Retina Issue

NEW IN DIGITAL RETINAL PHOTOGRAPHY P. 14 • RADIATION RETINOPATHY TREATMENT P. 48 EHR IN THE GLAUCOMA PRACTICE P. 60 • VALUE-BASED MEDICARE PAYMENT DEMYSTIFIED P. 20 WILLS EYE RESIDENT CASE SERIES P. 79 • RISC AND REWARD WITH INHIBITORY RNAS P. 56 Review of Ophthalmology Vol. XXII, No. 8 • August 2015 • Retinal Imaging • Next-Gen AMD Drugs • Radiation Retinopathy Treatment Drugs AMD • Next-Gen No. 8 • August 2015 Retinal Imaging Review of Ophthalmology Vol. XXII, Strategies

August 2015

reviewofophthalmology.com

ANNUAL RETINA ISSUE

• Retinal Imaging: The State of the Art P. 28

• Your Next AMD Drug P. 38

• Diabetic Retinopathy and Macular Edema P. 44

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RO0715_Haag Slit .indd 1 6/26/15 10:42 AM REVIEW NEWS Volume XXII • No. 8 • August 2015 A New Approach to Preserving Photoreceptors After RD

Researchers at the Massachusetts Eye nifi cant increase in the immune sys- ence Translational Medicine. and Ear/Harvard Medical School De- tem’s alternative complement path- Today’s state-of-the-art surgical partment of Ophthalmology have tak- way following retinal detachment techniques are highly effective at en a fi rst step in solving the problem and that this pathway facilitated physically reattaching the retina, and of preserving photoreceptor cells and early photoreceptor cell death after if surgery is timely, a positive visual avoiding irreversible vision loss in pa- injury. Injured photoreceptors lose outcome often results. Even so, patients following retinal detachment. important proteins that normally tients often complain of permanent Degeneration of photoreceptors is protect them from complement-me- vision loss accompanied by changes a primary cause of vision loss world- diated cell death, allowing for selec- in color vision. “Studies in both wide. Identifying the underlying tive targeting by the alternative com- humans and animal models have causes surrounding photoreceptor plement pathway. Additionally, by shown that photoreceptor cell death cell death is paramount in order to blocking the alternative complement is induced as early as 12 hours after develop new treatment strategies to pathway, through both genetic and detachment, indicating that early prevent their loss. Retinal detach- pharmacologic means, photorecep- intervention could potentially pre- ment and subsequent degeneration tors were protected from cell death. serve photoreceptors and improve of the retina can lead to progressive “When photoreceptors in a detached the visual function of patients who visual decline due to photoreceptor retina were removed from their pri- undergo reattachment surgery,” says cell death. Since photoreceptors are mary source of oxygen and nutrients, Dr. Connor. “Our research provides non-dividing cells, their loss results we found an increase in complement a new role for complement in retinal in irreversible visual impairment factor B, a key mediator of the al- detachment, and suggests that inhi- even after successful retinal reat- ternative complement pathway that bition of the alternative complement tachment surgery. leads to photoreceptor cell death,” pathway may be good therapeutic New research led by Kip M. Con- says Dr. Connor. “For the fi rst time target to prevent the initial photore- nor, PhD, a researcher and assistant these results provide evidence that ceptor cell loss. professor of ophthalmology at Mass the alternative complement pathway “What makes this research so excit- Eye and Ear, and colleagues analyzed exacerbates photoreceptor cell death ing is the potential impact it can have innate immune system regulators in and that inhibition of the pathway on our patients. Working closely with the eyes of human patients with reti- is protective,” said Kaylee Smith, a our colleagues in the clinic, we identi- nal detachment and correlated their member of the Connor Lab and confi ed a challenging issue, went back to fi ndings in an experimental model. tributing author on the manuscript. our laboratories to uncover a cause, They discovered that there was a sig- Their fi ndings were published Sci- and now have knowledge that may help us to develop therapies that will Five Years After EHR Adoption, 41 Percent ROI help to preserve our patients’ vision.” Switching to an EHR in 206 has netted one ophthalmology practice roughly $1.2 million over a fi ve-year period, according to a new report published in July’s Ophthalmology. Ini- tially, the practice’s costs increased due to the hiring of IT staff, software maintenance and NEI Study: scanning paper records. Eventually process changes driven by the EHR led to effi ciencies that lowered the staffi ng needs related to medical records, transcription, billing, check-out and appointment scheduling. The system also acted as a revenue-driver by enabling EHR Microglia and RP meaningful use incentive payments, increasing productivity in the later stages and making Microglia often play a benefi cial role by claims submission faster and more accurate. (For a more extensive look at EHR in ophthal- helping to clear dead cells and cel- mology practice, see p. 60.) lular debris and protect the central

August 2015 | reviewofophthalmology.com | 3

0003_rp0815_news.indd03_rp0815_news.indd 3 77/24/15/24/15 2:492:49 PMPM Ophthalmic Product Development Insights Aki Tobaru, Hiro Matsuda, PhD, & Matthew Chapin • Ora Inc., Andover, Mass. REVIEW

signifi cant business deal, as a proper initial Tips for Doing Business and Collaborations in Japan meeting is crucial for both parties and n prior columns we have discussed For example, when visiting with a Japanese helps to kick off a successful project. development strategies, fi nancing and company, the fi rst step should be for the The exchange of business cards is Ibusiness issues related to developing main contact persons from both parties considered a formal ritual. In the Japanese culture, offering a business card is quite new products, particularly geared towards to greet each other, and continue with the personal, as it represents the “face” of the the new entrepreneur. Global strategy is exchange of business cards. As a nod to individual. Giving a business card is equiva- another important issue to consider early seniority, the main contact person from the lent to providing someone with a signifi cant in business planning. As Japan is one of host company should introduce the other amount of information about yourself. It is the top markets outside the United States, members of the group, starting with the representative of the individual personally in this installment of Development Insights most senior personnel. During the meeting, the highest ranking person will likely make and professionally, and of the company. we will explore some elements related to During a business card exchange, Japa- Japanese business culture and customs opening remarks, followed by his or her second-in-command, who will then begin nese will present it with both hands, and that may be useful to consider as business prefer to receive business cards the same and development relationships are sought the meeting. While the meeting is proceed- ing, conversation can take place as it plays way, as it is a sign of respect. Additionally, after and formed in Japan. the card should be delivered face-up and There are many opportunities for entre- facing the recipient so he or she may read preneurs and start-up companies to ex- the card, with introduction of name plore global or regional partnerships and title. Finally, be sure to leave with pharmaceutical and biotech the card unmarked—it is companies in Japan, pursue not appropriate to write assets and engage inves- anything on a business tors from within Japan, card in front of the or try to bring products individual. being developed in the One fairly common United States into Japan. mistake by made by Historically there has in foreigners surrounds general been a signifi cant the use of the word lag between drug approvals “san.” Those unfamiliar in the two countries. Today, with Japanese culture may there is more focus on reduc- believe that using san at the ing that time-lag, which may involve end of a fi rst name is very polite engaging with global or regional Japanese and formal. However, san is rarely used in partners early in the process. Japan is a this manner among the Japanese. Among unique country, with a culture different out; however, great care should be taken to avoid interrupting any speakers. In Japan, friends and colleagues in Japan, san is from any other. Here, we will focus on most commonly used at the end of an three key concepts: respect; formality; and this is considered one of the highest forms of disrespect to the speaker, and signals individual’s last name. For those unac- long-term relationships. These customs tie customed to Japanese formalities, the together an underlying theme of respect a lack of listening and understanding by the person who interrupts. Straightforward best way to show formality is to use a title and building trust, moving toward a long- such as doctor, mister or miss until the term relationship that is important for the discussions are appropriate; however, it is recommended that you acknowledge points person indicates that you may use just his entrepreneur/developer who is forging a or her last name; and then it is appropriate new relationship in Japan. made by your Japanese partners before you introduce your ideas. This demonstrates to use the last name with san. Once you that you were listening and respect their have established a friendship and valued Respect opinion, even if you have differing thoughts. relationship, the person may ask you to use As in most, if not all cultures, respect is his or her given name. the ultimate form of acceptance and value, Formality Another common mistake surrounding and is highly revered in Japan. Japanese the use of san is its use to refer to your Japanese business always involves respect others, and they respect seniority. own colleagues. While in Japan, it is not formality. While we are in a digital age with One form of Japanese etiquette and respect commonplace to use san with last names social networking, and this practice is cer- best known outside of Japan is bowing. when speaking about anyone in your tainly accepted by the Japanese, the pre- In the Japanese culture, bowing signifi es company, including those that maintain ferred route of introduction, when possible greeting one another with respect. There higher positions. For example, you might and available, is through mutual friends. are still many people in Japan, especially say, “Our company president, Sato, believes For Japanese, being formally introduced by those of the older generations, who believe that innovation is the key for our company.” a common connection is considered to be that they cannot trust those who do not You simply refer to your own colleagues by a more personal and professional route of greet properly, as it denotes lack of respect. their last name, which shows formality and introduction. This is particularly important This concept is an important foundation politeness to others in Japan. when dealing with sensitive matters of a to those looking to do business in Japan. Specifi cally in the fi eld of science or

4 | Review of Ophthalmology | August 2015

003_rp0815_news.indd 4 7/24/15 2:49 PM REVIEW News academia, when meeting with professors Corporate-wide relationship-building and researchers at Japanese universi- can be much tougher than at an individual nervous system against infection. But ties, it’s proper etiquette to include doctor level because it involves multiple people a new study by researchers at the Na- or professor with their last names. This and moving parts. As with many develop- tional Eye Institute shows that they demonstrates your respect for their ac- ment programs, there may be longer-term also accelerate damage wrought by complishments. Should a professor or potential opportunity for a continued rela- blinding eye disorders, such as reti- researcher suggest that you call him by tionship beyond a single product or deal. In nitis pigmentosa. “These fi ndings are his last name, still use “sensei,” meaning stereotypical “U.S. fashion,” it is tempting “teacher,” accompanied by the last name. to try to put several topics and objectives important because they suggest that If he insists that you use his fi rst name, into one fi rst deal or project discussion microglia may provide a target for en- it is then appropriate to use that name. It and fi gure it all out at once. While, of tirely new therapeutic strategies aimed should be noted, however, that Japanese course, the desire for a long-term relation- at halting blinding eye diseases of the typically will not asked to be called by ship is a good thing to show, the Japanese retina,” said NEI Director, Paul A. their fi rst name until there is a sustained, company may want to take a step-by-step Sieving, MD. “New targets create un- long-lasting relationship. It’s always safer approach and focus on the fi rst item or tapped opportunities for preventing to use “sensei” at the fi rst meeting, and product deal. It is important to respect the when they say that they prefer to be called process and have patience for the benefi t disease-related damage to the eye, and by a fi rst name, move forward accordingly. of the long-term relationship. preserving vision for as long as pos- Formality at meetings is common, Trust and honesty are key components sible.” The fi ndings were published in and often can be misinterpreted. A very to creating such long-lasting relationships, EMBO Molecular Medicine. interesting example is nodding. Japanese and while this characteristic is not unique Research has shown links between business people tend to show politeness to to Japan, be prepared for what is typically a RP and several mutations in genes for the other party, and tend to nod, meaning longer process in Japan. The customs and photoreceptors. In the early stages of that they listen well and understand, even formalities all relate to respect and building at a negotiation table. However, Americans trust, which is ultimately what a successful the disease, rod photoreceptors are may interpret nodding to suggest agree- long-term relationship can be based on. lost, causing night blindness. As the ment. This is very common mistake and Each country naturally has its own busi- disease progresses, cone photorecep- can lead to misunderstandings. Therefore ness manner and customary practices, and tors can also die off, eventually leading it is very important to ensure alignment of course, you should value and respect all to complete blindness. and avoid misunderstanding, to confi rm of them. It is always important for you to Lead investigator, Wai T. Wong, via written minutes or summary what both be dedicated to sound and clear science MD, PhD, chief of the Unit on Neu- parties talked about, any decisions that and good business practices, and be true to were made, and action or follow-up items yourself without getting overly hung up with ron-Glia Interactions in Retinal Dis- discussed. tradition and formal details. As you prepare, ease at NEI, and his team studied mice present and defend details of a project, with a mutation in a gene that can also Long-Term Relationships don’t lose sight of the end goal. As long as cause retinitis pigmentosa in people. The Japanese value relationships, so it is you always try to value respect, trust and The researchers observed in these important to cultivate and build long-term integrity, Japanese business people will mice that very early in the disease pro- relationships. Certainly, building a long- certainly prefer a friendly approach, open cess, the microglia infi ltrate the outer discussion and creativity that sparks long term relationship takes time and likely re- nuclear layer, where they don’t usually quires many interactions with one another. relationships that have value for everyone. It is generally a good sign if an invitation venture. The microglia then create a to dinner is extended, and this is an Mr. Chapin and Mr. Tobaru are with the cup-like structure over a single photo- important time for continuing to build the Corporate Development group at Ora Inc. receptor, surrounding it to ingest it in a relationship with more casual conversa- Ora provides a comprehensive range of process called phagocytosis. Dr. Wong tion. Don’t be afraid to engage in business product development, clinical-regulatory and his team caught this dynamic pro- talk and/or topics that were discussed and product consulting for developers, cess on video. The whole feast, includ- investors and buyers; clinical trial services earlier in the day. Japanese business ing digestion, takes about an hour. people value honesty, and will appreciate and regulatory submissions; and asset and it if you can honestly talk about what you business partnering support in ophthalmol- In retinitis pigmentosa the research- need from the Japanese company. ogy. Dr. Matsuda is General Manager of ers found that the microglia target If you are invited to a social networking Ora Japan KK, based in Japan. Ora Japan damaged but living photoreceptors, in event, consider yourself to be a valued provides local support, consulting and clini- addition to dead ones. To confi rm that partner. If you have been able to cultivate cal trial services to clients and partners for microglia contribute to the degenera- a relationship with a Japanese company development in Japan and support for busi- tion process, the researchers geneti- ness collaborations between the U.S. and to such an extent that you are invited to cally eliminated the microglia, which gatherings of this type, you can expect Japan. We welcome comments or questions that your relationship is solid, and will related to this or other development topics. slowed the rate of rod photoreceptor benefi t you as you begin to expand your Please send correspondence to mchapin@ network across Japan. oraclinical.com. (continued on page 18)

August 2015 | reviewofophthalmology.com | 5

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RP0815_Reliance.indd 1 7/16/15 3:35 PM August 2015 • Volume XXII No. 8 | reviewofophthalmology.com Cover Focus 28 | Retinal Imaging: The State of the Art By Christopher Kent, Senior Editor Technology for scanning the back of the eye is outrunning our ability to treat—but probably not for long.

38 | Meet Your Next AMD Drug By Walter Bethke, Managing Editor A review of the likely next wave of drugs for age-related macular degeneration. 44 | Diabetic Retinopathy-Related Macular Edema: Treatment Update By Michelle Stephenson, Contributing Editor Laser treatment is still the treatment of choice for many patients with non-center-involving edema.

Cover illustration by Mark Erickson, jirehdesign.com

August 2015 | reviewofophthalmology.com | 11

011_rp0815_toc.indd 11 7/24/15 2:58 PM Departments

3 | Review News 48 14 | Technology Update Advances in Digital Retinal Photography

20 | Medicare Q&A What You Should Know About the VBPM

48 | Retinal Insider Radiation Retinopathy: Treatment Strategies The diagnosis and management of this condition are evolving, and choosing the right combination of treatments is critical.

56 | Therapeutic Topics 68 RISC and Reward with Inhibitory RNAs A new understanding of ribonucleic acid’s activity in cells may lead to breakthroughs.

60 | Glaucoma Management Electronic Health Records in The Glaucoma Practice Despite some downsides, electronic records have practical advantages—especially if you’re managing glaucoma.

68 | Refractive Surgery The Link to a New Refractive Procedure? Exploring the potential of cross-linking as a purely elective refractive procedure. 79 72 | Product News A Host of New Tools for a Range of Surgical Moves

76 | Classified Ads

79 | Wills Eye Resident Case Series

82 | Advertising Index

12 | Review of Ophthalmology | August 2015

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

Advances in Digital Retinal Photography A look at the upgrades and add-ons that 2015 has brought to non-mydriatic retinal cameras. Walter Bethke, Managing Editor

rom screening for retinal pathol- one-shot stereo imaging,” Mr. Torney Mr. Torney says users of Kowa’s Fogy to acquiring images for use adds. “It has two light pathways that older Nonmyd systems, such as those in telemedicine applications, non- allow two images taken non-mydriat- that used 2 or 5 MP, might be more mydriatic fundus cameras are a main- ically to come together in stereo. In inclined to upgrade to the higher res- stay in the exam suite. In an effort the stereo view you get a 3-D view olution. “The real advantages would to keep users on the cutting edge of of the optic nerve and, after you’ve be for the people taking images in the retinal photography, companies con- taken several of them, you can align 1-, 2- or 5-MP range,” he says. “Go- stantly upgrade their camera systems them, stack them and then play them ing to 24 will make a difference for and produce add-on hardware that back in a video to see if a patient’s them. So, really, for the upgrade, the increases their functionality. Here’s glaucoma condition has progressed or Nonmyd 2 MP and Nonmyd 7 MP a look at the latest upgrades and up- swelling in the optic nerve head has are essentially the same; you put a dates to non-mydriatic cameras that decreased.” Mr. Torney says captur- different camera back on them to get have arrived so far in 2015. ing the stereo images in non-dilated the higher resolution. If the user had pupils is possible in about 95 percent a WX, he could put the higher-resolu- Kowa WX3D and Nonmyd 7 of patients, though in some patients, tion camera back on it now. However, “they just have too small a pupil size.” there would be few who’d choose to Both the WX3D and Nonmyd 7 go that route since the earlier WX cameras from Kowa received up- cameras had 12-megapixel resolution, grades to their imaging systems in so going to 24 MP wouldn’t be a huge June, bringing them up to 24-mega- advantage.” pixel resolution. To upgrade the Nonmyd 7 camera “The 24-MP resolution is particu- system would involve purchasing a larly helpful when the imaging is in new computer that’s able to run the the macular area,” says Kowa’s Rick Windows 7 operating system, the soft- Torney, “since doctors are focused ware and a new camera, and would on catching abnormalities such as cost between $4,500 and $5,500. If a AMD in the macula area earlier. They user wanted to upgrade the WX to 24 need to be able to blow up that area a MP, it would cost about $1,500 since good deal, and doing that takes a lot of he already has most of the necessary megapixels. The Kowa WX3D allows users to perform equipment. For information, visit “The main feature of the WX is one-shot stereo imaging of the retina. kowa-usa.com.

14 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

014_rp0815_tech update.indd 14 7/24/15 2:26 PM An NSAID formulated to penetrate target ocular tissues PROLENSA® POWERED FOR PENETRATION Available in a 3-mL bottle size

PROLENSA® delivers potency and corneal penetration with QD efﬁcacy1,2 • Advanced formulation delivers corneal penetration1-3 • Proven efﬁcacy at a low concentration1,4

INDICATIONS AND USAGE PROLENSA® (bromfenac ophthalmic solution) 0.07% is a nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of postoperative inflammation and reduction of ocular pain in patients who have undergone cataract surgery. IMPORTANT SAFETY INFORMATION ABOUT PROLENSA® Warnings and Precautions Adverse Reactions • Sulfite allergic reactions The most commonly reported adverse reactions • Slow or delayed healing in 3%-8% of patients were anterior chamber • Potential for cross-sensitivity inflammation, foreign body sensation, eye pain, • Increased bleeding of ocular tissues photophobia, and blurred vision. • Corneal effects, including keratitis • Contact lens wear

Please see brief summary of Prescribing Information on adjacent page. References: 1. PROLENSA® Prescribing Information, April 2013. 2. Data on ﬁle, Bausch & Lomb Incorporated. 3. Baklayan GA, Patterson HM, Song CK, Gow JA, McNamara TR. 24-hour evaluation of the ocular distribution of 14C-labeled bromfenac following topical instillation into the eyes of New Zealand White rabbits. J Ocul Pharmacol Ther. 2008;24(4):392-398. 4. BROMDAY® Prescribing Information, October 2012. ®/™ are trademarks of Bausch & Lomb Incorporated or its afﬁliates. © 2015 Bausch & Lomb Incorporated. All rights reserved. Printed in USA. US/PRA/15/0015

RP0415_BL Prolensa.indd 1 3/19/15 9:54 AM PROLENSA® (bromfenac ophthalmic solution) 0.07% Brief Summary

INDICATIONS AND USAGE PROLENSA® ophthalmic solution following cataract surgery include: PROLENSA® (bromfenac ophthalmic solution) 0.07% is indicated for the anterior chamber inflammation, foreign body sensation, eye pain, treatment of postoperative inflammation and reduction of ocular pain in photophobia and vision blurred. These reactions were reported in 3 to patients who have undergone cataract surgery. 8% of patients. DOSAGE AND ADMINISTRATION USE IN SPECIFIC POPULATIONS Recommended Dosing Pregnancy One drop of PROLENSA® ophthalmic solution should be applied to Treatment of rats at oral doses up to 0.9 mg/kg/day (systemic the affected eye once daily beginning 1 day prior to cataract surgery, exposure 90 times the systemic exposure predicted from the continued on the day of surgery, and through the first 14 days of the recommended human ophthalmic dose [RHOD] assuming the human postoperative period. systemic concentration is at the limit of quantification) and rabbits Use with Other Topical Ophthalmic Medications at oral doses up to 7.5 mg/kg/day (150 times the predicted human PROLENSA ophthalmic solution may be administered in conjunction systemic exposure) produced no treatment-related malformations in with other topical ophthalmic medications such as alpha-agonists, beta- reproduction studies. However, embryo-fetal lethality and maternal blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. toxicity were produced in rats and rabbits at 0.9 mg/kg/day and Drops should be administered at least 5 minutes apart. 7.5 mg/kg/day, respectively. In rats, bromfenac treatment caused delayed parturition at 0.3 mg/kg/day (30 times the predicted human CONTRAINDICATIONS exposure), and caused dystocia, increased neonatal mortality and None reduced postnatal growth at 0.9 mg/kg/day. WARNINGS AND PRECAUTIONS There are no adequate and well-controlled studies in pregnant women. Sulfite Allergic Reactions Because animal reproduction studies are not always predictive of Contains sodium sulfite, a sulfite that may cause allergic-type reactions human response, this drug should be used during pregnancy only if including anaphylactic symptoms and life-threatening or less severe the potential benefit justifies the potential risk to the fetus. asthmatic episodes in certain susceptible people. The overall prevalence Because of the known effects of prostaglandin biosynthesis- of sulfite sensitivity in the general population is unknown and probably inhibiting drugs on the fetal cardiovascular system (closure of ductus low. Sulfite sensitivity is seen more frequently in asthmatic than in non- arteriosus), the use of PROLENSA® ophthalmic solution during late asthmatic people. pregnancy should be avoided. Slow or Delayed Healing Nursing Mothers All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including Caution should be exercised when PROLENSA is administered to a bromfenac, may slow or delay healing. Topical corticosteroids are also nursing woman. known to slow or delay healing. Concomitant use of topical NSAIDs and Pediatric Use topical steroids may increase the potential for healing problems. Safety and efficacy in pediatric patients below the age of 18 have not Potential for Cross-Sensitivity been established. There is the potential for cross-sensitivity to acetylsalicylic acid, Geriatric Use phenylacetic acid derivatives, and other NSAIDs, including bromfenac. There is no evidence that the efficacy or safety profiles for Therefore, caution should be used when treating individuals who have PROLENSA differ in patients 70 years of age and older compared to previously exhibited sensitivities to these drugs. younger adult patients. Increased Bleeding Time With some NSAIDs, including bromfenac, there exists the potential for NONCLINICAL TOXICOLOGY increased bleeding time due to interference with platelet aggregation. Carcinogenesis, Mutagenesis and Impairment of Fertility There have been reports that ocularly applied NSAIDs may cause Long-term carcinogenicity studies in rats and mice given oral increased bleeding of ocular tissues (including hyphemas) in conjunction doses of bromfenac up to 0.6 mg/kg/day (systemic exposure 30 with ocular surgery. times the systemic exposure predicted from the recommended It is recommended that PROLENSA® ophthalmic solution be used with human ophthalmic dose [RHOD] assuming the human systemic caution in patients with known bleeding tendencies or who are receiving concentration is at the limit of quantification) and 5 mg/kg/day (340 other medications which may prolong bleeding time. times the predicted human systemic exposure), respectively, revealed Keratitis and Corneal Reactions no significant increases in tumor incidence. Use of topical NSAIDs may result in keratitis. In some susceptible Bromfenac did not show mutagenic potential in various mutagenicity patients, continued use of topical NSAIDs may result in epithelial studies, including the reverse mutation, chromosomal aberration, and breakdown, corneal thinning, corneal erosion, corneal ulceration or micronucleus tests. corneal perforation. These events may be sight threatening. Patients with Bromfenac did not impair fertility when administered orally to male evidence of corneal epithelial breakdown should immediately discontinue and female rats at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, use of topical NSAIDs, including bromfenac, and should be closely respectively (systemic exposure 90 and 30 times the predicted human monitored for corneal health. exposure, respectively). Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial PATIENT COUNSELING INFORMATION defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), Slowed or Delayed Healing rheumatoid arthritis, or repeat ocular surgeries within a short period Advise patients of the possibility that slow or delayed healing may of time may be at increased risk for corneal adverse events which may occur while using NSAIDs. become sight threatening. Topical NSAIDs should be used with caution Sterility of Dropper Tip in these patients. Advise patients to replace bottle cap after using and to not touch Post-marketing experience with topical NSAIDs also suggests that use dropper tip to any surface, as this may contaminate the contents. more than 24 hours prior to surgery or use beyond 14 days post-surgery Advise patients that a single bottle of PROLENSA® ophthalmic may increase patient risk for the occurrence and severity of corneal solution, be used to treat only one eye. adverse events. Concomitant Use of Contact Lenses Contact Lens Wear Advise patients to remove contact lenses prior to instillation of PROLENSA should not be instilled while wearing contact lenses. PROLENSA. The preservative in PROLENSA, benzalkonium Remove contact lenses prior to instillation of PROLENSA. The chloride, may be absorbed by soft contact lenses. Lenses may be preservative in PROLENSA, benzalkonium chloride may be absorbed by reinserted after 10 minutes following administration of PROLENSA. soft contact lenses. Lenses may be reinserted after 10 minutes following Concomitant Topical Ocular Therapy administration of PROLENSA. If more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart ADVERSE REACTIONS Rx Only Clinical Trial Experience Manufactured by: Bausch & Lomb Incorporated, Tampa, FL 33637 Because clinical trials are conducted under widely varying conditions, Under license from: adverse reaction rates observed in the clinical trials of a drug cannot be Senju Pharmaceuticals Co., Ltd. directly compared to rates in the clinical trials of another drug and may Osaka, Japan 541-0046 not reflect the rates observed in clinical practice. Prolensa is a trademark of Bausch & Lomb Incorporated or its affiliates. The most commonly reported adverse reactions following use of © Bausch & Lomb Incorporated. 9317600 US/PRA/14/0024

RRP0415_BLP0415_BL PProlensarolensa PPI.inddI.indd 1 33/19/15/19/15 9:569:56 AMAM Technology

REVIEW Update

cus and it automatically jumps to high magnifi cation and moves the imaging to the back of the eye. This means the technician doesn’t need to know when to push that button—it automatically takes him there. This is helpful because this can be where some of the stumbling occurs in image acquisi- tion—if the patient suddenly moves and the user needs to go backward, you can press a button manually and do the rough alignment again, rather than having to go back to the very beginning of the whole process. Also, Stereo images of the optic nerve head taken by the Kowa WX3D can be “stacked” on top of if a technician is a little uncomfort- each other and then played back as a movie to illustrate subtle changes over time. able determining if it’s a good time to take the picture, he just looks at two Canon CR-2 AF The camera also has a function small dots on the screen. When the This is a new retinal camera that called auto fundus, which is basically dots are in a box on the screen and in was just launched in late May, and is the camera’s way of confi rming it’s got focus, the camera automatically takes equipped with several features that the fundus in sharp focus and is ready the picture because it knows it’s in may help users acquire better patient to begin shooting. “It works kind of focus.” The camera can get an image images. like the way you used a microscope in through pupils 2.7 mm in diameter or Since many patients have issues biology class in high school,” explains a bit smaller; it also comes with image that may make images appear less Mr. Laux. “When using a microscope management software that allows us- than ideal, such as early cataract, the to look at a slide, you’d start with the ers to save high-resolution images for CR-2 AF has a contrast-enhancement lowest magnification to get it semi- use in an electronic medical records function. “Contrast enhancement ex- focused, and then increase it until the system. amines the structures of the eye and subject was in focus. Similarly, in the The base price of the CR-2 AF then increases the contrast as need- CR-2 AF, you begin with a split image is $15,450. For information, visit ed,” says Canon’s Jim Laux. “This can of the eye in the camera. When the usa.canon.com. allow the user to see such things as eye is focused, the upper and lower the edges of the veins and arteries halves of the image come together Zeiss Visucam Pro NM more cleanly. As a corollary to this, the and form a single picture. When that camera also provides auto exposure. happens, the camera knows it’s in fo- The Visucam Pro NM will now fea- It does this by refl ecting an infrared ture fundus autofl uorescence, a func- signal off the back of the eye and us- tion that, until now, was only avail- ing that exposure information to drive able on the higher-end model of the the camera settings to generate an Visucam. optimal image. This means you don’t “Fundus autofluorescence lets need a highly skilled technician who, physicians see the condition of in the past, would have to bracket the the RPE layer,” says Zeiss’ Sunny exposure by changing the ISO and Virmani. “Certain parts of the retina fl ash intensity to take different photos will fl uoresce in different ways based at different exposure levels in order on their condition. In a normal retina, to get the level of contrast the doctor the fundus autofluorescence image wants. Because of this, the user can do would look like a black and white more with less fl ash intensity, which retinal image. However, if there’s avoids pupil shrinkage due to a bright any activity going on in parts of the flash or photophobia, and generally retinal pigment epithelium, they’ll makes it more comfortable for the The Canon CR-2 AF’s auto-exposure feature display as bright. The bright areas patient.” helps users get the right shot the fi rst time. are an indication that those areas are

August 2015 | reviewofophthalmology.com | 17

014_rp0815_tech update.indd 17 7/24/15 2:26 PM Technology REVIEW Update REVIEW News

FFA, with the main difference be- (continued from page 5) tween the two being that the latter can perform fl uorescein angiography, death and the loss of visual function in indocyanine green angiography and the mice. Inhibiting phagocytosis with fundus autofl uorescence. a compound had a similar effect. The Both cameras can shoot the retina microglia seem to ignore cone photore- through a 3.3-mm pupil, and have ceptors, which fi ts with the known early a nine-dot internal fi xation target to course of retinitis pigmentosa. use for creating mosaic images of “These fi ndings suggest that thera- the retina. “The 5200 FFA uses op- peutic strategies that inhibit microglial tical electromechanical integration activation may help decelerate the rate to combine digital fluorescein fun- of rod photoreceptor degeneration and dus photography, digital video cap- preserve vision,” Dr. Wong said. ture and image processing,” says U.S. What triggers microglia to go on this The Zeiss Visucam Pro NM now comes Ophthalmic’s Henry Morales. “It’s destructive feeding frenzy? Dr. Wong equipped with fundus autofl uorescence. capable of displaying both the con- and colleagues found evidence that tinuous, real-time, high-quality color photoreceptors carrying mutations un- in danger of dying. If there are any fundus photography image as well as dergo physiological stress. The stress areas of geographic atrophy or RPE the fl uorescein monochrome fundus then triggers them to secrete chemicals atrophy, they will look dark.” Fundus video image. The color images and dubbed “find me” signals, which at- autofl uorescence also aids in the vi- retinal fl uorescence photos can then tracts microglia into the retinal layer. sualization of retinal detachment and be stored and are available for image Once there, the microglia probe the central serous chorioretinopathy; the processing, report generation, lesion photoreceptors repeatedly, exposing detection of hereditary dystrophies, measurement, graphical editing and themselves to “eat me” signals, which such as Stargardt’s and Best’s disease; for use with electronic medical record then trigger phagocytosis. In response and the detection of changes due to systems.” to all the feasting, the microglia be- hydroxychloroquine toxicity. For information on either camera come activated. That is, they send out In addition to traditional non-myd- system, visit usophthalmic.com. their own signals to call other microglia riatic fundus photos and fundus auto- Canon’s Mr. Laux says the new to the scene and they release substanc- fl uorescence, the Pro NM has auto- features on fundus cameras remind es that promote infl ammation. focus, auto-fl ash and allows users to him of the advances in prenatal ultra- Other potential treatments for retini- image the anterior segment. sound. “When my wife had our fi rst tis pigmentosa, such as gene therapy, are For information on the Visucam child, the ultrasound was very basic,” progressing, but are not without chal- Pro NM, visit zeiss.com. he says. “Now, however, these ultra- lenges. Gene therapy requires replacing sounds are more like pictures of the defective genes with functional genes, Ezer EFC-5200/5200 FFA child. Fundus photography is similar. yet more than 50 distinct genes have With signal processing, higher-resolu- been linked to the disease in different Ezer, which distributes its camer- tion cameras and the way the image is families, so there’s no one-size-fits-all as through U.S. Ophthalmic (Doral, handled after it’s taken, retinal pho- gene therapy. A therapy targeting mi- Fla.), introduced two new cameras tography has become a more valuable croglia might complement gene therapy in June, the EFC-5200 and the 5200 tool.” because it’s an approach that’s independent of the specifi c genetic cause of reti- Non-mydriatic Retinal Cameras nitis pigmentosa, said Dr. Wong. A clinical trial is already under way Make and Model Website at NEI to see if the anti-infl ammatory Canon CR-2 AF usa.canon.com drug minocycline can block the acti- Centervue DRS centervue.com Ezer/U.S. Ophthalmic EFC-5200 usophthalmic.com vation of microglia and help slow the Kowa WX3D/Nonmyd 7 kowa-usa.com progression of retinitis pigmentosa. Nidek AFC-330 nidek.com The trial is currently recruiting par- Optovue iCam optovue.com ticipants. For more information, see Topcon TRC-NW400 topconmedical.com https://www.clinicaltrials.gov/ct2/show/ Carl Zeiss Meditec Visucam zeiss.com NCT02140164.

18 | Review of Ophthalmology | August 2015

014_rp0815_tech update.indd 18 7/24/15 2:27 PM ENRICH YOUR PRACTICE

Review of Ophthalmology delivers current and comprehensive information focusing on topics such as disease diagnosis, surgical techniques and new technologies. The Review Group offers eyecare practitioners quality informational The Review Group’s Ophthalmic Product Guide brings you the latest products and technology on the market. Published every February resources dedicated to the growth and July. and education of the profession. The TheT Review Group also distributes a variety Review Group offers a variety of print ofo supplements, guides and handbooks withw your subscription to Review of and online products to enrich your OphthalmologyO . These publications are patient care and practice needs. designedd to keep you informed on what’s newn and innovative in the industry on topics rangingr from cataract refractive surgery to ocularo surface disease.

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2014_rp_tsrad.indd 90 6/18/15 12:19 PM 020_rp0815_mqa.indd 20 A A link ofpaymenttoquality; rent system); no linkofpaymenttoquality( are: under thisinitiative.Thecategories payments aremadetoproviders Human Servicescategorizeshow reduce cost. ed toimprovehealth-carequalityand health-care paymentmodelsintend- for Value, NotVolume ,” describenew Healthier People:PayingProviders “ sheets andpressreleases,including for thecaretheydeliver. Severalfact providers regardingfuturepayments Q cost” programsthatmayaffectyourpracticereimbursements. The Value-Based PaymentModiferisoneofthree“qualityand About the VBPM What You Should Know 20 Q payment system? system? payment physicians? for structure reimbursement the change to intend Services Better Care,SmarterSpending,

• Category3–alternativepayment • Category2–fee-for-service witha • Category1–fee-for-service with REVIEW | ReviewofOphthalmology Donna McCune, CCS-P, COE, CPMA Medicare Q&A the DepartmentofHealthand The frameworkadoptedby delivered astrongmessageto Yes. OnJanuary26,2015,CMS timeline to this new new this to timeline and astructure there Is Medicare & Medicaid for Centers the Does | August2015 cur- A prove qualityandreducecost. day-to-day operationsthatwillim- for providerstomakechangesin 2018. HHScitestheimmediateneed and increasethisto90percentby in Category2or3by2016 Medicare fee-for-service payments small numberinCategory3. viders willfallintoCategory2witha ery.” Themajorityofeye-carepro- and efficiencyofhealthcaredeliv- ments variesbasedonthequality indicates “atleastaportionofpay- payment. tecture; and models builtonfee-for-service archi- the new payment structure? payment new the Q professionals andgrouppractices. imbursements forindividual eligible third qualityprogramthataffects re- “quality andcost”program.Itisthe bursements by2015.TheVBPMisa data incalculatingphysicianreim- that CMSincludecostandquality The AffordableCareActmandated

HHS expectstohave85percentof The descriptionforCategory2 • Category4–population-based program andfits intoCategory2. The VBPMisa“sharedsavings” Payment Modifi Payment Value-Based the does How er fi t into This articlehasnocommercial sponsorship. A A Medicare PartsAandB.The second patients; itincludespayments under cost isthetotalpercapitafor that offerhearingservices). ologists (forthoseeye-carepractices anesthesiologists; CRNAs;andaudi- cian assistants;nursepractitioners; gists; optometrists;osteopaths;physi- eye care,theyinclude:ophthalmolo- non-physician practitioners.Within sionals andincludesphysicians Security Actdefi nes eligibleprofes- Q Q tions apply. VBPM isrequiredandnoexemp- istration orspecificattestationfor and costofcareprovided.Noreg- penalizes providersforthequality the PQRSprogramandrewardsor grams. TheVBPMlinksdirectlyto the ElectronicHealthRecordpro- cian QualityReportingSystemand The othertwoprogramsarePhysi- ly weighstwocosts.Thefirst The costcompositescoreequal- eligible professionals.TheSocial The VBPMprogramincludesall component calculated? cost the is How VBPM program? program? VBPM the in included is Who 7/24/15 10:29 AM WHEN IT COMES TO EARLY GLAUCOMA DETECTION, EVERY SECOND COUNTS.

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cost is the per capita cost for benefi - Reimbursement adjustments, 2017. Failure with PQRS in 2015 ciaries with diabetes, coronary artery both upward and downward, associ- results in a 2-percent PQRS penalty disease, heart failure and chronic ated with the VBPM by CMS will and a 2- to 4-percent VBPM penalty, obstructive pulmonary disease. The be phased in from 2015 to 2017. depending on the size of the prac- process used to assign the per capita Reimbursement adjustments affect tice, in 2017. cost per patient is the same process only physician payments under the used to assign benefi ciaries to Medi- Medicare Physician Fee Schedule. Is there an accessible care Shared Savings Accountable It applies to Medicare paid amounts, Qreport that contains Care Organizations. The majority so co-insurance amounts are not af- practice-specifi c feedback of benefi ciaries will be “assigned” to fected. associated with the VBPM? primary-care providers. However, it is possible that some will be as- When do the payment Quality Resource and Use Re- signed to specialty-care providers if Qadjustments begin? Aports, also known as Physician the benefi ciary received the majority Feedback reports, contain quality- of primary-care services from other Payment adjustments of-care and cost performance rates eligible professionals. Aare based on on measures that will be used to participation two years compute the VBPM. To access your How will a prior to the year in report, you can log in to the CMS Qprovider be question. Utilizing Enterprise Portal with an Individu- analyzed? 2014 data, groups of als Authorized to Access the CMS 10 or more will be Computer Services (IACS) account. The simple analy- analyzed on their The 2013 reports are currently avail- Asis of the program cost and quality to able; they provide information as to indicates that eligible determine if they how you rate under the VBPM. The providers successfully are statistically 2014 interim reports were released participating in the PQRS better, the same in April 2015 and contain cost infor- program and considered or worse than mation for 2014 but do not contain high-quality and low- the national quality data. cost providers will be average. In eligible for a VBPM 2016, groups of Why are changes to the bonus. The VBPM 10 or more will Qexisting reimbursement applies at the Tax receive either a model necessary? Identification positive or neutral Number level payment adjustment The existing fee-for-service of an individ- based on their 2014 Amethodology is not sustainable. ual or a group performance. Group According to the 2014 Trustee Re- practice. practices of 10 or port, the Medicare Hospital Insur- more providers ance Trust Fund will be depleted What is the who were not by 2030. Initiatives that move away Qvalue of the successful with from the fee-for-service method to bonus? PQRS in alternative payment methods are the 2014 will be goal of HHS and private payers. The Currently the value of the assessed a VBPM is one component of the new Abonus is unknown because 2-percent payment framework affecting the fu- the program must be budget- reduction for ture of reimbursements. neutral; positive adjustments to both VBPM and those eligible must be offset by neg- PQRS in 2016. Ms. McCune is vice pres ident of the ative adjustments to others, and the In 2015, all providers are Corcoran Consult ing Group. Contact bonus cannot be calculated until the subject to the VBPM. Performance her at [email protected]. end of the PQRS reporting period. in 2015 affects reimbursements in

22 | Review of Ophthalmology | August 2015

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IMPORTANT SAFETY INFORMATION OMIDRIA must be added to irrigation solution prior to intraocular use. OMIDRIA is contraindicated in patients with a known hypersensitivity to any of its ingredients. Systemic exposure of phenylephrine may cause elevations in blood pressure. Use OMIDRIA with caution in individuals who have previously exhibited sensitivities to acetylsalicylic acid, phenylacetic acid derivatives, and other non-steroidal anti-infl ammatories (NSAIDs), or have a past medical history of asthma. The most commonly reported adverse reactions at 2-24% are eye irritation, posterior capsule opacifi cation, increased intraocular pressure, and anterior chamber infl ammation. Use of OMIDRIA in children has not been established. Please see the Full Prescribing Information for OMIDRIA at www.omidria.com/prescribinginformation. You are encouraged to report suspected adverse reactions to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

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INDICATIONS AND USAGE OMIDRIA is added to ophthalmic irrigation solution used during cataract surgery or intraocular lens replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

Reimbursement information is based on Omeros data on ﬁ le. Omeros does not guarantee reimbursement for any particular patient. Contact 1-844-OMEROS1 (1-844-663-7671) for more information about how to submit for OMIDRIA reimbursement.

References: 1. OMIDRIA [package insert]. Seattle, WA: Omeros Corporation; 2015. 2. Omeros data on ﬁ le. 3. Federal Register, April 7, 2000, 65 FR. 4. Kaiser Family Foundation analysis of the CMS Medicare Current Beneﬁ ciary Survey Cost and Use File, 2010. 5. Lindstrom RL, et al. Clin Ophthalmol. 2014;8:1735-1744. 6. Katsev D, Katsev C, Pinnow J. Intracameral ketorolac concentration after topical ketorolac administration prior to cataract surgery. Electronic poster session presented at: American Society of Cataract and Refractive Surgery. 2015 ASCRS-ASOA Symposium and Congress; 2015 Apr 17-21; San Diego, CA. Study sponsored by Omeros Corporation. 7. Florio V, Cowan L, Prusakiewicz JJ, Bentley E, Waterbury LD. Ocular tissue distribution of ketorolac after administration of OMS302 to dogs during IOL replacement. Electronic poster session presented at: American Society of Cataract and Refractive Surgery. 2015 ASCRS-ASOA Symposium and Congress; 2015 April 17-21; San Diego, CA. 8. Waterbury LD, et al. Curr Med Res Opin. 2006;22:1133-1140. 9. Hovanesian JA, et al. J Cataract Refract Surg. 2015 [in press].

RP0815_Omeros spread 1.indd 3 7/23/15 10:54 AM ® What you can expect with OMIDRIA (phenylephrine and ketorolac injection) 1% / 0.3%

FDA-approved OMIDRIA is added to the TOPICAL MEDICATIONS CAN WASH OUT6 irrigation solution used during cataract surgery and lens replacement for direct and continuous intracameral delivery of Topical ketorolac may 1 100% mydriatic and NSAID therapy. not go the distance. In of patients receiving fact, in a study evaluating topical ketorolac the presence of preoperatively had nominal SUPERIOR TO PHENYLEPHRINE OR preoperative topical or undetectable ketorolac KETOROLAC ALONE* ketorolac at the end levels at the end of of cataract surgery: In a phase 2b clinical trial, OMIDRIA was 4 to 6 times the procedure.6,† more effective in preventing pupil diameter of < 6 mm than intracameral phenylephrine or ketorolac.2 WITH OMIDRIA, NSAID LEVELS Percent of patients with pupil diameter <6 mm at 1 any time during surgery2,* MAINTAINED THROUGHOUT SURGERY OMIDRIA is delivered in the irrigation solution p<0.0001 50 continuously during surgery. In a study of

p=0.0004 conventional phacoemulsiﬁ cation and lens 40 replacement performed with OMIDRIA in 20 canines,

30 ketorolac levels measured throughout the structures p<0.0216 46% of the eye were sufﬁ cient to ablate COX-1 and -2 20 pathways for at least 10 hours postoperatively.7,8,‡

Patients (%) 35%

10 22% 6% Ketorolac tissue levels inhibited COX-1 and COX-2 0 pathways for at least 10 hours postoperatively7,8 Vehicle Ketorolac Phenylephrine OMIDRIA (n=53) (n=52) (n=49) (n=49)

Post hoc analysis 100

60 CONSISTENTLY MAINTAINS PUPIL DIAMETER2,5 40 In pivotal phase 3 clinical trials (N=808) in which Retinal COX-1 20 all patients received standard topical mydriatics Estimated inhibition (%) Retinal COX-2

preoperatively, OMIDRIA was superior to placebo 0 across all assessments of pupil size. In fact, 96% of 0 26810 OMIDRIA-treated patients had pupil diameter ≥ 6 mm Time postsurgery (hr) at the time of lens implantation.1,2,5

Pupil diameter <6 mm at start of lens implantation2,5 OMIDRIA EFFECTIVELY REDUCES POSTOPERATIVE OCULAR PAIN1

Study 1 Study 2 In two pivotal phase 3 clinical trials§ in which all

40 patients received standard anesthetic agents p<0.0001 preoperatively, patients treated with OMIDRIA were: 30

20 23 23 Patients (%) % % 50% 50% 30% 10 4 4 more likely to less likely to less likely to 0 % % Placebo OMIDRIA Placebo OMIDRIA be pain-free up have moderate- use analgesics 9 (n=180) (n=184) (n=180) (n=195) to 12 hours to-severe pain on day of after surgery9 and… surgery9

RP0815_Omerostwo.indd 2 7/23/15 11:00 AM Have conﬁ dence in reimbursement across payers

The Centers for Medicare and Medicaid Services OMIDRIA is covered by (CMS) granted pass-through reimbursement 100% of Medicare contractors status to OMIDRIA. Under the Outpatient across all Prospective Payment System, pass-through 50 states products are paid separately by CMS. and Puerto Rico as well as by Medicare Advantage • No co-payment in hospital outpatient departments (HOPDs) and commercial payers. • 20% co-payment in ambulatory surgery centers (ASCs) To ensure that patients under all payer types can beneﬁ t from - Approximately 90% of Medicare Part B patients have some OMIDRIA, Omeros is establishing a patient assistance program form of supplemental insurance, which covers co-payments and a commercial co-payment program.

Positive eff ect on facility fees3,4 No eff ect on physician fees3,4

Following expiration of its pass-through status on December 31, Payment to the surgeon for cataract surgery under Medicare’s 2017, OMIDRIA likely will be included in the bundled facility fees Physician Fee Schedule will be unaffected by the use of for cataract surgery. As a result, those fees will increase by an OMIDRIA or the pass-through payments related to OMIDRIA, amount that correlates with the magnitude of OMIDRIA now and in the future. utilization during its pass-through status.

No eff ect on the healthcare system3,4 Reimbursable across surgical facility types3,4

The pass-through regulation is budget-neutral to the OMIDRIA is also on the Federal Supply Schedule and on healthcare system. To the extent that ophthalmic surgeons/ 340B formularies. In partnership with ophthalmic surgeons facilities elect not to access pass-through payments, the funds and their teams, Omeros offers billing support services set aside will be used by other specialties. Any remaining (1-844-OMEROS1) and is establishing an OMIDRIA-focused: amount will be lost to the system. • reimbursement hotline • patient assistance program based on ﬁ nancial need • co-payment program for commercial beneﬁ ciaries

TO FIND OUT MORE ABOUT OMIDRIA, GO TO OMIDRIA.COM

IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE OMIDRIA must be added to irrigation solution prior to OMIDRIA is added to ophthalmic irrigation solution intraocular use. used during cataract surgery or intraocular lens OMIDRIA is contraindicated in patients with a known replacement and is indicated for maintaining pupil hypersensitivity to any of its ingredients. size by preventing intraoperative miosis and reducing Systemic exposure of phenylephrine may cause elevations postoperative ocular pain. in blood pressure. Use OMIDRIA with caution in individuals who have * Randomized, double-masked trial using a 4-arm factorial design previously exhibited sensitivities to acetylsalicylic acid, to show that OMIDRIA is superior to either agent alone.2 phenylacetic acid derivatives, and other non-steroidal † Study of ketorolac levels in aqueous humor of 14 patients at the anti-infl ammatories (NSAIDs), or have a past medical start and end of cataract surgery following multiday preoperative topical ketorolac administration.6 history of asthma. ‡ Canine study assessing ketorolac levels in retina, choroid, ciliary The most commonly reported adverse reactions at 2-24% body/iris, cornea, vitreous, lens capsule, and sclera samples are eye irritation, posterior capsule opacifi cation, increased following cataract surgery using OMIDRIA. COX-1 and COX-2 7,8 intraocular pressure, and anterior chamber infl ammation. inhibition was estimated using IC50 values. § Pooled analyses of post hoc analysis (Study 1) and secondary Use of OMIDRIA in children has not been established. endpoint (Study 2).9 Please see the Full Prescribing Information for OMIDRIA at www.omidria.com/prescribinginformation. You are encouraged to report suspected adverse reactions OMEROS® and the Omeros logo® are registered trademarks, and OMIDRIA® and the OMIDRIA ® to the FDA. Visit www.fda.gov/medwatch, logo® are trademarks, of OMEROS Corporation. or call 1-800-FDA-1088. © OMEROS Corporation 2015, all rights reserved. 2015-142

RP0815_Omerostwo.indd 3 7/23/15 11:00 AM Retina REVIEW Cover Focus Retinal Imaging: The State of the Art Christopher Kent, Senior Editor

Technology for hen it comes to imaging School of Medicine in Boston. “The the retina, there’s a kind of primary imaging tool used in retinal scanning the W“catch-22” dance that takes practice today is optical coherence place between new technology and tomography. One of the reasons OCT back of the eye clinical usefulness. New technology is so ingrained in clinical practice right often results in the discovery of new now is that the treatment paradigms is outrunning our information, but unless that informa- for diseases like wet macular degen- ability to treat—but tion impacts the management of a eration, diabetic macular edema and treatable disease, clinicians are not retinal vein occlusion are all based probably not for motivated to purchase and use the around the presence and quantifi ca- technology. Yet without the data gen- tion of abnormal collections of fl uid long. erated through clinical use, practical in or under the retina. For the past 10 connections to treatable disease can’t or 15 years we’ve been able to treat be demonstrated. abnormal retinal fluid with medica- Somehow, despite this awkward tions—fi rst cortisone, now anti-VEGF situation, new technologies continue drugs. We need to be able to tell if our to be developed, and—in large part therapies are working. If we didn’t thanks to clinical trials—many do have medical treatments that improve eventually become clinically relevant. fl uid leakage in the macula rapidly and Here, four retina experts share their measurably, OCT wouldn’t be nearly experience with current retinal imag- as popular. ing technologies and discuss how sev- “Beyond that, OCT helps us to make eral new technologies in the pipeline diagnoses,” he continues. “There are may impact clinical care. certain diseases that we’ve come to recognize from OCT scans. The prob- The OCT Factor lem at the moment is that not all of those diseases are treatable. For ex- “By far, the most important clinical ample, I’ve done a lot of research on utility for imaging in retinal practice is choroidal thickness and morphology. to help us diagnose and manage dis- But if you ask how many times imag- ease,” says Jay S. Duker, MD, direc- ing the choroid changes my diagnosis tor of the New England Eye Center or my management of patients, the and professor and chair of the depart- answer is rarely. In contrast, we use ment of ophthalmology at Tufts Medi- OCT to measure fluid in the retina cal Center and the Tufts University about 40 times a day.”

28 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

0028_rp0815_f1.indd28_rp0815_f1.indd 2828 77/24/15/24/15 3:213:21 PMPM Jay S. Duker, MD Today, several types of OCT are available (although not all are available in the United States), and several more are in the pipeline. “Ultra-high- resolution OCT refers to OCT with an axial resolution less than 3 µm,” says Dr. Duker. “There are three ways to increase OCT resolution. First, axial resolution is inversely proportional to the bandwidth of the light source, so increased axial resolution can be achieved with improved broadband light sources, using any type of OCT system. Second, higher resolution can The longer wavelength used in swept-source OCT makes it better able to visualize the be achieved by increasing pixel den- choroid than spectral domain OCT. Above: angiograms showing choroidal neovascularization. sity; to do that, you generally need a faster system. The third way to in- Swept-source vs. Spectral visualize the choriocapillaris. Professor crease resolution is by oversampling. Fujimoto has a paper coming out sug- This means scanning the same area “Swept-source OCT uses a longer gesting that changes in the choriocapil- multiple times, very rapidly; any dif- wavelength than spectral-domain,” laris may be some of the fi rst vascular ference between the scans is noise, notes Philip Rosenfeld, MD, PhD, changes that we’ll see in the progres- which the software eliminates. professor of ophthalmology at Bascom sion of macular degeneration. Once we “There are also three major ways Palmer Eye Institute in Miami and the come up with a therapy, particularly OCT images are created,” he contin- University of Miami Miller School of for dry macular degeneration, we’re ues. “They relate to different ways of Medicine. “The longer wavelength is going to be looking at the choriocapil- detecting reflectance patterns. The capable of better penetration into the laris to see whether these therapies are fi rst is time-domain, which has been choroid, and it’s able to scan at a faster having a benefi cial effect.” in clinical practices since 2002 and is speed. With increased speed and pen- Dr. Rosenfeld points out that the still in clinical use. In retinal practice etration the choroid can be visualized differences between the specific in- that type of OCT has largely been sup- with greater clarity, compared with struments are more complicated than planted by spectral-domain systems, spectral-domain technology.” simply whether the technology is spec- available since about 2006. Because Dr. Duker agrees. “With spectral- tral-domain or swept-source. “Differ- there are no moving parts, spectral- domain there’s an effect called sensi- ent instruments are using different domain systems are faster than time- tivity roll-off,” he says. “That means algorithms to analyze the signals they domain. Spectral-domain OCT has the deeper you image, the worse the detect,” he explains. “All the compa- become the standard for most retinal signal-to-noise ratio. Swept-source nies are trying to show that their algo- specialists at this point. OCT doesn’t have that problem.” rithms are better than their competi- “Swept-source OCT is an even fast- Dr. Rosenfeld says he believes this is tors’. But it’s becoming clear that it’s er way of detecting those reflection the greatest advantage of this imaging not just the algorithm that matters; it’s patterns,” he says. “The typical time- technology. “The holy grail for macular also the design of the instrument using domain system runs at 400 A-scans degeneration is what’s happening to it. The only way to determine that one per second. Clinically available spec- the choriocapillaris,” he notes. “It’s a is better than the other will be to test tral-domain systems run from 20,000 thin, microvascular layer right under that instrument on a particular disease to 70,000 A-scans per second. A the retinal pigment epithelium. We be- and see which instrument generates swept-source system made by Topcon lieve macular degeneration is a disease the best images that are relevant to (not available in the United States) of the photoreceptor-retinal pigment that disease and clinical practice.” runs at 100,000 A-scans per second. epithelium-choriocapillaris complex. SriniVas R. Sadda, MD, president And we have an investigational swept- We’ve been able to look at the photo- and chief scientific officer of the source system in our offi ce that runs at receptors using OCT and adaptive op- Doheny Eye institute, and the Stephen 400,000 A-scans per second, built by tics; but we haven’t really been able to J. Ryan-Arnold and Mable Beckman James G. Fujimoto at the Massachu- study the RPE well in high resolution, endowed chair and professor of oph- setts Institute of Technology.” and until now, no one has been able to thalmology at the University of Cali-

August 2015 | reviewofophthalmology.com | 29

028_rp0815_f1.indd 29 7/24/15 3:21 PM Cover Retina

REVIEW Focus

The Shifting Purpose of Retinal Imaging lution and depth has some current benefi ts, depending on your purpose. Steve Charles, MD, FACS, founder of the Charles Retina Institute in Memphis, Tenn., “It’s well-known that there’s a very notes that the purpose of retinal imaging has changed in recent years as treatments good correlation between nerve fi- have evolved. “In the past, our goal was to fi nd a lesion using angiography or OCT and ber layer thickness and glaucoma,” then target that with some destructive form of energy, laser or photodynamic therapy,” he says. “And, it may turn out that he says. “Feeder-vessel therapy is an example of that approach. That’s what I call ganglion cell layer thickness correlates visualization-based anatomic or structural targeting. well with visual fi eld fi ndings. But it’s “That approach served to eliminate some problematic tissues or vessels, but it wasn’t less clear that measuring other lay- very effective,” he continues. “Now, we do molecular targeting using drugs such as ers of the retina will help us to better ranibizumab and afl ibercept. Those work incredibly well and have virtually no side ef- manage retinal disease. There are ex- fects. Consider Protocol T, comparing anti-VEGF agents for diabetic retinopathy, recently amples where it appears that measur- released by DRCR.net. Anti-VEGF therapy can be considered molecular targeting; it ing the ganglion cell layer may help works phenomenally well when managing diabetic retinopathy. It is also incredibly effec- us manage certain neuro-ophthalmic tive for macular degeneration, retinal vein occlusion or retinopathy of prematurity. So the diseases, and we’ve always been inter- idea of using imaging for targeting or sub-group classifi cation doesn’t refl ect the reality ested in measuring the outer retina— of today’s treatments.” the photoreceptors—because that’s Dr. Charles notes that imaging companies and their physician advocates still promote the source of our vision. However, the idea that it’s crucial to locate problematic ischemic areas, vascular leakage or neo- measuring the photoreceptors is still vascularization with better and better images. “It’s become an imaging ritual,” he says. problematic because the photorecep- “That’s part of the philosophy behind wide-fi eld angiography—to locate ischemic areas tor layer is hard to quantify it when in the periphery and ablate them with targeted laser photocoagulation. The reality is, this it’s abnormal; the software has a hard doesn’t impact outcomes. That’s not the direction things are moving.” time correctly segmenting the layers. —CK “Of course, we can still do a qualita- tive assessment,” he adds. “We can fornia, Los Angeles, specializes in the imaging tumors, where swept-source judge the general appearance of a evaluation of new imaging hardware has such an advantage over spectral- scan. For example, we may look at the and technologies; he runs a software domain that will help it gain traction.” external limiting membrane in a scan engineering lab that develops new al- and see that the layers are disrupted, gorithms to analyze images automati- Is More Detail Better? which will probably correlate to poor cally, and also runs an ophthalmologi- visual function. But without a way to cal image-reading center. He notes The more advanced versions of quantify that, its usefulness is limited.” that the advantages of swept-source OCT defi nitely make it possible to see Dr. Sadda also acknowledges that OCT over spectral-domain are only fi ner details of the retina and its layers. simply getting a sharper picture may incremental. “Spectral-domain repre- But how much of an advantage is that not be a major benefit in the clinic sented a massive jump from time-do- to the clinician? today. “We need to have data that’s main, in terms of resolution and speed, “From a clinical utility standpoint, compelling, that says seeing this new which added a wealth of additional in- it’s hard to show that one version of level of detail will transform our clini- formation about the retina and deeper OCT is better than the other for most cal management,” he notes. “Unfor- structures. Having said that, though, clinical situations,” says Dr. Duker. tunately, you only get data like that I think swept-source is an important “As already noted, the number-one if you’re able to use these kinds of advance.” use for OCT in retinal practice to- technologies in well-designed clinical Dr. Sadda says that his group has day is measuring fl uid in or under the trials, but to do that they have to be worked with a prototype swept-source retina, and you can do that even with a somewhat time-effi cient and broadly OCT device from Carl Zeiss Meditec time-domain system. Image quality is available.” He notes that with some of in the past, and more recently with a defi nitely better with spectral-domain, the new technologies in the pipeline, Topcon swept-source OCT unit as part which is the reason most retina spe- that’s not the case—at least so far. of an approved research protocol. “You cialists in the United States now use get a deeper penetration with swept- spectral-domain, but around the world OCT angiography source, and looking at the choroid is there are still more time-domain sys- pretty spectacular,” he says. “There tems in use than spectral-domain.” “The biggest thing that’s happen- may be other applications, such as Dr. Duker notes that better reso- ing in OCT right now is OCT angiog-

30 | Review of Ophthalmology | August 2015

0028_rp0815_f1.indd28_rp0815_f1.indd 3030 77/24/15/24/15 3:213:21 PMPM Discover

in effi cacy As demonstrated in phase 3 clinical trials in patients with Wet AMD, Macular Edema following RVO, DME, and DR in patients with DME

Choose EYLEA® (afl ibercept) Injection from the start

Learn about EYLEA at EYLEA.us/ro

INDICATIONS AND IMPORTANT SAFETY INFORMATION INDICATIONS EYLEA ® (afl ibercept) Injection is indicated for the treatment There is a potential risk of arterial thromboembolic events of patients with Neovascular (Wet) Age-related Macular (ATEs) following intravitreal use of VEGF inhibitors, including Degeneration (AMD), Macular Edema following Retinal Vein EYLEA. ATEs are defi ned as nonfatal stroke, nonfatal Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic myocardial infarction, or vascular death (including deaths of Retinopathy (DR) in Patients with DME. unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the fi rst year was 1.8% CONTRAINDICATIONS (32 out of 1824) in the combined group of patients treated ® EYLEA (afl ibercept) Injection is contraindicated in patients with EYLEA. The incidence in the DME studies from baseline with ocular or periocular infections, active intraocular to week 52 was 3.3% (19 out of 578) in the combined group infl ammation, or known hypersensitivity to afl ibercept or of patients treated with EYLEA compared with 2.8% (8 out to any of the excipients in EYLEA. of 287) in the control group; from baseline to week 100, WARNINGS AND PRECAUTIONS the incidence was 6.4% (37 out of 578) in the combined Intravitreal injections, including those with EYLEA, have been group of patients treated with EYLEA compared with 4.2% associated with endophthalmitis and retinal detachments. (12 out of 287) in the control group. There were no reported Proper aseptic injection technique must always be used thromboembolic events in the patients treated with EYLEA in when administering EYLEA. Patients should be instructed the fi rst six months of the RVO studies. to report any symptoms suggestive of endophthalmitis or ADVERSE REACTIONS retinal detachment without delay and should be managed Serious adverse reactions related to the injection procedure appropriately. Intraocular infl ammation has been reported have occurred in <0.1% of intravitreal injections with EYLEA with the use of EYLEA. including endophthalmitis and retinal detachment. Acute increases in intraocular pressure have been seen The most common adverse reactions (≥5%) reported in within 60 minutes of intravitreal injection, including with patients receiving EYLEA were conjunctival hemorrhage, EYLEA. Sustained increases in intraocular pressure have also eye pain, cataract, vitreous fl oaters, intraocular pressure been reported after repeated intravitreal dosing with VEGF increased, and vitreous detachment. inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately.

Please see brief summary of full Prescribing Information on the following page.

EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc.

RP0815_Regeneron.indd 1 7/13/15 2:25 PM incidence of reported thromboembolic events in wet AMD studies during Table 3: Most Common Adverse Reactions (≥1%) in DME Studies the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies from baseline to Adverse Reactions Baseline to Week 52 Baseline to Week 100 week 52 was 3.3% (19 out of 578) in the combined group of patients EYLEA Control EYLEA Control treated with EYLEA compared with 2.8% (8 out of 287) in the control (N=578) (N=287) (N=578) (N=287) group; from baseline to week 100, the incidence was 6.4% (37 out of Conjunctival hemorrhage 28% 17% 31% 21% 578) in the combined group of patients treated with EYLEA compared Eye pain 9% 6% 11% 9% with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six Cataract 8% 9% 19% 17% BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION months of the RVO studies. Vitreous floaters 6% 3% 8% 6% 6 ADVERSE REACTIONS Corneal epithelium defect 5% 3% 7% 5% For complete details, see Full Prescribing Information. The following adverse reactions are discussed in greater detail in the Intraocular pressure 5% 3% 9% 5% 1 INDICATIONS AND USAGE Warnings and Precautions section of the labeling: increased EYLEA® (aflibercept) Injection is indicated for the treatment of patients • Endophthalmitis and retinal detachments Ocular hyperemia 5% 6% 5% 6% with Neovascular (Wet) Age-Related Macular Degeneration (AMD), • Increased intraocular pressure Vitreous detachment 3% 3% 8% 6% Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular • Thromboembolic events Foreign body sensation Edema (DME), and Diabetic Retinopathy (DR) in Patients with DME. 3% 3% 3% 3% 6.1 Clinical Trials Experience. Because clinical trials are conducted in eyes under widely varying conditions, adverse reaction rates observed in the 2 DOSAGE AND ADMINISTRATION Lacrimation increased 3% 2% 4% 2% 2.1 Important Injection Instructions. For ophthalmic intravitreal clinical trials of a drug cannot be directly compared to rates in other injection. EYLEA must only be administered by a qualified physician. clinical trials of the same or another drug and may not reflect the rates Vision blurred 2% 2% 3% 4% 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD). observed in practice. Intraocular inflammation 2% <1% 3% 1% The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) A total of 2711 patients treated with EYLEA constituted the safety Injection site pain 2% <1% 2% <1% population in seven phase 3 studies. Among those, 2110 patients were administered by intravitreal injection every 4 weeks (monthly) for the Eyelid edema <1% 1% 2% 1% first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal treated with the recommended dose of 2 mg. Serious adverse reactions injection once every 8 weeks (2 months). Although EYLEA may be dosed related to the injection procedure have occurred in <0.1% of intravitreal Less common adverse reactions reported in <1% of the patients treated as frequently as 2 mg every 4 weeks (monthly), additional efficacy was injections with EYLEA including endophthalmitis and retinal detachment. with EYLEA were hypersensitivity, retinal detachment, retinal tear, corneal not demonstrated when EYLEA was dosed every 4 weeks compared to The most common adverse reactions (≥5%) reported in patients receiving edema, and injection site hemorrhage. every 8 weeks. EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, 6.2 Immunogenicity. As with all therapeutic proteins, there is a intraocular pressure increased, and vitreous detachment. 2.3 Macular Edema Following Retinal Vein Occlusion (RVO). The potential for an immune response in patients treated with EYLEA. recommended dose for EYLEA is (0.05 mL or 50 microliters) administered Neovascular (Wet) Age-Related Macular Degeneration (AMD). The The immunogenicity of EYLEA was evaluated in serum samples. The by intravitreal injection once every 4 weeks (monthly). data described below reflect exposure to EYLEA in 1824 patients with wet immunogenicity data reflect the percentage of patients whose test results AMD, including 1223 patients treated with the 2-mg dose, in 2 double- were considered positive for antibodies to EYLEA in immunoassays. The 2.4 Diabetic Macular Edema (DME). The recommended dose for EYLEA masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months. detection of an immune response is highly dependent on the sensitivity is (0.05 mL or 50 microliters) administered by intravitreal injection every and specificity of the assays used, sample handling, timing of sample 4 weeks (monthly) for the first 5 injections followed by 2 mg (0.05 mL) Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies collection, concomitant medications, and underlying disease. For these via intravitreal injection once every 8 weeks (2 months). Although EYLEA Active Control reasons, comparison of the incidence of antibodies to EYLEA with the may be dosed as frequently as 2 mg every 4 weeks (monthly), additional EYLEA Adverse Reactions (ranibizumab) incidence of antibodies to other products may be misleading. efficacy was not demonstrated when EYLEA was dosed every 4 weeks (N=1824) (N=595) In the wet AMD, RVO, and DME studies, the pre-treatment incidence of compared to every 8 weeks. Conjunctival hemorrhage 25% 28% immunoreactivity to EYLEA was approximately 1% to 3% across treatment 2.5 Diabetic Retinopathy (DR) in Patients with DME. The recommended Eye pain 9% 9% groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by were detected in a similar percentage range of patients. There were Cataract 7% 7% intravitreal injection every 4 weeks (monthly) for the first 5 injections, no differences in efficacy or safety between patients with or without followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks Vitreous detachment 6% 6% immunoreactivity. (2 months). Although EYLEA may be dosed as frequently as 2 mg every Vitreous floaters 6% 7% 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA 8 USE IN SPECIFIC POPULATIONS was dosed every 4 weeks compared to every 8 weeks. Intraocular pressure increased 5% 7% 8.1 Pregnancy. Pregnancy Category C. Aflibercept produced embryo- 2.6 Preparation for Administration. EYLEA should be inspected Ocular hyperemia 4% 8% fetal toxicity when administered every three days during organogenesis visually prior to administration. If particulates, cloudiness, or discoloration Corneal epithelium defect 4% 5% to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal are visible, the vial must not be used. Using aseptic technique, the Detachment of the retinal pigment 3% 3% effects included increased incidences of postimplantation loss and fetal intravitreal injection should be performed with a 30-gauge x ½-inch epithelium injection needle. For complete preparation for administration instructions, malformations, including anasarca, umbilical hernia, diaphragmatic Injection site pain 3% 3% see full prescribing information. hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, Foreign body sensation in eyes 3% 4% spina bifida, encephalomeningocele, heart and major vessel defects, 2.7 Injection Procedure. The intravitreal injection procedure should be Lacrimation increased 3% 1% and skeletal malformations (fused vertebrae, sternebrae, and ribs; carried out under controlled aseptic conditions, which include surgical supernumerary vertebral arches and ribs; and incomplete ossification). hand disinfection and the use of sterile gloves, a sterile drape, and a Vision blurred 2% 2% The maternal No Observed Adverse Effect Level (NOAEL) in these studies sterile eyelid speculum (or equivalent). Adequate anesthesia and Intraocular inflammation 2% 3% was 3 mg per kg. Aflibercept produced fetal malformations at all doses a topical broad–spectrum microbicide should be given prior to the Retinal pigment epithelium tear 2% 1% assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. injection. Injection site hemorrhage 1% 2% Administration of the lowest dose assessed in rabbits (0.1 mg per kg) Immediately following the intravitreal injection, patients should be resulted in systemic exposure (AUC) that was approximately 10 times the monitored for elevation in intraocular pressure. Appropriate monitoring Eyelid edema 1% 2% systemic exposure observed in humans after an intravitreal dose of 2 mg. may consist of a check for perfusion of the optic nerve head or Corneal edema 1% 1% There are no adequate and well-controlled studies in pregnant women. tonometry. If required, a sterile paracentesis needle should be available. Less common serious adverse reactions reported in <1% of the patients EYLEA should be used during pregnancy only if the potential benefit Following intravitreal injection, patients should be instructed to report any justifies the potential risk to the fetus. symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, 8.3 Nursing Mothers. It is unknown whether aflibercept is excreted in pain, redness of the eye, photophobia, blurring of vision) without delay and endophthalmitis. human milk. Because many drugs are excreted in human milk, a risk to (see Patient Counseling Information). Macular Edema Following Retinal Vein Occlusion (RVO). The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg the breastfed child cannot be excluded. EYLEA is not recommended during Each vial should only be used for the treatment of a single eye. If the breastfeeding. A decision must be made whether to discontinue nursing or contralateral eye requires treatment, a new vial should be used and the dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT). to discontinue treatment with EYLEA, taking into account the importance sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection of the drug to the mother. needles should be changed before EYLEA is administered to the other eye. Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies 8.4 Pediatric Use. The safety and effectiveness of EYLEA in pediatric After injection, any unused product must be discarded. Adverse Reactions CRVO BRVO patients have not been established. 3 DOSAGE FORMS AND STRENGTHS EYLEA Control EYLEA Control 8.5 Geriatric Use. In the clinical studies, approximately 76% (2049/2701) Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (N=218) (N=142) (N=91) (N=92) of patients randomized to treatment with EYLEA were ≥65 years of (2 mg) for intravitreal injection. Eye pain 13% 5% 4% 5% age and approximately 46% (1250/2701) were ≥75 years of age. No 4 CONTRAINDICATIONS Conjunctival hemorrhage 12% 11% 20% 4% significant differences in efficacy or safety were seen with increasing age EYLEA is contraindicated in patients with in these studies. Intraocular pressure 8% 6% 2% 0% • Ocular or periocular infections increased 17 PATIENT COUNSELING INFORMATION • Active intraocular inflammation Corneal epithelium defect 5% 4% 2% 0% In the days following EYLEA administration, patients are at risk of • Known hypersensitivity to aflibercept or any of the excipients in EYLEA. developing endophthalmitis or retinal detachment. If the eye becomes red, Hypersensitivity reactions may manifest as severe intraocular inflammation Vitreous floaters 5% 1% 1% 0% sensitive to light, painful, or develops a change in vision, advise patients 5 WARNINGS AND PRECAUTIONS Ocular hyperemia 5% 3% 2% 2% to seek immediate care from an ophthalmologist (see Warnings and Foreign body sensation Precautions). Patients may experience temporary visual disturbances after 5.1 Endophthalmitis and Retinal Detachments. Intravitreal injections, 3% 5% 3% 0% including those with EYLEA, have been associated with endophthalmitis in eyes an intravitreal injection with EYLEA and the associated eye examinations and retinal detachments (see Adverse Reactions). Proper aseptic injection Vitreous detachment 3% 4% 2% 0% (see Adverse Reactions). Advise patients not to drive or use machinery until visual function has recovered sufficiently. technique must always be used when administering EYLEA. Patients should Lacrimation increased 3% 4% 3% 0% be instructed to report any symptoms suggestive of endophthalmitis or Injection site pain 3% 1% 1% 0% retinal detachment without delay and should be managed appropriately (see Dosage and Administration and Patient Counseling Information). Vision blurred 1% <1% 1% 1% 5.2 Increase in Intraocular Pressure. Acute increases in intraocular Intraocular inflammation 1% 1% 0% 0% pressure have been seen within 60 minutes of intravitreal injection, Cataract <1% 1% 5% 0% Manufactured by: All rights reserved. including with EYLEA (see Adverse Reactions). Sustained increases in Eyelid edema <1% 1% 1% 0% Regeneron Pharmaceuticals, Inc. Issue Date: March 2015 intraocular pressure have also been reported after repeated intravitreal 777 Old Saw Mill River Road Initial U.S. Approval: 2011 dosing with vascular edothelial growth factor (VEGF) inhibitors. Intraocular Less common adverse reactions reported in <1% of the patients treated Tarrytown, NY 10591-6707 pressure and the perfusion of the optic nerve head should be monitored with EYLEA in the CRVO studies were corneal edema, retinal tear, Regeneron U.S. Patents 7,070,959; and managed appropriately (see Dosage and Administration). hypersensitivity, and endophthalmitis. U.S. License Number 1760 7,303,746; 7,303,747; 7,306,799; 5.3 Thromboembolic Events. There is a potential risk of arterial Diabetic Macular Edema (DME). The data described below reflect EYLEA is a registered trademark of 7,374,757; 7,374,758; 7,531,173; thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, exposure to EYLEA in 578 patients with DME treated with the 2-mg dose Regeneron Pharmaceuticals, Inc. 7,608,261; 7,972,598; 8,029,791; including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial in 2 double-masked, controlled clinical studies (VIVID and VISTA) from © 2015, Regeneron 8,092,803; 8,647,842; and other infarction, or vascular death (including deaths of unknown cause). The baseline to week 52 and from baseline to week 100. Pharmaceuticals, Inc. pending patents. LEA-0721

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REVIEW Focus

raphy,” says Dr. Duker. “Using SriniVas R. Sadda, MD that impact the central macula, OCT with either spectral-domain such as diabetic macular edema, or swept-source systems, we’re wet macular degeneration and now able to create a 3-D repre- macular telangiectasia type II, sentation of the retinal and cho- or MacTel2. MacTel2 is a bilat- roidal vasculature. OCT instru- eral disease that only affects the ments designed to do this image central macula. Since we don’t the same area rapidly and repeat- currently have a treatment for edly; then the software uses the MacTel2, this technology is just multiple images to eliminate the helping us to better understand ‘noise.’ The only thing left chang- the disease and its progression. ing between the images will be But once we come up with treat- the blood fl ow. The machine can ments—and there is a clinical then use that information to cre- trial going on now with an im- ate a 3-D outline of the retinal plant from Neurotech—this vessels. The advantage of this ap- technology will let us determine proach is that you can get beauti- whether there’s a change in the ful images—in some cases, better An OCT angiography scan of a normal subject obtained microvasculature, without hav- quality than fl uorescein angiogra- using a prototype swept-source OCT (not FDA-approved). ing to perform fl uorescein angi- phy—without a dye injection, in ography at every visit.” about three seconds.” tages,” notes Dr. Duker. “First, you “We’ll not only be able to see the need a machine that images rapidly; Where OCTA Is Headed retinal microvasculature better than most machines in current practice will we can with fl uorescein, but also the not be able to be retrofi tted for this Dr. Rosenfeld points out that con- choroidal microvasculature, as clearly purpose. Second, because there’s no ventional OCT was in a position simi- as we can see it using indocyanine dye injection, there’s no dye leakage. lar to the current state of OCT angiog- green angiography—perhaps more Dye leakage from abnormal vessels raphy, back in 2001. “Back then, our clearly—without the use of any dyes,” is something that we’re interested in group conducted the Phase I and II adds Dr. Rosenfeld. “We often talk looking at in most—though not all— clinical trials of ranibizumab” he says. about multimodal imaging—using dif- cases. Third, the fi eld of view is very “We were the fi rst ones to incorporate ferent techniques such as OCT, auto- small. In fl uorescein angiography, the OCT into a trial of this type, using fl uorescence, infrared and color imag- trend has been to do very wide-fi eld it to follow the changes in the retina ing. OCT angiography introduces a angiograms up to 110 degrees to look that occurred within 24 to 48 hours new term: multidimensional imaging. at non-perfusion in the retinal periph- of treatment. Back then everyone was You can get a 3-D reconstruction of ery. OCT angiography can only im- saying we needed to repeat fl uores- the back of the eye and also look at age the macula in 3 x 3-, 6 x 6- or 9 x cein angiography every month just to the change in blood fl ow by repeating 9-mm cubes. And the larger the area see what was going on. But the data the scans over and over in a very short you image with OCT angiography, the from our studies showed unambigu- period of time. That adds the fourth more noise you have, and the worse ously that OCT was all we needed to dimension: time. Of course, we’re re- the signal-to-noise ratio. So, you lose manage patients with wet macular de- ally just beginning to learn about this image quality.” generation. We got a lot of push-back imaging strategy.” Dr. Rosenfeld agrees that the cur- for saying this, and it took about three “The clinical relevance of this is rent form of OCT angiography has years before using OCT became the something we’re trying to fi gure out limitations. “Right now we can only standard of care. now,” he adds. “The nice thing about get really high-resolution, detailed an- “We’re at the same stage right now OCT angiography is you can do this giographic images in the central mac- with OCT angiography,” he notes. intense image analysis but you still ula,” he says. “We get the best images “We don’t know how it’s going to be have the conventional OCT B-scans to if we scan a 3 x 3-mm area. Fujimoto’s used in clinical practice. Some people look at, too, so you get the best of both instrument can generate beautiful im- think that with wet macular degen- worlds with a single scan pattern.” ages at 6 x 6 mm; but retina special- eration patients we’re going to be fol- “The current version of this tech- ists using OCT angiography instru- lowing the neovascular lesions, even nology does have several disadvan- ments are just focusing on diseases when they’re not leaking, to see if the

August 2015 | reviewofophthalmology.com | 33

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REVIEW Focus

lesion changes shape and complexity. ally become a key part of our clinical down, they may fall outside the depth We could end up treating based on practice, but right now it’s a work in of fi eld you’re measuring and appear the shape of the neovascular complex, progress.” to be missing. Third, when applying rather than based on leakage and vi- Dr. Duker notes that no machine this technology to OCT, which several sion loss. People are now designing capable of doing this is currently avail- research labs are doing, the processing clinical trials to test this premise. Simi- able in the United States. “The Avanti takes a long time. Fourth, the technol- larly, some people think we’re going to from Optovue is OCTA-ready,” he ogy is quite expensive. For all of these be following the microvasculature in says. “The hardware is Food and Drug reasons, it hasn’t caught on commer- patients with diabetes. Richard Rosen Administration-approved, but the cially.” from New York has developed an al- software is not, as of today. The Avanti Dr. Sadda concurs. “The reason gorithm that allows you to quantify is available worldwide and more than OCT has been so transformative is the capillaries in the central macula. 300 units are in use. Meanwhile, all that it’s quick; thus, it’s compatible He skeletonizes the images so he can the other major OCT companies are with the speed of clinical practice,” he come up with a quantitative evaluation working on this technology. I think says. “Wide-fi eld imaging can also be of the ischemic areas. He thinks we’re this will be the next big thing in OCT, done quickly. In contrast, some tech- going to be following these areas of and it will be integrated into the next nologies such as adaptive optics have ischemia, and if they change in size, generation of OCT machines.” instruments that are not as robust and we’re going to start treatment—be- may require a lot of time to use or fore vision is affected and fluid ac- Adaptive Optics need regular maintenance.” cumulates in the macula. Maybe he’s Steve Charles, MD, FACS, found- right; maybe not. Those clinical trials “Adaptive optics is an optical imag- er of the Charles Retina Institute in are under way, and similar hypotheses ing system that eliminates higher-or- Memphis, Tenn., agrees that adaptive are being tested relating to vein oc- der aberrations,” explains Dr. Duker. optics technology has limited useful- clusion. “It can be applied to any imaging de- ness. “This technology has no role in “The advantages of OCT angiog- vice. You can use adaptive optics on a the clinic or operating room unless raphy go beyond simply increasing camera, a scanning laser ophthalmo- you’re part of a clinical trial involving speed or resolution,” says Dr. Sadda. scope or on OCT, where it allows us gene therapy or cell-based therapy for “We don’t do fl uorescein angiography to do things such as imaging the cone hereditary retinal degenerative dis- on every patient today because it’s in- mosaic in an en face image. ease,” he says. “As soon as the retina vasive—we have to inject dye. OCT has any structural distortion—epimac- angiography can be obtained when ular membrane, vitreomacular trac- you’re getting an OCT on the patient tion, a macular hole, subretinal fl uid anyway. So doctors may eventually For now, adaptive or macular degeneration—the retinal perform OCT angiography on virtu- optics is a niche structure changes and the rods and ally every patient that comes into the cones aren’t pointing in the direction clinic, just because it’s so easy to get. technology.” they’re supposed to point. Cones and With that much data, we’ll start to —Steve Charles, MD rods refl ect 30 dB less light back to learn new things, and new applications your adaptive imaging system if they’re are likely to arise. off-angle, so if you use adaptive optics “But right now, it’s still a technology to monitor any of the aforementioned that’s in its infancy,” he adds. “There “However, there are four problems diseases, it will appear that the rods are still lots of artifacts in the data, with using it in retinal practice,” he and cones are missing in many areas. and things we don’t fully understand. says. “First, measuring the cone mo- They’re not missing—they’re just not For example, we’re still learning how saic doesn’t really help us; so far, we’re pointed toward the light you’re direct- to best view and interpret the images. not able to treat patients who have ing into the eye. Should we be looking at them as mov- photoreceptor loss. As a result, the “So for now, adaptive optics is a ies? Should we be looking at the B- cone mosaic is not of clinical utility niche technology,” he says. “It’s great scans, as well as the en face images? at present. Second, this technology for improving resolution in conditions We need careful studies looking at has a very narrow depth of fi eld. So, if that involve only apoptosis with no repeatability and the impact of arti- you’re trying to measure the cone mo- structural distortion, especially geneti- facts when interpreting these images. saic and there’s a little bit of fl uid that cally driven conditions like retinitis I think OCT angiography will eventu- has shifted some of the cones up or pigmentosa, cone degeneration or

34 | Review of Ophthalmology | August 2015

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REVIEW Focus SriniVas R. Sadda, MD Stargardt’s disease. However, points out that in this case treatments for these conditions “wide-field” is a relative de- are a ways down the road. In scription. “Here, we’re talking the meantime, adaptive optics about a 12 x 12-mm area that won’t help to answer clinical encompasses the macula,” he questions such as: Does this says. “We’re not talking about patient have a macular hole? imaging the far periphery. I Should I operate? Was my sur- think everyone understands gery successful? Does the pa- the benefi t of getting a good tient need an injection of an macular image, like a conven- anti-VEGF compound? An- tional photographic image of swering these questions calls the back of the eye.” for more traditional imaging Dr. Sadda has also done a approaches.” Optos ultrawidefi eld fl uorescein angiogram from a patient lot of work with wide-fi eld im- Will adaptive optics eventu- with a retinal vein occlusion. Note the extensive aging (in the broader sense). ally become clinically useful? non-perfusion in the retinal periphery. “A lot of our imaging tech- “It may very well,” says Dr. nologies over the past few de- Duker. “But two things will have to to be the ILM is actually just the fi rst cades have focused on evaluating the happen for adaptive optics to catch refl ective surface on the retina. The macula and the area around the optic on clinically. First, it has to be fast and ILM itself is 3-µm thick and transpar- nerve—the posterior pole of the eye,” reproducible; second, it has to help us ent. The axial resolution of OCT today he notes. “But there’s a great deal of address a clinical problem. Once we ranges from 5 to 8 µm, so even in an information beyond the posterior pole have treatments that help us restore ideal viewing situation, it can’t possibly that’s relevant to diseases like diabetic photoreceptors to health, or prevent image the actual ILM. retinopathy and macular degenera- the loss of photoreceptors in a disease “Retinal surgeons need to peel off tion. Now we have technology like the like dry macular degeneration, that’s the ILM,” he continues. “So if OCT Optos device that allows us to capture when we’ll need a device that mea- can’t visualize it, what’s the point of images that extend all the way out to sures the photoreceptors and can tell having OCT in the operating room? the retinal periphery. That’s also been us if our therapy is working.” On the other hand, if you put a stain quite transformative. We’ve learned like brilliant blue in the eye, you can that there’s a lot of pathology out Intraoperative Imaging see the ILM beautifully during sur- there that we were missing that may gery. OCT is very useful in the offi ce, be relevant to various diseases, not “Imaging in the operating room is in but that doesn’t mean it will be useful just diabetic retinopathy and macular its infancy, and it’s not yet proven that in the operating room. Just because it’s degeneration but also retinal vein oc- there is an advantage to it for retinal great to have a swimming pool in your clusions, infl ammatory diseases and surgery,” notes Dr. Duker. “The fem- backyard doesn’t mean you should put hereditary disorders. We’ve learned tosecond lasers used in cataract sur- one in your car.” that there can be large areas in the gery have OCT integrated into them periphery that have no retinal blood to measure the depth of the cornea Wide-fi eld OCT fl ow, something we didn’t recognize and the anterior chamber. I think hav- before. So I think the next step will be ing imaging integrated into the micro- “There’s another OCT technology to develop a wide-fi eld OCT platform scope oculars or via a heads-up display that has great potential—wide-field allowing us to take OCTs out to the [for retinal surgery] will be a reality in OCT imaging using swept-source retinal periphery.” the future, but right now it’s investiga- technology,” says Dr. Rosenfeld. “This Dr. Rosenfeld notes that how much tional and unproven.” will allow us to get a 12 x 12-mm scan clinicians will benefi t from OCT in- Dr. Charles is concerned about the of the back of the eye. I think it’s going formation about the far periphery value of today’s OCT systems dur- to replace conventional fundus imag- remains to be determined. “My col- ing retinal surgery. “The problem is ing, although for now that remains to leagues who study diabetes, vein oc- that the axial resolution of OCT right be proven.” clusion, inflammatory diseases and now is such that you cannot image Dr. Rosenfeld notes that some even macular degeneration tell me the internal limiting membrane,” he surgeons remain unconvinced of the explains. “What people often assume value of wide-field imaging, but he (continued on page 59)

36 | Review of Ophthalmology | August 2015

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RP0415_Akorn.indd 1 3/23/15 9:54 AM Retina REVIEW Cover Focus Meet Your Next AMD Drug Walter Bethke, Managing Editor

A review of the rugs designed to inhibit vascu- that there are two types of cells re- lar endothelial growth factor in cruited into a choroidal neovascular AMD drugs Dpatients with wet age-related membrane,” he says. “These are endo- macular degeneration have revolution- thelial cells and pericytes. The recruit- furthest along ized treatment—but physicians and ed pericytes bind to the outer walls of researchers alike think there is room the endothelial cells, stabilizing the in the approval for improvement. This improvement lesion and limiting the effect of anti- process. might consist of a therapy that enables VEGF therapy as the lesion becomes ophthalmologists to reduce the num- more mature.” ber of injections patients need, a mo- Dr. Kaiser’s colleague at Wills, Sunir dality that yields better vision results Garg, MD, says it’s for these advanced or even one that might finally have lesions that Fovista may be useful. an effect on geographic atrophy. With “Anti-VEGF agents do a good job this in mind, here’s a look at the cur- of causing the choroidal neovascular rent results from the drugs leading the membrane to stop leaking, bleeding charge, the four agents that have ei- and growing,” Dr. Garg says. “How- ther begun their Phase III AMD trial ever, anti-VEGF doesn’t do a good job or have announced that such a trial is of getting the vessels to regress, espe- imminent. cially after the choroidal neovascularization has matured. If we are able to Fovista treat wet AMD of very recent onset with anti-VEGF agents alone, they will Retina experts view Ophthotech’s work really well. However, the more anti-platelet-derived growth factor typical AMD patient presents with a drug Fovista as the furthest along the more mature choroidal neovascular road to approval for the treatment of membrane in which anti-VEGFs help, exudative AMD, with its Phase III but they don’t get the abnormal blood trial already under way. It’s designed vessels to disappear. to work alongside an anti-vascular en- “Anti-PDGF agents such as Fovista dothelial growth factor drug such as work through a different mechanism,” ranibizumab. Dr. Garg continues. “As blood ves- Wills Eye Hospital’s Richard Kaiser, sels mature, pericytes surround and MD, describes where Fovista ﬁ ts in as stabilize them. Fovista weakens the a therapy, based on the way in which pericytes, which allows the anti-VEGF wet AMD develops. “The theory is agent to act on more of the vessels,

38 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

0038_rp0815_f2.indd38_rp0815_f2.indd 3838 77/24/15/24/15 4:284:28 PMPM which will hopefully get more of the le- • diabetes mellitus. volved in the activation of the alter- sion to regress to a greater extent than The trials’ structures will be simi- native complement pathway, a part it would with anti-VEGF alone.” lar to the Phase II trials. In the Fo- of the immune system. Genetic poly- In terms Fovista’s effectiveness, vista+Lucentis trial, 622 patients will morphisms as well as hyperactivity of the latest data that’s available is from be randomized to either combination the ACP have been implicated in the the drug’s Phase II trial. In the three- therapy with 1.5-mg Fovista and 0.5- development of AMD, including GA. armed, prospective, controlled trial, mg Lucentis or a sham Fovista injec- The MAHALO Phase II trial of researchers randomized 449 patients tion combined with 0.5-mg Lucentis. lampalizumab was the springboard with exudative AMD to a 0.3-mg dose They’ll be treated for two years, but for the larger-scale Phase III trials. In of Fovista combined with Lucentis, a the primary endpoint, mean change in it, 129 patients were divided into two 1.5-mg dose combined with Lucentis acuity, will be evaluated at 12 months. sham-injection groups (monthly, n=21; or Lucentis alone.1 The company re- In the other Phase III Fovista com- bimonthly, n=21) and two treatment ports that the 1.5-mg treatment arm bination trial that’s recruiting patients, groups who received lampalizumab gained a mean of 10.6 letters at 24 622 patients will be randomized be- 10 mg monthly (n=43) or bimonthly weeks compared to a gain of 6.5 let- tween two groups. The fi rst group will (n=44). Treatments lasted 18 months. ters for the Lucentis monotherapy receive Fovista and either 1.25-mg In the Phase II study, an analysis patients, a difference that was statisti- Avastin or 2-mg Eylea. The second of the change in GA size, the primary cally signifi cant (p=0.019). They add group will receive sham Fovista com- outcome measure, showed a 20.4-per- that, for treatment endpoints such as bined with either Avastin or Eylea. cent reduction in mean change from visual gains greater than three, four “The Phase II studies theoretically baseline with a p-value less than a and fi ve letters and fi nal vision of 20/40 showed that anti-PDGF could bring prespecifi ed signifi cance level of 0.2. and 20/25 or better, the results favored about regression of the choroidal There was no signifi cant change in the the 1.5-mg Fovista combination treat- neovascular membrane, which wasn’t rate of atrophy growth in the bimonth- ment arm. Also, using masked read- seen in any anti-VEGF study,” Dr. ly patients.3 ers and in a retrospective subgroup Kaiser says. “Stripping the pericytes Dr. Garg says one particular find- analysis, Ophthotech reports that pa- may cause lesions to actually regress as ing of MAHALO helped shape the tients receiving the 1.5-mg combina- opposed to remaining a fi brovascular, structure of the Phase III trials. “The tion therapy showed a greater mean static lesion. The Phase II data was en- other thing they’re looking at in the change of neovascularization area in couraging, so that’s why they’re doing lampalizumab trials has to do with the two subgroups for which that data was the Phase III trials.” fact that, in MAHALO, there was a available at baseline and 24 weeks. genetic biomarker, complement fac- Ophthotech has three Phase III Lampalizumab tor I, which seemed to correlate with studies planned, two of which are cur- the patients’ response to the drug,” he rently under way.2 The inclusion cri- As daunting as it’s been to find a says. “In MAHALO, patients with the teria are as follows: patients age 50 or treatment for wet AMD, dry AMD complement factor I biomarker had a over; active subfoveal CNV secondary has proven to be even tougher, with no 44-percent reduction in progression to AMD; and the presence of subreti- known treatment aside from the sup- compared to the 20.4-percent in the nal hyper-refl ective material on optical port of AREDS vitamins. Now, how- overall trial. So, in Phase III, the re- coherence tomography. The exclusion ever, Phase III trials have begun on searchers want to see if the geographic criteria are as follows: Roche’s lampalizumab, which demon- atrophy in patients with this biomarker • any prior treatment for AMD in the strated an effect on geographic atrophy progress differently and/or respond study eye prior to the day-one visit, in dry AMD in Phase II trials. If the differently to the drug than patients except oral supplements of vitamins late-stage trials are successful, it would who don’t have this biomarker. This and minerals; be the fi rst approved therapy for dry is one of the fi rst instances in our fi eld • any intravitreal treatment in the AMD. The Phase III trials are about in which a patient’s genetic biomarker study eye prior to the fi rst visit; to start. may help predict response to a medi- • any intraocular surgery or laser with- According to Roche, lampalizumab cation. It could be one of our fi rst for- in three months of entry, and any is an antigen-binding fragment of a ays into personalized medicine.” prior laser in the macular region, humanized, monoclonal antibody di- Even though the treatment slowed regardless of indication; rected against the enzyme known as the rate of progression but didn’t cause • subjects with subfoveal scar or sub- complement factor D. Complement the atrophy to regress, Frank Holz, foveal atrophy; and factor D is a rate-limiting enzyme in- MD, director of the eye clinic at the

August 2015 | reviewofophthalmology.com | 39

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REVIEW Focus

University of Bonn in Germany, says its tions at those visits. Everyone was fol- effect can still be beneﬁ cial. “In many lowed for 20 weeks. areas of medicine, if there is no cure After 16 weeks, mean acuity im-

or improvement in something, then MD Sunir Garg, provement was 8.2 letters for abici- the next best goal is to slow progres- par 2 mg, 6.3 for abicipar 1 mg and sion,” he says. “We’re used to that in 5.33 letters for ranibizumab. After 20 glaucoma, and it’s a common theme weeks, which was 12 weeks after the in oncology. Of course, we’d prefer last abicipar injection and four after something that restores vision, but to the last injection of ranibizumab, acu- save the life of the foveal tissue for a ity improvement from baseline was longer period of time in order to pre- If approved, Lampalizumab would be the nine letters for abicipar 2 mg, 7.1 for serve good central vision is still of high fi rst treatment for geographic atrophy. abicipar 1 mg and 4.7 letters for ra- clinical impact.” nibizumab. Two patients in the abici- Lampalizumab will be studied in the company. “They’re derived from a par 2-mg group and three in the 1-mg two identical, double-masked, ran- natural class of binding proteins called group experienced infl ammation. domized, prospective Phase III trials ankyrin and repeat proteins, which Dr. Zahnd says the infl ammatory re- named Chroma and Spectri. Each will nature has evolved to specifi cally at- action is being addressed. “The infl am- enroll approximately 936 patients and tach to other proteins in a way similar mation rate in REACH was at around will compare a 10-mg dose of the drug to antibodies. We used our molecu- 10 percent, which was still too high,” given via intravitreal injection every lar library to identify a DARPin that’s he says. “After significant improve- four or six weeks to sham injections. highly potent for neutralizing VEGF, ments of the manufacturing process To test the results in complement fac- abicipar. Specifically, it blocks sev- for Phase III, it’s expected that infl am- tor I, 188 biomarker-positive and 124 eral splice variants of VEGF-A from mation is under control.” biomarker-negative patients each will binding to its receptor, similar to what Abicipar’s Phase III program will be enrolled in the sham, lampalizumab Lucentis does. However, abicipar is consist of two trials, CEDAR and SE- q4w and lampalizumab q6w groups in a pegylated DARPin, so it carries a QUOIA, each recruiting around 900 each study. The primary endpoint is polyethylene tail. The reason for this patients. In each trial there will be the rate of GA progression, which will is to provide a longer intravitreal half- three arms. The fi rst arm will consist be evaluated at one year. life. Its longer half-life in the vitreous of abicipar 2-mg injections on day one, is proposed to lead to a longer duration week four and week eight, followed by Abicipar of action and thus less-frequent dosing injections every eight weeks through for patients.” In preclinical testing at week 96. The second arm will be abici- Though patients’ vision is at the fore- Molecular Partners, Dr. Zahnd says par 2-mg injections on day one, week front of companies’ research into AMD that, in a rabbit model, abicipar had a four and week 12, with injections every treatments, reducing the frequency of vitreous pharmacokinetic duration of 12 weeks through week 96. The third injections has also emerged as a prior- action of six days, compared to three arm, the control, will consist of ranibi- ity, since doing so would reduce the days and 4.5 days for ranibizumab and zumab injections on day one and then treatment burden for patients. It’s the afl ibercept, respectively. every four weeks until week 96. twin goals of improved vision and a Though the abicipar Phase II less-frequent dosing schedule that REACH study wasn’t powered to Squalamine Lactate drive the current research of abicipar show statistical signifi cance, it showed pegol for the treatment of wet AMD. enough positive trends in effi cacy to The anti-angiogenic drug squala- In early July, Allergan began enrolling give Allergan and Molecular Partners mine lactate (Ohr Pharmaceutical) has patients in the Phase III study of the the confi dence to go ahead with Phase gone through a couple of iterations drug as part of its partnership with the III. In REACH, 25 patients were ran- over the years, and its current form is a Swiss biotech fi rm Molecular Partners. domized to abicipar 1 mg, 23 to ab- topical drop. As its treatment protocol Abicipar is from a class of drugs icipar 2 mg and 16 to ranibizumab. is currently confi gured, the drop is to known as DARPins. “DARPins are All patients received doses at the start be administered b.i.d. in combination highly potent therapeutic proteins of the trial and then at four and eight with Lucentis injections in the hope that we’ve developed here at Molecu- weeks. Ranibizumab patients received that it will boost visual acuity gains and/ lar Partners,” says Christian Zahnd, additional doses at 12 and 16 weeks, or reduce the number of anti-VEGF MD, PhD, chief executive offi cer of while abicipar patients got sham injec- injections a patient needs. Ohr recently

40 | Review of Ophthalmology | August 2015

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RP0515_Haag Lenstar.indd 1 4/8/15 2:16 PM Cover Retina

REVIEW Focus

completed the Phase II trial of squalamine and, though it didn’t decrease the number of Lucentis injections (the primary endpoint), the company says Jason Slakter, MD Jason Slakter, the drug showed enough potential to increase visual acuity gains vs. Lucentis alone that a Phase III trial is warranted and will start this year. Squalamine lactate is described as a small-molecule, anti-angiogenic agent that acts against aberrant neovascu- Two different eyes from the squalamine IMPACT study. Though they differ greatly in larization by inhibiting multiple pro- appearance, they would both be classifi ed as classic-containing lesions. tein growth factors, including VEGF, PDGF and basic fi broblast growth fac- percent in the Lucentis monotherapy occult vessels may be more likely to be tor. “In order for VEGF, PDGF and group. Also, 22 percent of the com- affected by this combination. bFGF to exert their negative effects, bination patients gained four or more “So, instead of rushing forward with they bind to the receptor and signal lines and 14 percent gained at least a Phase III trial based on a group of intracellular actions that cause leak- fi ve lines at nine months, compared to patients with classic-containing lesions, age, vascular growth, scarring and all 7 percent and 7 percent, respectively, we went back and looked at how the the other things we’ve come to expect for the Lucentis monotherapy group. size of the occult neovascularization from neovascular diseases,” says Jason In the overall population, though, with component made a difference in the Slakter, MD, Ohr’s chief medical of- either classic-containing or occult-only outcome,” Dr. Slakter adds. “We found ficer. “When you apply squalamine lesions, Ohr says the mean gain was that, if you look at eyes with occult it reaches the back of the eye and is just 7.8 letters for the combination CNV at baseline of less than 10 mm2, taken up into the endothelial cells. group and 5.3 for Lucentis. or four disc areas in size, you get a very There, it binds to a molecule called Dr. Slakter says the Phase II results dramatic difference in outcome with calmodulin and pulls it away from the will help design a Phase III study. the combination treatment: an 11-let- inside of the receptors, silencing the “From a regulator’s standpoint, it ter mean gain in vision vs. a six-letter receptor activity.” doesn’t matter what your primary end- gain for Lucentis alone. What’s more, The most recent results with squal- point was in Phase II,” he says. “It only we actually had a larger group of pa- amine are from the Phase II trial, matters what it is in Phase III. What’s tients who met this occult size criteria named IMPACT. In IMPACT, 142 more important is that you have a valid compared to those with predominantly patients with wet AMD were random- endpoint to pursue for approval. From classic lesions: three-quarters of the ized between two groups: squalamine the point of view of regulators, it’s all patients vs. 50 percent. We’re now in drops b.i.d. combined with Lucentis about vision. The fact that we didn’t the process of fi nalizing what our pa- as-needed and a group receiving place- fi nd a difference in the number of in- tient population will be in Phase III. bo drops plus Lucentis as-needed. Ev- jections but did show a robust effect in Though we haven’t fully defi ned this eryone got an initial dose of Lucentis. visual outcomes allows us to sit back population yet, we believe that occult In a modified intent-to-treat and say, ‘Great, now we have the capa- size may be one of the most important population with lesions contain- bility to design and execute a Phase III factors in determining it.” ing classic CNV that consisted of 37 study with a high likelihood of success squalamine+Lucentis patients and 28 based on a visual acuity endpoint.’ ” Dr. Kaiser has a financial interest Lucentis-only patients, Ohr reports In terms of the better results occur- in Ophthotech and Dr. Holz is a con- that the former group showed visual ring in predominantly classic lesions, sultant to Roche. Dr. Garg receives acuity gains.4 In the combination-ther- that fi nding set Ohr researchers on a research support from Genentech and apy group, patients gained a mean of new course. “We carefully analyzed Allergan. Dr. Slakter is employed by 11 letters, vs. a mean gain of fi ve letters the data based on emerging informa- Ohr Pharmaceutical. with Lucentis alone, a difference the tion,” Dr. Slakter explains. “When you 1. Data on fi le, Ophthotech. company says was clinically meaning- look at the type of vessels that might be 2. www.clinicaltrials.gov. Phase III Fovista trials. Accessed 6 July 2015. ful. In addition, 44 percent of the com- more affected by the combination of an 3. Rhoades W, Dickson D, Do D. Potential role of lampalizumab for bination patients gained three or more anti-VEGF and an agent that’s going to treatment of geographic atrophy. Clin Ophthalmol 2015;9:1049– 1056. lines of vision at nine months, vs. 29 inhibit something such as PDGF, the 4. Data on fi le, Ohr Pharmaceutical.

42 | Review of Ophthalmology | August 2015

038_rp0815_f2.indd 42 7/24/15 4:29 PM Looking deeper Exploring innovation

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RP0815_Shire.indd 1 7/24/15 9:47 AM Retina REVIEW Cover Focus DR-Related DME: Treatment Update Michelle Stephenson, Contributing Editor

Laser treatment is wo anti-VEGF agents have re- visual impairment due to diabetic cently been approved by the macular edema were randomized to still the treatment TU.S. Food and Drug Admin- one of the three treatments. Ranibi- istration for the treatment of diabetic zumab alone (plus sham laser) was of choice for many retinopathy in patients with diabetic given for three months and then on macular edema. For diabetic retinop- an as-needed basis. Laser was given at patients with non- athy patients with center-involving baseline and then as needed. center-involving edema, anti-VEGF agents are now The study found that ranibizumab the first-line treatment. For those alone, as well as ranibizumab com- edema. with non-center-involving edema, la- bined with laser, were superior to ser treatment is still often used. laser alone in improving the mean change in best-corrected acuity let- Anti-VEGF Agents ter score from the baseline visit to months one through 12 (+6.1 for For years, laser was the treatment ranibizumab alone, +5.9 letters for of choice; however, studies have combination therapy, and +0.8 letters shown that it is not the most effective for laser alone). treatment, and it can cause damage In February, Lucentis (ranibizum- to the eye. “During the past 10 years, ab injection, Genentech) 0.3 mg be- anti-VEGF injections have become came the ﬁ rst eye medication to be the standard of care for diabetic mac- FDA-approved for the treatment of ular edema, mainly as a result of mul- diabetic retinopathy in patients with tiple clinical trials that have shown diabetic macular edema. Lucentis increased vision and better anatomic was previously approved by the FDA outcomes,” says Tom Stone, MD, to treat diabetic macular edema and who is in practice in Lexington, Ky. macular edema secondary to retinal “Today, we have several agents that vein occlusions. It is also approved to we can choose from, including Avas- treat wet age-related macular degen- tin, Lucentis and Eylea. All of these eration. work very well in most patients.” For patients with diabetic retinopa- In a study conducted in Sydney, thy, Lucentis is meant to be injected Australia, researchers compared ra- into the eye once a month and used nibizumab alone, ranibizumab com- along with appropriate interventions bined with laser, and laser monother- to control blood sugar, blood pres- apy.1 In this study, 345 patients with sure and cholesterol. The safety and

44 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

0044_rp0815_f3.indd44_rp0815_f3.indd 4444 77/24/15/24/15 3:153:15 PMPM Photos courtesy of Tom Stone, MD. efficacy of Lucentis proved vision in eyes to treat diabetic reti- with center-involved nopathy with diabetic diabetic macular ede- macular edema were ma, but the relative established in two effect depended on Phase III trials involv- baseline visual acuity.4 ing 759 participants When the initial visual who were treated and loss was mild, there followed for three were, on average, no years.2 In these two apparent differences studies, participants among study groups. being treated with At worse levels of ini- Lucentis showed tial visual acuity, Ey- significant improve- lea was more effective ment in the severity at improving vision. of their diabetic reti- This study was con- nopathy at two years ducted at 89 sites and compared to patients included 660 adults who did not receive with DME involving an injection. the macular center. The most common Patients received inside effects include travitreous afliber- conjunctival bleeding, cept at a dose of 2.0 eye pain, fl oaters and mg (224 participants), increased intraocular bevacizumab at a dose pressure. Serious side of 1.25 mg (218 par- effects include end- ticipants), or ranibi- ophthalmitis and reti- Figure 1. Optical coherence tomography image of diabetic macular edema. zumab at a dose of 0.3 nal detachments. mg (218 participants). In March, the FDA approved Eylea A third anti-VEGF, Avastin (bevaci- Injections were administered as often (afl ibercept injection, Regeneron) for zumab, Genentech), is not approved as every four weeks. the treatment of diabetic retinopa- for this use, but has been used off- Patients’ mean visual-acuity letter thy in patients with DME. Eylea’s label to treat these patients. scores were evaluated. Scores ranged safety and efficacy to treat diabetic “In patients who have central-in- from 0 to 100, with higher scores in- retinopathy in patients with diabetic volving macular edema, the fi rst-line dicating better visual acuity. As an macular edema were evaluated in treatment of choice is an anti-VEGF,” example, a score of 85 is approximate- 679 participants in two clinical trials says David S. Boyer, MD, who is in ly 20/20. From baseline to one year, where participants were randomly practice in Beverly Hills, Calif. “In study participants’ mean visual-acuity assigned to receive Eylea or macular patients who present with vision that letter score improved by 13.3 with laser photocoagulation.3 At week 100, is 20/40 or better, all three drugs afl ibercept, by 11.2 with ranibizumab participants being treated with Eylea [Avastin, Lucentis and Eylea] seem to and by 9.7 with bevacizumab. How- showed significant improvement in provide excellent results at reducing ever, while afl ibercept demonstrated the severity of their diabetic retinopa- vision loss. Patients who have 20/50 the greatest improvement, it was not thy compared to patients who did not or worse vision may want to start with clinically meaningful, because the dif- receive Eylea. bevacizumab until insurance clear- ference was affected by the eyes with The most common side effects ance is obtained; however, the effi cacy worse visual acuity at baseline. Just were conjunctival bleeding, eye pain, of Eylea has been clearly demonstrat- more than half of patients (51 per- cataracts, fl oaters, increased intraocu- ed in these patients.” cent) had an initial visual-acuity letter lar pressure and vitreous detachment. A recent study conducted by the score between 78 and 69 (equivalent Serious adverse reactions include Diabetic Retinopathy Clinical Re- to approximately 20/32 to 20/40), and, endophthalmitis and retinal detach- search Network has found that intra- in these patients, the mean improvements. vitreal injections of all three drugs im- ment was 8.3 with ranibizumab, 8.0

August 2015 | reviewofophthalmology.com | 45

044_rp0815_f3.indd 45 7/24/15 3:15 PM Cover Retina

REVIEW Focus

with afl ibercept and 7.5 with bevaci- few months ago, so we are just gaining cent of the control group). zumab. Additionally, when the initial experience with it,” Dr. Stone says. Results from the second trial were visual-acuity letter score was less than Dr. Boyer adds that Iluvien (fl uo- similar. The percentage of Iluvien pa- 69 (approximately 20/50 or worse), cinolone acetonide intravitreal im- tients gaining 15 or more letters over the mean improvement was 18.9 with plant, Alimera Sciences) will have a baseline was 33.9 percent at month aflibercept, 14.2 with ranibizumab place in the treatment of patients who 30, 29.6 percent at month 33 and 29 and 11.8 with bevacizumab. No sig- don’t have a pressure rise after being percent at month 36 compared to the nifi cant differences in the rates of se- treated with a steroid and in patients control group, which had less than 18 rious adverse events, hospitalization, who are going to have cataract surgery percent of patients gaining 15 or more death or major cardiovascular events or have had cataract surgery. “Iluvien letters. were observed among the groups. may be able to provide long-term In these two trials, Iluvien dem- Although anti-VEGF injections benefi t for some of our patients for onstrated a statistically significant are effective in many patients, they two years or more with one injection effect at week three, and this effect do not achieve visual improvement in the offi ce. Its exact place will be de- was maintained throughout the 36 in all eyes. “It is still not clear how termined by the market,” he explains. months, with 28.7 percent of Iluvien long we should treat a patient with an Iluvien was approved by the FDA patients and 16.2 percent of control anti-VEGF agent before switching to in September 2014 for the treatment patients having an improvement in another agent if there is no vision or of diabetic macular edema in patients BCVA of 15 letters or more over base- OCT improvement,” Dr. Boyer says. who have been previously treated line at month 24, 31.4 percent com- “Also, if we decide to switch agents, with a course of corticosteroids and pared with 15.1 percent at month 30, it is not clear whether to switch to did not have a clinically signifi cant rise and 28.7 percent compared with 18.9 another anti-VEGF or switch to a stein intraocular pressure. Two Phase III percent at month 36. roid. All ophthalmologists have their pivotal clinical trials were conducted ‘magic number’ at which they switch to assess the safety and efficacy of Laser Treatment and what they do when they switch. Iluvien in the treatment of diabetic Many people today start treatment macular edema. Patients were ran- In patients with non-center-involv- with Eylea, because of its success in domized to receive high-dose Iluvien, ing edema, laser treatment may be drying the retina and overall improve- low-dose Iluvien or control treatment. the best option. “Laser treatment is ment of vision in newly diagnosed In these two studies, a total of 376 still used in patients who have non- patients. After three treatments, if patients received Iluvien and 185 central-involving edema where areas there is not a good response, we may patients were in the control group. of leakage are far enough away from consider adding a steroid to the Eylea The primary endpoint for effi cacy was the foveal area that treatment can be treatment or just using a steroid.” the difference in the percentage of applied without any damage or any patients whose best-corrected visual potential damage in the future to the Steroids acuity improved by 15 or more let- foveal areas,” Dr. Boyer says. ters from baseline on the ETRDS A study conducted by the DRCR. If a steroid is needed, several op- eye chart at month 24 between the net examined the visual acuity and tions are available. “Triesence works treatment and control groups. Based anatomic changes from baseline to 12 fairly well,” Dr. Stone says. “More on the results at month 24, only the months after modifi ed ETDRS-style recently, there seems to be more clini- low-dose treatment group data were (focal/grid) photocoagulation in eyes cal acceptance of patients to Ozurdex, examined at month 36. with non-center-involved, clinically which tends to cause fewer pressure The fi rst trial demonstrated statisti- signifi cant macular edema.5 problems.” cally signifi cant therapeutic effects in The study included 22 eyes of 22 Dr. Boyer notes that “fi rst-line ste- 28.9 percent at month 30 and 28.4 patients who had 12 months of follow- roids include Ozurdex, which is FDA- percent at month 33 of Iluvien pa- up. Among these patients, medical approved, and Kenalog, which is not tients gaining 15 or more letters, com- visual acuity letter score remained FDA-approved.” pared to the control group, in which within one letter of baseline over 12 The disadvantage of these steroids is less than 17 percent of patients gained months. Additionally, the median that they wear off after a few months. 15 or more letters. At month 36, the central subfi eld retinal thickness de- “Finally, there is a new Iluvien in- therapeutic effect was maintained creased by 10 µm, the median total jection, which is a three-year steroid (28.4 percent of patients gained 15 implant. It was only FDA-approved a or more letters compared to 18.9 per- (continued on page 74)

46 | Review of Ophthalmology | August 2015

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RP0815_Optos.indd 1 7/20/15 11:49 AM Retinal Insider

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

Radiation Retinopathy: Treatment Strategies The diagnosis and management of this condition are evolving, and choosing the right combination of treatments is critical. Josh Wallsh, BS, Don Pham, BS, Jerry Shields, MD, Robert Johnson, MD, and Ron P. Gallemore, MD, PhD

adiation retinopathy remains ment strategies used for this disorder brachytherapy.1-5 The effects at the R a common cause of blindness and future directions for the fi eld. cellular level and the clinical fi ndings in patients following treatment for resemble those of diabetic retinopa- malignancies in or around the orbit. Mechanism and Classifi cation thy and, hence, a similar classifi cation The most common setting is follow- scheme has evolved.6 Nonprolifera- ing radioactive plaque brachytherapy Radiation retinopathy is the result tive radiation retinopathy (NPRR) for choroidal melanoma. Some pa- of delayed loss of endothelial cells and fi ndings include retinal hemorrhages; tients initially have excellent vision pericytes along with capillary closure cotton wool patches; exudates; telan- following successful management of following radiation exposure from ex- giectasia; and macular edema. Prolif- the melanoma, but proceed to lose ternal beam radiation, gamma knife erative radiation retinopathy (PRR) their vision after succumbing to RR. radiotherapy, proton beam radia- presents with neovascularization of Herein, we review the current treat- tion and—most commonly—plaque the disc or elsewhere with or without vitreous hemorrhage.7-11 Another classifi cation scheme is similar to that for retinal vein occlusion: ischemic and nonischemic.12 Each classifi cation

Figure 1. A 68-year-old patient was initially treated with periocular corticosteroid injections and only responded transiently, so he was treated with the extended- release ﬂ uocinolone acetonide implant. This only partially resolved his radiation retinopathy; therefore, it was combined with repeated intravitreal bevacizumab injections. He demonstrated an improvement in imaging and, following cataract extraction, realized an improvement in vision. Eventual pars plana Ahmed valve placement was required to manage corticosteroid-induced glaucoma in July 2012.

48 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

052_rp0715_rtinsider.indd 48 7/24/15 3:18 PM Figure 2. A 70-year-old patient with radiation retinopathy receiving multiple panretinal photocoagulation treatments from 7/21/2010 to 5/4/2011 with persistent leakage noted on ﬂ uorescein angiography. He was subsequently switched to monthly intravitreal bevacizumab injections and received this treatment from 5/24/2011 until 1/15/2013. He has since required no treatments, with improvement on ﬂ uorescein angiography from 4/30/2014.

scheme appears to have prognostic experience NPRR and 5.8 to 8 per- retinal vein occlusions. In the past, and therapeutic implications and, as cent PRR.4,5 These conditions may be the only strategies used for the man- discussed below, we use both. Other diagnosed anywhere from one month agement of RR were focal photoco- classifi cation schemes have also been to 15 years post-radiation treatment, agulation for NPRR-related macular proposed, including the Finger clas- but are most frequent between six edema and pan-retinal photocoagu- sification of radiation retinopathy,13 and 36 months.9 An increased risk of lation (PRP) for PRR and ischemic radiation maculopathy classification RR has been associated with younger RR.19-22 James L. Kinyoun, MD, scheme14 and Augsburger’s radiation age at onset, closer proximity to the studied 42 eyes with NPRR—19 fundopathy scheme. The radiation optic disc or fovea, thicker tumors, treated with focal photocoagulation maculopathy classification scheme those associated with retinal detach- and 23 untreated—with a decrease utilizes fluorescein angiography to ments, non-dome shaped tumors in mean visual acuity noted in both delineate ischemic and nonischemic and comorbidities such as diabetes groups. However, the photocoagu- maculopathy; grades radiation macu- or hypertension.4,15-17 Radiation optic lation group visual acuity decreased lar edema based on optical coherence neuropathy can also be seen following less (from 20/40 to 20/100) compared tomography findings; and proposes brachytherapy with a prevalence of 23 to the non-treatment group (20/50 the application of the Early Treat- percent and 53 percent after fi ve and to 20/200).23 Similar to diabetic reti- ment Diabetic Retinopathy Study 10 years, respectively, further compli- nopathy, advanced cases of RR can definition of clinically significant cating treatment.18 lead to proliferative disease resulting macular edema to radiation macu- in retinal, disc or iris neovasculariza- lar edema. This multi-modality ap- Treatments tion, vitreous hemorrhage, neovas- proach to classifying radiation reti- cular glaucoma and tractional retinal nopathy should prove to be useful Laser photocoagulation. As detachment.11,24,25 To assess the ef- when studying treatment protocols. noted, RR mimics other retinal vas- fectiveness of PRP in patients with It has been reported that within fi ve cular diseases. Strategies to treat RR, PRR, Dr. Kinyoun treated 23 patients years of plaque therapy for uveal mel- therefore, have centered on treat- with PRP and compared to fi ve who anoma 42 percent of patients may ments for diabetic retinopathy and went untreated. The PRP cohort

August 2015 | reviewofophthalmology.com | 49

052_rp0715_rtinsider.indd 49 7/24/15 3:18 PM Retinal

REVIEW Insider

Figure 3. A 79-year-old initially treated with monthly intravitreal bevacizumab injections for approximately two years with a single application of panretinal photocoagulation. She has subsequently been maintained on a treat-and-extend protocol while maintaining her vision at 20/25 nearly four years later. Fundus photograph, ﬂ uorescein angiography and optical coherence tomography demonstrate pre-treatment and most recent images.

on average lost fewer lines of vision Carol Shields, MD, and colleagues Anti-vascular endothelial (20/189 to 20/357) when compared treated 31 patients diagnosed with growth factor. The microvascular with the untreated cohort (20/170 to RR with a single IVTA injection and changes related to RR may be driven 20/1,371).23 Carlos Bianciotto, MD, appreciated stable or improved visual by the release of vascular endothe- and colleagues reported resolution acuity in 91 percent (n=20) and 45 lial growth factor in response to isch- of PRR in 63 (66 percent) patients percent (n=14) of patients after one emia, similar to the mechanism seen following PRP.4 We recommend a and six months, respectively. In addi- in diabetic retinopathy.31 With this in course of PRP laser in high-risk cases tion, these patients demonstrated an mind, the treatment of RR has turned or with early signs of RR, often com- improvement in mean foveal thick- to intravitreal anti-VEGF injections bined with other adjunctive therapies ness on optical coherence tomogra- such as bevacizumab (Avastin, Ge- as discussed below. phy from 471 µm at baseline to 207 nentech),32-35 ranibizumab (Lucentis, Triamcinolone acetonide in- and 292 µm at one and six months, Genetech),36 pegaptanib (Macugen, jections. Given the upregulation of respectively.28 This response to IVTA Pfi zer)37 and afl ibercept (Eylea, Re- infl ammatory mediators seen in RR, may only be transient, and additional generon). Use of intravitreal pegap- intavitreal corticosteroid injections injections are commonly required tanib was reported in a single case re- have been used for management of within a year of the fi rst treatment.29 view demonstrating an improvement RR. While no clinical trial has exam- Similarly, in clinical practice, we in vision following a single injection ined intravitreal corticosteroid treat- have found IVTA to be effective only after failed laser photocoagulation.37 ment in the setting of RR, comparable in the short-term for managing RR. Similarly, multiple case reports have research has been performed in the The risk of complications, such as cat- demonstrated an improvement in vi- setting of diabetic retinopathy. In the aract formation and corticosteroid-in- sual acuity associated with bevacizum- study, intravitreal triamcinolone ace- duced glaucoma, and the inadequate ab therapy.32,33 Although no random- tonide was compared to laser treat- long-term effectiveness have limited ized controlled studies have assessed ment for the management of diabetic our use of IVTA. However, periocular this treatment, multiple retrospec- retinopathy.26 Results of this study, and corticosteroid injections should also tive studies have been published.34,35 its subsequent follow-up study,27 were be considered, as this has been shown In 2007, John Mason, MD, and col- unclear as to the effi cacy of IVTA on to lower the risk of macula edema and leagues studied 10 patients treated diabetic macular edema as compared vision loss in RR.30 We have used this with a single bevacizumab injection, to laser treatment in the long term. in select cases (See Figure 1). demonstrating a vast improvement

50 | Review of Ophthalmology | August 2015

052_rp0715_rtinsider.indd 50 7/24/15 3:19 PM in foveal thickness (mean decrease of with continued maintenance therapy are currently under way to determine 198 µm) and only mild mean visual in most cases. Undertreatment may the efficacy of anti-VEGF therapy acuity improvement (from 20/100 to lead to ineffective management of in reducing the symptoms of radia- 20/89) after six weeks.34 Paul Finger, RR and, in some high-risk patients, tion retinopathy.39,40 Figure 3 dem- MD, (2008) treated 21 patients with a prophylactic treatment may even be onstrates a patient from our practice mean of 3.8 (one to seven) intravitreal required. Figure 2 demonstrates a pa- maintained with aggressive monthly bevacizumab injections over a mean tient from our practice who, following intravitreal bevacizumab injections, of 7.8 (two to 18) months with at least PRP laser, was treated monthly with up until a very recent transition to a stabilization of visual acuity in 86 per- intravitreal bevacizumab for cystic treat-and-extend protocol. This ap- cent of eyes.35 In the only published macular edema. While the treatment proach has sustained her 20/25 vision. study of ranibizumab injections, Dr. effectively managed the edema, the Corticosteroid implants. For Finger and Kimberly Chin, MD, per- patient went on to develop ischemic recalcitrant RR cases we have utilized formed a prospective trial of 10 eyes radiation retinopathy as well as ra- intravitreal corticosteroid implants treated monthly with ranibizumab diation optic neuropathy and further with both the surgically performed injections. At the end of the one-year vision loss. fluocinolone acetonide implant study, mean central foveal thickness Periodic injections of bevacizumab (Retisert, Bausch + Lomb) and the improved by 95 µm and mean visual and ranibizumab may be needed to dexamethasone implant (Ozurdex, acuity improved by 0.7 letters.36 show a decrease in macular edema Allergen). These provide similar We have found intravitreal anti- and retinal hemorrhages. Like dia- downregulation of cytokines and de- VEGF injections to be effective in the betic macular edema and exudative crease in capillary permeability wit- majority of cases in the management macular degeneration, monthly treat- nessed with other corticosteroid ther- of macular edema associated with ments appear to be required long- apies, but in a time-released capsule RR, but ﬁ nd that an aggressive treat- term to achieve good outcomes.35,38 allowing for upwards of six months and-extend protocol must be followed Larger randomized controlled trials of therapy. Multiple case reports

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REVIEW Insider

peripapillary choroidal melanoma fi ve years prior. She was initially managed with sectoral panretinal photocoagulation followed by a series of bevacizumab injections and several dexamethasone implants. The effects were not sustained and she did not toler- ate the injections well due to anxiety and post-injection discomfort. Vision recovered from as low as count fi n- gers to 20/100 and stabilized at 20/200 without further intervention two years out from her second fl uocinolone acetonide implant. Combination therapy. A com- binatorial approach may be effective for recalcitrant cases. By taking a mul- tidirectional approach and attacking more of the factors that may play a role in retinopathy, including pros- tanoids and VEGF-family proteins, several investigators have reported improvement following combination corticosteroids and anti-VEGF drug Figure 4. A 32-year-old patient initially had an excellent response to plaque therapy (89 injections.44,45 In our practices, we Gy) for choroidal melanoma with resolution of subretinal fl uid and improvement in vision. have found this combined approach She subsequently developed radiation retinopathy and was treated with two intravitreal to be effective for patients with RR dexamethasone implants due to concerns associated with pregnancy. After delivery she resistant to monotherapy. An example received a series of anti-VEGF injections, both bevacizumab and ranibizumab. Initially, she responded well to all these treatments, but then developed tachyphylaxis. She is shown in Figure 1. This patient re- subsequently underwent combination therapy with two treatments of combined intravitreal quired management with periocular dexamethasone implant plus intravitreal bevacizumab injection, with resolution of edema corticosteroid injections, fl uocinolone and recovery of vision. acetonide implant and multiple intravitreal anti-VEGF injections. How- have demonstrated improvements in vision decreased by a line following ever, he required both cataract extrac- macular edema in refractory cases of cataract development. Eventually a tion and glaucoma valve placement RR treated with dexamethasone im- combined approach was required for (for corticosteroid-induced glaucoma, plants; however, visual acuity results this patient, which will be discussed which developed following fl uocino- have been varied.41-43 While cataract below. With the fl uocinolone aceton- lone acetonide implantation). Simi- formation and corticosteroid-induced ide implant, patients must be aware larly, Figure 4 demonstrates a patient glaucoma remain concerns, the long- that two additional surgeries (cataract that developed tachyphylaxis to anti- term effi cacy of the implants and the extraction and glaucoma valve place- VEGF injections and was switched to more sustained levels of corticoste- ment) may ultimately be required. combination intravitreal dexametha- roids appear to provide better results We have had remarkable results re- sone implant and bevacizumab injec- for patients. Figure 4 illustrates the covering excellent vision using these tion with dramatic improvement in use of the dexamethasone implant in a strategies for patients who are willing edema and vision. 32-year-old pregnant female with ra- to pursue the treatments required Alternative Treatments. The diation retinopathy following brachy- to achieve the best outcome. Figure advent of the strong topical corti- therapy for choroidal melanoma. This 5 demonstrates the remarkable ana- costeroid difluprednate ophthalmic treatment approach was selected tomical response to two fl uocinolone (Durezol, Alcon) has allowed for the given the risk of anti-VEGF therapy acetonide implants placed 16 months topical management of certain cases during pregnancy. A prompt reduc- apart, experienced by a 43-year-old of NPRR. Combining topical diflu- tion in edema was achieved; however, female following brachytherapy for a prednate with a topical non-steroidal

52 | Review of Ophthalmology | August 2015

052_rp0715_rtinsider.indd 52 7/24/15 3:19 PM anti-infl ammatory drug and carbonic anhydrase inhibitor forms a triple therapy that can be effi cacious in treating cases of mild macular edema secondary to RR. There have been a few reports of patients developing choroidal neovascular membranes associated with RR.46,47 Sophie Bakri, MD, and Paul Beer, MD, noted that the use of vertepor- fin photodynamic therapy in such patients with CNV secondary to RR resulted in improved macular edema and visual acuity; therefore, they applied PDT to three Figure 5. A 43-year-old patient who had received multiple intravitreal bevacizumab injections and patients with RR not asso- intravitral dexamethasone implants without resolution of her macular edema, as demonstrated on ciated with CNV. All three optical coherence tomography topographical map and cross-section. Following fl uocinolone acetonide patients were noted to have injection she was noted to have considerable improvement in macular edema over the subsequent 1.5 years without further treatment required to maintain this improvement. a considerable decrease in hard exudates along with improvement or stabilization of visual to soft tissues in head and neck cancer zeaxanthin, are benefi cial in the man- acuity.48 There has been no further without providing similar protection agement of other retinopathies in- follow-up research reported regard- to the tumor.52 This differential re- cluding retinopathy of prematurity ing the use of PDT in the setting sponse by normal and neoplastic tis- and diabetic retinopathy.57 Their role of RR, and this option carries little sue is theoretically due to differences in RR remains to be explored but, promise as it was found to be ineffec- in alkaline phosphatase activity, pH in theory, select supplementation tive in the management of diabetic and vascularity, which allow increased may be beneficial. Excessive nutri- macular edema. conversion of amifostine to its active ent supplementation carries risk as Oral pentoxyphylline (Trental, metabolite in normal tissue.53 Silicone well, and in the absence of random- Sanofi -Aventis), a phosphodiesterase oil placement at the time of or prior to ized controlled studies, no guidelines inhibitor that may reduce infl amma- brachytherapy has also been utilized can be set forth. In patients with RR tory mediators as well as improve per- as prophylaxis with three patients fol- and fi ndings of macular degeneration, fusion via improved RBC fl exibility, lowed for 10 to 24 months who did an AREDS II supplement is recom- has been proposed, with little data not develop RR during that time.54 mended. In others, lutein at 10 mg to date.49 PDT has also been used In a case-control series, Tara McCan- per day and zeaxanthin at 2 mg per for “tumor consolidation”50 and is nel, MD, PhD, and Colin McCannel, day may be reasonable in the absence thought to reduce tumor infl amma- MD, demonstrated the development of contraindications such as the use tion and mediators. Drugs like ami- of abnormal macular fi ndings in sig- of warfarin, allergies to said supple- fostine that sop up free radicals may nifi cantly fewer patients with silicone ments, or vitamin A defi ciency. be of theoretical benefi t in preventing oil placement prior to brachytherapy Radiation retinopathy remains a the development of RR when used compared to control.55 There is also a difficult-to-manage complication of concurrently with radiotherapy, and report of hyperbaric oxygen therapy radiation therapy without a single an animal study supports the effect of for the management of radiation optic ideal treatment approach. Depend- this drug in particular.51 To date, there neuropathy with apparent effi cacy in ing on the circumstances, the afore- are no human trials on amifostine for some cases.56 mentioned treatment options all RR; however, its scavenger ability has Nutritional supplementation. provide varying degrees of efficacy. been demonstrated to be effective as There is growing evidence that the In our practices, we have found the protection against radiation damage xanthophylic carotenoids, lutein and most benefi t in a combined approach

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REVIEW Insider

2009;23(6):1254-68. 2013;23:850-6. utilizing multiple modalities over 12. Hayreh SS. Classifi cation of central retinal vein occlusion. 37. Querques G, Prascina F, Iaculli C, Delle Noci N. Intravitreal Ophthalmology 1983;90:458-74. pegaptanib sodium (Macugen) for radiation retinopathy following the course of treatment. Employing 13. Finger PT, Kurli M. Laser photocoagulation for radiation reti- episcleral plaque radiotherapy. Acta Ophthalmol 2008; 86:700-1. this approach seems to provide bet- nopathy after ophthalmic plaque radiation therapy. Br J Ophthal- 38. Mason III JO, Michael A, Albert JR, Persaud TO, et al. Intravit- mol 2005;89:730-8. real bevacizumab treatment for radiation macular edema after ter maintenance of visual acuity and 14. Horgan N, Shields CL, Mashayekhi A, Shields JA. Classifi ca- plaque radiotherapy for choroidal melanoma. Retina 2007;27(7), macular thickness than would be an- tion and treatment of radiation maculopathy. Curr Opin Ophthal- 903-7. mol 2010;21:233-8. 39. The New York Eye Cancer Center; Genentech. Effect of Intra- ticipated by repeated use of any single 15. Collaborative Ocular Melanoma Study Group. Collaborative vitreal Ranibizumab on Radiation Retinopathy Following Plaque treatment alone. ocular melanoma study (COMS) randomized trial of I-125 brachy- Brachytherapy for Choroidal Melanoma. In: ClinicalTrials.gov [In- therapy for medium choroidal melanoma: 1. Visual acuity after ternet]. Bethesda (MD): National Library of Medicine (US) 2000- 3 years COMS report no. 16. Ophthalmology 2001;108:348-66. [cited 2014 Jan 30]. Available from: http://clinicaltrials.gov/ct2/ Dr. Gallemore is the founder and 16. Sagoo MS, Shields CL, Emrich J, et al. Plaque radiotherapy for show/record/NCT00750399 NLM Identifi er: NCT00750399. director of the Retina Macula Insti- juxtapapillary choroidal melanoma: Treatment complication and 40. The New York Eye Cancer Center; Genentech. High Dose visual outcomes in 650 consecutive cases. JAMA Ophthalmol Intravitreal Ranibizumab for Recalcitrant Radiation Retinopathy. tute and Research Center, Torrance, 2014;132:697-702. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of 17. Krema H, Xu W, Payne D, Vasquez LM, et al. Factors predictive Medicine (US) 2000 – [cited 2014 Jan 30]. Available from: http:// Calif., and an assistant clinical pro- of radiation retinopathy post (125)Iodine brachytherapy for uveal clinicaltrials.gov/ct2/show/record/NCT01334879 NLM Identifi er: melanoma. Can J Ophthalmol 2011;46:158-63. fessor at Jules Stein Institute, UCLA NCT01334879. 18. Brown GC, Shields JA, Sanborn G, Augsburger JJ, et al. Ra- 41. Russo A, Avitable T, Uva M, et al. Radiation Macular Edema School of Medicine. Contact him at diation optic neuropathy. Ophthalmology 1982;89(12):1489-93. after RU-106 Plaque Brachytherapy for Choroidal Melanoma Re- 19. Chaudhuri PR, Austin DJ, Rosenthal AR. Treatment of radiation [email protected]. solved by an Intravitreal Dexamethasone 0.7-mg Implant. Case retinopathy. Br J Ophthalmol. 1981; 65:623-5. Mr. Wallsh is a research associate 20. Gass JDM. A Fluorescein Angiographic Study of Macular Rep Ophthalmol 2012;3:71-6. at the Retina Macula Institute and Dysfunction Secondary to Retinal Vascular DiseaseVI. X-Ray Irra- 42. Bui KM, Chow CC, Mieler WF. Treatment of recalcitrant radiation, Carotid Artery Occlusion, Collagen Vascular Disease, and diation maculopathy using intravitreal dexamethasone (Ozurdex) Research Center and student at Al- Vitritis. Arch Ophthal. 1968; 80(5):606-17. implant. Retin Cases Brief Rep 2014;8:167-70. bany Medical College, Albany, N.Y. 21. Kinyoun JL, Chittum ME, Wells CG. Photocoagulation 43. Tarmann L, Langmann G, Mayer C, et al. Ozurdex reduces the treatment of radiation retinopathy. Am J Ophthalmol. 1988; retinal thickness in radiation maculopathy refractory to bevaci- Mr. Pham is a research associate at 105(5):470-8. zumab. Acta Ophtalmol 2014;92:e694-6. the Retina Macula Institute and Re- 22. Hykin PG, Shields CL, Shields JA, Arevalo JF. The effi cacy of 44. Bakri SJ, Larson TA. The Variable Effi cacy of Intravitreal Beva- focal laser therapy in radiation-induced macular edema. Ophthal- cizumab and Triamcinolone Acetonide for Cystoid Macular Edema search Center, Torrance, Calif. Dr. mology 1998;105(8):1425-9. Due to Radiation Retinopathy. Semin Ophthalmol 2013 [Epub Shields is the director of the Ocular 23. Kinyoun JL. Long-term visual acuity results of treated and ahead of print] untreated radiation retinopathy (an AOS thesis). Trans Am Oph- 45. Shah NV, Houston SK, Markoe A, Murray TG. Combination Oncology Service at Wills Eye Hos- thalmol Soc 2008;106:325-35. therapy with triamcinolone acetonide and bevacizumab for the pital and professor of ophthalmol- 24. Lommatzsch PK, Alberti W, Lommatzsch R, Rohrwacher F. Ra- treatment of severe radiation maculopathy in patients with poste- ogy at Thomas Jefferson University, diation effects on the optic nerve observed after brachytherapy of rior uveal melanoma. Clin Ophthalmol 2013;7:1877-82. choroidal melanomas with 106Ru/106Rh plaques. Graefe’s Arch 46. Boozalis GT, Schachat AP, Green WR. Suberetinal neovas- Philadelphia. Dr. Johnson is in private Clin Exp Ophthalmol. 1994;232(8):482-7. cularization from the retina in radiation retinopathy. Retina practice at West Coast Retina and is a 25. Gall N, Leiba H, Handzel R, Pe’er J. Severe radiation retinopa- 1987;7:156-61. thy and optic neuropathy after brachytherapy for choroidal mela- 47. Berker N, Aslan O, Batman C, Elgin U, Ozkan SS. Choroidal clinical professor of ophthalmology at noma, treated by hyperbaric oxygen. Eye 2007;21(7):1010-2. neovascular membrane in radiation retinopathy. Clin Experiment California Pacifi c Medical Center, San 26. Diabetic Retinopathy Clinical Research Network. A random- Ophthalmol 2006;34:625-6.. ized trial comparing intravitreal triamcinolone acetonide and 48. Bakri SJ, Beer PM. Photodynamic therapy for maculopathy focal/grid photocoagulation for diabetic macular edema. Ophthal- Francisco. due to radiation retinopathy. Eye 2005;19:795-9. mology 2009;115:1447-9. 49. Gupta P, Meisenberg B, Amin P, Pomeranz HD. Radiation reti- 27. Diabetic Retinopathy Clinical Research Network. Three-year 1. Irvine AR, Wood IS. Radiation retinopathy as an experimental nopathy: The role of pentoxifylline. Retina 2001;21:545-7. follow-up of a randomized trial comparing focal/grid photocoagu- model for ischemic proliferative retinopathy and rubeosis iridis. 50. Tuncer S, Kir N, Shields CL. Dramatic regression of amelanotic lation and intravitreal triamcinolone for diabetic macular edema. Am J Ophthalmol 1986;103:790-7. choroidal melanoma with PDT following poor response to brachy- Arch Ophthalmol 2009;127(3):245-51. 2. Archer DB, Amoaku WM, Gardiner TA. Radiation retinopathy- 28. Sutter FK, Gillies MC. Intravitreal triamcinolone for radiation- therapy. Ophthalmic Surg Lasers Imaging 2012;43:e38-40. clinical, histopathological, ultrastructural and experimental cor- induced macular edema. Arch Ophthalmol 2003;121:1491-3. 51. Akkus Yildirim B, Cetin E, Topkan E, et al. Prevention of radi- relations. Eye 1991;5:239-51. 29. Shields CL, Demirci H, Dai V, Marr BP, et al. Intravitreal tri- ation-induced retinopathy with amifostine in wistar albino rats. 3. Gragoudas ES, Seddon JM, Egan K, Glynn R, et al. Long-term amcinolone acetonide for radiation maculopathy after plaque Retina 2015 [Epub ahead of print] results of proton beam irradiated uveal melanomas. Ophthalmol- radiotherapy for choroidal melanoma. Retina 2005;25(7):868-74. 52. Gu J, Zhu S, Li X, et al. Effect of amifostine in head and neck ogy 1987;94:349-53. 30. Horgan N, Shields CL, Mashayekhi A, Salazar PF, et al. Perioc- cancer patients treated with radiotherapy: A systematic review 4. Bianciotto C, Shields CL, Pirondini C, Mashayekhi A, et al. Pro- ular triamcinolone for prevention of macular edema after plaque and meta-analysis based on randomized controlled trials. PLoS liferative radiation retinopathy after plaque radiotherapy for uveal radiotherapy of uveal melanoma: a randomized controlled trial. One 2014;9:e95968. melanoma. Ophthalmology 2010;117:1005-12. Ophthalmology 2009;116:1383-90. 53. Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: The fi rst 5. Gunduz K, Shields CL, Shields JA, Cater J, et al. Radiation reti- 31. Aiello LA, Avery RL, Arrigg PG, et al. Vascular endothelial selective-target and broad spectrum radioprotector. Onocologist nopathy following plaque radiotherapy for posterior uveal mela- growth factor in ocular fl uid of patients with diabetic reinopathy 2007;12:738-47. noma. Arch Ophthalmol 1999;117:609-14. and other retinal disorders. N Engl J Med 1994;331:1480-7. 54. Ahuja Y, Kapoor KG, Thomson RM, et al. The effects of 6. Zamber RW, Kinyoun JL. Radiation retinopathy. West J Med 32. Loukianou E, Brouzas D, Georgopoulou E, et al. Intravitreal intraocular silicone oil placement prior to iodine 125 brachy- 1992;157:530-3. bevacizumab for macular edema due to proton beam radiother- therapy for uveal melanoma: A clinical case series. Eye (Lond) 7. Brown GC, Shields JA, Sanborn G, Augsburger JJ, et al. Radia- apy: Favorable results shown after eighteen months follow-up. tion retinopathy. Ophthalmology 1982;89:1494-501. 2012;26:1487-9. Ther Clin Risk Manag 2010;6:249-52. 8. Stack R, Elder M, Abdelaal A, Hidajat R, et al. New Zealand 55. McCannel TA, McCannel CA. Iodine 125 brachytherapy with 33. Arriola-Villalobos P, Donate-Lopez J, Calvo-Gonzalez C, et al. experience of I125 brachytherapy for choroidal melanoma. Clin vitrectomy and silicone oil in the treatment of uveal melanoma: Intravitreal bevaciuzmab (Avastin) for radiation retinopathy neo- Experiment Ophthalmol 2005; 33(5):490-4. 1-to-1 matched case-control series. Int J Radiat Oncol Biol Phys vascularization. Acta Ophthalmol 2008;86:115-6. 9. Durkin SR, Roos D, Higgs B, Casson RJ, et al. Ophthalmic and 2014; 89:347-352. 34. Mason JO, Albert Jr MA, Persaud TO, Vail RS. Intravitreal adnexal complications of radiotherapy. Acta Ophthalmol Scand 56. Gall N, Leiba H, Handzel R, Pe’er J. Severe radiation retinopa- bevacizumab treatment for radiation macular edema after plaque 2007; 85:240-50. thy and optic neuropathy after brachytherapy for choroidal mela- radioatherapy for choroidal melanoma. Retina 2007;27:903-7. 10. Archer DB, Amoaku WMK, Gardiner TA. Radiation retinopa- noma, treated by hyperbaric oxygen. Eye (Lond) 2007;21:1010-2. 35 Finger PT. Radiation retinopathy is treatable with anti-vascular thy—clinical, histopathological, ultrastructural and experimental 57. Gong X, Rubin LP. Role of macular xanthophylls in prevention endothelial growth factor bevacizumab (Avastin). Int J Radiat On- correlations. Eye 1991;5(2):239-51. of common neovascular retinopathies: Retinopathy of prematu- col Biol Phys 2008;70(4):974-7. 11. Wen JC, Oliver SC, McCannel TA. Ocular complications fol- rity and diabetic retinopathy. Arch Biochem Biophys 2015 [Epub 36. Finger PT, Chin KJ. High-dose (2.0 mg) intravitreal ranibi- lowing I-125 brachytherapy for choroidal melanoma. Eye ahead of print] zumab for recalcitrant radiation retinopathy. Eur J Ophthalmol

54 | Review of Ophthalmology | August 2015

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RP0515_Haag Imaging.indd 1 4/8/15 2:14 PM Therapeutic Topics REVIEW

RISC and Reward with Inhibitory RNAs A new understanding of ribonucleic acid’s activity in cells may lead to breakthroughs in ophthalmic treatment. Mark B. Abelson, MD, CM, FRCSC, FARVO, and Connie Slocum, PhD, Andover, Mass.

nformation flow is fundamental recognized. Drs. Fire and Mello were small interfering RNAs as a therapeu- I to all biological systems, an attribute awarded the 2006 Nobel Prize in tic platform for a host of ophthalmic that helps us understand the nature medicine, and before that prize was conditions have accelerated over the and function of a cell, an organ or an even announced, Sirna Therapeutics past decade. organism. A central dogma of that had initiated a Phase I clinical trial for Theoretically, a targeted siRNA has flow is that it’s directional: The ge- treatment of age-related macular de- the potential to provide treatment netic code is deciphered from DNA generation with an interfering RNA for any human disease by interfering to RNA intermediates, and ﬁ nally to targeting the type 1 vascular endo- with disease-associated genes in a se- the structural and metabolic proteins thelial growth factor receptor.3 While quence-specific manner.5 Designing from which we’re built. But a flaw that trial yielded encouraging data, small RNA fragments to interfere with in this orderly arrangement became it didn’t progress.4 Despite this, the mRNA in the cytoplasm has the added clear by the end of the 20th century, potential for this treatment approach theoretical benefit of inhibiting the as we began to understand that those was validated and efforts to develop downstream synthesis of targeted pro- RNA intermediates carry the informational flow in both directions, as The ABCs OF RNAs messenger RNA translated into pro- Single-strand encoding for tein and as regulators of gene expres- mRNA messenger RNA sion in the form of microRNAs and individual protein interfering RNA.1 This month, we’ll Converts mRNA triplets tRNA transfer RNA look at the timeline of RNAi develop- into amino acids ment and consider what the future Forms complex for may hold for this singular therapeutic rRNA ribosomal RNA protein translation modality. Synthetic (exogenous) RNA siRNA small, interfering RNAs Two Decades of RNAi used to direct gene expression Hairpin or double-stranded The process of RNA interference miRNA micro RNA endogenous RNA, processed to was comprehensively described by smaller fragments for RNAi Andrew Fire, PhD, and Craig Mello, Process by which small RNAs 2 RNAi RNA interference PhD, in the late 1990s, and the sig- regulate gene expression niﬁ cance of this discovery was instantly

56 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

0052_rp0815_ttops.indd52_rp0815_ttops.indd 5656 77/24/15/24/15 4:324:32 PMPM 6 teins. This new therapeutic magic bul- The Path to RNA Interference cleaves complementary host mRNA, let was of particular interest for target- thereby preventing translation and se- ing genes that had traditionally been lectively silencing gene expression.7 Long dsRNA considered “undruggable” by other DICER Although longer, double-stranded methods, such as small molecules.6,7 Synthetic Endogenous RNA has the potential to be delivered The discovery of RNAi as a poten- dsRNAs Processing by therapeutically, it is generally accepted tial therapeutic modality led to an era DICER that siRNA technology offers the best fi lled with bidding wars for RNAi in- combination of specifi city, potency and 12 tellectual property and publication of DICER versatility as a therapeutic. a number of controversial fi ndings in Complex Since siRNA must reach the cytosol high-profi le journals. Early efforts to of the cell to trigger RNAi, chemical exploit RNAi technologies did not live modifications are required to bring up to their hype, and thus a period RISC siRNA to its site of action without in- of general backlash and fi nancial re- Complex ducing adverse effects,7 and to mini- strictions ensued.8 After great initial mize recognition by the innate immune DICER/RISC/RNA 5 promise came a series of disappoint- Complex system. The potential for RNAi for- ments followed by a steady progress to mulations to activate innate immunity therapeutic success. Many of the ther- was a signifi cant hurdle for the early ef- apeutics in the clinical pipeline now forts to develop RNAi therapies.8 This benefit from the scientific rationale Target mRNA issue has been largely circumvented by AAAAA derived from the historical trial-and- mRNA Cleavage a combination of chemical modifi ca- error of earlier RNAi therapeutic ef- AAAAA tions to the introduced RNA and by forts, so we may have reached a second Double-stranded RNAs (dsRNAs) are alterations in RNA structural design. phase of therapeutic progress, with a processed into siRNA duplexes by the In addition, newer siRNAs incorporate growing number of RNAi therapies enzyme DICER. These short, dsRNAs are principles that ensure proper strand currently in various phases of clinical subsequently unwound and assembled into selection, avoid partial hybridization to trials.6 Despite the mothballing of Big the RISC, which can direct RNA cleavage non-target mRNAs, and thus minimize Pharma RNAi programs in the past, and translational repression using anti- potential off-target gene silencing.7 it seems that it is more of a question sense strands from either endogenous or of when, rather than whether, RNAi exogenous dsRNAs. SiRNA and Ocular Disease therapeutics will reach their potential as a unique and valued treatment mo- increasingly used as biomarkers of dis- Early efforts to apply siRNA thera- dality.8 ease states, and have been specifi cally peutics to ocular conditions targeted linked to a host of ocular conditions. retinal degenerative diseases due to MicroRNAs, DICER and RISC In the cornea, recent reports identify the number of conditions with lim- specifi c miRNAs that may participate ited successful therapeutic options and The endogenous process of tran- in cellular events of wound healing.10,11 difficulty in formulating topical ap- scribing genetic signals from DNA to By examining up- and downregulation plication of siRNA therapy that will RNA, and ultimately expressing pro- of miRNAs associated with specific be stable and penetrate the ocular teins, is an evolutionarily conserved, states, it’s been possible to identify new surface. These studies faced the same multistep pathway that involves tis- mechanisms underlying both healthy difficulties that all retinal drugs do: sue-specifi c microRNAs and a series and pathologic healing processes. physical barriers; rapid clearance; and of enzyme complexes that drive the It’s at this point in the endogenous heterogeneous disease etiology. The regulatory process. The miRNAs are gene regulatory process that therapeu- isolated compartment of the eye, how- trimmed to size by a specifi c ribonu- tic siRNAs enter. Whether generated ever, provides advantages for siRNA clease called DICER and then paired by DICER or introduced exogenously, delivery compared to other tissues and with a target mRNA in a multiprotein short, 18- to 25-nucleotide RNA du- organ systems in that the siRNA can be RNA-induced silencing complex called plexes assemble into the RISC and directly delivered.13 While most siRNA RISC.5 The complexity of this cellular the double-stranded siRNA is sepa- programs to date have delivered thera- apparatus serves to underscore the rated, resulting in a single RNA strand peutics by direct intravitreal injection,5 importance of miRNAs as regulatory coupled to RISC. The resulting RISC/ opportunities for new delivery meth- molecules.9 In the eye, miRNAs are RNA strand complex identifies and ods are likely to impact the future suc-

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REVIEW Topics

Trials of RNAi-based Therapies

Company Drug Name Gene Target Disease Target Delivery Method Clinical Status*

Bevasiranib Opko Health VEGF wet AMD intravitreal injection Phase III – terminated (Cand5) Sirna-027 Allergan VEGFR1 AMD intravitreal injection Phase II – terminated (AGN211745) Quark AMD intravitreal injection Phase II – completed Pharmaceuticals PF-655, others RTP801 DME intravitreal injection Phase II – completed

Phase II/III NAION Quark pre-recruitment QPI-1007 caspase-2 intravitreal injection Pharmaceuticals AACG Phase II – ongoing

POAG Phase IIb – recruiting Sylentis SYL040012 ADRB2 topical ocular hypertension Phase I – complete ocular pain Phase Ib – recruiting Sylentis SYL1001 TRPV1 topical dry-eye syndrome Phase II – recruiting *from clinicaltrials.gov, 11 June 2015

cess of siRNA in the eye. peutics. In animal models, QPI-1007 TRPV1 that encodes the receptor for The first clinical application of has been shown to provide ocular neu- capsaicin, the active ingredient in chili RNAi-based therapy was in 2006 by roprotection through preservation of peppers. The gene product of TRPV1 the intravitreal injection of a siRNA, retinal ganglion cells.12 QPI-1007 has is a key component of nociceptive sen- Cand5, targeting vascular endothe- successfully completed Phase I stud- sory nerve endings, and silencing of lial growth factor for the treatment ies for the treatment of non-arteritic this receptor via siRNA will be evalu- of AMD.4 Although Cand5 showed ischemic optic neuropathy, and is also ated for the treatment of ocular pain initial promise in clinical trials, it was being evaluated in Phase II for acute, associated with dry-eye syndrome in a terminated in Phase III for its lack of primary angle-closure glaucoma. Phase Ib study. effi cacy.14 By 2011, two additional siR- Another avenue for the application NAs had been evaluated by direct in- of siRNA for ocular disease therapy The Future of siRNA Therapies travitreal administration for their treat- comes from Sylentis. The siRNA ment of retinal degenerative diseases SYL040012 was developed as a ther- Despite the $2.5 to $3 billion that in humans. Sirna-027 [sic] was also de- apy for primary open-angle glaucoma; was invested in RNAi therapeutics signed to target the VEGF pathway it’s designed to inhibit the synthesis of from 2005 to 2008, we have yet to by silencing the VEGF receptor. Like the β2-adrenergic receptor, ADRB2.6 see such a therapy come to market.8 Cand5, Sirna-027 was studied in trials In contrast to previous siRNA thera- A huge barrier to successful siRNA for the treatment of AMD but was pies that are delivered by intravitreal therapeutics has been their intracellu- terminated in Phase II. An additional injection, SYL040012 is the fi rst RNAi lar delivery, which signifi cantly impacts siRNA, PF-655, also developed for therapeutic to be administered as a their clinical effi cacy. siRNAs are large the treatment of AMD, was made to topical formulation. SYL040012 is cur- and negatively charged, so they must silence RTP801, a propriety gene tar- rently being assessed in a Phase IIb be chemically modifi ed or formulat- get owned by Quark Pharmaceuticals.7 clinical trial for POAG. ed to promote tissue distribution and Silencing the synthesis of the apop- The newest siRNA to enter clinical cellular uptake. It is likely that future totic protein, caspase-2 is another tar- development, SYL1001, is also from siRNA therapeutics will be designed get for siRNA-mediated ocular thera- Sylentis. SYL1001 targets the gene with new drug delivery systems that

58 | Review of Ophthalmology | August 2015

0052_rp0815_ttops.indd52_rp0815_ttops.indd 5858 77/24/15/24/15 4:334:33 PMPM Cover Retina

REVIEW Focus

will have a profound impact on im- (continued from page 36) Most retina specialists are current- proving the therapeutic outcomes for ly using swept-source OCT; more ad- ophthalmic applications. One group that wide-field imaging is revealing vanced versions of OCT are not yet of researchers has recently predicted new information,” he says. “I don’t available in the United States. How- that nanocarriers may be this delivery think it can be discounted. Wide-fi eld ever, that will change in the years system, due to their reported ability imaging in some diseases is almost ahead. Should a clinician be thinking to increase drug bioavailability while certain to be helpful. This should be about upgrading? “If I was in the reducing side-effects and the need for particularly true for ocular tumors in market for a new OCT device, and I repeated intraocular injections.5 Until the far periphery. It’s possible that could buy a swept-source OCT, what then, there remains hope that products ultra-wide-field swept-source OCT would be the disadvantage?” asks Dr. in development can demonstrate ap- could even replace ultrasound as the Sadda. “As long as I have normative propriate safety and effi cacy. Despite best way to follow ocular tumors.” data to use for comparisons when its early promise, developing therapeu- following my patients, which will tics that employ the siRNA platform What the Future Holds presumably exist when these devices has resembled swimming upstream, are cleared, then the only advantage but recent success may indicate that It seems clear that OCT-based spectral-domain might have over going against the fl ow may ultimately technologies hold tremendous prom- swept-source OCT would be cost. I be worth the risk. ise for retina management. “OCT has think swept-source is the future of revolutionized the way we care for OCT devices.” Dr. Abelson is a clinical professor patients,” says Dr. Rosenfeld. “A few “OptoVue has a spectral-domain of ophthalmology at Harvard Medical months ago I had color fundus imag- instrument that seems to have a head School. Dr. Slocum is a medical writer es done, as well as autofl uorescence start in the marketplace,” notes Dr. at Ora Inc. and infrared refl ectance images. It Rosenfeld. “The company has placed was torture! But with OCT, you don’t hundreds of their instruments in the 1. Elbashir SM, Harborth J, Lendeckel W, et al. Duplexes of 21-nucleotide R11NAs mediate RNA interference in cultured even have to be dilated, and you can hands of retinal specialists around the mammalian cells. Nature 2001;411:6836:494-8. do a scan in three or four seconds. world. But other companies, includ- 2. Fire A, Xu S, Montgomery MK, et al. Potent and specifi c genetic It’s a remarkable technology, and pa- ing Carl Zeiss Meditec, Heidelberg, interference by double-stranded RNA in C. elegans. Nature 1998;391:806-811. tients rarely complain. Most impor- Nidek and Topcon, are also develop- 3.https://clinicaltrials.gov/ct2/results?term=NCT00363714 tant, you can repeat it as often as you ing these instruments. Heidelberg accessed 30 June 2015. 4. Kaiser PK, Symons RC, Shah SM, et al. RNAi-based treatment like. It’s fast, and it’s not painful.” and Nidek are developing spectral- for neovascular age-related macular degeneration by Sirna-027. Dr. Sadda notes that many doctors domain-based technology, but Top- Am J Ophthalmol 2010;150:33-39. 5. Thakur A, Fitzpatrick S, Zaman A, et al. Strategies for ocular still make mistakes when imaging the con and Zeiss have swept-source siRNA delivery: Potential and limitations of non-viral nanocarriers. retina with current OCT technology. instruments that are being tested in J Biol Eng 2012;6:1:7. “One common error is to look at the clinics right now. So, there’s an open 6. Moreno-Montanes J, Sadaba B, Ruz V, et al. Phase I clinical trial of SYL040012, a small interfering RNA targeting β-adrenergic thickness maps alone—the automatic competition going on for the hearts receptor 2, for lowering intraocular pressure. Mol Ther 2014; data that comes from the device—and and minds of the vitreoretinal com- 22:1:226-32. 7. Kanasty R, Dorkin JR, Vegas A, et al. Delivery materials for simply assume it’s correct,” he says. munity. We should see a huge trans- siRNA therapeutics. Nat Mater 2013;12:11:967-77. “Those maps can be erroneous be- formation in the marketplace over the 8. Haussecker D. The business of RNAi therapeutics in 2012. Mol Ther Nucleic Acids. 2012;1:2:e8. cause it’s very hard for the software to next year. A number of instruments 9. Hammond SM. An overview of microRNAs. Adv Drug Deliv Rev. calculate retinal thickness accurately should get FDA approval, so there Epub ahead of print, May 12, 2015. when you have disease disrupting the will be lots of competition.” 10. An J, Chen X, Chen W, et al. MicroRNA expression profi le and the role of miR-204 in corneal wound healing. Invest Ophthalmol various retinal layers. For that reason Vis Sci 2015;56:3673–3683. it’s important to look at the individual Dr. Rosenfeld has received research 11. Funari VA, Winkler M, Brown J, et al. Differentially expressed wound healing-related microRNAs in the human diabetic cornea. B-scans and the data that underlies grants in collaboration with Carl Zeiss PLoS One 2013 Dec 20;8:12:e84425. the quantitatively derived data. And Meditec; Dr. Duker receives research 12. De Fougerolles A, Vornlocher HP, Maraganore J, et al. Interfering with disease: A progress report on siRNA-based of course, there are other artifacts, support from Carl Zeiss Meditec and therapeutics. Nat Rev Drug Discov 2007;6:6:443-53. such as conjugate image artifacts, that OptoVue. Dr. Sadda has received re- 13. Lee DU, Huang W, Rittenhouse KD, et al. Retina expression can also be misleading. This is the search support from and served as a and cross-species validation of gene silencing by PF-655, a small interfering RNA against RTP801 for the treatment of ocular reason we have training course at the consultant to Carl Zeiss Meditec and disease. J Ocul Pharmacol Ther 2012;28:3:222-30. Academy and other meetings. Even Optos. Dr. Charles has no fi nancial 14. Ahmed Z, Kalinshki H, Berry M, et al. Ocular neuroprotection by siRNA targeting caspase-2. Cell Death Dis 2011;16;2:e173. with the current OCT technology, ties to any products or technologies there’s still a lot to learn.” mentioned.

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

EHR and Glaucoma: Perfect Together? Despite some downsides, electronic records have practical advantages—especially if you’re managing glaucoma. Joel S. Schuman, MD, Pittsburgh

he switch to electronic health 15 percent had implemented EHR he’ll be willing to switch back to paper T records is seen by many as—at for some of their doctors or were in charts. In 2010, for example, a survey best—a mixed blessing. In addition the process of implementation; and was done here at the University of to the challenges that come with another third planned to implement Pittsburgh Medical Center. In that any kind of sweeping change, using EHR in the next couple of years. Of survey, about 30 percent of the people EHR can be more time-consuming the doctors already using EHR, half who had been using UPMC’s chosen than using paper charts, and it comes were satisfi ed or extremely satisfi ed outpatient system (EpicCare) for less with some pitfalls that don’t exist with their system. Forty-two percent than three months said they’d prefer with the traditional system. On the reported stable or increased overall to return to paper charts. But among other hand, it offers some signifi cant productivity; 20 percent reported those who had used the system for benefi ts—and some of those benefi ts that overall costs were stable or had six months, the number dropped to are of particular use to those of us who decreased. Half of those using EHR 15 percent. The percentage was the manage glaucoma. said they would recommend their same at one year, but by two years, it Here, I’d like to discuss what some EHR to fellow ophthalmologists. dropped to 5 percent. surveys are showing about doctors’ These numbers are hardly over- Here at UPMC, we’ve looked at reactions to implementing EHR; re- whelming, but most ophthalmologists the acceptance of electronic records view some of the benefi ts and down- might fi nd them surprisingly positive. across our entire system. (UPMC en- sides of using EHR; and highlight a Even I was a little surprised that this compasses 20 hospitals with about few of the reasons EHR can be advan- many people were happy with their 3,500 employed physicians and more tageous when managing glaucoma. EHR systems, for the simple reason than 60,000 employees overall; it’s that they are a part of practice that a $12 billion-a-year global health Reacting to Change doctors love to hate. However, if you enterprise.) In 2010 and 2011 we ask physicians who have made the surveyed a random subset of our Recent surveys conducted by the switch to EHR whether they’d be doctors and support staff. We found American Academy of Ophthalmol- willing to go back to paper charts, only that about 70 percent of those sur- ogy provide a sense of where ophthal- a small number say yes. veyed thought EpicCare was an mologists stand in terms of adopting The data suggest that the answer effective tool that gave good access to EHR. In 2013, 1,500 Academy mem- to that last question changes over test results; that result didn’t change a bers were surveyed about this; 500 time as people get used to working year later. Asked whether the system replied. A third of the responding with EHR. The longer a doctor has was more accurate than paper charts, practices said they already had EHR; used EHR, the less likely it is that whether the switch had contributed

60 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

060_rp0815_gm.indd 60 7/24/15 2:30 PM positively to the patient’s care, and whether it made prescribing easier, 55 to 60 percent said yes in 2010; that rose about 10 percentage points by the following year. However, only about 40 percent agreed that the system improved communication, and only 15 percent felt that it increased their confidence in the data. Those numbers did not change between 2010 and 2011. (We’ll talk about the probable reason for those answers shortly.)

Earnings Impact

We also looked at return on in- vestment, using data from a four- One advantage some electronic records programs have when managing glaucoma is the year longitudinal study with a six- ability to show multiple parameters onscreen at once, and how they’ve changed over time. year follow-up. The four-year study Some programs can also graph multiple parameters simultaneously, making it easy to see looked at a fi xed group of clinicians— whether your patient is stable or getting better or worse. The graphs can also show when people who were already in a stable an intervention took place (see sample, above) or highlight the period of time when the practice—for the two years before patient was on one particular medication for comparison to other periods. implementation of the EHR, which took place in 2006, and then two signifi cant difference. • It can be more time-consuming years post-implementation. Our pur- One area in which we did find for the physician. About half of the pose was to look at the impact of im- change was testing; we found more physicians surveyed at UPMC felt plementing an ambulatory EHR in testing was being billed after imple- that using EHR added a couple of an academic ophthalmology practice, mentation of EHR than before. Prior hours to the workday. This is true, based on clinical productivity mea- to implementation the numbers for in part, because EHR forms require sures that could be quantifi ed. testing were fl at (from 2004 to 2006). more extensive input than traditional We found no difference in average After implementation there was a big paper records. However, 30 percent number of office encounters per rise in testing. Then, from 2008 to said there was no change, and about month between pre-implementation 2014, we found no change. We think 10 percent thought it was actually and post-implementation. (See charts, the reason for this is not that more more effi cient and took less time than p. 62.) There was an intentional drop testing was being done, but that more paper charts. in offi ce encounters during the period testing was being captured and billed My experience has been that it does of implementation itself, but then for. When doctors have to fill out a add time to the workday. Probably the numbers came right back up paper superbill, they may forget to the biggest reason for this is that the within a month of implementation; bill for some of the tests. Maybe they electronic record requires you to implementing EHR had no effect on didn’t complete their interpretation of provide much more information than volume. The same was true six years the results. With the EHR, every test you would provide in a traditional out; volumes were stable. is captured, and the system forces you paper chart. Also, in a paper chart We also looked at charges and to complete your interpretation. (For you can abbreviate things or use your work relative value units, or wRVUs. the record, the unchanged rate of own shorthand; that’s a lot faster than The charges were unchanged from income per offi ce encounter did not providing every piece of information two years before to two years after refl ect the change in testing income.) the EHR system is asking for. implementation (see chart, p. 64), and However, it’s worth noting that the there was no difference in charges EHR Downsides extra work time people notice when per offi ce encounter per faculty per using EHR may be offset—at least a month. The same thing was true six Managing patients using EHR does little—by the fact that when you’re years later in 2014—there was no have some drawbacks: done, you’re done. At the end of

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REVIEW Management

the day, when you close the charts, Avg. Offi ce Encounters Per Faculty: July 2004 - June 2008 that’s it; you’ve completed all of your required tasks. Among other things, 250 the letters to referring physicians are done; they go out the same day or the next day. (Academic medical centers 200 have typically been notorious for the lag between a patient being seen and 150 communication with the referring physician. On the other hand, not 100 every referring physician is thrilled to receive a fi ve-page letter that’s fi lled 50 with information the physician wasn’t looking for.) 0

• It’s harder to manage images.

07/04

09/05 03/07 11/05 05/07 01/06 01/07 11/06 05/05 09/07 01/05 05/08 11/07 11/04 03/05 03/08 09/06 01/08 09/04 07/07

03/06

05/06

07/05 For ophthalmologists, one of the big- LIVE GO gest problems with EHR is storing and retrieving images, such as scans, Avg. Offi ce Encounters Per Faculty: July 2008 - June 2014 photographs and visual fi elds. Because many systems don’t provide an easy 250 way to do this, many doctors are using one system for text and another 200 system for images. Sometimes the image system integrates with the text 150 system; sometimes it doesn’t. Another side to the issue of manag- 100 ing images is that many of us like to draw what we’re seeing. I used 50 to draw what I saw on gonioscopy, and draw the optic nerve; I don’t do 0 that any more because it’s just too cumbersome to do on a computer. 07/08 09/08 11/08 01/09 03/09 05/09 07/09 09/09 11/09 01/10 03/10 05/10 07/10 09/10 11/10 01/11 03/11 05/11 07/11 09/11 11/11 01/12 03/12 05/12 07/12 09/12 11/12 01/13 03/13 05/13 07/13 09/13 11/13 01/14 03/14 05/14 However, not being able to create a drawing is somewhat offset by the fact Data from two studies at the University of Pittsburgh Medical Center looking at the impact that I have photos, OCTs and visual of implementing an ambulatory EHR system in an academic ophthalmology practice. The fi rst, four-year study looked at clinicians who were in a stable practice for two years before fi elds that I can access immediately. and after implementation. The data showed no difference in average number of offi ce They usually give me the information encounters per month between the pre-implementation and post-implementation periods, I would have gotten from a drawing. except for an intentional drop in offi ce encounters during the period of implementation. (Plus, the information is presented (The numbers came back up within a month.) At six years out, volumes were still stable. in a more standardized and objective way.) entry, but you need to make sure that objection to EHR is having to type • Accuracy of chart information you change the relevant parameters information into the computer during isn’t guaranteed. Based on my own to refl ect your patient’s current status. the patient visit. The more time we experience with this system, I’d say • Some systems require multiple spend typing, the less time we’re that electronic records can be a very log-ins. People are often annoyed by interacting with the patient. I think effective tool. However, I wouldn’t having to log in over and over again this is a tremendous waste of time for say the patient data is more accurate. to access different programs. (Our a doctor, so I use a scribe; some of Incorrectly entered data can and system includes a tap-and-go feature the other physicians here at UPMC does occur. Also, the carry forward that circumvents most of this. It saves do the same. Scribes make things go function may lead to the inclusion us a lot of time during the day.) much faster and allow you to interact of outdated information. The carry • Interference with patient inter- directly with the patient throughout forward function can speed up data action. Perhaps the most common the visit, as opposed to sitting behind

62 | Review of Ophthalmology | August 2015

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RO0715_Akron Zioptan.indd 1 7/2/15 9:41 AM Glaucoma

REVIEW Management

a monitor typing. Of course, there’s Avg. wRVUs Per Offi ce Encounter Per Faculty: July 2004 - June 2008 some cost associated with having a scribe in the room, but we have found 250 that it increases your productivity enough that that the increase in patient volume far exceeds the cost of 200 the scribe. 150 EHR Benefi ts 100 Despite the drawbacks listed above, the advantages EHR offers to the 50 patient and physician are signifi cant: • No more lost charts. Many large 0 practices have about a 10-percent rate 07/04 09/04 11/04 01/05 03/05 05/05 07/05 09/05 11/05 01/06 03/06 05/06 09/06 11/06 01/07 03/07 05/07 07/07 09/07 11/07 01/08 03/08 05/08

of not being able to locate the pa- GO LIVE tient’s chart when the patient shows Another study at the University of Pittsburgh Medical Center looked at charges and work up. That’s not an issue when you’re relative value units two years before and after EHR implementation. Charges were using electronic records. unchanged before and after implementation, and the same thing was true six years later. • Remote access to records. With EHR you can access a patient’s record a topical beta-blocker. It’s very helpful patient. At the same time, it reduces from anywhere in the world. That to have that clinical information at the power of the physician a little, means you can address a problem your fi ngertips. because the patient is in control of your patient is having even if you hap- • Notes are legible and easy to her own information. It’s something pen to be in Mexico, Europe or Asia. locate. The notes in a chart are al- of a brave new world for us as doctors, • Electronic management of pre- ways easy to read, standardized and because the patient can take that scriptions. This is a huge bonus for in the same place. I can’t tell you information and go anywhere. Of the patient and the physician. For how many times during my training course, that doesn’t include digital example, when you enter in the name and as a fellow and faculty member records such as visual fi elds—so far. of a drug you want to prescribe, the I would look in a chart and be unable But some countries already have system can tell you whether or not that to decipher the prior notes. (This medical systems that make all of that drug is in the patient’s formulary. This was true sometimes even if I had available to patients, and I predict prevents follow-up phone calls from written the prior notes myself!) So that will happen here within a few the pharmacy saying, “You prescribed having the information in a typed or years. this, but the patient’s insurance won’t graphical form, and being able to fi nd • Easier doctor-patient com- pay for it. What else can the patient it at a glance because you know where munication. EHR makes it easy take?” You’ll know if there’s a problem everything is on the electronic form for the patient to communicate with while you’re still with the patient. is a big plus. Also, in the operating the physician and the physician’s • More complete information room the postoperative notes are usu- offi ce online. Patients can schedule, about the patient. If your EHR is ally templated and standardized, so confirm and cancel appointments; connected to a larger health system, they’re quick and easy to do. they can exchange secure messages the electronic record may contain all • Patients can access their re- with the physician; they can request of the other physician information cords. EHR technology also has a few a prescription renewal; they can that has been entered regarding a profound advantages for the patient. get their eyeglass prescription given patient. That gives you a sense One of those is giving patients the automatically; they can even have of the overall health of the patient and ability to get their own test results an online e-visit with a physician to also helps to guide your prescribing and medical history remotely at address some common conditions. (assuming the list of medications is their convenience; that includes up-to-date, which isn’t guaranteed, information about their allergies, Benefi ts: Managing Glaucoma thanks to human error). For example, medications and health problems, as if the patient is taking an oral beta- well as lab and test results. Because of issues that are unique blocker, there’s no point to prescribing This is empowering for the to managing glaucoma, EHR is

64 | Review of Ophthalmology | August 2015

0060_rp0815_gm.indd60_rp0815_gm.indd 6464 77/24/15/24/15 2:302:30 PMPM particularly advantageous: on Simbrinza, this was the pressure. to avoid confusion I may just show • It can help monitor adherence. This program gives us information at the patient how the IOP changed and EHR can tell you whether and when a glance that in the old days we’d have what effect each intervention and the patient’s prescription was fi lled, to go thumbing through the chart medication had. If the patient has a which gives you a hint regarding the to identify, and it gives it to us in a glaucomatous abnormality such as a patient’s adherence to therapy. You way that could not be presented on nerve fiber layer loss or visual field wouldn’t be able to easily get that paper. We have the ability to compare defect, I can call up the OCT and information any other way. different parameters on the fl y. visual fi eld with a click of the mouse • It can present and graph mul- and show the patient exactly where tiple parameters and how they’ve the abnormality is. (Many programs changed over time. One feature highlight the abnormal area in red.) of some EHR systems (including It’s much easier for It’s much easier for patients to ours) is so useful as to be considered understand a visual presentation than disruptive technology—particularly patients to understand a verbal description. That helps the if you’re treating glaucoma. Our a visual presentation patient understand why we’re using system includes a program called a certain medication, and it may even Synopsis that allows us to see all of than a verbal help encourage compliance. the discrete parameters that we’re description. Note: When graphing or comparing tracking, over time, on-screen, all at multiple results over time it’s once. We can look at different tests important to remember that you results obtained at different times and may need to eliminate some results compare them directly. That means Furthermore, we can link the text from the series you’re comparing we can look at the visual field data and image systems so that the patient’s or graphing. If you’re following a from a series of visits; we can also test images come up automatically glaucoma patient over time and the look at visual fi elds and OCT data at when you open that patient’s text- patient had a bad day for some reason, the same time, allowing us to look based chart. This is a big advantage, or there was something wrong with for correspondence in structure and because the fewer steps you have to the test at one visit, you can eliminate function. Even better, it allows us to take to see what you need to see, the that test data from the series. More graph up to four of those parameters better. important, if the patient had a surgical simultaneously. (See example, p. 61.) This is one example of a disruptive intervention during the follow-up In addition to graphing IOP over technology that can be a part of EHR period, you can eliminate the test time, you can look at nerve fi ber layer that enables the physician to provide results from before the surgical thickness and visual field index or better patient care. And it’s something intervention. If you fail to do that mean deviation. This makes it easy you can only do with the help of a and you compare the results from to see whether or not your patient computer. the beginning, the patient will appear is stable or getting better or worse, • It helps with patient education. to be on a downward slope, simply and whether you have the IOP under Adherence is always a problem when because the surgical intervention good control. managing a silent, often asymptomatic changed the patient’s trajectory. It’s The graphs can also show when disease like glaucoma. EHR can help important to check for this, because interventions took place and what by making it easy to show the patient even in academic medical centers medications the patient was on during the problem on-screen and show you don’t always get the correct tests a given period, as well as when they how your interventions are impacting included in the analysis. stopped using a given medication. it. Seeing this on-screen can help Another thing to remember is to In our program, if you hover over motivate patients to make the effort manually store any part of the exam a medication with the mouse, it to follow your instructions. that isn’t automatically captured by highlights the period of time when For example, I can show patients the the EHR system. In our case, I al- the patient was on that medication. trend of their IOP over the past two, ways store the statistical-analysis That makes it easy to compare what fi ve or 10 years, and what medications portion of the visual fi eld printout so happened on different medications. they were on during that time. I can that I can see what’s happened over When the patient was on timolol, this even show them what was happening time with the patient, instead of just was the pressure; when the patient was to their visual fi eld and retinal nerve comparing one fi eld to the next. Our on latanoprost, this was the pressure; fi ber layer during that time, although system doesn’t do this automatically;

August 2015 | reviewofophthalmology.com | 65

0060_rp0815_gm.indd60_rp0815_gm.indd 6565 77/24/15/24/15 2:302:30 PMPM Glaucoma

REVIEW Management

we have to upload the image into the managing glaucoma. A good system Using EHR is a different experience image storage and retrieval system. will allow you to evaluate your than using paper charts, and it can However, there is a system called patient’s progress over time much be slightly more cumbersome. But Forum, made by Carl Zeiss Meditec, more easily than you could with for somebody taking care of patients that allows you to send the visual fi eld a paper chart, showing the data with glaucoma, a good EHR system information and the OCT information graphically and interactively; it will let is a boon in so many ways that from their machines into a single you interpret tests in a more intuitive the advantages far outweigh the database on a server; it acquires the fashion and compare structure and annoyances and disadvantages. data, as well as the image. It also function, looking at tests of both allows you to remove confounding simultaneously, without having to fl ip Dr. Schuman is Distinguished testing data from the database. I’m pages. It can be a great tool for patient Professor, The Eye and Ear Foun- not sure if any other systems offer this education; it makes prescribing easier dation Endowed Chair in Ophthal- option, but having software that will and prevents corrections because a mology and chairman of the de- integrate the data and allow you to drug wasn’t on the patient’s formulary; partment of ophthalmology at the selectively include certain data points it lets you know if a patient hasn’t University of Pittsburgh School of in the analysis makes data analysis fi lled a prescription; and it makes it Medicine, professor of bioengineering much less cumbersome. much easier for the patient to get hold at the University of Pittsburgh and of information and communicate with director of the UPMC Eye Center. A Step in the Right Direction you. You’ll defi nitely be tracking tests He receives royalties for intellectual better than you were with pen and property related to OCT licensed by Overall, I believe EHR is better paper; the system will capture all the MIT and MEEI to Zeiss; he otherwise both for the doctor and the patient, tests that were done and help ensure has no financial interest in any and that’s especially true when that you get paid for your work. product discussed in this article.

060_rp0815_gm.indd 66 7/24/15 2:35 PM RP0815_Lombart.indd 1 7/21/15 10:07 AM Refractive Surgery

REVIEW Edited by Arturo Chayet, MD

The Link to a New Refractive Procedure? Surgeons are perfecting the use of corneal collagen cross-linking for the treatment of refractive errors. Walter Bethke, Managing Editor

he therapeutic modality known that when you make isolated focal or the cone, and it gradually grades out T as corneal collagen cross-linking topography-guided changes in corneal or blends as you move away from the has intrigued surgeons for several biomechanics, it can change the cor- tip of the cone. You can take this con- years now, as it’s shown potential for neal shape and give a refractive out- cept a step further: If you focally treat stabilizing some corneas that may come,” he explains. “The equipment the center of the cornea with custom- have been on the road to corneal needs to have the ability to change ized patterns, you can get correction of transplants without such treatment. treatment sizes, powers and patterns, modest amounts of myopia, hyperopia Recently, researchers outside of the as well as the ability to have an eye and astigmatism.” Dr. Hersh says PiXL United States and one of the com- tracker so it can put the treatment in treatments usually use higher levels panies behind several cross-linking the right position. of energy delivered centrally than are devices, Avedro, have begun investi- “PiXL can be approached in a couple used in standard cross-linking. “For gating the ability of cross-linking to of ways,” Dr. Hersh continues. “First, instance, where it’s standard to use create a refractive change in corneas in irregular corneas and those with ker- 5.4 mJ for cross-linking, we are looking that are otherwise healthy. Here’s a atoconus, a surgeon can treat the cone at doubling or tripling this in a graded look at what they’ve found so far. itself, or treat the corneal topography, pattern for the treatment of irregular so to speak, by doing a focal applica- cornea PiXL patients and refractive PiXL tion over the cone. Typically, this is a PiXL patients,” he avers. “We don’t graded application, meaning there’s know what powers are optimal yet, but The technique and technology be- more UV energy delivered right over that’s the thinking.” ing investigated by Avedro is known John Kanellopoulos, MD, of Ath- as photorefractive intrastromal cross- ens, Greece, has used PiXL in some linking, or PiXL; it uses the company’s patients so far in his practice and de- KXL II device, which features an ac- scribes the myopic protocol: “The light tive eye tracker. proﬁ le is a very small-diameter beam Teaneck, N.J., surgeon Peter Hersh, of 4 mm placed at the corneal apex

MD, who is on the medical advisory MD Peter Hersh, All images: with a very high level of UV light at the board for Avedro, says the treatment magnitude of 15 mJ and a ﬂ uence of needs both the energy to make the 45 mW/cm2,” he says. “And it uses a tissue alteration and the ability to put riboflavin solution of 0.25%, which the energy in the proper place. “What One application for PiXL involves applying it is about three times more than the PiXL does is take advantage of the fact on the cone in keratoconus patients. standard solution used in the Dres-

68 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

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REVIEW Surgery

The PiXL treatment with the KXL II device treats myopia by placing the energy with a higher concentration in the central cornea and then gradually decreasing the intensity away from the center. In this myope, nine months post-PiXL treatment, the surgeon was able to achieve a little more than 2 D of ﬂ attening.

den protocol. The hyperopic profi le is PiXL-specifi c complications.” Dr. Hersh says the procedure’s pre- more of a doughnut shape 1-mm wide Matthias Elling, MD, senior physi- dictability is a result of a host of factors. starting at 4 mm or 6 mm, similar in cian at Ruhr University Bochum in “These are very early studies,” he says. appearance to a hyperopic excimer Germany, is a researcher in a study of “And they’ve shown fairly reproducible ablation. The depth of the treatment 33 PiXL eyes with six months of follow- results. Postop, on average, surgeons in an endothelium-off treatment is up. “We observed that if patients had are getting 1.25 to 1.5 D of correction deeper, extending to about 60 percent -3 D preop, we weren’t able to reach with these treatments. These are pa- of corneal thickness. In epithelium-on emmetropia completely,” he says. “But tients who start out -1 or -2 or so. Yes, treatments, it extends to a third or half in lower myopes we came nearer to some people are getting more correc- of the corneal thickness.” it. The refractive outcome is stable, tion than others, just as they did in the and the median uncorrected acuity is early days of PRK. I think centration PiXL’s Performance 0.8 [20/25] postop. So, the early re- of the treatment is ultimately an is- sults show it’s possible to do a refractive sue, as is proper alignment and proper Though PiXL is proving to have an treatment with cross-linking, and we’re registration. Clearly, since you’re trying effect, some surgeons say that, like any able to correct up to 2 D.” to meticulously place the treatment new procedure, nomograms need to Dr. Kanellopoulos sees poten- energy, all of these will be important be worked out in order to increase the tial in the procedure but has run components.” procedure’s predictability. into the variability, as well. “In our Singapore surgeon Jerry Tan, who The Czech Republic’s Pavel patients, 80 percent were within has experience with cross-linking, Stodulka, MD, PhD, has performed 0.5 D of intended correction up to a thinks that PiXL’s biggest hurdle may PiXL on 10 patients. “I’ve performed year postop,” he says. “We didn’t see be current procedures. “I have used the it in two patient groups,” he says. “I’ve any adverse effects or complications, technology and I think it will work,” he done it in keratoconus patients and with the exception of one case in the says. “However, treatment times and in patients with low myopic refractive epithelium-on group developing a healing times are too long. Currently, surprises after IOL implantation. Both small epithelial defect, and some epi- LASIK is very fast and accurate—mak- the predictability and efficacy were thelium-off cases having a delayed epi- ing a LASIK fl ap takes 10 seconds and quite low in both groups. Our best case thelialization. The only issue of relative treating a low myope takes fi ve to 10 was a 52-year-old pseudophakic lady concern was that we did encounter a seconds. How can you get any faster with a refraction of -1.25 -0.25 x 0 and few young patients who had a minimal than that? Plus, LASIK patients see uncorrected distance visual acuity of refractive effect, even though a higher very well after a few hours with hardly 0.1 [20/200] and best-corrected dis- refractive effect was anticipated. For any discomfort. PiXL has a tough act tance acuity of 1.0 [20/20]. She became instance, one 34-year-old woman, in to follow.” [20/20] uncorrected a month after whom 2 D of correction was planned PiXL treatment. She was an outstand- via a transepithelial treatment, only Drs. Hersh and Kanellopoulos are ing case, but we didn’t get any other achieved 0.5 D. This procedure has consultants to Avedro. Drs. Stodulka, similar result. Corneal haze wasn’t re- proven its feasibility but needs further Elling and Tan have no fi nancial in- ally a problem and we didn’t see any study to refi ne a nomogram.” terest in the products mentioned.

August 2015 | reviewofophthalmology.com | 71

068_rp0815_rs.indd 71 7/24/15 10:26 AM REVIEW Product News A Host of New Tools for a Range of Surgical Moves

eaver-Visitec International CustomEyes kits. The benefits of B has introduced two new prod- single-use instruments include im- ucts—Bonn Forceps and Tying For- proved patient safety; consistent per- ceps—that follow the capsulorhexis formance; time saving and greater forceps launched in 2014, with the convenience; and optimization of same design features: cost and budget control. • developed for micro-incision For information on any BVI prod- cataract surgery; ucts, call 1 (866) 906-8080 or visit • ergonomic handle provides su- visit beaver-visitec.com. perior control; • precise and consistent tip align- New Trio from Rhein Medical ment; and hein Medical has debuted three • safety—easily identifiable as R new surgical instruments. The single-use. Tearse Meibomian Expressor For- The Bonn Forceps offer excellent ceps, developed with James Tearse, tissue grasping and grip strength; MD, are ideal for expressing mei- blunt teeth for minimal tissue trau- bomian glands in all four lids and ma; and a precise platform alignment designed to be used while probing to grip sutures. glands. Specially angled compres- The Tying Forceps feature round- sion plates squeeze the lids to direct ed platform edges to ensure sutures meibum fl ow out of the orifi ce. The are not cut; fine tips for accuracy; physician can control compression lids. Unique compression plates are designed to express either 5 mm or 8 mm by rotating the handle. The stainless steel forceps are reusable, autoclavable and guaranteed for life. The Younger 360 Degree Cap- sule Polisher, developed with Jared R. Younger, MD, features a special angulated shaft that allows quick and easy, full 360-degree polishing and a precise platform alignment to pressure from soft to of both the anterior and posterior grip sutures. very fi rm. The handle is ambidextrous capsules with one instrument. The BVI offers a wide range of single- and allows use for both upper and unique angulation eliminates the use instruments for ophthalmic sur- lower lids, while a compression stop need for using two instruments, or gery, available individually or in BVI prevents crushing of the glands and having to exit and enter through a

72 | Review of Ophthalmology | August 2015 This article has no commercial sponsorship.

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072_rp0815_products.indd 73 7/24/15 2:36 PM Product Cover Retina

REVIEW News REVIEW Focus

launched mVT Service, an innovative ments because of its convenient (continued from page 46) medical device that conveniently and home monitoring. accurately tracks the progression of The new mVT Service is the only macular volume decreased by 0.2 mm3 maculopathies. simple, FDA-cleared, low-cost, mo- and median fl uorescein leakage area The device is available only by bile, validated method available for within the grid decreased by 0.7 disc prescription and consists of an easily these patients to test their vision at areas. downloaded app that can be used on home. Patients take a simple four These researchers found that focal/ any Apple smartphone or tablet. Pa- to six minute self-test, performed grid laser in these non-center-involved tient test data are automatically up- on the timetable recommended by eyes was associated with relatively sta- loaded to a physician portal, where the doctor (usually twice a week). ble visual acuity and retinal thickness licensed eye-care professionals can Patient test results are automatically measurements and decreased fluo- monitor all patient test results. In delivered to a HIPAA-compliant da- rescein leakage area at one year. The the studies the device showed value tabase and analyzed for prescriber ETDRS had previously recommended in features important in a screening review. considering the use of focal/grid la- tool: predictive response; stability of For information, visit myvision ser in eyes with non-center-involved, results; ability to detect visual func- track.com or call 1 (844) 267-8019 clinically significant macular edema. tion improvement; and reliability. for information; for complete data Although this study is small, the in- Researchers in San Francisco and from all four studies visit http:// vestigators found that considering the Berkeley, Calif., assessed the Service myvision track.com/for-physicians. use of focal/grid laser still seems ap- against nine other tools for predic- propriate. tive response, or the ability to pre- “In patients who have few symp- dict which patients are at the great- toms, decent vision and a cluster of est risk of progressing to advanced leakage outside the center, many oph- disease. mVT showed the most pre- thalmologists are still recommending dictive promise. University of Liv- laser, because immediate results are erpool researchers investigated the not needed and because laser may stability of mVT results. Stability pri- have a longer-term benefi t,” Dr. Stone or to disease onset in at-risk eyes is says. “In fact, the Diabetic Retinopathy essential for a reliable screening test; Clinical Research Network is evaluat- stability of the mVT was confi rmed. ing what to do with these patients, and The investigators also commented they have randomized patients who that unlike other tests, the mVT is have center-involved diabetic macular convenient and users report no test- edema but good vision to anti-VEGF ing diffi culties. agents, laser or observation.” The National Institutes of Health supported a diabetic retinopathy Dr. Stone’s practice has ongoing re- study in Dallas to see if the mVT Partnership Announces Halo search projects with Genentech and Service detects visual function im- Sterile Cornea Regeneron, and Dr. Boyer is a consul- provement from anti-VEGF treat- tephens Instruments has part- tant to Regeneron and Genentech. ments. Results indicated that mVT S nered with Lions VisionGift to 1. Mitchell P, Bandello F, Schmidt-Erfurth U. The RESTORE study: clearly detects visual function im- deliver the Halo Sterile Cornea Al- Ranibizumab monotherapy or combined with laser versus laser provement and, in fact, appears to lograft. Developed at Lions Vision- monotherapy for DME. Ophthalmology 2011;118:4:615-625. be more sensitive than either visual Gift’s Vision Research Lab, the Halo 2. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: acuity or letter contrast sensitivity in Sterile Cornea is a shelf-stable, e- RISE and RIDE. Ophthalmology 2012;119:789-801. detecting changes. The fourth study, beam sterilized graft for glaucoma 3. Korobelnik JF, Do DV, Schmidt-Erfurth U, et al. Intravitreal afl ibercept for diabetic macular edema. Ophthalmology 2014;121:2247- also supported by NIH, investigated tube-shunt coverage, deep anterior 2254. the strength of the shape discrimina- lamellar keratoplasty and tectonic use. 4. The Diabetic Retinopathy Clinical Research Network. Afl ibercept, tion hyperacuity test methodology Halo Sterile Cornea features patented bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372:1193-1203. of the mVT. Results confirmed its easy-peel packaging for quick and safe 5. Scott IU, Danis RP, Bressler SB, et al for the Diabetic Retinopathy reliability and accuracy. Research- introduction in the OR, no rinsing or Clinical Research Network. Effect of focal/grid photocoagulation on visual acuity and retinal thickening in eyes with non-center involved ers noted mVT should be especially reconstitution required. For informa- clinically signifi cant diabetic macular edema. Retina 2009;29:613- valuable for longer-duration treat- tion, visit halograft.org. 617.

74 | Review of Ophthalmology | August 2015

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Review of Ophthalmology® Alcon

2015_CSE_3rd_glauc_print.indd 87 5/20/15 9:29 AM 079_rp0815_wills.indd 79 unremarkable. was lightercentrallyandextendedbeyondthesuperiorarcade chamber. Fundusexaminationofthelefteyerevealedoccasionalvitreouscellandasubtleannularsubretinallesionthat in therightand0/8left. left eye.Extraocularmotilitywasfullbilaterallyandintraocularpressurenormalinbotheyes.Colorplateswere full eye atpresentationwithoutanyimprovementonpinhole.Apositiverelativeafferentpupillarydefectwaspresentin the Examination opportunistic infectionsorsexuallytransmitteddiseases.Hehadnoknowndrugallergies. or otherillicitdruguse.Hedidreportahistoryofunprotectedsexwithmen,thoughhedeniedany mg daily, lisinopril2.5mgdailyandfenoﬁ lipidemia andchronickidneydisease.Hismedicationsincludedabacavir/lamivudine600mg/300mgdaily, raltegravir400 count, butstatedthathisviralloadwasmostrecentlyundetectable.Othermedicalhistoryincludedhypertension,hyper- Medical History Presentation Nathan Cutler, MD, andEhsanRahimy, MD HIV-postive manseekstreatmentatWills. After noticingablackspotinhiscentralvisiontwoweeksearlier, an eye, asubtlesubretinal annularlesionispresent. Figure 1.Colorfundusphotographs oftherightandlefteye respectively. Intheleft tenderness orjawpain.Onreviewofsystems,hedeniedanyrecenttrauma,fever, rash,cough,weightlossorrecentillness. and hadnotchangedinappearancesinceitsonset.Hedeniedanyassociateddiplopia,pain,redness,photophobia,scalp What isyourdifferentialdiagnosis? Whatfurtherworkupwouldyoupursue?Please turntop. 80

External examination was unremarkable. Anterior slit-lamp examination revealed occasional cell in the left anterior External examinationwasunremarkable.Anteriorslit-lamprevealedoccasionalcellintheleftanterior The patientwasafebrilewithstablevitalsigns.Hisvisualacuity20/25intherighteyeandcountfi ngers intheleft The patientwasHIV-positive, fi rst diagnosedin2009.HewascompliantonHAART therapywithanunknownCD4 A 67-year-old malepresentedwithatwo-weekhistoryofseeingcentralblackspotinhislefteye.Thescotomawasfi REVIEW Wills Eye Wills Eye brate54mgdaily. Thefamilyhistorywasunremarkable.Hedeniedanytobacco Resident CaseSeries Edited by Alia Durrani, MD . Fundus examination of the right eye was (See Figure1).Fundusexaminationoftherighteyewas August 2015 | reviewofophthalmology.com xed xed |

79 7/24/15 3:08 PM 079_rp0815_wills.indd 80 reagin (RPR)withahightiterof showed apositiverapidplasma fi was made.Thisdiagnosiscon- rior placoidchorioretinitis(APPC) diagnosis ofacutesyphiliticposte- and fi ndings onimagingstudies,a Figure 4). macular regionofthelefteye(See inner/outer segmentbandinthe ening andlossofthephotoreceptor phy demonstratedchoroidalthick- domain opticalcoherencetomogra- oid lesion(SeeFigure3).Spectral hypofl green angiographydemonstrated was unremarkable.Indocyanine (See Figure2).FA oftherighteye also amildamountofdiscleakage staining oftheouterrim.Therewas cence ofthelesionwithprogressive strated earlypatchyhyperfluores- metastatic disease. etiologies, includinglymphomaor retinitis. Lesslikelywereneoplastic rior placoidchorioretinitis;andviral maculopathy; acutesyphiliticposte- choroidopathy; persistantplacoid liopathy (APMPPE);serpiginous multifocal placoidpigmentepithe- tial. Theseincludedacuteposterior etiologies werehighonthedifferen- sion, inflammatoryandinfectious of aunilateralisolatedmacularle- 80 as 2012-2013. creased incidenceevenasrecently has sincebeenontherisewithin- 2000 at2.1per100,000people,it in theUnitedStateshitalow Discussion United Statestoday. cent ofnewsyphiliscases inthe with men,whoaccountfor 75per- nerable groupismenwhohavesex Diagnosis, Workup andTreatment rmed withserologictesting,which REVIEW Given theclinicalpresentation Fluorescein angiographydemon- Given thepatient’s acuteonset While theincidenceofsyphilis | ReviewofOphthalmology Resident CaseSeries uorescence ofthelargeplac- 1 Aparticularlyvul- | August2015 macula demonstrating lossoftheIS/OSband. Figure 4.Spectral-domain opticalcoherence tomography ofthelefteye throughthe the lesionhadcompletelyresolved his lefteye.Atone-yearfollow-up 20/60 visionin improvement to had significant four hoursand lion unitsevery dose of3mil- of IVPCNata two-week course He receiveda IV penicillinG. treatment with neurosyphilis the hospitalfor admitted to was promptly syphilis. He ing treatedfor denied everbe- (FTA-ABS) test. body absorption treponemal anti- tive fluorescent 1:256 andaposi- between secondaryand tertiary to 10weeks.Latentsyphilis occurs papular rash,whichcanlast forfour fever andarthralgia)amaculo- systemic symptoms(e.g.,malaise, Secondary syphilishasnonspecifi cre thatlastsfortwotosixweeks. characterized byapainlesschan- into fourstages.Primarysyphilisis The patient Acquired syphiliscanbedivided progressive hyperfluorescence ofthemacularlesion. Figure 2.Fluorescein angiography ofthelefteye. Notethe hypofluorescence ofthemacularlesion. Figure 3.ICGangiography ofthelefteye. Notethepersistent c returned to20/30. on examinationandhisvisionhad lis caninfectnearlyevery ocular secondary andlatentstages. stage, butismostcommon during infection. curs monthstoyearsafterinitial neurological manifestationsandoc- syphilis includescardiovascularand last foryearstodecades.Tertiary stages, isclinicallysilentandcan Ocular syphiliscanoccuratany 3 Syphi- 7/24/15 3:08 PM structure ranging from the conjunc- absorption (FTA-ABS), treponema month intervals until the CSF white tiva and sclera, to the uvea and lens, pallidum particle agglutination as- blood cell count is normal and CSF- to every section of the posterior say (TPPA), and syphilis enzyme VDRL is nonreactive. Non-falling segment including the retina, cho- immunoassay (EIA). The trepone- titers or positive CSF fi ndings are roid and vasculature.4 Most of these mal tests usually remain reactive an indication for repeat treatment manifestations are nonspecifi c, and for life, regardless of treatment. with antibiotics. there is no pathognomonic feature RPR or VDRL titers are used to Acute syphilitic posterior plac- of the disease. Uveitis is the most measure response to treatment. oid chorioretinitis is a rare disease frequent manifestation of ocular Recently, EIA tests, which detect entity that can be the presenting syphilis. It has been shown that 8 specifi c IgM and IgG antibodies to sign of syphilis. While much more percent of all uveitis cases can be Treponema pallidum, have become common in HIV-positive patients, attributed to syphilis.2 more common as the initial test of APPC has been described in im- APPC is a rare manifestation of choice due to ease of laboratory munocompetent individuals as ocular syphilis. The clinical find- automation.7 well.10 Patients with APPC and oth- ings of APPC show a large, placoid, Testing algorithms now generally er forms of ocular syphilis should yellowish lesion with central fad- start with EIA or another trepone- be treated as having neurosyphilis, ing at the level of the retinal pig- mal test followed by a nontrepone- with 10 to 14 days of intravenous ment epithelium in the macular and mal titer for confi rmation (RPR ≥32 penicillin. With prompt antibiotic peripapillary areas.5 Fluorescein indicates increased risk of reactive treatment, patients have a good vi- angiography demonstrates a char- CSF-VDRL).8 Patients positive for sual prognosis. Ophthalmologists acteristic early hypofl uorescense or syphilis should be tested for HIV can play an important role in the faint hyperfl uorescence, often with given the high rate of co-infection, early detection and treatment of scattered hypofl uorescent spots, a and all positive patients should be this disease. pattern referred to as leopard spot- reported to the local health author- ting.5 Later-phase FA shows pro- ity so that sexual partners can be The author would like to thank gressive staining, especially at the notifi ed. the Wills Retina Service for assis- rim of the lesion. The lesion shows Patients with ocular syphilis tance in preparing this case report.

hypofl uroescence on ICG angiog- should be managed as having neu- 1. Anon. 2013 STD Surveillance Syphilis | CDC. Available at: raphy and hyperautofl uorescence. rosyphilis. This includes obtaining http://www.cdc.gov/std/stats13/syphilis.htm [Accessed May 7, 2015]. The SD-OCT fi ndings described in a lumbar puncture with cerebro- 2. Tamesis RR, Foster CS. Ocular syphilis. Ophthalmology APPC include disruption of the IS/ spinal fluid examination. Ocular 1990;97:1281-1287. OS band; nodular thickening of the syphilis is treated as neurosyphilis, 3. Eandi CM, Neri P, Adelman RA, et al. Acute syphilitic posterior placoid chorioretinitis: Report of a case RPE; loss of the external limiting regardless of CSF fi ndings. Treat- series and comprehensive review of the literature. Retina membrane; accumulation of sub- ment consists of penicillin G3 to 4 2012;32:1915-1941. 4. Chao JR, Khurana RN, Fawzi AA, et al. Syphilis: Reemer- retinal fluid; and punctate hyper- million units IV every four hours gence of an old adversary. Ophthalmology 2006;113:2074- refl ectivity in the choroid.6 or 24 million units continuous IV 2079. 5. Gass JD, Braunstein RA, Chenoweth RG. Acute Other associated findings on infusion for 10 to 14 days. Alter- syphilitic posterior placoid chorioretinitis. Ophthalmology examination can include variable natively, penicillin G procaine 2.4 1990;97:1288-1297. 6. Pichi F, Ciardella AP, Cunningham ET, et al. Spectral do- amounts of vitreous infl ammation million units IM daily, in addition main optical coherence tomography fi ndings in patients with (present in up to 90 percent of pa- to probenecid 500 mg four times acute syphilitic posterior placoid chorioretinopathy. Retina tients); retinal hemorrhages; retinal daily orally for 10 to 14 days can be 2014;34:373-384. 7. Dicker LW, Mosure DJ, Steece R, Stone KM. Laboratory vasculitis; disc edema; and subreti- used. Patients who have an allergy tests used in US public health laboratories for sexually trans- nal fl uid.3 APPC presents bilaterally to penicillin should be desensitized mitted diseases, 2000. Sex Transm Dis 2004;31:259-264. 8. Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fl uid in roughly half of patients. before undergoing treatment with abnormalities in patients with syphilis: Association with clini- Diagnosis of syphilis involves penicillin.9 cal and laboratory features. J Infect Dis 2004;189:369-376. 9. Centers for Disease Control and Prevention, Workowski the use of serum nontreponemal Monitoring of therapy should KA, Berman SM. Sexually transmitted diseases treatment tests, venereal disease research be done with RPR or VDRL titers guidelines, 2006. MMWR Recomm Rep Morb Mortal Wkly Rep Recomm Rep Cent Dis Control 2006;55:1-94. laboratory (VDRL) and RPR, and at six, 12 and 24 months following 10. Joseph A, Rogers S, Browning A, et al. Syphilitic acute serum treponemal specific tests, treatment. Repeat lumbar punc- posterior placoid chorioretinitis in nonimmuno-compromised fluorescent treponemal antibody tures should be performed at six- patients. Eye Lond Engl 2007;21:1114-1119.

August 2015 | reviewofophthalmology.com | 81

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