trained personnel and laboratory preparation. Multiple reports have confirmed that APE 0.4–1.2 IU can successfully cause vitreous liquefaction and induce a PVD in humans.3–5,7,27,28 No ERG abnormalities or ultrastructural changes to the ILM and retina are seen at concentrations up to 10 times the effective dose.16

Nattokinase (subtilisin NAT) is a serine protease that is produced by Bacillus subtilis (natto). It hydrolyzes collagen fibers, enhances plasminogen activators, and inactivates a plasminogen activator inhibitor.29,30 Nattokinase has been shown to cause a PVD in rabbit eyes without histologic damage to the retina at a dose of 0.1 fibrin degradation units.30 Despite these findings, its use in research studies is limited, and there are no reports of nattokinase use in humans.

Microplasmin (ThromboGenics, Dublin, Ireland) is a recombinant protein that is a truncated form of human plasmin.31 It is approximately one-third the size of plasmin enzyme (29 versus 88 kDa), but it retains its active protease site.31 This smaller size is thought to allow for increased epiretinal tissue penetration.2 In contrast with plasmin enzyme, it can be prepared quickly without the need for venepuncture. Animal models have demonstrated microplasmin’s ability to induce vitreous liquefaction8,9 and a complete PVD2,20,32 with a single intravitreal injection in a doseand time-dependent fashion (Figure 47.1). A dose of 125 g has been shown to cause a PVD in human cadaver and rabbit eyes.2,32 In addition, this dose appears to be nontoxic as it does not alter the ultrastructure of the inner retina in postmortem human2 and in vivo animal eyes,2,32 and it does not cause significant ERG changes.32 It is interesting to note that plasmin, microplasmin, and nattokinase appear to be the most effective enzymes for PVD induction, and all three compounds may utilize the same mechanism of action via plasmin.

INDICATIONS

SURGICAL ADJUNCT

An abnormal vitreoretinal interface plays an important role in the pathogenesis of many retinal disorders and may contribute to significant patient morbidity. Traction at this interface has been implicated in the development of vitreomacular traction (VMT), diabetic macular edema, macular pucker, proliferative diabetic retinopathy, proliferative vitreoretinopathy, macular holes, retinal detachments, and other conditions. The surgical management of such disorders often targets the

abnormal vitreoretinal junction by separating the posterior hyaloid from the ILM, thereby creating a mechanical PVD. The creation of a mechanical PVD with vitrectomy may not remove all of the vitreous or completely separate the vitreoretinal junction, as cortical vitreous fibrils are left behind on the ILM.33 Incomplete removal of the vitreous may result in surgical failure.34,35

Vitrectomy with removal of the ILM requires direct mechanical manipulation of the macula.15,16 Although it is generally safe, surgical separation of the posterior hyaloid from the retina may cause retinal or optic disc trauma.36 Therefore, creating a PVD with an intravitreal injection of a pharmacologic agent may enhance surgical separation of the posterior hyaloid, thus reducing intraoperative time and potential complications. Enzyme-assisted vitrectomy may be indicated in many retinal disorders involving abnormal vitreoretinal adhesions.

NONSURGICAL INDICATIONS

In addition to its use as a surgical adjunct, a pharmacologically induced PVD may be indicated for prophylactic treatment or as a substitute for surgical intervention. For example, a complete PVD is a strong negative risk factor for the progression of diabetic retinopathy.37 In addition, it has been suggested that complete posterior vitreous separation allows for resolution of diabetic macular edema.5 Thus, a pharmacologic PVD has the potential to reduce diabetic macular edema and remove the vitreous scaffold for neovascularization. This may even eliminate the need for surgery in select cases. Furthermore, persistent attachment of the posterior vitreous cortex to the macula has been suggested to be a risk factor for the development of exudative age-related macular degeneration (AMD).38 If this theory is upheld, then the induction of a prophylactic PVD may significantly alter the natural history of AMD.

Microplasmin is currently being investigated in phase II clinical trials. The European Microplasmin for Vitrectomy IIT (MIVI-IIT) study is a phase II, randomized, double-masked clinical trial of intravitreal microplasmin injection for the nonsurgical treatment of VMT. Early results from this study have demonstrated encouraging findings (P. Stalmans, presentation at the annual meeting of the American Society of Retina Specialists, 2007). In some cases, the closure of macular holes and complete resolution of VMT were seen after microplasmin injection (Figure 47.2). The US microplasmin clinical trial (MIVI-III) is a phase IIb study that has completed patient enrollment to determine the use of microplasmin as a surgical adjunct in vitrectomy surgery. A phase III study is actively recruiting participants to determine if microplasmin can be used instead of surgical therapy for patients with pathologic vitreoretinal adhesions.