRODUCTION

Cystoid macular edema (CME) is a condition with a loose definition. CME is characterized by intraretinal fluid contained in cystoid spaces caused by vessel leakage. The condition can be described by clinical or angiographic means, or by Optical Coherence Tomography (OCT). Clinical CME is associated with a decrease in visual acuity to 6/12 (20/40) or worse and macular swelling diagnosed by biomicroscopic fundus exam. However, with patients’ higher expectations following cataract surgery, the definition is becoming stricter, and some clinicians advocate that macular edema leading to vision of 6/7.5 (20/25) is clinically significant. Angiographic CME is defined as typical foveal petalloid leaks of fluorescein, along with late optic disc hyperfluorescence.

S. Bourgault; K. Chmielewska; E. Tourville — Département d’ophtalmologie, Faculté de médecine, Université Laval, Québec, Canada; Centre universitaire d’ophtalmologie de Québec (CUO), Hôpital du Saint-Sacrement, Centre hospitalier affilié universitaire de Québec (CHA), Québec, Canada. Correspondence to: Dr. Eric Tourville, Centre universitaire d’ophtalmologie de Québec (CUO), Hôpital du Saint-Sacrement, 1050, Chemin Ste-Foy, Québec, Québec, G1S 4L8; E-mail: tourvillesoucy@hotmail.com

This optic nerve hyperfluorescence is actually key in differentiating Irvine-Gass syndrome (IGS) from diabetic macular edema (DME) (Fig. 1A,B). OCT is an important tool in the diagnosis of CME since it can detect even the slightest increase in retinal thickness not detectable by the human eye, which can help explain unexpected suboptimal postoperative results. It is also very helpful in monitoring CME treatment response. OCT findings include a diffuse increase in retinal thickness and cysts, located mainly in the inner nuclear and outer plexiform layers (Fig. 2). CME can be caused by many inflam- matory, vascular and surgical conditions. IGS is a term reserved for CME following cataract extraction or other intraocular surgeries. Very rarely, severe cases can be associated with vitritis and optic nerve swelling.

OVERVIEW OF IGS

The peak incidence of pseudophakic CME occurs 6 to 10 weeks after surgery and it is clinically significant in 1% to 2% of patients following uncomplicated phacoemulsification. 1 CME lasting for more than 6 months is defined as chronic CME. Angiographic CME is more frequent and occurs in about 30% of patients. 1 Spontaneous resolution occurs within 2 years in as many as 90% of uncomplicated cases. 2 This makes it a very tough condition to study since very few diseases have such a high rate of spontaneous cure; hence the unequivocal need for placebo-controlled studies. Until today, however, few randomized clinical trials (RCTs) have compared medications we currently use to observation alone, and the duration of treatment required remains to be clarified. This explains why so few treatments are approved by Health Canada for IGS. The incidence of CME following cataract extraction increases with surgical complications such as posterior capsule break, vitreous loss, iris prolapse, uveitis, vitreous adhesions to the iris or the wound, and, presumably, photic effects. 3,4 Other risk factors include history of retinal vein occlusion, epiretinal membrane (ERM), preoperative prostaglandin use or diabetes. 1 Finally, use of iris-fixated intraocular lenses, important postoperative inflammation, hypertension, age over sixty years and retinitis pigmentosa may also increase risk of IGS. 1,2

A
A
B
B

Fig. 1 (A) Irvine-Gass syndrome. Late phase fluorescein angiogram showing typical foveal petalloid leaks of fluorescein, along with florid optic disc hyperfluorescence. (B) Diabetic macular edema. Late phase fluorescein angiogram showing diffuse pattern of fluorescein leakage and small areas of hypofluorescence corresponding to retinal hemorrhages. Optic disc hyperfluorescence is absent.

retinal hemorrhages. Optic disc hyperfluorescence is absent. Fig. 2 OCT image showing diffuse retinal thickening and

Fig. 2 OCT image showing diffuse retinal thickening and cysts, located in the inner nuclear and outer plexiform layers (same patient as Figure 1A).

DIFFERENTIAL DIAGNOSIS

With many diabetic patients undergoing cataract surgery, it is important to distinguish IGS from DME (Table I). Observation of intraretinal hemorrhages or micro- aneurysms in the macula leans more towards diabetes, vein occlusion or ERM involvement (Fig. 3). We do not recall having seen any blood associated with pure IGS. Optic nerve hyperfluorescence is of paramount importance in differentiating the two clinical entities. The diagnosis of clinically significant macular edema (CSME) is made by direct observation of the posterior pole using the well-known Early Treatment Diabetic Retinopathy Study (ETDRS) criteria. ETDRS recommends focal laser photocoagulation of any CSME, whereas pure IGS is never treated using photocoagulation.

TREATMENT OPTIONS

Corticosteroids Topical corticosteroids. Topical corticosteroids are routinely used after cataract surgery and are the only treatment of CME approved by the Food and Drug Administration (FDA) and Health Canada. 5 Corticosteroids inhibit both cyclooxygenase and lipooxygenase pathways and could therefore be expected to be more potent than nonsteroidal anti-inflammatory drugs (NSAIDs) in reducing inflammation. To our knowledge, no RCT has compared topical corticosteroids with placebo for CME treatment. In a randomized prospective trial of 26 eyes, Heier et al compared prednisolone acetate 1.0% (Pred Forte ® , Allergan), ketorolac tromethamine 0.5% (Acular ® , Allergan) and a combination of the two in the treatment of acute CME after cataract surgery. 6 Patients with combination therapy were more likely to experience a gain of 2 lines or more of Snellen visual acuity and to note improvement in contrast sensitivity. The prednisolone group showed an average improvement of 1.1 lines compared with 3.8 lines with combination therapy. Another small study of 10 patients investigated the use of the same combination therapy versus ketorolac tromethamine 0.5% in the treatment of acute and chronic pseudophakic CME. 7 The studies showed no statistically significant difference between the two regimens regarding visual acuity in acute and chronic CME. However, both studies were underpowered given the small number of subjects. No prospective randomized study has ever demonstrated the benefit of topical steroids in chronic

Table I Irvine-Gass syndrome vs diabetic macular edema

 
 

IGS

DME

Microaneurysms/Hemorrhages

No

Common

Exudates

Only if chronic

Common

FA Pattern of leakage Late optic disc hyperfluorescence

Typically petalloid

Focal or diffuse No (except NVD)

Common

IGS = Irvine-Gass syndrome; DME = diabetic macular edema; FA = fluorescein angiography; NVD = neovascularisation of the disc

pseudophakic CME. Moreover, the chronic use of topical corticosteroids is not without risk, with 30% of patients developing steroid-response. 8 Therefore, we recommend not using topical corticosteroids in chronic pseudophakic CME unless there is anterior chamber inflammation.

Subtenon corticosteroids. Recently, Negi et al demon- strated that subtenon injection of corticosteroids is as valuable as using topical steroids after a cataract extrac- tion. 9 In this prospective RCT of 54 eyes, intraoperative triamcinolone acetonide (Kenalog ® , Westwood-Squibb) (20 mg or 30 mg) was compared to topical betamethasone sodium phosphate 0.1% (Betnesol ® , Shire). They showed that injection of 30 mg of triamcinolone is safe and effective in diminishing postoperative inflammation and, possibly, CME. None of the patients in the 30 mg injection group (17 eyes) developed CME after 90 days. These results were statistically significant, but the number of patients treated is too small to extrapolate conclusions. Kim et al compared subtenon injection of triamcinolone (dosage unknown) plus prednisolone acetate 1% drops versus prednisolone drops alone in 46 eyes of 23 noninsulin dependant diabetic patients. 10 Each patient’s second eye served as control in this study. They showed that the mean central macular thickness measured by OCT and best-corrected visual acuity (BCVA) were both significantly better in the triamcinolone group at 1 month postoperatively, but there was no difference between the 2 groups at 6 months. Nevertheless, the incidence of CME was significantly lower in the triamcinolone group, suggesting a beneficial effect for noninsulin dependant diabetic patients to receive a subtenon injection of corticosteroids following cataract surgery, on top of the usual drops. Intraoperative subtenon injection of 30 mg of triamcinolone acetonide could be an option in high-risk patients: those with pre-existing CSME prior to cataract, diabetes or poor compliance to drops. As with topical steroids, care must be taken to monitor intraocular pressure (IOP).

Intravitreal corticosteroids. Corticosteroids can also be delivered into the vitreous for a more potent local action. Two series described the effects of 4 mg of intravitreal triamcinolone acetonide (IVTA) for IGS on more than

triamcinolone acetonide (IVTA) for IGS on more than Fig. 3 Fundus color photograph corresponding to the

Fig. 3 Fundus color photograph corresponding to the fluorescein angiogram shown in Figure 1B. Note mild nonproliferative diabetic retinopathy associated with diffuse macular edema.

10 patients and are worth mentioning. 11,12 The first retrospective study reviewed 14 patients who presented CME for more than 6 months and were unresponsive to other therapies. 11 CME was evaluated using visual acuity, OCT and multifocal electroretinography (ERG). The visual acuity improved in 11 patients after one year. The retinal thickness measured by OCT decreased significantly after 3 months, but not at 6 and 12 months. Multifocal ERG showed improvement in the foveal area that persisted after 12 months and so did the visual acuity for 11 of the 14 patients. This implies that the beneficial effect of IVTA persist for at least a year. IOP was elevated in 3 patients. In the second retrospective study, 21 eyes of 20 patients were treated with IVTA for IGS (15 of which had cataract extraction, while the remaining had vitrectomy [3] or combined phacoemulsification and vitrectomy [3]). 12 Eighteen eyes showed some improvement of visual acuity that persisted for at least 6 months. To our knowledge, no prospective trial establishing intravitreal corticosteroids potency in IGS was published. Given the natural history of CME, it is hard to quantify the degree to which injection of IVTA actually works. However, this treatment can be tried in some unresponsive and refractory cases bearing in mind the potential steroid response.

Topical NSAIDs Prophylactic use. NSAIDs are cyclooxygenase inhibitors that block prostaglandin synthesis. NSAIDs are approved by the FDA and Health Canada to reduce miosis during cataract extraction, as well as to control postoperative pain and inflammation. None is approved to treat IGS. In

Canada, there are currently four available topical NSAIDs:

ketorolac tromethamine 0.5% and 0.4% (Acular LS ® , Allergan), diclofenac sodium 0.1% (Voltaren ® , Novartis) and nepafenac 0.1% (Nevanac ® , Alcon). Older topical NSAIDs such as indomethacin (Indocin ® , Merck) and flurbiprofen (Ocufen ® , Allergan) are no longer available. Numerous studies have explored the off-label use of NSAIDs for prophylaxis and treatment of IGS. Benefits of NSAIDs for prophylaxis of CME in routine cataract

surgery have been demonstrated but remain controversial. 13

A meta-analysis of 12 randomized clinical trials indicated

that NSAIDs reduce the incidence of clinical CME. 14 Unfortunately, the duration of follow-up in most of these studies was less than 3 months after surgery and 56.3% of trials were based on intracapsular cataract extraction.

In a randomized study of 179 eyes, Yavas et al compared

three different treatment regimens, all combined with topical prednisolone: topical indomethacin 3 days preoperatively and 1 month postoperatively, topical

indomethacin 1 month postoperatively and placebo. 15 No patient in the first group developed angiographic CME at

3 months compared to 15.0% in the second group and

32.8% in the control group. In a retrospective review of

450 cases with a limited follow-up of 1 month, Wolf et al observed visually significant CME (suboptimal BCVA) confirmed by OCT in 2% of patients treated with prednisolone alone and in no patient treated with prednisolone and nepafenac. 16 More recently, in a large prospective RCT of 546 patients, Whittpenn et al showed a decrease of clinical CME (evident on slit-lamp examination) from 1.8% to 0% in patients treated post- operatively with ketorolac tromethamine 0.4%, starting

3 days prior to surgery, and prednisolone compared with

prednisolone only. 17 The incidence of definite or probable CME based on OCT analysis was also statistically lower

(2.4% versus 0%). However, no statistically significant difference was found between the 2 groups regarding BCVA, and the maximum follow-up length was only

6 weeks. In another study, based on OCT analysis of total

macular volume, a group of patients receiving ketorolac tromethamine 0.5% starting 2 days preoperatively, in addition to prednisolone, experienced 45.8% less macular swelling compared to a group receiving prednisolone

only. 18 Two trials comparing NSAIDs alone (diclofenac sodium 0.1%) with cortico-steroids alone (betamethasone sodium 0.1% and fluorometholone acetate 0.1% [Flarex ® , Alcon]) showed lower incidence of angio- graphic CME at 5 weeks with NSAIDs but no difference was noticed in respect to visual acuity. 3,19

Pre-op dosage. The optimal preoperative administration regimen of NSAIDs was assessed by Donnenfeld et al. 20 One hundred patients were randomly assigned to one of

4 treatment groups: ketorolac tromethamine 0.4% for

3 days, 1 day, 1 hour or placebo before phacoemulsification. At 2 weeks, the incidence of clinically significant CME (BCVA worse than 6/9 [20/30] and OCT confirmation)

was not statistically different. No patient using ketorolac for 1 or 3 days had CME compared to 12% of control group and 4% of patients in the 1-hour group. By

3 months, there was no statistically significant difference with respect to BCVA.

Prophylaxis with NSAID in diabetic patients. In a prospective study of 92 eyes, Shimura et al found no statistical difference of BCVA at 8 weeks in eyes treated postoperatively with diclofenac sodium 0.1% in one group and with betamethasone sodium phosphate 0.1% in the other. 21 All patients in this study had type II diabetes with no or mild nonproliferative retinopathy. Mean foveal thickness was also similar through the clinical course. Diclofenac was shown to suppress initial thickening but the effect was not sustained. Henderson et al recommended prophylactic use of NSAIDs in patients at high risk of CME (diabetes, intraoperative posterior capsule tear or vitreous loss) based on their retrospective review of 1659 consecutive cataract surgeries. 2 These high-risk patients showed no increase in incidence of CME when placed on NSAIDs.

NSAID for established IGS: Acute. Once CME has developed postoperatively, topical NSAIDs represent the first line treatment for most surgeons. In a systematic review based on the Cochrane Collaboration methodology, Sivaprasad et al identified 3 RCTs that evaluated the effects of NSAIDs on acute pseudophakic CME. 22 As mentioned earlier, Heier et al demonstrated that combination therapy with prednisolone acetate 1.0% and ketorolac tromethamine 0.5% was superior to prednisolone only in the treatment of acute IGS. 6 Moreover, combination therapy was superior to ketorolac alone with 89% of patients presenting a 2-line improvement (average of 3.8 lines) compared to 67% (average of 1.6 lines). In a second RCT, Rho et al investigated whether diclofenac sodium 0.1% was as efficacious as ketorolac tromethamine 0.5% in the treatment of acute pseudophakic CME in 34 patients. 23 No difference was found in respect to CME resolution within a 26-week period with a “cure” rate of 78% with diclofenac and 75% with ketorolac. Fluorescein angiogram was performed initially and repeated only if clinical CME persisted; that is, in patients with decreased visual acuity and evidence of CME on slit-lamp biomicroscopy. Mean time to CME elimination was respectively 13.6 and 12.8 weeks. The third study was conducted by Flach in 22 patients and showed no statistically significant difference between ketorolac tromethamine 0.5% and placebo in achieving a

2-line improvement of Snellen visual acuity at 4 weeks:

36% versus 18%. In recent years, small case series were published on the efficacy of nepafenac 0.1% in the treatment of IGS. 24,25 Warren and Fox conducted a prospective open-label study to evaluate the efficacy of nepafenac 0.1% in treating acute pseudophakic CME in patients with a history of IOP elevation following administration of topical corticosteroids. 5 Eleven patients, with a mean duration of CME of 3.3 months, had significant visual improvement of 2.55 lines at 4 weeks and 3.0 lines at 12 weeks. However, only 54% of patients maintained stable vision at 6 months, which is 3 months after discontinuation of nepafenac.

NSAID for established IGS: Chronic. Treatment of chronic pseudophakic CME, defined as duration over

6 months, was also evaluated by Sivaprasad et al in their

systematic review based on the Cochrane Collaboration methodology. 22 They identified four RCTs but the two older studies included only intracapsular cataract surgeries and eyes were left aphakic. 26,27 In one of the two other trials, Flach et al compared ketorolac tromethamine 0.5%

with placebo for a total duration of 60 days. 28 More patient in the treatment arm (8/13 patients) had a 2 or more lines improvement of Snellen visual acuity compared to placebo arm (1/13 patients). In the second and larger trial, Flach et al compared the same treatment regimens (ketorolac tromethamine 0.5% versus placebo) for

90 days duration in 120 patients. 29 Significant visual

improvement, defined as a 2 or more lines gain, was observed in the ketorolac-treated group as compared to placebo-treated group at 30, 60 and 120 days. The benefit of treatment with ketorolac remained statistically significant one month after discontinuation of treatment. These four trials were pooled together in a meta-analysis

conducted by Rossetti et al. 14 Combined results showed

a positive effect favouring improved visual acuity (at least

2 Snellen lines) in patients treated with NSAIDs with an

odds ratio of 2.67. Topical ketorolac tromethamine 0.5% was evaluated in two trials, 28,29 topical fenoprofen sodium

1% (Nalfon ® , Lilly) in one 27 and oral indomethacin in the last one. 26 Weisz et al studied topical ketorolac tromethamine 0.5% in treatment of very late (more than

24 months after surgery) chronic pseudophakic CME. 30

Six out of 10 eyes experienced a 2 or more lines visual acuity improvement after 3 months of treatment. However, recurrence of edema was noted in all of these eyes on follow-up examination 3 months after ketorolac was stopped. Authors stated that persistent use of ketorolac would have probably been required. In another report on 13 patients with chronic or recalcitrant IGS treated with nepafenac alone or in combination with prednisolone acetate, Harriprasad et al reported visual improvement in all cases but one. 25

8 Clinical & Surgical Ophthalmology 28:2, 2010

NSAID take home message. To conclude, topical NSAIDs seem to have some efficacy in the treatment of acute and chronic IGS but double-blinded studies with

larger populations are warranted to clearly inform practice as the current literature remains divided. Some studies show they work and others say they do not. It is also important to bear in mind to what degree each study is sponsored by the company selling the NSAID that is supposed to work better than the non-existent placebo group! NSAID use in CME can be of greater interest in patients at risk for glaucoma. Prolonged therapy may be needed for more than 3 months and the disease can relapse. In this situation, compliance can be a greater issue than when therapy consists of only one steroid injection. Some evidence exists to start prophylaxis 1 to

3 days prior to surgery. Based mainly on experts’

opinions, O’Brien recommends preoperative dosing of

NSAIDs for 1 to 2 days followed by an average of 3 to

4 weeks postoperative dosing in patient without risk

factors. 31 The hardest criticism of this recommendation would relate to the cost-effectiveness of this prophylactic measure as the occurrence of clinically significant IGS is so low and once it has established, it is still treatable. It would be interesting to have a needed number to treat! It is important to note that topical NSAIDs carry side effects such as corneal toxicity. Furthermore, as of today, no available NSAID has proven itself clinically superior to the others.

ORAL ACETAZOLAMIDE

One trial randomized 10 patients to receive either oral acetazolamide (Diamox ® , Wyeth-Ayerst) or placebo to treat their macular edema. 32 Out of the 5 patients receiving acetazolamide, 4 (80%) withdrew from the study because of side effects. Therefore, it is hard to recommend its use as standard care.

INTRAVITREAL ANTI-VEGF

With the current increase in the use of antibodies against vascular endothelial growth factor (VEGF), some authors have tried it as part of the armamentarium against IGS. The current literature concerning treatment of pseudo- phakic CME with an anti-VEGF molecule is also controversial. Spitzer et al found no significant benefit in treating 16 eyes with intravitreal injections of bevacizumab (Avastin , Hoffmann-La Roche) in IGS refractory to standard treatment (NSAIDs, topical or systemic cortico- steroids, IVTA or acetazolamide). 33 However, Barone recently published a series of 10 patients with refractory IGS (all patients were treated with ketorolac and some were treated additionally with oral acetazolamide or prednisone) who did improve their BCVA by at least

2 ETDRS lines and whose mean macular thickness

decreased for 6 months after intravitreal bevacizumab

injections. 34 Moreover, Arevalo et al showed improvement in visual acuity and macular thickness for a mean follow-up of 32 weeks in 20 of 28 eyes treated with bevacizumab as a first-line agent in treating CME. 35 As for other modalities, better studies are needed before we can make strong recommendation on anti-VEGF use in IGS. However, it is safe and could be considered as treatment in chronic cases or in selected patients who do not do well on topical drops due to poor compliance, or in those with a history of steroid-induced ocular hypertension.

VITRECTOMY

Finally, surgical approach has been attempted in some cases, especially when medical treatment has failed. One prospective trial has been conducted in the early eighties to compare observation versus vitrectomy in chronic aphakic CME. 36 It was found that approximately twice as many patients had visual acuity improvement in the vitrectomy group. No prospective randomized trial is available for pseudophakic CME. In one retrospective trial, 23 eyes showed resolution of CME on biomicroscopic exam and improvement of visual acuity of 3.3 Snellen lines. 37 Surgery can thus be considered for patients for whom topical and local treatment failed, especially when there is vitreo- macular traction, anterior vitreous prolapse or residual pro-inflammatory lens material.

CONCLUSION

Please keep in mind that almost all treatments explored in this paper are off-label. As much as we want to help our patients, we must first do them no harm. Based on this large literature review and our personal experience, we recommend starting 1 to 3 days prior to cataract surgery prophylaxis with NSAIDs for patients at high risk of IGS. Amongst them are diabetic patients, patients with history of IGS in the former eye or a history of retinal vein occlusion, ERM, chronic uveitis, retinitis pigmentosa or when complications occurred during cataract extraction. Topical NSAID prophylaxis in routine cataract surgery remains controversial despite a number of recent flawed studies advocating it. Treatment of established acute or chronic IGS could begin with the use of topical NSAID and should probably last at least 3 months. It is hard to determine whether corticosteroids should be added to NSAIDs systematically in acute IGS because that conclusion is supported by only one study on 26 patients. We do not recommend their addition routinely and they could be reserved for patients with important anterior segment inflammation. Their penetration in the vitreous is very low. Topical steroids should never be used alone in the treatment to IGS and seem to be of no benefit in addition to NSAIDs in chronic IGS. On the other hand, topical steroid use can be of interest to establish the risk of steroid response prior to ocular injection. Subtenon or

intravitreal injection of triamcinolone can be effective and can be used in patients who do not respond to drops and in diabetic patients who may have a component of CSME. Steroid injections can also be offered to patients when compliance to drops regiment could be an issue. Anti- VEGF injections are an option in cases of refractory IGS, when associated with vein occlusions, diabetes or in steroid-responders. Patients in whom vitreal traction is suspected to be contributing to the macular edema should be referred for vitrectomy.

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