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Glaucoma is a progressive optic neuropathy which represents the final common pathway of a number of different disorders which affect the eye. Most, but not all, of these are associated with elevated intraocular pressure (IOP), which is the most important known risk factor for optic nerve damage, but is still only a risk factor and not the disease itself. The progressive loss of retinal ganglion cells and their axons leads to a characteristic clinical pattern of optic nerve head and corresponding visual field damage. Non-IOP independent mechanisms of glaucomatous damage are not confined to “normal tension” glaucoma, but can be operative in any patient, although they predominate when glaucomatous damage occurs at the lower end of the pressure spectrum. The goal of glaucoma filtering surgery is to reduce or eliminate the pressure dependent component of the disease process.
Filtration surgery to lower IOP has been in use for over a century. Limbal trephination, described by Elliot in 1909,1 became the most popular operation until the 1940s, when it fell out of favour because the very thin conjunctival bleb predisposed to late endophthalmitis. Thermal cautery combined with peripheral iridectomy,2 and posterior lip sclerectomy,3became the most widely used operations until guarded filtration procedures were developed. All of these full thickness procedures, however, were complicated by frequent flat anterior chambers, ciliochoroidal detachments, occasional choroidal haemorrhages, and a high incidence of subsequent cataract formation. Late endophthalmitis was common.
Improvements in microsurgical instrumentation and fewer postoperative complications led to the rapid acceptance of guarded filtration techniques following the introduction of trabeculectomy by Cairns in 1968.4 Although the incidence of late endophthalmitis was significantly reduced, the IOP was not lowered to as great an extent and certain subsets of patients, such as those with neovascular glaucoma, uveitis, and previous surgery had high rates of failure. The introduction of 5-fluorouracil (5-FU) and mitomycin C (MMC) markedly improved the surgical success rates not only in these eyes, but also in routine filtration surgery, so much so that most glaucoma surgeons use antifibrosis agents for virtually all cases, in an attempt to provide the pressure lowering effect of full thickness surgery with the safety of trabeculectomy. Combined with postoperative laser suture lysis, allowing tighter scleral flap closure, and earlier postoperative manipulation to encourage bleb formation, complications such as flat anterior chamber have been markedly reduced. However, the thin, avascular, cavitated blebs produced, particularly with MMC, have led to a resurgence of chronic hypotony, bleb leaks, bleb infections, and endophthalmitis. Many of these patients also complain of ocular pain or discomfort related to the presence of a large or elevated bleb, a condition known as bleb dysethesia. We have termed the postoperative constellation of complications associated with antifibrosis agents the HELP syndrome (hypotony, endophthalmitis, leak, pain).
In this issue of the BJO (p 1349), Lehmann and colleagues have assessed risk factors for the development of late endophthalmitis following glaucoma filtering surgery. In a well designed, retrospective, case-controlled series, they report that bleb infection, diabetes mellitus, and use of antifibrosis agents increase the risk of developing late endophthalmitis. Patients receiving antifibrosis agents tended to develop infection considerably earlier than those individuals who did not receive them. They attribute this increased risk of infection to the altered bleb morphology (thin walls, denuded epithelium, abnormal stroma, leakage, avascularity) characteristic of 5-FU and MMC filtering blebs. Endophthalmitis led to a significant loss of vision and bleb function in a large proportion of eyes.
This article is important for several reasons. Firstly, it supports the findings of others. Since our initial report of late bleb related ocular infection following 5-FU trabeculectomy5 and the coining of the term “blebitis”,6 we have treated many patients with late bleb related complications and infections. These reports have included children,7 recurrence in previously infected eyes,8 and institution-wide surveillance documenting 49 episodes (42 patients) over a 10 year period,9 with bleb leakage being a common predisposing condition to both infection and associated with antifibrosis use.10 11 Secondly, the article by Lehmann and colleagues documents that this problem is worldwide in scope. Late bleb related ocular infection involves all ethnic and racial groups, although the infecting organisms may vary geographically. Thirdly, bleb related infection can be a serious cause of permanent vision loss and may interfere with bleb function. An association with diabetes may reflect the greater predisposition of such patients to infection in general, and might give us pause to consider in which subsets of patients it might be advisable to exercise greater caution in deciding whether or not to use MMC. Finally, the article confers renewed attention on this important aspect of the HELP syndrome and on our need to rethink the use of these potent compounds.
The morbidity associated with HELP syndrome should cause us to reflect on the widespread, often indiscriminate, use of antifibrosis agents. Although the rate of progressive glaucoma damage is lower the lower the postoperative IOP, not every patient requires an IOP in the single digits or low teens to prevent further significant injury. Most patients would be able to retain useful vision for the duration of their lives with somewhat higher pressures and we should tailor our therapeutic intervention to the particular needs of the individual patient, rather than reach, often reflexively and without thought, for the application of MMC. The literature comparing the efficacy of adjunctive 5-FU with MMC for uncomplicated, previously unoperated eyes is surprisingly scant, and a recent report by Singh and colleagues suggests that the pressure lowering effect is similar for these two drugs in this group of patients.12 Some might argue that MMC be reserved primarily for eyes with extremely advanced damage, reoperation, or complicated or combination surgeries. Each individual surgeon needs to reassess his or her use of these medications based upon personal experience, patient population, and spectrum of patient disease severity, and make a thoughtful decision regarding the appropriate, judicious use of these medications.
Looking to the future, is it possible to achieve our IOP reduction goals without the severe alteration of bleb morphology present following the use of 5-FU or MMC? The Moorfields group has been at the forefront of the search for safer, more effective, and more physiological means of wound healing modification. An excellent review of the topic of potential avenues for immune modification in wound healing has recently been published.13
Transforming growth factor β (TGFβ) is a potent stimulator of human Tenon's capsule fibroblast activity, suggesting its stimulatory role in the conjunctival scarring response.14-16 The use of antihuman TGFβ antibody in reducing conjunctival wound healing is one such innovative avenue.17 We look forward to seeing the results of human clinical trials currently under way.
Supported by the Donald Engel Research Fund of the New York Glaucoma Research Institute, New York, USA.