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In this issue of the BJO (p6), Gandorfer and colleagues contribute to the recent burgeoning of research on enzymatic vitreolysis. Vitreoretinal surgeons, the beneficiaries in recent years of many surgical advances—silicone oil and long acting gas tamponade, perfluorocarbon liquids, photodynamic therapy—nevertheless harbour a collective “wish list” of surgical agents and devices awaiting development. Such a list would include long term heavy liquid tamponade, retinal adhesives, antifibroproliferative drugs, and antiangiogenic treatments. But none figures so prominently as enzymatic vitreolysis, which for years has held the promise of minimally invasive solutions for surgical problems in vitreoretinal diseases such as diabetic retinopathy and macular hole.
The goal is to develop chemicals which when injected into the vitreous produce selective vitreolysis, in the form of either posterior vitreous detachment (PVD) or vitreous liquefaction. Enzymatic vitreolysis is envisaged to augment or even replace standard mechanical vitrectomy, over which it presents important advantages. It offers lower operative risks, less surgeon time, lower costs, greater patient access, and a transition to office based vitreoretinal procedures.
A number of vitreolytic substances have been investigated, including hyaluronidase, dispase, tissue plasminogen activator, and chondroitinase. Plasmin has perhaps received the most attention; it is a non-specific protease with action against components of the vitreoretinal interface—namely, laminin and fibronectin. By degrading the links between the cortical vitreous and the internal limiting membrane (ILM), it becomes possible to produce therapeutic PVD. Gandorfer and colleagues demonstrate ultrastructurally that it is indeed possible to use intravitreal injection of plasmin to create a complete PVD. In controlled experiments in postmortem pig eyes, light and scanning electron microscopy verified that at sufficient concentrations and incubation times, plasmin injected eyes showed PVD with the retinal surface smooth and free of cortical vitreous remnants. It is significant that enzymatic action alone was sufficient to induce PVD without adjuvant gas bubble injection or cryotherapy necessitated in other studies.
The full realisation of an effective agent for enzymatic vitrectomy holds the promise of creating a raft of new therapeutic strategies for vitreoretinal disease. Macular hole repair offers a good example; in conventional surgery removal of the posterior cortical vitreous is considered critical to relieve tractional forces on the macular hole. However, mechanically peeling the hyaloid from the retinal surface can be technically difficult, is associated with the risk of retinal breaks, and has even been implicated in postoperative visual field loss. Trese and colleagueshave recently presented results of plasmin assisted vitrectomy in patients with stage 3 macular hole; injection of autologous plasmin before standard vitrectomy was reported to achieve satisfactory PVD and facilitate surgical repair of the hole. Furthermore, the procedure has shown promise in the more challenging cases of macular holes caused by ocular trauma. It becomes conceivable that an office based procedure utilising vitreolytic PVD, perhaps with injection of expansile gas tamponade, could in some cases obviate standard vitrectomy in macular hole repair.
In diabetic vitreous haemorrhage, enzymatic vitreolysis is being investigated as a means of accelerating visual resolution as well as allowing earlier application of panretinal photocoagulation. Enzymatic vitrectomy could eventually prove useful in diabetic tractional retinal detachment (TRD), as an adjunct to surgery to relieve vitreoretinal traction. Furthermore, it offers a means to induce PVD in patients with proliferative diabetic retinopathy at risk for developing TRD. Enzymatic PVD could neutralise the ability of the vitreous to act as a scaffolding for neovascular ingrowth and subsequent traction retinal detachment. Could enzymatic PVD become a prophylactic intervention for diabetic patients in the early stages of proliferative or even non-proliferative retinopathy as a way of pre-empting vision threatening complications?
Other applications can be envisaged. Enzymatic vitreolysis might be useful as a supplement to pneumatic retinopexy for rhegmatogenous retinal detachment repair; injecting an enzyme at the time of gas injection to additionally release vitreous traction could potentially increase the success rate of this office based procedure. As another example patient complaints associated with vitreous floaters are all too familiar to ophthalmologists, but the risk-benefit profile for surgery for vitreous floaters is prohibitive. Could enzymatic vitreolysis reduce risks sufficiently to become viable for the large number of patients with this relatively benign but annoying visual problem? The arrival of enzymatic vitreolysis may expand vitreoretinal practice in ways that can't be predicted.
Before enzymatic vitreolysis enters the mainstream central questions will need to be addressed—effectiveness, inflammatory responses, retinal toxicity, long term complications. And years of work in the field of vitreolytic enzymes have yet to yield a widely accepted alternative to mechanical vitrectomy. Nevertheless, as the limits of conventional vitrectomy are being approached vitreoretinal surgeons continue to look forward over the next years to a new generation of therapies with vitreolytic enzymes.