Chapter 241 – Antifibrotic Agents in Glaucoma Surgery
PENG TEE KHAW
One of the major areas of advance in the surgical management of glaucoma over the past 20 years has been the use of antimetabolites to prevent scarring after glaucoma filtration surgery. Antimetabolites have gone from occasional use in high-risk patients in the 1980s to use of mitomycin C (MMC) in more than 50% of cases undergoing primary trabeculectomy by university-based glaucoma physicians in the United States. The Advanced Glaucoma Intervention Study (AGIS) has shown that target intraocular pressures (IOPs) around 12?mmHg are required to arrest glaucomatous progression over a decade, rather than just an IOP lower than 21?mmHg (2.8?kPa).  Therefore, the concept that the healing response should be modulated after all surgery has become increasingly important. The healing response is the major determinant of long-term IOP levels after glaucoma surgery. Therefore, modulation of this response together with appropriate surgical techniques may enable the surgeon to set the IOP at the lowest level that is safe, not just in high-risk patients but in every patient who undergoes filtration surgery.
ANTIFIBROTIC AGENTS AND STRATEGIES
Although most attention has been focused on antimetabolites such as 5-fluorouracil and MMC, it must not be forgotten that many strategies exist to prevent fibrosis and scarring after glaucoma filtration surgery (summarized in Table 241-1 ). Many of these have been used experimentally, but some such as the human
TABLE 241-1 — WOUND HEALING AND POSSIBLE MODIFICATION AFTER GLAUCOMA SURGERY
Primed damaged conjunctiva “preactivated” cells
Stop medical therapy especially adrenaline
Less invasive surgical techniques
Damage to connective tissue
Release of plasma proteins and blood cells
Hemostasis (Vital: blood can reverse mitomycin!)
Activation of clotting and complement
Fibrin/fibronectin/blood cell clot
Agents preventing/removing fibrin (e.g., heparin, tissue plasminogen activator, hirudin)
Release of growth factors from blood
Antagonists to growth factor production (e.g., antibodies to growth factors humanized anti–TGF-ß2)
Antibody (CAT 152) or receptors
Antisense oligonucleotides, ribozymes
Less specific antagonists, e.g., tranilast, genistein, suramin
Aqueous released from eye
Blood-aqueous barrier stabilizing agents (e.g., steroids)
Some breakdown of blood-aqueous barrier
Release of growth factors into aqueous
Nonsteroidal anti-inflammatory agents
Aqueous begins to flow through wound
Migration and proliferation of polymorphonuclear neutrophil cells, macrophages, and lymphocytes.
Anti-inflammatory agents (e.g., steroids/cyclosporine)
Antimetabolites, e.g., 5-fluorouracil/MMC
Activation, migration, and proliferation of fibroblasts
Preoperative steroids to reduce activation
Antimetabolites MMC 5-fluorouracil
Anticontraction agents (e.g., colchicine, taxol)
Fibroblast synthesis of tropocollagen, Glycosaminoglycans, and fibronectin
Collagen cross-linking and modification
Anti–cross-linking agents (e.g., ß-inopropionitrile/penicillamine)
Blood vessel endothelial migration and proliferation
Inhibitors of angiogenesis (e.g., angiostatin)
Resolution of healing
Death receptor ligands
Disappearance of fibroblasts
Stimulants of apoptosis pathways
Fibrous subconjunctival scar
Modified from Khaw PT, Occleston NL, Schultz GS, et al. Acticvation and suppression of fibroblast activity. Eye. 1994:8;188–95.
Events and agents have overlapping time duration and action.
antibody to transforming growth factor ß2 (TGF-ß2) are now undergoing clinical trials. Many of the agents given in Table 241-1 have multiple actions on the healing cascade. It is particularly important to remember that agents such as corticosteroids, although routinely used, may not be used optimally. However, the antifibrotic agents used most commonly at present are discussed in this chapter; namely the antimetabolites. The term antimetabolites is a broad generic term, used herein to describe agents that interfere with cellular processing at every level, from DNA to protein.
The use of the antimetabolite 5-fluorouracil, given by postoperative injections, was popularized by the work of Parrish and colleagues from Miami in the 1980s, following work on 5-fluorouracil for experimental proliferative vitreoretinopathy. More recently, 5-fluorouracil has been used as a single intraoperative sponge application, a development stimulated by the intraoperative topical application of MMC and cell culture results  which suggested that long-term effects could be achieved with convenient, single, short intraoperative applications. Intraoperative MMC application was first used clinically by Chen in 1981; since the late 1980s its use has increased exponentially worldwide because of the ease of application and its dramatic effects. However, these powerful agents potentially have sight-threatening side effects. In this chapter, current views on the use of these antifibrotic agents are summarized.
TABLE 241-2 — RISK FACTORS FOR SCARRING AFTER GLAUCOMA FILTRATION SURGERY
Risk (+ to +++)
Neovascular glaucoma (active)
Previous failed filtration surgery
Previous conjunctival surgery
Chronic conjunctival inflammation
Previous cataract extraction (conjunctival incision)
Aphakia (intracapsular extraction)
Previous intraocular surgery
Depends on type of surgery
Recent surgery (within last 30 days)
Uveitis (active, persistent)
A red, injected eye
May vary (e.g., West versus East African–American Africans, elderly versus young)
Previous topical medications (ß-blockers + pilocarpine)
Previous topical medications (ß-blockers + pilocarpine + epinephrine)
New topical medications
Particularly if they cause a red eye
High preoperative intraocular pressure
Higher with each 10?mmHg (1.3?kPa) rise
Age <40 years with no other factors
Inferiorly located trabeculectomy
PATIENT GROUPS THAT REQUIRE ANTIMETABOLITES
A number of patient factors increase the risk of scarring and failure after glaucoma surgery, as summarized in Table 241-2 . However, the risk may still vary within subgroups. Patients who suffer from uveitis may have chronic persistent uveitis, which may carry a much worse surgical prognosis than that for patients who suffer episodic uveitis. Patients may also be subject to more than one risk factor, which may increase their overall risk. There may be hidden risk factors for failure in what were previously regarded as low-risk “first time surgery” groups.
Broadway et al. showed that the success rate of trabeculectomy as primary surgery without medical treatment was 90%, similar to that in the group treated with ß-blockers (93%). The success rate for patients treated with both ß-blockers and miotics was significantly lower (72%), and for the group treated with ß-blockers, miotics, and sympathomimetics, the success rate was only 45% (worse than for previous failed trabeculectomy or cataract extraction with conjunctival incision), with enhanced scarring a significant problem ( Fig. 241-1 ). Interestingly, it has been found that the fornices of patients who have received topical medications are contracted. The role of topical medications is not understood completely ; however, what is clear is that even a small increase in risk with topical medications has a profound effect on surgical success worldwide, as this group of patients accounts for the majority of patients who undergo surgery in developed countries.
High-Risk Patient Groups
Patient factors that carry a high risk of surgical failure include previous failed trabeculectomies, previous cataract surgery through a conjunctival incision, neovascular glaucoma, chronic persistent uveitis, and multiple previous intraocular surgery. Most glaucoma specialists agree that some form of antimetabolite treatment be used in these patient groups. The most definitive study of 5-fluorouracil injections was the randomized, prospective National Eye Institute 5-Fluorouracil Filtration Surgery Study, which showed a 51% failure rate after filtration surgery in patients who had failed trabeculectomy previously or had undergone cataract surgery with a conjunctival incision. In the randomized group that received 5-fluorouracil 5?mg injections (twice a day for days 1–7, once a day for days 8–14, total 21 injections), the failure rate was only 51% compared with 74% in the placebo group after 5 years. Since then, several randomized studies undertaken to compare intraoperative MMC application (0.4–0.5?mg/ml) with postoperative 5-fluorouracil injections (approximately ten 5?mg injections)   have shown that in high-risk
Figure 241-1 Adrenochrome deposits. Topical treatment may worsen the prognosis of filtration surgery because of an enhanced scarring response.
patients a single application of MMC provides superior long-term pressure control compared with injections of 5-fluorouracil without the risk of keratopathy. Corneal epithelial complications are much more common with injectable 5-fluorouracil, but both groups had thin avascular blebs, these being more prominent in the MMC-treated groups.
The intraoperative MMC regimen, rather than the postoperative subconjunctival 5-fluorouracil injection regimen, is rapidly becoming the treatment of choice for these high-risk patients because of the increased efficacy, ease of application, and virtual absence of corneal side effects. However, longer periods of follow-up are required to monitor the development of bleb leaks, hypotony, and endophthalmitis after the two treatment regimens, in view of the thinner and highly avascular blebs seen with MMC.
With regard to intraoperative 5-fluorouracil application, Egbert et al. carried out a randomized prospective study in a group of West African patients in whom there was a high risk of failure. They showed success rates of 83% in the 5-fluorouracil–treated group versus 39% in the control group, with a mean follow-up of 282 days. Singh et al. compared intraoperative 5-fluorouracil application (50?mg/ml for 5 minutes) against MMC application (0.5?mg/ml for 3 minutes) in a group of West African patients, with short-term follow-up averaging 10 months. They found lower average IOPs in the MMC-treated group, but because of the relatively small numbers, no short-term difference in complications was found in this group of higher risk patients. Therefore, in this particular group, intraoperative MMC application offers better results than intraoperative 5-fluorouracil application with no large short-term penalty in terms of complication rates; MMC, therefore, appears to be superior in the short term.
Antimetabolites may also be used after other glaucoma procedures that are usually associated with a strong healing reaction—for example, after tube implant surgery and after combined cataract extraction and glaucoma filtration surgery. The blebs seen after MMC treatment, combined with tube implants, are much less avascular and cystic. It has yet to be proved conclusively that intraoperative MMC improves the prognosis for tube surgery as opposed to trabeculectomy. In combined glaucoma filtration and cataract surgery, both postoperative subconjunctival 5-fluorouracil and intraoperative MMC have been used. However, the majority of publications suggest that neither 5-fluorouracil injections nor intraoperative MMC has a very significant effect on pressure control after combined cataract and glaucoma surgery.
Intermediate- or Low-Risk Patient Groups
Antimetabolite use in eyes with no previous surgery of any kind and no significant intraocular disease apart from glaucoma is much more controversial. 5-Fluorouracil injections have been used in lower risk groups, which include first-time filtration surgery, young patients, and normal tension glaucoma, to achieve lower IOPs, and superior success rates are found in the treated groups. Complications such as cornea epithelial change and hypotony are more common but only in the short term. Intraoperative MMC application increases the success rate of surgery but also increases the incidence of hypotony. Hypotony usually occurs in the younger patients, particularly those who are myopic.  
In the low-risk patients, a single application of intraoperative 5-fluorouracil may provide the convenience of single-application MMC but without the same incidence of hypotony and the very thin and completely avascular blebs often seen with MMC. Cell culture experiments suggest that a single 5-minute application of 5-fluorouracil can inhibit fibroblasts for several weeks without severe long-term damage and may be equivalent to low-dose 5-fluorouracil injections.  
Several studies using single applications of intraoperative 5-fluorouracil with short-term follow-up have reported promising
Figure 241-2 Diffuse relatively noncystic bleb. This arose after ß-radiation adjunctive treatment with a large surface area to prevent scarring.
Figure 241-3 Cystic avascular bleb. This arose after the use of a limbus-based flap with a small rectangular sponge soaked in mitomycin C 0.4?mg/ml. Safer diffuse noncystic blebs can now be created with a simple change in operative technique.
results in low-risk patients. Smith et al. originally reported the use of intraoperative 5-fluorouracil application in combination with postoperative injections. Lanigan et al. reported a success rate of 77% in high-risk patients (neovascularization, previous failed filter, aphakia, uveitis, or multiple risk factors), with a 100% success rate in the low-risk group (medications >3 years, or <40 years age, or African-Caribbean). Also, Feldman et al. reported an overall success rate of 85% in high-risk patients and a success rate of 92.9% in low-risk patients; no hypotony was reported in the Feldman study. However, both studies were short term with no controls. Therefore, failure occurs in higher risk patients who have a prolonged or aggressive healing response, but in lower risk patients the success rate is very good (>90%) with no clinically significant hypotony. An improvement in survival was also found for patients in East Africa with a single 5-minute application of 5-fluorouracil 25?mg/ml, interestingly with a much lower failure rate in the control group compared with patients in West Africa. A single application of intraoperative beta-radiation (750?cGy) delivered by a strontium-90 probe may be similar to a single-dose intraoperative 5-fluorouracil application.  The advantage of intraoperative beta-radiation is that it appears to give rise to blebs that are more diffuse and less cystic than those elicited by 5-fluorouracil or MMC use ( Figs. 241-2 and 241-3 ).
Moorfields Eye Hospital/University of Florida (More Flow) Regimen.A
LOW-RISK PATIENTS (NOTHING OR 5-FLUOROURACIL 50?MG/ML* 5 MINUTES)†
No risk factors
Topical medications (ß-blockers)
INTERMEDIATE-RISK PATIENTS (5-FLUOROURACIL 50?MG/ML 5 MINUTES* OR MMC 0.2?MG/ML 3 MINUTES)†
Topical medications (pilocarpine/adrenaline) or others that cause a red eye
Previous cataract surgery without conjunctival incision (capsule intact)
Several low risk factors
Combined glaucoma filtration surgery/cataract extraction
Previous conjunctival surgery (e.g., squint/detachment surgery)
HIGH-RISK PATIENTS (MMC 0.5?MG/ML 3 MINUTES)†
Chronic persistent uveitis
Previous failed trabeculectomy/tubes with or without antimetabolites
Chronic conjunctival inflammation
Multiple risk factors
Aphakic glaucoma (a tube with antimetabolites may be more appropriate in many of these cases)
An intraoperative, single-dose regimen for scarring after glaucoma filtration surgery. (This regimen is still evolving.) Other factors may also determine the choice of agent, such as the need for a low target pressure due to advanced disease (require a stronger antimetabolite treatment).
* Intraoperative beta-radiation 750–1000?cGy can also be used. Most of the newer agents currently being tested in pilot studies, e.g., CAT-152 humanized anti–TGF-ß2 antibody, are probably appropriate for the low- and intermediate-risk groups. These groups do, however, account for the majority of patients undergoing glaucoma filtration surgery.
†Postoperative 5-fluorouracil injections can be given in addition to the intraoperative applications of antimetabolite
A single antimetabolite regimen may not be adequate for all patients. The type and dose of drugs may need to be titrated depending on the individual patient’s risk factors and healing response. The authors use a “titratable” regimen that is based on laboratory  and clinical data gained from experience using the different single-application agents and concentrations [the authors call this the Moorfields/Florida regimen (More Flow) regimen]. This regimen evolves constantly, but the present regimen is summarized in Box 241-1 . Also, subconjunctival postoperative injections of 5-fluorouracil may be used in addition to the application of intraoperative antimetabolites.
APPLICATION TECHNIQUE (INTRAOPERATIVE ANTIMETABOLITES)
The significant variations in technique used to deliver intraoperative antimetabolites are not addressed sufficiently in the literature, which may account for some of the variations in efficacy and complications published. It is important for individual surgeons to maintain a consistent technique and to reevaluate periodically their experience using this technique. We now understand better how antimetabolites, particularly MMC, work in vivo causing long-term tissue cell death and growth arrest.  There is remnant functional activity in peripheral fibroblasts that form a ring of scar tissue around the bleb (“ring of steel”). This has allowed us to evolve strategies in antimetabolite delivery to improve our success rate ( Box 241-2 ) and to change bleb morphology dramatically ( Fig. 241-4 ). This has reduced the number of cystic blebs from 90 to 29% and reduced bleb-related complications, particularly endophthalmitis, from 15% to 0% over a 3-year follow-up period. If this result is extrapolated to the United States, where many trabeculectomies are done with MMC, this could reduce bleb-related complications in many thousands of patients. A summary of the improvements in antimetabolite use over the years is presented in Fig. 241-5 .
Figure 241-4 Diagram showing technique changes that result in more diffuse noncystic blebs. “Safe Surgery System” for glaucoma surgery.
Figure 241-5 Focal cystic bleb prone to leakage, infection, and dysesthesia in left eye (limbus-based conjunctival flap, small scleral flap, and smaller area of MMC 0.4?mg/ml treatment). Diffuse noncystic bleb appearance in right eye of the same patient (fornix-based flap, larger scleral flap, and larger area of MMC 0.5?mg/ml treatment).
Improvements in the Use of Intraoperative Antimetabolites
Use of weaker agents (intraoperative 5-fluorouracil), lower concentrations of MMC for lower risk individuals or individual at high risk of hypotony or other complications of antimetabolites
Non-fragmenting sponges (polyvinyl alcohol rather than methylcellulose)
Protection of cut edge with special clamp (Duckworth and Kent, or John Weiss, UK) to prevent dehiscence
Treat under both scleral flap and conjunctival flap. The use of the sponge both under the scleral flap and the conjunctiva seems to enhance the success rate
Measures to secure scleral flap—smaller sclerostomy, larger scleral flaps, multiple tight sutures that are both adjustable (adjustable suture control or ASC) and releasable.
Measures to produce diffuse noncystic blebs—large scleral flaps, fornix-based conjunctival flap or extremely posterior limbus-based incision and large surface area of antimetabolite treatment. Big (treatment area, scleral flap) and backward (aqueous flow direction) is better!
Time of Exposure, Concentration and Type of Intraoperative Agent
The optimum concentration of intraoperative MMC still needs to be established. Chen et al. reported results in high-risk patients since 1981 without failures but a 66% rate of hypotony with MMC 0.4?mg/ml, a 22% failure rate with no hypotony with
MMC 0.2?mg/ml, and a 37% failure rate with no hypotony with MMC 0.1?mg/ml. In a randomized, prospective study of Japanese patients given primary surgery, Kitazawa et al. had a 100% success rate with MMC 0.2?mg/ml (but transient hypotony maculopathy and cataract progression in 18%) and a 64% success rate with MMC 0.02?mg/ml with no hypotony or cataract progression. For intraoperative 5-fluorouracil, both concentrations, 50?mg/ml and the weaker 25?mg/ml, have been used, but no direct comparison has been made between the two.
The choice of agent is still not certain, particularly for first-time surgery patients. Singh et al. compared intraoperative 5-fluorouracil (50?mg/ml for 5 minutes) against MMC (0.5?mg/ml for 3 minutes) in a group of West African patients with short-term follow-up that averaged 10 months. They found lower average IOPs in the MMC-treated group but because of the relatively small numbers no short-term difference in complications in this moderate- to high-risk group of patients. However, surprisingly, a trial of 5-fluorouracil 50?mg/ml versus MMC 0.2?mg/ml in first-time trabeculectomy in the United States has not shown any statistically significant differences to date in efficacy or side effects.
The optimum time of exposure has also not been determined. Megevand et al. retrospectively compared eyes treated with MMC 0.2?mg/ml for 2 minutes or 5 minutes. There was no statistically significant difference in success rate or complications, but hypotony and endophthalmitis still occurred. In another study MMC was administered intraoperatively at 0.5?mg/ml for 5 minutes or 0.4?mg/ml for 3 minutes in Indian patients. No significant difference occurred in postoperative IOP, hypotony, or postoperative filtration failure rate. However, the group treated with the higher concentration for 5 minutes had a higher incidence of serous choroidal detachment. One patient from each group developed postoperative endophthalmitis during the study period. Shorter applications of 2–3 minutes, compared with 5 minutes, appear to have the same efficacy, but if applications are shortened to less than 2 minutes, suboptimal cellular and tissue absorption may occur. In a study of 5-fluorouracil uptake in tissues the concentrations reached a plateau at 3 minutes. Even shorter application times may result in greater variations in drug delivery. Changes in the concentration of the agent are more likely to give reproducibly titratable effects than are variations in exposure time. Therefore, to achieve consistent and predictable results, it is probably more important that the individual surgeon becomes accustomed to, and experienced with, one or two concentrations and one exposure time.
Type of Sponge and Method and Area of Treatment
Small variations in technique may have profound effects on the clinical result and complications. The type of sponge may affect significantly the amount of drug delivered. Chen et al. originally used a Gelfoam sponge, but most clinicians use commercially available sponges (e.g., Weck cell, Merocel), which have different retention and drug-releasing capabilities and which may be cut to different sizes. We currently use polyvinyl alcohol sponges (Network Medical Products, Yorkshire, UK) as these sponges do not disintegrate as methylcellulose does and leave fragments in the wound. Based on clinical observation, we started treating larger areas several years ago and this has considerably reduced bleb-related complications. This clinical finding has been confirmed subsequently by our group.
It is also important not to touch the cut edge of conjunctiva or the cornea, as the agents affect the cells mainly in the contact area and leave other areas relatively normal. Based on this principle, we have designed special clamps for use during either limbal or fornix-based surgery (Duckworth and Kent, UK, 2-686 and 2-687, and John Weiss) to protect the conjunctival edge from exposure ( Fig. 241-6 ).
We now treat under both scleral flap and conjunctival flap, particularly in resistant cases. We have found clinically during reexploration
Figure 241-6 Intraoperative antimetabolite being applied. The cut edge of conjunctiva is protected by a special clamp (Duckworth and Kent, UK) during surgery. As large an area as possible is treated to achieve a diffuse noncystic bleb.
that the flaps are sometimes sealed with scar tissue. If the scleral flap is only cut partially down the sides, the filter paper or a thin polyvinyl sponge is inserted between the two flaps to ensure treatment. The use of the sponge under both the scleral flap and the conjunctiva seems to enhance the success rate.
DRAINAGE AREA POSITION
The positioning of the scleral flap and treated area is very important. Interpalpebral and inferiorly placed blebs have a high incidence of endophthalmitis, particularly in association with antimetabolites. A series of five patients in whom scleritis developed 3–24 weeks after intraoperative MMC all had inferior trabeculectomies with MMC. If no space exists for a superior trabeculectomy with antimetabolite, better alternative methods may include tube drainage devices or cyclodestructive procedures.
CLOSURE OF SCLERAL FLAP
Conjunctival healing may be inhibited markedly by antimetabolites, and hypotony is prevented primarily by the resistance afforded by the scleral flap. Therefore, this flap has to be sufficiently thick and wide relative to the sclerostomy to provide this resistance; it has to be sutured adequately enough to achieve this resistance and yet be adjustable gradually. This adjustability is achieved by laser suturelysis or releasable sutures, although too early release of sutures may be associated with long-term hypotony. It is important to remember that when antimetabolites (particularly MMC) are used, suturelysis (even several months after surgery) may result in hypotony; this also applies to occluding sutures left within or around the tube lumen after tube implant surgery. Late choroidal effusions and hemorrhage after suture removal have been reported, even many months after the surgery.
After the use of MMC, sutures should be released late. In particular, tie the releasable suture(s) tight, but check IOP in patients who have marked visual field loss in the first few hours after surgery. If the pressure is raised on the first postoperative day, gentle pressure is applied to the back of the scleral flap, which very slightly loosens the flap, allows outflow of aqueous, and lowers the opening pressure without the complete loss of tension that occurs when sutures are released. Alternatively, the new technique of adjustable suture control that we have devised can be used in which a special pair of polished duck-billed forceps (Duckworth and Kent, Khaw 2-502) can be used transconjunctivally
Figure 241-7 Adjustable suture control (ASC). A, Sutures being adjusted through the conjunctiva with duck-billed forceps to ensure gradual lowering of intraocular pressure after antimetabolite use. B, Adjustable suture forceps (Duckworth and Kent 2-502 with polished duck-billed ends to prevent conjunctival damage during trans-conjunctival adjustment).
to adjust the sutures and hence the IOP downward gradually until the target pressure is reached ( Fig. 241-7 ).
Subconjunctival injections of 5-fluorouracil may be used postoperatively on their own or in combination with intraoperative MMC or 5-fluorouracil if the pressure rises and the healing response is still marked. The original regimen of 21 injections of 5?mg of 5-fluorouracil given 180° from the bleb (twice a day for 1 weeks then once a day for 1 week) has now evolved, and most ophthalmologists give less than 10 injections with longer intervals in between injections. These lower dose regimens may result in a lower incidence of corneal side effects. However, it is important to note that meta-analysis suggests that three injections or less may have had no impact on long-term success and only five injections or more may be effective. 
The technique of injection is very important. The 5-Fluorouracil Filtration Surgery Study regimen was 5-fluorouracil 5?mg in a volume of 0.5?ml given 180° from the filtration site. There have been other refinements ( Fig. 241-8 ) that include giving injections nearer the bleb (but avoiding intraocular entry as the pH is 9), which may increase the efficacy. It is logical to deliver the injection of 5-fluorouracil as close as possible to the bleb but without entering the bleb itself ( Box 241-3 ). Corneal side effects may also be reduced by a long subconjunctival needle track and small needles (29 or 30gauge). Based on our pharmacokinetic studies, we also sometimes use a subconjunctival viscoelastic injection (Haelon GV, Pharmacia, NJ) and then inject the 5-fluorouracil on the far side of the viscoelastic, which prevents any 5-fluorouracil reflux into the tear film. This also lengthens the duration of action. Corneal side effects are rare with this regimen. The advent of intraoperative antimetabolite treatment has meant that injections are more commonly used as
Figure 241-8 Subconjunctival injection of 5-fluorouracil. The injection is given as close as possible to the bleb without entering the bleb area. Viscoelastic can be used to prolong the duration of action.
Improvements in Injectable 5-Fluorouracil
Reduction in number of injections given
Injections given closer to bleb area—increased efficacy for same dose
Long injection track—reduction in epitheliopathy
Use of small-bore needle (e.g., 30 gauge)
Injection of viscoelastic—prolonged release and no corneal side effects
Use in conjunction with intraoperative antimetabolites—reduced need for injections
adjunctive treatment supplementing intraoperative treatment rather than the main treatment.
Subconjunctival injections of MMC have been advocated and described particularly with procedures such as needling, but given the cytotoxicity of MMC this technique is not in widespread use because of fears of toxicity. A case has been described in which a needling procedure for a failing bleb was followed by a subconjunctival injection of MMC (0.3?ml of 0.5?mg/ml). The visual acuity decreased from 20/100 (6/30) to hand motions at 1?m (3.3?ft). Occlusion of the central retinal vein occurred with hemorrhages in the periphery and narrow arterioles, and fluorescein angiography revealed an unusual combined occlusion of both the arterial and venous vasculature of the retina. Although successful needling revisions of blebs have been reported using subconjunctival injections of smaller volumes (0.01?ml at 0.4?mg/ml), the potential risks of subconjunctival MMC appear substantial. An intraocular injection of MMC 0.05?ml into the rabbit anterior chamber resulted in irreversible damage to the cornea.
Many complications of filtration surgery are described, and the use of antimetabolites increases the incidence of some of these. In particular, short- and long-term hypotony associated with maculopathy (which may be irreversible), choroidal effusions, or hemorrhage may occur with an increased incidence. The other major concern is the potentially high long-term incidence of endophthalmitis, especially with avascular cystic blebs seen particularly with the use of higher concentrations of MMC. These can be considerably reduced by using appropriate surgical techniques. A list of major potential complications is presented in Table 241-3 , together with possible ways to prevent some of these.
TABLE 241-3 — POTENTIAL COMPLICATIONS OF ANTIMETABOLITES
Particularly if scleral flap not adequately closed or high dose MMC used
Close scleral flap securely—releasable sutures are very useful. May require multiple sutures particularly if MMC used.
Do not make scleral flap too small or thin, particularly if MMC used, otherwise outflow cannot be adequately restricted.
Do not release sutures too early—if MMC used, suture release even months after surgery may result in hypotony.
Adjustable suture control (ASC)—gradual loosening of sutures down to target pressures with special adjustable forceps.
COMPLICATIONS OF HYPOTONY
Including maculopathy. which may be irreversible even after pressure is restored; choroidal effusions and bleeding; cataract; and phthisis
Caution when using strong antimetabolites in high-risk patients (e.g., myopes who appear more prone to have hypotony associated problems such as maculopathy (soft sclera).
Use intraoperative infusion (Lewicky cannula) to gauge outflow from sclerostomy. Do not finish until flow secured.
WOUND EDGE LEAKS
Ensure wound is securely closed; vascular needle prevents buttonholing.
Mattress sutures if fornix-based flap—test at end of surgery to ensure watertight.
Protect cut edge of conjunctiva from drug (e.g., special clamp).
Mainly with injected 5-fluorouracil, which leaks into tear film.
Use intraoperative sponge technique.
Use long injection track for injections to prevent reflux into tear film and washout tear film after injection.
Use viscoelastic to prevent tear film reflux in susceptible patients (e.g., surface problems).
INTRAOCULAR PENETRATION AND DAMAGE
Intraocular damage can include endothelial damage and ciliary body destruction—possibly with high-concentration MMC (controversial) Retinal damage has been reported with injected MMC
Treat with antimetabolite sponge and washout before cutting into the eye.
Great care when injecting 5-fluorouracil subconjunctivally close to the bleb, particularly in a soft eye.
High risk if MMC is injected.
INFECTION—BLEBITIS AND ENDOPHTHALMITIS, BLEB BREAKDOWN, AND LEAKAGE
Try to avoid overtreating—use appropriate antimetabolite for patient.
Use large surface area treatment and large scleral flap—radically reduces incidence of cystic blebs prone to infection and leakage.
Avoid interpalpebral or inferiorly sited blebs—infection rate may be 5–10 times higher than bleb under upper lid.
Occurs particularly with interpalpebral/inferior blebs.
Avoid interpalpebral and inferior blebs.
Avoid areas of scleral thinning.
Avoid using if any chance of pregnancy in patient.
None reported to date 30+ years after topical mitomycin
Long-term cumulative effects
On both patient and medical staff.
Careful handling and disposal of cytotoxics required.
FUTURE STRATEGIES TO PREVENT FIBROSIS
Although current agents (particularly MMC) are extremely effective in the prevention of fibrosis, considerable room still exists for improvement. Long-term complications may become apparent only many years later. A key area for the future lies in a better understanding of the cellular and molecular processes involved in the healing processes and of the exact effects of the various agents used to modulate the process. Biological factors may have profound effects. We have shown that one growth factor, TGF-ß, stimulates more scarring than the other growth factors in aqueous. This growth factor may also reverse the action of antimetabolites partially, even of MMC.  Differences in the levels of some of these factors may help to explain the variances in response to therapy. A new human antibody to TGF-ß has been shown to be effective in reducing scarring in vivo and in pilot human studies with relatively diffuse noncystic blebs ( Fig. 241-9 ). A multicenter international study is now under way.
Ultimately we will use antiscarring agents in all patients, possibly in combination, analogous to the situation in cancer chemotherapy. For example, we have shown for the first time that the addition of heparin to intraoperative 5-fluorouracil during vitreoretinal surgery results in a 50% reduction in proliferative
Figure 241-9 Bleb following treatment with human anti–transforming growth factor antibody. The bleb is diffuse and noncystic.
vitreoretinopathy in high-risk patients, thereby returning 5-fluorouracil to the vitreoretinal surgeons 25 years later in an effective form. Ultimately, these combination regimens will evolve to give us the safe, prolonged, long-term, maximal lowering of IOP that is associated with minimal or no glaucomatous progression—the “holy grail” of glaucoma.
1. Chen PP, Yamamoto T, Sawada A, et al. Use of antifibrosis agents and glaucoma drainage devices in the American and Japanese glaucoma societies. J Glaucoma. 1997;6:192–6.
2. AGIS Investigators. The Advanced Glaucoma Intervention study (AGIS) 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130, 429–40.
3. Araujo SV, Spaeth GL, Roth SM, Starita RJ. A ten-year follow-up on a prospective, randomized trial of postoperative corticosteroids after trabeculectomy. Ophthalmology. 1995;102:1753–9.
4. Heuer DK, Gressel MG, Parrish RK II. Topical fluorouracil. II. Postoperative administration in an animal model of filtration surgery. Arch Ophthalmol. 1986;104:132–6.
5. Blumenkranz M, Hernandez E, Ophir A, Norton EWD. 5-Fluorouracil: new applications in complicated retinal detachment for an established antimetabolite. Ophthalmology. 1984;91:122–30.
6. Khaw PT, Sherwood MB, MacKay SL, et al. Five-minute treatments with fluorouracil, floxuridine, and mitomycin have long-term effects on human Tenon’s capsule fibroblasts. Arch Ophthalmol. 1992;110:1150–4.
7. Jampel HD. Effect of brief exposure to mitomycin C on viability and proliferation of cultured human Tenon’s capsule fibroblasts. Ophthalmology. 1992;99:1471–6.
8. Broadway DC, Grierson I, O’Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. Arch Ophthalmol. 1994;112:1446–54.
9. Schwab IR, Linberg JV, Gioia VM, et al. Foreshortening of the inferior conjunctival fornix associated with chronic glaucoma medications. Ophthalmology. 1992;99:197–202.
10. Gwynn DR, Stewart WC, Pitts RA, et al. Conjunctival structure and cell counts and the results of filtering surgery. Am J Ophthalmol. 1993;116:464–8.
11. The Fluorouracil Filtering Surgery Study Group. Five-year follow-up of the fluorouracil filtering surgery study. Am J Ophthalmol. 1996;121:349–66.
12. Kitazawa Y, Kawase K, Matsushita H, Minobe M. Trabeculectomy with mitomycin. A comparative study with fluorouracil. Arch Ophthalmol. 1991;109:1693–8.
13. Katz GJ, Higginbotham EJ, Lichter PR, et al. Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Ophthalmology. 1995;102:1263–9.
14. Lamping KA, Belkin JK. 5-Fluorouracil and mitomycin C in pseudophakic patients. Ophthalmology. 1995;102:70–5.
15. Egbert PR, Williams AS, Singh K, et al. A prospective trial of intraoperative fluorouracil during trabeculectomy in a black population. Am J Ophthalmol. 1993;116:612–16.
16. Singh K, Egbert PR, Byrd S, et al. Trabeculectomy with intraoperative 5-fluorouracil vs mitomycin C. Am J Ophthalmol. 1997;123:48–53.
17. Wilkins M, Indar A, Wormald R. Intra-operative mitomycin-C for glaucoma surgery (Cochrane Review). Cochrane Database Syst Rev (England) 1(CD002897). 2001.
18. Goldenfeld M, Krupin T, Ruderman JM, et al. 5-Fluorouracil in initial trabeculectomy: a prospective randomized, multicenter study. Ophthalmology. 1994;101:1024–9.
19. Whiteside-Michel J, Liebmann JM, Ritch R. Initial 5-fluorouracil trabeculectomy in young patients. Ophthalmology. 1992;99:7–13.
20. Wilson RP, Steinman WC. Use of trabeculectomy with postoperative 5-fluorouracil in patients requiring extremely low intraocular pressure levels to limit further glaucoma progression. Ophthalmology. 1991;98:1047–52.
21. Kupin TH, Juzych MS, Shin DH, et al. Adjunctive mitomycin C in primary trabeculectomy in phakic eyes. Am J Ophthalmol. 1995;119:30–9.
22. Stamper RL, McMenemy MG, Lieberman MF. Hypotonous maculopathy after trabeculectomy with subconjunctival 5FU. Am J Ophthalmol. 1992;114:544–53.
23. Doyle JW, Sherwood MB, Khaw PT, et al. Intraoperative 5-fluorouracil for filtration surgery in the rabbit. Invest Ophthalmol Vis Sci. 1993;34:3313–19.
24. Khaw PT, Doyle JW, Sherwood MB, et al. Prolonged localized tissue effects from 5-minute exposures to fluorouracil and mitomycin C. Arch Ophthalmol. 1993;111:263–7.
25. Smith MF, Sherwood MB, Doyle JW, Khaw PT. Results of intraoperative 5-fluorouracil supplementation on trabeculectomy for open-angle glaucoma. Am J Ophthalmol. 1992;114:737–41.
26. Lanigan LP, Stuermer J, Baez KA, et al. Single intraoperative applications of 5-fluorouracil during filtration surgery: early results. Br J Ophthalmol. 1994;78:33–7.
27. Feldman RM, Dietze PJ, Gross RL, Oram O. Intraoperative 5-fluorouracil administration in trabeculectomy. J Glaucoma. 1994;3:302–7.
28. Yorston D, Khaw PT. A randomised trial of the effect of intraoperative 5FU on the outcome of trabeculectomy in East Africa. Br J Ophthalmol. 2001;85:1028–30.
29. Khaw PT, Ward S, Grierson I, Rice NSC. The effects of beta-radiation on proliferating human Tenon’s capsule fibroblasts. Br J Ophthalmol. 1991;75:580–3.
30. Miller MH, Rice NSC. Trabeculectomy combined with beta irradiation for congenital glaucoma. Br J Ophthalmol. 1991;75:584–90.
31. Occleston NL, Daniels JT, Tarnuzzer RW, et al. Single exposures to antiproliferatives. Long term effects on ocular fibroblast wound healing behavior. Invest Ophthalmol Vis Sci. 1997;38:1998–2007.
32. Wells AP, Cordeiro MF, Bunce CV, Khaw PT. Cystic bleb related complications in limbus versus fornix based flaps in paediatric and young adult trabeculectomy with high dose mitomycin C [abstract]. Invest Ophthalmol Vis Sci. 2001;42:S544.
33. Chen C-W, Huang H-T, Bair JS, Lee C-C. Trabeculectomy with simultaneous topical application of mitomycin-c in refractory glaucoma. J Ocul Pharmacol. 1990;6:175–82.
34. Kitazawa Y, Suemori-Matsushita H, Yamamoto T, Kawase K. Low-dose and high-dose mitomycin trabeculectomy as an initial surgery in primary open-angle glaucoma. Ophthalmology. 1993;100:1624–8.
35. Singh K, Mehta K, Shaikh NM, et al. Trabeculectomy with intraoperative mitomycin C versus 5-fluorouracil. Prospective randomized clinical trial. Ophthalmology. 2000;107:2305–9.
36. Megevand GS, Salmon JF, Scholtz RP, Murray AD. The effect of reducing the exposure time of mitomycin C in glaucoma filtering surgery. Ophthalmology. 1995;102:84–90.
37. Neelakantan A, Rao BS, Vijaya L, et al. Effect of the concentration and duration of application of mitomycin C in trabeculectomy. Ophthalmic Surg. 1994;25:612–15.
38. Wilkins MR, Occleston NL, Kotecha A, et al. Sponge delivery variables and tissue levels of 5-fluorouracil. Br J Ophthalmol. 1999;84:92–7.
39. Cordeiro MF, Constable PH, Alexander RA, et al. The effect of varying mitomycin-C treatment area in glaucoma filtration surgery in the rabbit. Invest Ophthalmol Vis Sci. 1997;38:1639–46.
40. El Sayyad F, Belmekki M, Helal M, et al. Simultaneous subconjunctival and subscleral mitomycin C application in trabeculectomy. Ophthalmology. 2000;107:298–301.
41. Wolner B, Liebmann JM, Sassani JW, et al. Late bleb-related endophthalmitis after trabeculectomy with adjunctive 5-fluorouracil. Ophthalmology. 1991;98:1053–60.
42. Fourman S. Scleritis after glaucoma filtering surgery with mitomycin C. Ophthalmology. 1995;102:1569–71.
43. Perkins TW, Cardakli F, Eisele JR, et al. Adjunctive mitomycin C in Molteno implant surgery. Ophthalmology. 1995;102:91–7.
44. Wormald R, Wilkins MR, Bunce C. Post-operative 5-fluorouracil for glaucoma surgery. Cochrane Database Syst Rev (England) 2(CD001132). 2000.
45. Mardelli PG, Lederer CM Jr, Murray PL, et al. Slit-lamp needle revision of failed filtering blebs using mitomycin C. Ophthalmology. 1996;103:1946–55.
46. Nuyts RMMA, Van Diemen HAM, Greve EL. Occlusion of the retinal vasculature after trabeculectomy with mitomycin C. Int Ophthalmol. 1994;18:167–70.
47. Derick RJ, Pasquale L, Quigley HA, Jampel H. Potential toxicity of mitomycin-C. Arch Ophthalmol. 1991;109:1635–1635.
48. Khaw PT, Occleston NL, Schultz GS, et al. Activation and suppression of fibroblast activity. Eye. 1994;8:188–95.
49. Doyle JW, Smith MF, Garcia JA, et al. Treatment of bleb leaks with transforming growth factor-ß in the rabbit model. Invest Ophthalmol Vis Sci. 1997;38:1630–4.
50. Cordeiro MF, Gay JA, Khaw PT. Human anti-transforming growth factor-beta2 antibody: a new glaucoma anti-scarring agent. Invest Ophthalmol Vis Sci. 1999;40:2225–34.
51. Siriwardena D, Khaw PT, Donaldson ML, et al. A randomised placebo-controlled trial of human anti-TGF2 monoclonal antibody (CAT-152): a new modulator of wound healing following trabeculectomy. Ophthalmology. 2002;109:427–31.
52. Asaria RHY, Kon CH, Bunce C, et al. Adjuvant 5-fluorouracil and heparin is prevents proliferative vitreoretinopathy: results from a randomised double blind controlled clinical trial. Ophthalmology. 2001;108:1184–6.