Discussion

This study demonstrates the efficacy of a long-term and intensive topical corticosteroid treatment to improve DS outcome. As far as we know, this is the first prospective study that compares two different postoperative treatment dosages of topical corticosteroids for DS in terms of efficacy. In this study, a long-term and intensive therapy with topical corticosteroids postoperatively led to a greater and more sustained IOP decrease after DS.

It is important to point out there were no significant differences in median IOP at 1 week postoperative visit, whereas there was a statistical significance from 1-month-visit until 2-year-visit. This result suggests an influence of postoperative treatment. The number of medications was also reduced in both groups to 0 although it is statistically significant because we are using median value and not the mean one. There was not difference between extra procedures required to decrease IOP comparing both treatment groups. However, LTCT needed more goniopuncture (considered by many authors as a normal step in the postoperative period) whereas in STCT group 4 rescue surgeries were needed. Therefore, although the amount of procedures in both groups is similar, the quality of them points out a greater failure rate in STCT.

Cheng et al performed a systematic review of the efficacy of several non-penetrating glaucoma surgical procedures, including DS. Twenty-nine randomised clinical trials were included in the meta-analysis trials and 1455 patients were evaluated, eight arms reporting DS. IOP reduction at 24 months was 35.2% (CI 95% 30.0% to 40.4%) and complete success rate was 44% (CI 18.9% to 72.5%). The qualified success rate at the endpoint was 71.7% for the DS. Moreover, they observed a gradual loss of IOP-lowering effect over time.5 In our study, the complete success rate in STCT group at 24 months was 54.5%, which is comparable to previously published data. However, complete success rate in LTCT group was 87% at 24 months follow-up which is higher than those reported to date. Therefore our study suggests a beneficial effect of postoperatively long-term topical corticosteroids treatment in improving DS outcome.

The use of either goniopuncture or glaucoma medication increased the success rate, but it is difficult to compare the results because many studies include additional interventions as normal practice to get success, introducing a bias. In this meta-analysis, the success rate of the trabeculectomy at 2 years was 62.1% (CI 49.4% to 73.4%) and the qualified success at the endpoint was 90.8% (CI 85.4% to 95.4%).

The beneficial effect of corticosteroids is due to a well-known action in the inflammatory cascade and also related to a more theoretical mechanism where the decreased outflow in the trabecular meshwork (TM) leads to an increased outflow to the created scleral lake.

Glaucoma filtering surgery failure is usually due to excessive wound healing under the conjunctiva.

Four phases have been described in the healing process: coagulative, inflammatory, proliferative and remodelling. In the coagulative phase, the blood cells and platelets from the incised vasculature release prostaglandins, leukotrienes, histamine and serotonin. Platelets also release Platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and insulin-like growth factor. In the inflammatory phase, monocytes differentiate into tissue macrophagues. These release PDGF, fibroblast growth factor and transforming growth factor-ß. The fibroblasts are the main cell involved in proliferative phase. They transform into myofibroblasts, a more contractile phenotype. Extracellular matrix degradation is mediated by metallo-proteinases via the removal of hyaluronan and fibronectin from the tissue leading to apoptosis of fibroblasts, main event of remodelling phase.6 ,7

The key of success in glaucoma surgery involves an optimal balance between conjunctival healing and scar formation in the filtering bleb. Several approaches have been suggested to achieve this delicate goal.

Most of the efforts to reduce glaucoma surgery failure are based on the development of antifibrotic agents. These antimetabolites (MMC and 5-FU) have contributed to better outcomes in terms of postoperative IOP control but their use have also increased the complication rate of filtration surgery. One of the most undesirable side effects is the late-onset leak related to bleb ischaemia. This leak can lead to a severe hypotony maculopathy, shallowing of the anterior chamber, cataract formation, corneal decompensation, choroidal effusion, blebitis and endophthalmitis.1 In order to decrease these complications, the Moorfield’s safer surgery was developed using a fornix-based conjunctival incision and a larger antimetabolite treatment area. Newer techniques in delivering antimetabolites are being investigating.

Other forms to modulate wound healing with more acceptable side effects have been explored. As we mentioned before, VEGF plays an important role in angiogenesis and its relation with the healing process in filtering bleb has been also investigated.8 Lopilly Park et al found a significant association between IOP and VEGF level in the Tenon’s tissue.9 So, a VEGF inhibition in the bleb would improve surgery outcomes. However, no conclusive evidence has been found in the efficacy and in dosage or method of delivery in several studies.10–17

Two randomised clinical trials evaluated the benefit of subconjunctival hyaluronate. Lopes et al compared hyaluronate versus balance salt solution without finding significant differences after a mean follow-up of 12 months.18 Naravanaswamy did not observe differences comparing hyaluronate mixed 5-FU versus 5-FU alone either.19

Glucocorticoids modify the inflammatory process at several stages of the cascade of inflammation including reduction in concentration, migration and activation of leucocytes, inhibition of activity of macrophagues, mitigation the reaction of immune system to presented antigens and reduction in vascular permeability.6

In spite of the action in nearly all the levels of inflammatory response, corticosteroids have been considered a rudimentary form of scarring suppressor. No many studies have been performed in order to study the efficacy and optimal dosage.

Corticosteroids must be used after any filtering surgical procedure. However, this treatment can cause a rise in IOP in a percentage of subjects, especially those suffering from glaucoma and this is one of the most concerns with an intensive and long use. This has been described before in previous studies, where corticosteroids induced an increase of IOP response in both normal and glaucomatous eyes, patients with glaucoma being more susceptible. In open-angle glaucoma, 46%–92% of patients may develop a steroid-induced IOP rise whereas the prevalence decreases to 17%–36% in operated patients with glaucoma.20 Steroid-induced ocular hypertension is associated with specific changes in the TM, such as an increased deposition of extracellular matrix and an altered TM cell function. Although this IOP increase can happen in operated eyes, the proportion is considerably less important.

The most accepted explanation is that in operated eyes a great amount of aqueous humour bypasses the TM through the ostium in trabeculectomy or the TMD in DS.

However, in our study, despite intensive topical corticosteroid treatment, any of the patients developed an IOP rise postoperatively. The intensified corticosteroid therapy after glaucoma surgery is not new. A 10-year follow-up of a prospective randomised trial of postoperative corticosteroids reported that an intensified therapy in the first 4 weeks was beneficial to stabilise IOP after trabeculectomy.21 In the most extended postoperative treatment after trabeculectomy, the regimen used is two hourly prednisolone acetate or dexamethasone drops during waking hours for the first month before slowly tapering the frequency over the following months.22 However, this kind of regimen had not extended to DS because a more educed inflammation after DS than in trabeculectomy and the absence of iridectomy. Our study shows this treatment is also useful in DS.

It has been suggested that the trabecular pathway outflow is reduced after a successful trabeculectomy. In fact, the diameter of Schlemm’s canal decreases after filtration surgery because of a probable underperfusion of the TM.7 23 24 On the other hand, although the mechanism of glucocorticoid-induced outflow obstruction is not very well known, it has been associated with the accumulation of extracellular matrix material, particularly in the juxtacanalicular tissue.25

The most important study limitation is the small sample size. Nevertheless, the difference between the two treatment regimens was so significant in the preliminary results in favour of long-term and intensive treatment that 6-month treatment was established as postoperative protocol for DS surgeries. Therefore, recruitment of patients in the STCT group was discontinued.

In conclusion, we demonstrated that a long-term and intensive topical corticosteroid postoperative treatment enhances success rate in DS compared with the standard protocol. A greater IOP reduction, lower need of postoperative medications and further surgeries and a longer efficacy were achieved in the LTCT compared with STCT. No complications associated with this regimen were found.