Elsevier

Survey of Ophthalmology

Volume 48, Issue 3, May–June 2003, Pages 314-346
Survey of Ophthalmology

Diagnostic and surgical techniques
Antifibrotics and Wound Healing in Glaucoma Surgery☆

https://doi.org/10.1016/S0039-6257(03)00038-9Get rights and content

Abstract

When medical and laser therapy fail to control intraocular pressure, glaucoma filtration surgery needs to be performed. Glaucoma surgery is unique in that its success is linked to interruption of the wound-healing response in order to maintain patency of the new filtration pathway. In this article we will review the wound-healing pathway and the pharmacologic interventions that have been employed clinically and experimentally to interrupt wound healing, particularly steroids and the antifibrotic agents 5-fluorouracil and mitomycin C. A review of the published literature looking at use of these agents to enhance success as well as the associated complications are presented, critiqued, and interpreted in order to put the studies in proper perspective. Future directions and recommendations regarding use of these agents are available and an introduction to newer wound modulating agents such as anti-transforming growth factor beta 2 is presented.

Section snippets

Wound Healing Pathway

Injury to tissue following physical trauma, whether surgical, chemical, or radiation-induced, results in a sequence of biologic events leading to repair. Repair involves two distinct processes: replacement and regeneration. Replacement results in scar tissue formation in lieu of restoration of the normal epithelial and stromal architecture. In contrast, regeneration results in restoration of the original architecture leaving no trace of injury. Complete regeneration can occur when the

Effect of IOP-Lowering Drugs on Wound Healing

It has been shown that chronic use of topical antiglaucoma agents, especially adrenergic agonists, results in long-term morphologic effects on the conjunctiva and Tenon's capsule.13., 99. Specifically, subclinical conjunctival inflammation associated with an increased number of conjunctival inflammatory cells and fibroblasts has been noted.14 Such histologic changes may prime the post-surgical fibroblastic response resulting in increased fibrosis, thus increasing the risk of bleb failure

Anti-inflammatory Agents

Anti-inflammatory agents have long been part of the strategy for modulating inflammation and wound healing in the eye. Steroid hormones can be viewed as the prototype. Steroidal hormones are naturally produced by the adrenal gland. There are three major classes of steroidal hormones: glucocorticoids, mineralocorticoids, and the sex steroids. The glucocorticoids are the class of hormones involved in inhibiting inflammation and wound healing.

Antifibrotics

The trabeculectomy originally described by Cairns in 1968 has been the prototype glaucoma-filtering procedure performed over the last three decades. Despite modifications of the original technique and evolution of new laser and surgical filtering procedures, the trabeculectomy remains the most commonly performed glaucoma incisional surgical procedure. The success rate of glaucoma-filtering surgery unfortunately has been limited by postoperative scarring. Scarring most commonly occurs at the

5-Fluorouracil

5-Fluorouracil (5-FU) is a chemotherapeutic agent that specifically mediates its antiproliferative effect by antagonizing pyrimidine metabolism, hence its classification as an antimetabolite. It initially undergoes anabolic transformation into ribosyl and deoxyribosyl nucleotide metabolites. Specifically, one of these metabolites, 5-fluoro-2′deoxyuridine 5′-phosphate (F-dUMP), binds covalently to thymidylate synthetase and its cofactor N5,10-methylene tetrahydrofolate to form a ternary complex

Mitomycin C (Tables 4 and 5)

Prior to the original pilot study using 5-FU supplementation after glaucoma surgery, Chen found that mitomycin C used in conjunction with filtering surgery was successful in enhancing bleb survival. However, in spite of this discovery, use of this agent with regularity did not commence until the early 1990s.23 Mitomycin C is an antibiotic agent with antiproliferative properties. It is derived from the soil fungus Streptomyces caespitosus. Its pharmacological effect is probably derived from all

Mitomycin C Versus 5-Fluorouracil

Because mitomycin C is more potent than 5-FU and has longer lasting effects on cultured fibroblasts, clinicians tend to favor mitomycin C over 5-FU in especially complicated, difficult-to-control glaucomas. Notwithstanding these differences, there have been few clinical trials specifically designed to compare the two antifibrotics directly. In a randomized prospective clinical trial, Katz and co-workers compared single intraoperative mitomycin C application (0.5 mg/ml for 5 minutes) with

Other Anti-Scarring Agents: Old and New

Whereas antiproliferative agents inhibit scarring through direct inhibition of fibroblast proliferation and function, there have been limited studies published evaluating drugs that inhibit collagen secretion and cross-linking. These agents thus inhibit scarring later in the wound healing pathway than do 5-FU and mitomycin C. β-aminoproprionitrile (BAPN), D-penicillamine, and colchicine are all inhibitors of collagen cross-linking. BAPN specifically inhibits lysyl oxidase. This enzyme catalyzes

DAUNORUBICIN

Daunorubicin is an anthracycline antibiotic derived from Streptomyces peucetius var caesius. Pharmacologically this agent, through intercalation, leads to blockade of both DNA and RNA synthesis and causes DNA strand scission. It also binds to membranes altering fluid and ion transport and generates semi-quinone and oxygen free radicals.15Clinically, daunorubicin is primarily used in the management of acute myelogenous leukemia. However, there have been a few published clinical trials in the

Growth Factor Inhibitors

Both 5-FU and mitomycin C are useful in inhibiting fibroblast growth and replication and thus improving surgical success rates when used adjunctively during or following filtration surgery. However, the complications from use of these agents can be very severe because such agents cause widespread fibroblast cytotoxicity and apoptosis. Optimally, one would like to inhibit postoperative scarring without the inherent risks of antiproliferative therapy such as thin leaking blebs, hypotony, or

Recommendations

Although use of antiproliferative agents during or following filtering surgery has been shown to improve surgical success rates through wound modulation, there is considerable toxicity associated with these agents that may lead to serious ocular morbidity and visual loss. It is thus imperative that all physicians who intend to perform glaucoma-filtering surgery with these adjuncts have thorough knowledge and understanding of all aspects of these agents to maximize patient safety and limit the

LONG-TERM SURVIVAL CURVES

Although adjunctive use of antiproliferative agents in glaucoma surgery has been shown to improve bleb survival, close scrutiny of the data reveals that the results are not ideal. Aside from methodological differences between studies including criteria defining success, many of the studies were of short duration with relatively few patients. Moreover, few patients were actually followed for three years or longer. In view of this limitation, the authors used Kaplan–Meier survival curves to

Summary

The weight of the evidence from antifibrosis studies demonstrates that antiproliferative therapy is extremely useful in augmenting early filtering surgery success rates. However, long-term success rates of blebs supplemented with antiproliferative agents are not as promising as desired with survival curves that eventually parallel those blebs that did not receive antiproliferative therapy. Furthermore, variability between studies is great and multifactorial in origin. Patient demographics,

Method of Literature Search

Medline and Ovid were used to search literature from 1966 to 2002. Key words used were glaucoma, glaucoma filtering surgery, antimetabolites, 5-fluoruracil, mitomycin C. English language literature and English language abstracts of foreign literature were included in the search.

References (129)

  • S.F. Freedman et al.

    Mitomycin C-augumented trabeculectomy with postoperative wound modulation in pediatric glaucoma

    J AAPOS

    (1999)
  • S.A. Gandolfi et al.

    5-fluorouracil in combined trabeculectomy and clear-cornea phacoemulsification with posterior chamber intraocular lens implantation. A one-year randomized, controlled clinical trial

    Ophthalmology

    (1997)
  • M. Goldenfeld et al.

    5-Fluorouracil in initial trabeculectomy. A prospective, randomized, multicenter study

    Ophthalmology

    (1994)
  • M.G. Gressel et al.

    5-fluorouracil and glaucoma filtering surgeryI. An animal model

    Ophthalmology

    (1984)
  • D.K. Heuer et al.

    5-Fluorouracil and glaucoma filtering surgeryIII. Intermediate follow- up of a pilot study

    Ophthalmology

    (1986)
  • E.J. Higginbotham et al.

    Bleb-related endophthalmitis after trabeculectomy with mitomycin C

    Ophthalmology

    (1996)
  • H.D. Jampel et al.

    Trabeculectomy with 5-fluorouracil for adult inflammatory glaucoma

    Am J Ophthalmol

    (1990)
  • G.J. Katz et al.

    Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Extended follow-up

    Ophthalmology

    (1995)
  • A. Knapp et al.

    Serious corneal complications of glaucoma filtering surgery with postoperative 5-fluorouracil

    Am J Ophthalmol

    (1987)
  • K.A. Lamping et al.

    5-Fluorouracil and mitomycin C in pseudophakic patients

    Ophthalmology

    (1995)
  • K.A. Lamping et al.

    5-Fluorouracil and mitomycin C in pseudophakic patients

    Ophthalmology

    (1995)
  • D. Lee et al.

    The effect of adjunctive mitomycin C in Molteno implant surgery

    Ophthalmology

    (1997)
  • D.A. Lee et al.

    Glaucoma filtration surgery in rabbits using bioerodible polymers and 5-fluorouracil

    Ophthalmology

    (1987)
  • P.R. Lichter et al.

    Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery

    Ophthalmology

    (2001)
  • J.M. Liebmann et al.

    Initial 5-fluorouracil trabeculectomy in uncomplicated glaucoma

    Ophthalmology

    (1991)
  • J.S. Mora et al.

    Trabeculectomy with intraoperative sponge 5-fluorouracil

    Ophthalmology

    (1996)
  • M.E. Nimni

    Collagen: structure, function, and metabolism in normal and fibrotic tissues

    Semin Arthritis Rheum

    (1983)
  • J.M. O'Grady et al.

    Trabeculectomy, phacoemulsification, and posterior chamber lens implantation with and without 5-fluorouracil

    Am J Ophthalmol

    (1993)
  • C.J. Patitsas et al.

    Glaucoma filtering surgery with postoperative 5-fluorouracil in patients with intraocular inflammatory disease

    Ophthalmology

    (1992)
  • E.J. Rockwood et al.

    Glaucoma filtering surgery with 5-fluorouracil

    Ophthalmology

    (1987)
  • R.F. Rothman et al.

    Low-dose 5-fluorouracil trabeculectomy as initial surgery in uncomplicated glaucoma: long-term followup

    Ophthalmology

    (2000)
  • R.S. Rubinfeld et al.

    Serious complications of topical mitomycin-C after pterygium surgery

    Ophthalmology

    (1992)
  • J.M. Ruderman et al.

    A randomized study of 5-fluorouracil and filtration surgery

    Am J Ophthalmol

    (1987)
  • M.B. Sherwood et al.

    Long-term morphologic effects of antiglaucoma drugs on the conjunctiva and Tenons capsule in glaucomatous patients

    Ophthalmology

    (1989)
  • D.H. Shin et al.

    Primary glaucoma triple procedure in patients with primary open-angle glaucoma: the effect of mitomycin C in patients with and without prognostic factors for filtration failure

    Am J Ophthalmol

    (1998)

  • —: The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators

    Am J Ophthalmol

    (2000)

  • —: Five-year follow-up of the Fluorouracil Filtering Surgery Study. The Fluorouracil Filtering Surgery Study Group

    Am J Ophthalmol

    (1996)
  • Y.A. Akova et al.

    Scleromalacia following trabeculectomy with intraoperative mitomycin C

    Eur J Ophthalmol

    (1999)
  • N. Anand et al.

    Modification of trabeculectomy with single-dose intraoperative 5-Fluorouracil application

    Acta Ophthalmol Scand

    (1998)
  • M. Araie et al.

    Postoperative subconjunctival 5-fluorouracil injections and success probability of trabeculectomy in Japanese: results of 5-year follow-up

    Jpn J Ophthalmol

    (1992)
  • A. Azuara-Blanco et al.

    Simultaneous use of mitomycin-C with Baerveldt implantation

    Ophthalmic Surg Lasers

    (1997)
  • A. Azuara-Blanco et al.

    Oral prednisone in guarded filtration procedures supplemented with antimetabolites

    Ophthalmic Surg Lasers

    (1999)
  • A. Azuara-Blanco et al.

    Filtration procedures supplemented with mitomycin C in the management of childhood glaucoma

    Br J Ophthalmol

    (1999)
  • R.W. Bell et al.

    Long-term results and complications after trabeculectomy with a single per-operative application of 5-fluorouracil

    Eye

    (1997)
  • L. Brancato et al.

    Effect of dexamethasone and D-penicillamine in filtration surgery

    Invest Ophthalmol Vis Sci

    (1983)
  • D. Broadway et al.

    Adverse effects of topical antiglaucoma medications on the conjunctiva

    Br J Ophthalmol

    (1993)
  • D.C. Broadway et al.

    Adverse effects of topical antiglaucoma medicationI. The conjunctival cell profile

    Arch Ophthalmol

    (1994)
  • D.C. Broadway et al.

    Adverse effects of topical antiglaucoma medicationII. The outcome of filtration surgery

    Arch Ophthalmol

    (1994)
  • D.C. Broadway et al.

    Reversal of topical antiglaucoma medication effects on the conjunctiva

    Arch Ophthalmol

    (1996)
  • D.L. Budenz et al.

    Comparison of phacotrabeculectomy with 5-fluorouracil, mitomycin-C, and without antifibrotic agents

    Ophthalmic Surg Lasers

    (1999)

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    ☆

    Supported in part by unrestricted grants from Research to Prevent Blindness and The Glaucoma Research and Education Foundation. The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.

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