Pharmacologic vitreolysis--premise and promise of the first decade.

Pharmacologic Vitreolysis— Premise and Promise of the First Decade The term pharmacologic vitreolysis first appeared in the world’s literature one decade ago in the pages of the journal Retina.1 The coining of this term formalized a new field and was predicated on a premise and a promise. The premise was that we now understood enough about the molecular organization, structure, and physiology of vitreous and its role in retinal disorders, and that this knowledge could be used to enhance vitreoretinal surgery with pharmacologic adjuncts. The promise was that this novel form of therapy could one day supplant surgery by mitigating the pathophysiology of vitreous at the earliest stages of disease and also improve ocular physiology and metabolism. Although there have been many interesting developments during the first decade, most recently the results of MIVI III (Microplasmin Intravitreous Injection III, a Phase IIb multicenter, randomized, controlled clinical trial evaluating microplasmin, which showed the release of vitreo-macular traction without surgical intervention in 30% of patients), too few of these objectives have been met to date. There are important lessons to be learned in considering why there has not been more rapid progress. Vitreous is believed to play an important role in ocular health and disease.2,3 Posterior vitreous detachment (PVD) is characterized by gel liquefaction (synchisis) and vitreoretinal dehiscence with collapse (syneresis) of the posterior vitreous away from the retina.2,3 It is plausible that much like the phenomenon of apoptosis, PVD is preprogrammed to happen, because PVD occurs in the overwhelming majority of individuals. Furthermore, it is currently believed that in a variety of diseases, such as diabetic retinopathy4,5 and age-related macular degeneration,6,7 complete PVD protects against more advanced stages of disease. In a minority of cases, however, liquefaction occurs without sufficient dehiscence at the vitreoretinal interface to allow for clean separation of the posterior vitreous cortex from the retina. This is known as “anomalous PVD.”8 The sequelae of anomalous PVD vary depending on where the gel is most liquefied and where the posterior vitreous cortex is most firmly adherent to the retina. The clinical setting is also extremely important insofar as anomalous PVD may have very different effects in an individual with diabetes as compared with a nondiabetic patient, or in the setting of a genetic predisposition to certain forms of age-related macular degeneration. Thus, the interplay of these multiple factors is an important consideration. Also important is whether the posterior vitreous cortex that remains adherent to the retina is full or partial thickness, the latter a consequence of splitting in the posterior vitreous cortex, known as vitreoschisis.9 Histopathologic studies10 have shown that vitreoschisis is present in 80% of eyes with proliferative diabetic retinopathy. Clinical investigations11 using combined optical coherence tomography and scanning laser ophthalmoscopy have detected vitreoschisis in half of the eyes with macular holes and macular pucker. The various permutations of anomalous PVD are diagrammed in Figure 1. As can be appreciated, seemingly disparate diseases can in fact be perceived as different consequences of the same initiating event, i.e., anomalous PVD. Our enhanced understanding of the role of vitreous in retinal disorders has led investigators to use pharmacologic vitreolysis in diseases such as diabetic retinopathy,12 macular holes,13 retinopathy of prematurity14 and even congenital retinoschisis.15 Since initial attempts all used enzymes as adjuncts to surgery, the term “enzymatic vitreolysis” prevailed in the early literature.16,17 However, in 1998, the term “pharmacologic vitreolysis” was proposed,1 so that vitreolytic agents could be grouped according to their mechanism of action as either “enzymatic” or “nonenzymatic.” Furthermore, it was proposed that these agents could be grouped, as either nonspecific agents, such as tissue plasminogen activator,18 plasmin,19,20 microplasmin,21,22 and nattokinase23; or substrate-specific agents, such as chondroitinase,24,25 dispase,26,27 and hyaluronidase.28,29 Although this perspective does have intellectual appeal on theoretical grounds, the original classification system seems to have little relevance today, because other than two nonenzymatic approaches (urea/vitreosolve30 and Arginine-GlycineAspartate (RGD) peptides31), the overwhelming maReprint requests: Jerry Sebag, MD, FACS, FRCOphth, VMR Institute, 7677 Center Avenue, Suite 400, Huntington Beach, CA 92647; e-mail: [email protected]