Use of Antimetabolites With Tube Shunt Surgery
Glaucoma surgeons struggle with the adverse effects of scarring on a daily basis. Tube shunts were able to increase the success rate of filtration surgery in certain complex glaucomas and eyes that had either failed or were unable to undergo a trabeculectomy. However, they were still limited to varying degrees by the nature of the fibrotic capsule that formed over the distal plate of the shunt. The ability of 5-fluorouracil (5-FU) and mitomycin C (MMC) to increase the success rate of trabeculectomy stirred interest among glaucoma surgeons to investigate their effects with tube shunts.
Tube Versus Trabeculectomy
Before we assess the potential role for antimetabolite use in glaucoma implant surgery, it is helpful to look at how implants without antimetabolites compare with standard trabeculectomy with mitomycin C. In 2009, the 3-year follow-up results were published for the Tube Versus Trabeculectomy (TVT) Study. This study was a multicenter US trial that included open-angle glaucoma patients with previous trabeculectomy or cataract extraction with intraocular lens (IOL) implantation, or both, and uncontrolled glaucoma with intraocular pressure (IOP) between 18 and 40 mm Hg, inclusive. Patients were randomized to undergo either a 350-mm2 Baerveldt glaucoma implant or trabeculectomy with MMC. Of the 212 patients enrolled, the mean IOP at 3 years was 13.0 ± 4.9 mm Hg on 1.3 ± 1.3 glaucoma medications in the tube group, and 13.3 ± 6.8 mm Hg on 1.0 ± 1.5 glaucoma medications in the trabeculectomy group. Interestingly, the cumulative probability of failure was 15.1% in the tube group and 30.7% in the trabeculectomy group during this 3-year follow-up. It was also interesting to note that 39% of patients in the tube group and 60% in the trabeculectomy group developed some postoperative complication, although most were transient and self-limited. As we discuss the role for antimetabolites in tube shunt surgery, the results of the TVT trial demonstrate the effectiveness of the Baerveldt glaucoma implant in controlling pressure without the use of antimetabolites. The question remains as to whether we can safely augment the IOP reduction from tube shunt surgery with antimetabolites in a manner similar to that seen with trabeculectomy.
Early Animal Studies
The first published report of the use of MMC with a tube shunt was in 1993 by Choi and colleagues, using an anterior chamber silicone tube to an expanded polytetrafluoroethylene membrane in rabbit eyes. Histologically, the capsules that formed over the membrane in the MMC group were less cellular and less dense, with less proliferating fibrous connective tissue and more microcystic spaces, suggesting higher permeability to aqueous humor. Another rabbit study done by Prata, Minckler and colleagues investigated the use of 0.5 mg/mL MMC for 5 minutes with Baerveldt glaucoma implants followed for 24 weeks postoperatively. No postoperative steroids were used. The MMC eyes had thinner and less cellular capsules with less dense collagen layers over the implant compared to the controls. The IOP was lower in the MMC-treated eyes at all time points, but the difference was only statistically significant up to 8 weeks postoperatively. The control eyes demonstrated a “hypertensive phase” that peaked at 4 weeks, but a gradual rise in IOP until 6 weeks followed by a gradual decline through the 11th week. The MMC-treated group demonstrated a minimal “hypertensive phase” with only a small rise in IOP by 6 weeks. Resistance to flow was lower in the MMC-treated group at all time points, but this difference was only statistically significant through 6 weeks postoperatively. Flow rates through the implant bleb were also higher at all time points in the MMC-treated group, and were statistically significant at 2, 4, 6, and 24 weeks postoperatively. The complication rate was also higher, with wound dehiscence, bleb leaks, and extraocular muscle hemorrhagic necrosis observed only in some of the MMC-treated eyes, but none of the controls. It is important to keep in mind that the extraocular muscle capsule has been noted to be thinner in rabbits than humans. This may help explain the higher rate of related complications in the MMC group.
Human Clinical Studies
There have been a number of publications on the use of MMC with tube shunts in humans. Some have been prospective and randomized, while others have been observational retrospective case series. These studies vary in the type of implant used, MMC application, length of follow-up, definitions of success, etc. Two early studies by Susanna et al and Perkins et al compared MMC in the implantation of Molteno implants to historical controls where no MMC was used. These studies suggested a beneficial effect of MMC. Cantor et al prospectively randomized patients under-going double-plate Molteno implantation to either MMC 0.4 mg/mL for 2 minutes or a balanced salt solution control. Costa et al prospectively randomized patients undergoing Ahmed glaucoma valve implantation to an intraoperative application of either MMC 0.5 mg/mL for 5 minutes or balanced salt solution. Neither of these studies found a statistically significant difference between the MMC and control groups in IOP, number of anti-glaucoma medications, or complications. Three retrospective studies that used a historical control group also found no evidence of higher surgical success with adjunctive MMC in single-plate Molteno, Baerveldt 350 mm2, and Ahmed valve tube shunts, respectively.
In another retrospective comparative series in a pediatric population, Al-Mobarak and Khan found a shorter survival at 2 years’ follow-up with Ahmed valves implanted with intraoperative MMC than those without MMC in children during the first 2 years of life (mean age at implanta-tion: 11.1 months). Pakravan et al found comparable outcomes between trabeculectomy with MMC versus Ahmed valve with MMC for the treat-ment of aphakic glaucoma in children under the age of 16.
The classic hypertensive phase after tube shunt surgery is a period of IOP elevation that begins typically approximately 5 weeks postoperatively from the formation of a bleb capsule over the plate of the shunt and can last up to 6 months postoperatively. It is presumed to be due to the lower permeability of the initial capsule that forms over the plate of the shunt. Through wound remodeling, the permeability of the capsule slowly increases, resulting in a gradual decline in IOP. Ellingham et al showed that MMC (0.3 mg/mL for 3 minutes) applied to Tenon’s capsule over the secondary plate of double-plate Molteno implants was able to blunt the hypertensive phase. However, no significant difference was seen with the use of MMC on the hypertensive phase in the Cantor study. Part of the rise in IOP that occurs approximately 3 to 4 weeks postoperatively in nonvalved shunts that are ligated and receive venting slits is due to fibrosis around the tube in the area of the venting slits. Trible and Brown investigated the effect of 5-FU and MMC applied locally only to the sclera in the area of a standardized venting slit (but not directly to the area over the plate where the bleb would form) after the plate was secured to the sclera. There was no statistically significant difference between the 5-FU and MMC groups. Susanna studied the effect of adjunctive MMC in Ahmed glaucoma valve surgery with or without partial Tenon’s capsule resection. They found no benefit or no increase in complications from partial Tenon’s capsule resection.
MMC has also been studied and used with tube shunt revisions. Zarei and Shahhosseini found limited benefit to needling bleb revision with MMC for failed Molteno tubes. The success rate was 87.5% at 3 months, 37.5% at 6 months, and 12.5% at 24-months follow-up. The reader is also referred to an excellent Cochrane review analyzing all of the published lit-erature on aqueous shunts in glaucoma by Minckler et al in 2006.
Freedman and Goddard studied aqueous humor samples obtained from eyes that underwent Molteno implants, trabeculectomy, and cataract surgery. They found that transforming growth factor beta (TGF-β) and pros-taglandin E2 (PGE2) levels were higher in the Molteno and trabeculectomy eyes than in cataract surgery eyes. There was also a trend toward higher lev-els of PGE2 and TGF-β in patients with a higher IOP. They postulated that a sustained IOP rise, such as that seen with encapsulated blebs and during the hypertensive phase, stimulates production of PGE2 and TGF-β. These factors mediate ongoing inflammation, progressive fibrosis, and a sustained rise in IOP.
Occleston et al showed that one 5-minute in vitro exposure of 5-FU or MMC significantly inhibited cultured human Tenon’s capsule fibro-blast migration and decreased growth factor production, growth factor receptor expression, and extracellular matrix production initially. The effects were greater with MMC than 5-FU as expected. However, these values gradually returned to control levels starting approximately 1 week after the exposure and reached control levels approximately 5 weeks after the exposure. In addition, even the growth-arrested cells appeared to be capable of producing growth factors, expressing growth factor receptors, and producing extracellular matrix. This may perhaps explain the inabil-ity of antimetabolites to completely prevent failure from fibrosis in all glaucoma surgeries.
I first began to use MMC with tube shunts in 2002, based on the goal of trying to achieve lower IOPs and reduce the need for adjunctive medical therapy. Minimizing topical therapy is particularly important when manag-ing glaucoma in eyes with complex ocular surface disease, such as those that have undergone limbal stem cell transplantation. It was felt that the poten-tial inflammatory effects of IOP-lowering eye drops could adversely affect the limbal stem cell transplants.
I have not observed any higher incidence of complications since begin-ning to use MMC, nor do my complication rates seem higher than pub-lished reports. Although I have not performed a comparative trial, it is my impression that MMC does help achieve lower IOPs and may also reduce the dependence on medications to achieve IOP control. It is also my clinical impression that MMC helps to blunt the hypertensive phase.
When one begins to use an agent like MMC, it is advised to use the standard concentration that one is already familiar with when perform-ing trabeculectomies. I recommend starting with a relatively short dura-tion of 30 to 60 seconds. Observe the clinical course of these patients and then gradually adjust the exposure as needed. MMC has been accepted to increase the success rate of trabeculectomies and has been widely adopted in that setting. Animal studies with MMC and tube shunts have also suggested a (mostly) beneficial effect on the exposed tissue. However, it is curious that the majority of the clinical studies have not shown any significant long-term benefit from adjunctive MMC with tube shunts. The answer may well be multifactorial. The Occleston study, showing that growth-arrested cells still produce growth factors, may shed light on at least part of the cause. It is also possible that an inadequate dose of MMC has been used.
- The 3-year results of the TVT study showed comparable results between Baerveldt 350 tube shunts without MMC and trabeculectomy with MMC.
- Adjunctive use of MMC during tube shunt implantation in rabbit eyes created less dense and less cellular fibrous capsules over the implant plate, and less resistance to outflow compared to controls.
- Human clinical studies have shown mixed results, but the majority of them have not shown any long-term benefit from MMC. One study did show a positive effect on the hypertensive phase from MMC use.
- Some evidence suggests a correlation between elevated levels of TGF-β and PGE2 in eyes that have an elevated IOP after tube shunt surgery.
- In vitro evidence indicates incomplete inhibition of fibroblasts from a single exposure of 5-FU or MMC and a gradual loss of the physiologic effects on the fibroblasts over 1 to 5 weeks after the exposure.
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