Complications Associated with Modulation of Wound Healing in Glaucoma Surgery

Introduction

Glaucoma surgery is often associated with postoperative complications unique to the underlying goal of creating a permanent fistula between the anterior chamber and the sub-Tenon's space. Antifibrotic agents play an important role in achieving this goal. Mitomycin C (MMC), 5-fluorouracil (5-FU), and corticosteroid use, both intraoperatively and postoperatively, have improved the chances for filtration success in eyes at risk for surgical failure. These antifibrotic agents help produce filtering blebs with excellent pressure control, but with an increased risk for complications. Unfortunately, the filtration blebs change with time and some eventually fail to maintain adequate intraocular pressure or remain complication-free. The authors will discuss the common difficulties associated with wound healing modulation in glaucoma surgery, and techniques used to manage the associated complications.

Many surgeons augment their trabeculectomy surgery with immunomodulating (antifibrosis, 5-FU, and MMC are not strictly speaking immune-modulating) agents, especially in eyes at risk for bleb failure, to achieve reliably low postoperative pressures. The risks for failure include young age, African-American race, failed prior surgery, aphakia, pseudophakia, neovascular glaucoma, and active uveitic glaucoma. High-risk eyes require careful manipulation of surgical technique and antifibrotic agents to maintain a pressure in the low teens, retain baseline visual acuity, and have minimal progression of glaucomatous optic neuropathy. Unfortunately, many post-trabeculectomy eyes have pressures that are too high or too low, lose vision due to cataract formation or hypotony maculopathy, and continue to sustain optic nerve damage. The fact that there are so many variations of trabeculectomy surgical technique, antifibrotic dose, and exposure time indicates that no one method is perfect. The current surgical trend favors a fornix-based approach with judicious use of MMC or 5-FU, depending on preoperative risk factors for bleb failure. Some surgeons use antifibrotic agents during all trabeculectomy cases, while others believe that their routine use is not justified owing to their increased risk for complications.

The three main immunomodulating agents employed routinely during trabeculectomy surgery have diverse mechanisms of action and duration of effect. Inhibition of inflammation and wound healing by corticosteroids is mediated by leukocyte suppression and function, as well as their effect on vascular permeability. Macrophage function is impaired temporarily and vessels leak less serum and fewer clotting factors, which leads to less fibrin formation. 5-FU works by antagonizing pyrimidine metabolism and inhibiting DNA synthesis, which suppresses fibroblast activity. MMC, an alkylating agent, interferes with all phases of the cell cycle and not only inhibits DNA replication, but also prevents fibroblast mitosis, endothelial cell growth, and protein synthesis. MMC inhibits the postoperative scarring response by cross-linking DNA in conjunctival and episcleral fibroblasts and reducing their ability to proliferate. Mitomycin-C also induced fibroblast death by apoptosis. Loss of cell viability may account for increased complication rates. The greater potency and duration of action of MMC versus 5-FU or corticosteroids correlates with the increased complication rate seen with MMC use.

Histopathology of Episcleral Fibrosis

Both 5-FU and MMC reduce fibroblast activity at the trabeculectomy site; however, MMC's influence tends to be more long-lasting. 5-FU is successful for the first few postoperative years owing to inhibition of fibroblast proliferation and function. Long-term success with 5-FU wanes because uninhibited late fibrosis leads to bleb failure. The long-term effect of MMC on scar tissue at the trabeculectomy site was examined histologically using specimens from surgical failures. Specimens from postsurgical eyes without MMC showed dense scar tissue with many fibroblasts, much ground substance, parallel-oriented collagen fibers, and contractile intracellular proteins within the fibroblasts. Tissue from specimens treated with MMC revealed few fibroblasts, no contractile proteins, and randomly arranged collagen fibers with less ground substance. Even after 10 months, scar tissue was noted to be distinctly different between the antifibrotic-treated group and the untreated groups, demonstrating that MMC has long-term in vivo effects with regard to scar formation.

Corticosteroid Use

Preoperative corticosteroid use may improve the chances for early filtration success, especially in patients with active inflammation or who have had chronic therapy with intraocular pressure (IOP)-lowering drugs. Patients with a long history of glaucoma medication use are often noted to have subclinical inflammation associated with an increased number of conjunctival inflammatory cells. The fibroblasts may have already been primed, prior to trabeculectomy surgery, thus increasing the risk of bleb failure. Investigators pretreated trabeculectomy patients with 1% fluorometholone q.i.d. for 1 month prior to surgery. The corticosteroid-treated eyes demonstrated a reduction in the number of inflammatory cells and fibroblasts in conjunctival biopsy specimens. A comparison of pretreated patients with matched controls revealed that preoperative corticosteroid use may have improved the 12-month success rate of trabeculectomy from 50% to 81%.

The authors routinely use topical corticosteroids during postoperative management of glaucoma surgical procedures until all intraocular inflammation has subsided. The rate of corticosteroid taper is gauged according to how quickly the initial inflammation resolved and the level of residual inflammation. A 10-year follow-up on a prospective, randomized trial showed that postoperative corticosteroids after guarded filtration procedures were correlated with better glaucoma control. The corticosteroid-treated patients were more likely to have thin, cystic blebs than the nontreated controls. They also had lower pressures and required fewer medications. Unfortunately, the thinner blebs may be associated with a higher risk of bleb leaks and possible infection. Although long-term use of topical prednisolone acetate is effective in suppressing inflammation, it may also lead to earlier cataract formation, infectious keratitis, blebitis, and endophthalmitis.

Intraoperative Complications

Complications encountered during trabeculectomy surgery, such as scleral or conjunctival buttonholes, are often exacerbated by antifibrotic agent use. 5-FU and MMC compromise the normal healing process and make spontaneous buttonhole repair unlikely. The authors prefer to use nontoothed forceps when handling the conjunctiva to avoid buttonhole formation. The Tenon's tissue should be grasped, rather than the overlying conjunctiva, when dissecting a tissue plane over the sclera. Ideally, an inadvertent conjunctival hole will be repaired intraoperatively to prevent a persistent wound leak and hypotony. If a large buttonhole is created early in the surgery, it may be best to select another quadrant for the trabeculectomy. Small buttonholes can be closed with a 10/0 or 11/0 nylon suture on a noncutting vascular needle, in a purse-string or mattress fashion. The authors use a Seidel test to confirm that the defect is closed. Larger holes can be marginalized by undermining adjacent conjunctiva and rotating the perforation away from the scleral flap and future filtering bleb. Postoperative topical corticosteroids can be reduced, during the early postoperative period, to expedite ‘healing’ of the conjunctival buttonhole. Short-acting aqueous suppressants, such as brimonidine, dorzolamide, or acetazolamide, may also facilitate wound closure during the first few postoperative days by reducing flow through the residual hole.

Dissection of a scleral flap that is too thin, and treated subsequently with MMC or 5-FU, may result in flap dehiscence, maceration, or avulsion during later manipulation. The dehisced flap can turn the guarded filter into a full-thickness procedure with resultant overfiltration and hypotony. The authors use a 10/0 nylon suture on a noncutting needle to repair the torn scleral flap. If necessary, donor sclera or Tutoplast can be used to create a new scleral flap and sewn over the prior trabeculectomy site. A flap buttonhole can be plugged with Tenon's tissue, Tutoplast (Innovative Ophthalmic Products Inc., Costa Mesa, CA), or split-thickness sclera harvested from an adjacent area of the operated eye. The tissue plug is secured over the hole using 10/0 nylon bolster sutures ( Fig. 93-1 ).

Most surgeons apply MMC- or 5-FU-soaked sponges to the subconjunctival space and scleral flap prior to entering the eye to reduce the possibility of corneal endothelial toxicity from the antifibrotic agents. These agents should not be allowed to enter the anterior chamber either during the initial trabeculectomy or during postoperative needling procedures. Studies reveal that intraocular exposure to undiluted MMC (200–500 µg/mL), with inadvertent entry into the anterior chamber during dissection of the scleral flap bed, results in prompt destruction of the corneal endothelium. Interestingly, 5-FU, at a concentration of 50 mg/mL, was noted to be less toxic to the corneal endothelium than MMC at a concentration of 1 mg/mL. If an antifibrotic agent enters the eye accidentally, the anterior chamber should be rinsed immediately with sterile balanced salt solution (BSS, Alcon, Ft. Worth, TX) through a paracentesis.

Selecting the correct sponge type and posterior sponge placement during antiproliferative delivery can increase the chance of successful bleb formation. The authors prefer cut pieces of polyvinyl alcohol sponge (PVA Spears, Eyetec Ophthalmic Products, Altomed Ltd, UK), rather than cellulose sponges, because the PVA spears do not leave behind microfragments. There are reports of bleb inflammation and a foreign body granulomatous reaction from the cellulose fragments left in filtering blebs following trabeculectomy with MMC. The authors place multiple MMC- or 5-FU-soaked sponges, as far posteriorly as the equator, to help create a thick, diffuse bleb. These diffuse blebs are less prone to late leaks than the thin, avascular blebs often seen with single, anterior sponge placement. The authors avoid sponge contact with the conjunctival flap edge to facilitate limbal healing and avoid an early wound leak ( Figs 93-2 and 93-3 ).

Bleb Failure

Complete healing of the filtering bleb is a significant complication after trabeculectomy surgery, as it usually portends loss of pressure control. Surgeons can utilize minimally invasive surgical techniques and prescribe medications to reduce the chance of bleb failure. Preoperative anti-inflammatory treatment and reduction or discontinuation of topical medications have a positive effect on postoperative conjunctival wound healing and often influence the success or failure of the operation. Gentle tissue handling during surgery can reduce inflammation and scar tissue formation. As early as 24 hours after injury, fibro­blasts begin producing collagen, elastin, and mucopolysaccharides. Preemptive use of corticosteroids, 5-FU, or MMC prevents these fibroblasts from scarring the trabeculectomy site closed. The decision regarding postoperative 5-FU injections and topical corticosteroid use is influenced by close examination of the bleb thickness, height, extent, and intraocular pressure ( Fig. 93-4 ).

Blebs require continued surveillance and occasional intervention to avert bleb failure. Intraoperative 5-FU appears to increase the likelihood of successful filtration in the first few years after surgery due to fibroblast inhibition. Long-term success, however, continues to diminish at a rate similar to that in controls who were not subjected to perioperative antiproliferative agents. Even blebs with well-controlled IOP can succumb to renewed fibroblast activity, become encapsulated, and scar closed. Increased vascularity, progressive bleb wall thickening, and loss of conjunctival microcysts are all signs of impending failure. Bleb needling, in conjunction with prior subconjunctival injections of MMC or 5-FU, has proved useful in rejuvenating failing blebs. Care should be taken to avoid inadvertent intraocular injection of either antifibrotic agent. Complications associated with needling procedures using 5-FU or MMC are similar to those following trabeculectomy: hypotony, keratitis, choroidal effusions, wound leak, and hyphema.