Cataract Surgery: Calling an Audible

Review of Ophthalmology Vol. XXV, No. 5 • May 2018 • Planning Surgery in Post-refractive Patients • What’s Wrong with Doing a YAG? • Handling the Unhappy Patient Premium • A CIOLs IOL HIGH-TECH IOLs IN THE PIPELINE P. 12 • LVC IN COLLAGEN VASCULAR DISEASE P. 22 DIGGING DEEPER INTO PROTOCOL U P. 60 • REVIEWING THE LATEST LITERATURE P. 64 DIAGNOSING EARLY GLAUCOMA P. 66 • WILLS RESIDENT CASE REPORT P. 71

MayMay 20182018

reviewofophthalmology.comreviewofophthalmology.com Cataract Surgery: Calling an Audible

How to adapt and succeed when a situation turns out to be less than ideal.

• Planning Surgery in Post-refractive Patients P. 26

• PCO: What’s Wrong with Doing a YAG? P. 34

• Handling the Unhappy Premium IOL Patient P. 46

• No Capsular Support: Do ACIOLs Still Make Sense? P. 52

ALSO INSIDE: Is a Private Equity Deal Right for You? Pt. 2 P. 40

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RP0518_JJ Catalys.indd 1 4/5/18 2:39 PM REVIEW NEWS Volume XXV • No. 5 • May 2018 AMD Patients Recover Vision After Stem Cell Treatment

In a clinical trial designed as a Phase I, covery in both cases. The Early Treat- study’s design. “We’re looking at se- open-label, safety and feasibility study, ment Diabetic Retinopathy Study vere or sudden vision loss because due researchers from London studied the letter chart was used to defi ne best- to its sudden nature—they were able implantation of a human embryonic corrected vision, which improved over to see the day before—we know all stem cell (hESC) retinal pigment 12 months from 10 to 39 and from 8 the ocular structures must be intact,” epithelium patch in two patients to 29 letters in patients one and two, he says. “We know that the disease is with acute wet age-related macular respectively. There was no increase in centered in this area. These conditions degeneration and recent rapid vision intraocular pressure in either patient. are optimal for the particular type of decline. They reported their primary Lyndon da Cruz, PhD, FRCOphth, transplant that we’re doing. Specifi - and secondary outcomes from the FRACO, one of the study’s authors, cally, we want to look at patients with fi rst two patients of the series in an says the treatment may home in on sudden vision loss with a large hem- article published in the journal Nature the ocular anatomy that’s crucial for a orrhage or a pigment epithelial tear. Biotechnology in March. Based on the good outcome. “In AMD, the primary When they present, we can resolve results, the researchers say that this part of the eye that’s affected is the whatever has happened to cause their stem-cell-based tissue transplantation retinal pigment epithelium,” he notes. sudden vision loss, while sliding the is a potentially effective strategy for “If that’s damaged but the rest of the patch into the layer so we can also re- treating neurodegenerative diseases structures remain the same, what cover their vision. However, we also with otherwise irreversible cell loss. we’ve been able to do is replace it with know if you leave the bleeding—or The researchers used a surgical a perfect copy we’ve grown in the lab- whatever the problem is—for six to delivery tool to place one RPE patch oratory. That’s the breakthrough. The- eight weeks, the rest of the layers will in the subretinal space, under the oretically, this could conceivably work be damaged, so there’s a small window fovea, in the affected eye of each pa- for any disease where it is isolated in right after they’ve suddenly lost their tient. They verifi ed its placement with that layer and all other [layers] remain vision during which we can perform stereo-biomicroscopy, fundus photog- the same. this procedure.” raphy and spectral domain optical co- “Now because this is our fi rst test of Dr. da Cruz is excited about the fu- herence tomography. this in humans, we’re taking a select ture of the study. “The fi rst cases are For both patients, hESC-RPE was group that has very sudden or severe the hardest,” he says. “We’d like to do present over the full area of the patch vision loss, so that if it doesn’t work, more in order to show that this is as at 12 months. The patches showed there’s no vision loss involved,” Dr. da reproducible as the fi rst two patients. uneven autofl uorescence, which the Cruz continues. “But if it does work, We want to show this works, then go researchers say suggests functioning then we have these great visual recov- on to a more defi nitive study involving RPE phagocytosis. The investigators eries. This is what we’ve been able to a control group and maybe look at a add that the patients also presented achieve while showing the proof-of- licensing study. We’d also want to look with darker-pigmented areas contigu- principle. It’s a lower risk to patients at a broader array of patient groups, ous with the patch, which may rep- and a clear-cut signal that the trans- maybe including people with early resent RPE cell migration from the plant of the layer works because they dry macular degeneration or, in some patch onto adjacent RPE-defi cient have a visual recovery. We were able cases, we may look at patients with areas. These areas spread from the to replace the damaged layer of the early inherited retinal dystrophies and patch edge outward over the fi rst six retina.” then run a pilot study to see if there’s months after surgery. Dr. da Cruz says patients with sud- any chance this implant will work for The researchers observed visual re- den vision loss were a key part of the them, as well.”

May 2018 | reviewofophthalmology.com | 3

0003_rp0518_news.indd03_rp0518_news.indd 3 44/12/18/12/18 11:3511:35 AMAM Ophthalmic Product Development Insights AkiAkkki ToTobaru,bbarara uu, HiroHiro MMatsuda,atatssudada, PPhD,hDD,D & MatMatthewtthet ewwC CChapinhappinn ••O OOrara InInc.,nc.,, AndAndover,oover,r MMasMass.s.s REVIEW Matthew Chapin • Andover, Mass. Drug Repurposing: A Case Study of Accelerated Development

s a new physician-entrepreneur, you shows the proposed product is identical FDA-approved. In this situation, one can’t may have an idea for targeting a spe- to a previously approved product [section simply ask the FDA to rely on these other Acifi c pharmacologic mechanism and 505(j)]. fi ndings of safety and/or effi cacy, because are weighing your options regarding which We’ve looked at the 505(b)(2) approach that product is not yet approved and hasn’t type of lead drug to focus on: You can previously, but there are different cases been fully reviewed and deemed safe. To synthesize a new chemical entity and take where reference to other regulatory fi les use that data in a development program advantage of fresh intellectual property on come into play that are treated differently. A for a product not yet approved, you need a a novel composition of matter; license and 505(b)(2) application can rely on informa- right of reference with the other applicant. repurpose an approved medication; use tion from published literature or the FDA’s a known compound available generically; previous fi nding of safety and/or effective- Case Example: Okogen or make use of an existing platform that’s ness for an approved product. One key The Okogen experience is a great example being developed by another company for difference to understand when planning a of a company leveraging the right-to- other, non-ocular indications. Discussions fi ling strategy is that, according to its pur- reference approach. Okogen has been suc- of repurposing are relevant in ophthalmolo- pose, a 505(b)(2) can help avoid duplication cessful in recognizing and forming a plan gy, due to the diverse disease mechanisms of data that already exists but also requires around an unmet need (viral conjunctivitis), seen in the eye. Furthermore, since most the applicant to provide notice of certain identifying a drug with a novel approach ophthalmic drugs are administered locally, patent information to the NDA holder and to a non-ocular indication currently in generally speaking, the systemic exposure patent owner for the product(s) being development, securing funding, and moving to these agents is well within the safety referenced. Sometimes there’s an option to a program towards Phase II trials. A large part of its strategy and success in securing margins of the toxicology identifi ed in pursue either a full NDA or 505(b)(2), and funding was leveraging the ability to refer- studies of the drugs’ other indications. This there are multiple factors infl uencing that makes repurposing one of these agents an ence a product from a separate indication attractive option. in order to reduce the risk involved In prior columns, we’ve with pursuing approval of the analyzed examples of drug, and to accelerate its some of the options advance to a clinical trial. listed above. This Okogen was founded by month, we’ll look at a small team of industry the case of licensing veterans. With fi rsthand the ocular rights for experience in business a drug in develop- development at Allergan and ment for non-ocular Shire, Chief Executive Offi cer indications but which Brian M. Strem saw a large un- isn’t yet FDA-approved for met need in viral conjunctivitis, those other indications. Along and precedents for deal structures the way, we’ll also examine some key in that arena. The company’s lead considerations that we’ve encountered decision, one of which is the intellectual drug is based on the active pharmaceutical ingredient ranpirnase, a low-molecular- in such cases, and describe a current property disclosure requirement. weight protein extracted from the eggs example of a program currently in develop- How does a 505(b)(2) relate to a product of Rana pipiens (northern leopard frog). ment. that’s not yet approved but which is being Ranpirnase preferentially enters into the developed for another indication (or a cytoplasm of virally infected cells due to Review of Regulations study that’s already been terminated)? An First, let’s look at a few key regulatory electrostatic interactions, halts protein example of this is a situation in which key synthesis by targeted degradation of mam- considerations when taking a repurposing information is referenced from a publication approach. malian tRNA, blocks NFkB (pro-infl amma- that the applicant doesn’t own or have right tory) downstream signaling, and induces Section 505 of the Food, Drug and Cos- of reference to (right of reference refers metic Act outlines three types of new drug cellular apoptosis. These mechanisms to the ability to refer to studies of a drug drive inhibition of viral replication, reduce applications: 1) A New Drug Application conducted by someone else). Even though that contains full reports of investigations infl ammation and induce virally-infected the approach to this situation is clearly outof safety and effectiveness; 2) an applica- cell death. This triple mechanism of activity lined in an FDA Guidance Document [FDA tion where at least some of the information contributes to the ultimate target product Guidance: Applications Covered by Section required for approval comes from studies profi le, reducing viral burden and subse- 505(b)(2)], we raise the point here because not conducted by or for the applicant and quent length of contagion, and acceleration for which the applicant has not obtained a we’ve received questions about how to of sign-and-symptom resolution. right of reference [section 505(b)(2)]; and reference information from programs in Ranpirnase was initially developed as an 3) an application for a generic drug that which an IND was active for a non-oph- intravenous anti-cancer drug, Onconase, thalmic indication but the product wasn’t and, as such, its preclinical safety fully

4 | Review of Ophthalmology | May 2018

003_rp0518_news.indd 4 4/12/18 11:36 AM ®

E DITORIAL STAFF

supported clinical trials in cancer patients As we’ve discussed in previous columns, Editor in Chief through Phase III. Unfortunately, it missed there’s a benefi t to having an early pre-IND Walter C. Bethke the primary effi cacy endpoint in the second meeting with the FDA in order to help refi ne (610) 492-1024 of the global Phase IIIb trials in patients with budgets for the IND-enabling work. Typical- [email protected] unresectable malignant mesothelioma, and ly, it’s most useful to include in the pre-IND the oncology program was discontinued. package a description of the intended fi nal Senior Editor Alfacell, the sponsor of those studies, was formulation and a justifi cation of how you Christopher Kent restructured into Tamir Biotechnology. Prior plan to bridge the ocular use to the already (814) 861-5559 to restructuring, scientists had identifi ed completed toxicology safety data derived [email protected] the broad-spectrum antiviral potential of from systemic dosing. The latter may ranpirnase and the new management team require some preliminary, possibly non-GLP, at Tamir is leading the effort to develop data on systemic absorption following ocu- Senior Associate Editor ranpirnase as the fi rst approved antiviral for lar dosing. Having such data ensures that Kristine Brennan human papillomavirus genital warts. the FDA has enough information to provide (610) 492-1008 The company had demonstrated effi cacy you with complete responses and guidance [email protected] in preclinical models against a wide range that can help you plan and budget your of viruses, including adenovirus. Okogen remaining IND-enabling activities. Associate Editor identifi ed the opportunity for repurposing it, In the case of Okogen, in addition to safety Liam Jordan and licensed the ocular use for ranpirnase, information, since ranpirnase had previ- (610) 492-1025 effectively using existing IP for methods ously been in clinical trials under an IND, for treating viral infections. As part of that signifi cant chemistry, manufacturing and [email protected] arrangement, Tamir has granted Okogen full control information was also available for rights of reference to existing data and reg- use, including the other company’s analyti- Chief Medical Editor ulatory fi lings, including preclinical studies, cal methods, manufacturing process and Mark H. Blecher, MD as well as the safety data collected from all specifi cations. Further, as new inventions clinical studies completed with the IV drug. are generated, Okogen is building its own, Art Director The existing information on genotoxicity and wholly-owned IP portfolio, providing mul- Jared Araujo toxicology following systemic administra- tiple layers of patent protection. tion was used to support the assertion of a (610) 492-1032 reasonable safety margin based on absorp- [email protected] tion from ocular dosing. With the additional Conclusions In our ongoing survey of business issues toxicology work, per Good Laboratory Prac- Senior Graphic Designer and case studies within the industry, the tices, done by Okogen for ocular dosing, the Matt Egger ocular studies then completed the package case of Okogen demonstrates the success- (610) 492-1029 as a basis for initiating the Phase II trial. ful referencing of a drug from a previously [email protected] Another question that comes up is whether failed systemic program. Because it was or not non-GLP systemic studies from the able to structure and execute a license reference program can be used. In order for the drug and relevant data package International coordinator, Japan for prior work to be useful, and to defi nitely for repurposing, it realized signifi cant cost Mitz Kaminuma avoid the need to repeat studies, those sys- savings in its development program, and [email protected] temic studies need to have been conducted with Okogen’s recent $10 million fi nancing round, the company’s able to deploy funds as per GLP regulations, unless there’s a Business Offi ces and rapidly move toward a Phase II trial. specifi c justifi cation to deviate from GLP. 11 Campus Boulevard, Suite 100 (Cost savings isn’t an acceptable justifi ca- Ultimately, it’s important to understand the Newtown Square, PA 19073 tion for the FDA.) Make sure to verify that best way to reference prior data, whether GLP was observed in the studies if you’re it’s from an existing approved drug (with or (610) 492-1000 considering referencing other work. without right to reference), a primary peer- Fax: (610) 492-1039 For a new drug, the FDA usually requires reviewed publication, or from another ongo- ocular toxicology from two species. In the ing development program. Early interaction Subscription inquiries: context of repurposing a drug, however, with the FDA can help clarify the proper United States — (877) 529-1746 the question of whether the agency will path to approval and confi rm which parts of Outside U.S. — (845) 267-3065 a development program you can avoid. accept the IND with ocular toxicology from E-mail: just one species depends on the situation. [email protected] Unless there’s a specifi c justifi cation, if the Mr. Chapin is senior vice president of cor- Website: reference drug isn’t yet approved for other porate development at Ora Inc. The author www.reviewofophthalmology.com purposes, then you will most likely need two welcomes your comments and questions species for GLP ocular toxicology. So, it’s regarding product development. Send cor- best to plan for the use of two species until respondence to [email protected] the FDA confi rms otherwise. or visit www.oraclinical.com.

0003_rp0518_news.indd03_rp0518_news.indd 5 44/12/18/12/18 11:3611:36 AMAM Editorial

REVIEW Board

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6 | Review of Ophthalmology | May 2018

0003_rp0518_news.indd03_rp0518_news.indd 6 44/12/18/12/18 11:3611:36 AMAM STRIVE TO SEE THE BEST RESULTS POSSIBLE Regular fixed-interval dosing of long-term treatment with anti-VEGFs has been shown to provide better gains and maintenance of vision, compared to PRN or treat-and-extend dosing regimens, in some patients with Wet AMD and DME.1-6

Ask your Regeneron representative what we can do to help ensure patients come in for their scheduled treatment.

anti-VEGF = anti–vascular endothelial growth factor; AMD = Age-related Macular Degeneration; DME = Diabetic Macular Edema. References: 1. Heier JS et al. Ophthalmology. 2016;123(11):2376-2385. 2. Rosenfeld PJ et al. N Engl J Med. 2006;355(14):1419-1431. 3. Ho AC et al. Ophthalmology. 2014;121(11):2181-2192. 4. Nguyen QD et al. Ophthalmology. 2012;119(4):789-801. 5. Kaiser PK et al. Ophthalmol Retina. 2017;1(4):304-313. 6. Peden MC et al. Ophthalmology. 2015;122(4):803-808. © 2018, Regeneron Pharmaceuticals, Inc. All rights reserved. 777 Old Saw Mill River Road, Tarrytown, NY 10591 01/2018 US-OPH-13911

RP0318_Regeneron.indd 1 2/13/18 2:56 PM May 2018 • Volume XXV No. 5 | reviewofophthalmology.com Cover Focus 26 | Planning for the Best Outcomes Kristine Brennan, Senior Associate Editor Do more than just hope for them with intelligent cataract surgery planning for post-refractive eyes. 34 | PCO: What’s Wrong with Doing a YAG? Leslie Sabbagh, Contributing Editor A lot of effort is being devoted to avoiding PCO, but some surgeons say a YAG isn’t that bad.

46 | Handling Unhappy Premium IOL Patients Asim Piracha, MD An ounce of prevention is worth a pound of cure, says this surgeon.

No Capsular Support: 52 | Do ACIOLs Still Make Sense? Christopher Kent, Senior Editor New alternatives have surgeons shying away from ACIOLs, but there’s still a place for them.

Feature Article Is Private Equity Right for You? (Pt 2) 40 | Christopher Kent, Senior Editor Surgeons and business experts answer doctors’ key questions. (Part two of two.)

8 | Review of Ophthalmology | May 2018

011_rp0518_toc.indd 8 4/12/18 11:15 AM Departments

3 | Review News 12

12 | Technology Update High-tech IOL Options in the Pipeline Three revolutionary ideas may help to raise the bar for post-surgery refractive outcomes.

22 | Refractive/Cataract Rundown Is LVC Possible in CVD Patients? Collagen vascular disease may not always be a bar for carefully selected patients.

60 | Retinal Insider Digging Deeper into Protocol U The DRCR Network’s study of two treatments for DME revealed the pros and cons of the approaches. 22

63 | Product News New Vitrectomy Cutters Approved

64 | Research Review Outcomes of Laser Peripheral Iridotomy

66 | Glaucoma Management Diagnosing Early Glaucoma: Pearls and Pitfalls In our ongoing attempts to detect the disease at its earliest stages, new technologies are showing promise.

69 | Advertising Index

70 | Classifieds 71

71 | Wills Eye Resident Case Series

May 2018 | reviewofophthalmology.com | 9

011_rp0518_toc.indd 9 4/12/18 11:15 AM It’s time for Triton.

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RP0318_Topcon Triton.indd 3 2/27/18 11:02 AM Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

New High-Tech IOL Options in the Pipeline Three revolutionary ideas may help to raise the bar for post- surgery refractive outcomes and patient satisfaction. Christopher Kent, Senior Editor

s every cataract surgeon knows, system. Once the focusing system is surgeons use. “The laser has a docking Agetting an ideal refractive out- placed on the eye, the software is able system similar to the cone-based sys- come when implanting an intraocular to locate the implanted lens and then tem,” he says. “The patient lies down lens is a challenge. It’s still impossible direct the laser to a 50-µm area inside on a bed. There’s a unit that stabilizes to know for sure exactly where the im- the lens, where it makes whatever re- the eye itself; then the laser docks to planted lens will end up sitting inside fractive adjustment is desired without a ring, so the eye can be held steady the eye; there are a limited number of having any disruptive effect on the during the procedure. It’s a very quick options for correcting a poor refrac- optical characteristics of the lens, or procedure that takes only a few sec- tive outcome (should it occur); and the comfort or vision of the patient. onds. addressing presbyopia via a premium (According to the company, the la- “It’s almost like creating a lens with- implant is far from a sure thing. ser energy used is far less than the in a lens,” he continues. “The change Not surprisingly, a number of new amount required for YAG procedures doesn’t add any thickness or alter the technologies that may offer solutions or cataract surgery.) The goal is to cor- shape of the overall lens; instead, it to these problems are in the pipeline. rect refractive errors remaining after changes the hydrophilicity of the lens. Here, three of the most promising the implantation of a lens, or to make The laser excites certain molecules are profi led by surgeons familiar with other adjustments requested by the inside the lens, causing the refractive them. patient. Perhaps most remarkable, index to change. The bottom line is, this technology appears to work on instead of cutting a flap and doing Postop Refractive Adjustment almost any implanted lens, from any corneal surgery, you just change the manufacturer. power of the lens and you’re done. One of the most interesting new Y. Ralph Chu, MD, founder and The changes take place inside the eye, refractive options under development medical director of Chu Vision Insti- so there’s no pain, no corneal dryness is the Perfect Lens (Perfect Lens tute in Bloomington, Minnesota, and and no recovery period. Furthermore, LLC, Irvine, California). Despite its adjunct associate professor of oph- it’s not specifi c to just one company’s name, the product is not actually an thalmology at the University of Min- lens. Right now they’re working with intraocular lens; instead, it’s a system nesota, is on the scientific advisory acrylic lenses, and so far, they can do that’s capable of altering the refractive board for Perfect Lens. (He has no this with any one of them, includ- power of an IOL that’s already been fi nancial interest in the technology.) ing lenses from J&J Vision, Bausch + implanted inside the eye, using a laser. He notes that the version of the tech- Lomb, Zeiss and Alcon, among oth- The laser system comprises a fem- nology that he’s seen uses a femtosec- ers. That’s why it’s so exciting.” tosecond laser and an optical focusing ond laser that’s similar to what today’s Dr. Chu says that Ruth Sahler, ex-

12 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

012_rp0518_tech.indd 12 4/12/18 1:14 PM The Perfect Lens laser system uses a femtosecond laser to make refractive adjustments to a previously implanted intraocular lens. So far, the process appears to work on lenses from any manufacturer. Changes appear to be extremely precise and can range up to 10 D, and include the ability to change a multifocal to a monofocal, or vice versa. The graphs above show the refractive proﬁ le of a multifocal IOL before (left) and after adjustment (right). Lenses can be altered multiple times, and the refractive changes appear to be stable.

ecutive vice president and director of basically put in a 20-D lens in every he says. “They’ve taken a multifocal research and development at Perfect patient. If the patient needs a 24-D and turned it into a monofocal; then Lens, developed the optical pattern lens, you could make a 4-D adjust- back into a multifocal; then back into system that changes the refraction or ment—and it could be made in either a monofocal. There’s no time limit dioptric power of the IOL with the direction, plus or minus. that I’m aware of. There’s no leaching assistance of Josef Bille, vice president “What may be of particular interest of material and no alteration in the ad- at the company. “The system is very to surgeons is that this technology can justed refraction over time, from what precise, down to 0.01 D,” Dr. Chu reverse multifocality,” he continues. they’ve seen in the lab in animals. says. “At one point they took about “It can take a monofocal and make it It’s not like it wears off in a year and 15 different IOLs and altered their multifocal, or take a multifocal lens then you have to do it again. The lens refractions to make them 20 D. The and make it monofocal. (See example, is solid. You’re just making a change lenses ended up being within 0.01 D above.) It’s like an eraser. This will be inside the lens, and it stays that way.” of each other. Meanwhile, the pro- a boon to surgeons offering premium One obvious question is how this cess leaves the optical quality of the lenses such as multifocals because of technology differs from the Light Ad- lens unchanged, so the modulation the diffi culty of predicting who will justable Lens (RxSight) which was transfer function curves look excel- tolerate a multifocal lens. If the pa- recently approved by the U.S. Food lent. There’s very little degradation.” tient isn’t happy, we can eliminate the and Drug Administration. Dr. Chu Dr. Chu notes that today, the focus multifocality of the lens. It’s not an says he has no fi rsthand experience in cataract surgery is on getting a pre- IOL exchange; we simply reverse it. with the LAL, but notes there are cise outcome. “A big part of that has Furthermore, I think this capability significant differences between the been managing the challenge of pre- will be useful for every surgeon that two products. “Because of the LAL’s dicting where the lens will sit in the wants to do refractive cataract sur- technology, the altered prescription is bag,” he points out. “That’s challeng- gery, even if you don’t offer premium ‘locked in’ using ultraviolet light,” he ing because every eye is different. But IOLs. If a patient wants to try mono- notes. “That requires implanting their with this technology, you can simply vision using monofocal IOLs, you’ll proprietary lens, then protecting your wait until the foundation for the lens be able to adjust one eye. If they don’t eyes from UV light with special glasses is set and the IOL is settled, and then like the result, you can adjust it back.” until the right moment, which could adjust the power to get the precise Dr. Chu adds that apart from lim- take weeks, and potentially coming outcome you’re trying to achieve.” ited space inside the IOL, there’s no back to the offi ce multiple times to Dr. Chu says he’s not aware of any apparent limit to how many times a lock in the prescription. In contrast, limit to how much the refractive pow- lens can be changed or how far into the Perfect Lens technology doesn’t er can be changed. “The data so far the future changes can be made. “In require the patient to wear protec- suggests the system can make changes the lab they’ve switched refractive tive glasses. You simply implant your of 10 D or more,” he says. “You could power back and forth multiple times,” lens of choice and give it four to six

May 2018 | reviewofophthalmology.com | 13

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REVIEW Update

weeks to stabilize. Then, if the patient desires, you can perform—for lack of a better term—an enhancement to the IOL. The patient just goes about living life, and if you want to change the prescription next month, or six months from now, or 20 years from now, you can do it.” Dr. Chu says the company is gear- ing up to begin human trials in the United States. “I believe that will start this year at the University of Utah,” he says. “At the moment the technology is still in the prototype phase, but things are moving forward quickly. I believe any obstacles we encounter will be surmountable, because we’re using two familiar technologies: femtosecond lasers and IOLs. Marrying the two is an exciting prospect.”

A Small-aperture IOL

Most ophthalmologists are familiar with the KAMRA corneal inlay from SightLife Surgical (originally developed by AcuFocus), which works by using the pinhole effect—aka small- aperture optics—to alleviate distortion and expand depth-of-ﬁ eld. Acu- Focus has now created a monofocal intraocular lens that uses the same principle to achieve similar refractive results. The IC-8 IOL is a 6-mm-di- The IC-8 intraocular lens from AcuFocus uses the pinhole effect to extend depth-of-focus ameter one-piece hydrophobic acryl- dramatically and compensate for factors such as astigmatism, corneal aberrations and ic lens that incorporates a 3.23-mm failure to hit the intended post-surgical refractive target. doughnut-shaped opaque mask with a central 1.36-mm hole through which sign is based on the well-established cohort of patients, and work is being light can pass. (See picture, above small-aperture principle; it works by done to optimize this option for sur- right.) The lens is available in powers allowing only the central, focused geons and patients.” of 15.5 to 27.5 D in 0.5-D steps. It’s light to reach the retina, removing the Dr. Dick says a recent multi- implanted via a single-use injector blur caused by peripheral defocused center study of the small-aperture through a 3.2- to 3.5-mm incision. light. This results in the highest qual- IOL showed excellent visual perfor- “The IC-8 IOL is an aspheric mono- ity of vision over the broadest con- mance, safety, patient satisfaction focal IOL that has an opaque mini- tinuous range of any premium IOL and tolerance to residual astigma- ring embedded in it to extend depth- currently available. It provides up to tism six months after implantation. of-focus from near to far without gaps 3 D of range-of-vision with excellent “At six months, patients achieved, in vision,” says Dr. H. Burkhard Dick, visual quality, providing relief from on average, 20/16 for distance, 20/20 chairman of the University Eye Hos- presbyopia. Currently, the IC-8 IOL for intermediate and 20/25 for near pital in Bochum, Germany, and lead is implanted monocularly, usually in uncorrected visual acuity,” he says. investigator of the clinical trials in- the nondominant eye. Binocular im- “Outcomes can be further optimized volving the IC-8 IOL. “The lens de- plantation has been done in a small by achieving the refractive targets

14 | Review of Ophthalmology | May 2018

012_rp0518_tech.indd 14 4/12/18 1:14 PM of -0.75 D in the IC-8 IOL eye and has no infl uence on the effi cacy of the retinal exams, Dr. Dick says the im- plano in the companion eye. Ninety- IC-8 lens.” pact is minimal. “Despite the pos- six percent of the patients said they terior positioning of the IC-8 IOL, would have the surgery again.”1 fundus photography and angiogra- Dr. Dick points out that a lens based phy are entirely possible,” he says. on the small-aperture principle may Patients of any “Physicians treating patients with the have several advantages over multifo- age, regardless of early small-aperture IOL implants cal IOLs. “First, the IC-8 produces report few differences in retinal im- high quality, full-range vision without their work-lighting aging from the fellow eye implanted blurry zones,” he says. “Second, the conditions, can with a monofocal IOL. I myself have lens is very tolerant of refractive error performed retinal surgeries includ- misses. A deviation of more than 0.5 be considered as ing membrane peel, vitrectomy with D from the intended refractive target candidates for the indentation, air fl uid exchange, cryo- will result in a loss of one or two lines therapy and retinal lasering with suc- of vision with a typical monofocal or IC-8 implant.” cess. The presence of the mask does multifocal IOL; the IC-8 IOL will — H. Burkhard Dick, MD require surgeons to modify their tech- provide a reliable range of vision with nique, but visualization and stereopsis as much as a 1-D deviation from the are still good and procedures can be intended refractive target. In clinical performed without incident.” studies, 100 percent of patients receiv- A common concern with small- ing the IC-8 IOL maintained 20/40 or aperture optics is the possibility of The Omega Gemini Capsule better UDVA, even with a [postop- consequences caused by the re- erative] refractive error ranging from duced amount of light reaching the Another unique development relat- 0.50 to -1.50 D.2 Third, if the eye has retina. “Although the retina receives ing to intraocular lenses is the Gemini an irregular cornea, multifocality can less light due to the elimination of Refractive Capsule, from Omega. The result in poor quality of vision and se- peripheral rays, binocular contrast Gemini Refractive Capsule is a three- vere photic phenomena, among other sensitivity is equivalent to that of a dimensional device designed to be issues. The small-aperture design of monofocal IOL,” Dr. Dick says. “At implanted inside the capsular bag, the IC-8 IOL eliminates peripheral the 2017 European Society of Cata- holding the space open and allowing defocus and aberrated light, result- ract and Refractive Surgeons meet- controlled placement of a refractive ing in improved quality and range of ing, Pablo Artal, PhD, reported that lens—and potentially other items—at vision.” patients treated with a small-aper- a known distance relative to the front Dr. Dick adds another important ture implant over time adapt to the and back of the eye. benefit of the small-aperture op- reduced light and actually perceive The company notes that tradition- tics; the IC-8 compensates for up to there to be between 30 and 60 per- al cataract surgery has an inherent 1.25 D of corneal astigmatism, with cent more light than what is actually “Achilles heel:” A standard IOL is no effect on visual acuity. “This means reaching the retina. So, after a period about one-fifth the thickness of the the 82 percent of patients who pres- of adaptation, patients are unlikely to cataractous lens that’s being removed. ent for cataract surgery with less than notice the reduced light, unless they That makes it diffi cult or impossible 1.5 D of corneal astigmatism can en- compare the IC-8 eye directly to the to determine the final position of joy the benefit of astigmatism cor- fellow eye. Other research has shown the lens implant inside the eye. This rection without the risks associated that, over time, neuroadaptation pro- device is intended to eliminate that with toric IOLs,” he says. “Further- duces a stereoacuity effect similar to concern, while simultaneously creat- more, if astigmatism is induced dur- normal binocular vision, wherein the ing the possibility of other uses for ing surgery, the effects are mitigated dominant eye negates poor visual per- the intracapsular space. (The com- by the small-aperture optics. This also formance resulting from low light- pany notes that the device is associ- simplifi es the surgical process for the ing.3,4 Patients of any age, regardless ated with more than 40 patents issued surgeon, as there is no IOL axis to of their work-lighting conditions, can and pending in the United States and align and, as a result, no marking or be considered as candidates for the around the world.) intraoperative alignment equipment IC-8 implant.” “This device is designed to keep the needed to implant the lens. Addition- Asked whether the embedded ring capsular bag open, and it allows for ally, post-implantation IOL rotation might interfere with postoperative modularity,” explains John Berdahl,

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REVIEW Update

retinal periphery when it’s in position? “I don’t think that will be the case,” Dr. Berdahl says. “Even with a lens like the AcuFocus IC-8, you’re still able to see light from the peripheral retina because the lens is located near the nodal point. Furthermore, the capsule opacifies when it contracts around a traditional IOL, but that doesn’t obstruct the surgeon’s view. So any opacity that’s created by the peripheral frame of the Gemini Capsule is unlikely to affect our ability to see the peripheral retina.” Asked if he’s aware of any drawbacks to this technology, Dr. Berdahl says it’s too early to know if any will arise. (The device has been implanted in humans, but the company hasn’t initiated U.S. Food and Drug Admin- istration trials yet.) “Once we evaluate the implant in humans and see The Gemini Refractive Capsule from Omega is a three-dimensional device designed to be how predictable it is and how well it implanted inside the capsular bag, holding the space open and allowing controlled responds, we’ll know more,” he says. placement of a refractive lens at a known distance relative to the front and back of the eye. “The principles behind it are sound, Other items such as sensors and drug-delivery devices could also be placed in the Capsule. but we always learn things when we go into clinical trials. We’re excited to MD, a partner at Vance Thompson tinues. “One possibility would be an see what those data show.” The com- Vision in Sioux Falls, South Dakota, extra lens to alter the refractive re- pany notes that the design incorpo- and associate professor at the Univer- sult, whether that involves simply ad- rates tried-and-true optical principles sity of South Dakota. (Dr. Berdahl is justing the refraction or adding some and materials, which should minimize a consultant to Omega.) “It contains new multifocal technology that comes obstacles to FDA approval. tiny shelves designed to allow place- along in the future. Sensors of differ- Dr. Berdahl believes the future of ment of an IOL in a particular posi- ent types could also be placed inside cataract surgery and IOLs will be a tion relative to the cornea. The idea the capsule. That area is important conversation about the adjustability of is that because you’ll know exactly real estate that can allow us to gain lenses, rather than their upgradability where the Gemini Capsule is, you’ll a lot of insights into how the eye is and exchangeability. “It’s an exciting know exactly what the position of the functioning and how the body is func- time for IOLs because we’re doing lens is. Furthermore, you can later tioning. Drug-delivery devices could things to them after they’re placed move the lens to a different shelf if be placed there as well.” in the eye, in order to get better out- you need to. That should result in Obviously, the device is larger than a comes,” he says. “I think that’s where fewer postoperative enhancements, typical intraocular lens. “We deﬁ nitely things are heading.” as well as letting the surgeon alter want this to be able to go through a 1. Dick H, Piovella M, Vukich J, Vilupuru S, Lin L. Prospective the refraction in the future as the eye small incision,” notes Dr. Berdahl. multicenter trial of a small aperture intraocular lens in cataract ages, even if you nailed the refraction “That’s part of the reason the device surgery. J Cataract Refract Surg 2017;43:7:956-968. 2. Paley GL, Chuck RS, Tsai LM. Corneal-based surgical in the original surgery. In addition, the is modular; the two separate, ﬂ exible presbyopic therapies and their application in pseudophakic device is designed to work with intra- parts of the device will be inserted in patients. J Ophthalmol 2016;2016:5263870. operative aberrometry, so those kind two steps so you don’t have to put the 3. Fernandez EJ, Schwarz C, Prieto PM, Manzanera S, Artal P. Impact on stereo-acuity of two presbyopia correction approaches: of adjustments could be made while full volume of the device through the Monovision and small aperture inlay. Biomed Opt Express 2013; the patient is on the operating table. incision all at once.” 4:822-830. 4. Schwarz C, Manzanera S, Artal P. Binocular visual performance “The extra shelves could also be Given the size of the device, might with aberration correction as a function of light level. J Vision used to add other inserts,” he con- it obscure the surgeon’s view of the 2014;14;14;6.

16 | Review of Ophthalmology | May 2018

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RP0418_Keeler.indd 1 3/22/18 4:26 PM Trehalose & Eye Care

Trehalose & Eye Care A Molecule Poised to Revolutionize Ocular Surface Care By Marguerite McDonald, MD, FACS

cular surface disease and dry eye disease are prevalent and What is Trehalose? pervasive diseases impacting the eye health of patients. The Dry Eye Workshop II (DEWS II) and current research offer new Oinsights on the characteristics of pathophysiology of Dry Eye Disease (DED), as well as best practices for treatment and management. Therapeutic strategies that support the ocular surface, counteract hy- Trehalose—a bisacetal, non- perosmolarity and restore the tear fi lm can aid in rehabilitating the eye’s reducing homodisaccharide in structures. This knowledge offers an opportunity to introduce new ways to which two glucose units are linked together in a α-1,1-glycosidic stabilize the tear fi lm and improve patient comfort through rehydration, re- linkage (α-d-glucopyranosyl- duction of surface infl ammation, and protection against future dessication. α-d-glucopyranoside; mycose, An expanding pool of clinical data is supporting the benefi ts and sus- mushroom sugar)1—is found tained effi cacy of therapies that include bioprotectants such as trehalose abundantly in nature and in the biological world. The “extraordi- to protect cells against hyperosmolarity and promote exit of the vicious nary” properties of trehalose are cycle of DED physiopathology.1 responsible for this molecule’s As such, lubricant eye drops enhanced with trehalose can provide bioprotective role.1 1. Jain NK, Roy I. Effect of trehalose on protein patients with a new, successful way to rehabilitate the tear film in structure. Protein Sci. 2009 Jan;18(1):24-36. Ocular Surface Disease (OSD) and DED.

OSD & DED Prevalence From a pathophysiological stand- significant quality-of-life impacts. A & Impact point, DED ampliﬁ es hyperosmolarity number of studies have reported mea- The 2017 Gallup Study of Dry Eye in an unforgiving cycle either directly surable negative effects of DED on dai- (conducted by Multi-sponsor Surveys, or by inducing a cascade of inflam- ly-living tasks such as reading, carrying Inc.) revealed that 56% of adults re- matory events, contributing to a loss out professional tasks and driving. port experiencing dry eyes frequently of epithelial and goblet cells that de- (14%) or occasionally (42%).2 Projected creases surface wettability and pro- Insights on Addressing to the U.S. population, this translates motes early tear ﬁ lm breakup.3 the Problem to a staggering 140 million dry eye In addition to the physical toll this The Tear Film & Ocular Surface sufferers.2 disease takes on patients, it also has Society (TFOS) published the Dry Eye

Sponsored by 18 | REVIEW OF OPHTHALMOLOGY | MAY 2018

000_rp0518_theraMD_v4.indd 18 4/13/18 2:35 PM ADVERTORIAL

Trehalose – Enhancing junctiva, which may have suffered the Clinical Support as an Excipient sequelae of dry eye. for Trehalose New research shows that recent Studies have shown that trehalose offers Excipient—an inactive substance attempts to counteract tear hyper- the following ocular surface benefi ts: that serves as the vehicle or medium osmolarity in DED have included • Protection of human corneal epithelial for a drug or other active substance. It bioprotectant features and small or- cells from desiccation-induced death confers a therapeutic enhancement on ganic molecules used in many cell in culture.7 One trehalose-containing the active component in the form of, for types throughout the natural world to solution was found to be “effective example, additional absorption, solubility restore cell volume and stabilize pro- and safe” for treatment of moderate to or strength. tein function.1 These molecules may severe dry eye syndrome. directly protect cells against hyperos- • Increased tear fi lm thickness after Essentially, an excipient serves to molarity and promote exit from the vi- instillation of one trehalose-containing enhance the effectiveness of an active cious circle of DED physiopathology.1 drop up to 240 minutes compared with drops without trehalose.8 ingredient. There is an expanding pool of clinical • Better patient satisfaction and a data on the efficacy of DED thera- therapeutic advancement in treat- pies that include trehalose, whose ment of moderate to severe DED when Workshop II report, which includes unique properties have shown ex- comparing an eyedrop containing a more comprehensive DED defini- ceptional osmotic and bioprotectant hyaluronic acid-trehalose with an HA- tion that keenly accounts for the piv- abilities enabling them to act as a wa- only eyedrop.9 otal role that tear fi lm hyperosmolarity ter replacement and prevent against • Increased tear production at day 14 of plays, often resulting in ocular surface desiccation stress.1,4,5 treatment in a dry eye mouse model.10 inflammation. As well, DEWS II, an • Decreased eye surface apoptosis at evidence-based report involving 150 How Trehalose Works day 14 of treatment in a dry eye mouse worldwide experts, further illuminates Trehalose maintains cell protein model.10 the pathophysiology of dry eye and integrity during drying and rehydra- • Improved appearance of ocular surface its central mechanism of evaporative tion, and it has been shown to protect epithelial disorders through suppression water loss leading to hyperosmolar against oxidative strain and stabilize of apoptosis and serum-like response tissue damage.3 protein function.6 upon topical application, as well as 10 When it comes to DED treatment, The mechanism by which this mem- maintained corneal health. longstanding research advocates the ber of the polyhydroxyl compound • Suppressed infl ammatory and proteo- use of lubricating eye drops as a pal- molecules works is by increasing com- lytic MMP-9 and HSP70 expression and keratinization, and restored ocular liative technique for symptom relief pactness and stability in organisms, surface integrity in mice with dry eye to rehabilitate some of the eye struc- thereby aiding in the overcoming of damaged by a desiccative model.11 tures, such as the cornea and con- stress conditions such as heat, cold

Reawakening Dormant Desert Life

Anastatica hierochuntica or white mustard ﬂ ower, commonly called Rose of Jericho, is found in arid areas in the Middle East and the Sahara Desert.1 After the rainy season, the plant dries up, drops its leaves and curls its branches into a tight ball to hibernate. Once re-wetted in a subsequent rainy season, the ball uncurls and awakens from its dormant state, causing the capsular fruits to open and disperse seeds. The plant’s extraordinary ability to achieve this reawakening activity is attributed to the presence of trehalose, a disaccharide sugar involved in several mechanisms of cryptobiosis.2

1. Friedman J, Stein J. The Inﬂ uence of Seed-Dispersal Mechanisms on the Dispersion of Anastatica Hierochuntica (Cruciferae) in the Negev Desert, Israel. Journal of Ecology 1980;68(1):43-50. 2. Wickens GE. Ecophysiology of Economic Plants in Arid and Semi-Arid Lands HYDRATED 1st ed. Berlin, Germany: Springer-Verlag Heidelberg; 1998. DEHYDRATED

MAY 2018 | REVIEW OF OPHTHALMOLOGY | 19

000_rp0518_theraMD_v4.indd 19 4/13/18 2:29 PM Trehalose & Eye Care

Trehalose Use Trehalose helps retain moisture in the tear ﬁ lm when the in Dry Eye Disease patient is in a desiccating environment, thereby assisting in increas-

Trehalose has been shown to: ing tear fi lm thickness. It decreases future irritation by protecting 1. Rehydrate Tear Film corneal epithelial cells from apoptosis after desiccation. It also sup- • Retain moisture when drying out • Help increase tear fi lm thickness8 ports homeostasis of the tear fi lm by restoring osmotic balance to 2. Protect Against Future Irritation the ocular surface.”— Marguerite McDonald, MD, FACS • Help improve corneal staining7 • Help protect corneal epithelial cells from apoptosis after desiccation3,5 3. Support Homeostasis of Tear Film lubricant eye drops enhanced with I think that trehalose will increase • Restore osmotic balance trehalose. the efficacy of artificial tears in the to ocular surface10 With dry eye, trehalose helps re- treatment of dry eye. This unique • Help maintain homeostasis tain moisture in the tear fi lm when the disaccharide offers the bioprotec- of corneal cells10 patient is in a desiccating environ- tant benefi ts that lead to comfort and ment, thereby assisting in increasing maintenance of a stable tear film, tear fi lm thickness. It decreases future which yields better and more stable irritation by protecting corneal epi- vision. and desiccation.6 As a result, trehalose thelial cells from apoptosis after des- has the unique ability to stabilize pro- iccation. It also supports homeostasis Dr. McDonald practices at Ophthal- teins and the lipid bilayer.6 of the tear fi lm by restoring osmotic mic Consultants of Long Island, a Dry Remarkably, trehalose can also act balance to the ocular surface. Eye Center of Excellence in Lynbrook, as a water substitute. Classified as a The increased bioprotectant fea- New York. kosmotrope or water-structure maker, tures and enhancement of tear fi lm this molecule is involved in various bio- thickness contribute to greater pa- 1. Baudouin C, Aragona P, Messmer EM, et al. Role of hyperosmolarity in the pathogenesis and management of dry 6 protective actions. tient comfort and less fl uctuating vi- eye disease: proceedings of the OCEAN group meeting. Ocul sion—the end goal of any ocular sur- Surf. 2013 Oct;11(4):246-58. Future of Treatment face therapy. 2. The 2017 Gallup Study of Dry Eye Sufferers (conducted by Multi-sponsor Surveys, Inc.). New trehalose-containing solutions Clinicians should absolutely consider 3. Nelson JD, Craig, JP, Esen A, et al. TFOS DEWS II Report. Ocul are becoming available to help eye using these drops as a fi rst-line treat- Surf 2017; 2017 July;15(3):269-650. care professionals offer patients an al- ment against OSD and DED. Artifi cial 4. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017 Jul;15(3):575-628. ternative treatment and management tears are considered fi rst tier treatment 5. Matsuo T. Trehalose protects corneal epithelial cells from ® strategy. As one example, TheraTears for even the mildest of dry eyes, and death by drying. Br J Ophthalmol. 2001;85:610-2. is launching a new lubricant eye drop, continue to be a part of the treatment 6. Jain NK, Roy I. Effect of trehalose on protein structure. Protein TheraTears® EXTRA Dry Eye Therapy, algorithm for moderate and severe dry Sci. 2009 Jan;18(1):24-36. 7. Matsuo T, Tsuchida Y, Morimoto N. Trehalose eye drops in which contains trehalose as an excipi- eyes. the treatment of dry eye syndrome. Ophthalmology. 2002 ent, serving to enhance the action of For more advanced cases, eye care Nov;109(11):2024-9. the solution’s active ingredient, Car- professionals should consider using 8. Schmidl D, Schmetterer L, Witkowska KJ, et al. Tear fi lm thickness after treatment with artifi cial tears in patients with boxymethylcellulose (CMC). Doctors trehalose-containing lubricants in con- moderate dry eye disease. Cornea. 2015 Apr;34(4):421-6.s are excited about the potential of junction with a prescription medication. 9. Chiambaretta F, Doan S, Labetoulle M, et al. A randomized, controlled study of the effi cacy and safety of a new eyedrop formulation for moderate to severe dry eye syndrome. Eur J Ophthalmol. 2017 Jan 19;27(1):1-9. 10. Chen W, Zhang X, Liu M, et al. Trehalose protects against Trehalose Current and Future Uses ocular surface disorders in experimental murine dry eye through • Major industries: Food, cosmetics, medicine suppression of apoptosis. Exp Eye Res. 2009 Sep;89(3):311-8. 11. Li J, Roubeix C, Wang Y, et al. Therapeutic effi cacy of ® ® ® ® • An excipient in each of: Herceptin , Avastin , Lucentis and Advate trehalose eye drops for treatment of murine dry eye induced • Future applications: Solid dosage formulations, most notably in quick-dissolving tablets by an intelligently controlled environmental system. Mol Vis 2012;18:317-29.

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Trehalose is a natural disaccharide found in plants with moisture retention properties that help organisms survive in absence of water. In ophthalmic products, trehalose enhances active ingredients to help1: • Protect corneal cells from desiccation • Restore osmotic balance to the ocular surface • Maintain the homeostasis of corneal cells

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000_rp0518_theraMD_v4.indd 21 4/13/18 2:29 PM Refractive/Cataract

REVIEW Rundown Edited by Arturo Chayet, MD

Is LVC Possible In CVD Patients? Long considered an absolute contraindication, collagen vascular disease may not always be a bar for carefully selected patients. Kristine Brennan, Senior Associate Editor

ollagen vascular diseases comprise them a strong, but relative, contra- of patients with CVD,” Dr. Moshirfar Ca group of autoimmune diseases in indication in affected patients. At continues, citing a 2006 study that fol- which the body’s own immune system the time FDA approval studies were lowed 49 eyes that underwent LASIK attacks connective tissues, skin and or- done for LASIK and PRK, known in patients with conditions including gans. Examples include rheumatoid CVD patients were excluded and, as a SLE, RA and psoriatic arthritis over a arthritis, systemic lupus erythematosis, group, tended to present clinically as period spanning more than six years. Sjögren’s syndrome and scleroderma. more symptomatic than they do now. The authors concluded that LASIK While blanket prevalence estimates “There was a time when our patients could be safe for patients with autoim- are hard to come by, arthritis and rheu- with RA, for example, were not really mune diseases under good control. matic conditions present large public- controlled with any medication and “That was one study that helped make health challenges.1 So it stands to rea- were pretty sick, so they didn’t really it seem a little bit more acceptable for son that some patients looking for laser even ask for such refractive surger- these patients to undergo refractive corneal refractive surgery will have one ies,” Dr. Moshirfar recalls. surgery,” he says. (or more) of these conditions. Should “But as refractive surgery outcomes Dr. Moshirfar emphasizes that the you always turn them away? Below, and predictability became better literature on refractive cornea surgery an expert corneal refractive surgeon thanks to the increasing precision of in CVD remains “very skimpy,” how- shares his thoughts on balancing his equipment and lasers, people began ever, cautioning,“There’s no reason to duty to protect his patients with allow- asking themselves, ‘Now that the ﬂ aps get on a loudspeaker and offer LASIK ing a select few to have these proce- are better and we have better ways of to patients with lupus, for example. dures. doing things, why not try?’ ” he contin- We must not be cavalier about doing Until fairly recently, operating on ues, adding that rheumatologic treat- corneal refractive surgery on patients CVD patients was practically verbo- ments for CVD have also improved. with CVD.” ten, according to Majid Moshirfar, “Rheumatologists can now diagnose To be considered for these surger- MD, FACS, research director of the these patients at much younger ages, ies, Dr. Moshirfar has a list of criteria HDR Research Center and professor when they’re healthier. They can also patients must meet: of ophthalmology at the University of treat them with immunosuppressive • The treating rheumatologist Utah’s Moran Eye Center. The FDA’s and immune-modulating medications must be involved. CVD patients with original approval of LASIK designat- that were previously unavailable,” he good topographic maps, TBUT, stain- ed CVDs and autoimmune diseases as says. ing, and no sign of cataract formation absolute contraindications, although “I remember when Robert Malo- must also be in active treatment with a many surgeons currently consider ney co-wrote a paper2 about a group rheumatologist. “The ophthalmologist

22 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

022_rp0518_rcr.indd 22 4/12/18 11:27 AM SAVE THESE DATES 3RD YEAR RESIDENTS CONTINUING SPECIALIZED EDUCATION 3RD YEAR RESIDENT PROGRAMS & WET LAB

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REVIEW Surgery Majid Moshirfar, MD, FACS needs an offi cial document from the them LASIK. But what about SMILE? rheumatologist acknowledging that the When you do LASIK on these patients, patient wants to undergo surgery. You you’re cutting the corneal nerves and need a new rheumatologic examina- creating a neurotrophic keratopathy, tion and a new titer of serologic testing. and they may not heal as well as oth- The rheumatologist needs to certify er patients. Maybe SMILE would be that the patient hasn’t had a relapse of better because instead of creating a any systemic problems in their body 270-degree incision all the way around, or joints in the last 18 months, in my you’re just making a little 30-degree opinion,” says Dr. Moshirfar. Keratoconjunctivitis sicca due to Sjogren’s incision superiorly underneath the • Find out why the patient wants syndrome. Although select CVD patients eyelid, possibly reducing the risk of a LVC—and give strong warnings. may be able to safely undergo LVC, SS may problem,” he says. “Once patients meet the medical con- remain strongly contraindicated. • Treat topically and systemi- ditions, you as a physician need to fi nd cally. “If you proceed with any laser out why the patient is looking for sur- • Choose the procedure wisely. vision correction, you’ll have to ag- gery,” says Dr. Moshirfar. “Are they Dr. Moshirfar prefers LASIK to PRK gressively optimize the corneal sur- contact-lens intolerant? If not, that for these patients, and it appears he’s face. Studies suggest that if you put makes things somewhat more promis- not alone. On the question of whether these patients on cyclosporine, you ing; but if they are becoming contact- to perform LASIK or PRK on patients improve the nerve-growth factors,” lens intolerant, then you need to really with CVD, A 2014 review of the litera- says Dr. Moshirfar. “You basically do dwell on the question of whether or ture on laser vision correction in CVD the surgery on several weeks of prior not to do this surgery. and other conditions led the authors, cyclosporine. After surgery, if these “Do not be cavalier in making rec- from the Wilmer Eye Institute, to patients become a lot drier than ex- ommendations,” he warns. “These pro- lean towards LASIK over PRK due to pected, that’s when you need to be cedures are still a strong relative con- LASIK’s faster healing time in corneas aggressive. You basically throw every- traindication in these patients. I always with potentially compromised epithe- thing but the kitchen sink at them: I tell them, ‘You may go blind. You may lial cells, and LASIK’s relatively lower think that these patients respond really develop corneal melt. You may need risk of stromal haze and scarring in well to tacrolimus 0.03% or 0.01%. I a corneal transplant. Your life may these eyes.3 sometimes also put these patients on change as a result of this.’ I say that to “I think PRK carries a higher risk of 5% albumin. I also think blood serum all my patients—and most definitely stromal reactions, melt, thinning and has a role, but not at 20%—more like to patients in this category.” After this necrosis of the keratocytes. In LASIK, 50%—for these patients. Plug them, conversation, Dr. Moshirfar sends pa- the boundary of the epithelium is not and use both oil-based and aqueous tients home for further deliberation. insulted as much,” he says. “With PRK artifi cial tears. If we don’t respect the “I tell patients to go home and talk you’ve taken the epithelium and Bow- integrity of the epithelium within the with family, and to really think about it man’s layer off; for six or seven days, fi rst eight to nine weeks postop, these before calling us back,” he says. “Don’t the stroma is exposed, even though patients will defi nitely regress and be- let patients make the decision on the you place a bandage contact lens. I’m come more myopic, and they will not spot right after you’ve talked to them.” not saying you can never do PRK on only have very bad UCDVA; they will • Enhance your informed con- a patient with RA, but if I ever had to also have very poor best-corrected vi- sent. A key element of Dr. Moshirfar’s do a refractive procedure on a patient sion,” he emphasizes. due diligence is customized informed- with well-controlled RA, I’d prefer to Increased risk of corneal melt means consent language. “I write into the in- do SMILE or LASIK.” that topical NSAIDS need to be used formed consent that the laser that we’re Although he hasn’t performed judiciously, if at all. Signs of melt should going to use is not FDA-approved for SMILE on any CVD patients, Dr. prompt a call to the rheumatologist to patients with autoimmune diseases; Moshirfar has on patients with sub- discuss doubling up on immunosup- that we have very limited literature, clinical dryness on the ocular surface; pressant drugs, says Dr. Moshirfar. “If and that we currently don’t know what patients with lagophthalmos; and Bell’s they develop a fl ap-edge necrosis and the long-term results will be. Then I palsy patients. “There are patients who start to have actual melts, you need sign it and have the patient countersign will walk into our offi ces with Sjögren’s to topically and systemically ramp up it. This is an addendum to the standard syndrome, RA, and SLE, and we’ll everything,” he says. “You most likely informed consent,” he says. likely decide that we don’t want to give need to talk with the rheumatologist

24 | Review of Ophthalmology | May 2018

022_rp0518_rcr.indd 24 4/12/18 11:29 AM SLIT LAMPS

and increase the dosages of the ex- CVD with no history of ocular involve- NEW LED isting immunosuppressants. Working ment; no systemic multidrug regimen; with the rheumatologist, add another a minimum of six months without Illumination medicine to the existing medications. symptom fl are; clearance from a treat- Let’s say they’re on methotrexate; add ing rheumatologist and/or uveitis spe- Cellcept to it. If they’re on Cellcept, cialist; normal preop testing, including More than 50,000 add valproic acid. Also immediately Schirmer’s and TBUT; and informed hours of clear, cool put them on oral prednisone, usually consent regarding the off-label nature illumination. 1 to 5 mg/kg/day, for anywhere from of LASIK and PRK for them, may two to 10 weeks. The systemic steroid be suitable candidates.3 The authors is important in the acute phase of ex- also recommended that patients have acerbation.” negative serology for Sjögren’s, and Amped-up immunosuppression concluded that a large, multicenter, can create additional risks, however, controlled trial should take place ex- including postop herpes. “These pa- amining the safety and effi cacy of LRS tients are at risk for viral keratitis and for patients with CVD and other sys- bacterial infections, especially during temic diseases. A 2016 retrospective the acute phase, specifi cally because case series looking at a larger popula- they’re immunosuppressed. In doing tion of patients with CVDs (622 pa- LASIK on these patients, I haven’t tients; 1,224 eyes) led the authors to had a case like that, probably because conclude that excimer laser refractive

they’re on steroids for a short interval. surgery could be safely performed on But I’ve had patients referred to me patients with well-controlled disease, who were on long-term topical ste- although they recommended against roid drops, and they can run into prob- it for Sjögren’s patients or patients lems,” says Dr. Moshirfar. with keratoconjunctivitis sicca.4 The Dr. Moshirfar has also seen on refer- authors also acknowledged the study’s ral the results of ill-advised laser cor- retrospective nature as a limitation. neal refractive surgery. “Unfortunately, Dr. Moshirfar says that LVC patients I’ve encountered that,” he says. “The with CVDs and other autoimmune patient had scleroderma, which in my diseases are not as uncommon as opinion is an absolute contraindica- one might think, and agrees that they tion to corneal refractive surgery. This merit more study. “We all have a few patient had defi nite scleroderma fi nd- such patients that have undergone ings that you could see even without surgery, and some are 10 or 15 years a workup. In cases like this, you need out,” he says. “If you talk with a to use contact lenses; sometimes you group of surgeons, you’ll hear, ‘Yeah, have to use therapeutic bandage con- I have patients like that.’ We need to tact lenses. The patient may even need collect more data in order to help the to be fi tted long-term with the PROSE literature advance.” Easier observation of contact lens (BostonSight; Needham, minute details. Massachusetts).” Dr. Moshirfar reports no relevant

ﬁ nancial interests. Color temperature The Unknowns Persist 1. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the maintained through the full prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 2008;58:1:15-25. range of illumination The only consensus on corneal re- 2. Smith RJ, Maloney RK. Laser in situ keratomileusis in patients fractive surgery in CVD appears to with autoimmune diseases. J Cat Refract Surg 2006;32:1292-5. adjustment. 3. AlKharashi M, Bower KS, Stark WJ, Daoud YJ. Refractive be that the research must evolve. The surgery in systemic and autoimmune disease. Middle East Afr review of the literature conducted by Ophthalmol 2014;21:1:18-24. 4. Schallhorn JM, Schallhorn SC, Hettinger KA, Venter JA, et al. researchers at the Wilmer Eye In- Outcomes and complications of excimer laser surgery in patients stitute led them to conclude that pa- with collagen vascular and other immune-mediated inﬂ ammatory diseases. J Cat Refract Surg 2016;42:1742-52. tients with mild and well-controlled 250 Cooper Ave., Suite 100 Tonawanda NY 14150 www.s4optik.com I 888-224-6012 Sensible equipment. Well made, well priced.

022_rp0518_rcr.indd 25 4/12/18 11:29 AM IOL Calculation REVIEW Cover Focus Planning for the Best Outcomes

Kristine Brennan, Senior Associate Editor

Do more than just hat happens when patients K’s break down. Number two, the who’ve demonstrated assumptions used by IOL calcula- hope for them with Wthe willingness to pursue tion formulas to calculate effective spectacle independence through lens position break down, because intelligent cataract laser refractive surgery develop the determined keratometry no lon- cataracts? Can they realistically ex- ger reﬂ ects the shape of the anterior surgery planning pect excellent visual outcomes with chamber.” IOLs? According to surgeons, the “In these eyes, we are making as- for post-refractive answer is a qualified “yes.” Here, sumptions about the relationship they share their pointers for yield- between the curvature of the an- eyes. ing the best possible results with terior and posterior corneal sur- these tricky eyes. face—a relationship that is different Two things happen with laser once you alter the anterior surface refractive surgery, says Daniel H. of the cornea,” concurs Elizabeth Chang, MD, of Empire Eye and Yeu, MD, partner at Virginia Eye Laser Center in Bakersﬁ eld, Cali- Consultants and an assistant pro- fornia. “Number one, the ratio of fessor at Eastern Virginia Medical the anterior and posterior corneal School in Norfolk. “The bigger pic- curvature changes, so assumptions ture is that if you don’t adjust your used by keratometers to measure preop planning, you’ll end up with Elizabeth Yeu,MD

Corneal topography of a post myopic LASIK eye shows irregular astigmatism within the central cornea and a high degree of coma. Such an eye is a poor candidate for an EDOF lens, and may be better suited to a monofocal IOL.

26 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

026_rp0518_f1.indd 26 4/12/18 1:28 PM SLIT LAMPS

hyperopic outcomes in your post- in both eyes,” she says. “The post- SEE MORE - myopic LASIK patients and myopic operative refractive results can lend outcomes in your post-hyperopic insight to the second-eye planning. Exceptional LASIK patients,” she says. “Accurate keratometry is one of Another thing that makes these the core pieces to really reﬁ ne your Optics eyes challenging when it’s time for outcomes to be within a half- or cataract surgery is the fact that la- quarter-diopter spherical equiva- S4OPTIK’s ser ablative techniques and their lent of your prediction error,” Dr. effects have changed over time. Yeu continues. She uses an Atlas converging “Not all post-refractive eyes are topographer (Carl Zeiss Meditec; binoculars the same,” says Michael Lawless, Jena, Germany) as her primary to- MBBS, FRANZCO, of Vision Eye pographer in post-refractive eyes. DOORZHƪRUWOHVV Institute, Chatswood, New South “With the Atlas specifically, you maintenance of Wales, and a clinical associate pro- can enter the central 4 mm zone fusion. fessor at Sydney Medical School in into the ASCRS post-refractive Australia. “Some patients come in calculator,” she says. “We also get having had PRK or LASIK for high extra diagnostic information for myopia in the 1990s, for example. post-refractive eyes.” In addition European These eyes have a large amount of to collecting more data with the induced spherical aberration and Cassini corneal shape analyzer craftsmanship and are often very long in terms of axial (Cassini Technologies; The Hague, engineering provide length. They also commonly have The Netherlands) and the Lenstar reliable optics at some induced irregular corneal (Haag-Streit; Keoniz, Switzerland) astigmatism, a reﬂ ection of the laser for these patients, she also uses an- DOOPDJQLƬFDWLRQV technology, lack of tracking, etc., terior segment OCT. IRUFRQƬGHQW from that period,” he says. Dr. Chang starts by trying to as- examinations. sess how important spectacle inde- Measure for Success pendence is to patients, plus their satisfaction with the prior refractive Although there’s not a single, surgery. “I like to ask them how perfect way to work up a post-re- happy they had been with their fractive eye for cataract surgery, vision after the initial refractive thoroughness on each step of the surgery. Sometimes, mostly with process is important. “You should RK, but often with commercial

do your best preop. Each step in- LASIK and PRK as well, they’ll H-Series Z-Series creases your chance of getting it say, ‘You know, it was never quite right,” says Dr. Chang. right.’ These patients should be ap- Dr. Yeu, whose practice has surgi- proached with caution, since some cal counselors on staff, always starts factor such as irregularity, decen- with the nondominant eye in post- tration or the like may continue to refractive patients. “The reason for affect their quality of vision after that is that if you have similar axial cataract surgery as well. However, lengths and similar ﬂ at Ks in a post- if they say, ‘It was great, but then myopic patient, for example, the it recently got worse,’ then you can response to the first-eye surgery, assume the cataract made vision in terms of residual refractive er- worse, so cataract surgery will help Vertical and compact ror, can truly help guide what you them,” he says. He adds that this FRQƬJXUDWLRQVDYDLODEOH need to do with the second eye. line of questioning also helps alert This is even more important than him to hard-to-please personality in a naïve cornea. These patients in types. “If they were big complainers particular have average Ks of around after their ﬁ rst surgery, then there’s

38.5 and axial lengths of about 26 mm a good chance they’ll be complain- 250 Cooper Ave., Suite 100 Tonawanda NY 14150 www.s4optik.com I 888-224-6012 Sensible equipment. Well made, well priced.

026_rp0518_f1.indd 27 4/12/18 1:28 PM Cover IOL Calculation

REVIEW Focus

Even though the ASCRS calculator has ﬁ elds for historical data regarding prior refractive surgery, many surgeons enter current measurements from placido disc and Scheimpﬂ ug topography systems to get suggested IOL powers for their post-refractive patients.

ing after this surgery as well. intraoperative aberrometery in his 2017, is a new option that may help “On exam, I look at the quality measurements. “These eyes are hard mitigate some of the variability in and condition of the cornea, assess- to get right, and benefit from in- visual outcomes that can plague ing the quality of the optical zone traoperative aberrometry,” he says. these eyes after cataract surgery. and any possible incisions (e.g., “They may also benefi t from IOLs “There are two ways of approach- LASIK fl ap or RK incisions) that are that can be manipulated postop to ing the problem of post-refractive present,” continues Dr. Chang, who refi ne a residual refractive error.” eyes,” says Dr. Chang. “Number gets placido disk topography with one is to make better calculations an Atlas. “The topography tells me Selecting IOLs and measurements. Number two is two things: number one is whether to make better implants. You could they’ve had a myopic or hyperopic Patients with prior refractive sur- use lenses with some refractive for- refractive procedure. Number two gery can choose from a variety of giveness, or the Light-Adjustable is the size, centration, and degree of IOL types. The Light-Adjustable Lens, where you don’t have to hit the previous treatment zone.” Lens (RxSight; Aliso Viejo, Califor- the target, but can instead lock Like Dr. Yeu, Dr. Lawless includes nia), approved by the FDA in late them in later. In my experience,

28 | Review of Ophthalmology | May 2018

026_rp0518_f1.indd 28 4/12/18 1:29 PM it’s always better to hit the target, real option for post-refractive eyes. achieved distance visual acuity and however.” “I never used to actually consider refractive results equivalent to post- Although Dr. Lawless also says a diffractive multifocal or diffrac- LASIK eyes implanted with Alcon’s that light-adjustable lenses may tive-optic IOL for post-refractive Acrysof SN60WF monofocal IOL, merit consideration in surgical patients seeking spectacle indepen- while also achieving very good inter- planning for post-refractive eyes, dence and a range of vision. But mediate and good near vision. Only he notes that he can get excellent now, patients who have nice, well- 4/44 eyes studied from both groups results without them. “By paying centered ablations and who do not had a spherical equivalent refrac- attention to everything and opti- have astigmatism do very nicely us- tive error >0.5 D from the intended mizing the ocular surface, I expect ing the EDOF lenses, in my experi- refractive target; all of these had a to be within +/- 0.5 D for both ence. The pseudoaccommodating history of hyperopic LASIK. sphere and cylinder 90 percent of platform, such as the Crystalens or Dr. Chang notes that gaining the time. So it’s hard to justify us- Trulign (both Bausch + Lomb; Roch- some refractive forgiveness with an ing an IOL that can be manipulated ester, New York), is also an option in EDOF is not as simple as aiming postop in fewer than 10 percent of all post-refractive eyes with good vi- for plano and implanting the lens, eyes, especially when any errors sion potential, although I have much however. “With the Symfony, you can readily be treated with a small more experience with the EDOF actually have to target a little bit amount of PRK,” he says. IOL platform,” she says. hyperopic to gain the EDOF advan- Dr. Chang finds that extended tage,” he says. “This EDOF lens has depth-of-focus lenses are suitable a better depth of focus only on the for some of his post corneal refrac- “I tell post-refractive myopic side of the defocus curve. tive surgery patients, and may offer Therefore, to maintain good visual better visual range than monofo- patients that whatever quality at optical infi nity, you actu- cals. “With EDOFs, theoretically, I do, there’s going to ally have to aim a little positive to you can get better-quality vision gain that advantage. Consequently, through a range of refractive be a higher chance the sacrifi ce involved is to the read- change, but I don’t promise that of being off, and a ing, or near vision, but in return to patients, because as a practical I have the ability to give patients matter it’s diffi cult to achieve.” higher chance of with corneal aberrations a higher Dr. Yeu says that EDOFs can enhancement. You potential of getting great distance work well for patients who are in- vision without correction. In these terested in crisp distance vision and should essentially be patients, I’ll take a Symfony and aim willing to consider fi ne-tuning their prepping your patient for +0.5 D. The main goal is uncor- refractive outcomes postop. While rected distance vision, and as long EDOF IOLs can be successfully im- for that because of the as you tell patients this in advance, planted in post-refractive eyes, cor- increased variability they’ll be happy. If they do get some neal topography is vital to this deter- good near vision, that’s great: But if mination. “If patients are looking for in outcomes with these not, they’re already primed in terms distance vision with EDOF lenses, eyes. I think that’s of their expectations,” he explains. they should have a well-centered For post-refractive patients who ablation zone with no evidence of important.” aren’t good candidates for premium irregular astigmatism. If they go —Daniel Chang, MD IOLs, Dr. Yeu selects the sphericity with a refractive package like this in of monofocals with care. “In general our practice, then postop enhance- if there’s any question at all, I’m us- ments—for which these eyes are at ing zero-sphericity monofocal IOLs. higher risk—are performed after Another viable option for these pa- This helps to at least avoid adding postoperative month two or three at tients appears to be low-add diffrac- any further aberrations. When you no additional charge,” she says. tive multifocal IOLs. In a small retro- look at the higher-order aberrations She adds that improved lens of- spective chart-review study1 partially profi le, while there is a signifi cant ferings, together with thorough funded by Alcon, post-LASIK eyes range, on average, fl attened corneas preoperative workups, have helped implanted with the Acrysof IQ have a greater amount of positive make presbyopia-correcting lenses a ReSTOR +2.5 (Alcon Laboratories) spherical aberration. So you could

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REVIEW Focus Arun Gulani, MD go with either a zero-sphericity lens, or with a negative-spherical-aberration lens. For a more prolate hyperopic-LASIK eye, which has greater amounts of negative spherical aberration in the cornea, zero-sphericity IOLs are great: You wouldn’t want to use a negative-spherical-aberration lens, like a lot of the today’s aspheric monofocals. You actually want to use a zero-sphericity IOL, or an older, positive-spherical-aberration lens for these patients to neutralize what’s going on with the cornea,” she says. Dr. Yeu and colleagues conducted a prospective study that showed a positive correlation between higher-order aberrations and depth of focus in eyes with prior myopic or hyperopic Patients with prior RK should be counseled to expect a hyperopic outcome in the early PRK and LASIK. That study postoperative days due to the RK’s fl attening effect on the cornea. Refractive stability should also infl uenced her practice pat- settle in at close to plano at around six weeks post cataract surgery, surgeons say. terns when choosing the sphericity of IOLs for post-refractive the fi rst 4 mm of placido disk rings Dr. Lawless, who with colleagues eyes.2 from the Atlas into the ASCRS post- conducted a review of refractive re- refractive calculator really helps to sults of known IOL formulas for Calculating Lens Power zero in on the lens calculations.” post-refractive eyes,3 says that the Dr. Chang also uses the ASCRS Barrett True K most consistently When it’s time to calculate sug- calculator for these eyes. “I put my produces refractive outcomes close gested lens powers, the ASCRS IOL topography data into the ASCRS to emmetropia in post-refractive Calculator (iolcalc.ascrs.org) and the calculator,” he says. “It prints out eyes. “We have internal data on a Barrett True K formula are valued one page with all the potential for- large number of eyes to satisfy us resources for post-refractive eyes. mulas applicable to my biometry, that this is the best formula,” he “I’m really grateful for the contribu- topography and imaging data, and says. The Asia Pacifi c Association of tions of Doug Koch and Li Wang provides suggested IOL powers. It’s Cataract and Refractive Surgeons and Graham Barrett,” Dr. Yeu says. a really nice resource. You can click (www.apacrs.org) advances the Bar- “It’s been further refi ned over time, myopic or hyperopic laser vision rett True K for IOL power calcula- especially with greater input utiliz- correction, punch in your name, tions in post-refractive eyes. ing Galilei information and anterior your patient name, some basic in- “Between the Barrett True K and segment OCT. In my experience, formation, plug in all the biometric the ASCRS post-refractive calcula- my results validate what we see in measurements you have, and it spits tor, enhancements are, fortunately, the literature: The information that out the IOL numbers. The way I see few and far between,” says Dr. Yeu, you get with the calculator for the it, the more formulas you compare, who offers this pearl when entering suggested lens powers is even more the better, and the calculator makes data from post-refractive eyes into accurate than just having the histori- that easy.” the ASCRS calculator: “For post- cal method, where you begin with One recent update in the ASCRS refractive eyes, when you’re putting the original surgical data. So we use calculator involves the addition of data into the ASCRS post-refractive the ASCRS Calculator, plus the Bar- the Barrett True K formula for myo- calculator, don’t use the ‘optimize rett True K formula, on everybody. pic and hyperopic LASIK and PRK, axial length’ adjustment. You want Inputting the concentric mires of as well as eyes with a history of RK. to put the patient’s original axial

30 | Review of Ophthalmology | May 2018

026_rp0518_f1.indd 30 4/12/18 1:29 PM length into the calculator,” she says, more accurate power calculations Educating Your Patients because optimizing would produce without it.” myopic results. “Two weeks post- Dr. Chang agrees that K values For all the advancements in IOL operatively, if the patient still ends collected during the preop workup selection, measurement and power up being a little bit more myopic for cataract surgery are a more reli- calculation for post-refractive eyes, than you expected, you can some- able basis for lens calculation than visual outcomes are still more subject times use that information to guide those from some prior refractive to variability than in virgin corneas.2 you with regard to what IOL option surgery would be. “Previous refrac- “The most important thing is not you’re going to use in the second tive surgery data is not any better to over-promise,” says Dr. Chang. eye, if that patient’s preop ocular than any of the current measure- “I tell post-refractive patients that keratometry and axial lengths were ment and IOL calculation formu- whatever I do, there’s going to be similar.” a higher chance of being off, and Dr. Yeu’s second pearl is that a higher chance of needing an en- post-refractive eye data entered hancement. You should essentially into the calculator should yield sug- “In post-RK eyes, be prepping your patient for that gested IOL powers within a specifi c because of the increased variability range—and if not, it should alert they’ll have a in outcome with these eyes. I think you that something is probably off. hyperopic outcome for that’s important.” “Generally speaking, you’ll be get- Dr. Yeu says that her practice’s ting IOL numbers that are going about the fi rst three clinical counselors initiate that im- to be average because they’re post- to six weeks. It’s just portant conversation with post-re- refractive,” she says. “So the IOL- fractive patients. “They discuss the power numbers should be some- the effect of the RK fact that our outcomes, while they’re where in the range of about 19 to wounds. So they start very good, are not as accurate as 24. If they’re not, then I always go those calculated for a naïve cornea back and look at the information off a little hyperopic in an average eye, because of the to see why they may not be in that and you expect that. In changes to the cornea induced by average-power range. Sometimes the prior surgery. So these patients it’s because they’ve regressed over a post-RK eye, on day are advised that they’re at a slightly time; or they may have evidence of one, that conversation higher risk of requiring a touch-up ectasia or something else going on. to get them to the uncorrected vi- But in general, these eyes should needs to be had.” sion that they’re looking for, or that have average IOL powers popping —Elizabeth Yeu, MD they’re at higher risk of needing up in the calculator as recommenda- glasses for all ranges of vision,” she tions.” says. Dr. Yeu adds that one subcategory Making History Optional las,” he says. “The general thinking of post-refractive eyes calls for extra is moving away from using historical patient education, since the early Dr. Yeu and Dr. Chang both say data, which is nice. I think one big postop refractive outcome is off as a that current preoperative measure- factor is that pre-LASIK Ks were matter of course. “In post-RK eyes, ment and IOL power calculation probably just sim Ks measured to they’ll have a hyperopic outcome for techniques for post-refractive eyes guide the laser ablation and were about the fi rst three to six weeks,” yield excellent results without data never meant to be used for IOL she says. “It’s just the effect of the from prior refractive procedures. calculations. Therefore, there’s no RK wounds. So they start off a little “Five-plus years ago, I really harped real benefi t to having prior surgical hyperopic and you expect that. In a on trying to fi nd the historical data data. I like to keep things simple. post-RK eye, on day one, that conver- if I could,” Dr. Yeu recalls. “But as If you do more work getting prior sation needs to be had. I usually tend it turns out, we often aren’t able to data, it doesn’t hurt to look at it. But to wait about six weeks in between get that historical data, and in my we don’t track prior data, and we eyes for those patients because it clinical experience, using the calcu- haven’t tracked it for years. Most takes a little bit longer for their fi nal lator and having good K-value input people don’t have it and it’s hard to refractive outcome to settle in. I al- from multiple devices actually gives get.” ways caution them, ‘Your vision will

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REVIEW Focus

The Barrett True K formula for eyes with a prior history of LASIK or PRK has found favor with ophthalmologists tasked with planning cataract surgery. The Asia Paciﬁ c Association of Cataract and Refractive Surgeons provides a calculator at www.apacrs.org.

be blurred at ﬁ rst.’ If they end up at selected group of people who’ve Alcon. Dr. Yeu reports that she has around +2 to start with, that’s exactly already demonstrated a desire for consulted for Bausch + Lomb, Al- where I want them to be, because at spectacle independence and good con and Johnson & Johnson Vision. week six, they’ll end up being close vision. “Someone who’s had previ- Dr. Chang has consulted with Carl to plano. On the other hand, if they ous refractive surgery has obviously Zeiss Meditec on the IOLMaster and end up plano and 20/25 on day one, demonstrated a desire for spectacle IOLMaster 700, and with Johnson and they’ve got an eight-cut RK or independence at some point in his or & Johnson Vision for products re- more, then by week six they’re go- her life. You have to consider that,” lated to cataract, including the Sym- ing to end up being myopic. It’s just says Dr. Chang of cataract surgery fony IOL and multifocal IOLs. because of the hyperopic flatten- planning for post-refractive eyes. 1. Fisher B, Potvin R. Clinical outcomes with distance- ing effect of the RK wounds, even By enhancing your already-careful dominant multifocal and monofocal intraocular lenses in when you don’t see any clinically preop workup by collecting some post-LASIK cataract surgery planned using an intraoperative aberrometer. Clin Exp Ophthalmol. 2018 Jan 23. doi: evident corneal edema. They can extra measurements, and carefully 10.1111/ceo.13153. [Epub ahead of print]. Accessed 2 April have a pristine-looking cornea on weighing your patients’ suitability 2018. 2. Yeu E, Wang L, Koch DD. The effect of corneal wavefront day one; it’s just a side effect of hav- for premium IOLs, you can get the aberrations on corneal pseudoaccommodation. Amer J ing the RK wounds. These are the odds of good outcomes for these Ophthalmol 2012;153:972-81. 3. Hodge C, McAlinden C, Lawless M, Chan C, Sutton G, trickiest post-refractive eyes to deal eyes ﬁ rmly on your side. Martin A. Intraocular lens power calculation following laser with,” she says. refractive surgery. Eye and Vision 2015;2;7: https://doi.org/10.1186/s40662-015-0017-3. Accessed Post-refractive patients are a self- Dr. Lawless is a consultant for February 3, 2018.

32 | Review of Ophthalmology | May 2018

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2018_opg_ad_fullpge_rp.indd 1 3/27/18 4:28 PM YAG Capsulotomy REVIEW Cover Focus PCO: What’s Wrong With Doing a YAG?

By Leslie Sabbagh, Contributing Editor

A lot of effort is y most accounts, it’s one of square edges and were followed-up the most common and trusted at 90,120 and 150 days, and then six being devoted to Bprocedures in ophthalmology, months and one year post-Nd:YAG with a long track record. Cataract sur- capsulotomy. Some were followed out avoiding PCO, but geons have banked on its effi cacy and to 10 years (2003 to 2013). He found reliability for decades. the conventionally cited 1 to 2 percent some surgeons So why are some experts re- RD rate “overstates the truth ... the thinking the risk/benefit ratio of rate is substantially lower, between 0.5 say a YAG isn’t Neodymium:YAG (Nd:YAG) laser and 1 percent.”1 capsulotomy for posterior capsule The incidence of retinal detach- that bad. opacification after phacoemulsifica- ment was 0.87 percent at fi ve months tion and intraocular lens implanta- post Nd:YAG; the rate of retinal tears tion? Controversy swirls around old after Nd:YAG capsulotomy at five vs. new data, long-term side effects, months was 0.29 percent. The fi nd- and the true rate of retinal and other ings suggest that RD risk is highest in complications. Here, surgeons weigh the fi rst fi ve months post-procedure. in on the topic. Dr. Rudnisky says that when RD occurs two years post-Nd:YAG it would Old Data vs. New Techniques be hard to prove the YAG caused it. Older surgical and YAG capsulot- The risk of causing retinal detach- omy techniques and older implant ment is the first factor cataract sur- technology may account for the dis- geons cite when debating the need crepancy between “what the text- for a posterior capsulotomy. And even books and literature said and what we though the conventionally accepted saw in practice. I tell patients the risk incidence of 1 to 2 percent is low, the is about one in 200 or 0.5%,” he says. reality may be much lower, according “Even though our paper shows that to research1 conducted by Christo- the incidence of retinal detachment pher Rudnisky, MD, a professor at the is lower than what we thought, it’s still University of Alberta in Edmonton, not zero. It’s a life-changing event for Canada. the patient who develops one.” Dr. Rudnisky evaluated the inci- Michael Snyder, MD, associate pro- dence of RD from an administrative fessor of ophthalmology at the Univer- dataset of patients from all age groups sity of Cincinnati, is somewhat skep- who received foldable implants with tical that the YAG causes most RDs

34 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

0034_rp0518_f2.indd34_rp0518_f2.indd 3434 44/12/18/12/18 12:3512:35 PMPM after capsulotomy. “Rather, PCO,” he says. “At two years, coincidence with the natu- that rate is low single digits.” ral history of retinal detach- Dr. Koch puts the rate of ment plays a bigger role PCO development at ﬁ ve to than stresses induced at the seven years postop at “prob-

time of capsulotomy,” he FOPS CRA, James Gilman, ably 75 percent, even with says. Dr. Snyder acknowl- contemporary square-edged edges that the YAG proce- IOLs. I tell my patients most dure is “a cost and an incon- will get this between two and venience, and access to care four years postop.” can be a problem in some So, despite initial low PCO rural communities, but it re- rates reported at three years mains a good solution.” postop with high-quality hy- Many surgeons agree drophobic acrylic IOLs with the 1 to 2 percent RD rate Polishing techniques, chemical treatments and other types of true sharp edges and slim following Nd:YAG capsu- lasers have been tried in the war against PCO. haptic-optic junctions, “PCO lotomy may not be repre- rates at five and eight years sentative of today’s clinical practice. to eliminate PCO,” Dr. Koch says. may still increase sharply,” according to Among them is Eric Donnenfeld, MD, Opinions also differ as to the actual Rupert Menapace, MD, PhD, FEBO, clinical professor of ophthalmology at incidence of PCO over time. Most a professor at the Medical University New York University. “This rate is of- surgeons agree, however, that early of Vienna. He notes this delayed “bar- ten questioned as being too high,” he or later onset is correlated with IOL rier failure” is caused by Soemmering´s notes. However, some sub-populations type, length of follow-up, and whether ring formation. Dr. Menapace says the are at more risk—speciﬁ cally men with the cataract surgery was performed in reality may be even bleaker for patients high myopia in their 50s and early 60s, a developing country. “The percent- in the developing parts of the world says Douglas Koch, MD, professor age of patients who get PCO is highly where “cheap one-piece hydrophilic and chair at the Cullen Eye Institute, variable and dependent on the type IOLs with broader haptic-optic junc- Baylor College of Medicine in Dal- of IOL implanted, surgical technique, tions are often used.” His evaluation of las. “Their incidence of retinal tears/ cleaning of cortical material, and care two hydrophilic, small-incision IOLs detachments just after cataract surgery in removing lens epithelial cells from showed early and high PCO rates re- alone could be 5 percent or higher, the anterior capsule,” notes Dr. Sny- sulting in YAG laser rates of up to 49 and that rate probably increases after der. In his practice, long-term PCO percent.2 posterior capsulotomy,” he says. development is under 20 percent. “But it depends on how long patients More Complications The Incidence of PCO live—eventually they all might develop Not all ophthalmologists Although today’s tech- agree on YAG laser capsu- nologies and techniques lotomy’s overall safety record. appear to have decreased “The incidence of retinal de- the incidence of PCO, they tachment is reported to be may only have delayed its 0.6 to 2.5 percent and 0.1 to onset. The prevention 3.6 percent for cystoid mac- of PCO through IOL de- FOPS CRA, James Gilman, ular edema,” Dr. Menapace sign, and the elimination notes.3 of proliferating lens epithe- The sheer number of pa- lial cells with various cap- tients undergoing the proce- sule polishing techniques, dure makes an assumed 1 per- chemicals and lasers has cent retinal detachment rate been attempted for decades. not insigniﬁ cant: “If you’re in But “the bottom line is we that 1 percent, you will prob- haven’t achieved anything Surgeons say to hold off on a posterior YAG capsulotomy for about ably not consider it safe,” says that approaches a good way three months postop just in case a lens exchange is warranted. H. Burkhard Dick, MD, PhD,

May 2018 | reviewofophthalmology.com | 35

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Tim Schultz,MD become lessnoticeable.Inasmall per- increased floaters,whicheventually ser capsulotomymanypatients note surgery. in eyesthathaveundergoneﬁ mend cautionwhenusingtheNd:YAG IOP control. ing bleb,causingsubsequentlossof have anegativeimpactontheﬁ that Nd:YAG lasercapsulotomymay lectomies. Arecentstudypostulates is possibleinpatientswithtrabecu- Another, less-well-knownproblem ma anddamagedIOLsarealsoseen. ments: Epiretinalgliosis,macularede- cedure don’t endwithretinaldetach- lem] isnottrivial,”Dr. Kochnotes. these ratesarestilllow, but[theprob- ments, includinggiantretinaltears-- have moreproblematicretinaldetach- rarely clearcut...highmyopesmay say. “Retinalsurgicaloutcomesare risks ofanIOLexchange,surgeons self increasesthecomplexityand vitreous face,andthecapsulotomyit- my almostalwaysdisruptstheanterior Bochum, Germany. versity ofBochumEyeHospitalin ment ofophthalmologyattheUni- director andchairmanofthedepart- 36 posterior capsulestartstocurlup. attheendofsurgery,treatment isperformed afterIOLimplantation.Right: Immediatelyafterthetreatment, the Left: posteriorlasercapsulotomy.View throughtheinfrared camera ofthefemtosecondlaserduringprimary The In thefirstfewdaysfollowingla- Late consequencesafterthepro- Neodymium:YAG lasercapsuloto- REVIEW |

Focus Cover Review ofOphthalmology 4 Theresearchersrecom-

YAG Capsulotomy | May2018 ltering ltering lter- according toBecker’s ASCReview. cost putstheprocedureatnumber10, and YAG capsulotomy’s $65million comes inatnumberfi ve ($96million); procedures; complexcataractsurgery care paymentsforambulatorysurgery cataract surgerywithIOLtopsMedi- significant. At$1.1billionannually, fractures.” the increasedincidenceoffallingand reopsis, whichcouldbeafactorfor actually reducesbinocularityandste- develops inoneeye,unilateralPCO many patientsdon’t realizewhenPCO has clinicallydisturbingPCO.Though has severePCOandthesecondeye says Dr. Menapace.“Typically, oneeye patients presentwithbilateralPCO,” versial thanRDandfl some surgeonsfind evenmorecontro- problematic visualsymptoms.” YAG, andthendevelopanew setof then losevisionduetoPCO,havea recover visionaftercataractsurgery, describes atypicalscenario:“Patients ever, thefloaterspersist.Dr. Koch centage offrustratedpatients,how- Is PCOPreventionPossible? Finally, thefinancialburdenis There areadditionalaspectsthat Most expertsagreethatmeticu- oaters. “Many oaters. 5

proved. Theothernewtechnology Europe andhasjustbeenFDA ap- fication. Thesystemisavailable in can preventposteriorcapsuleopaci- layer oftheposteriorcapsule,which also beusedtoremovethelaminin phacoemulsification. Thelasercan the handpieceinamannersimilarto rial isaspiratedoutoftheeyethrough this approach,theemulsifiedmate- Laser ofNuremberg,Germany. In hind thecurrenttechnologyisA.R.C. to emulsifythelens.Thecompanybe- 1990s, andusesNd:YAG laserenergy Dr. JackDodick’s initialworkinthe Dodick phacolysis,wasderivedfrom PCO. been toutedaskeystopreventing laser-generated capsulotomies have cal cleanup,square-edgedIOLsand niques toeliminatePCO.Bettercorti- devising newtechnologiesandtech- ers andclinicianshavespentdecades the anteriorcapsularrimintact.” thelial layerontheposteriorsideof while keepingtheanteriorlensepi- material fromthecapsularequator mends “thoroughremovalofcortical junctions. Dr. Menapacealsorecom- posterior edgesandslimhaptic-optic vises usingIOLsthattrulyhavesharp Another technique, originally called Another technique,originallycalled Ophthalmic companies,research- IOL optic.”Head- tial overlapofthe mm circumferen- opening whichen- terior capsule and centeredan- a “perfectlysized lieves, istocreate Dr. Menapacebe- avoid PCOtoday, best methodto implantation, the in-the-bag IOL fer. With standard techniques dif- prevent PCO,but first, bestwayto lous surgeryisthe sures a 0.25 to 0.5 sures a0.25to0.5 4/12/18 12:36 PM that may make a difference is the Zep- after IOL implantation, Dr. Dick says where access to the Nd:YAG laser is to capsulotomy device. “The Zepto this OCT scan “demonstrates that 70 limited at best, are among the “most has been shown to reduce PCO,” Dr. percent of patients have a Berger’s compelling reasons to eliminate YAG Donnenfeld says. “It’s a nice way to space of suffi cient depth to perform a capsulotomy,” Dr. Barlow says. make capsulotomies. The problem is safe PPLC .... This is a safe technique Whether laser-assisted capsulorhex- that it’s not reimbursable, so that adds with consistent results and represents is is worth the expense and time con- cost to the procedure. However, it’s a solution to prevent PCO.” tinues to be debated, and proponents become part of many surgeons’ pre- Other ways to eliminate or retard for the Zepto, femtosecond laser or mium cataract packages.” PCO rely on mechanical or chemical manual continuous circular capsu- Less high-tech, but still effective, methods to destroy LECs. Despite its lorhexis cite both research and per- Dr. Menapace explains, is a manual initial appeal, however, total elimina- sonal experience to support their indi- posterior capsulorhexis. He says the tion of LECs may not be a panacea, vidual preferences.8-12 procedure is controlled and safe. “It warns Dr. Koch. Although rare, he can and should be learned by all cata- says that “dead bag syndrome” can To YAG or Not To YAG ract surgeons,” he declares. “It works occur, in which there’s no secondary with any IOL design and material, and proliferation of lens epithelial cells. Despite a relatively safe track re- should be a routine part of cataract If this happens, the capsule becomes cord, timing and circumstances are surgery.” He says that manual poste- diaphanous and fl oppy, unable to sup- critical factors when performing a rior capsulorhexis can be performed port the IOL, and subsequently dislo- YAG laser capsulotomy. Examples in- on virtually all cataract cases. “Ad- cates. “If, for some reason, you have clude dysphotopsias related to mul- ditional posterior entrapment of the to suture through the capsule, it falls tifocal IOLs or lenses in general. optic into the posterior capsulorhexis apart,” Dr. Koch says. “Unfortunately, often the surgeon’s opening completely eradicates PCO,” Nick Mamalis, MD, professor of fi rst reaction is to YAG that patient,” he says, citing an evaluation of 1,000 ophthalmology and director of ocular says Dr. Mamalis. “There are a lot of consecutive cases showing “excellent pathology at the University of Utah’s potential risks involved. If you open long-term effi cacy and safety.”6 Some John Moran Eye Center in Salt Lake the capsule, then an IOL exchange surgeons have pointed out the draw- City, says “There are fairly good data becomes more diffi cult to perform. I backs of this technique: It’s technically that show polishing LECs decreases would very much recommend looking more challenging than conventional the ACO incidence, but does not low- hard at the patient’s symptoms prior to cataract surgery, as it requires opening er the PCO rate [after aggressive ante- considering a YAG laser.” the posterior capsule, possibly inviting rior capsule polishing].” He says that For example, the majority of nega- the vitreous to come forward. Also, if a one widely accepted reason is that the tive dysphotopsias (a temporal hood- lens removal or exchange is required anterior and posterior capsule don’t ing or darkening of vision) resolve in later, an anterior vitrectomy will also fuse as rapidly, so migrating cells are about three months, surgeons say. be necessary. more likely to get past the edge of a Patients with positive dysphotopsias Dr. Dick also thinks opening the square-edged IOL before the fusion (dazzling, disabling light) may not get posterior capsule at cataract surgery occurs. better over time. “YAG laser does not prevents PCO. He advocates a pri- The balance between overly aggres- improve this,” Dr. Mamalis notes. mary posterior laser capsulotomy us- sive and not enough capsule cleanup He recommends holding off a mini- ing the femtosecond laser (he uses the is a delicate one. But most surgeons mum of three months before doing a Catalys Precision Laser System from agree that some residual LECs help YAG laser in patients with side effects J&J Vision) after IOL implantation. fi brose the capsule and stabilize the such as blurry vision, glare and halos. The laser targets the posterior cap- IOL. “We try to determine how to “Unfortunately, in our tertiary care sule in front of Berger’s space, a tiny control this amount ... so that we get center we frequently see patient refer- anatomical gap between the posterior just the right amount of capsule fi bro- rals after a YAG was performed for capsule and the anterior hyaloid mem- sis to hold onto the lens, but not so IOL-related symptoms, but we end up brane. He says the femtosecond laser’s much that PCO occurs,” says William having to perform an IOL exchange, three-dimensional optical coherence Barlow Jr., MD, assistant professor at which can be very diffi cult due to the tomography imaging functions per- the Moran Eye Center. open bag,” Dr. Mamalis says. The ex- mit the surgeon to survey the altered Pediatric cases, which tend to have changed lens may have to be sulcus topography of the anterior segment much more aggressive PCO, and cata- fi xated and, when the capsule is open, immediately after surgery. Minutes ract surgery in developing countries it’s diffi cult to remove the IOL with-

May 2018 | reviewofophthalmology.com | 37

0034_rp0518_f2.indd34_rp0518_f2.indd 3737 44/12/18/12/18 12:3612:36 PMPM 034_rp0518_f2.indd 38 At onetime,Dr. Mamalissays,“peo- ity, yetstill keepthecapsuleelastic. fi modulate theLECssothattheydon’t surgeons say. contact, PCOmightbeprevented, capsular bagandprecludescapsule are openandabroadhapticfi the anteriorandposteriorbagedges may retardtheopacifi different substancesintheaqueous through partofthebag.Presumably, bag allowsaqueoushumortocirculate reason maybethatanopencapsular plains. of PCOisdelayed,”Dr. Mamalisex- lar bagcompletely, thedevelopment model, whenthelensfi lls thecapsu- modating mechanism.Intherabbit haptics thatareinvolvedintheaccom- sion’s IOLhaslargeballoon-shaped bag willdecreasePCO.“PowerVi- bulky IOLthattotallyfi lls thecapsular preventing PCO,”Dr. Mamalissays. look atdifferentwaysofretardingor eventually occurs.“We reallyneedto design, signifi PCO, butdespitethematerialorlens edged acrylicIOLsdelaytheonsetof geons say. Posterior, square- problems, isdebatable,sur- any YAG-capsulotomy-related prevented, therebyeliminating ogy. the designofnewIOLtechnol- to eliminatePCOisfocusedon attention ofsomewhoaretrying vision post-YAG? That’s whythe the patient’s prospectsforgood commodating IOL,whatare Future Directions cystoid macularedema. have anincreasedincidenceof geons notethatthesecasesalso out disturbingthevitreous.Sur- 38 brose anddon’t causecapsuleopac-

New research is focusing on ways to New researchisfocusingonwaysto So, whydoesthismodelwork?One Current researchsuggestsalarge, Whether PCOitselfcanbe If thefutureholdsatrulyac- REVIEW |

Focus Cover Review ofOphthalmology cant incidenceofPCO

YAG Capsulotomy cation. Also,if | May2018 lls the lls Eric Donnenfeld, MD dysphotopsias. A YAG laserposteriorcapsulotomywon’t improve positive diminish withLECproliferation, re- IOL movementinthecapsule will fi movement. Theconcernforcapsule- capsule torespondciliarybody require continuousflexibilityofthe that restwithinthecapsularbagand ment andalreadyinclinicaltrials leafl ing theanteriorandposteriorcapsule will reduceopacifi cation by separat- accommodating IOLsintrialsthat he says.“Onthehorizonarenewer them comparedtosingle-focusIOLs,” glare andhalosareassociatedwith cent ofthetime.“Buttherearemore focus intraocularlensesabout15per- multifocals andextended-depth-of- comes thebiggerissue. in thesecases,fi shape requiresafl exible capsule,and commodating IOLthatchangesits sules becomeavailable.Atrulyac- IOLs thatrelyonintactposteriorcap- importance asnew, accommodating bag andkeepithealthy.” retaining someLECstomaintainthe we’re sayingmaybethere’s benefi ple wantedtoremoveallLECs.Now xated accommodating IOLsisthat There areIOLsbothindevelop- Dr. Donnenfeldsaysthatheuses Preventing PCOwillbeofincreased ets.” ets.” brosis/contraction be- brosis/contraction t to to t technology. 2016;123:2:255–264. Ophthalmology Preclinical safety andperformanceofanewcapsulotomy 11. ChangDF, MamalisN, Werner L. Precisionpulsecapsulotomy: surgery.cataract JCRS2013;39:10:1581–1586. infemtosecondlaser–assisted ofcapsulorhexis evaluation A, Vecchiarino L, DiIorioD. Scanningelectronmicroscopy 10. MastropasquaL, Toto L, CaliennoR, PA, Mattei Mastropasqua implantation. CurrOpinionOphthalmol2018;29:1:54-60. phacoemulsifi extractionandintraocularlens forcataract cation 9. EweSY, Abell RG, Vote BJ. Femtosecond laser-assisted versus 2017;65:12:1411–1414. technology.and disposablecapsulotomy IndianJOphthalmol 8. ChangD. Zeptoprecisionpulsecapsulotomy: A newautomated Refract Surg1990;16:1:31-7. technique.of thecontinuouscircularcapsulorhexis JCataract 7. GimbelHV, Neuhann T. Development, advantages, andmethods 2008;246:6:787-801. 1,000 consecutivecases. Graefes Arch ClinExpOphthalmol of sharp-edgedintraocularlenses? A criticalanalysisof buttonholing: implantation tostandardin-the-bag An alternative 5.Becker’sReview. ASC BMC Ophthalmol2017;17:1:18. Nd:intraocular pressurerisefollowing Yag lasercapsulotomy. coding-billing-and-collections/medicare-payment-for 6.Mena asc-procedures-by-case-volume.html discussed. cial interestintheproductsthatthey posterior Network. 3. SteinertR. Nd:YAG LaserPosterior Capsulotomy, AAO ONE a randomizedclinical trial. Acta Ophthalmol. 2015;93:4:342-7. iMics Y-60H andMicro AY intra-ocularlenses: 3-yearresultsof opacificapsular andNd:YAGcation withthe rates capsulotomy 2. Schriefl SM, LeydoltC, StifterE, R. Menapace Posterior Refract Surg2017;43:923-928. and detachmentafterneodymium:YAG capsulotomy. JCataract 1. Wesolosky JD, Tennant M, RudniskyCJ. ofretinaltear Rate 4. Diagourtas Diagourtas A, Petrou P, GeorgalasI, etal. Blebfailureand None ofthesurgeonshaveafi pace R. Posterior combinedwithoptic capsulorhexis . Accessed 2 April 2018. .2 April -capsulotomy-3 Accessed the future. management andavoidancein will playimportantrolesinPCO of trulyaccommodatingIOLs eratively andthedevelopment demand forsharpvisionpostop- tain eyes,patients’increasing of YAG laserproceduresincer- clear thatunwantedsideeffects PCO/YAG debateyou’reon,it’s notes. low-up isneeded,”Dr. Koch postoperatively, butlongerfol- good responseuptotwoyears accommodative IOLsshowing change. “Thatsaid,thereare the accommodativeIOLpower ducing orpossiblyeliminating No matterwhatsideofthe https://www.aao.org/current-insight/ndyag-laser- https://www.beckersasc.com/asc- . Accessed 2 2018.April nan- -10-top- 4/12/18 12:36 PM A PUBLICATION BY

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2017_retinaspecialist_housead.indd 1 1/16/18 4:30 PM Private Equity REVIEW Feature Is a Private Equity Deal Right for You? (Pt 2)

Christopher Kent, Senior Editor

Surgeons and s noted last month in Part 1 John Pinto, president of J. Pinto of this article, the phenom- & Associates, an ophthalmic prac- business Aenon of private equity firms tice management consulting firm, buying ophthalmology practices has points out that it’s early to predict experts answer proliferated in recent years. Given the potential impact that private eq- the widespread nature of this phe- uity may have on patient care. “In ophthalmologists’ nomenon and the huge potential my experience, there hasn’t been ramifi cations for a practice that un- any change at all in how practices main questions. dertakes such a partnership, doctors are run following private equity are asking a host of questions. In deals,” he says. “The private equity (Part two of two.) this article, two surgeons who have companies I’ve followed are being successfully partnered with private relatively hands-off. They’re trying equity firms, and two consultants to centralize some services, but I who have helped doctors navigate haven’t heard of any cases in which these waters, address 15 of the most the private equity company has said often-asked questions. to the doctor, ‘We don’t want you In Part 1 of this article our experts to have that updated laser,’ or, ‘We discussed nine questions regarding don’t want you to hire the techs that the historical context of this phe- you need in the back offi ce,’ or, ‘We nomenon; the potential benefi ts and think you should get out of this or downsides of partnering with a pri- that line of service because it’s not vate equity fi rm; and which kinds of profi table.’ practices are more likely to do well “We’re not seeing that type of in this situation. This month, they granular encroachment, and we may address the six remaining questions, never see it,” he continues. “The pri- covering the ways in which a private vate equity companies are buying up equity deal is likely to impact your practices they deem to be accept- practice (as well as the fi eld of health able—or better—in terms of their care), and steps you can take to en- current operations and their quality sure a positive outcome if you decide of care. They wouldn’t buy a practice to proceed with a private equity deal. otherwise. Remember: The private equity people are not in the medical How will these partner- business; they’re in the fi nance busi- 10 ships impact the care we ness. From what I’ve seen, they’re provide our patients? sticking to their jobs—they’re not

40 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

040_rp0518_f3.indd 40 4/12/18 1:31 PM trying to play doctor at all. Of course, there are exceptions. And that could change further down the line if some of the companies get in trouble, or if some of them decide that improving the practice is something they should be doing.” Even if the private equity company doesn’t attempt to alter practice management, wouldn’t the fact that doctors are receiving a smaller salary dis- courage, for example, the purchase of a new laser? “First of all, it’s not a fixed amount of money that the private Though a private equity company will have a say in how much you can spend on such things as new capital equity takes out of the equipment, doctors say the companies often are OK with such purchases if they grow the business. practice,” Mr. Pinto explains. “Typically, the private equity aged and borrowed—in order to buy lump sum and retiring. That’s not the company will take a percentage of these practices, which they see as case for the younger doctors, who earnings. So if the doctor who just got earning streams. These transactions will have reduced earnings for years a really big check for his buyout feels are highly tax-favored, and the model to come. That’s one of the built-in that there’s a piece of equipment that works, seen strictly through the eyes traps in this situation, and it’s just as he needs, both the company and the of the private equity company. But much an issue today as it was in the doctor will be paying for it. The doc- the transaction leaves the acquired 90s. That’s why I have mixed feelings tor might still want to go ahead and practice with fewer dollars available about what I’m seeing right now.” buy that piece of equipment.” for doctors’ salaries. Richard L. Lindstrom, MD, man- “That’s a perfectly great tradeoff aging partner at Minnesota Eye Con- How will lower salaries if you’re a senior doctor who is look- sultants—now part of Unifeye Vision 11 impact my practice? ing for a payout,” he continues. “The Partners—explains how his practice In return for investing in the pur- payout from a private equity transac- evaluated the cut in salary that would chased practice, the private equity tion can be twice or more what you accompany proceeding with their partner takes a share of practice prof- would get if you sold your practice to private equity deal. “Our group has its. This means that at least some a fellow physician. For some clients, 10 partners,” he explains. “We sat of the doctors in the practice will it’s a marvelous succession option around the table, and asked every- be taking home a smaller amount of to consider, but I think it’s going to body to write down what they needed money each year. leave others quite disappointed. to make over the next decade to live “Today, private equity companies “For example, suppose your prac- comfortably. Eventually, we came to are buying up practices at about six tice has a mix of older and younger a consensus that we’d all be comfort- to eight times the practice’s annual doctors,” he says. “The senior doctors able making X. We thought we might profit—in some cases much more are going to be in the boardroom end up taking about a 30-percent than that,” Mr. Pinto explains. “The raising their hands and saying, ‘Let’s reduction in income after the deal, reason a private equity company can do this deal.’ The smaller salary in but everyone still found the numbers do that is that they’re taking money the years ahead won’t impact them acceptable. Then we calculated how from investors—money that’s lever- as much because they’re taking their much practice proﬁ t would remain.

May 2018 | reviewofophthalmology.com | 41

040_rp0518_f3.indd 41 4/12/18 1:34 PM 0040_rp0518_f3.indd 42 4 0 _ r p 0 5 1 8 _ f

3 Richard L. Lindstrom, MD that possibilityalittlebit.” than hype,soyouhavetodiscount could turnouttobenothingmore IOLs, andsoforth.However, that al marketing,we’lldomorepremium ties, we’regoingtodosomeaddition- to expandourcash-payopportuni- that we’regoingtogrow, we’regoing increased proﬁ the moneywe’vegivenup,thanksto takes offwemightevenearnback sible thatifthepracticegrowthreally than weexpected.Ofcourse,it’s pos- in income,”headds.“That’s better taken abouta15-percentreduction first year, weappear tohaveonly could work. there wasmoneyleftover, sothedeal of residualearnings.Asitturnedout, ue thepracticeintermsofamultiple uity wouldn’t work,becausetheyval- If therewasnothingleft,privateeq- 42 cessful privateequitypartnerships. Baltimore, hasbeenpartof two suc- ident ofKatzenEyeGroup, based in in thepractice? 12 . i n The “Promise” ofaPrivate EquityPartnership d “Interestingly, at theendofour Brett W. Katzen,MD,FACS, pres- REVIEW d | Feature

Review ofOphthalmology

4 Ability tomonetize 2

for theyoungerdoctors Is thisarrangementbad equity ts. Thehypeisalways Facilitate succession

planning Private Equity Private | May2018 Assist withpractice management many ofmydoctors be incentivizedtomakemore—and he continues.“Infact,theyshould employee doctorsareearningatall,” taking homelessmoney. cash and/orstock,sotheownersare ers areinvestinginexchangeforthe the business’s profi by thebusiness.Thatpercentageof get apercentageoftheprofi in. Ifyou’reanowner, youwouldalso percentage oftherevenuetheybring an arrangementthatdoctorsgeta cut,” heexplains.“We’ve always had younger doctorsdidn’t takeapay deal isnegotiated.“Inourdeal,the in apracticewilldependonhowthe uity dealaffectstheyoungerdoctors He pointsoutthathowaprivateeq- earn morethanbefore.” so theyatleasthavethepotential to and higher-quality instrumentation, now theyhavebetterpatientflow same percentagetheydidbefore,but ture. Theemployeedoctorsearnthe invested somuchinourinfrastruc- because theprivateequitycompany his bestyeareverlastyear, partly now. Mymaincataractsurgeonhad “Our dealdidn’t changewhatthe Dr. Lindstrom agreesthatthe capital forgrowth capital Provide sourceof Leverage resourcesto Leverage achieve greater scale achieve greater tiswhattheown- are makingmore t made t in thegroup,andthey’llhave the in ourpracticedidchooseto invest to invest.Alloftheyounger doctors is resold,withmoreopportunities three bitesoftheappleasgroup “those doctorsaregoingtogettwoor you can. to borrowforyourkid’s education, way. Andalongtheway, ifyouneed save thatmuchmoneyinanyother There’s nowayayoungdoctorcould by thetimeyou’rereadytoretire. $2 million,you’reupto$16million eight milliondollars.Ifyoustartwith ahead, fromonetotwofour ing out,you’vegotthreedoublings every 10years.Ifyou’rejuststart- that amountofmoneywilldouble getting 8percentannualinterest, ronment suchasanIRA.Ifyou’re you putthatinatax-deferredenvi- you getamilliondollarstoday, and salary,” hesays.“Meanwhile,let’s say doctors wouldbepaidanadequate payment, wemadesuretheyounger retirement. “Inadditiontoacash tice thanforthedoctorscloserto for theyoungerdoctorsinprac- up, itwasarguablyevenabetterdeal of thewayhispractice’s dealwasset tice? Dr. Lindstromsaysthatbecause on theyoungerdoctorsinprac- generators leave.) and letalloftheprimaryrevenue ty companyisgoingtobuyapractice notes, however, thatnoprivateequi- through thenexttransaction.”(He recommit andstayanotherfi issue ifIwentaway. ButIdecidedto doctor outof26,soitwouldn’t bean theory, Icouldretirenow;I’mone ners wouldhavebeenabletopay. In be muchgreaterthanwhatourpart- and theamountweleavewithwill a doctortoexitifheorshewantsto, he says.“Ourspecifi tor likeme,it’s agreatwaytoleave,” ment tocashout.“Foranolderdoc- great wayforadoctorclosetoretire- private equitypartnershipcanbea “Not onlythat,”hecontinues, What abouttheimpactofdeal c dealwillallow ve years 44/12/18 1:32 PM / 1 2 / 1 8

1 : 3 2

P M chance for another recapitalization Richard L. Lindstrom, MD in fi ve or six years. In theory, this will Sample Acquisition Considerations repeat every fi ve or six years, possibly reaching an opportunity for an IPO Size / Structure Considerations • Have a range of $1 to $5M of EBITDA somewhere along the line. So our • Able to invest a fi nite amount of equity over the life of the deal deal has turned out to be good even for the younger doctors.” Practice • Dense regional presence (ideally the Considerations leading group in the geographic area) Will this undercut our • Diversifi ed group of physicians (not 13 ability to recruit doctors dependent on one or two key physicians in the future? for the majority of revenue) “Younger doctors who are looking • Have infrastructure to facilitate growth for a career and considering join- • Surgery center ownership ing a practice that’s owned by a pri- • Physician alignment/ownership vate equity company will realize that some of their potential earnings have already been pledged to the private tors they need.” duction,” he says. “Nobody’s lowered equity fi rm and taken off the table,” Dr. Lindstrom says that so far, his that percentage.” notes Mr. Pinto. “That’s a problem group hasn’t had any trouble hiring because it’s getting harder and hard- new young doctors, despite the new How is this trend likely er to recruit doctors. We have fewer arrangement. “Our goal is to recruit 14 to work out in the long residency slots, and more older doc- the best and brightest, and so far run? tors are retiring, so the demand is go- we haven’t seen a problem there,” Mr. Pinto sees the current wave of ing up. That trend is blotting up all of he says. “The package we offer is private equity purchases as a limited the available doctors, and base sala- still competitive, both in salary and phenomenon, rather than something ries for new doctors are going to con- in terms of opportunity to earn eq- that will become a huge, sweeping tinue to rise materially in the years uity. For example, we recently hired trend. “We’re certainly not going to ahead. As a result, the private equity a glaucoma/cataract surgeon, and end up in a world in which 90 percent companies will fi nd it more and more those are among the most highly of practices are owned by private eq- diffi cult to hire young doctors as the in-demand ophthalmologists today. uity companies,” he says. “But we senior doctors retire. I think it’s a That individual had many other of- are moving inexorably toward more ticking time bomb for many of these fers but still chose to join us. At the consolidation, whether it’s in the companies.” same time, I would say that our buy- form of private equity, or hospitals Mr. Pinto acknowledges that some in, because our practice is pretty buying practices, or large practices of this might be offset in certain situ- valuable, was intimidating to a lot of buying smaller practices. This era of ations. “If an organization has be- young doctors. Given the uncertain- increased consolidation will probably come very large-scale, with revenue ties that exist about the future, some continue for some years. over $100 million, and it’s located in would take a look and say, ‘You’re “What we’re seeing right now is a a desirable market that’s attractive asking me to pay something that series of private equity transactions to younger doctors, it may work out has a lot of zeroes behind it to be an that are allowed to happen because fi ne,” he says. “A group in that situa- equal partner in your practice. I’m of broad financial conditions, taxa- tion will have the scale to allow more already in debt, and that’s scary.’ So I tion policy, and other current fac- effi ciency with operations, and will think the reaction new young doctors tors,” he continues. “I would fore- be able to be effective when nego- will have to joining us will depend cast on the negative side for most of tiating managed-care contracts. But on the individual. Hopefully, the fact these transactions because for most many others won’t have the scale to that we can offer an equity opportu- of them, the underlying enterprise be able to overcome these diffi cul- nity will make a difference.” model is fl awed. I’ve spoken to about ties. And they may not be located in Dr. Katzen says that because of the half of the private equity companies, parts of the country that are easy to way his deal is structured, it hasn’t and a signifi cant percentage of them recruit to. So the reduced salaries undercut the group’s ability to hire are going down the same rabbit hole they’ll have to offer to young doctors new doctors. “If you’re not an owner, that we did in the 1990s. Yes, there won’t be suffi cient to attract the doc- you’re paid a percentage of your pro- are a few thoughtful folks doing this

May 2018 | reviewofophthalmology.com | 43

0040_rp0518_f3.indd40_rp0518_f3.indd 4343 44/12/18/12/18 1:321:32 PMPM 0040_rp0518_f3.indd 44 4 0 _ r p 0 5 1 8 _ f 3 lic. So,atthispointwehaven’t seen of theverymaturegroups go pub- other fields,andwe’veseen afew uity transactionsindermatologyand We’ve alsoseenseveralprivateeq- was Varsity, andthatwentwell. pany selltoasecondinvestor;that already seenoneprivateequitycom- transaction willbelike,butwe’ve some questionaboutwhatasecond acknowledges. “Ofcourse,there’s anything ispossible,”Dr. Lindstrom going tofail,butinthecurrentworld, years fromnow?“Idon’t believeit’s it inthepunch.” kept bringingmorerumandputting the partygoingbecausesomeone ital. Backthenwewereabletokeep companies havebetteraccesstocap- companies,” Mr. Pintosays.“Public then thecompanieswerepublic little fasterthistime,becauseback ago? “Ithinkthingswillunwinda pen thewayithappened20years at thisasabubble.” or threeyearspeoplewilllookback and they’lldowell.ButIthinkintwo and thewaytheirbusinessworks, will evolvetheirtransactionmodel now thatwillprobablysurvive.Some 44 . i n that, ifyou’reinterestedintheopportunity.” interested evenifyou’rewillingtogiveyourpracticeaway. toconsider Ithink youhave you’ll beabletochoosethecultureyouwant. infi Itcouldbethat ve yearsnoonewillbe a qualitypracticelookingtoexpand, you’llprobablyfi nd multipleinterestedbuyers, and cludes. equity, forprivate inophthalmology “But rightnow it’s aseller’s market. Ifyou’re teeth andapullback. ofopportunitymaycloseThe window forawhile. years ahead, forexample, occurstherewillbealotofanxietyandgnashing andifthat This maynotbetrueafewyearsfromnow. A stockmarketcorrectionislikelyinthe ishotandtheeconomydoingreasonablywell. becauseophthalmology than average the fi nancial benefi ts ofadeallikethis—ifthat’s what’s drivingyou—arealittlebetter period oftime. discoveredophthalmology, equitycompanieshave private Rightnow and they missedit!Similarly, willprobablyonlybe equitywindow thisprivate ‘hot’ forashort openedandclosed—although“The PPMCwindow I’msuresomepeoplewerehappy Lindstrom, equityfi withaprivate whosepracticehasenteredintoanagreement rm. d

What ifthemodelfailsﬁ If thebubblecollapses,willithap- REVIEW Should IWait orActNow? d “Again, equitydealisnotgoingtomakesenseformostpractices,” aprivate hecon- ofopportunityopenandclose,”“Windows surgeonRichard notesMinneapolis |

Feature Review ofOphthalmology

4 4

Private Equity Private ve orsix | May2018 your goalistogrow. result: strategies willhelpensureapositive work foryouandyourpractice,these a privateequitypartnershipcould come? have acleargoal,thenyou cande- number infrontofyoureyes. Ifyou cause somebodycallsandwaves abig You shouldn’t pursuethisjustbe- pursue thisoption,abusinessplan. you needtohaveagoal,reason tant, portunity togrow, andequallyimpor- nership] arethosethathavetheop- right practices[forthistypeofpart- Dr. Lindstrom.“Forthatreason,the ing toenhancepracticegrowth,”says and goodbusinessjudgment,help- capital, bothhumanandfinancial, company fertilizesthepracticewith a growthstock,theprivateequity so good.” that thiscouldendbadly, butsofar, perfectly reasonabletobeconcerned saw withthePPMCs.Ofcourse,it’s any failuresorcrasheslikethosewe 15 • If you’vedecidedthatpursuing Don’t pursuethisunless want

the chanceofagoodout- How canwemaximize togrow. Attheveryleast, “Just aswith —CK “That’s notnecessarilyhowaprivate 10 to20years,”saysMr. Maller. likely tobesustainablefor the next these arrangementssothatthey’re to besmartabouthowyouconstruct the longterminmind. do that?’” back andwondering,‘Whydidwe to makesureyouwon’t belooking are verycomplicated.It’s important counsel, becausethesetransactions retaining goodlegalcounselandtax decision togoahead,Iguidethemon to agoodbusinessdecision.Ifit’s a and negatives,helpingtoguidethem educating clientsaboutthepositives educate you.Ispendalotoftime haps mostimportant,theycanhelp what’s thebestcourseofaction.Per- consensus amongthepartnersabout help youclarifyyourvisionandbuild ing people.Thoseindividualscan gal, accountingandbusinessconsult- you knowandtrust—includingle- stead, surroundyourselfwithpeople and decision-making,”hesays.“In- let youregoguideassessment understand yourlimitations.“Don’t to endingupwithagooddealis Consulting Group,saysthatakey chief executiveoffi Maller, founder, presidentand sors youknowandtrust. self-fulfi vidual either, soitwillendupbeinga probably wouldn’t wantthatindi- same time,aprivateequitygroup others involvedindecisions.Atthe probably wouldn’t behappyhaving want torunthingstheirownway Dr. Lindstromsays.“Maverickswho private equitymaynotmakesense,” doesn’t wanttoworkwithapartner, independent andcannotorsimply is asolopractitionerwhofi of yourpractice. your chancesofachievingthatgoal.” partner willenhanceordetractfrom cide whetherornotaprivateequity • • • When negotiatingadeal,keep Surround yourselfwithadvi- Be willingtosharecontrol lling prophecy.” cer ofTheBSM “If anindividual “You have ercely Bruce 44/12/18 1:32 PM / 1 2 / 1 8

1 : 3 2

P M equity fi rm thinks. They think about Mr. Pinto says that one of the big- talking about something that can be creating value in the next three to gest unforeseen problems that oc- clawed back later on, but the irre- fi ve to seven years and then selling curred back in the 90s was the reac- vocable payment you receive at the that interest, to make sure that they tion of many doctors to the infl ux of front end when the ink is drying. satisfy their obligations to their pri- cash. “Each of these doctors had a “The second condition is that vate equity investors.” pretty good-sized check coming in at you’re not emotionally attached to • Make your decisions for the the front end for the purchase,” he what happens to the practice next,” right reasons. “The worst possible notes. “Some of what they received he continues. “Some doctors would reason to go down this path is be- was stock, but some was cash. That be carried over their fi nancial fi nish cause someone you know did it and caused a lot of them to back off their line by such a deal, but they’d be an- got a big payoff,” notes Mr. Maller. productivity. A lot of doctors said, guished if their practice was run into “Even with a big paycheck you can ‘Now that I’m over my fi nancial re- the ground, or if key policies were end up very unhappy. If money is tirement fi nish line, I don’t need to changed, or key staff members were the only thing you’re thinking about, work so intensely.’ dismissed. Such a doctor should not your decisions are not likely to pro- sell to a private equity fi rm.” duce ideal results.” • Consider how the deal is go- For Better or Worse ing to impact younger employee “[When negotiating a physicians in your practice. “Your deal] surround yourself In the fi nal analysis, is this trend younger employees may be at the going to be a good thing for the fi eld greatest risk,” Mr. Maller points out. with people you know of ophthalmology? “They may not have been involved in and trust—including “I’m torn about what I’m seeing,” the original transaction, and they’re says Mr. Pinto. “I see many of these most likely to suffer if the next inves- legal, accounting companies heading in the wrong di- tor, a few years down the line, isn’t as and business rection. It’s too early to observe the friendly or as concerned about how a consequences, but I think in a few deal affects them as the fi rst investor consulting people.” years we’ll see a signifi cant number hopefully was.” —Bruce Maller of practices partnered with private • Be aware that a big payoff equity firms that will be unhappy can alter a doctor’s level of mo- with the level of administrative sup- tivation. “Key doctors in the prac- port they get, or the limitations that tice may become less motivated as a “Unfortunately, if a doctor cuts they’ll fi nd themselves dealing with, result of the fi nancial change,” says his patient volume by just 10 per- fi nancially and operationally.” Mr. Maller. “Once physicians have cent, the profi ts of the practice can Mr. Maller says he’s not “for” or sold the practice and put money in do down as much as 20 percent,” he “against” this trend. “I think a private the bank, some may lose their inter- says. “That’s a risk the private equity equity investor can bring a tremen- est and passion, realizing they don’t companies are taking, and I’m sure dous amount of value to a practice need to work so hard to ensure their that they’re going to be experiencing in the right situation,” he says. “The fi nancial future. In fact, some may that as well.” right situation is where you have the not even be motivated to stay. After • See if the deal passes the two- right type of practice, and everybody a while some may say, ‘This isn’t very part “acid test.” Mr. Pinto says his goes in with their eyes wide open, much fun anymore, I’m just coming advice to a physician considering this and no one loses sight of what it takes to work and collecting a paycheck. type of a deal is to use a simple two- to build a great business over the I got all that money up front; may- part “acid test.” “A deal like this can next 25 years.” be I should terminate. I’ve signed be an absolutely fantastic thing to Dr. Katzen notes that there are a noncompete, so maybe I’ll take a do, and very appropriate as a busi- plenty of naysayers when it comes couple of years off. Maybe later I’ll ness and professional next step, un- to the private equity phenomenon. come back and start over again!’ Of der two conditions: The fi rst is that “They can come up with plenty of course, their interest and passion is the money you receive up front in reasons to be negative,” he notes. what made the practice great in the the transaction is enough to take you “But the reality is, this can work. I’m fi rst place, so this is not a good thing comfortably over your personal fi- proof of that, because I’ve already for the practice.” nancial fi nish line,” he says. “I’m not succeeded.”

May 2018 | reviewofophthalmology.com | 45

0040_rp0518_f3.indd40_rp0518_f3.indd 4545 44/12/18/12/18 1:331:33 PMPM Unhappy Patient REVIEW Cover Focus Handling the Unhappy Premium IOL Patient

Asim Piracha, MD, Louisville, Ky.

An ounce of ven the best products and ex- tion after premium lens implants, we periences in life will fall short need to be able to address our pa- prevention is Eof expectations from time to tients’ concerns and symptoms. time: Your new sedan doesn’t shift worth a pound gears crisply enough, the summer Preop Measures home’s air conditioning never seems of cure, says this to work when you want it to, and yes, There’s an old maxim among play- sometimes, a patient’s vision with a wrights who are struggling with a surgeon. new premium intraocular lens isn’t script: “Third-act problems are actu- as good as he’d hoped it would be. ally fi rst-act problems.” The same is Whether the problem is with the pa- true in many cases of less-than-suc- tient, the surgery or a mix of both, cessful premium IOL surgery. Thor- it’s your job to ferret out the cause oughly discussing the pros and cons of and correct it as best you can. In this the procedure with patients ahead of article, I’ll share some techniques that time, and performing a careful exam, will help. can avoid many postop issues. • Talk to the patient. The fi rst step A Rare Problem to better patient satisfaction with premium IOLs is to talk and listen to the The reality is that the vast majority patient and understand what she ex- of patients receiving premium intra- pects to achieve through the surgery. ocular lens implants are very happy Be sure to conduct a thorough exam, and would have the procedure again. review all of the patient’s measure- In fact, patients are very likely to rec- ments and engage in a detailed discus- ommend a modern premium lens to sion about the surgical options. Dur- friends and family—as many as 94 ing this discussion, it’s important to percent in the Concerto Study and get to know the patient’s personality, 98 percent in the Harmony Study.1 In occupation, hobbies and visual needs. the U.S. FDA trials for newer-genera- The surgeon should also explain to tion multifocal IOLs, 94 to 97 percent the patient what each lens or surgical would choose to have the lens again procedure is capable of achieving and as compared to only 88 percent with the true limitations of the technology, a monofocal lens.2 But, for those who with a heavy emphasis on the fact that aren’t fully satisfi ed with their quality no surgery or lens can do everything of vision, uncorrected vision or func- for everyone.

46 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

0046_rp0518_f4.indd46_rp0518_f4.indd 4646 44/12/18/12/18 11:1311:13 AMAM It’s also very important to of premium IOLs is visu- understand what the patient’s ally significant epiretinal goals are after surgery—not just membrane formation or what your goals are for him. macular degeneration. Some individuals are perfectly Not only can ERM affect fine wearing glasses after sur- patients’ best-corrected vi- gery and don’t feel the need to sion and quality of vision, spend the extra money on pre- there is also a higher risk mium lenses or femtosecond of cystoid macular edema lasers. Others would prefer to that should alter your post- see well at near and wear glass- operative drop regimen to es for distance activities, while include an NSAID for at some patients prefer high qual- least six weeks postop.3,4 ity daytime and night vision with If the ERM is mild, opti- glasses rather than good vision cal coherence tomography without correction for near and can help determine if it’s distance. Along these lines, I’m clinically signifi cant. Due reluctant to recommend MF to some loss of contrast IOLs when the patient is very sensitivity with multifocal happy with monovision; the IOLs (less so with extend- use of multifocal IOLs not only ed-depth-of-focus lenses) adds the need for the patient to and imaging artifacts, the neuro-adapt to manage postop visual function and postop tasks, but patients also have to OCT measurements may pay extra for the lenses. be less reliable. There may • The exam. Preoperatively, When preparing the ocular surface for premium surgery, also be zonular instability you have to evaluate every pa- conditions such as this pterygium must be treated. in glaucoma patients that tient carefully, looking at every- could affect the long-term thing from the ocular surface to centration of the IOL. the macula. When considering IOLs, tectomy preoperatively and won’t The other concern is that the ERM or be sure to choose the correct technol- proceed with surgery until the ocular glaucoma can progress, so even mild ogy for a patient’s current refractive surface is healthy and the refraction is cases of ERM or glaucoma may not error and his visual needs and wants. stable. We’ve seen refractive improve- have excellent long-term outcomes In the end, patients may not be good ments of up to 1.25 D (mean: 0.64 D) with multifocal and EDOF lenses. candidates for premium lenses due to after EBMD treatments, and up to For these reasons, we’re cautious in either their clinical fi ndings or their 6 D sphere (mean: 1.71 D) and 4.5 D recommending multifocal and EDOF expectations and ability to function of cylinder (mean: 1.57 D) after treating lenses in patients with macular or within the limitations of the current SND. (For more on these treatments, optic nerve diseases. I’m more com- premium IOL technology. see “The Benefi ts of Pre-treating Cor- fortable with monofocal toric IOLs On clinical examination, I look for neas” in Review’s April 2010 issue). in these cases, as long as there’s no ocular surface issues like dry eyes, poor If there’s any significant pterygia zonulopathy. tear film, epithelial basement mem- present, we prefer to treat these fi rst Once we determine that the patient brane dystrophy, Salzmann’s nodular with excision and conjunctival auto- is a good candidate for a premium degeneration and pterygium. If any grafts. It takes two to three months for lens based on the clinical exam, we of these are present, I address them the refraction to stabilize after these then review all the measurements and preoperatively. I’ll initiate aggressive procedures—sometimes longer if studies to rule out irregular astigma- dry-eye treatment with artifi cial tears, there is any concurrent dry eye or lid tism, abnormal topography and high lid hygiene, oral omega-3 fatty acids margin disease. Purkinje vs. limbal chord lengths. Re- and topical anti-inflammatory drops A detailed dilated exam is impor- garding the last factor, I evaluate the (i.e., Lotemax, Restasis or Xiidra). If tant for ruling out any macular or op- distance between the center of the there is EBMD or SND present, I tic nerve disease. The most common limbus, or horizontal white-to-white treat these surgically with a burr kera- fi nding that prevents the implantation measurement, (i.e., the optical center)

May 2018 | reviewofophthalmology.com | 47

046_rp0518_f4.indd 47 4/12/18 11:13 AM Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series Welcome to the third year of Mackool Online CME! With the generous support of several ophthalmic companies, I am honored to have our viewers join me in the operating room To view CME video as I demonstrate the technology and techniques that I have go to: found to be most valuable, and that I hope are helpful to www.MackoolOnlineCME.com many of my colleagues. We continue to edit the videos only to either change camera perspective or to reduce down time – allowing you to observe every step of the procedure. Richard J. Mackool, MD As before, one new surgical video will be released monthly, Episode 29: and physicians may earn CME credits or just observe “The Use of Intraoperative the case. New viewers are able to obtain additional CME credit by reviewing Aberrometry to Confi rm Toric previous videos that are located in our archives. IOL Power Calculation in a I thank the many surgeons who have told us that they have found our CME Highly Myopic Eye” program to be interesting and instructive; I appreciate your comments, Surgical Video by: suggestions and questions. Thanks again for joining us on Mackool Online CME. Richard J. Mackool, MD CME Accredited Surgical Training Videos Now Video Overview: Available Online: www.MackoolOnlineCME.com After fi rst removing the anterior subcapsular cataract Richard Mackool, MD, a world renowned anterior segment ophthalmic in a highly myopic patient, I microsurgeon, has assembled a web-based video collection of surgical then demonstrate the use of cases that encompass both routine and challenging cases, demonstrating both intraoperative aberrometry to familiar and potentially unfamiliar surgical techniques using a variety confi rm the toric IOL power of instrumentation and settings. calculation. Discussions This educational activity aims to present a series of Dr. Mackool’s surgical include how to best manage videos, carefully selected to address the specifi c learning objectives of this a signifi cantly deep chamber activity, with the goal of making surgical training available as needed online for and how to correct the rare surgeons motivated to improve or expand their surgical repertoire. occurrence of a toric IOL that Learning Objective: rotates postoperatively. After completion of this educational activity, participants should be able to: • Demonstrate and discuss problems frequently encountered when performing phacoemulsifi cation on a highly myopic eye with an extremely deep anterior chamber • Demonstrate the use of the intraoperative aberrometry to verify IOL power

Satisfactory Completion - Learners must pass a post-test and complete an evaluation form to receive a certifi cate of completion. Your chosen sessions must be attended in their entirety. Partial credit of individual sessions is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certifi cation board to determine course eligibility for your licensing/certifi cation requirement. Physicians - In support of improving patient care, this activity has been planned and implemented by Amedco LLC and Postgraduate Healthcare Education. Amedco LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team

JOINTLY ACCREDITED PROVIDERTM Credit Designation Statement - Amedco designates this live activity for a maximum of .25 AMA PRA Category 1 CreditsTM. INTERPROFESSIONAL CONTINUING EDUCATION Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Additionally Supported by: Endorsed by: Jointly provided by: Supported by an unrestricted independent Review of Ophthalmology® medical educational grant from: Glaukos Video and Web Production by: MST & Crestpoint Management JR Snowdon, Inc Alcon Carl Zeiss Meditec 046_rp0518_f4.indd 49 rett Universalformula,advanced bi- mulas liketheHill-RBFand the Bar- surgery, byusingmodernIOLfor- hancements arearealitywithIOL be agoodﬁt forpremiumlenses. help screenoutpatientsthatmaynot the numberofpostopissuesandalso educate thepatientpreopwillreduce fully correcthisvision. may belimitedoptionsaftersurgeryto be educatedpreoperativelythatthere not anLVC candidate,thenheshould ser visioncorrection.Ifthepatientis should benocontraindicationsforla- phy shouldbenormalandthatthere lar surfaceandtopography/tomogra- tive error. Thismeansthattheocu- option tocorrectanyresidualrefrac- tion, sinceenhancementsmustbean as theywouldforaLASIKevalua- screened inthesameway gery, andpatientsshouldbe is, ineffect,refractivesur- astigmatism. expectation ofsomeresidual the “off-label”useand tailed discussionexplaining cylinder, butonly afterade- er atoricIOLtoreducethe IOLs; however, Imayconsid- of ectasia,Iavoidpresbyopic regular astigmatismorsigns EDOF lenses. IOLs—not justmultifocal/ and evenasphericmonofocal is alsohelpfulwithtoricIOLs 0.5 mm.Thismeasurement when thisvaluewaslessthan acuity atnearanddistance of 20/20uncorrectedvisual found ahigherpercentage In myowncaseseries,we decreased qualityofvision. higher-order aberrationsand there willbesomeinduced greater than0.5mm,then visual axis).Ifthisdistanceis and thecornealapex(i.e.,

• Formulafactors.Althoughen- The extratimeandefforttakento Premium IOLsurgery If thetopographyshowsir- REVIEW Focus Cover

Unhappy Patient Unhappy angle alphameasurement. This multifocalIOLiscentered onthevisualaxisandhasalow alpha) isgreater than0.5mm, more aberrations willbeinduced. If thedistancebetweenopticalcenterandvisualaxis(angle that theocularsurfaceisunstable. measurements, thenthismaybeasign between thetwoeyesor is stable.Ifthere’s abigdifference an enhancementoncetherefraction patient thatsheismorelikelytoneed narrow chamberdepths,informthe short axiallengths,highorlowKs, ments haveoutliers,suchaslongor ing theIOLpower. Ifthemeasure- and Tracey iTrace) beforecalculat- devices (IOLMaster700,Pentacam the Kreadingsfromthreedifferent ally usemultipleformulasandreview surprises youexperience.Iperson- can reducethenumberofrefractive Lenstar, andmultipleKreadings,you ometry fromtheIOLMaster700or Intraoperative Tips

“Perfect”cataract/intraocular lens May 2018 some maybechronicand need to over timewithneuroadaptation and plaints, sincesomeissueswill improve the durationandtimingofcom- what hewasbeingoffered. fered orthepatientdidn’t understand ments—but theywereeithernotof- with acoupleofverysimpletreat- could havebeenmarkedlyimproved IOL patientswhosevisualfunction seen ahandfulofunhappypremium game plantoaddresstheissues.I’ve derstand hisconcernsandcreatea issues earlyandofteninordertoun- complaints. It’s criticaltolistenhis become defensiveordismissiveofhis premium IOLpatient,youshouldn’t happy. be theoccasionalpatientwhoisun- aforementioned advice,theremaystill It’s alsoimportanttounderstand When meetingwithadissatisfied | reviewofophthalmology.com The Postop Period postop dayone. and achieveclearcorneason reduce elapsedphacotime ment thelensinorderto addition, Iprefertofrag- rotation postoperatively. In reduce theincidenceofIOL extended-depth-of-focus) to IOLs (bothmonofocaland down to4.8mmfortoric standard diameterof5mm the capsulotomyfroma alignment. We alsoreduce marks tofacilitatetoricIOL dure ormakepreopcorneal matic keratotomyproce- with anintrastromalastig- address cornealastigmatism all premiumIOLcases.We second laser, theCatalys,for we prefertouseafemto- gery asprecisepossible, implants. To makethesur- pecially withpremiumIOL tions isalwaysthegoal,es- surgery withoutcomplica- Even whenyoufollowthe 5,6,7 |

49 4/12/18 11:13 AM 0046_rp0518_f4.indd 50 4 6 _ r p 0 5 1 8 _ f 4 patient has mixed astigmatism with an patient hasmixedastigmatism withan visual recoveryandcomfort. Ifthe is agoodcandidate,duetothe quicker options. IpreferLASIKifthepatient tism, LASIKandPRKareexcellent the capsuleorzonulesaren’t intact. exchange overpiggybacklensesunless IOL aregoodoptions.Ipreferan IOL exchangeorsecondarypiggyback high sphericalrefractiveerror, thenan distance; andnightvision.Ifthere’s a affects everything:near;intermediate; tion postop.Residualrefractiveerror aren’t functioningwellwithoutcorrec- is themostcommonreasonpatients an enhancement,ifneeded. satisfaction, andtopreparetheeyefor fully rehabilitatedtoimprovepatient mon, andtheocularsurfaceshouldbe aggressively. Dryeyesareverycom- the surfaceshouldalwaysbetreated visual function,andanyproblemswith quality ofvision,patientcomfortand ocular surfacecanseverelyaffectthe with premiumlenses: prove patientsatisfactionandfunction eral areasthatcanbeaddressedtoim- been exhausted. all theotherless-invasiveoptionshave and Itypicallyonlyrecommendthisif IOL. Thisistheexception,however, to exchangethelensforastandard be casesinwhichthebestsolutionis no premiumlensisperfect,theremay to improvetheirvisualfunction.Since planted. Indoingso,we’vebeenable the lenstechnologythattheyhadim- us educatethemonthelimitationsof fears andregaintheirtrust.Thishelps their advocate,we’reabletoallay tening tothemcarefullyandbeing unhappy withtheirresults,afterlis- in whichpremiumIOLpatientsare to sixmonthspostop.Inmanycases nitely improveduringtheﬁ to functionbetteratneartasksdeﬁ vision disturbancesandlearninghow be addressed.Forinstance,night- 50 . i n d

For compoundormixedastigma- • Residualrefractiveerror. • Ocularsurfacedisease. In thepostopperiod,therearesev- REVIEW d |

Focus Cover Review ofOphthalmology

5 0

Unhappy Patient Unhappy rst three rst | May2018 The This This - difficulties orquality-of-vision com- present andtherearenight-vision tion. of recurrentrotation. time oftherotationtoreducerisk to placeacapsulartensionringatthe lengths/WTW measurements,Iprefer decentration ofthelensorhighaxial If thereisanyzonularinstabilityor is performedtoosoonpostoperatively. the IOLcanshiftagainifrotation two weekspostopbutnotearlier, as IOL, Irecommenddoingthisoneto If you’regoingtoberotatingatoric tion andocularsurfacetostabilize. weeks postoptoallowfortherefrac- necessary, theidealtimeisaboutsix needing twoseparatesurgeries. I preferanLVC enhancementtoavoid after idealalignmentoftheIOL,then nifi determine thattherewillstillbesig- the OPD-ScanIIIfromNidek).IfI fractive error(suchastheiTrace or the lensandexpectedresidualre- that assessestheproperalignmentof (such as use oneofthemanyonlinecalculators the idealpostopaxis;ifitisn’t, thenI’ll toric IOL,IdetermineiftheIOLison is undercorrectedfromthesurgery. ther ofwhichworkswellifthecylinder then youcanofferanAKorLRI,ei- essentially planosphericalequivalent, www.assort.com to theirnewvisionwith to learnhowadapt months orsix • Posteriorcapsularopacifica- If acornea-basedenhancementis If there’s residualcylinderaftera cant residualrefractiveerroreven It maytakepatients three days, If there’s anysignificantPCO a premiumlens. www.astigmatismfi ) orinstrumentation x.com and and available today. limitations ofthetechnology wehave their outcomes,giventheinherent all youcanaftersurgerytooptimize avoid thesesituations,andthendo to doallyoucanpreoperatively after surgeryand,therefore,it’s best patients, it’s achallengingdiscussion correction forallactivities.Forthese to be100-percentfreeofspectacle operatively thattheyshouldn’t expect informed themmultipletimespre- glasses foranyfunction,evenifyou tients aredisappointediftheyneed ing bothdayandnight.Manypa- range ofvisionfromneartofardur- time, ormaybeheexpectedaperfect his problemsachancetoresolveover sion diffi Maybe he’s nottolerantofnight-vi- … butthepatientstillisn’t satisfi with excellentoutcomesaspredicted Often, thesurgeryisnearlyperfect, IOL. focal orEDOFlensforamonofocal should bereadytoexchangeamulti- not everadaptand,forthem,we their newvision.Somepatientsmay to adjustandlearnhowadapt three days,monthsorsix improve overtime.Itmaytakethem patients’ nearvisionandnightto specialist. then considerareferraltoretinal CME ordecreasedqualityofvision, thought tobeacauseofpersistent fully resolved.IfERMispresentand detected, CMEmustbetreateduntil OCT isindicatedtoruleoutCME;if an IOLexchangeorrotation. capsulotomy ifyou’restillconsidering also waitonperformingaposterior tial fordevelopingCME.You should IOL isstableandtoreducethepoten- best towaitlongerensurethatthe as sixweekspostoperatively, butit’s cated. Thiscanbeperformedassoon plaints, aYAG capsulotomyisindi- In summary, premiumIOLs have • Goodsurgery, wrongpatient. • Neuraladaptation. • Cystoidmacularedema. culties orisn’t willingtogive We expect AnSD- ed. 44/12/18 11:14 AM / 1

2 / 1 8

1 1 : 1 4

A M come a long way in the past decade, and can provide excellent visual function and spectacle independence for Improve Your the great majority of patients. Some, however, will not be happy with their outcomes. A detailed history, exami- 5WTIKECN'HƂEKGPEy nation, biometry/IOL calculations and discussion are critical to preventing misunderstandings and poor out- With Premium Quality comes with premium lens implants. In completing this process, treat a Single-Use Instruments premium lens patient like a refractive surgery patient in terms of her preop • Market leading portfolio evaluation, and make it a point to rule • Designed for excellent out conditions that may lead to poor outcomes or limit her options for im- clinical performance proving her vision after surgery. The only way to completely eliminate unhappy postoperative premium lens patients from our practice is to not perform the surgery. How- ever, by using the preop, intraop and post op management tips outlined in this article, you can expect very high success rates and patient satisfaction with premium IOLs.

Dr. Piracha is an associate professor of ophthalmology at the Univer- sity of Louisville and the University of Kentucky. He is a consultant to Carl Zeiss Meditec.

1. DOF2016CT0024 (Concerto Study Report) and DOF2015OTH0009 (Symfony Harmony Observational Study). 2. Patient information brochure: J&J Tecnis ZKB00 and ZLB00. 3. Henderson BA, Kim JY, Ament CS, et al. Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg 2007;33:9:1550-1558. 4. Wittpenn JR, Silverstein S, Heier J, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid BVI Portfolio Features Malosa™ vs steroid alone in low-risk cataract surgery patients. Am J Ophthalmol 2008;146:4:554-560. Single-Use Instruments 5. Conrad-Hengerer I, Hengerer FH, Al Juburi M, Schultz T, Dick HB. Femtosecond laser-induced macular changes and anterior segment inﬂ ammation in cataract surgery. J Refract Surg 2014;30:4:222-6. 6. Hengerer FH, Dick HB. Corneal endothelial cell loss and For ordering information, please call customer service corneal thickness in conventional compared with femtosecond laser-assisted cataract surgery: Three-month follow-up. J Cataract Refract Surg 2013;39:1307–1313. Beaver-Visitec International, Inc. 7. Takacs AI. Central corneal volume and endothelial cell count following femtosecond laser-assisted refractive cataract US: 1-866-906-8080 surgery compared to conventional phacoemulsiﬁ cation. J EU: 44 (0) 1865 601256 Refract Surg 2012; 28:387–39. bvimedical.com

046_rp0518_f4.indd 51 4/12/18 11:14 AM Anterior-chamber IOLs REVIEW Cover Focus No Capsular Support: Do ACIOLs Still Make Sense?

Christopher Kent, Senior Editor

New alternatives few years ago, when a cataract a widely-used technique, the prolene surgeon was faced with an eye can erode over time, often resulting have many Athat had minimal or no capsular in the lens dropping to the back of the support, there were only two surgical eye 10 years later. In contrast, Gore- surgeons shying options: insert an anterior chamber Tex doesn’t erode.) lens or suture a lens into the posterior “Today, we have options that are away from ACIOLs chamber. Today, the options for pos- more cornea-friendly and angle- terior lens fi xation have proliferated, friendly,” agrees Nicole Fram, MD, —but there’s still a changing the nature of that choice. managing partner at Advanced Vision “Lack of capsular support is some- Care in Los Angeles and a clinical in- place for them. thing we’ve always been concerned structor of ophthalmology at the Stein about and tried to prepare for in cata- Eye Institute, University of California, ract surgery, but our options for man- Los Angeles. “There have been many aging this situation have increased exciting advances in scleral fi xation. If through the years,” says Kendall E. you can offer someone a more physi- Donaldson, MD, MS, medical direc- ologically appropriate procedure with tor of Bascom Palmer Eye Institute’s the lens placed away from the cornea Plantation, Florida, location and asso- and iris, I think you should.” ciate professor of ophthalmology and Given the expansion of manage- co-director of the corneal fellowship ment alternatives in this situation, the at Bascom Palmer Eye Institute. “To- question arises: Is the placement of day we see more iris-fi xated posterior an anterior chamber lens—with its at- chamber lenses. We have glued IOLs, tendant possible complications—still thanks to Amar Agarwal, MD, in In- a viable option? Here, surgeons expe- dia. We have the relatively new Ya- rienced in anterior and posterior lens mane technique, which involves plac- placement share their experiences ing the haptic through a channel and and opinions. then cauterizing the tip, which causes it to enlarge so we can tuck it into the ACIOLs: A Riskier Option? sclera. And, we have the option of using long-lasting Gore-Tex to suture an One of the most obvious reasons Akreos lens in place. In the past, we to question the validity of placing an would have used prolene to suture a anterior chamber lens is that ACIOLs lens to the sclera.” (She explains that sit in a place that nature didn’t intend although suturing with prolene is still to hold a lens. That makes this option

52 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

0052_rp0518_f5.indd52_rp0518_f5.indd 5252 44/12/18/12/18 12:2212:22 PMPM rior chamber IOLs than with ACIOL placement. “Of course,” she adds, “all of this is only true if you’re properly trained in the technique you’re using.”

Kendall E. Donaldson, MD, MS MD, Kendall E. Donaldson, Challenges Placing an ACIOL

Another concern that can exacer- bate the inherent potential problems with a lens sitting close to the cornea is that anterior chamber lenses are challenging to fi t. Mitchell P. Weikert, MD, associate professor at the Cullen Eye Institute at the Baylor College of Medicine in Houston, says he believes that anterior chamber lenses still have a place when performing surgery on Anterior chamber IOLs like the one above can work well, with minimal side effects, when a patient with weakened zonules—if the anterior chamber is deep and the IOL is properly sized and positioned. However, new ways of fi xating posterior chamber IOLs have many surgeons favoring that alternative. they fit well. “If they fit well in the anterior chamber, they usually do very well and have very few complications,” susceptible to a list of potential com- syndrome; or cystoid macular edema. he says. “However, proper fi tting can plications that can result in damage to Sometimes we see all three. Most dis- be a challenge, for several reasons. the cornea, iris or angle. appointing is when we fi nd chronic in- “For one thing, we have limited “Posterior chamber lenses are gen- fl ammation, a decompensated cornea sizes available to us,” he says. “For ex- erally thought of as being healthier for and mismanagement of iris defects, ample, Alcon offers three sizes of ante- the eye because they’re farther from resulting in extensive peripheral an- rior chamber lenses; Bausch + Lomb the corneal endothelium,” says Dr. terior synechiae with secondary glau- offers two sizes. The size of everyone’s Donaldson. “They’re at a more physio- coma. That limits the possibility of us- anterior chamber is a little different, so logic location, behind the iris. Anterior ing more cutting-edge procedures for it can sometimes be challenging to fi nd chamber lenses sit close to the corneal visual rehabilitation that would result the right lens. Second, the dimensions endothelium, and as a result the pain faster recovery, such as Descemet’s of the anterior chamber horizontally tient will lose some endothelial cells membrane endothelial keratoplasty and vertically can be a little different. over time. That could lead to corneal (DMEK). There’s no question that Third, not every OR stocks a full ar- edema—or even a corneal transplant. over time, a malpositioned ACIOL ray of the ACIOLs that are available. For that reason, many surgeons think will eventually induce one or all of Although we may plan to use an AC- of anterior chamber IOLs as making these co-morbidities. IOL in some cases, they’re more com- the most sense when a patient is older. “In contrast, I believe that if you monly used following a complication Older patients will have fewer decades have the patience and skill set to fi xate that precludes the use of a posterior for corneal issues to develop.” posterior chamber IOLs, whether it’s chamber IOL. Unless you’ve ordered Working in a tertiary referral prac- intrascleral fixation or suture scleral a special lens ahead of time, the OR tice, Dr. Fram often encounters those fixation, and you obey the basic te- may not have the one you need.” problems. “We see many complica- nets of performing proper anterior Dr. Weikert also notes another tions caused by malpositioned— vitrectomy or pars-plana-assisted an- problem. “These lenses fi t in the angle, and even properly placed—anterior terior vitrectomy, you won’t have as so we ideally need to know the angle- chamber IOLs,” she says. “In the vast high an incidence of complications,” to-angle measurement,” he points out. majority of cases we see at least one she says. “Any secondary IOL-fi xation “Typically we don’t have that. We can of the following complications: en- technique can result in endothelial get it with ultrasound biomicroscopy dothelial failure with corneal edema; failure, chronic infl ammation or CME. or with an optical coherence tomogra- chronic intraocular infl ammation, or However, in our experience, those are phy scan that spans the entire anterior uveitis-glaucoma-hyphema (UGH) far less common with fixated poste- segment, but these measurements are

May 2018 | reviewofophthalmology.com | 53

052_rp0518_f5.indd 53 4/12/18 12:23 PM 052_rp0518_f5.indd 54 quicker recovery.” create astigmatism,andmayleadtoa through asmallincisionislesslikelyto smaller, foldablelensthatyoucanﬁ heal. Incontrast,sclerallyfixatinga a while,soitcantakelongtimeto you’ll havetoleavethesuturesinfor at riskforcreatingastigmatism.Also, surgery. However, that’s whenyou’re counter complicationsduringcataract to 6mminsertthelensiftheyen- enlarge theirclearcornealincision ber lens;manysurgeonswillsimply neal incisionforananteriorcham- he says.“Ofcourse,youcandoacor- to accommodatethelargeincision,” to haveenoughrealestateontheeye take downconjunctiva,andyouneed quires ascleralincision,soyouhaveto an anteriorchamberlenstypicallyre- an anteriorchamberlens.“Implanting need alarge,6-mmincisiontoinsert four-point ﬁxation ispreferable.” Kelman-design lenswith than others.Generally, a lenses aremoreflexible ber sizes,althoughsome different anteriorcham- they’ll adaptalittlebitto “the lensesareforgiving; the sulcusmeasurement. measurement, oreven the actualangle-to-angle fairly poorcorrelationto it’s beenshowntohave is commonpractice,but a millimeter. Doingthat to-white distanceandadd just measurethewhite- implant anACIOL,we’ll in theORandneedto tients. Instead,ifwe’re preoperatively inallpa- not typicallyperformed 54 techniques forfixatingaposterior comes withseveralcaveats,so domost Posterior FixatedLensIssues Dr. Weikert alsopointsoutthatyou “Fortunately,” headds, Although implantinganACIOL REVIEW | Focus Cover

Review ofOphthalmology

Anterior-chamber IOLs uveitis-glaucoma-hyphema (UGH)syndrome;andcystoid macularedema. edema;chronicendothelial failure intraocular withcorneal infl A malpositionedanteriorchamber IOL. These canbeassociatedwith | May2018 t fully.” they deserveandmonitorthem care- cases andpatientswiththerespect detachment. You havetotreatthese to verifythatthere’s noretinaltearor send thepatienttoaretinalspecialist ing signsuchasfl ashes orfl rhage, oraretinaldetachmentwarn- tient hasasignifi cant vitreoushemor- months formaintenance.Ifthepa- Patients arethenfollowedeverysix week, threeweeksandtwomonths. perform acarefulretinalexamatone ment,” shesays.“Forallofmycases,I higher riskforretinaltearordetach- in theparsplanasuturingyou’reata lenses cantilt,andanytimeyou’re be anissue,”notesDr. Donaldson. ing effectivelenspositionwillalways to endupwithlenstilt,andanticipat- chamber fi xated lensesaremorelikely also havecomplications.“Posterior terior chamberinclude: challenging. of whichoptiontopursuealittlemore chamber lens.Thatmakesthechoice • Dr. Framagrees.“Obviously, the • Issues withlensesfixated inthepos- Posterior chamberlensescan Fixating aposteriorchamber oaters, I’ll I’ll oaters, ammation, or a bigdifferencewhenputting inan are alotofsmalldetailsthatcan make how tomakeagoodwound. There astigmatism, andyouhavetoknow so youdon’t inducealotofcorneal have toknowhowsutureproperly ripheral iridotomy,” shesays.“You chamber lens.“You havetodoape- associated withplacingananterior there isalsoasmalllearningcurve with theavailablesurgicaloptions.” much experiencethesurgeonhashad tient mayhavealottodowithhow these proceduresisbestforthepa- occur. Sotheanswerastowhichof plications ofonetypeoranotherwill surgeon, themorelikelyitisthatcom- tinues. “Theless-experiencedthe ence willbeafactorhere,”shecon- proper preparationandpractice. thing youjustrunoutanddowithout ously thesetechniquesarenotsome- can talkaboutthatfortwohours,obvi- shared thepropertechnique.Ifwe thing theydidwrong.Otherspeakers were showingtheirnightmares,every- focused oncomplications;people Yamane technique.Onesectionwas

Dr. Donaldsonacknowledgesthat “For thatreason,surgeonexperi- Nicole Fram, MD Fram, Nicole tion dedicatedtothe whole two-hoursec- at whichtherewasa cently at a symposium cently atasymposium support. Iwasre- absence ofcapsular chamber lensinthe to placeaposterior be learnedinorder technique thathasto defi Donaldson. “Thereis minutes,” notesDr. only takesfiveto10 IOL, whichusually an anteriorchamber difficult thanplacing much moretechnically terior chamberIOLis turing orgluingapos- cally difficult.“Su- lens ismoretechni- nitely muchmore 4/12/18 12:23 PM Keep Learning Given that new techniques for fi xating posterior chamber lenses out that today it’s possible to practice the newer, more challeng- keep appearing, it makes sense to take the time to learn at least ing procedures using simulation technology. “Simulation training a few of them. “Lack of capsular support is a situation we all systems such as the SimulEye surgical training models allow us encounter,” notes Kendall E. Donaldson, MD, MS, medical director to practice these techniques before a situation occurs at the time of Bascom Palmer Eye Institute’s Plantation, Florida location. “If of surgery,” she says. “You can practice your anterior vitrectomy you didn’t encounter it in residency, it will defi nitely happen to you technique using triamcinolone, or practice different IOL-fi xation later on. So, be prepared to perform multiple types of procedures. suturing techniques. “To learn a new procedure, watch videos, talk to colleagues “For example,” she continues, “you can practice intrascleral and observe colleagues performing the procedure in question, fi xation with the Yamane double-needle fi xation technique. Then, because we can really learn a lot from each other,” she continues. when you need to use it during surgery, you have the muscle “You’ll fi nd many videos of any given procedure online, or at the memory and the step-by-step process already in your head. Or, ASCRS or Academy websites. And there are plenty of seminars you can practice these techniques in a non-stressful environment and symposia at meetings where we discuss these topics and by taking on a case of a patient who’s aphakic, where the eye is everyone shares their good and bad videos. Those can be great vitrectomized. Later, when you’re in a situation in which you lose learning experiences.” the capsule or the zonules, you’re going to be more technically Nicole Fram, MD, a clinical instructor of ophthalmology at the and emotionally prepared for it.” Stein Eye Institute, University of California, Los Angeles, points —CK

anterior chamber lens, but they’re eas- that received anterior chamber IOLs anterior chamber lenses,” she points ily learned. I just think the learning to those receiving sutured posterior out. “Today we have open-loop an- curve is longer with some of the poste- chamber IOLs,” says Dr. Donald- terior chamber lenses that cause less rior chamber techniques, compared to son. “We found more postoperative fi brosis and less infl ammation in the properly placing an anterior chamber astigmatism in the posterior chamber angle. The older lenses had a higher lens.” lenses, but overall, we found a similar incidence of UGH syndrome; it was so • Posterior surgeries take longer. incidence of complications in the two common with those older model ante- “This can be a problem if the patient groups.”1 rior chamber lenses that we developed has retinal issues or a history of uve- Dr. Fram agrees that the research a name for it! We still see it, but it’s not itis,” notes Dr. Donaldson. “You’re published to date suggests that wheth- as common as it used to be. Patients more likely to have a vitreous hemor- er an anterior or posterior lens is cho- do much better with the modern ante- rhage or retinal complications with sen, the outcomes tend to be similar. rior chamber lenses.” a longer, more complex case that in- “The Wagoner paper from 2003 com- Nevertheless, Dr. Fram says she volves suturing to the sclera, and you pared properly placed anterior cham- prefers to use a fi xated posterior lens. may experience iris chafing or uve- ber IOLs to scleral- and iris suture- “I’ve never met an anterior chamber itis with iris-sutured lenses. And of fi xation techniques and found that all IOL that I liked over the long term,” course, the likelihood of these prob- of the options were equivalent,” she she says. “That’s why I was determined lems will be greater in an older patient says.2 to learn other secondary IOL-fi xation or a complex case when the patient “Of course, we don’t have long-term techniques.” has several pre-existing conditions.” data for some of the newer techniques Dr. Donaldson notes that the option for scleral fi xation, to compare them to a surgeon chooses is usually based on Do We Have a Winner? anterior chamber fi xation,” Dr. Weik- factors such as surgeon experience, ert notes. “But to date, the literature patient age and any co-morbid con- Given that both anterior and poste- shows them to be about the same un- ditions such as glaucoma or retinal rior chamber lenses have drawbacks, der comparable circumstances.” problems. Dr. Weikert offers another should surgeons favor posterior cham- Dr. Donaldson adds that despite all perspective: “Ultimately,” he says, ber IOLs? of its potential problems, the anterior “you’re choosing between potential “In a retrospective study I partici- chamber lens option is less problemat- intraoperative complications and po- pated in at Bascom Palmer in the early ic than it was in the old days, thanks to tential postoperative complications.” 2000s, we compared the outcomes improvements in lens design. “Thirty Surgeons offer the following tips for in eyes with poor capsular support or 40 years ago we had closed-loop managing a situation involving weak or

May 2018 | reviewofophthalmology.com | 55

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An anteriorchamber lensthathasdevelopeduveitis-glaucoma-hyphema (UGH)syndrome. Kendall E. Donaldson, MD, MS ber. Ideally we’dalsogetspecularmi- have thedepthofanterior cham- planning iskey. We shouldalready son. “Inthatsituation,preoperative capsular support,”notesDr. Donald- higher riskforanissuewithlackof anticipate whichpatientswillbeat “About 90percentofthetimewecan to implantananteriorchamberlens.” and hasagoodcornea,Imightdecide vor scleralﬁ xation. Ifthepatient is75 the eyehasnocapsulesupportI’llfa- aphakic andneedsasecondarylens,if tient comesinwho’s hadtrauma,oris younger,” hesays.“Ifa50-year-old pa- terior chamberlensifthepatientis have. “I’mlessinclinedtouseanan- effect ananteriorchamberlensmight thelial cellcountandthelong-term to keepinmindthepatient’s endo- limited capsularsupport,it’s important time thatyou’relikelytobemanaging Weikert saysthatifyouknow aheadof consider thepatient’s age. Dr. limited capsularsupport: Before GoingtoSurgery or ﬁxate aposteriorchamberlens. ciding whethertoimplantanACIOL nonexistent zonularsupportandde- 56

• • If youknowthatyou’redealingwith REVIEW |

When choosing your approach, When choosingyourapproach, Focus Cover Get additionalmeasurements Review ofOphthalmology

Anterior-chamber IOLs | May2018 . everything we can to get you the best everything wecantogetyou thebest we havesomeoptions,and we’ll do an alternativeposition.Fortunately, be, I’llbepreparedtoputthelensin to toleratealenswherewe’dlikeit be, butifyoureyeisn’t strongenough the lensexactlywherewewantitto going todoeverythingwecanput in whichtowork.Itellthem,‘We’re angle thatdoesn’t giveusmuchspace factors, suchashavingaverynarrow syndrome is.Imayalsomentionother eye.’ Iexplainwhatpseudoexfoliation pears tobeweakerthantheaverage after surgeryifacomplicationoccurs. makes foramucheasierconversation patient aboutitpreoperatively. That what compromised,youcantalktothe know thecapsularsupportissome- pseudoexfoliation syndromeandyou terior lenscapsule.Ifthepatienthas pseudoexfoliative materialonthean- unpredictable eyes,andyoumaysee years old,”shesays.“Theymayhave are older. “Theymightbe90or93 tients withpreopzonularproblems for surgery. Shenotes thatmanypa- complex whenpreppingthepatient the realitythatthissurgerycouldbe aldson saysit’s importanttoaddress cells.” croscopy tolookattheendothelial “For example,I’llsay, ‘Your eyeap- • Talk tothepatient.Dr. Don- other optionsavailable,”says Dr. technique, I’llmakesurethat Ihave “Even whenI’mplanningto useone for anyofseveraloptionsonhand. In theOR for later.” fi to beasstressed.Doyoureasycases time ifyouneedit,sodon’t have Donaldson. Thatwayyou’llhaveextra toward theendofday,” saysDr. complicated case,schedulethatcase of time.“Ifyouknowyou’redoinga schedule itwhenyouhaveplenty calmly andclearlyinthosesituations.” you dothat,you’llfi nd ittoughtothink think onyourfeet,”sheadds.“Until sible nonroutinescenarios,youcan es youoffguard. you’re notreadyandaproblemcatch- ready. Therealdiffi culties arisewhen It’s yourobligationasasurgeontobe to bepreparedwithmultipleoptions. nesis ontheslitlampexam,youhave vitrectomies andyoufindphacodo- you knowthatapatienthashadthree the zonulescouldbeaffected,orif a patienthaspseudoexfoliationand OR,” Dr. Framnotes.“Ifyouknow A, BandCreadywhenyougointothe always saysthatyouhavetoplans expected challenges. discussion.” it.’ Itopensthewindowforfurther ing extradropsandsoforthtohandle able toplacethelens.We’ll justbeus- weaker thanaverage,butwewerestill expected, wefoundthatyoureyewas wanted ittobe,oryoucansay, ‘As fectly andthelensisrightwhereyou either saythateverythingwentper- versation iseasier,” shesays.“You can before surgery, thepostoperativecon- possible outcome.’ rst andsavethemorestressfulcases • Once you’rereadytooperate: • “Once youlearntomanagethepos- • “Once youhavethatconversation Have the tools you might need Have thetoolsyoumightneed Be preparedtodealwithun- If thecasewillbecomplex, “Dr. Masket 4/12/18 12:23 PM

Mitchell P. Weikert, MD Weikert. “If I’m planning for scleral fixation with, say, the Yamane technique, I’ll also make sure an anterior chamber lens is available, just in case. We recently had a case at our veterans hospital where we were going to use the Yamane technique, but we encountered some diffi culties with our scleral passages; so, we just changed gears and placed an anterior chamber lens. The patient was older—late 60s, early 70s—and had a good cornea. The bottom line is, no matter what you do, it’s always best to have multiple options.” The Yamane technique (above) is one of a number of recently developed ways to fi xate a Dr. Donaldson agrees. “In a lot of posterior chamber IOL. Fixating a lens posteriorly is presumed to be safer for the cornea these complicated cases in which we than anterior chamber placement, but these techniques can be challenging and time- know that the eye is not normal, we consuming to perform, and lenses in this location are also associated with complications. might go in with two or three different IOLs,” she says. “We’ve already done chronic iritis and CME, and eventu- diffi cult surgery, the cornea is barely the calculations for them. We also ally have corneal decompensation. It’s hanging on and/or the patient is get- make sure we have the extra tools that better to leave a patient aphakic and ting restless, you might create other can help us normalize a compromised come back to place a secondary IOL issues if you try to implant an IOL. capsule and allow us to put a posterior than to place a malpositioned IOL.” “For example,” he continues, “in chamber lens in the bag, such as cap- • When implanting an anterior our practice we’ve seen complications sular tension rings and Ahmed seg- chamber lens, make sure you seat such as UGH syndrome or cystoid ments. We wouldn’t have been able to it in the angle carefully. “If you see macular edema resulting from single- do that years ago, and I’m thankful to any iris distortion or ovalization of piece IOLs being placed in the ciliary our colleagues that have come up with the pupil, recheck how the lens foot- sulcus because the surgeon didn’t feel these tools.” plates are seated in the angle,” says Dr. comfortable leaving the patient apha- • Be careful when choosing the Weikert. “If you can’t get the ovaliza- kic after a surgical complication. If size of an anterior segment lens. tion to go away by repositioning the the appropriate IOL model isn’t avail- “The problem is, we were taught to lens, consider putting in a smaller lens, able, it’s far better to leave the patient measure the white-to-white length leaving the patient aphakic or shifting aphakic and come back on a different and then add 1 mm [when gauging the to scleral fi xation. day to implant an IOL under optimal size of the space],” Dr. Fram notes. “The dimensions of the anterior conditions.” “That may not be accurate for a given chamber are usually a little shorter Dr. Fram points out that in some patient. For one thing, the measure- vertically than horizontally,” he adds. stressful situations a surgeon might ment will be different if you measure “That means you can always rotate the be tempted to try performing a pro- the white-to-white horizontally or ver- lens inside the anterior chamber if you cedure that he or she has only done tically, so placement and location of think it might sit better. If your inci- a few times before, such as suturing the lens haptics matter. It could be sion is temporal and the lens appears a posterior chamber IOL to the iris that white-to-white plus 0.5 mm is loose after insertion, it may actually sit or sclera. “That might not be the best more appropriate in some patients. better in a vertical position.” choice,” she says. “If you’re caught off Furthermore, many surgery centers • Don’t be afraid to leave the guard and you don’t know whether the and hospitals don’t stock all the differ- eye aphakic. “If things didn’t go as eye is a good candidate for an anterior ent lens sizes, so surgeons often end planned, and you don’t feel confi dent chamber lens, there’s nothing wrong up putting in a lens that’s too big or that you’re going to end up with a with leaving the patient aphakic and too small. A lens that’s too small ends good result after placing a lens at the cleaning everything up and coming up bouncing around and causing pig- time of primary surgery, just leave the back another day. If I’m doing a sur- ment dispersion and corneal endothe- patient aphakic and come back later,” gery and it’s an unstable situation and lial failure. If it’s too big, you can get says Dr. Weikert. “If it’s been a long, it’s already been two-and-a-half hours

May 2018 | reviewofophthalmology.com | 57

052_rp0518_f5.indd 57 4/12/18 12:23 PM 052_rp0518_f5.indd 58 detachment repair. ofmaculardegeneration andretinal rehabilitation forthismonocularpatientwithahistory Placement ofan forvisual decompensationrequiring DSEKsurgery ACIOL ledtocorneal giants,” shesays. trained toperformthesesurgeriesby ies. “I’vebeenfortunatetohave the complexanteriorsegmentsurger- Masket, MD,trainedhertoperform tice partnerformanyyears,Samuel Eye HospitalandUCSF, andherprac- aphakic becausehermentorsatWills rarely endsupleavingherpatients take courage.” best thingtodo.Admittedly, itdoes aphakic, inmanysituations,that’s the seem sacrilegioustoleavethepatient back atalaterdate.Althoughitmay tomy, lettheeyecalmdownandcome proper triamcinolone-assistedvitrec- often bettertocleanuptheeyewitha scleral sutureﬁxation atthatpoint.It’s in theOR,I’mnotgoingtostarta 58 course thatshouldbeyour proce- sition theanteriorchamber IOL, of and youknowhowtoproperly po- generate minimalastigmaticchanges, scleral tunnelwithafrownincisionto deep, you’rewell-trainedtomakea measurements right,thechamberis skill set,”Dr. Framsays.“Ifyougetthe an ACIOL,especiallyifthat’s yourbest ACIOLs: StillWorth Using? Kendall E. Donaldson, MD, MS Dr. Framnotesthatsheherself “I dobelievethere’s stillaplacefor REVIEW | Focus Cover

Review ofOphthalmology

Anterior-chamber IOLs | May2018 rior chamberIOL,that’s yourchoice or youperformascleral-fi ACIOL that’s beencarefullyplanned surement. a truewhite-to-whiteorsulcusmea- propriate lensesavailablebasedon prior toplacement,andhaveap- chamber depthandcornealhealth it’s importanttoevaluatetheanterior technique. However, inthatsituation port anintrascleralorsuture-fi anticoagulants, ortheeyecan’t sup- patient can‘taffordtostop[systemic] ACIOLs eachyear, whenIbelievethe she says.“Iprobablyputinoneortwo high-risk thesurgerymaybecome,” patient’s coagulationstatusandhow consider theageofpatient, terior segmentlens.“You haveto she doesoccasionallyimplantanan- prefers posteriorsegmentplacement, refractive outcome.” tive ofthestabilityIOLand see patientseverysixmonthsirrespec- not detectedpromptly. Thisiswhywe erosion canleadtoendophthalmitisif fi course, thisisalsothecaseforscleral- be exchangedifproblemsarise.Of monitored closely, andthelensshould dure. Butthosepatientsneedtobe xated IOLs, because suture or haptic xated IOLs,becausesutureorhaptic “Whetheryouendupusingan Dr. Framsaysthatalthoughshe xated poste- xation xation and safeforthepatient.” that yourinterventionsaresuccessful the patientafterwardstomakesure dure wellandreproducibly, andcheck says. “Justbesuretodoyourproce- chosen, fixatedandmonitored,”she using aslongtheIOLisproperly what secondaryIOLtechniqueyou’re fortable performing.“Itdoesn’t matter use thetechniqueyoufeelmostcom- bad rap.” chamber lenshaskindofgottena have doneverywell.Theanterior chamber lensesformanyyearsand some patientswho’vehadanterior about long-termcomplications,Ihave surgery. Anddespitetheconcern can’t undergoamorecomplicated sick eyeorforanolderpatientwho easy, andmaybethebestchoiceina an anteriorchamberlensisquickand an anteriorchamberlens.Puttingin fellows needtobetrainedplace says. ”Ithinkallofourresidentsand that’s appropriateineverycase,”she ed, soclearlythere’s noperfectoption the yearsouroptionshaveproliferat- support isweakormissing.“Through terior chamberlenseswhencapsular there isdefi nitely stillaplaceforan- consider anIOLexchange.” cation happens,dealwithitearlyand syndrome andCME.Andifacompli- for cornealedema,glaucoma,UGH surgery well,andmakesureyouwatch the optionsareequivalent.Justdo another, we’regoingtohavesaythat true superiorityofonetechniqueover spective studycomesoutshowingthe as thesurgeon,”sheadds.“Untilapro- of Ophthalmology. 2003;110:4:840-59. Ophthalmology support:absence ofcapsular A reportbythe American Academy Academy ofOphthalmology. inthe Intraocularlensimplantation 2. Wagoner MD, Cox TA, RG,Ariyasu JacobsDS, KarpCL; American support.poor capsular RefractSurg2005;31:5:903-9. JCataract and suturedposteriorchamberintraocularlensesineyeswith 1. DonaldsonKE, GorscakJJ, BudenzDL, etal. Anterior chamber company mentioned. Weikert havenofi nancial tiestoany for Alcon.Drs.Donaldsonand Dr. Framsaysultimatelyyoushould Dr. Donaldsonsaysshebelieves Dr. Framhaspreviouslyconsulted 4/12/18 12:27 PM ENRICH YOUR PRACTICE

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2018_rp_tsrad.indd 90 4/13/18 11:28 AM Retinal Insider

REVIEW Edited by Carl Regillo, MD, and Emmett T. Cunningham Jr., MD, PhD, MPH

Digging Deeper Into Protocol U The DRCR Network’s study of two treatments for diabetic macular edema revealed the pros and cons of the approaches.

Raj Maturi, MD, Indianapolis

he DRCR Network recently complet- edema over the next six months com- visual loss (worse than BCVA of 20/25 Ted Protocol U, a short-term study pared to Lucentis alone. on a standardized ETDRS refraction). comparing the addition of a dexameth- For the study, we enrolled 236 pa- A total of 129 subjects who still had asone implant (Ozurdex) to ranibi- tients who had received at least three edema and vision loss were random- zumab (Lucentis) in patients who have injections of any anti-VEGF over the ized to either receive a combination continued diabetic macular edema.1 prior 20 weeks, but who continued to of Ozurdex and Lucentis or to con- The impetus for this study was to see have macular edema and visual loss. tinue with Lucentis alone. It’s impor- whether combined treatment with a These subjects were all given addi- tant to note that among those who corticosteroid and an anti-VEGF agent tional injections of Lucentis every four were not eligible for randomization, would improve vision, since, on aver- weeks for 12 weeks (i.e., three addi- many had either resolution of macu- age, about 40 percent of patients with tional doses). At the end of this enroll- lar edema or improvement of vision DME will continue to have retinal ment period, subjects were evaluated before randomization with three ad- thickening as well as reduced vision to see whether they still had macular ditional injections of Lucentis, again despite regular anti-VEGF injections edema (over 300 µm on SD-OCT) and demonstrating the beneﬁ t of contin- over six months. This result was shown in DRCR Protocol I (in the Lucen- tis groups), as well as in Protocol T (where aflibercept groups had even lower rates of residual edema). In this article, I’ll explain how we National Eye Institute National Eye DRCR network researchers designed Protocol U, and what its findings might mean for the clinician.

The Study’s Design

In Protocol U, we wanted to see whether adding a steroid implant every three months to eyes that continued to have edema would result in improved visual acuity and decreased macular

60 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

060_rp0518_retinal_Insider.indd 60 4/12/18 11:48 AM ued anti-VEGF treatment. While patients had to have persistent edema despite at least three injections of Lucentis prior to enrollment, we found that providing these same eyes with three additional injections of Lucentis in the enrollment phase resulted in continued improvement in vision and edema. Their vision in the enrollment phase improved on average by three letters, and their edema was reduced by more than 50 µm on average. In fact, about a third of the enrolled subjects either showed resolution of macular edema or achieved vision better than 20/25, and thus were exited from the study. The remaining eligible 129 subjects were randomized per protocol and received an average of 5.6 injections of Lucentis over the next 24 weeks, with the combination group receiving nearly two dexamethasone implants, on average, over the study period as well. Thus, subjects had close to maximal treatment through the duration of the study. Results of the primary endpoint analysis were consistent with results from previous smaller single-center trials: We found no overall differences in visual acuity between the two groups (Lucentis alone vs. Lucentis + dexamethasone implant). Both groups improved by approximately three additional letters in the randomized, 24th-week phase of the study. However, on pre-planned subgroup analysis, we found that there was a greater proportion of subjects with a 15-letter or greater improvement in vision in the combination vs. the Lucentis-alone group (11 percent vs. 2 percent, p=0.03). We also found that the combination group had a small increase in the proportion of patients with a decrease in vision greater than 10 letters (13 percent vs. 6 percent, p=0.09), though this wasn’t statistically signifi cant. We also found that the central subfi eld thickness decreased signifi cantly more in the combination group compared to the Lucentis-alone group (110 µm vs. 62 µm, p<0.001). More- PASSIONATE ABOUT PATIENT CARE? over, about half of the combination group had a fl at retina at week 24 compared to 31 percent of the Lucentis-alone group (p=0.02), and the improvement in OCT thickness was His sight depends rapid and sustained in the combination group. This would be expected, as dexamethasone implants were provided every 12 on your confidence. weeks, and not every 24 weeks as per the label, since we felt that the duration of action of these implants required implan- Ocular Response Analyzer® G3 tation at shorter intervals. The entry criteria for the study were rather strict with Corneal Hysteresis, a more objective predictor regard to potential subjects not having any history of cortico- of glaucoma progression. CPT code 92145. steroid responsiveness. For example, subjects with a history of developing ocular hypertension in response to topical corticosteroids in the fellow eye at any time in their history were Watch the videos at reichert.com/glaucomaconfidence excluded. Despite this careful exclusion, about 30 percent of the combination group had a signifi cant rise in intraocular pressure, with 20 percent of subjects in the combination group requiring treatment for increased IOP. We found no visual acuity benefi t in the combination group © 2018 AMETEK, Inc. & Reichert, Inc. (03-2018) · Made in USA

Ocular Response Analyzer is a registered trademark of Reichert, Inc. · www.reichert.com ·

060_rp0518_retinal_Insider.indd 61 4/13/18 10:00 AM Retinal

REVIEW Insider

1 show that a patient can have stable Protocol U Visual Acuity Results after DME Treatment and even improving vision in the presence of edema for at least two years. Dexamethasone + Lucentis 22 However, we may be missing some Sham + Lucentis visual function that is useful for the 14 patient, even if it’s not measurable 11 13 % with high contrast ETDRS testing. For example, a patient’s low-contrast 665 2 acuity, useful in the dark, may be limited with increased edema. We just ≥ 15 Letter ≥ 10 Letter ≥ 10 Letter ≥ 15 Letter don’t know, as few studies look at such improvement improvement worsening worsening variables closely. Despite the potential benefit of corticosteroids for reducing edema over the Lucentis-alone group six enrollment, and thus received three by about 50 percent more than anti- months after randomization. It’s pos- additional injections in the run-in VEGF alone, the side-effect profi le sible that we would have had different phase. Therefore, many subjects in of intraocular corticosteroids makes results had the study been longer in the combination group received only them a less desirable choice. In pha- duration. However, the visual benefi ts six total injections of anti-VEGF prior kic patients, the risk of cataracts is suf- of adding steroids appear limited in to receiving dexamethasone implants. fi ciently high that I try to avoid their this population. While there was a This group’s visual acuity didn’t im- use. Other studies have shown com- signifi cant improvement in macular prove compared to subjects who had parable benefi t to using steroids with thickness in the combination group, a longer duration of anti-VEGF prior anti-VEGF vs. steroids alone, fi nding this benefi t must be balanced by the to enrollment. Thus, in this study, ear- that this approach may limit both the high incidence of IOP rise. lier treatment with dexamethasone treatment and the cost burdens. How- implants didn’t appear to result in im- ever, before going this route, it’s best Subgroup Analyses proved acuity over anti-VEGF alone. to confirm that the underlying dia- Again, the relevance of this fi nding is betic retinopathy is well-controlled, as We did multiple subgroup analyses limited by the small sample size. I believe corticosteroids don’t regress on these subjects: diabetic retinopathy as well as anti- • Pseudophakic patients. The Personal Experience VEGF agents do. In addition, while study was initially conceived as a dexamethasone implant placement pseudophakic subject-only study. In my clinical practice, I use intra- may require treatment only every 12 However, it was very diffi cult to re- ocular corticosteroids, mostly dexa- weeks, many patients will require in- cruit for the study, so we fi nally ex- methasone implants, in select cases. traocular pressure monitoring every panded the study to include phakic I’m most likely to use the implant in four to eight weeks. subjects. We examined the pseudo- patients who continue to have mild In summary, there are defi nite ana- phakic subgroup and found that the edema despite the use of anti-VEGF tomic benefi ts to using Ozurdex over visual acuity tracked in line with the therapy, particularly when they’re using Lucentis as studied in Proto- phakic subgroup acuity through week scheduled for cataract surgery in col U. However, though overall acu- 20. At the end of the study (week 24 the near future. Pretreatment with a ity was similar in both groups in the after randomization) the pseudopha- dexamethasone implant in these cases study, the benefits of steroids, and kic subgroup on combination treat- seems to prevent a worsening of mac- therefore their usage, are limited by ment had a fi ve-letter gain in acuity ular edema that can occur following their side-effect profi le. while the phakic subgroup treated surgery. Otherwise, I believe there’s with Lucentis alone had a gain of two only a very limited role for corticoste- Dr. Maturi is an associate professor letters. This difference at this single roids in phakic patients. at the Indiana University School of time point didn’t reach statistical sig- There may be a benefi t to having Medicine. He receives grant support nifi cance. a retina without edema vs. a retina from Allergan and Genentech.

• Duration of DME. Approxi- that continues to have edema, even 1. Maturi RK, et al. Effect of adding dexamethasone to continued mately half the subjects had only if the measured ETDRS visual acu- ranibizumab treatment in patients with persistent diabetic macular edema. A DRCR Network phase II randomized clinical trial. JAMA three injections of anti-VEGF prior to ity is the same. The DRCR studies Ophthalmol 2017; DOI:10.1001/jamaophthalmol.2017.4914.

62 | Review of Ophthalmology | May 2018

0060_rp0518_retinal_Insider.indd60_rp0518_retinal_Insider.indd 6622 44/12/18/12/18 11:4911:49 AMAM REVIEW Product News Bausch + Lomb’s New Vitrectomy Cutters

n late March, Bausch + Lomb announced the in- the pupil on the Itroduction of 25- and 27-gauge Bi-Blade dual port x, y and z vitrectomy cutters for the Stellaris Elite vision en- planes), hancement system. easy-to- Bausch + Lomb says its Bi-Blade cutters cut in both read and the forward and backward di- print re- rections, enabling two ports, and cuts per cycle, as op- automat- posed to single- ic calibra- port cutters. The tion and design used with brightness the Stellaris Elite measure- surgical plat- ment. form offers up to The SK-650A 15,000 cuts per retinal camera minute, allowing is a nonmyd- for increased flow riatic camera efficiency and control. For more information on Bausch + that is also DICOM-compatible. Lomb’s new vitrectomy cut- The device features an auto mo- ters, visit Bausch.com. saic function (a nine-point fixation system allowing for auto-mosaic Coburn’s New Visual Field photography over a large retinal Analyzer and Retinal Camera area), red-free visual testing for Coburn Technologies recently comparison of nerve fiber layer im- introduced two new products: the ages over time, and a new optical SK-850A visual field analyzer and design that Coburn says features the SK-650A retinal camera. full 45-degree image capture in or- The SK-850A comes in two differ- der to avoid losing fundus informa- ent models (standard and expert), with tion. the expert design coming equipped with For more information on enhanced features for more advanced Coburn’s new visual field testing. The SK-850A also includes analyzer and retinal camera, auto gaze tracking (3D fixation moni- visit coburntechnologies. toring with infrared light tracking of com.

This article has no commercial sponsorship. May 2018 | reviewofophthalmology.com | 63

063_rp0518_products.indd 63 4/12/18 11:23 AM Research Review REVIEW

Outcomes of Laser Peripheral Iridotomy

n a retrospective chart review, LE for each year older at baseline. tion resulted in comparable repre- Iresearchers from the department Each 1 mmHg higher IOP was as- sentation of keratoconus and ecta- of ophthalmology at the University sociated with 1.08-fold increased sia after refractive surgery in the of Edinburgh, U.K., examined the odds of LE. two treatment arms. Fellow eyes outcomes of laser peripheral iri- Based on these results, a large (n=207) were treated with five- dotomy for primary angle closure portion of patients with angle clo- minute dosing and considered in and determined predictors of fu- sure treated with LPI went on to the safety analysis. ture lens extraction. require LE. Patients with features The mean reduction in maximum The investigators analyzed 218 associated with higher odds of keratometry from baseline was eyes from 128 consecutive patients needing LE might be considered statistically equivalent in the two- who underwent LPI between 2010 for LE as a primary procedure, the and five-minute riboflavin dosing and 2012 at a university hospital. researchers say. intervals at six months (0.97 and Baseline factors included age, peak J Glaucoma 2018;27:275-280 0.76 D, respectively; 90 percent intraocular pressure before LPI, Bo J, Vhangulani T, Cheng ML, Tatham AJ confidence interval for treatment diagnosis (primary angle closure difference, -0.23 to 0.66; per-pro- suspect, primary angle closure, Riboflavin Dosing Intervals in tocol population). With both dos- primary angle closure glaucoma) Corneal Cross-linking ing intervals, the mean improve- and acute or nonacute presenta- Researchers from the Cornea Re- ment in corrected distance visual tion. search Foundation of America in acuity was 3.5 letters at six months. Ninety-one of 218 eyes (41.7 Indianapolis investigated whether Of the 635 study and fellow eyes percent) initially treated with LPI riboflavin dosing frequency affects examined at six months, 134 (21 had LE during follow-up. For eyes corneal cross-linking efﬁ cacy and/or percent) gained and 32 (5 percent) with nonacute presentation, 12 safety, given that isotonic riboflavin lost two or more lines of CDVA. percent, 25 percent and 32 per- solution is viscous and each instilla- Three eyes (0.4 percent) devel- cent had LE at one, two and three tion coats the corneal surface with a oped sterile infiltrates, one (0.1 years, respectively. For eyes with ﬁ lm that absorbs some of the incident percent) had delayed epithelial acute presentation, 27 percent, 42 ultraviolet-A light. healing with dendrites and three percent and 50 percent had LE In this prospective, randomized, (0.4 percent) had recurrent ep- at one, two and three years, re- single-center equivalence trial, re- ithelial defects. Three eyes (0.4 spectively. In univariable analysis, searchers studied patients (n=510) percent) were retreated. older age, higher IOP, worse visual with progressive keratoconus or The researchers concluded that field and primary angle closure ectasia after refractive surgery. the two riboflavin dosing regimens glaucoma diagnosis were associ- One eye per patient was prospec- produced equivalent reduction in ated with LE, with older age and tively randomized to two-minute the maximum keratometry value, higher IOP remaining significant or five-minute riboflavin dosing with a favorable safety profile. in multivariable analysis. There intervals with standard corneal Ophthalmol 2018;125:505-511 was a 1.09-fold increase in odds of cross-linking. Block randomiza- Price MO, Fairchild K, Feng MT, Price FW Jr.

64 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

0064_rp0518_rr.indd64_rp0518_rr.indd 6464 44/12/18/12/18 11:2211:22 AMAM Long-term Remission of Association Between BMI association to be statistically sig- Neovascular AMD and Open-angle Glaucoma nificant in women and those in the Researchers from the Shiley Eye A study was conducted to inves- youngest age stratum. Institute, University of California, tigate the association between body J Glaucoma 2018;27:239-245 conducted a study to determine the mass index and open-angle glaucoma Lin SC, Pasquale LR, Singh K, Lin SC presenting characteristics of patients in a sample of the South Korean pop- with neovascular age-related macular ulation. Trabeculectomy Alone vs. degeneration with long-term remis- The researchers looked at a Trabs with Ex-Press Shunts sion, which was defined as the ab- group that consisted of a cross-sec- Scientists compared postopera- sence of intraretinal/subretinal fl uid tional, population-based sample of tive interventions and outcomes be- or hemorrhage, and the absence of 10,978 participants, 40 years of tween conventional trabeculectomy leakage on fl uorescein angiography, age and older, enrolled in the 2008 and trabeculectomy with the Ex- for longer than six months while on to 2011 Korean National Health Press mini glaucoma shunt device, as as-needed antivascular endothelial and Nutrition Examination Sur- part of a retrospective, comparative, growth factor treatment. vey. All participants had measured single-facility study. The presenting characteristics intraocular pressure <22 mmHg They analyzed the cases of 108 of patients with LTR were com- and open anterior chamber angles. individuals with glaucoma who un- pared with a control group includ- OAG was defined using disc and derwent trabeculectomy and were ing 32 eyes of 28 age-, gender- and visual field criteria established followed for longer than a year. Thir- ethnicity-matched patients who by the International Society for ty-nine eyes underwent a conven- did not achieve LTR. Geographical and Epidemiologi- tional trabeculectomy (conventional Seventy-four percent of patients in cal Ophthalmology. Multivariable group), and 69 eyes underwent a the LTR group had Type-1 choroidal analyses were performed to de- trabeculectomy with an Ex-Press. neovascular membrane, and 18.5 per- termine the association between Scientists examined postoperative cent had retinal angiomatous prolif- BMI and OAG. These analyses intraocular pressure, the surgical eration. In the control group, 28 eyes were also performed in a sex-strat- success rate, postoperative compli- had Type-1 choroidal neovascular ified and age-stratified manner. cations, and the number of days to membrane (87.5 percent), and none After adjusting for potential laser suture lysis and needling. of the patients had retinal angioma- confounding variables, lower BMI The trabeculectomy significant- tous proliferation. Overall, there was (<19 kg/m) was associated with ly decreased IOP values from 27.8 a signifi cant difference in lesion types greater risk of OAG compared ±7.9 to 11.1 ±3.9 mmHg in the between the two groups (p=0.036). with normal BMI (19 to 24.9 kg/m) conventional group (p<0.001) and Eyes with LTR at presentation had [odds ratio, 2.28; 95 percent confi- from 27.7 ±9.2 to 11.5 ±3.7 mmHg significantly thinner subfoveal cho- dence interval (CI), 1.22-4.26]. In in the Ex-Press group (p<0.001) roidal thickness (147 vs. 178 µm, sex-stratified analyses, low BMI after one year. The success rate p=0.04). There was more intraretinal remained related to glaucoma in wasn’t significantly different be- fl uid and less subretinal fl uid at pre- women (OR, 3.45; 95 percent CI, tween groups. The timing of the sentation in the remission group (59.3 1.42-8.38) but not in men (OR, first laser suture lysis was sig- percent intraretinal fluid and 11.1 1.72; 95 percent CI, 0.71-4.20). In nificantly sooner in the Ex-Press percent subretinal fluid) compared age-stratified analyses, lower BMI group, but the Ex-Press group with the control group (28.1 percent was related to glaucoma among showed significantly less choroidal intraretinal fluid and 34.4 percent subjects 40 to 49 years old (OR, detachment due to low IOP. subretinal fl uid, p=0.03). 5.16; 95 percent CI, 1.86-14.36) The authors concluded that, in According to the results of the study, but differences in glaucoma prev- individuals whose trabeculectomy the presence of retinal angiomatous alence weren’t statistically sig- treatment included an Ex-Press, proliferation, thinner choroidal thick- nificant between those with low earlier laser suture lysis was re- ness, more intraretinal fl uid and less versus normal BMI in other age quired to obtain outcomes com- subretinal fl uid at presentation were strata. parable to those of conventional associated with LTR in patients receiv- Based on these results, lower trabeculectomy. ing as-needed treatment for AMD. BMI was associated with increased Clin Ophthalmol 2018;12:643- Retina 2018;38:516-522 odds of OAG in this population. 50. Muftuoglu IL, Alam M, You QS, et al. Multivariate analysis revealed the Tojo N, Otsuka M, Hayashi A, et al.

May 2018 | reviewofophthalmology.com | 65

0064_rp0518_rr.indd64_rp0518_rr.indd 6565 44/12/18/12/18 11:2211:22 AMAM Glaucoma Management

REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD

Diagnosing Early Glaucoma: Pearls and Pitfalls In our ongoing attempts to detect the disease at its earliest stages, new technologies are showing promise.

Angelo P. Tanna, MD, Chicago

hen it comes to managing findings that can be confused with there is a certain amount of loss that W glaucoma, we want to stop glaucomatous fi eld defects. The same occurs in both neural tissue thickness damage as early in the disease as is true for the retinal nerve fi ber layer and visual function simply as a result possible. For that reason, earlier di- and macular ganglion cell complex— of normal aging. That means even a agnosis and treatment is obviously anomalous structural characteristics healthy patient will show some losses desirable, and thanks to technology can confound our ability to accurately over time. The interesting twist to this such as optical coherence tomography, distinguish between glaucomatous is the fact that automated perimetry we can better detect structural dam- and normal eyes. The normative data- software inherently accounts for nor- age early in the disease course, often bases we use every day in the United mal, age-related changes in visual before functional abnormalities are States to see if our patients fall into function; however, no optical coher- detectable with perimetry. This al- the green, yellow or red zones are ence tomography imaging platform most certainly should result in fewer primarily composed of patients who currently makes such an adjustment. patients suffering significant vision are not highly myopic and do not have The issue is further complicated loss as a result of glaucoma. Simul- anomalous structural findings; they when trying to make a diagnosis in taneously, however, we must avoid are “squeaky clean” normals. That’s a patient with high myopia. Myopic making an inaccurate diagnosis of not always a fair comparison, and it eyes often have a glaucomatous- glaucoma in patients with anomalies can lead one to incorrectly diagnose looking optic disc, even in the absence that can be mistaken for disease. glaucoma. of glaucoma. That’s a bit of a double- In a patient with an anomalous optic edged sword, because myopia is a Challenges to Early Diagnosis disc, or other ocular characteristics risk factor for developing the disease. such as high axial length, the best way That means you could be looking One of the biggest challenges to accurately establish a diagnosis at someone who has myopia and when trying to diagnose glaucoma of glaucoma may be to follow the suspicious-looking optic nerves, and in its earliest stages is the signifi cant patient over time, in order to look you might attribute those structural variation in the appearance of the optic for signifi cant structural or functional anomalies to the myopia rather than disc and peripapillary region found in change. If a substantial loss of glaucoma. Of course, you might be normal eyes. Some anomalous optic neural tissue is detected, and other correct, but that patient will still need discs can be very diffi cult or impossible causes have been ruled out, one can to be monitored regularly because to distinguish from glaucomatous establish the diagnosis of glaucoma myopia is a risk factor for glaucoma. discs. Eyes with such optic discs with a higher degree of certainty. To The presence of myopia simply makes may even have abnormal visual-fi eld complicate matters further, however, it harder to make the diagnosis.

66 | Review of Ophthalmology | May 2018 This article has no commercial sponsorship.

066_rp0518_gm.indd 66 4/12/18 12:04 PM Monitoring with OCT

The reference standard for detecting progressive structural damage used to be comparing stereo photographs of the optic nerve taken over time. With the advent of OCT, that approach is used less frequently, in part because it’s more time-consuming than using the automated methods built into the various OCT platforms. There’s no question that it’s important to use one of these options, but I don’t believe it’s necessary to use both. If I had a choice of only one of these, I’d rather rely on OCT imaging, but others may disagree. They’d point out the one notable advantage of photographs: Unlike OCT, some argue that this technology doesn’t change over time, so you can always compare photographs. OCT technology changes periodically, This 52-year-old Caucasian man with moderate myopia had ocular hypertension with IOPs sometimes making it diffi cult to com- ranging from 19 to 26 mmHg. Central corneal thickness was about 560 µm OU; baseline pare current data to older data. average peripapillary RNFL thickness was 96 µm OS (top). Less than seven years later, With photography, however, tech- an 11-µm decline in thickness was observed (bottom). The visual fi eld remained normal. nology can change as well. For ex- Imaging studies were of good quality and signal strength, with no segmentation errors, and the change was reproducible at a subsequent follow-up visit. The fairly focal nature of ample, when Kodachrome film the change in RNFL thickness is highly characteristic of progression. was no longer available, the color balance in photographic images disc, looking at such factors as the nerve fi ber layer, or the vertical C/D changed. In addition, if exposure cup-to-disc ratio; cup volume; the ratio or the ganglion cell complex, values differ between photographs, rim area; the rim volume; and the the diagnostic accuracy is better for the cup can look larger in the image BMO-MRW (Bruch’s membrane the peripapillary retinal nerve fiber that’s relatively overexposed. Finally, opening, minimum rim width). At layer thickness and macular ganglion progressive cataract can be more the moment I fi nd assessing the optic cell thickness than for optic disc char- problematic for photographs than for disc with OCT less valuable than the acteristics. OCT, particularly if the OCT signal other measurements because the One promising possibility for strength is good—for example, 7 or measurement is not as reproducible detection of early disease relates to higher with Zeiss’ Cirrus OCT. as the RNFL and macular thickness a theory that in patients with POAG, When we use OCT for glaucoma measurements—at least using today’s the initial site of injury to the optic diagnosis and monitoring, there technology. BMO-MRW can be very nerve is at the level of the lamina are two things we usually focus on: useful, however, in eyes with RNFL cribrosa. Damage to the lamina crib- the thickness of the peripapillary imaging artifacts. rosa may cause an interruption in the retinal nerve fiber layer and the What do studies teach us about axons’ axoplasmic transport, even- thickness of the macular ganglion the relative diagnostic ability of the tually leading to the loss of the axons. cell layer. (Different OCT platforms different things we can measure It’s increasingly feasible to image use different anatomical criteria for with OCT? One study published in the lamina cribrosa with OCT, so it’s macular thickness that may or may 2013 compared the sensitivity and possible that ultimately, this could not include the retinal nerve fiber specificity of different spectral-do- prove to be the best place to look for layer and/or the inner plexiform main-OCT measures for diagnosing early glaucomatous damage. layer, for example.) It can also be preperimetric glaucoma.1 Basically, Many studies have shown the helpful to use OCT to assess the optic whether you’re looking at the retinal utility of measuring the peripapillary

May 2018 | reviewofophthalmology.com | 67

066_rp0518_gm.indd 67 4/12/18 12:05 PM Glaucoma

REVIEW Management

RNFL thickness for diagnosing and abnormalities in glaucoma earlier ask whether pushing the envelope on monitoring glaucoma. One par- than standard 24-2 or 30-2 visual being able to detect glaucoma earlier ticularly strong recent prospective fi elds. The same is true for frequency truly benefits patients. In reality, study demonstrated that progressive doubling technology. However, most glaucoma is usually a slow disease RNFL thinning determined by GPA of us have abandoned short-wave- process. There’s no overwhelming, (Guided Progression Analysis) is length automated perimetry because convincing evidence that you’re on predictive of detectable functional of its poor specifi city. a slippery slope once the disease has decline in glaucoma.2 If you choose There are also a number of electro- progressed a very small amount. So to use this approach, these pearls are physiological testing strategies that going to heroic lengths to conduct important to keep in mind: can be used to diagnose glaucoma, tests that might reveal very early • Make sure that you have good, such as pattern electroretinography disease is arguably not necessary. reliable baseline and follow-up (ERG). Vittorio Porciatti, DSc, at Obviously it’s useful to be attentive images. This means that the images Bascom Palmer, was an early inves- when monitoring patients who are don’t have artifacts and were obtained tigator in the use of pattern ERG glaucoma suspects, and it makes with good signal strength. to detect glaucoma. His group sense to try to get a diagnosis while • When you’re monitoring the showed that many eyes with ocular the disease is still at an early stage. patient over time, know how much hypertension show improvement In some cases you may fi nd an early change is significant. A ≥5-µm in pattern ERG amplitudes when visual field defect that matches a change in the average retinal nerve their intraocular pressure is lowered. defect in the nerve fi ber layer that’s fiber layer thickness could be im- There’s a prevailing, widely accepted visible on OCT, for example, so it’s portant, because that amount exceeds belief that structural damage oc- possible to detect glaucoma early the OCT test/retest variability. It’s curs before functional damage in without going to unusual lengths. also important to remember that the glaucoma, but these results suggest For the time being, I don’t believe 95 percent confidence interval for that this may depend on how you’re that excessive and repetitive testing— normal age-related change in average looking at structural and functional especially testing that’s still on the RNFL thickness is very close to 1 µm damage. They also raise the possibility boundaries of what is proven to be per year.3 So if you see a change that that other approaches to looking at useful, such as pattern ERG—has any exceeds that rate, you have strong function, such as pattern ERG, might utility outside of research. However, evidence that your patient’s disease actually be superior to visual field I do believe strongly that standard process is worsening. Additionally, a testing, although in my opinion this is perimetry and OCT imaging of the very nice study that followed normal still investigational. macula and peripapillary RNFL on an subjects for three years showed that if A relatively new approach to de- annual basis is important. the baseline average RNFL thickness tecting early glaucoma that’s showing When it comes to making a diagnosis is very high, the rate of normal, age- promise is OCT angiography. This of early glaucoma and deciding related change that occurs can be technology rapidly scans the same whether to initiate treatment, these even greater than 1 µm per year.4 tissue area multiple times and strategies are worth keeping in mind: • If your measurements indicate analyzes changes in the tissues, thus • Use all of the data that are that deterioration may have oc- revealing the presence of blood available to you. This should curred, repeat the test to verify the vessels and the amount of blood fl ow. certainly include information about progression is real. This principle There is some early evidence that the the optic disc appearance, the visual also applies to visual fi eld tests. reduction in blood flow detectable fi eld test results and imaging data. with this technology is predictive • Know what to look for. Different Alternative Testing Methods of RNFL thinning. For example, a patterns of damage can result from 2017 study demonstrated that vessel glaucoma. When following a patient As technology has evolved, new density attenuation in both affected over time, focal damage—in which an ways to potentially detect and confi rm and intact hemiretinas was associated area of the visual fi eld, or the retinal the diagnosis of glaucoma in its earliest with the extent of visual fi eld damage nerve fiber layer or the ganglion stages have appeared, and some of in the corresponding hemifi elds.5 cell complex is distinctly damaged them show promise. In terms of func- compared to surrounding tissue—is tional testing to detect glaucoma, Using All the Information generally easier to detect than diffuse there is strong evidence that 10-2 damage, such as when the entire visual fields can sometimes detect Of course, a clinician might well nerve fi ber layer has thinned.

68 | Review of Ophthalmology | May 2018

0066_rp0518_gm.indd66_rp0518_gm.indd 6868 44/12/18/12/18 12:0512:05 PMPM Advertising

REVIEW Index

• Take into account the quality the likelihood that we’ll arrive at that For advertising opportunities contact: of the data you’ve captured. In diagnosis incorrectly. So the real Michele Barrett (215) 519-1414 or [email protected] particular, be on the lookout for question is, how early do we need to measurement artifacts associated with detect glaucoma, and to what degree James Henne (610) 492-1017 the technology you’re using. should we compromise specificity or [email protected] • When you see a change or a in order to accomplish that? Since new abnormality, repeat the test glaucoma is usually slowly progressive, Michael Hoster (610) 492-1028 or [email protected] to verify that the fi ndings are ac- we usually have the luxury of time; curate. Given test-retest variability, if we monitor our glaucoma suspect Akorn Consumer Health 18-21 avoid drawing conclusions based on a patients on an annual or semiannual Phone (800) 579-8327 single test result without confi rming basis, it’s very unlikely that patients www.akornconsumerhealth.com that result fi rst. with early disease will progress in • Take into account other im- a fashion that results in noticeable portant risk factors that are as- visual impairment. There’s little risk in Beaver-Visitec International, Inc. 51 sociated with glaucoma. If the waiting until you’re sure. Phone (866) 906-8080 patient has a suspicious retinal I think it’s important to explain this Fax (866) 906-4304 nerve fiber layer and an optic disc to patients who are being monitored as www.beaver-visitec.com hemorrhage, that defi nitely increases glaucoma suspects. We can tell them the likelihood that the patient has that at this point in time it’s not possible glaucoma. to be certain about their diagnosis. Johnson & Johnson Surgical Vision, Inc. 2 • Take family history into However, we can also reassure them https://surgical.jnjvision.com account. In the Ocular Hypertension that the disease generally progresses Treatment Study, family history slowly. I tell patients that with careful Keeler Instruments 17 was not identified as risk factor for monitoring we will be able to detect Phone (800) 523-5620 conversion to glaucoma; however, any signifi cant changes early because Fax (610) 353-7814 most of us believe that this was of all of the advanced testing we’re because the patients’ histories may able to do. And as soon as we do detect not have been ascertained accurately concrete evidence of a problem—if Regeneron Pharmaceuticals, Inc. 7 in the study. we ever do—we can initiate therapy. Phone (914) 847-7000 • Take the patient’s age and I think that’s an important message to www.regeneron.com general health into account. This be able to give patients. could be relevant in terms of decid- Reichert Technologies 61 ing how important it is to diagnose Dr. Tanna is an associate professor of glaucoma very early, and even whe- ophthalmology, director of glaucoma Phone (888) 849-8955 ther to initiate treatment. and vice chair of the Department Fax (716) 686-4545 of Ophthalmology at the Feinberg www.reichert.com Doing What We Can School of Medicine at Northwestern University in Chicago. S4OPTIK 25, 27 There’s no question that there’s 1. Lisboa R, Paranhos A Jr, Weinreb RN, et al. Comparison Phone (888) 224-6012 an advantage to detecting glaucoma of different spectral domain OCT scanning protocols for diagnosing preperimetric glaucoma. Invest Ophthalmol Vis Sci early. Unfortunately, the earlier you 2013;13:54:5:3417-25. try to detect glaucoma, the more 2. Yu M, Lin C, Weinreb RN, et al. Risk of visual fi eld progression Shire Ophthalmics 75, 76 in glaucoma patients with progressive retinal nerve fi ber sensitive your testing algorithm has layer thinning: a 5-year prospective study. Ophthalmology www.shire.com to be, and the more testing you have 2016;123:6:1201-10. to do. In general, when trying to 3. Leung CK, Ye C, Weinreb RN, Yu M, Lai G, Lam DS. Impact of age-related change of retinal nerve fi ber layer and Topcon Medical Systems 10-11 diagnose glaucoma early using the macular thicknesses on evaluation of glaucoma progression. Ophthalmology 2013;120:12:2485-92. Phone (800) 223-1130 diagnostic methodologies available 4. Leung CK, Yu M, Weinreb RN, Ye C, Liu S, Lai G, Lam DS. to us today, higher sensitivity of the Retinal nerve fi ber layer imaging with spectral-domain optical Fax (201) 599-5250 coherence tomography: a prospective analysis of age-related diagnostic algorithm comes at the loss. Ophthalmology 2012;119:4:731-7. cost of lower specificity. In other 5. Yarmohammadi A, Zangwill LM, Diniz-Filho A, et al. Peripapillary This advertiser index is published as a convenience and macular vessel density in patients with glaucoma and single- and not as part of the advertising contract. words, the earlier we try to establish hemifi eld visual fi eld defect. Ophthalmology 2017;124:5:709- Every care will be taken to index correctly. No the diagnosis of glaucoma, the higher 719. allowance will be made for errors due to spelling, incorrect page number, or failure to insert.

May 2018 | reviewofophthalmology.com | 69

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70 | Review of Ophthalmology | May 2018

ROPH0518.indd 70 4/9/18 11:07 PM 071_rp0518_wills.indd 71 What isyourdiagnosis? furtherworkupwouldyoupursue?Thediagnosis appearsonp. 72. dal lesions,allmeasuring1mmorlessindiameterwithdiffuseoverlyingorangepigment(Figure1B). nasally andinferonasally(Figure1A).Thelefteyeshowedsimilarbutlessadvancedfindings withthreepigmentedchoroi- in therighteye,rangingfrom1mmto6diameter, andtherewasextensivesubretinalorangepigment,particularly bilateral cataractwithmoderatenuclearsclerosis,andanteriorposteriorsubcapsularopacifi cation inbotheyes. left eye. pupillary defect.Applanationtonometryrevealedintraocularpressureof17mmHgintherighteyeand12 the eye and20/40withnopinholeimprovementintheleft.Thepupilswereequal,roundreactivetolightwithoutafferent Examination noncontributory andsocialhistorywasnotableforbeingaformersmoker. Hewasallergictociprofl was notableforaretinaldetachmentintherighteyethathadbeenrepairedwithsurgery12yearsprior. Familyhistorywas ditional medicationsincludeddexamethasone,prochlorperazine,lorazepam,oxycodoneandgranisetron.Pastocularhistory supraclavicular, mediastinalandretroperitonealregion.Hehadcompletedfive cyclesofdocetaxelforthemalignancy. Ad- Medical History for asecondopinion. with oneinjectionofintravitrealbevacizumab,andhewasreferredtotheOcularOncologyServiceatWills EyeHospital developed progressivevisionlossintherighteyewithsubsequentinvolvementofleft.Hissymptomsdidn’t improve retinal fl uid intherighteyesuggestiveof centralserouschorioretinopathy. Hewasinitiallyfollowedforonemonthbut Presentation Samir N. Patel, MD, andCarol L.Shields, MD presumed caseofcentralserouschorioretinopathy. A middle-agedmanwithesophagealcancerpresentsa

On dilated fundoscopic examination, both eyes had multifocal subtle pigmented choroidal lesions. There were six lesions On dilatedfundoscopicexamination,botheyeshadmultifocalsubtlepigmentedchoroidallesions.Thereweresixlesions External examinationwasunremarkable.Anteriorsegmentrevealedsymmetricconjunctivalinjectionand On ophthalmicexaminationtheuncorrectedvisualacuitywascountingﬁ ngers withnopinholeimprovementintheright Six monthspriortopresentation,hewasdiagnosedwithstageIVesophagealcancernodalmetastasisinvolvingthe A 58-year-old mannotedprogressivevisionlossinbotheyes.Hewasseenbyaretinaspecialistandfoundtohavesub- REVIEW Wills Eye Wills Eye Resident CaseSeries Edited by Thomas Jenkins, MD lipofuscin pigment, andsubretinal ﬂ submacular andperipheral geographic orange diffuse nummularretinal pigmentepithelialloss, multifocal subtlepigmentedchoroidal lesionsand right eye (A)andlefteye (B)revealing bilateral Figure 1.Montagecolorfundusphotograph ofthe May 2018 | reviewofophthalmology.com oxacin. uid. |

71 4/12/18 12:29 PM 071_rp0518_wills.indd 72 sion withthepatient’s primaryoncologist,thepatient’s junctival injection,theleadingdiagnosiswasBDUMP. tumors andassociatedrapid-onsetcataractscon- liform maculopathy;and eration (BDUMP); included: pofuscin pigment.Thedifferentialdiagnosis mottling andprominentsubretinalorangeli- fluid, cystoidmacularedema,extensiveRPE pigmented choroidallesionswithsubretinal geal cancerandnew-onsetbilateralmultifocal noted inthelefteye. pofl ing. Thepigmentedchoroidallesionswerehy- epithelial loss.Therewascircumpapillarystain- represent “windowdefects”ofretinalpigment sites ofearlyhyperfl in therighteyerevealedextensivemultifocal edema (Figure2).Fluoresceinangiography tiple areasoffreshsubretinalfl 1 Workup, DiagnosisandTreatment 72 hyperfluorescence ofRPEdefectsandmildstaining. Similarfi inthelefteye.ndings were observed multiple nummularretinal pigmentepithelialatrophiclesions.Mid-(B)andlate-phase (C)angiograms showing persistent Figure 3.Fluorescein angiography oftherighteye. Early-phaseangiogram (A)revealing a “window defect” hyperfluorescence ofthe ). Opticalcoherencetomographyshowedmul- REVIEW Plasmapheresis wasconsidered,butafterdiscus- Given thebilateralmultifocalpigmentedchoroidal • medication-associatedretinopathyfromdocetaxel. • acuteexudativepolymorphousparaneoplasticvitel- • cancer-associated retinopathy; • bilateraldiffuseuvealmelanocyticprolif- • metastases; • melanoma; • multifocalchoroidalnevi; In summary, thispatienthadstageIVesopha- Fundus photographywasperformed( | uorescent (Figure 3).Similarfi uorescent ReviewofOphthalmology Resident CaseSeries uorescence, presumedto | May2018 uidandmacular ndings were ndings Figure loss ofchoroidal vascular details, suggestiveofinfi subretinal fluid withRPEnodularity. Notethediffusechoroidal thickening with the retinal pigmentepithelium.B) The lefteye demonstrates multipleareas of intraretinal fluid withfocaldestructionoftheretinal layers andnodularityof left eyes. A) The righteye demonstrates multipleareas ofsubretinal and Figure 2.Spectral domainopticalcoherence tomography oftherightand lost tofollow-up. intravitreal triamcinolone.Thepatientwassubsequently started onanintraocularcorticosteroidwith2mgof The patientwastaperedofftheoralcorticosteroidsand fundoscopic examinationrevealedunchangedfi right eye,withadeclineto20/150inthelefteye.The revealed persistentpoorvisionofcountingfi prednisone 80mgperday. Follow-uponemonthlater anti-retinal antibodytesting.Hewasstartedonoral pheresis atthattime.Thepatientdeclinedtoundergo clinical statuswasconsideredinappropriateforplasma- ltration. ngers inthe ndings. 4/12/18 12:29 PM Discussion

BDUMP is a rare paraneoplastic lines—including human dermal fi- systemic malignancy, varied treat- syndrome resulting in severe bilater- broblasts, keratinocytes and ovarian ments of the primary malignancy by al vision loss and proliferation of cho- cancer cells—that were treated with combinations of surgery, radiation roidal melanocytes. Retina specialist plasma from BDUMP patients con- and/or chemotherapy may confound J. Donald Gass and co-workers de- taining the CMEP factor didn’t show reported visual outcomes. Based on scribed the fi ve cardinal signs for the proliferation. a recent review article, the treat- diagnosis of BDUMP, including: 1) Another study further supported ment options for BDUMP include multiple, subtle, round, orange-red these findings by demonstrating no treatment, primary tumor treat- subretinal patches in the fundus; 2) changes in melanocyte proliferation ment, intraocular surgery (e.g., reti- multifocal early hyperfl uorescence of based on the presence or absence nal detachment surgery with subreti- these patches on fl uorescein angiog- of the CMEP factor in BDUMP pa- nal fl uid drainage), ocular radiation, raphy; 3) focally elevated pigmented tients undergoing plasmapheresis.8 local and systemic steroid treatment, and non-pigmented uveal melano- In this study, the plasma of a patient cataract surgery, intravitreal beva- cytic tumors with diffuse choroidal with BDUMP before systemic treat- cizumab injection and plasmapher- thickening; 4) exudative retinal de- ment induced growth of cultured esis.10 tachment; and 5) rapidly progressive melanocytes, confirming the pres- BDUMP is partly characterized by cataract formation.1 A characteristic ence of the CMEP factor; however, cataract formation, which can occur ‘‘giraffe pattern’’ on fundus autofl uo- plasma from a patient treated with rapidly. This is hypothesized to result rescence can be seen in BDUMP. It plasmapheresis did not induce me- from ciliary body tumor invasion, is believed to be secondary to num- lanocyte proliferation.8 Collectively, leading to inadequate aqueous vol- mular or polygonal RPE alterations these fi ndings suggested that treat- ume or poor nutrient composition.11 and lipofuscin accumulation.2,3 ment of the underlying malignan- Cataract surgery is a common treat- In nearly half of the cases of cy and plasmapheresis eliminated ment option and serves as a tempo- BDUMP, there is a current or remote CMEP and potentially reduced ocu- rizing measure for visual acuity im- diagnosis of non-ocular malignancy lar manifestations of BDUMP. In- provements but hasn’t been shown at the time of diagnosis.4 BDUMP deed, the presence of the circulating to improve vision permanently when has no gender predilection and is as- CMEP factor may explain why ap- used as a sole intervention.4,10,11 sociated with multiple visceral malig- proximately 26 percent of BDUMP Recently, plasmapheresis has nancies including cancer of the lung, patients have pigmented lesions in emerged as a promising novel treat- colon, pancreas, gallbladder, ovary, extraocular tissues such as the skin ment for improving visual acuity in uterus and cervix.4 Salient aspects of and mucous membranes.5 Our pa- patients with BDUMP. Based on its causes and management include tient declined to undergo serum test- the suspicion of a circulating CMEP the following: ing due to cost considerations. factor, plasmapheresis theoretical- • Pathogenesis. The pathogenesis Other studies have suggested a ly could remove the inciting factor of BDUMP is poorly understood, possible role of anti-retinal antibod- from the serum. There have been but multiple theories have been sug- ies in photoreceptor destruction, several cases identifi ed in the litera- gested.5-7 One proposed hypothesis as these circulating antibodies have ture employing plasmapheresis for is that there may be production of been detected in BDUMP patients; the treatment of BDUMP.8,9,12-18 One melanocytic growth factors by the however, their signifi cance is unclear group postulated the use of plasma- remote cancer cells with subsequent as these studies were confounded by pheresis in BDUMP and described release into the circulation. A group the presence of multiple paraneo- an example of a 71 year-old woman of investigators recently studied the plastic retinopathies.7,9 Some investi- with metastatic papillary serous ad- serum of patients with BDUMP and gators have proposed that there may enocarcinoma of the endometrium isolated an IgG antibody called cul- be a common oncogenic stimulus ini- with a visual acuity of 20/40 OU and tured melanocyte elongation and tiating both the ocular and nonocular fundoscopic fi ndings consistent with proliferation (CMEP) factor that tumors.6,7 BDUMP.13 She underwent a course was involved in human melanocyte • Management. Treatment op- of plasmapheresis with seven volume proliferation.5 This proliferation was tions for BDUMP are poorly under- exchange sessions every other day. found to be selective for melano- stood and produce variable respons- She continued on the chemotherapy cyte growth factor, since other cell es. As BDUMP is stimulated by a regimen for malignancy control and

May 2018 | reviewofophthalmology.com | 73

0071_rp0518_wills.indd71_rp0518_wills.indd 7733 44/12/18/12/18 12:3012:30 PMPM 071_rp0518_wills.indd 74 Than AnywhereElse. Jobsʉ Techniciansʉ More Ophthalmic Staff? Ophthalmic Hiring BDUMP. 20/150 OUwhowasdiagnosedwith ovarian cancerandvisualacuityof a 59year-old womanwithmetastatic study documentedasimilarcaseof sual acuitywas20/25OU.Another remained stableinsize,andhervi- up, thepigmentedfunduslesions ract extraction.At13-monthfollow eventually underwentbilateralcata- tinue toevolveinorderimprove prognosis, butnoveltreatmentscon- diagnosis ofBDUMPhaveapoor malignancy exists.Patientswitha whether ornotaknownhistoryof tifocal pigmentedchoroidallesions, nosis ofpatientswithbilateralmul- considered inthedifferentialdiag- follow-up. her visioninbotheyesatfourmonths reported subjectiveimprovementin pheresis threetimesperweekand motherapy andunderwentplasma- localeyesite.com

In summary, BDUMPshouldbe REVIEW Resident CaseSeries On LocalEyeSite 14 Thepatientdeclinedche- Find for bilateral diffuseuvealmelanocyticfor bilateral proliferation: A focuson 10. Moreno TA, Patel SN. Comprehensivereviewoftreatments 2011;129:9:1235-1238. and visualresponsetoplasmapheresis. Arch Ophthalmol melanocytic withapositiveophthalmoscopic proliferation 9. MetsRB, GolchetP, Adamus G, etal. diffuseuveal Bilateral Br JOphthalmol2015;99:7:943-948. ofparaneoplasticmelanocyticsuccessful treatment proliferation. 8. JansenJC, Van CalsterJ, PulidoJS, etal. and Earlydiagnosis retinopathy. Am JOphthalmol2005;140:5:942-945. melanocytic withcancer-associated inapatient proliferation 7. Saito W, KaseS, Yoshida K, etal. diffuseuveal Bilateral 1982;100:2:249-255. neoplasms. A recentlyrecognizedsyndrome. Arch Ophthalmol melanocytic withsystemicmalignant uvealtumorsassociated 6. BarrCC, ZimmermanLE, Curtin VT, Font RL. diffuse Bilateral human melanocytes. Retina2012;32:9:1959-1966. uveal melanocytic ofcultured causesproliferation proliferation diffuse withparaneoplasticbilateral fraction ofserumpatients 5. MilesSL, NilesRM, PittockS, etal. A factorfoundintheigG Ophthalmol2013;58:5:430-458. Surv andopticneuropathy:retinopathy andmanagement. Evaluation 4. RahimyE, SarrafD. Paraneoplastic andnon-paraneoplastic melanocytic proliferation. 2016;123:3:483. Ophthalmology 3. RahimyE, SoheilianM. diffuseuveal ofbilateral Giraffepattern 2005;139:5:933-935. nummular lossofthepigmentepithelium. Am JOphthalmol 2. Wu S, SlakterJS, ShieldsJA, SpaideRF. Cancer-associated occult carcinoma. Arch Ophthalmol1990;108:4:527-533. diffuseuvealmelanocytic with Bilateral inpatients proliferation 1. GassJD, GieserRG, Wilkinson CP, BeahmDE, Pautler SE. comes. their quality oflifeandvisualout- 2017:2474126417724656. with plasmapheresis. Journalof VitreoRetinal Diseases diffuseuvealmelanocytic ment ofbilateral proliferation 18. MSJ, Katz LederHA, Choudhury T. Successfultreat- tion. Eye(Lond)2013;27:9:1058-1062. melanocytic indiffuseuvealmelanocytic proliferations prolifera- 17. PulidoJS, Flotte TJ, RajaH, etal. Dermalandconjunctival 22, 2014. doi: 10.1136/bcr-2014-204387. cytic proliferation: dilemma.A management BMJCaseRep. May 16. Alrashidi S, Aziz AA, KremaH. diffuseuvealmelano- Bilateral Brief Rep2015;9:2:106-108. tumor. oftheprimary andtreatment plasmapheresis RetinCases uveal melanocytic withgoodclinical proliferation responseto 15. SchelvergemKV, Wirix M, NijsI, Leys A. diffuse Bilateral Cases BriefRep2017;11:1:71-74. diffuse uvealmelanocytic proliferation: A casereport. Retin 14. Alasil T, PA, Coady Koudsi S, M, Mathur MA. Materin Bilateral 2011;26:6:356-361. Clin Apher diffuse uvealmelanocytic proliferation: A reportoftwocases. J forbilateral potential roleofplasmaexchangeasatreatment 13. JabenEA, PulidoJS, PittockS, MarkovicS, Winters JL. The 2011;42:e103-106. Lasers Imaging diffuseuvealmelanocyticbilateral proliferation. OphthalmicSurg nummular lossofRPE: Expandingtheclinical spectrumof 12. EV, Navajas Simpson ER, KremaH, etal. Cancer-associated plastic syndrome. Ophthalmol2003;48:6:613-625. Surv carcinoma: reviewofthisparaneo- A casereportandliterature fuse uvealmelanocytic withpancreatic associated proliferation 11. O’NealKD, ButnorKJ, Perkinson KR, Proia AD. dif- Bilateral plasmapheresis. IntOphthalmolClin2017;57:1:177-194. 4/12/18 12:30 PM VGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV the recommended human ophthalmic dose [RHOD], based on VJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEGJWOCPU[UVGOKE GZRQUWTGVQNKƂVGITCUVHQNNQYKPIQEWNCTCFOKPKUVTCVKQPQH:KKFTC Rx Only CVVJG4*1&KUNQYVJGCRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJG risk of Xiidra use in humans during pregnancy is unclear. Animal Data BRIEF SUMMARY: .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8 KPLGEVKQP Consult the Full Prescribing Information for complete product VQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ECWUGF information. an increase in mean preimplantation loss and an increased INDICATIONS AND USAGE KPEKFGPEGQHUGXGTCNOKPQTUMGNGVCNCPQOCNKGUCVOIMI Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG FC[TGRTGUGPVKPIHQNFVJGJWOCPRNCUOCGZRQUWTGCV VTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'& the RHOD of Xiidra, based on AUC. No teratogenicity was QDUGTXGFKPVJGTCVCVOIMIFC[ HQNFVJGJWOCP DOSAGE AND ADMINISTRATION RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% +PVJGTCDDKV Instill one drop of Xiidra twice daily (approximately 12 hours an increased incidence of omphalocele was observed at the CRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT&KUECTF NQYGUVFQUGVGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOC VJGUKPINGWUGEQPVCKPGTKOOGFKCVGN[CHVGTWUKPIKPGCEJG[G GZRQUWTGCVVJG4*1&DCUGFQP#7% YJGPCFOKPKUVGTGFD[ Contact lenses should be removed prior to the administration +8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[UVJTQWIJ#HGVCN0Q QH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPI 1DUGTXGF#FXGTUG'HHGEV.GXGN 01#'. YCUPQVKFGPVKƂGFKP administration. the rabbit. CONTRAINDICATIONS Lactation 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Xiidra is contraindicated in patients with known hypersensitivity VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVUKPVJG milk, the effects on the breastfed infant, or the effects on milk RTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUVHTQO formulation. ocular administration is low. The developmental and health ADVERSE REACTIONS DGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGFCNQPIYKVJ Clinical Trials Experience the mother’s clinical need for Xiidra and any potential adverse Because clinical studies are conducted under widely varying effects on the breastfed child from Xiidra. conditions, adverse reaction rates observed in clinical studies Pediatric Use of a drug cannot be directly compared to rates in the clinical 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH VTKCNUQHCPQVJGTFTWICPFOC[PQVTGƃGEVVJGTCVGUQDUGTXGF years have not been established. KPRTCEVKEG+PƂXGENKPKECNUVWFKGUQHFT[G[GFKUGCUGEQPFWEVGF YKVJNKƂVGITCUVQRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCV Geriatric Use NGCUVFQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV No overall differences in safety or effectiveness have been 6JGOCLQTKV[QHRCVKGPVU JCFŰOQPVJUQHVTGCVOGPV observed between elderly and younger adult patients. GZRQUWTGRCVKGPVUYGTGGZRQUGFVQNKƂVGITCUVHQT NONCLINICAL TOXICOLOGY approximately 12 months. The majority of the treated patients Carcinogenesis, Mutagenesis, Impairment of Fertility YGTGHGOCNG 6JGOQUVEQOOQPCFXGTUGTGCEVKQPU Carcinogenesis: Animal studies have not been conducted TGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQP VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV dysgeusia and reduced visual acuity. Other adverse reactions Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro TGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQP #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo conjunctival hyperemia, eye irritation, headache, increased mouse micronucleus assay. In an in vitro chromosomal lacrimation, eye discharge, eye discomfort, eye pruritus and aberration assay using mammalian cells (Chinese sinusitis. JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV Postmarketing Experience concentration tested, without metabolic activation. 6JGHQNNQYKPICFXGTUGTGCEVKQPUJCXGDGGPKFGPVKƂGFFWTKPI Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV postapproval use of Xiidra. Because these reactions are KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ reported voluntarily from a population of uncertain size, it is not HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG always possible to reliably estimate their frequency or establish TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH a causal relationship to drug exposure. NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP Rare cases of hypersensitivity, including anaphylactic reaction, fertility and reproductive performance in male and bronchospasm, respiratory distress, pharyngeal edema, swollen female treated rats. tongue, and urticaria have been reported. Eye swelling and rash have been reported. USE IN SPECIFIC POPULATIONS Pregnancy /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# There are no available data on Xiidra use in pregnant women to (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN KPHQTOCP[FTWICUUQEKCVGFTKUMU+PVTCXGPQWU +8 CFOKPKUVTCVKQP Marks designated ®CPFvCTGQYPGFD[5JKTGQTCPCHƂNKCVGFEQORCP[ QHNKƂVGITCUVVQRTGIPCPVTCVUHTQORTGOCVKPIVJTQWIJ 5JKTG75+PE5*+4'CPFVJG5JKTG.QIQCTGVTCFGOCTMUQT IGUVCVKQPFC[FKFPQVRTQFWEGVGTCVQIGPKEKV[CVENKPKECNN[ TGIKUVGTGFVTCFGOCTMUQH5JKTG2JCTOCEGWVKECN*QNFKPIU+TGNCPF relevant systemic exposures. Intravenous administration of .KOKVGFQTKVUCHƂNKCVGU NKƂVGITCUVVQRTGIPCPVTCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGF Patented: please see JVVRUYYYUJKTGEQONGICNPQVKEGRTQFWEVRCVGPVU an increased incidence of omphalocele at the lowest dose .CUV/QFKƂGF5

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Indication Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGF Xiidra is the only prescription HQTVJGVTGCVOGPVQHUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'& eye drop to show symptom relief from Important Safety Information eye dryness in 2 out of 4 clinical trials :KKFTCKUEQPVTCKPFKECVGFKPRCVKGPVUYKVJMPQYPJ[RGTUGPUKVKXKV[VQ NKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVU IN AS LIITTLE AS 2 WEEKS +PENKPKECNVTKCNUVJGOQUVEQOOQPCFXGTUGTGCEVKQPUTGRQTVGF KPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQPF[UIGWUKCCPF TGFWEGFXKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKPVQ Check it out at Xiidra-ECP.com QHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCNJ[RGTGOKC G[GKTTKVCVKQPJGCFCEJGKPETGCUGFNCETKOCVKQPG[GFKUEJCTIG (QWTTCPFQOK\GFFQWDNGOCUMGFYGGMVTKCNU G[GFKUEQOHQTVG[GRTWTKVWUCPFUKPWUKVKU GXCNWCVGFVJGGHƂECE[CPFUCHGV[QH:KKFTCXGTUWU 6QCXQKFVJGRQVGPVKCNHQTG[GKPLWT[QTEQPVCOKPCVKQPQHVJGUQNWVKQP XGJKENGCUCUUGUUGFD[KORTQXGOGPVKPVJGUKIPU RCVKGPVUUJQWNFPQVVQWEJVJGVKRQHVJGUKPINGWUGEQPVCKPGTVQVJGKT OGCUWTGFD[+PHGTKQT%QTPGCN5VCKPKPI5EQTGQP G[GQTVQCP[UWTHCEG CUECNGQHVQ CPFU[ORVQOU OGCUWTGFD['[G &T[PGUU5EQTGQPCUECNGQHVQ QH&T['[G %QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQVJGCFOKPKUVTCVKQPQH &KUGCUG 0 :KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPICFOKPKUVTCVKQP 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH[GCTU JCXGPQVDGGPGUVCDNKUJGF

For additional safety information, see accompanying Brief Summary of Safety Information on the adjacent page and Full Prescribing Information on Xiidra-ECP.com.

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RP0518_Shire.indd 1 4/12/18 9:55 AM