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Enzymatic vitreolysis may change treatment paradigm
Anomalous adhesions at the vitreoretinal interface have long been thought to be the root cause of a variety of vitreoretinal disorders. Traction exerted by such adhesions is directly responsible for the development of lamellar and full-thickness macular holes and foveoschisis. It has also been seen to play a role in the pathogenesis of diabetic macular edema, proliferative diabetic retinopathy and age-related macular degeneration, among others.
The advent of optical coherence tomography has added to our knowledge about the dynamic changes at the vitreoretinal interface and has led to the development of a new classification system based on objective findings. Now, vitreomacular traction (VMT) can be identified even before it becomes symptomatic.
Role of vitreous detachment and enzymatic vitreolysis
Posterior vitreous detachment (PVD) is a natural age-related process. Incomplete detachment due to strong vitreomacular adhesions precipitates traction, leading to metamorphopsia and reduced visual acuity. Vitrectomy was the only option for such long-standing symptomatic VMT and full-thickness macular holes. It would be desirable to induce complete separation of vitreous using pharmacologic agents, which would obviate the need for surgery and the attendant risks. Induction of PVD is also a necessary step during vitrectomy. It is especially difficult in young patients due to strong adhesions.
Proliferative retinopathies make vitrectomy more challenging and dissection more difficult due to dense adhesions between the vitreous, retina and fibrovascular tissue. Also, with 23- and 25-gauge vitrectomies, there is a concern about incomplete vitreous removal and prolonged surgical time. Surgery can be made relatively easy if enzymatic vitreolysis is done before surgery. There is also increasing evidence that separation of vitreous can be protective against DME as well as AMD. A search for a minimally invasive, low-risk way of inducing PVD in a controlled manner has been on for the past 30 years. Many agents have been tried for pharmacologic vitreolysis. With gathering evidence about the safety and efficacy of ocriplasmin, enzymatic vitreolysis has gained ground, and although initially developed as an adjunct to surgery, it is now looking at replacing vitrectomy.
Ocriplasmin
Jetrea (ocriplasmin, ThromboGenics/Alcon) is the only drug that is commercially available. It is a recombinant, truncated part of plasmin molecule with a molecular weight of only 29 kDa. It targets fibronectin, laminin and collagen and leads to vitreous liquefaction as well as vitreous separation from the retina. Other agents tried previously, such as autologous plasmin, chondroitinase, dispase, nattokinase and hyaluronidase, were all found to be either ineffective and/or toxic.
In a large phase 3 trial, a single injection of ocriplasmin was effective in inducing PVD and closing macular hole even without a vitrectomy. In addition, there was also improvement in visual acuity. Ocular adverse events were mild and transient. No incidence of infection or retinal detachment was reported. Electroretinographic studies and electron microscopic studies have reported no toxicity of ocriplasmin to the retina. The use of ocriplasmin potentially extends to the treatment of macular hole, intractable DME, proliferative diabetic retinopathy with dense fibrovascular adhesions, AMD, and also advanced stages 4 and 5 retinopathy of prematurity. With increased experience, the indications for its use may grow to include diseases with abnormal vitreoretinal adhesions, such as Stickler syndrome or retinoschisis.
A new panacea?
In all this excitement surrounding ocriplasmin and its wonderful results, one must not overlook the possible disadvantages of enzymatic vitreolysis. Are we being overzealous and over-treating patients with VMT who may have resolution of the adhesions in the natural course? Also, more than 50% of patients treated with ocriplasmin may still need to undergo vitrectomy, doubling the financial expenditure for the patient. As with any intraocular injection, a serious risk of intraocular infection exists for ocriplasmin. A possibility of precipitating retinal tears and retinal detachment cannot be completely ruled out. There is also a concern about causing cataract progression as a result of improved oxygenation to the lens. However, some of these issues can be overcome with proper patient selection.
A lot of clinical trials are under way to explore the role of enzymatic vitreolysis in various vitreoretinal disorders, ranging from AMD to uveitic cystoid macular edema and many pediatric retinal conditions. While it is envisaged that in the not-too-distant future we may witness an important paradigm change in our current concept of vitreous surgery, we have to be cautious about the possible side effects of the drug, which may only be revealed when enough clinical data are available.
References:
Nazari H, et al. J Ophthalmic Vis Res. 2010;5(1):44-52.
Sakuma T, et al. Invest Ophthalmol Vis Sci. 2005;doi:10.1167/iovs.04-1517.
Stalmans P, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1110823.
Tsui I, et al. J Biomed Biotechnol. 2012;doi:10.1155/2012/354979.
For more information:
Dennis S.C. Lam, MD, FRCOphth, can be reached at State Key Laboratory in Ophthalmology, Sun Yat-Yen University, 54 South Xianlie Road, Guangzhou 510060, People’s Republic of China; +852-3997-3266; fax +852-3996-8212; email: dennislam.gm@gmail.com.
Dhanashree Ratra, MS, DNB, FRCS, can be reached at the Department of Ophthalmology, Apollo Hospitals,154/11, Opp IIM, Bannerghatta Road, Bangalore 560076; +0091-404-344-1066.
Disclosure: Prof. Lam and Ratra have no relevant financial disclosures.