CME Activity Supplement to May/June 2012

Symptomatic Vitreomacular Diagnosis, Adhesion: Pathologic Implications and Management

FEATURING: Pravin U. Dugel, MD David F. Williams, MD, MBA Timothy G. Murray, MD, MBA, FACS Carl D. Regillo, MD Symptomatic Vitreomacular Adhesion

Release date: June 2012. Expiration date: June 2013. Jointly sponsored by the Dulaney Foundation and Today. Supported by an educational grant from ThromboGenics.

Statement of Need ous retinal , and the benefits of induced PVD Symptomatic vitreomacular adhesion is a condition in vs anomalous PVD. Mastery includes knowledge of the which the vitreous gel adheres in an abnormally strong clinical implications of VMA and the results of recent manner to the retina. VMA can lead to vitreomacular clinical trials on both surgical and pharmacologic PVD traction (VMT) and subsequent loss or distortion of induction, an understanding of vitreolysis agents and visual acuity. Anomalous posterior vitreous detachment their differences, and the ability to identify patients who (PVD) is linked to several retinal disorders including may benefit from PVD induction. macular pucker, macular hole, age-related macular gen- *Ocriplasmin has been granted priority review by the eration (AMD), macular edema, and retinal tears and US Food and Drug Administration, but is not yet avail- detachment. able in the United States. The incidence of VMA has been reported to be as high 1. Koerner F, Garweg J. [Diseases of the vitreo-macular interface]. Klin Monbl Augenheilkd. as 84% in cases of macular hole; 100% in vitreomacular 1999;214(5):305-310. traction syndrome; and 56% in idiopathic epimacular 2. Takahashi MK, Hikichi T, Akiba J, Yoshida A, Trempe CL. Role of the vitreous and macu- 1 lar edema in branch retinal vein occlusion. Ophthalmic Surg Lasers. 1997;28(4):294-299. membrane. The incidence of VMA in macular edema 3. Kado M, Jalkh AE, Yoshida A, et al. Vitreous changes and macular edema in central retinal appears to depend on the severity of the underlying vein occlusion. Ophthalmic Surg. 1990;21(8):544-549. 2,3 3-12 4. Lambert HM, Capone A, Jr., Aaberg TM, et al. Surgical excision of subfoveal neovascular condition. In AMD, the rates vary but have been membranes in age-related . Am J Ophthalmol. 1992;113(3):257-262 reported to be as high as 59% in exudative AMD.12 5. Weber-Krause B, Eckardt U. [Incidence of posterior vitreous detachment in eyes with and without age-related macular degeneration. An ultrasonic study]. Ophthalmologe. Currently, pars plana (PPV) is used to surgi- 1996;93(6):660-665. cally induce PVD and release the traction on the retina 6. Ondes F, Yilmaz G, Acar MA, et al. Role of the vitreous in age-related macular degenera- tion. Jpn J Ophthalmol. 2000;44(1):91-93. for selected cases. A vitrectomy procedure, however, is 7. Krebs I, Brannath W, Glittenberg C, et al. Posterior vitreomacular adhesion: a potential risk not without risk. Complications with standard PPV12-15 factor for exudative age-related macular degeneration? Am J Ophthalmol. 2007;144(5):741- 16-20 746. and more recently with small-gauge PPV have been 8. Lee SJ, Lee CS, Koh HJ. Posterior vitreomacular adhesion and risk of exudative age- reported and include , retinal tears, related macular degeneration: paired eye study. Am J Ophthalmol. 2009;147(4):621-626 e1. 9. Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion in active and end-stage age- , and postoperative formation. related macular degeneration. Am J Ophthalmol .2009;148(1):79-82. Additionally, PPV may result in incomplete separation, 10. Wheatley HM. Posterior vitreomacular adhesion and exudative age-related macular degeneration. Am J Ophthalmol. 2008;145(4):765; author reply -6. and it may potentially leave a nidus for vasoactive and 11. Schmidt JC, Mennel S, Meyer CH, Kroll P. Posterior vitreomacular adhesion: a vasoproliferative substances, or it may induce develop- potential risk factor for exudative age-related macular degeneration. Am J Ophthalmol. 2008;145(6):1107; author reply -8. ment of fibrovascular membranes. Further, as with any 12. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion invasive surgical procedure, PPV introduces trauma to in age-related macular degeneration: spectral optical coherence tomography and surgical 21,22 results. Am J Ophthalmol. 2008;146(2):218-227. the vitreous and surrounding tissues. 13. Doft BH, Wisniewski SR, Kelsey SF, Groer-Fitzgerald S; Endophthalmitis Vitrectomy There are data showing that nonsurgical induction of Study Group. Diabetes and postcataract extraction endophthalmitis. Curr Opin Ophthalmol. 2002;13(3):147-151. PVD using ocriplasmin, a vitreolysis agent, can offer the 14. Doft BM, Kelsey SF, Wisniewski SR. Retinal detachment in the endophthalmitis vitrec- benefits of successful PVD while eliminating the risks tomy study. Arch Ophthalmol. 2000;118(12):1661-1665. 15. Wisniewski SR, Capone A, Kelsey SF, et al. Characteristics after cataract extraction or associated with a surgical procedure. Pharmacologic vit- secondary lens implantation among patients screened for the Endophthalmitis Vitrectomy reolysis has the following advantages over PPV: It induces Study. . 2000;107(7):1274-1282. 16. Gupta OP, Weichel ED, Regillo CD, et al. Postoperative complications associated with complete separation, creates a more physiologic state of 25-gauge pars plana vitrectomy. Ophthalmic Surg Lasers Imaging. 2007;38(4):270–275. the vitreomacular interface, prevents the development of 17. Liu DT, Chan CK, Fan DS, Lam SW, Lam DS, Chan WM. Choroidal folds after 25 gauge transconjunctival sutureless vitrectomy. Eye. 2005;19(7):825–827. fibrovascular membranes, is less traumatic to the vitre- 18. Scott IU, Flynn HW Jr, Dev S, et al. Endophthalmitis after 25-gauge and 20-gauge pars ous, and is potentially prophylactic.21,22 plana vitrectomy: incidence and outcomes. Retina. 2008;28(1):138–142. 19. Kunimoto DY, Kaiser RS; Wills Eye Retina Service. Incidence of endophthalmitis after 20- Additionally, vitreolysis obviates the costs associated and 25- gauge vitrectomy. Ophthalmology. 2007;114(12):2133–2137. with surgery and allows earlier intervention, whereas 20. Kaiser RS. Complications of sutureless vitrectomy and the findings of the Micro-Surgical Safety Task Force. Paper presented at: Retina Subspecialty Day, Annual Meeting of the surgery is reserved for more advanced cases. In 2 phase American Academy of Ophthalmology; November 7-8, 2008; Atlanta, GA. 3 studies, a single injection of ocriplasmin was shown 21. de Smet MD, Gandorfer A, Stalmans P, et al. Microplasmin intravitreal administration in 23,24 patients with vitreomacular traction scheduled for vitrectomy: the MIVI I trial. Ophthalmology. to be safe and effective for PVD induction, provid- 2009;116(7):1349-1355. ing further evidence that pharmacologic vitreolysis with 22. Goldenberg DT, Trese MT. Pharmacologic vitreodynamics and molecular flux. Dev Ophthalmol. 2009;44:31-36. ocriplasmin may provide a safe and effective alternative 23. Jumper J, Pakola S. The MIVI-007 trial. Phase 3 evaluation of single intravitreous to PPV for inducing PVD. Retina specialists and other injection of microplasmin or placebo for treatment of focal vitreomacular adhesion. Paper presented at: the American Society of Retina Specialists; August 31, 2010; Vancouver, BC. ophthalmologists must be educated on this new treat- 24. Packo K, Pakola S. The MIVI-006 trial. Phase 3 evaluation of single intravitreous ment for symptomatic vitreomacular adhesion. injection of microplasmin or placebo for treatment of focal vitreomacular adhesion. Paper To address these educational gaps, retina specialists presented at: the American Society of Retina Specialists; August 31, 2010; Vancouver, BC. and other ophthalmologists must master insights on the pathogenesis of VMA, the role that VMA plays in vari-

2 Supplement to RETINA TODAY May/June 2012 TARGET AUDIENCE DISCLOSURE This certified CME activity is designed for retina spe- In accordance with the disclosure policies of the cialists and general ophthalmologists involved in the Dulaney Foundation and to conform with ACCME and management of patients with retinal disease. US Food and Drug Administration guidelines, anyone in a position to affect the content of a CME activity is LEARNING OBJECTIVES required to disclose to the activity participants (1) the Upon completion of this activity, the participant existence of any financial interest or other relationships should be able to: with the manufacturers of any commercial products/ 1. explain the process by which VMA occurs; devices or providers of commercial services and (2) 2. identify the disease states with which VMA is associ- identification of a commercial product/device that is ated; unlabeled for use or an investigational use of a product/ 3. identify the clinical implications of anomalous PVD; device not yet approved. 4. identify the pros and cons of a surgical vitrectomy vs. pharmacologic vitreolysis to induce PVD; FACULTY CREDENTIALS 5. explain the mechanism of action of pharmacologic Pravin U. Dugel, MD, is Managing Partner of Retinal vitreolysis Consultants of Arizona in Phoenix; Clinical Associate 6. differentiate between the various agents that can be Professor of Ophthalmology, Doheny Eye Institute, used for pharmacologic vitreolysis in terms of their com- Keck School of Medicine at the University of Southern position, advantages, and disadvantages; and California, Los Angeles; and Founding Member of the 7. discuss the available data on the safety and efficacy Spectra Eye Institute in Sun City, AZ. of vitreolysis agents for PVD induction. David F. Williams, MD, MBA, is in private prac- tice at VitreoRetinal Surgery PA in the Twin Cities of METHOD OF INSTRUCTION Minnesota and is an Assistant Clinical Professor of Participants should read the CME activity in its Ophthalmology at the University of Minnesota. entirety. After reviewing the material, please complete Timothy G. Murray, MD, MBA, FACS, is a Professor the self assessment test, which consists of a series of mul- of Ophthalmology with a Secondary Appointment in tiple choice questions. To answer these questions online Radiation Oncology at Bascom Palmer Eye Institute and receive real-time results, please visit http://www. at the Miller School of Medicine of the University of dulaneyfoundation.org and click “Online Courses.” Upon Miami. completing the activity and achieving a passing score Carl D. Regillo, MD, is the Director of the Retina Service of over 70% on the self-assessment test, you may print of Wills Eye Institute and a Professor of Ophthalmology at out a CME credit letter awarding 1 AMA PRA Category 1 Thomas Jefferson University, Philadelphia. Credit.™ The estimated time to complete this activity is 1 hour. FACULTY/STAFF DISCLOSURE DECLARATIONS Dr. Dugel states that he is a consultant to Alcon, ACCREDITATION AND DESIGNATION AMO, Macusight, Neovista, ArcticDx, Ora, Regeneron, This activity has been planned and implemented in and ThromboGenics; and is a minor shareholder in accordance with the Essential Areas and Policies of the Macusight and Neovista. Accreditation Council for Continuing Medical Education Dr. Williams states that he is a consultant to Genentech. (ACCME) through the joint sponsorship of the Dulaney Dr. Murray states that he is a consultant to Alcon Foundation and Retina Today. The Dulaney Foundation Laboratories Inc. and ThromboGenics. is accredited by the ACCME to provide continuing Dr. Regillo states he receives research grant support from education for physicians. The Dulaney Foundation des- Alimera, Allergan, Genentech, GlaxoSmithKline, Regeneron, ignates this enduring material for a maximum of 1 AMA ThromboGenics, ACT, Johnson & Johnson, and QLT, and PRA Category 1 Credit.™ Physicians should claim only the that he is a consultant to Alimera, Genentech, Regeneron, credit commensurate with the extent of their participa- GlaxoSmithKline, and Alcon Laboratories Inc. tion in the activity. All of those involved in the planning, editing, and peer review of this educational activity report no financial relationships. n

May/June 2012 Supplement to RETINA TODAY 3 Symptomatic Vitreomacular Adhesion

The Evolution of Understanding of Vitreomacular Adhesion Advanced imaging and a new pharmacologic solution have changed the way we think about this condition.

By Pravin U. Dugel, MD

osterior vitreous detachment (PVD) is largely Advanced Imaging and VMA viewed as a fairly simplistic event; however, this is The condition in the top panel of Figure 1 can be Pnot necessarily the case. PVD is composed of described by a number of names: VMT, stage 1 macular 2 biologic phases that must work in synchrony— hole, or macular cyst. Therefore, the lack of accuracy of liquefaction of the vitreous and separation of the vit- our nomenclature betrays continued understanding of reous from the retina. If these 2 phases do not work this condition. in synchrony, a normal vitreous detachment will not Because we now have access to advanced imaging tech- occur. Instead, what results is known as an anomalous, niques, from time-domain optical coherence tomography or pathologic, vitreous detachment and vitreomacular (OCT) to spectral-domain (SD) OCT, we are further ahead adhesion (VMA), in which an area of attachment of the in our understanding of VMA, VMT, and macular hole. Our vitreous exists where it should not. VMA at the macula causes , or visual distortion. Historically, we have had agents that can induce 1 phase of the PVD, but again, liquefaction and separation must occur in synchrony. Hyaluronidase was first introduced in 1943 and was more recently reintroduced as Vitrase (Ista). This agent did not work well because it achieves only liquefaction, not separation. Another agent, dispase, which is a cleaving agent, also did not work well because, conversely, it causes interface separation without liquefac- tion. Ocriplasmin (ThromboGenics) is the only agent that induces both liquefaction and separation of the vitreous from the retinal interface. Currently, for most patients with VMA who main- tain good vision, the only reasonable available option is observation, due to the risks involved with a surgical intervention. This can be frustrating to patients because they come to our offices with true symptoms of poor vision and distortion and, because we can do nothing for them, they leave unhappy. By choosing watchful waiting, we are hoping for spontaneous separation of the vitreous from the retina. As David Williams, MD, MBA, discusses in his article beginning on page 6, however, spontaneous separation is a relatively rare event. Rather, what seems to hap- pen more frequently is vitreomacular traction (VMT), resulting in cystic and retinal pigment epithelium changes and subsequent visual acuity loss. Macular hole is another possible consequence of VMA that is left to Figure 1. The condition in this figure can be described as observation. VMT, stage 1 macular hole, or macular cyst.

4 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

Even with older time-domain OCT, it is apparent that VMA plays a larger role in retinal disease than was previously understood.

Figure 2. VMT; visual acuity of 20/30. Summary Currently, we have a convergence of several forces, nomenclature, however, lags far behind, which can lead to 2 of which I have discussed. The first is the increased confusion and misunderstanding. understanding of the role that the vitreous plays in reti- It is quite formidable to think of how far we have nal disease, fueled by advances in ocular imaging. The come with our imaging technology. When I performed second is the availability of an agent that can achieve my medical retina fellowship with J. Donald M. Gass, MD, what could only be achieved previously by a surgical he was using a Hruby lens, which no one else was using procedure. More data on all the available approaches to at the time, and was able to see in an unprec- symptomatic VMA, along with information that shows edented fashion. Imagine what he could have done using its role in other retinal disease states, will be discussed in our current imaging technologies. the following pages. Even with older time-domain OCT, it is apparent that VMA plays a larger role in retinal disease than was Pravin U. Dugel, MD, is Managing Partner previously understood. The advances in OCT technol- of Retinal Consultants of Arizona in Phoenix; ogy are related to an increased understanding as to the Clinical Associate Professor of Ophthalmology, prevalence of VMA. SD-OCT has allowed improved Doheny Eye Institute, Keck School of Medicine visualization of the vitreoretinal interface and has at the University of Southern California, Los revealed the larger role that VMA plays in retinal disor- Angeles; and Founding Member of the Spectra ders such as age-related macular degeneration, diabetic Eye Institute in Sun City, AZ. He can be reached retinopathy, , cystoid macular at [email protected]. edema, and retinal vein occlusion(RVO).1-9 Based on this new understanding, a new ICD-9 diagnostic code 1. Ezra E. Idiopathic full thickness macular hole: natural history and pathogenesis. Br J Ophthalmol. 2001;85(1):102-108. 379.27 was designated for VMA. 2. Koerner F, Garweg J. Vitrectomy for macular pucker and vitreomacular traction syndrome. Doc Ophthalmol. 1999;97(3-4):449-458. Applying Pharmacologic Vitreolysis 3. Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J Figure 2 shows a patient with 20/30 vision and meta- Ophthalmol. 2007;144(5):741-746. morphopsia. Although this patient might complain 4. Bertelmann T, Ki’ová N, Messerschmidt-Roth A, Irle S, Sekundo W, Mennel S. The vitreo- about poor vision, I would not consider surgery because macular interface in retinal vein occlusion. Acta Ophthalmol. 2011;89(4):e327-331. 5. Kakehashi A, Schepens CL, Trempe CL. Vitreomacular observations. I. Vitreomacular the vision is too good and so the benefits of surgery adhesion and hole in the premacular hyaloid. Ophthalmology. 1994;101(9):1515-1521. do not outweigh the risks. This patient, in my opinion, 6. Ghazi NG, Ciralsky JB, Shah SM, Campochiaro PA, Haller JA. Optical coherence would be a perfect candidate for ocriplasmin. tomography findings in persistent diabetic macular edema: the vitreomacular interface. Am J Ophthalmol. 2007;144(5):747-754. I would also use ocriplasmin in a patient with a full- 7. Robison CD, Krebs I, Binder S, et al. Vitreomacular adhesion in active and end-stage age- thickness macular hole, or for a patient who has VMA related macular degeneration. Am J Ophthalmol. 2009;148(1):79-82. causing a macular cyst or a stage I macular hole. 8. Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion: a potential risk factor for exudative age-related macular degeneration? Am J For patients with RVO and macular edema, I would Ophthalmol. 2007;144(5):741-746. consider using ocriplasmin to increase the sustainability 9. Carpineto P, Di Antonio L, Aharrh-Gnama A, Ciciarelli V, Mastropasqua L. Diagnosing and of anti-VEGF injections. treating vitreomacular adhesion. Eur Ophthalmic Rev. 2011;5:69-73.

May/June 2012 Supplement to RETINA TODAY 5 Symptomatic Vitreomacular Adhesion

The Watchful Waiting Approach to Vitreomacular Adhesion Increased patient expectations drive the need for better options.

By David F. Williams, MD, MBA

hen considering anomalous posterior vitreous pucker. Figure 1 shows the relationship of anomalous detachment (PVD) and vitreomacular adhe- PVD to several retinal disorders. Wsion (VMA), it is useful to have some sort of What are our options for macular holes? For stage conceptual framework on which to hang your thought 1 macular holes, the most common strategy is watch- processes in understanding what is happening within ful waiting because many of these will resolve. Once it the eye. becomes a full-thickness macular hole, spontaneous clo- Partial-thickness vitreous detachment traditionally sure is uncommon, and if the patient is sufficiently symp- has been called vitreoschisis, which is typically seen in tomatic, surgical intervention, which will be discussed in complex diabetic pathology such as a diabetic tractional an article beginning on page 8, is appropriate. detachment. Vitreoschisis, however, is a more common occurrence than previously thought. VMA + VMT: Natural History Partial thickness vitreous detachment may lead to The majority of patients with VMA and vitreomacu- epiretinal membranes (ERMs), which in the setting of lar traction (VMT) present with cystoid changes in the centrifugal traction may lead to macular hole or macular macula. Microscopically, small cysts may be present,

Anomalous PVD = VMA Anomoly

Partial Thickness = Vitreoschisis Full Thickness = Partial PVD

Peripheral Separation Posterior Separation Posterior Traction Peripheral Traction Epiretinal Membrane

Centrifugal Centripetal Contraction Contraction Macular Traction Optic Disc Traction

Retinal Tears Macular Hole Macular VMT nvAMD, DR Vitreopapillary and Pucker Syndrome DME, RVO Traction Detachment

Figure 1. The implications of anomalous PVD. Information courtesy of J Sebag, MD.

6 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

Increased patient expectations has created a situation in which having a pharmacologic solution [for VMA] that can address visual symptoms without the risks of surgical intervention would be advantageous.

Figure 2. Patient with dry age-related macular degeneration. Macular changes and an attachment of the vitreous to the jump the gun with surgery. central macula can be seen, but there is no elevation of the Figure 3, however, shows a different case. This patient macula and no visible cystoid changes. has a classic VMT, and the tractional effects are visible. Some ERM is present, and there are chronic cystoid changes to the retina. We know from experience that a case like this is unlikely to resolve, so if the patient is symptomatic and is bothered the visual distortion, I then intervene. In the past, I have performed surgery, but this is a perfect case for a medical intervention with a pharmacolytic agent if it were available. There is nothing wrong with waiting, and there was a time when we would wait until the visual acuity was 20/70 or worse. Patients’ expectations, however, have changed, and they tend to be less tolerant of metamor- Figure 3. Classic VMT with visible traction. phopsia than in years past. This is an important point. I am hesitant to operate on a patient who does not nec- which are easier to visualize with spectral-domain OCT essarily appreciate that they have a problem because he (SD-OCT). Hikichi et al1 showed that 81% of patients or she may very well notice the symptoms after I have in their study presented with cystoid changes in the operated and misinterpret them to be a result of the retina at the time of diagnosis of VMT; only 19% had no surgical procedure. cystoid changes at the time of diagnosis. Over a median of 60 months, more than 90% of those with cystoid Summary changes experienced severe vision loss, persistent cystoid Watchful waiting remains a reasonable approach to changes, or development of new cystoid changes. In some cases of asymptomatic VMA; however, increased terms of visual acuity, 64% of the patients in this study patient expectations have created a situation in which lost more than 2 lines of vision, and 32% lost more than having a pharmacologic solution that can address visual 6 lines of vision at 60 months. symptoms without the risks of surgical intervention The experience in this study with the natural history would be advantageous. The surgical approach to VMA of VMT leads us to believe that the watch-and-wait and the associated risks will be discussed by Timothy approach may not be the best for many of our patients. G. Murray, MD, MBA, FACS, in the next article in this supplement. Case Examples Figure 2 shows the fluorescein angiography and cor- David F. Williams, MD, MBA, is in private responding OCT image of an eye of a patient with dry practice at VitreoRetinal Surgery PA in the age-related macular degeneration. Macular changes and Twin Cities of Minnesota, and is an Assistant an attachment of the vitreous to the central macula can Clinical Professor of Ophthalmology at the be seen, but there is no elevation of the macula and no University of Minnesota. visible cystoid changes. This is the type of case I see often on referral. Although there is a persistent VMA, I can see 1. Hikichi T, Yoshida A, Trempe CL. Course of vitreomacular traction syndrome. Am J no traction and the patient’s vision is 20/40, so I will not Ophthalmol. 1995;119(1):55-61.

May/June 2012 Supplement to RETINA TODAY 7 Symptomatic Vitreomacular Adhesion

The Surgical Approach to Vitreomacular Traction Syndrome Advanced imaging and the use of intraoperative steroids can improve outcomes.

By Timothy G. Murray, MD, MBA, FACS

avid F. Williams, MD, MBA, discussed the watch- and-wait approach to vitreomacular adhesion Dand macular hole and the fact that with stage 1 I advocate the use of intravitreal macular hole, there is up to a 50% rate of spontaneous steroids in vitrectomy, resolution. What about our patients, however, who may require surgical intervention? not for staining of the vitreous, We do not currently have a uniform approach to sur- but for their direct gery for vitreomacular traction (VMT) syndrome with pharmacologic properties. or without macular hole, nor for epiretinal membrane (ERM). In my opinion, it is advantageous to release the ERM tractional component by removing the internal Bascom Palmer Eye Institute with intravitreal steroids limiting membrane (ILM). There are data showing how used during surgery and there is strong evidence to altered anatomy via ILM removal results in a signifi- support that they modulate macular thickening par- cantly lower incidence of recurrent ERM, persistent ticularly in the immediate postoperative period with traction, or recurrent macular hole.1-3 Ten years ago, I minimal risk of secondary glaucoma.4 do not think that ILM removal would be considered in the setting of standard surgical ERM management. Combined Phaco/Vitrectomy Case I also advocate the use of intravitreal steroids in vit- A man aged 66 years was referred to the Bascom rectomy, not for staining of the vitreous, but for their Palmer Eye Institute Corneal Service by an outside phy- direct pharmacologic properties. It is true that there sician. He presented with 20/200 vision that was dispro- has been controversy regarding the occurrence of sec- portionate to his cataract. A brief look at the macula ondary sequelae, such as glaucoma or cataract forma- revealed dense ERM and VMT with metamorphopsia tion, but we have performed ongoing evaluations at (Figure 1). The fellow eye had some drusen (Figure 2)

A B

Figure 1. Imaging shows dense ERM and VMT. A B

Figure 2. Drusen is present in the fellow eye, but there is no other significant pathology.

8 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

A B

Figure 3. Postoperative imaging of the affected eye shows improvement. The patient was unhappy, however, because of residual metamorphopsia.

but no other significant pathology. With ICG, however, I can easily identify residual ILM In this setting, I am a proponent of combining cata- and am able to engage the tissue for removal. ract and vitrectomy surgery as vitrectomy alone would One week after surgery, some traumatic impact sites not recover best visual acuity and the patient would remain from the peel but the membrane is gone and have to undergo cataract surgery at a later date to the contour has improved. Eight months later, he is ensure the best visual acuity. Combined pars plana vit- psuedophakic, his metamorphopsia has decreased, and rectomy and phacoemulsification surgery is the norm his vision has improved to 20/30 (Figure 3), but he is for patients managed outside of the United States with incredibly unhappy. Why? retinal pathology requiring surgical intervention and The reason for his dissatisfaction is that he continues concommitant significant lens opacity. These combined to have some persistent metamorphopsia. One thing procedures are much less commonly performed in the that I am seeing more frequently in my practice is that United States but appear to be increasing in frequency now that we have the ability to significantly improve with the shift to microincisional vitrectomy surgery and visual acuity, patients are more focused on quality of clear cornea torsional phacoemulsification. vision, almost as they would with refractive surgery. I In this case, first I made the sclerotomies, and insert- typically tell my patients to expect a 2/3-line improve- ed valved trocars (Alcon Laboratories Inc.) to stabilize ment in visual acuity in a case such as that I have the fluidics. I performed torsional phaco through a described. So in this case, I advised the patient that he clear corneal wound and implanted a foldable intraocu- would most likely be 20/50 after surgery and his vision is lar lens, leaving the viscoelastic in the eye. I proceeded even better at 20/30. I am thrilled. He is unhappy. This is, in my opinion, a result of increased patient expectations and is simply a consequence of our success in managing patients’ disease. The complications that are associated with surgery for VMT include a Considerations in Surgery for VMT potentially higher incidence of retinal The complications that are associated with surgery breaks, both intraoperatively and for VMT include a potentially higher incidence of postoperatively, retinal detachments, retinal breaks, both intraoperatively and postopera- tively,5 retinal detachments,6-11 and endophthalmitis.3-11 and endophthalmitis. Additionally, there is a possibility of incomplete separa- tion of the vitreous, ERM, or ILM, with the potential for vasoactive and vasoproliferative substances affecting reti- to core vitrectomy, peeling the hyaloid membrane by nal function, the possibility for development of fibrovas- engaging it with the vitrector. I prefer to remove the cular membranes, and iatrogenic trauma to the retina. hyaloid anterior to the equator but not all the way The risk of complications is higher in more complex to the ora serrata. Using indocyanine green (ICG) as a cases, so this must also be considered. staining agent, I peeled the ERM and the ILM. I peel the I am a strong believer in the use of a staining agent ERM first, because it is difficult to engage the ILM over to facilitate ILM removal. It is also my experience that the ERM. the use of adjunct intravitreal triamcinolone during vit- Staining agents have revolutionized my approach to rectomy can enhance resolution of intraretinal edema. membrane peeling. When I was in training, the theory Further, in my opinion, a combined approach when was that when you peeled the ERM, you never went visually significant cataract is present is better than back and peeled the ILM because intraretinal edema having the patient undergo 2 separate procedures, and and striae from the ERM peel compromised visibility. it is critical to stabilize the anterior segment prior to

May/June 2012 Supplement to RETINA TODAY 9 Symptomatic Vitreomacular Adhesion

vitrectomy. Finally, optical coherence tomography has helped improve our understanding of which patients with VMT will benefit from surgery. Optical coherence tomography has helped improve our understanding Timothy G. Murray, MD, MBA, FACS, is a of which patients with VMT will Professor of Ophthalmology with a Secondary benefit from surgery. Appointment in Radiation Oncology at Bascom Palmer Eye Institute at the Miller School

of Medicine of the University of Miami. Dr. 7. Doft BH, Wisniewski SR, Kelsey SF, Groer-Fitzgerald S; Endophthalmitis Vitrectomy Murray may be reached at +1 305 326 6166; Study Group. Diabetes and postcataract extraction endophthalmitis. Curr Opin Ophthalmol. 2002;13(3):147-151. or via email at [email protected]. 8. Doft BM, Kelsey SF, Wisniewski SR. Retinal detachment in the endophthalmitis vitrectomy study. Arch Ophthalmol. 2000;118(12):1661-1665. 1. Kwok AK, Lai TY, Yuen KS. Epiretinal membrane surgery with or without internal limiting 9. Wisniewski SR, Capone A, Kelsey SF, et al. Characteristics after cataract extraction or membrane peeling. Clin Experiment Ophthalmol. 2005;33(4):379-85. secondary lens implantation among patients screened for the Endophthalmitis Vitrectomy 2. Kwok AK, Lai TY, Li WW, Woo DC, Chan NR. Indocyanine green-assisted internal limiting Study. Ophthalmology. 2000;107(7):1274-1282. membrane removal in epiretinal membrane surgery: a clinical and histologic study. Am J 10. Gupta OP, Weichel ED, Regillo CD, et al. Postoperative complications associated with Ophthalmol. 2004;138(2):194-199. 25- gauge pars plana vitrectomy. Ophthalmic Surg Lasers Imaging. 2007;38(4):270–275. 3. Mester V, Kuhn F. Internal limiting membrane removal in the management of full-thickness 11. Liu DT, Chan CK, Fan DS, Lam SW, Lam DS, Chan WM. Choroidal folds after 25 gauge macular holes. Am J Ophthalmol. 2000;129(6):769-777. transconjunctival sutureless vitrectomy. Eye. 2005;19(7):825–827. 4. Parke III DW, Sisk RA, Houston SK, Murray TG. Glaucoma After Intravitreal Triamcinolone 12. Scott IU, Flynn HW Jr, Dev S, et al. Endophthalmitis after 25-gauge and 20-gauge pars with Vitrectomy and Phacoemulsification. Clin Ophthalmol. 2012. In press. plana vitrectomy: incidence and outcomes. Retina. 2008;28(1):138–142. 5. Chung SE, Kim KH, Kang SW. Retinal breaks associated with the induction of posterior 13. Kunimoto DY, Kaiser RS; Wills Eye Retina Service. Incidence of endophthalmitis after 20- vitreous detachment. Am J Ophthalmol. 2009;147(6):1012-1016. and 25-gauge vitrectomy. Ophthalmology. 2007;114(12):2133–2137. 6. Mojana F, Cheng L, Bartsch DU, et al. The role of abnormal vitreomacular adhesion in 14. Kaiser RS. Complications of sutureless vitrectomy and the findings of the Micro-Surgical age-related macular degeneration: spectral optical coherence tomography and surgical Safety Task Force. Paper presented at: Retina Subspecialty Day, Annual Meeting of the results. Am J Ophthalmol. 2008;146(2):218-227. American Academy of Ophthalmology; November 7-8, 2008; Atlanta, GA.

10 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

Ocriplasmin for the Treatment of Symptomatic Vitreomacular Adhesion Favorable phase 3 data on safety and efficacy prove the benefits of this pharmacologic option to induce posterior vitreous detachment.

By Carl D. Regillo, MD

he definition of pharmacologic vitreolysis is the A intravitreal use of pharmacologic agents to cleave T the vitreoretinal interface and alter the molecular organization and structure of the vitreous to reduce or eliminate its role in disease formation.1 The potential treatment benefits to pharmacologic vitreolysis include complete atraumatic posterior vitreous separation, creation of a more physiologic vitreomacular interface, prevention of fibrovascular proliferation, and pro- phylaxis or treatment of macular edema and exudation. As David F. Williams, MD, MBA, noted in his article, vitreomac- ular adhesion (VMA) is implicated in many different retinal disease states, including not only macular hole and macular B pucker, but possibly also age-related macular degeneration, proliferative and macular edema from diabetic retinopathy and retinal vein occlusion. Table 1 shows the various agents that have been evalu- ated for vitreolysis. The evolution of understanding of how these pharmalytic agents work have led to ocriplasmin (ThromboGenics), the only agent that can produce both liquefaction and separation of the vitreous from the retina. Additionally, as seen in the Table, there is no toxicity asso- ciated with ocriplasmin, unlike many of the agents that Figure 1. Histological studies of a normal mouse eye (A) and have been investigated for vitreolysis. Lastly, it is the only PVD induction after ocriplasmin injection (B). agent to have successfully gone through phase 3 studies. plasmin injection. Not only did the vitreous separate from Preclinical Data the retina surface, but there is less fibronectin and Ocriplasmin is manufactured with recombinant technol- within the after ocriplasmin injection. The ogy to target fibronectin, laminin, and collagen and cleanly results of these preclinical studies confirmed the hypothesis separate the vitreous from the internal limiting membrane that ocriplasmin is a potential pharmacologic therapy for (ILM), inducing both liquefaction and vitreous detachment.2 vitreomacular adhesion (VMA).3 The proof-of-concept studies of ocriplasmin in both post- mortem human eyes and mouse eyes evaluated the enzy- Phase 3 Data matic agent for its vitreolytic effect, its efficacy for inducing The phase 3 studies for ocriplasmin, the MIVI-Trust posterior vitreous detachment, and safety of its intravitreal program, randomized a total of 652 patients to either a injection. Figure 1A shows histological studies of a normal single injection of 125 µg ocriplasmin (n=464) or placebo mouse eye and Figure 1B shows PVD induction after ocri- (n=188). The placebo group received an equal volume

May/June 2012 Supplement to RETINA TODAY 11 Symptomatic Vitreomacular Adhesion

Pharmacologic Vitreolysis Agents1 Dispase Nattokinase Description • Neutral protease obtained from Bacillus polymyxa • Serine protease produced • Preferentially cleaves fibronectin and collagen by Bacillus subtilis • Potent fibrinolytic activity, enhances plasminogen activators and inactivates a plasminogen-activator inhibitor Advantages • Evidence of PVD induction in vitro and in vivo • Demonstrated PVD in rabbits Disadvantages • Recently showed evidence of retinal hemorrhages • No human studies • Breaches in the ILM • Epiretinal membrane • Reduction in baseline electroretinogram amplitude • Ultrastructural damage to the retina Hyaluronidase Chondroitinase Collagenase Description • Cleaves hyaluronan and • Maintains gel state of • Clostridiopeptidase A collagen complex, result- vitreous by bridging adja- (bacterial collagenase) in ing in liquefaction of the cent collagen fibrils a highly purified form vitreous Advantages • Has potential to increase • Reported to induce PVD • Has been used during diffusion rate of erythro- without damage to ILM, vitrectomy to facilitate cytes and facilitate their detach epiretinal the removal of epiretinal clearance by lysis and membranes, and facilitate membranes phagocytosis vitreous removal Disadvantages • Sufficient clearance of • No reports of its use on • Promotes digestion of hemorrhage not demon- human eyes published. retinal vessels, causing strated in Phase III (Vitrase, hemorrhages Ista) • No data on PVD effect Plasmin Tissue Plasminogen Ocriplasmin Activator (t-PA) Description • Nonspecific serine • Alternative to autologous • Recombinant product protease plasmin • Contains only the catalytic • Acts on laminin and • Converts endogenous domain of human plasmin fibronectin (both in VRI) plasminogen of the • Agent showing greatest • Facilitates PVD by vitreous into plasmin potential1 activating endogenous metalloproteinases Advantages • Does not degrade • Readily available as a • Much more stable than collagen, a major compo- recombinant DNA the original molecule nent of the ILM product for human use • Easy storage and simple administration Disadvantages • Not readily available • May cause retinal toxicity • May cause temporary • Autologous • Requires breakdown of visual acuity changes • Nature yields unstable blood-retinal barrier product 1. Rheaume MA, Vavvas D. Semin Ophthalmol. 2010;25(5-6):295-302.

12 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

Figure 2. OCT imaging demonstrates that smaller adhesions Figure 3. The mean visual acuity gain was 7.3 letters in ocri- were more easily resolved at day 28. plasmin-treated VMT patients who achieved VMA resolution. This is significant considering the good baseline visual acuity injection of saline, which negated any volumetric effect of these patients. Seven patients lost vision. Patient 1: -1 letter on vitreous separation and confirmed that the difference (73 ≥72). VMA resolution by day 7. Also had cystoid macular between the 2 arms was indeed a drug effect. dystrophy in study eye. Patient 2: -2 letters (74 ≥72). VMA The primary endpoint of the studies was pharmaco- resolution by day 28. Patient also had drusen, cataract and dry logic resolution of VMA at day 28. Secondary endpoints AMD in study eye. Patient 3: -2 letters (73 ≥71); VMA resolution included total PVD at day 28, nonsurgical closure of full- by D7; myopia in study eye. Patient 4: -2 letters (83 ≥81). VMA thickness macular holes, change in visual acuity, the need resolution by day 7. Patient also had dry eye and cataract in for a vitrectomy procedure, and responses on a visual study eye. Patient 5: -5 letters (60 ≥55). VMA resolution by day function questionnaire. 14. Patient also had drusen and dry AMD in study eye. Patient Patients were required to be symptomatic. It is important 6: -6 letters (72 ≥66). VMA resolution by day 7. Patient initially to note that patients with very good baseline visual acu- lost 12 letters and was recovering vision when lost to follow-up ity were allowed into this study, ≤20/25, because this could (3 months). Patient 7: -11 letters (53 ≥42). VMA resolution by result in a ceiling effect with regard to visual acuity gains. day 7. Patient also had a cataract in the study eye. Additionally, patients with epiretinal membrane could be included in the study. Patients with high myopia (>8 D), prior which was from a good baseline visual acuity approach- vitrectomy or laser, macular holes >400 µm, and other retinal ing nearly 68 letters (20/50). diseases that could affect visual function were excluded. The mean visual acuity gain was 7.3 letters in ocriplas- The trials were comprised of 3 different “buckets” of min-treated VMT patients who achieved VMA resolu- patients: those with macular hole (as noted, they could tion. This is significant considering the good baseline also have had ERM as well, and 23 patients had baseline visual acuity of these patients. Seven of the patients lost macular hole and ERM); patients with ERM (baseline vision, but each of those patients did experience VMA ERM, no baseline macular hole; it is important to note resolution from between day 7 to day 28 and had some that ERM was not being treated, but that VMA associat- other pathology in the study eye, including cystoid mac- ed with ERM was being treated); and vitreomacular trac- ular dystrophy, drusen, cataract, dry age-related macular tion (VMT) syndrome (with no baseline macular hole or degeneration, myopia, and dry eye (Figure 3). ERM). All patients were required to have VMA confirmed by a central reading center (Duke Reading Center). Macular Hole Subgroup Analysis The proportion of patients who had VMA resolution The differences between ocriplasmin and placebo at day 28 was 29.8% vs 7.7% in the active treatment groups were even more pronounced in patients who group vs placebo group, respectively. If you take the were included in the macular hole subgroup. These extent of adhesion into account, the resolution rates patients were required to have stage 2 full-thickness in the ocriplasmin group were even higher in eyes with macular holes, such as these seen on OCT in Figure 4. smaller areas of adhesion (≤1500 µm), approaching In this subgroup, 40% of full-thickness macular holes 34% in patients with smaller adhesions as opposed to closed with a single injection of ocriplasmin. These holes broader adhesions. Optical coherence tomography closed early (by day 28) and remained closed at month 6. (OCT) imaging demonstrates that smaller adhesions Smaller macular holes (≤250 um) closed at a much were more easily resolved at day 28 (Figure 2). higher rate than did larger holes (>250 um). Again, these In terms of visual acuity outcomes, approximately holes closed early and remained closed. 41% of ocriplasmin-treated VMT patients who achieved In terms of visual acuity, 77% of patients gained 2 or VMA resolution gained 2 or more lines at 6 months, more lines with hole closure at 6 months after a single

May/June 2012 Supplement to RETINA TODAY 13 Symptomatic Vitreomacular Adhesion

A B C

Figure 4. All patients in the macular hole subgroup were required to have stage 2 full-thickness macular holes. A B C

Figure 5. The closing of a macular hole and resolution of VMA in a patient in the macular hole subgroup after a single injection of ocriplasmin.

injection of ocriplasmin, which was to be expected consid- to the lower number or no incidences in the patients ering the patients’ mean baseline visual acuity (54.8 letters, who received placebo injection. Beyond 7 days out to 20/80). It is important to note that vision gains occurred 6 months, most of these side effects drop off to where over time, demonstrating that, as is the case with surgery, there is little to no difference between the groups. the drug works quickly to close the macular holes, but the Because of these data, it is apparent that ocriplasmin improvement in visual acuity is gradual. injection can cause temporary visual acuity changes, and The mean visual acuity gain was 14.1 letters in ocriplasmin- this is why it is important to counsel patients so that treated macular hole patients who achieved hole closure they are aware of this transient effect. with drug treatment only. Only 1 patient in this subgroup In terms of more serious side effects associated with lost vision. This patient’s macular hole (387 µm) closed at day induced PVD, such as retinal tears and detachment, the 7 and the eye lost 1 letter of vision (74 to ≥73 letters). The rates were actually lower in the ocriplasmin group than patient also had pterygium, cortical cataract, cupping of the with placebo. optic disc, retinal pigment epithelial changes, vascular narrow- ing, and macular edema in the study eye at diagnosis. Summary Figure 5 shows the closing of a macular hole and reso- These data show that a single injection of ocriplasmin lution of VMA in a patient in the macular hole subgroup results in increased rates of PVD and full-thickness macu- after a single injection of ocriplasmin. lar hole resolution. Resolution of VMA and macular hole The rate of macular closure with placebo alone was resulted in visual improvement in most patients, and 17%, as compared to 40.6% in patients with ocriplasmin most of the adverse events were transient and occurred alone. For patients who received placebo or ocriplasmin in the immediate week following injection. and did not have full-thickness macular hole closure and Further, ocriplasmin did not preclude future vitrec- went on to have a vitrectomy, the rates of closure were tomy if the drug did not result in macular hole closure. 92.3% for the placebo group vs 93.1% for the ocriplasmin Should ocriplasmin become available, pharmacovitre- group, demonstrating that ocriplasmin did not affect the olysis will offer physicians an attractive alternative for ability to close a macular hole with vitrectomy. our patients who have symptomatic VMA.

Safety Data Carl D. Regillo, MD, is the Director of the Retina Because many of patients who have the potential Service of Wills Eye Institute and a Professor of to benefit from ocriplasmin are among those who Ophthalmology at Thomas Jefferson University, we would watch and wait and not perform surgery, Philadelphia. He may be reached at +1 800 331 the safety data are critical. From day 0 to day 7 after 6634; or via email at [email protected]. injection, there were a small number of incidences of , eye pain, photopsia, blurred vision, reduced 1. Rhéaume MA, Vavvas D. Pharmacologic vitreolysis. Semin Ophthalmol. 2010;25(5- visual acuity, visual impairment, retinal and macular 6):295-302. 2. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by micro- edema, anterior chamber cell flare, and photophobia plasmin. Invest Ophthalmol Vis Sci. 2004;45(2):641-647. in the patients who received ocriplasmin as compared 3. Data on file, ThromboGenics.

14 Supplement to RETINA TODAY May/June 2012 Diagnosis, Pathologic Implications And Management

Instructions for CME credit 1 AMA PRA Category 1 Credit™ Expires June 2013

CME credit is available electronically via www.dulaneyfoundation.org. To answer these questions online and receive real-time results, please visit www.dulaneyfoundation.org and click “Online Courses.” If you are experiencing problems with the online test, please e-mail us at [email protected] or call +1-610-619-0414. Alternatively, you may fax your exam to us at +1-610-771-4443. Certificates are issued electronically, so supply your e-mail address below. Please type or print clearly, or we will be unable to issue your certificate. Name ______o MD participant o non-MD participant Phone (required) ______o E-mail (required) ______City ______State ______

CME Questions

1. The best-case scenario for posterior vitreous detachment 5. Ocriplasmin is manufactured with recombinant (PVD) includes which biologic phase(s)? technology to target ______. a. liquefaction a. collagen b. A and C in synchrony b. VEGF c. separation of the vitreous from the retina c. fibronectin d. synesis d. edema e. B and D 2. Hyaluronidase achieves interface separation without f. A and C liquefaction; Dispase causes liquefaction. a. true 6. What is a reasonable approach for a patients with dry b. false age-related macular degeneration who presents with the fol- lowing: macular changes on optical coherence tomography, 3. Which complications are associated with surgery to visible attachment of the vitreous, no visible cystoid changes, induce PVD? and relatively good visual acuity of 20/40? a. retinal detachment a. surgery b. lid disease b. watch and wait c. endophthalmitis c. intravitreal injection of anti-VEGF d. A and C d. none of the above

4. Vitreomacular adhesion (VMA) has been implicated in the 7. Ocriplasmin can cause temporary visual acuity changes. following disease states: a. true a. diabetic retinopathy b. false b. age-related macular degeneration c. uveitis d. A and B e. A and C

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May/June 2012 Supplement to RETINA TODAY 15 Symptomatic Vitreomacular Adhesion

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16 Supplement to RETINA TODAY May/June 2012