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HIGH-TECH TRACKING IMPROVES OUTCOMES P. 22 • WILLS RESIDENT CASE SERIES P. 79 THE FORGOTTEN PIECE OF THE COMPLIANCE PUZZLE P. 66 • GENE THERAPY FOR RETINAL DISEASES P. 56 eiwo ptamlg o.X,N.1 Otbr21 DyEeIse• h aetDansi ol Making Dry-Eye Treatment Proﬁ The Latest Diagnostic Tools • Dry Eye Issue • 2013 • October Review of Ophthalmology Vol. XX, No. 10 • USING MODELS IN CLINICAL TRIALS P. 62 • PHAKIC LENS DOS AND DON’TS P. 73

October 2013 • revophth.com tbe•Tackling Fungal Infections table •

Dry-Eye Diagnosis: 21st-Century Tools P. 28 Dry Eye & Your Practice’s Bottom Line P. 48

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fc_rp1013.indd 1 9/20/13 2:06 PM Toric outcomes: The evidence is overwhelming

Measuring Up to Today’s Surgical Standards The IOLMaster® has been used extensively in peer-reviewed, published studies of toric IOL implantation.1 In these studies, excellent surgical outcomes were reported using IOLMaster keratometry measurements.

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Agreement with Manual Keratometry The IOLMaster measures up to another important standard. Excellent agreement exists between the IOLMaster and manual keratometry for mean power, cylinder power and axis, with superior repeatability and reproducibility.2

RP1013_Zeiss Meditec.indd 2 9/17/13 1:31 PM With clinical evidence that is truly overwhelming, it's no wonder the IOLMaster is the preferred method of keratometry for toric IOL calculations.3

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1 Bullimore MA, The IOLMaster and Determining Toric IOL Power, 2013 2 Bullimore MA, Buehren T, Bissman W. Agreement between a partial coherence interferometer and 2 manual keratometers. J Cataract Refract Surg. 2013 Jul 19. 3 Leaming DV, 2012 Practice Styles and Preferences of the U.S. ASCRS Members Survey

RP1013_Zeiss Meditec.indd 3 9/17/13 1:31 PM REVIEW NEWS Volume XX • No. 10 • October 2013 Florida Surgeon Hopes to Fill Acute Need for Eye Care in Syria

As the confrontation over the use of nerve ian American Medical Society, and SAMS is set up to accept both used gas dominates the headlines, civil set about through SAMS and other medical and surgical equipment, and strife in Syria has captured the world’s aid groups to equip three hospitals in fi nancial donations as well. Informa- attention. Out of the spotlight, a Syr- the rural north near the border with tion on the group is available at sams- ian-American ophthalmologist from Turkey with ophthalmic equipment. use.net. In addition to medical care, Pensacola, Fla., has been working with For his fi rst shipment, he was able to SAMS is involved in humanitarian colleagues and aid groups on site to collect $70,000 to purchase a vitrec- efforts to restore decimated rural vil- provide eye-care services to the coun- tomy machine, a laser, a microscope lages with the means to support them- try’s devastated populace. and some ancillary equipment. Work- selves, such as a project to donate cows Raised in Syria, with his residency ing with colleagues from the United to farming areas. Another group pro- and fellowship in the United States, States and the UK, Dr. Rafai now has viding relief and humanitarian services retina specialist Aref Rifai, MD, has about 10 to 12 surgeons who make to Syria is savingfamiles.org. been concentrating his efforts near week-long rotations every two or three Even when the immediate crisis Aleppo in the country’s northern sec- months to supplement the efforts of is resolved, Dr. Rafai expects a long tion, and offers it as an example of the local Syrian ophthalmologists. process before the needs of the Syrian need: “Aleppo is a city of 2.5 million “A lot of the injuries are ruptured people are met. “The infrastructure people and used to have about 2,000 globes or patients who have shrapnel has taken a tremendous hit,” he says. physicians,” says Dr. Rifai. “Today, in their eyes that require surgery,” he “I’d estimate that 30 percent of the there are fewer than 100, and probably says. “On my last visit, I did 17 or 18 population is internally displaced; they fewer than 10 ophthalmologists cover- surgeries in four days, working around don’t have a home to go to.” ing the entire city.” the clock one day” on both routine and Dr. Rafai is a member of the Syr- injury-related retinal cases. Gene Variant Tied to AMD An international team of researchers, led by scientists at the Genome Institute at Washington University School of Medicine in St. Louis and the Uni- versity of Michigan School of Public Health in Ann Arbor, has identifi ed a gene mutation linked to age-related macular degeneration. It’s not the fi rst gene variation linked to AMD, but it is the fi rst to suggest a mechanism where the variant may contribute to the disease. The researchers report that a change in the C3 gene, Pensacola, Fla., retina specialist Aref Rifai providing eye-care services in his native Syria. which plays a role in infl ammation and His group is accepting donations of used ophthalmic equipment to equip hospitals there. in the body’s immune response, also

4 | Review of Ophthalmology | October 2013

004_rp1013_news.indd 4 9/20/13 2:09 PM contributes to macular degeneration. The study was published online Sept. 15 in Nature Genetics. “In past studies of AMD, there is a clear relationship between the Nasal & Temporal complement pathway and the onset of this disease,” said co-senior inves- Speculums

tigator Elaine R. Mardis, PhD. “The less ain , St um cul complement system is part of the im- pe st S Po le mune system that helps amplify or rip T n* w ‘complement’ the efforts of immune ro B : 4 6 1 cells to ﬁ ght infections. So the idea is 8 -0 8 0 ss that the gene variant interferes with le in ta S the complement pathway’s normal l, sa a N function throughout life, and that , m um lu i u an c can damage the retina over time, it e T p , S m t lu s which ultimately leads to AMD’s u o ec P p m S le u t p i s i n emergence.” o r T a P it e * T l p n , The researchers sequenced DNA ri l w a T o s * r a n B N - from 10 regions of the genome that w * , o * r t r m B u : e l n had been linked to AMD in previous 5 i u 0 e c 1 t e 7 S p - : S genetic studies. They analyzed a to- 5 S t 0 - s 4 o 6 P tal of 57 genes in 2,335 patients with 1 e 8 l 0 p - i macular degeneration. Then the re- 8 r T 0 *

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gene, and an alteration that had been 2 5

0 re identifi ed in previous studies of mac- gu Fi ular degeneration. “Finding the variant that had been Special Fenestrated Blades Improve identifi ed previously helped confi rm Exposure And Access that we were on the right track,” ex- To Superior Surgical Approaches By Supporting plained Dr. Mardis, a professor of & Elevating The Middle Of The genetics and co-director of the Ge- Lids As Seen In The Following:

nome Institute. “And it’s likely this Figure 1, Temporal Blades With Drape. new variant was discovered because of the very large number of patients Figure 2, Temporal Blades With Out Drape. whose DNA we sequenced. By analyzing so many AMD patients, it was Call 727-209-2244 For More Information. possible to ﬁ nd variants that may not have been identiﬁ ed in a smaller patient sample and to establish that this C3 gene variant is unique to people with AMD.” The two gene variants together contribute to a threefold increased

risk for macular degeneration. Dr. 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 s4EL s&AX Mardis and her co-investigators hy- %MAIL)NFO 2HEIN-EDICALCOMs7EBSITEWWW2HEIN-EDICALCOM pothesize that the mutations work $EVELOPED)N#OORDINATIONWITH2EAY("ROWN -$ $EVELOPED)N#OORDINATION7ITH2OGER&3TEINERT -$ ,EONARDO$A6INCI 5NNAMED

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004_rp1013_news.indd 5 9/20/13 2:09 PM REVIEW News

in tandem to increase AMD risk by Eastern Finland played a leading disease, body mass index and mea- interfering with the inactivation of role in the study, which also involved sures of frailty and comorbid disease. complement in the retina. research groups from Italy, Germany Follow-up visits took place fi ve and “When you have these mutations, and Hungary. 10 years after the baseline exam. interactions between the proteins AMD is a storage disease in which Previous research had indicated that cascade in the complement harmful protein accumulations de- that older persons with visual im- pathway are altered,” Mardis said. velop behind the retina. These ac- pairment were likely to have greater “And when they’re altered, the sec- cumulations are indicative of the se- mortality risk than their age peers ondary response to infection, which verity of the disease. As the disease with normal vision, and that cataract involves complement, also is altered. progresses, retinal sensory cells in surgery might reduce this risk. These So our hypothesis is that over time, the central vision area are damaged, studies, unlike the Blue Mountains because of the role of the comple- leading to loss of central vision. The Eye Study, compared people who ment pathway in the retina, damage cell biological mechanisms underly- had undergone cataract surgery with begins to accrue, and eventually that ing protein accumulations remain those in the general population or leads to vision loss.” largely unknown. with those who had not had cataract The next step is to look at addi- This is the fi rst time that impaired surgery, and did not link vision status tional DNA regions in the more than lysosomal autophagy, which renders to the surgical status. 2,000 patients and controls who were the cells in the fundus unable to dis- “Our fi nding complements the involved in this study. The research- pose of old, deformed or otherwise previously documented associations ers will broaden their look across the faulty proteins, has been implicated between visual impairment and in- genome and go beyond the 10 DNA in AMD, the researchers say. Drugs creased mortality among older per- regions analyzed in this study. inhibiting the impairment of auto- sons,” said Jie Jin Wang, PhD, of the “We hope to identify new genes, phagy could possibly even stop the Westmead Millennium Institute and perhaps more genes in the comple- progression of AMD. one of lead researchers of the study. ment pathway, perhaps genes in “It suggests to ophthalmologists that other infl ammatory response path- correcting cataract patients’ visual ways, or in areas we wouldn’t have Cataract Surgery impairment in their daily practice re- anticipated fi nding any genes related sults in improved outcomes beyond to AMD,” she said. “We’re taking a Cuts Mortality Risk that of the eye and vision, and has im- wide look at the genome to see what People with cataract-related vision loss portant impacts on general health.” turns up.” who have had cataract surgery to The association between correc- improve their sight are living longer tion of cataract-related visual impair- than those with visual impairment ment and reduced mortality risk is who chose not to have the proce- not clearly understood, but plausible Impaired dure, according to an Australian co- factors may include improvements in hort study published in September’s physical and emotional well-being, Autophagy Ophthalmology. After comparing the optimism, greater confi dence associ- two groups, the researchers found a ated with independent living after vi- 40-percent lower long-term mortal- sion improvement, as well as greater Tied to AMD ity risk in those who had the surgery. ability to comply with prescription A new study published in the PLoS The research data was gathered in medications. One journal challenges conventional the Blue Mountains Eye Study. A to- One limitation of the study is that wisdom on the pathogenesis of age- tal of 354 persons aged 49 years and participants with cataract-related vi- related macular degeneration. The older and diagnosed with cataract- sual impairment who did not have researchers found that degenerative related vision impairment – some of cataract surgery could have had oth- changes and loss of vision are caused whom had undergone surgery and er health problems that prevented by impaired function of the lysosom- others who had not – were assessed them from undergoing surgery, and al cleanup mechanism, or autophagy, between 1992 and 2007. Adjust- that these other health problems in the fundus. The results open new ments were made for age and gen- could partly explain the poorer sur- avenues for the treatment of dry der as well as a number of mortality vival among non-surgical partici- AMD, which currently lacks an ef- risk factors, including hypertension, pants. This issue is addressed by the fi cient treatment. The University of diabetes, smoking, cardiovascular researchers in a subsequent study.

6 | Review of Ophthalmology | October 2013

004_rp1013_news.indd 6 9/20/13 2:09 PM RP0413_Tearlab.indd 1 3/11/13 10:04 AM REVIEW News

First Animal half develop eye complications, ac- Though researchers have previ- cording to the study’s lead author, J. ously developed animal models of Model to Simulate Paul Banga, PhD, of King’s College Graves’ disease, these were challeng- London School of Medicine in the ing to replicate and none were able Graves’ Disease United Kingdom. These complica- to simulate the eye problems seen in Researchers have developed the fi rst ani- tions include Graves’ orbitopathy, people with Graves’ disease. mal model simulating the eye com- where swelling of tissue behind the To develop the new model, re- plications associated with the thyroid eyes causes them to bulge outward. searchers injected mice with small, condition Graves’ disease, a break- The condition can cause pain and circular, double-stranded DNA through that could pave the way for lead to blindness. molecules called plasmids. Over the better treatments, according to a re- “Current treatment options for course of three months, scientists cent study accepted for publication eye complications associated with used electronic pulses to ensure the in the Endocrine Society’s journal Graves’ disease are limited,” Dr. DNA molecules were absorbed into Endocrinology. Banga said. “Better treatments are the cells of each mouse. Mice that Graves’ disease is an autoimmune needed for Graves’ orbitopathy to underwent this procedure developed disorder that causes the body to pro- reduce the risks of permanent disfi g- eye problems like those seen in hu- duce antibodies that attack the thy- urement and social stigma. Having man patients who have Graves’ dis- roid gland. The condition causes the an animal model to test preventative ease, while the control group of mice thyroid gland to become overactive treatments could lead to important did not develop these complications. and produce too much thyroid hor- advances that will ultimately benefi t “The new animal model opens the mone. About 1 percent of Caucasian people with Graves’ disease.” door for scientists to conduct needed women have autoimmune thyroid The condition is currently treated mechanistic studies and identify pre- disease where the thyroid is either with steroids, which can cause un- ventative therapies to minimize this over- or underactive. Among those desirable side effects such as weight painful and debilitating condition,” who have Graves’ disease, more than gain and osteoporosis. Dr. Banga said. Review

REVIEW Letters o the Editor: Feldstein describes a three-suture of reported cases. TI read “When Plastics Issues Com- technique,2 and indeed advancing the This possibility of postoperative plicate Cataract Surgery” (July 2013), dehisced retractor may stabilize the entropion that might need surgical and this article is certainly of interest, inferior tarsal border from rotating correction, reported by a number especially regarding both postopera- forward, thereby correcting the entro- of sources, should therefore be dis- tive ptosis, as well as lower lid prob- pion, just as advancing the thinned or cussed with the prospective cataract lems that may follow an otherwise un- disinserted levator aponeurosis may patient along with discussion of the complicated cataract procedure. solve postoperative ptosis—since they other conditions thoroughly noted Entropion following a cataract pro- are analagous structures. in your article. Preoperative ﬁ ndings cedure has also been reported1 and, Involutional entropion has several of horizontal lower lid laxity, another although infrequent, it should be dis- contributing causes,3 one of which is predisposing cause for entropion, cussed as a possible postoperative oc- dis-insertion of the capsulopapebral might make this discussion a priority currence which might require surgical fascia from the inferior tarsal bor- even in an individual with good lower correction. der followed by pre-septal orbicu- lid position. In many ways, postoperative en- laris moving upward to override the Stuart M. Terman, MD tropion is analogous to the more pre-tarsal orbicularis,4 resulting in Solon, Ohio 44139 commonly developing postoperative entropion. Although usually not as- 1 1. Levine MR, Enlow MK, Terman SM. Spastic Entropion After ptosis, and advancement or re-attach- sociated with any inciting ocular ir- Cataract Surgery Ann Ophthalmology 1992:24:195-198. ment of the capsulopalpebral fascia to ritation, cataract surgery has indeed 2. Feldstein M. A method of surgical correction of entropion in aged persons. Ear Nose Throat J 1960:39:730-731. repair this is analogous to repair of the been reported to directly precede, 3. Levine MR. Involutional entropion. Geriatric Ophthamology dis-inserted or thinning of the levator and likely to have contributed, to the 1986:1:14-21. 4. Jones CT. The anatomy of the lower eyelid and the cause and aponeurosis for upper lid repair. postoperative entropion in a number cure of entropion. Am J Ophthalmol 1960:49:29-36.

8 | Review of Ophthalmology | October 2013

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Untitled-2 1 9/17/13 3:50 PM Editorial

REVIEW Board

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004_rp1013_news.indd 10 9/20/13 2:10 PM RETINA ONLINE E-NEWSLETTER

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RP1013_Accutome.indd 1 9/20/13 10:12 AM October 2013 • Volume XX No. 10 | revophth.com Cover Focus 28 | Dry-Eye Diagnosis: 21st-Century Tools By Christopher Kent, Senior Editor As technology advances, our ability to uncover and monitor dry eye continues to improve.

42 | Can Treating Dry Eye Boost Your Bottom Line? By Michelle Stephenson, Contributing Editor New technologies and the proper approach may tip the balance between the extra chair time required and additional profits.

Feature Article 48 | Meeting the Challenge Of Fungal Keratitis By Walter Bethke, Managing Editor Cornea experts provide tips and techniques for dealing with these difficult infections.

October 2013 | Revophth.com | 13

013_rp1013_toc.indd 13 9/20/13 4:08 PM Departments

22 4 | Review News

17 | Editor’s Page 18 | Medicare Q&A Floaters Pose Reimbursement Challenge

22 | Technology Update Better Outcomes Follow Tech Advances Three separate efforts aim to improve patient care by helping doctors understand their data.

56 | Retinal Insider Gene Therapy for Retinal Diseases The eye represents a unique target organ for 73 gene therapy. A look at some of the current avenues of research.

62 | Therapeutic Topics Modern Wisdom: Clinical Models in Drug Discovery Disease models can yield useful information on ailments and potential treatments.

66 | Glaucoma Management A Forgotten Piece in the Compliance Puzzle Getting your glaucoma patients to come in as recommended may be just as important as proper medication use. 79 73 | Refractive Surgery The Dos and Don’ts of Phakic IOLs These lenses can give excellent results in selected patients, but there’s both an art and a science to their implantation.

76 | Classified Ads

79 | Wills Eye Resident Case Series

82 | Advertising Index

14 | Review of Ophthalmology | October 2013

013_rp1013_toc.indd 14 9/20/13 4:08 PM Proof positive for more eyes

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References: 1. Bacitracin Ophthalmic Ointment [Package Insert]. Locust Valley, NY; Fera Pharmaceuticals, LLC;2009. 2. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing antibiotic susceptibility. Ophthalmol Clin N Am 2003;16:1-9. 3. Freidlin J, Acharya N, Lietman TM, Cevallos V, Whitcher JP, Margolis TP. Spectrum of eye disease caused by methicillin-resistant Staphylococcus aureus. Am J Ophthalmol 2007;144:313-315. 4. Recchia FM, Busbee BG, Pearlman RB, Carvalho-Recchia CA, Ho AC. Changing trends in the microbiologic aspects of postcataract endophthalmitis. Arch Ophthalmol 2005;123:341-346. 5. http://fingertipformulary.com/drugs/Bacitracinopthalmicointment/ ©2012 Fera Pharmaceuticals, LLC Printed in USA FAB-001 02/12

RP0312_Fera.indd 1 2/15/12 1:52 PM BACITRACIN OPHTHALMIC OINTMENT USP STERILE

EVERY MONDAY DESCRIPTION: Each gram of ointment contains 500 units of Bacitracin in a low melting special base containing White Petrolatum and Mineral Oil.

ACTION: The antibiotic, Bacitracin, exerts a pro- found action against many gram-positive pathogens, including the common Streptococci and Staphylococci. It is also destructive for certain gram- Have you been negative organisms. It is ineffective against fungi. receiving and INDICATIONS: For the treatment of superficial ocular infections involving the conjunctiva and/or reading custom e-blasts from cornea caused by Bacitracin susceptible organisms. Review of Ophthalmology? CONTRAINDICATIONS: This product should not be If not, you’re missing out on used in patients with a history of hypersensitivity valuable information! to Bacitracin. You’re a busy practitioner and not surprisingly, your e-mail PRECAUTIONS: Bacitracin ophthalmic ointment inbox is often full. Fortunately, when you scan through the should not be used in deep-seated ocular infec- sender list, determining which messages to delete and tions or in those that are likely to become systemic. which to save or read, you can feel conﬁ dent knowing that The prolonged use of antibiotic containing prepa- e-blasts from Review of Ophthalmology, a Jobson Medi- cal Information, LLC publication, contain the most current rations may result in overgrowth of nonsuscep- and comprehensive information available in the ﬁ eld to tible organisms particularly fungi. If new infections keep you on the cutting edge. develop during treatment appropriate antibiotic or chemotherapy should be instituted. Review of Ophthalmology’s online stable of products includes editorial newsletters and promotional information ADVERSE REACTIONS: Bacitracin has such a low about new products, treatments and surgical techniques, incidence of allergenicity that for all practical pur- as well as alerts on continuing education courses for poses side reactions are practically non-existent. ophthalmologists. However, if such reaction should occur, therapy • Our FREE weekly e-newsletter, Review of Ophthalmolo- should be discontinued. gy Online, brings you the latest in ophthalmic research, as well as industry news. In an effort to keep eyecare DOSAGE AND ADMINISTRATION: The ointment professionals informed, this resource is waiting in your should be applied directly into the conjunctival sac inbox every Monday morning. 1 to 3 times daily. In blepharitis all scales and crusts • Retina Online, our free monthly e-newsletter, is for should be carefully removed and the ointment retina specialists and general ophthalmologists inter- then spread uniformly over the lid margins. Patients ested in enhancing their knowledge on the topics of should be instructed to take appropriate measures retina and related disease diagnosis and treatment, as to avoid gross contamination of the ointment when well as the latest in surgical procedures. applying the ointment directly to the infected eye. Your time is valuable — and so is your practice. These HOW SUPPLIED: 3.5 g (1/8 Oz) sterile tamper e-products are the most effective way for you to receive updates on breaking news and research — all just a click proof tubes, NDC 48102-007-35. away. Don’t miss out!

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016_ro1013_houseads.indd 16 9/20/13 11:47 AM ® Editor’s Page Christopher Glenn, Editor in Chief REVIEW E DITORIAL S TAFF

Editor in Chief Christopher Glenn (610) 492-1008 [email protected]

Managing Editor Convincing Your Walter C. Bethke (610) 492-1024 [email protected] Partner to Participate Senior Editor Christopher Kent (814) 861-5559 The word partnership has long been on their medical care. Certainly, [email protected] used to describe the relationship be- they’re not targeting the chronically tween physician and patient. In many ill such as glaucoma or diabetes pa- Associate Editor cases, it’s a stretch. The best-laid tients. And if you had to today fi nd Kelly Hills (610) 492-1025 treatment plans rely on both partners 5 percent of your patient base that is [email protected] performing as agreed and, in the real eagerly involved in their care to this world, it just doesn’t go as planned. degree (to be clear—you don’t) most Chief Medical Editor It’s been estimated in diabetes care, doctors could. Mark H. Blecher, MD for example, that less than 60 percent But the concept of an incentive to of patients take 80 percent or more of drive this kind of patient engagement Senior Director, Art/Production their prescribed medications. is established. There is, likewise, con- Joe Morris (610) 492-1027 In glaucoma, even patients who re- sideration of providing not just pro- [email protected] member to take their drops may be viders but patients with fi nancial and splashing more of them down their other incentives in order to motivate Art Director cheeks than reach their target. Given healthy behaviors and improve their Jared Araujo the multitude of issues that can derail performance as medical “partners.” (610) 492-1023 medical management of glaucoma, In the Deloitte 2013 Survey of [email protected] it’s not surprising that much of the U.S. Physicians, participants were Graphic Designer research and literature on compli- asked for their perceptions about the Matt Egger ance has focused on drug delivery types of incentives that might work (610) 492-1029 mechanisms, patient education, re- best with consumers. “A majority of [email protected] duced dosing, and other factors out- physicians (71 percent) believe that if side of the clinic. This month, our consumer incentives were widely in- International coordinator, Japan Glaucoma Management department troduced, fi nancial ones (e.g., direct Mitz Kaminuma (p. 66) looks at a less widely discussed payments, reduced insurance premi- [email protected] area of compliance—keeping follow- ums or reduced co-pays) might work Business Offi ces up visits. It’s an interesting take on an best with consumers in an attempt to 11 Campus Boulevard, Suite 100 issue that can greatly affect outcomes motivate them to engage in healthy Newtown Square, PA 19073 even in patients who follow their behaviors,” the authors report. An (610) 492-1000 drug regimen. equal number agree that “consumer Fax: (610) 492-1039 One the key tenets of the new Af- incentives could be very helpful to Subscription inquiries: fordable Care Act is taking physi- achieve better treatment compli- United States — (877) 529-1746 cian/patient partnership into some ance.” Outside U.S. — (847) 763-9630 uncharted territory. In an effort to The search for an engaged partner E-mail: increase patient engagement in their goes on. [email protected] own care, meaningful use incentives Website: www.revophth.com are being offered to hospitals as well as certain eligible providers who can Professional Publications Group demonstrate that 5 percent of their Jobson Medical Information LLC patients are using their patient portal or EHR system to send secure electronic messages and enter data

October 2013 | Revophth.com | 17

017_rp1013_edit.indd 17 9/23/13 2:02 PM 018_rp1013_mqa.indd 18 fl A A treating withtreating lasers? laser vs. treatment support not to record medical patient’s the successful? fl vitreous of treatment Isintervention? laser fl Q Q do, knowingtheappropriateCPTcodesisanecessity. Most vitreousfl oaters donotrequiretreatment,butforthosethat Floaters Lasering With Issues Reimbursement 18 Q some successwiththistreatment. tween 2002and2005,describing ist, datingbacktobe- number ofarticlesex- be successful. Asmall ment mayornot and nottherule.Treat- theexceptionproach is ability tofunction.Thisap- compromising thepatient’s signifi oaters requirenotreatment. oaters treated? REVIEW | ReviewofOphthalmology Donna McCune, CCS-P, COE Medicare Q&A have meritwhenafloater is Yes. Surgicaltreatmentmay reassurance, asmost Most patientsaretreatedwith documented factors in specifi there Are treated with surgical Are fl vitreous with suffer who patients most are How vision and cant, limiting oaters everoaters c oaters oaters | October2013 odsol indicatethatthere is a should cord A

cal procedures, themedicalre- cal procedures, As withmanyophthalmicsurgi- severe handicap, the patient’s activities ofdaily living arese- physician riously hin- and pa- and the dered by the float- tient have over time ers, the deter- solved patient mined not re- has had that symp- have toms that the This articlehasnocommercial sponsorship. the risk. benefi before treatment. ered. It’s besttoconfirmcoverage mental” andthereforeitisnotcov- treatment “investigationalandexperi- treatment. Somepayersconsiderthe A A vitreous fl Q Q so youwoulduseCPT67299 instead. severed, CPT67031doesnot apply, ized bytheYAG laser, rather than line ofsight.Whenafl oater isvapor- bottom ofthevitreousandout tachment, allowingittosinkthe opaque fl fromitsat- oater issevered CPT 67031whenavisuallysignifi apply tolaseringvitreousfl oaters. Use procedure, posteriorsegment or morestages)and67299( branes oropacities,laser surgery, one vitreous faceadhesions,sheets,mem- ( Yes, actually. CPTcode67031 coverage policiesexistonthis Maybe. Unfortunately, veryfew describing this treatment? codes CPT any there Are for treatment laser cover payers Will third-party ts oflasertreatmentoutweigh Severing ofvitreousstrands, oaters? Unlisted ) both cant cant 9/20/13 11:49 AM RP0113_Allergan Lumigan.indd 1 12/10/12 1:43 PM ® USE IN SPECIFIC POPULATIONS LUMIGAN 0.01% AND 0.03% Pregnancy: Pregnancy Category C Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and (bimatoprost ophthalmic solution) rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood Brief Summary—Please see the LUMIGAN® 0.01% and 0.03% package AUC levels. insert for full Prescribing Information. At doses at least 41 times the maximum intended human exposure based on blood INDICATIONS AND USAGE AUC levels, the gestation length was reduced in the dams, the incidence of dead LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) is indicated for the fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup reduction of elevated intraocular pressure in patients with open angle glaucoma or body weights were reduced. ocular hypertension. There are no adequate and well-controlled studies of LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) administration in pregnant women. Because CONTRAINDICATIONS animal reproductive studies are not always predictive of human response LUMIGAN® None should be administered during pregnancy only if the potential benefit justifies the WARNINGS AND PRECAUTIONS potential risk to the fetus. Pigmentation: Bimatoprost ophthalmic solution has been reported to cause changes Nursing Mothers: It is not known whether LUMIGAN® 0.01% and 0.03% is excreted to pigmented tissues. The most frequently reported changes have been increased in human milk, although in animal studies, bimatoprost has been shown to be pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is excreted in breast milk. Because many drugs are excreted in human milk, caution expected to increase as long as bimatoprost is administered. The pigmentation should be exercised when LUMIGAN® is administered to a nursing woman. change is due to increased melanin content in the melanocytes rather than to Pediatric Use: Use in pediatric patients below the age of 16 years is not an increase in the number of melanocytes. After discontinuation of bimatoprost, recommended because of potential safety concerns related to increased pigmen- pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tation following long-term chronic use. tissue and eyelash changes have been reported to be reversible in some patients. Geriatric Use: No overall clinical differences in safety or effectiveness have been Patients who receive treatment should be informed of the possibility of increased observed between elderly and other adult patients. pigmentation. The long term effects of increased pigmentation are not known. Hepatic Impairment: In patients with a history of liver disease or abnormal ALT, Iris color change may not be noticeable for several months to years. Typically, the AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver brown pigmentation around the pupil spreads concentrically towards the periphery function over 48 months. of the iris and the entire iris or parts of the iris become more brownish. Neither nevi OVERDOSAGE nor freckles of the iris appear to be affected by treatment. While treatment with ® LUMIGAN® 0.01% and 0.03% (bimatoprost ophthalmic solution) can be continued in No information is available on overdosage in humans. If overdose with LUMIGAN patients who develop noticeably increased iris pigmentation, these patients should 0.01% and 0.03% (bimatoprost ophthalmic solution) occurs, treatment should be examined regularly. be symptomatic. Eyelash Changes: LUMIGAN® 0.01% and 0.03% may gradually change eyelashes In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not and vellus hair in the treated eye. These changes include increased length, thickness, produce any toxicity. This dose expressed as mg/m2 is at least 70 times higher ® and number of lashes. Eyelash changes are usually reversible upon discontinuation than the accidental dose of one bottle of LUMIGAN 0.03% for a 10 kg child. of treatment. NONCLINICAL TOXICOLOGY Intraocular Inflammation: LUMIGAN® 0.01% and 0.03% should be used with Carcinogenesis, Mutagenesis, Impairment of Fertility: Bimatoprost was not caution in patients with active intraocular inflammation (e.g., uveitis) because the carcinogenic in either mice or rats when administered by oral gavage at doses inflammation may be exacerbated. of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times Macular Edema: Macular edema, including cystoid macular edema, has been the recommended human exposure based on blood AUC levels respectively) for reported during treatment with bimatoprost ophthalmic solution. LUMIGAN® 0.01% 104 weeks. and 0.03% should be used with caution in aphakic patients, in pseudophakic Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse patients with a torn posterior lens capsule, or in patients with known risk factors for lymphoma test, or in the in vivo mouse micronucleus tests. macular edema. Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day Angle-closure, Inflammatory, or Neovascular Glaucoma: LUMIGAN® 0.01% and (at least 103 times the recommended human exposure based on blood AUC levels). 0.03% has not been evaluated for the treatment of angle-closure, inflammatory or PATIENT COUNSELING INFORMATION neovascular glaucoma. Potential for Pigmentation: Patients should be advised about the potential for Bacterial Keratitis: There have been reports of bacterial keratitis associated with increased brown pigmentation of the iris, which may be permanent. Patients the use of multiple-dose containers of topical ophthalmic products. These containers should also be informed about the possibility of eyelid skin darkening, which may had been inadvertently contaminated by patients who, in most cases, had a be reversible after discontinuation of LUMIGAN® 0.01% and 0.03% (bimatoprost concurrent corneal disease or a disruption of the ocular epithelial surface. ophthalmic solution). Use With Contact Lenses: Contact lenses should be removed prior to instillation ® Potential for Eyelash Changes: Patients should also be informed of the possibility of LUMIGAN 0.01% and 0.03% and may be reinserted 15 minutes following of eyelash and vellus hair changes in the treated eye during treatment with its administration. LUMIGAN® 0.01% and 0.03%. These changes may result in a disparity between ADVERSE REACTIONS eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs, Clinical Studies Experience: Because clinical studies are conducted under widely and/or direction of eyelash growth. Eyelash changes are usually reversible upon varying conditions, adverse reaction rates observed in the clinical studies of a drug discontinuation of treatment. cannot be directly compared to rates in the clinical studies of another drug and may Handling the Container: Patients should be instructed to avoid allowing the tip of not reflect the rates observed in practice. the dispensing container to contact the eye, surrounding structures, fingers, or any In clinical studies with bimatoprost ophthalmic solutions (0.01% or 0.03%) the other surface in order to avoid contamination of the solution by common bacteria most common adverse reaction was conjunctival hyperemia (range 25%–45%). known to cause ocular infections. Serious damage to the eye and subsequent loss of Approximately 0.5% to 3% of patients discontinued therapy due to conjunctival vision may result from using contaminated solutions. hyperemia with 0.01% or 0.03% bimatoprost ophthalmic solutions. Other common When to Seek Physician Advice: Patients should also be advised that if they reactions (>10%) included growth of eyelashes, and ocular pruritus. develop an intercurrent ocular condition (e.g., trauma or infection), have ocular Additional ocular adverse reactions (reported in 1 to 10% of patients) with surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid bimatoprost ophthalmic solutions included ocular dryness, visual disturbance, reactions, they should immediately seek their physician’s advice concerning the ocular burning, foreign body sensation, eye pain, pigmentation of the periocular continued use of LUMIGAN® 0.01% and 0.03%. skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, Use with Contact Lenses: Patients should be advised that LUMIGAN® 0.01% and ocular irritation, eyelash darkening, eye discharge, tearing, photophobia, allergic 0.03% contains benzalkonium chloride, which may be absorbed by soft contact conjunctivitis, asthenopia, increases in iris pigmentation, conjunctival edema, lenses. Contact lenses should be removed prior to instillation of LUMIGAN® and may conjunctival hemorrhage, and abnormal hair growth. Intraocular inflammation, be reinserted 15 minutes following its administration. reported as iritis, was reported in less than 1% of patients. Use with Other Ophthalmic Drugs: Patients should be advised that if more than one Systemic adverse reactions reported in approximately 10% of patients with topical ophthalmic drug is being used, the drugs should be administered at least five bimatoprost ophthalmic solutions were infections (primarily colds and upper (5) minutes between applications. respiratory tract infections). Other systemic adverse reactions (reported in 1 to 5% of patients) included headaches, abnormal liver function tests, and asthenia. © 2012 Allergan, Inc., Irvine, CA 92612 Postmarketing Experience: The following reactions have been identified during ® ® marks owned by Allergan, Inc postmarketing use of LUMIGAN 0.01% and 0.03% in clinical practice. Because they Patented. See: www.allergan.com/products/patent_notices are reported voluntarily from a population of unknown size, estimates of frequency Made in the U.S.A. cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to LUMIGAN®, or APC70EN12 based on 71807US13. Rx only a combination of these factors, include: dizziness, eyelid edema, hypertension, nausea, and periorbital and lid changes associated with a deepening of the eyelid sulcus.

RP0113_Allergan Lumigan PI.indd 1 12/10/12 1:37 PM Medicare

REVIEW Q&A

How frequently are Can we expect similar • Within Medicare, unlisted codes Q these codes utilized? Q reimbursement rates from are ineligible for ASC facility fee re- Will the frequent use of these other third-party payers? imbursement; codes attract attention from • Each claim stands alone; reim- Medicare? Possibly. In all cases, other third- bursement for one case does not set A party payers set their own rates, precedent for the next. These codes are rarely used. which may vary considerably from A Medicare data from 2011, the Medicare. If coverage and most recent year available, indicates Q reimbursement rates are CPT 67031 was reimbursed 3,014 uncertain, should we consider times; this number is actually lower pre-authorization with third- than it has been in prior years. The Physicians who party payers? unlisted CPT code 67299 was reim- perform this procedure bursed 522 times in 2011, but remem- If a payer permits pre-authori- ber that it applies to other procedures may attract unwanted A zation, you should always secure as well as lasering vitreous fl oaters. attention from it in writing. They may or may not be It is worth noting that physicians willing to reveal reimbursement rates who perform this procedure may Medicare; they will be but you can ask. Unfortunately, Medi- attract unwanted attention from considered outliers and care will not preauthorize. Medicare and other payers because they will be considered outliers and thus subject to extra If the patient has thus subject to extra scrutiny. scrutiny. Q Medicare, how can we indemnify ourselves when What is the Medicare coverage is uncertain? Q reimbursement rate for the procedure coded with 67031? Is there a postop period You can ask the patient to sign Is the physician reimbursed Q with CPT code 67031? A an Advance Benefi ciary Notice differently if the laser is of Noncoverage prior to treatment. performed in an ambulatory Yes. This laser is considered a By signing an ABN, the Medicare surgery center or hospital A major procedure and carries a beneficiary acknowledges that he 90-day global period. All other rules has been advised that Medicare outpatient department? associated with major procedures ap- will probably–or certainly–not The national Medicare Physician ply. pay. The beneficiary also agrees to A Fee Schedule amount in 2013 be responsible for payment, either for CPT 67031 is $401.81 if the pro- Are there challenges personally or through another cedure is performed in the offi ce. If Q associated with the insurance, including Medicaid. the procedure is performed in an ASC unlisted code 67299 if that or HOPD, the physician will incur a code applies? If the patient has a site of service reduction. The 2013 Q commercial insurance, national Medicare reimbursement Numerous challenges do exist can we utilize an ABN in case rate for 67031 with the SOS reduction A with all unlisted codes, including insurance denies the claim? is $368.81. 67299: • There is no stipulated reimburse- Yes. You can develop a fi nancial Is there facility ment schedule for physicians; A waiver form similar to Medicare’s Q reimbursement for an ASC • Claims are evaluated and an ap- ABN. This waiver informs the patient or HOPD in CPT code 67031? propriate payment rate is selected on of potential financial liability and a case-by-case basis; secures an agreement to pay for the Yes. The national Medicare • There is no published global pe- service in the event of a denial. A HOPD reimbursement is riod; $410.79 in 2013. For ASCs, the 2013 • HOPD reimbursement for CPT Ms. McCune is vice pres ident of the national Medicare allowed amount is code 67299 is the same as for a YAG Cor coran Con sult ing Group. Con tact $230.51. capsulotomy ($410.79); her at [email protected].

October 2013 | Revophth.com | 21

018_rp1013_mqa.indd 21 9/20/13 11:49 AM Technology Update

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

Better Outcomes Through Technology A computer with an Internet connection can give you access to powerful tools for learning more about your results. Walter Bethke, Managing Editor

xchanging data instantly via the an invite- and inquiry-based log-in sys- One of the fi rst things the surgeon EInternet has revolutionized social tem. You create a free account and log can do on the site is track his surgically networking and retail business, and in with your name. Second, we wanted induced astigmatism. To do this, he it didn’t take long for medicine to a free way to properly track cataract inputs all the variables he’d need for feel the effects. With the touch of a outcomes. SIA calculation, focusing on the astig- button, you can track your cataract “Initially the site allowed you to re- matism amount, preexisting keratom- outcomes, get a better understand- cord what your surgery’s target was, etry and the location of the incision. ing of the effects of your anti-VEGF what lens you put in and then your Next, the physician can delve into the injections and compare your glau- actual result,” Dr. Kumar continues. intraocular lens calculation formulas coma treatment results with ophthal- “However, we decided that we could to help choose a lens. mologists around the country. Here do a lot with preop planning as well, “If you go to the New Preop sec- are three new Internet-server-based using surgeons’ outcome data to plan tion, used for planning the next case, technologies—two of them free—that future surgeries. So, by using your ac- you fi rst determine an identifi er you may be able to help you maximize tual postop outcomes data, the site want to use for the case,” explains Dr. your results. calculates everything for your future Kumar. “Then you do the data input cataract surgeries. Also, all this infor- you’d need for the IOL calculation Threeplus.org mation is backed up on a server, so and determining SIA, which is basi- there’s no worry over losing your data.” cally the K readings, the axial length The free website Threeplus.org was and the axis of astigmatism, all derived created by Aaron Lee, MD, and Gokul from whatever source you want. All Kumar, MD, as they completed their the other data points you can enter are ophthalmology residency at Washing- optional. ton University in St. Louis. The site MD Gokul Kumar, “Step three involves picking your offers several options for outcomes blade,” Dr. Kumar continues. “So, tracking and surgical planning. people can add custom blades and “It’s a combination of several see what SIAs result from their use things,” explains Dr. Kumar, currently of them. We also have default values, chief resident at Washington Uni- The free website Threeplus.org allows you such as -0.5 D SIA for a 2.75-mm versity. “First, we wanted to create a to virtually rotate your incision location to blade, which is what the Alcon IOL professional networking site just for different meridians until you fi nd the one Calculator uses. Or you can have your professional ophthalmologists on both that results in the least induced cylinder. actual data calculated, and the site

22 | Review of Ophthalmology | October 2013 This article has no commercial sponsorship.

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RP1013_Advanced Vision TT.indd 1 9/16/13 11:00 AM Technology

REVIEW Update

will allow you to pick your blade size, world. “The problem is that random- incorporating your own data, or you ized clinical trials are done on a very can enter a custom blade. In the next homogeneous subset of people, but step you pick where to put the inci- once a treatment is approved by the

sion. On our site, you ‘hold’ the inci- PhD Christine Curcio, FDA it’s then used on people who are sion virtually on the screen and move very different from those who were it around the cornea. As you do this, in the clinical trials,” Dr. Rich says. the system tells you what your antici- “So, with a registry such as this, we pated residual astigmatism would be. will be able to fi nd out which one of It also tells you what your anticipated Project MACULA provides high-res these drugs, devices or procedures is residual cylinder would be for all the histology images of multiple retinal layers. actually effective for large populations current toric lenses.” Here, histology revealed the presence of a and for subgroups of populations.” He The next three steps involve lens subretinal drusenoid deposit. adds that this type of tracking will be calculations. “Pick whatever lens you valuable as Medicare metrics change want to go with, and on the back end track outcomes with an eye toward im- in the future. “Now, we get paid on we have all three major third-genera- proving them, provide opportunities how we treat the patient in front of us,” tion formulas—the Hoffer Q, Holla- for new research and help practices he says. “But, starting in 2015, you’ll day I and SRK-T—and our site calcu- comply with new electronic reporting get paid for how you treat the whole lates your lenses and their anticipated standards mandated by the govern- patient population. For instance, you residual sphere outcome,” explains ment. can pull out all the diabetics under Dr. Kumar. “It does this for all the data The key element of the registry your care and see how they do, as well that you’ve entered, so it shows you is a program called the Systems In- as how they compare to other diabet- your personalized outcome estimates tegrator, created by software maker ics in other practice populations in the as well as what the ULIB [User Group FigMD. “The Systems Integrator soft- United States.” for Laser Interference Biometry] esti- ware sits on top of the practice’s EHR IRIS also allows users to slice and mates would be.” program and draws out the data as dice their data in different ways to look Membership on the site is by invita- it’s entered,” explains Dr. Rich. “For for trends. “You can see how many tion, but surgeons can get an invita- instance, it enters the outcomes from glaucoma patients are on generic vs. tion by e-mailing support@threeplus. cataract patients and loads them into non-generics and if there’s a differ- org and providing details about their the registry without affecting the prac- ence in safety or efficacy between ophthalmology training, contact infor- tice’s workfl ow.” If a practice doesn’t generic and non-generic drugs,” Dr. mation and current professional email have an EHR program, it can enter Rich explains. address. Though the site will continu- the data via an on-line portal, though “Floppy-iris syndrome, for instance, ously add new lenses and other fea- Dr. Rich acknowledges this route took us almost a decade to discover,” tures to stay current, Dr. Kumar says would be more time-consuming. Dr. Rich continues. “David Chang it will remain easy on the wallet: “It’s Dr. Rich says the IRIS Registry will discovered he was having more com- a free site and we intend on keeping it enable practices to do some things plications, and had a fellow look at free,” he says. their EHR systems do not. “The EHR the records of the patients he had a doesn’t help you measure the qual- complication with, and they found that AAO’s IRIS Registry ity of your outcomes,” he says. “For these patients were 95 percent male. example, the registry will take every They then looked at their medica- Capitalizing on a trend in other user’s input for a glaucoma patient or tion history and made the connection. medical specialties in which physi- a cataract surgery case and, within 48 With the IRIS Registry, you’d just cians constantly update a registry with hours of completing the treatment, have to push a button and ask: How their latest outcomes from surgery the physicians will be able to com- many broken capsules are there, and and other interventions, the American pare their results with anyone in their is there any race, sex or use of meds Academy of Ophthalmology is roll- group, their region, or with a national in which this complication is greater? ing out a database of its own: the In- database. That aggregated data is in- You could figure this out in a week telligent Research In Sight Registry. credibly powerful.” rather than in 10 years.” William Rich III, MD, the Academy’s Dr. Rich says tracking outcomes in a The AAO plans to roll out the IRIS medical director of health policy, says registry will allow physicians to gauge Registry offi cially at the 2013 national the system will, among other things, a therapy’s effectiveness in the real meeting. The cost to be enrolled will

24 | Review of Ophthalmology | October 2013

022_rp1013_tech update.indd 24 9/20/13 11:51 AM Optimize Care, Enhance Your Practice Improve Lipid Secretions, Increase Comfort, Satisfy Patients

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RP1013_Tear Science.indd 1 9/12/13 3:22 PM ETL Approved

014_rp0913_Varitronics.indd 1 8/13/13 4:27 PM Technology

REVIEW Update

be $500 per year. However, Dr. Rich by Laminar Analysis. OCT image. Users can zoom in on the says that, during the initial roll-out Project MACULA is a website fund- features up close using the patented phase, the first 2,000 practices that ed by the National Eye Institute that GoogleMaps technology famous for enroll can use the registry free for two contains large, digitized sections of the detailed geographic mapping. years. To fi nd out more about the early macula taken from eye-bank speci- Dr. Curcio says the project even re- enrollment, e-mail irisregistry@aao. mens of wet and dry AMD, as well as vealed features never before seen: “I org. For more information about the from normal retinas. “It’s effectively went through each individual section registry, visit aao.org/iris-registry. online digital microscope views,” ex- of the specimens at defi ned locations,” plains Dr. Curcio. “The idea here is she says. “So they’ve been systemati- Project MACULA to aid ophthalmologists and eye-care cally, objectively surveyed. I crossed professionals in their interpretation of each layer with a vertical probe and For physicians who follow patients clinical imaging, such as OCT, by pro- noted what I saw. One of the big fi nd- with age-related macular degenera- viding histopathology. The images are ings was subretinal drusenoid deposits. tion, especially those who use ocular from specimens that I received from This feature had been seen clinically coherence tomography, it can be chal- Alabama Eye Bank; they’re short post- in patients but its histopathological lenging to match up the digital images mortem with a range of AMD pathol- correlate was uncertain before these to what’s actually going on in the ret- ogy.” The eyes, which will eventually images.” ina. To help make this interpretation number 140 and come with multiple Dr. Curcio says that the website easier, Christine Curcio, PhD, director images of different layers, also have (http://projectmacula.cis.uab.edu/) of the AMD Histopathology Lab at the 13,000 annotations that can inform should be done by late October 2013. University of Alabama, Birmingham, doctors about certain features of the “I hope clinicians fi nd information on helped create the free website Project AMD pathology and show where the how to better interpret their diagnostic MACULA, or MACulopathy Unveiled features are located in relation to the images from this site,” she says.

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022_rp1013_tech update.indd 27 9/20/13 11:51 AM 028_rp1013_f1.indd 28 Christopher Kent, SeniorEditor 28 21st-Century Tools Dry-Eye Diagnosis: REVIEW |

Review ofOphthalmology Cover Focus Cover disease continues ability touncover and monitorthe advances, our As technology to improve. | October2013 D to rely on the patient’sto relyonthe history, plus dry eye.“Overtheyearswe’ve had that there’s nogoldstandardtestfor Institute ofthePalmBeaches,agrees gery ServiceatBascomPalmerEye Refractive Sur-and directorofthe Breyer RodgersDistinguishedChair fessor ofophthalmology, Charlotte the patient’s status.” and testresultstogiveusanideaof a constellationofsignsandsymptoms diagnosing dryeye.We havetorelyon exam finding oreven symptomfor nately, thereisnogoldstandardtest, tion, orevaporativedryeye.Unfortu- eye; andmeibomianglanddysfunc- classically beenconsideredtobedry or aqueousdeficiency—whichhas categories: decreasedtearproduction, as fallingintotwosomewhatartiﬁ in Philadelphia.“Ithinkofdryeye Department attheWills EyeInstitute co-director oftheRefractiveSurgery director oftheCorneaServiceand MD, professorofophthalmology, ease,” saysChristopherJ.Rapuano, group togetherasocularsurfacedis- different conditionsthatIgenerally diagnose. “Dryeyeisanumberof lenge totreat—andachallenge multiple causeshavemadeitachal- Terrence P. O’Brien,MD,pro- by ophthalmologists,butits mon problemsencountered ry eyeisoneofthemostcom-

cial cial Dry Eye Dry This articlehasnocommercial sponsorship. testing thisonefactor. to howmuchcanbedetermined by widely used,thereappeartobelimits Osmolarity Test. Althoughthetestis tic toolstoappearwastheTearLab The FirstWave: TearLab are profiled below. pipeline. Eightofthemostpromising stillinthe States,andothers United ments—some alreadyavailableinthe of every-more-sophisticatedinstru- and theresultisanincreasingnumber searchers andcompaniesintoaction, agnostic toolshasspurredmanyre- disease.” objective diagnostictestsfordryeye cryingforbetter patients areliterally 72 percentspecifi city. Cliniciansand have about80percentsensitivityand though they’vebeenvalidated,only al- the disease;andquestionnaires, ily onlyhelpfullateinthecourseof specifi up timeismoresensitivebutlacks percent sensitivity;tear-film break- “The Schirmertesthaslessthan50 don’t matchtheclinicalsigns,”hesays. because thepatient’s symptomsoften tests tomakeadiagnosis—especially symptoms andacompositeofclinical “Changes inosmolarity and One ofthefi rst high-techdiagnos- The needfor betterdry-eyedi- city. Cornealstainingisprimar- 9/20/13 11:38 AM ™

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RP1111_FCI.indd 1 10/11/11 2:01 PM Cover Dry Eye

REVIEW Focus

infl ammation are cited in Terrence P. O’Brien, MD a little dry-eye evaluation the defi nition of dry eye form we ask them to fi ll out, from the 2007 Dry Eye to hopefully alert us to the Workshop report,” notes problem before anything Dr. O’Brien. “So measur- else happens. ing osmolarity should be “I think the TearLab is a helpful. The TearLab de- nice addition to our arma- vice, which does this reli- mentarium,” he concludes. ably, is easy to use, and “I don’t think it’s the end-all it’s been shown to have and be-all, but it’s helpful, analytical accuracy. How- especially when it gives a re- ever, in practice one of sult I’m not expecting. If I the challenges has been The TearLab device allows the clinician to monitor the osmolarity of think the patient has really reproducibility and in- the tear fi lm, a factor known to correlate with dry eye. bad dry eye but the tear os- terpretation. Compensa- molarity is low, then I look tory mechanisms often affect the eyes falsely low or high. The reliability im- back and consider other possibilities I transiently and asymmetrically, giv- proves with multiple readings, but that might not have been thinking about. If ing rise to variability so that we have gets to be costly. In my opinion, a sin- the osmolarity reading is unexpectedly to test both eyes; and tear instability gle measurement in the offi ce is valu- high, I know that dry eye may be more leads to evaporative tear loss, which able primarily if it’s abnormally high. of an issue than I initially thought. can change the osmolarity. As a result, If the test is normal but you think the That only happens on occasion, but the TearLab osmometer gives you an patient has dry eye, you’re probably that’s when I fi nd it most helpful.” accurate reading, but what the read- going to go ahead and treat the patient ing means at a given moment in the regardless of the TearLab result.” The RPS Infl ammaDry clinical course may be up for debate. Dr. Rapuano says his clinic has used “The severity of the condition also the TearLab machine for about six One of the newer dry eye diagnostic matters,” he continues. “Less severe months. “Osmolarity is a reasonable tools is the InflammaDry Detector eyes, which are often more challenging surrogate for dry eye,” he notes. “We from Rapid Pathogen Screening in to diagnose, have considerable vari- decided to try the TearLab because Sarasota, Fla., which detects levels of ability in osmolarity readings, so the it was the most mature of the newer matrix metalloprotease 9, or MMP-9, test is less useful. The device seems tests and seemed to have the most in a tear sample. MMP-9 is consid- to work pretty well for eyes that have potential. Generally, the results con- ered to be a reliable marker for the more severe dryness; in those cases, fi rm the impression we get from the presence of infl ammation, commonly it provides a baseline of severity and slit-lamp exam. It is useful to have a associated with dry eye. gives you a way to track the recovery somewhat objective number to look Dr. O’Brien says he’s excited about or normalization of the osmolarity in at; it gives us an idea of where patients the potential of using infl ammation as response to therapy. However, those are at this point in time.” a biomarker to aid in the diagnosis of usually aren’t the patients we debate Dr. Rapuano notes that a key part dry eye. “A number of infl ammatory about in terms of a diagnosis. So when of getting an accurate TearLab mea- markers have been identifi ed in tears,” diagnosing patients with less severe surement is taking the measurement he notes. “Lactoferrin, lysozyme, cy- disease, we’ve found the TearLab plat- before anything else has been done to tokines and other tear-film markers form to be most useful in combination the eye. “You can’t put drops in, ma- offer great potential, and having the with other tests, rather than by itself.” nipulate the eye or do an exam before ability to detect infl ammation can be “There’s no question that tear osmo- using TearLab,” he explains. “It has useful both for diagnosis and tracking larity goes up in dry eye, and there is to be done fi rst. That means you can’t response to therapy. So we’re excited a threshold,” agrees Stephen C. Pfl ug- examine a patient and say, ‘Oh, you about having a device that can reliably felder, MD, professor and director of have dry eye, now I’m going to do a and accurately detect levels of MMP-9 the Ocular Surface Center at Baylor TearLab on you.’ In that situation, we in the tear fi lm. College of Medicine’s Cullen Eye In- usually tell the patient that we’ll do the “Increased MMP-9 can contribute stitute in Houston. “The problem is TearLab test the next time he comes to a number of problems, including that the TearLab instrument is fairly in, before anyone has touched his eye. disruption of the corneal epithelial variable, so a single reading could be When new patients come in, we have barrier, decreased surface regularity

30 | Review of Ophthalmology | October 2013

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RP1013_Medflowehr.indd 1 9/19/13 9:40 AM Cover Dry Eye

REVIEW Focus

it’s a more sensitive diagnostic marker Another advantage of measuring than clinical signs, and it correlates MMP-9 is that it appears to indicate well with our exam fi ndings. The sen- a likelihood that certain treatments sitivity is 85 to 90 percent, with a spec- will be effective. “When MMP-9 is ifi city around 95 percent. That’s quite elevated above 40 µg/ml, patients will Terrence P. O’Brien, MD O’Brien, P. Terrence benefi cial. respond better to anti-infl ammatory “Our data suggests that people with- therapies, both corticosteroids and im- out dry eye or other ocular surface munomodulatory agents like cyclospo- disease have between 3 and 40 µg/ml rine, tacrolimus and others,” says Dr. of MMP-9 in their tears; above 40 µg/ O’Brien. “Knowing the osmolarity, in ml is elevated and abnormal,” he con- contrast, is less helpful in terms of di- tinues. “The readings correlate well recting your therapy or predicting pa- with the different levels of dry-eye tient response to specifi c treatments.” severity, based on the DEWS severity criteria. I think this is a good test, Monitoring Tear Film Instability especially since it demonstrates a good correlation in milder cases, which can “One key to diagnosing tear dysfunc- be problematic to detect with the os- tion or dry eye is instability of the tear molarity test.” fi lm,” notes Dr. Pfl ugfelder. “Instability Is MMP-9 the best choice of marker is pretty much found in all tear dys- to measure? “There are a variety of function problems—including meibo- The RPS Infl ammaDry Detector detects proteins altered in dry eye, but MMP- mian gland dysfunction, conjunctivo- levels of matrix metallo-protease 9, or 9 is one that’s consistently been shown chalasis, aqueous tear dysfunction and MMP-9, in a tear sample. MMP-9 is to be elevated with dry eye and nor- Sjögren’s syndrome—whether there’s considered to be a reliable marker for the mal in people without dry eye,” Dr. a low tear volume or not. One new de- presence of infl ammation, commonly O’Brien notes. “Clearly there are oth- vice that can help measure that factor associated with dry eye. er conditions in which MMP-9 can be is the Tear Stability Analysis System, or and increased cell turnover,” he ex- elevated, but those are obvious from TSAS, from Tomey. plains. “It really is a marker for dry the clinical presentation. Even though “The TSAS device was developed eye; studies have confi rmed that pa- it’s only one matrix metalloprotease, in Japan,” he continues. “As far as we tients who have ocular surface disease it’s a common one that’s been well- know, we’re the only center in the with dry eye have elevated levels of studied and shown to be abnormal in United States that has published a MMP-9 in the tears. In fact, I think these patients.” study using the device. It’s very useful. Tomey USA

Tomey’s Tear Stability Analysis System reﬂ ects rings off the surface of the tear ﬁ lm while taking a series of pictures, one per second. The instrument then calculates the number of areas of irregularity appearing over time and displays the results graphically. Physicians report that a more rapid climb in the irregularity score correlates with the severity of dry eye.

32 | Review of Ophthalmology | October 2013

028_rp1013_f1.indd 32 9/20/13 11:38 AM Tomey USA

The Tear Stability Analysis System.

Over a period of six seconds, it takes a series of images of rings reflected off the tear fi lm, one per second. The software then analyzes the images and calculates the number of what the company calls bright spots, which Parasol® are areas of irregularity. The higher the number of bright spots, the more unstable or irregular the tear fi lm is becoming. You can plot that out over A PERFECT FIT the six seconds to show how rapidly the tear fi lm becomes irregular. ODYSSEY MEDICAL + BEAVER VISITEC “In the study we conducted, we used this technology with dry eye of The Odyssey Parasol® Punctal Occluder is now part of different clinical severity levels, from Beaver-Visitec International (BVI), a leader of trusted one to four,” he says. “We found a world ophthalmic brands. Not only is the Parasol® a perfect clear correlation: The more clinically fi t for your dry eye patients, but combining BVI with the severe the dry eye, the more rapidly the irregularity score went up. It pro- outstanding success of the Parasol®, continues the tradition vided valuable information, even early of superior knowledge, products and services. in the disease. It’s a test I would use on every patient, except that we can’t get For those of you who depend on a quality product from reimbursed for it. Right now there’s Odyssey Medical, WELCOME TO BVI. no billing code. It’s approved, but not Your new ordering information: reimbursable.” 866-906-8080 Meibography Plus [email protected] www.odysseymed.com Another factor potentially contrib- www.beaver-visitec.com uting to dry eye is the condition of the meibomian glands. Several new devices that have appeared in the recent past aim to make meibography quicker and easier. One that includes multiple dry-eye-related tests is the Beaver-Visitec International, Inc. | 411 Waverley Oaks Road Waltham, MA 02452 USA | BVI, BVI Logo and all other trademarks (unless noted otherwise) are property of a Beaver-Visitec International (“BVI”) company © 2013 BVI

028_rp1013_f1.indd 33 9/20/13 11:38 AM Cover Dry Eye

REVIEW Focus Kelly Nichols, OD, MPH, PhD, FAAO

The Oculus Keratograph 5M (above) performs multiple tests relating to dry eye, including meibography (right). Automatic enhancement of the images allows easier visualization of the meibomian glands.

Keratograph 5M from Oculus. This provides a level of accuracy that a grayed-out circle in the center of “We bought the Oculus Kerato- you couldn’t get looking through a slit your view which you overlay on top graph 5 because of the meibography, lamp, even with a reticule. Also, be- of the iris and pupil to mask them out but we use it in a couple of ways,” cause you’re measuring an image, you of the picture. Then you press go, and explains Kelly Nichols, OD, MPH, don’t have to worry about the patient the instrument gives you a measure of PhD, FAAO— FERV Professor at moving. You can take measurements limbal and conjunctival redness. This the University of Houston College of all the way across the lid margin, if is mostly helpful as an objective way Optometry and director of The Ocular desired. to monitor improvement and show Surface Institute at the university. “In “Actually, we use this more in clini- the patient that you’re making prog- terms of meibography, when taking cal research than in clinical practice,” ress but that’s sometimes a valuable images the instrument provides a little she notes. “I believe that in practice a service.” more guidance than previous models, global assessment of whether the pa- Dr. Nichols notes two other, more such as showing you where to center tient has tear prism or not is almost as qualitative measurements that can be the lid in the box. Once you’ve taken good as having a quantifi ed measure. made with the instrument’s dry-eye the picture, it automatically enhances But it might be valuable for comparing suite at the push of a button. “The de- the contrast of the image so you can how contact lenses affect the tear fi lm, vice allows you to view the lipid layer get a clearer view of the glands. The or if the eyes have signifi cant differ- of the tear fi lm, giving you an inter- company is also working on a grading ences in epiphora.” ferometry pattern,” she says. “A lot of algorithm for what’s normal and ab- Dr. Nichols says the Keratograph colored fringes indicate a thicker lipid normal; I’m hopeful that in the future 5M also does a noninvasive tear break- layer. There’s no measurement map we’ll be able to compare a patient to up time test. “It gives you a color map associated with that, but if you use it a an age-matched sample, or to previous showing what regions of the tear fi lm lot, I believe you could learn to gauge images of the same patient. are breaking up,” she explains. “The whether the lipid layer seems nor- “The Keratograph 5M also has tests map looks a lot like a topography map; mal or not. This is similar to what the that were not part of the previous color coding tells you how quickly the LipiView does, although the LipiView model, as well as tests that have been tear fi lm broke up in each area. How- goes one step further; it measures the enhanced, which the company refers ever, we’ve found this test takes some color of the output and gives you a to as the dry-eye suite,” she continues. practice to run. To me it seems like it number—an average lipid layer thick- “That includes a tool for measuring starts counting while the patient is still ness. tear meniscus height. Once you have blinking, so it can be slightly off. New “The device also allows you to see a photograph of the eye, you use a users might have trouble getting it to the speed at which the tear fi lm moves little onscreen widget tool that looks work, but with training staff can easily upward after a blink,” she adds. “You like a Roman capital letter I. You put perform the test.” focus two white dots on the tear plane. the top bar of the capital I at the top Dr. Nichols says the instrument also As the patient blinks, you can see how of the tear meniscus, and the bottom quantifi es conjunctival redness. “To do fast the tear movement is occurring on bar at the lid margin; the program this, you take a color photo,” she says. the ocular surface, without any need then gives you an exact measurement. “When you click the button, it creates to use a dye. A fast speed is normal;

34 | Review of Ophthalmology | October 2013

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RP0413_Care Credit.indd 1 3/11/13 10:22 AM Cover Dry Eye

REVIEW Focus TearScience Inc

The LipiView interferometer, part of the TearScience system that includes the LipiFlow treatment device, analyzes the thickness of the lipid layer of the tear ﬁ lm.

if it’s very sluggish, or you see a lot of aside from the dry-eye tests and mei- view of all of the meibomian glands speckly stuff, that would be another bographer, this is a topographer fi rst along the upper or lower eyelid, with- indicator of an irregular tear fi lm or and foremost. But given all the func- out causing the patient any discomfort. lipid layer.” tions it performs, I think you get a lot The device is available for import but Dr. Nichols notes one other feature for your money. And like the LipiView, is currently not approved by the Food of the Keratograph that she appreci- it’s a step toward a functional, more and Drug Administration. (For more ates: the camera. “For the money, it objective way to evaluate the tear fi lm on this, see “Breaking New Ground in has a fantastic camera,” she says. “It and ocular surface in dry eye and other Meibography” in the July 2013 issue wouldn’t be ideal for some purpos- common diseases.” of Review.) es, such as taking pictures of corneal Dr. O’Brien’s Ocular Surface Cen- degenerations or small things on the ter clinic also has an Oculus Kerato- Analyzing the Lipid Layer cornea that require high magnifica- graph 5M. “This technology allows us tion and a slit beam; but for a general to evaluate the condition of the mei- Another tool that may be of use photograph of the ocular surface— bomian glands; many people are now when diagnosing dry eye is the Lipi- cornea, conjunctiva, lids, lashes, even saying this may be useful in diagnosis,” View interferometer, part of the Tear- fl uorescein and tear breakup time, it he says. “The preliminary results are Science system that includes the Lipi- provides a fantastic picture. Onscreen, encouraging, in terms of being able Flow treatment device. The LipiView you can digital zoom, fi x the lighting, to detect MGD and tearfi lm breakup is designed to analyze the thickness turn the gain up or down and make time with more quantitative accuracy. of the lipid layer of the tear fi lm. Dr. real-time adjustments. It takes bet- The chief problem with diagnosing Rapuano says his clinic uses the deter fl uorescein photographs than any dry eye has been the semi-quantitative vice. “We didn’t buy it separately; it other method I’ve seen, without hav- nature and variability with all of the came with the LipiFlow device, and ing to do any optimization. In contrast, tests, so the more quantifi able, repro- we use it because we have it,” he ex- most cameras attached to a slit lamp ducible and accurate the test, the bet- plains. “Like the TearLab osmolarity aren’t optimized for viewing through a ter it will be. Oculus and several others test, the LipiView needs to be done cobalt fi lter, for example. are showing great promise as a means before any drops are put in—certainly “My opinion of all the extra tests in to provide that.” before you’ve examined the patient the Oculus dry-eye suite is that they Another new meibography tool is a and pressed on the lids and gotten any do add some didactic value,” she says. portable, handheld, pen-shaped de- lipids to come out. It’s a completely “Clinically, I don’t know if I would use vice developed in Japan and manu- noninvasive test; the patient sits and all of them; I probably would still do factured by Topcon. The non-contact blinks at the screen. Since we like to my regular tear breakup time test, and device incorporates an infrared LED use both tests, we do the LipiView I’d look through the slit lamp at the light source and a sensitive video cam- fi rst; the TearLab has a little collector elements of the tear fi lm moving and era that can be connected to a monitor that touches the eye, which could the- tear meniscus height, etc. In any case, or computer; it provides a panoramic oretically alter the LipiView results.

36 | Review of Ophthalmology | October 2013

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RP0913_Keeler PSD.indd 1 8/26/13 1:17 PM Cover Dry Eye

REVIEW Focus Advanced TearDiagnostics “The LipiView test is designed to croAssay System also measures an measure the thickness of the lipid lay- allergy-related marker (IgE) is very er, but we have not found that to be helpful. “One of the big advantages very helpful,” he continues. “It doesn’t of this system is that the IgE reading seem to correlate too well with peo- tells me if the problem is more irrita- ple’s slit lamp exams or symptoms, or tion from allergy than dryness,” he with what we think of as the severity says. “There’s a lot of overlap between of blepharitis. I’m not sure whether aqueous-defi ciency dryness, evapora- that’s a technological issue, or if the tive dryness and allergy dryness. thickness of the lipid layer really isn’t “This kind of consistent, reproduc- a determinant of lipid layer function. The TearScan MicroAssay System ible data will help tease out some of It doesn’t really help us determine quantifi es levels of lactoferrin (a dry-eye this overlap and help us fi ne-tune our whether the patient is a good candi- marker) and IgE (an allergy marker) in the treatment regimen,” he notes. “We date for LipiFlow; instead, I deter- tear fi lm, helping to distinguish dry eye won’t have to do a shotgun approach from allergy problems. mine that based on the slit lamp exam and put every patient on the same and the symptoms. Nor does it cor- thing. Maybe we can say, ‘Yours is re- relate with whether the patient is suc- lations. “It produces very intriguing ally more of an aqueous production cessful with LipiFlow. high-tech images, but the interpreta- problem; let us help you make more “The most interesting part of the tion is still diffi cult,” he says. “I’m not tears.’ Or, ‘Yours has an allergy compo- LipiView test, in fact, is the little video sure we fully understand yet exactly nent to it, so we’ll treat for both allergy of the patient blinking that you record what the patterns mean or how they and dry eye.’ Now we’re addressing as part of the test,” he says. “The de- correlate to clinical disease. However, more of the actual problem. vice gives you a printout that shows it’s been useful for catching partial “Of course, this is all new; no one you who the partial blinkers are. This blinkers, and it’s been useful as a pa- has been routinely measuring lacto- has nothing to do with the lipid layer tient education tool, letting us show ferrin in the tear fi lm,” he says. “We thickness that the instrument is mea- patients why they’re uncomfortable or don’t fully understand what the role suring, but for many patients, a partial having problems.” of lactoferrin is. For that reason we’re blink is a big part of their problem. gathering data to get a better idea of Unfortunately, there’s no easy way to The TearScan MicroAssay the clinical consequences of different eliminate partial blinking, but at least lactoferrin levels. Does this indicate we can tell the patient, ‘This is why the Another new tool designed to allow more aqueous defi ciency dry eye, or 20 medications and treatments you’ve quantifi cation of key markers in the evaporative dry eye?” tried for this issue have not worked. tear fi lm is the TearScan MicroAssay Dr Choi says he believes this infor- You’re not completely blinking, so the System from Advanced Tear Diag- mation will become even more useful lower half of your cornea is getting nostics; it measures markers relating as time goes on, and may have a role dried out as the day goes on.’ ” to both dry eye and allergy. “There’s beyond just diagnosing and treating Dr. Nichols also has used the Lipi- a lot of art to treating dry eyes, and dry eyes. “For example, this could be View device. “In practice, we’ve found the science is lagging behind,” notes an important tool for screening LASIK patients with seemingly normal lipid Young Choi, MD, medical director patients, because lactoferrin may layer thickness on the LipiView test; of InVision Ophthalmology in Home- make a difference in outcomes,” he but you look at their secretions and wood, Ala., who has used the TearScan says. “An ARVO poster a few years ago their meibography and they’re not MicroAssay System for almost a year. reported an association between lacto- normal,” she says. “Maybe they just “However, I think the diagnostic ma- ferrin level and whether LASIK eyes rubbed the eye and expressed some chines are starting to catch up. This came out over- or undercorrected. lipid. There’s a lot we don’t know yet, instrument, for example, is able to Since it gives us a precise number, we but it’s clear that you can’t use any one quantify both lactoferrin and IgE in may be able to associate specifi c levels of these tests alone.” the tears. It’s extremely sensitive and of lactoferrin with specifi c amounts of Dr. O’Brien says the Ocular Surface specific. It’s reproducible and accu- over- or undercorrection.” Center clinic at Bascom Palmer Eye rate, and we know that lactoferrin lev- Dr. Choi says he believes the Institute has a LipiView device, but el is indicative of dry eye. So it tells you TearScan MicroAssay System is ready has only recently been gaining experi- a lot about your patient’s condition.” for prime time. “It’s only a few thou- ence with screening dry-eye popu- Dr. Choi says the fact that the Mi- sand dollars, which is a fraction of

38 | Review of Ophthalmology | October 2013

028_rp1013_f1.indd 38 9/20/13 11:39 AM the cost of some other machines out there,” he observes. “The data is consistent and reproducible, and there’s evidence that lactoferrin levels are associated with dry eyes. You have something you can hang your hat on. I see this as a big step forward in terms of putting more science into diagnosing and treating dry eyes.”

Diagnosing Dry Eye with OCT

“Several of the currently available optical coherence tomography devices can help the clinician determine whether the tear volume is reduced, by noninvasively measuring tear meniscus dimensions,” says Dr. Pfl ugfelder. “That tells us whether the patient has an aqueous defi ciency or not, which can point the diagnosis in a different direction. We use the Op- tovue OCT for this; Zeiss makes the Cirrus OCT, and there may be other OCTs with this capability. In fact, our Optovue has software specifi cally designed to measure the tear meniscus dimensions. “We find this feature extremely helpful, and we now use it on every patient,” he continues. “We can measure the height, width or area of the lower meniscus, which has been found to be a good measure of total tear volume. It just takes a few seconds to image that, and it gives you a good sense of how much aqueous fl uid is on the eye. It can replace more inaccurate tests like the Schirmer test. Unfortunately, OCT is not approved for imaging the tear fi lm yet, so we can’t bill for this test as a dry-eye diagnostic.” A number of Dr. O’Brien’s colleagues at Bascom Palmer have been working on the possibility of diagnosing dry eye using real-time high- resolution OCT. “Our group has developed a prototype custom-built ultra-high-resolution spectral domain OCT device, or UHR-OCT, to study the ocular surface of dry-eye patients in a noninvasive fashion down to

028_rp1013_f1.indd 39 9/20/13 11:39 AM Cover Dry Eye

REVIEW Focus Mohamed Abou Shousha, MD resolutions of 2 to 3 µm,” explains conjunctival impression, required Victor L. Perez, MD, associate pro- anesthetic and was not reliable in 20 fessor of ophthalmology, microbiol- to 40 percent of cases; you often did ogy and immunology at the Bascom not end up with enough biological Palmer Eye Institute. “Utilizing material to conduct the test. In ad- UHR-OCT we’ve microscopically dition, it was more time-consuming mapped the ocular surface; we’ve and cumbersome and a bit painful found that dry-eye patients have Optical coherence tomography can be used to for the patient. That’s what inspired specific surface irregularities on assist in dry eye diagnosis. Some current in-offi ce us to create the EyePrim device.” devices can be used to measure tear meniscus their corneal epitheliums that can (Mr. Roy notes that the idea origi- dimensions; newer, ultra-high resolution OCT be measured and quantified us- is able to create a map of epithelial irregularity nated with Christopher Baudouin, ing a diagnostic index that we’ve (example above) and quantify it. Researchers have MD, professor and chair of ophthal- named epithelial irregularity factor, found that this can not only differentiate healthy mology at Quinze-Vingts Hospital or EIF. (See example, right.) Those eyes from dry eyes, it can accurately indicate the in Paris.) epithelial irregularities are most severity of the dryness, useful for both diagnosis Currently, the device simply har- likely the microscopic structural and monitoring during treatment. vests cells from the conjunctival sur- injurious effects that dry-eye syn- face, but the company is working to drome imposes on the ocular surface. them to a laboratory for testing is a develop it into a point-of-service test Those microscopic structural changes more complex approach than some of for dry-eye markers. “For example, seem to be readily detected by the the new point-of-service tests, it offers you might sample the cells and dis- unprecedented high resolving power the advantage of allowing a far more cover that the ocular surface is missing of recently developed imaging devices detailed analysis—and the testing of mucous cells,” he says. “That could such as our UHR-OCT. the cells may soon become an in-offi ce explain the dry eye. And of course, we “Our preliminary data has demon- capability. Ironically, one reason this could also test for infl ammatory bio- strated that our novel dry-eye diag- has been little used in the clinic is the markers that are exploited by the cells nostic index, the EIF, provides a non- difficulty of sampling cells from the when dry eye is present. Polymerase invasive qualitative and quantitative ocular surface. Some companies are chain reaction testing is another pos- means to diagnose dry-eye syndrome trying to address that. sibility we’re exploring. that correlates accurately with pa- “The EyePrim is a sampling device “The device is simple to use,” he tients’ signs and symptoms,” he con- that’s used to procure cells from the continues. “You open the sterile, sin- tinues. “Moreover, our preliminary ocular surface for biological testing,” gle-use pack and ask the patient to data have shown that EIF could be a explains Pierre Roy, CEO of OPIA look down or up, depending on the tool for objectively and subjectively Technologies in Paris, France. “It’s area being sampled. You place the monitoring dry-eye response to treat- reliable, fast, effi cient and painless for tip against the conjunctiva and gen- ment, and could be used to develop the patient, without the need to use tly press the plunger for a couple of and test new therapies.” any anesthetic. The old technique, seconds. Then you remove the device

“These results are really excit- OPIA Technologies from the surface of the eye and ing,” he adds. “They show that EIF eject the sample into the container could address many of the limi- that will be used for shipping to tations of the currently available the laboratory. diagnostic techniques. Spectral “The conjunctiva is a mucous domain OCTs with such high reso- tissue that is constantly renewing lution have already moved from itself, like skin,” he notes. “The research laboratories to clinics, and EyePrim samples the most super- commercial models will soon be- ficial layer of cells, cells that are come available to help improve the about to be ejected into the tear standard of care of our patients.” film. The cells simply adhere to the surface; there’s no scraping in- Harvesting Cells for Testing volved. The device is very safe, and The EyePrim device allows quick, painless and the patient doesn’t feel anything. Although removing cells from reliable sampling of conjunctival cells, which can then There’s no visible change on the the surface of the eye and sending be analyzed for markers of dry eye or other disease. surface of the eye, and the sampled

40 | Review of Ophthalmology | October 2013

028_rp1013_f1.indd 40 9/20/13 11:40 AM area heals within a matter of hours.” The EyePrim is currently being an important parameter to measure. To test the efficacy of the device used in several clinical trials to mea- Also, Restasis increases the number Mr. Roy says the company has con- sure biomarkers and evaluate the of goblet cells; that may be one of its ducted several clinical studies, one efficacy of the different treatments major mechanisms of action. So this of which was done with a team from that are progressing toward market- might be a way to identify patients Birmingham, England. “They found ing. The device, approved but not yet who would be good candidates for that that this procedure is about two times reimbursable, is distributed in the treatment. In any case, the EyePrim is faster than the old procedure,” he United States by Ocular Surface Di- a great device.” says. “It’s also more effi cient; they re- agnosis Innovation in Tampa. OSDI trieved enough material for testing in also offers biomarker-based diagnostic Dr. O’Brien has been a non-sal- 100 percent of the cases. On average, services, so samples can be shipped to aried ad hoc consultant/advisor for the device collected two to fi ve times them for testing. Rapid Pathogen Screening, TearLab, more cells than the older procedure, Dr. Pfl ugfelder has used the Eye- Advanced Tear Diagnostics and Tear without the pain. That’s especially im- Prim. “This kind of test would be Science. Dr. Choi is a consultant for portant in a clinical trial, because if very useful for diagnosing dry eye,” Advanced Tear Diagnostics. Drs. you sample patients three times over he continues. “It’s well-known that Shousha and Perez have submitted a the course of the trial and 20 percent patients with aqueous tear defi ciency United States Provisional Patent Ap- of your sampling fails to produce suf- show a decrease, and sometimes an plication for the HR-OCT technology. fi cient material for testing, you could absence, of goblet cells. Furthermore, Dr. Nichols has no fi nancial interest in have a 50-percent data loss. The ease the severity of irritation, light sensitiv- Oculus or TearScience or their instru- of use was also clear; nurses are now ity and corneal/epithelial disease has ments. Drs. Pfl ugfelder and Rapuano using the device to take the samples been found to correlate with the num- have no fi nancial ties to any company instead of the doctors.” ber of goblet cells. So this would be or product mentioned.

028_rp1013_f1.indd 41 9/20/13 11:35 AM 042_rp1013_f2.indd 42 Of Fungal Keratitis Meeting the Challenge Walter Bethke, ManagingEditor 42 REVIEW |

Review ofOphthalmology Feature dealing withthese difﬁinfections. cult provide tipsand Cornea experts techniques for | October2013 and treatthemproperly. how todiagnosefungalinfectionsearly In thisarticle,cornealexpertsreview treatment canyieldagoodoutcome. obstacles, promptdiagnosisandquick to produce.However, despitethese requiring acompoundingpharmacy able antifungalagent—withtherest there isonlyonecommerciallyavail- days tocultureandweeksheal, penetrate deepintothecornea,take are notoriouslyresistanttotreatment, behind yourback:Fungalinfections suspicion of a fungal cause since that suspicion ofafungalcausesince that for example,thatshouldraise your he hasrecentlytraveledtoSingapore, humid areas.Ifanulcerpatientsays ciﬁ gal infections,andfungalkeratitisspe- Scripps ClinicinLaJolla,Calif.“Fun- Mah, MD,acornealspecialistatthe or hasvisitedrecently,” saysFrancis practices andwherethepatientlives major riskfactoriswheretheclinician with medications.Herearetheirtips: ing thefungusearlyandhittingithard chances ofsavingthecorneabycatch- Clinching theDiagnosis T •Watch fortheriskfactors.“A • Physicians saythatyouincreaseyour cally, arealotmorecommoninhot,

tling a bear with one hand tied tling abearwithonehandtied tling fungalkeratitisislikewres- it, bat- o hearphysicianstell Fungal Keratitis This articlehasnocommercial sponsorship.

Sadeer Hannush, MD case, isariskfactorforfungalinfection. transplant, ofcorneal A history asinthis of involvescorneasinwhich ocular “The otherclinicalsettingto be wary pave thewayforafungalinfection. an agentsuchastacrolimus.” on systemicimmunomodulationwith on immunomodulationintheeyeor occur intransplantpatients causes can at Wills EyeInstitute.“Medication tending surgeonontheCorneaService MD, at- tions,” saysSadeerHannush, AIDS ordiabetes,frommedica- ther biologicallythroughcancer, HIV/ tor canbeimmunocompromise,ei- ting ofreducedimmunity. “Ariskfac- a frequentfactor.” Also, contactlensuseormisusecanbe from aplant,willbecommonfactor. causes, orcausesinvolvingtrauma the history. Specifically, agricultural The secondfactortobeawareofis could betheregionwhereitstarted. An unstableocularsurfacecanalso A funguscanalsothriveintheset- 9/20/13 11:47 AM RP1013_Hai Labs.indd 1 9/19/13 10:27 AM 042_rp1013_f2.indd 44 i.e., non-bacterial,specifi cally fungus.” quiet eye,Ithinkatypicalkeratitisfi an intactepithelium—witharelatively an intactepithelium—orevenwithout dense infi ltrate, featheryornot,with with abacterialinfection.SoifIsee often muchquieterthanyou’dexpect Hannush, “infungalkeratitistheeyeis ulcer growsbeneathit.“Also,”saysDr. will actuallybeintactwhilethefungal theysay,some cases, epithelium the go. In defects thatcomeand thelial whichinvolveendo- ery bordersand to bewatchfulforulcerswithfeath- teria usuallygo.”Physiciansalsosay out andtendtogodeeperthanbac- cornea. Then,theinfection willreach pinpoint areas ofinfectionacross the sions,” Dr. Mahcontinues.“Theseare suspicion offungus. building forweeks,thatmayraiseyour the patientsayshisconditionhasbeen the next.Fungitaketimetogrow, soif painful withsignifi eye willbenormalonedayandthen ally acuteprocess,”saysDr. Mah.“The and evenwith fections thatstandout.“With bacteria, there aresomefeaturesoffungalin- corticosteroid.” there’s aconcomitantuseoftopical rial presentintheformofsuturesand compromised, thereisforeignmate- which thepatient’s cornealnervesare as wellaftercornealtransplantin a flapandassociateddennervation, keratitis afterLASIKwithcreationof Medicine. “We’ve alsoobservedfungal University ofMiamiMillerSchool the BascomPalmerEyeInstitute, MD, professorofophthalmologyat other fungi,”aversTerrence O’Brien, tion byayeast,notably infec- ocular surfacethatcanpromote sation contributingtoanunhealthy disease ischronic,withalteredsen- 44 Cultures, StainsandTests REVIEW “Withsee satellitele- fungus, you’ll Physicians say Fungalfeatures.Physicians say • Corneal specialists say that, to make Corneal specialistssaythat,to make |

Feature Review ofOphthalmology Acanthamoeba, it’s are- cant inﬂ cant

Fungal Keratitis Candida, or ammation | October2013 rst,

Daljit Singh, MS, DSc corneal perforation isaconstantthreat.corneal Since fungalinfectionstendtogrow deep, thiol broth,”saysDr. O’Brien. andbrain-heart infusion/gentamicin agar, chocolate agar, Sabouraudagar, lective culturemedia,suchasblood need toplatematerialonmultiplese- microbial infection.“Insuchcasesyou thus promotesfungalgrowth. it containsanantibacterialagent,and Sabouraud agarispreferred because on thioacrylatebrothorbloodagar.” agar, butfunguswillfrequentlygrow the idealculturemediumisSabouraud aggressively. Whenyougetasample, “And, youwillhavetoscrapepretty to debrideitfi rst,” saysDr. Hannush. the epitheliumisintact,youwillhave pathogen isafungus,physicianssay. “If a specimenforculturingwhenthe fungal cellwall.” white canalsobeusedtohighlightthe the hyphalfragments,andcalcofl silver isastainthataidsvisualizationof he says.“Also,Gomorimethenamine identify thehyphalfungalfragments,” “Giemsa stainingcanbehelpfulto nostic stainscanbeemployed,aswell. phia. Dr. O’Brienaddsthatotherdiag- Jefferson MedicalCollegeinPhiladel- sistant professorofophthalmologyat is,” saysColleenHalfpenny, MD,as- when I’mnotcertainwhatthemicrobe I dospecifi cally forfungus, especially stain, specifi cally KOHstain,iswhat fi treatment, testsaremandatory. a defi nitive diagnosisbeforeinitiating rmation, stainsareanoption. “Gram There mayalsobeinstancesofpoly- Cultures.Itisusuallyeasytoget • Stains. • Forapossiblequickcon- uor for biopsy. sample aspecifi ed area ofthecornea to precisely, less-invasivelyandsafely ly, lasercanbeused afemtosecond perform ashavingbiopsy.” Bard-Parker sterile,single-usebladeto of theinfiltrateandthenusea#11 use a0.12forcepstograsptheedge with PCRtesting.Othertimes,youcan ogy orevenmolecularmicrobiology mit itformicrobiology, histopathol- material fromthecorneaandthensub- he says.“Thepunchisusedtoobtain skin punchofaspecifieddiameter,” a single-use,sterile,dermatological ing amanualbiopsy. “Onecanemploy O’Brien explainsmethodsforperform- opsy canhelpmakethediagnosis.Dr. tures willbeinconclusive,andabi- specialists say, themicrobiologicalcul- sion tothemicrobiologylaboratory.” rectly ontheculturemediaforsubmis- scissors, cutpiecesofitofftoplacedi- zone ofsuspicionand,usingsterile ture, whichhaspassedthroughthe You canthencarefullyremovethesu- at thelevelofsuspectedinfi an 8-0silksuturethroughthecornea ful,” saysDr. O’Brien.“Onecanpass passage ofasterilesuturecanbehelp- into thecornea,onemethodinvolving branching fi the surfaceisuninvolvedbutthereare briding thetoplayerofcornea.“If obtain materialforculturewithoutde- tact, someclinicianssayyoucanstill you maycauseacornealperforation.” because ifsomemeltinghasoccurred don’t wanttogothebaseofulcer put thatonthecultureplate.Also,you of theviableepitheliumifyoucanand ture theedgesofulcer. Grabalittle the organism.Instead,youwanttocul- and youdon’t actuallygetthatmuchof that’s leftinthecenterisnecrotictissue he says.“Thisisbecauseusuallyall to culturetheverycenterofanulcer,” can affecttheresults.“You neverwant Dr. O’Brienaddsthat,morerecent- Biopsy. Insomecases,corneal • In caseswheretheepitheliumisin- Dr. Mahsaysthewayyouculture lamentous infi lamentous deep ltrates ltrate. 9/20/13 11:48 AM “Life-Changing” “Dramatically Helped” “Symptoms Gone”

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RP1013_Ocusoft.indd 1 9/12/13 3:33 PM 042_rp1013_f2.indd 46 if the epithelium is pretty well healed if theepitheliumisprettywell healed cornea well,”saysDr. Halfpenny. “So, cin nor amphotericin penetrates the intact inmaycases.“Neithernatamy- ulcers istheepithelium,sinceitcanbe the drops.” unless thereissignifi cant toxicityfrom provement, soI’mnotquicktotaper take severalweekstoseeclinicalim- on thepatient’s response.Itoftenmay every twohoursafterthat,depending the clockforfi rst week,andthen the dropstobeusedhourlyaround non-fi tamycin. Forbothfilamentousand lished, Itendtostartwithtopicalna- results werepub- since theMUTT 1%,” saysDr. Halfpenny. “However, tamycin 5%ortopicalvoriconazole ment ofchoicewouldbetopicalna- therapeutic penetratingkeratoplasty. less likelytosufferaperforationorneed azole, withnatamycinpatientsbeing trial, natamycinoutperformedvoricon- Mycotic UlcerTreatment Trial. In the as aresultoftherecentmulticenter azole first,butallthathaschanged fungi, theyusedtoreachforvoricon- expensive andhardertoget,however.” amphotericin. Capsofunginismore if thereistoomuchtoxicityfromthe at certaincompoundingpharmacies capsofungin 0.5%canalsobeprepared prepare,” saysDr. Halfpenny. “Topical most compoundingpharmaciescan be topicalamphotericin0.15%,which dida yeast, whichismostcommonlyCan- tion that’s non-fi pounded. Herearetipsfortreatment. Alcon), whiletherestmustbecom- available agentisnatamycin(Natacyn, experts say. Theonlycommercially variety offungusyou’redealingwith, nate thefungalulcerdependon Treatment 46 REVIEW One issue with treatment of fungal One issuewithtreatmentoffungal “For fi lamentous fungus,mytreat- saythat,forfi Physicians Medicaltherapy. “Foraninfec- • The agentoragentsusedtoelimi- |

Feature Review ofOphthalmology , my treatment of choice would , mytreatmentofchoicewould lamentous, Itypicallyprescribe lamentous ormostly

Fungal Keratitis lamentous lamentous | October2013 1 ophthalmologist’s bestefforts,medical treatment couldlastformonths. ment andbeginstoconsolidate.The ulcerrespondstotreat- week ifthe out thevisitstoweeklyoreveryother they’re onhourlytreatment,spreading tients dailyoreveryotherdaywhile the satellitelesions.” contiguous spreadandthecontrolof solidation oftheinfi ltrate, nosignof signs ofclinicalresponseareacon- seeing spreadofthefungus.Positive it’s justmoreinfl amed butyou’renot actually asignofsomeimprovement— matory reactioninthecornea.Thisis kill thefungi,there’s agreaterinfl “This isbecauseastreatmentbeginsto actually getsbetter,” saysDr. O’Brien. apy isthatitmaygetworsebefore it itself. “Oneofthedictumswithther- on therapyisasintensethe of antifungaltherapy. been showntoinhibittheeffectiveness in fungalulcermanagement,asthey’ve general, theyavoidtheuseofsteroids studies.” Cornealexpertssaythat,in than topicalvoriconazoleinverysmall be safe,butnotmuchmoreeffective Halfpenny. “Thishasbeenshownto intrastromal voriconazole,”says Dr. can give good topicalpenetration,you deep andyoudon’t thinkyou’regetting gal injection.“Iftheinfectionisvery physicians useanintrastromalantifun- be monitoredagaineverytwoweeks.” have liverfunctiontestsatbaselineand Halfpenny. “However, theyneedto mg oralvoriconazoleb.i.d.,”saysDr. all patientswithdeeperulcerson400 to treatment.“Iwillcommonlystart may needatwo-prongedapproach that fungalulcersareoftendeep,and though, Iwon’t scrape.” ment. Ifhehasanepithelial defect, the overlyingepitheliumbeforetreat- grown outfungus,I’lltypicallyscrape when youseethepatientbuthehas Therapeuticgraft. • thepa- follow Clinicians saythey’ll Clinicians sayfollowingthepatient Finally, forverydeepulcers,some The othertreatmentchallengeis Despite the Despitethe am- less cytotoxicity.” action, greaterantifungalactivityand compounds withnovelmechanismsof to bothdiscoveranddevelopnewer medical failures,”hesays.“We have ly intooculartissuesand have fewer more rapidly, penetratemoreeffi of betterantifungalagentsthatwork made soon.“We’re indesperateneed signifi to cornealhealth,Dr. O’Brienhopes fungal infectionposesasaglobalthreat glaucoma surgerypostop.” specialist orevenrequireasecondary patient mayneedtoseeaglaucoma meshwork tissue. Inlightofthis,the have beenknowntodestroytrabecular in thepostopperiodbecausefungi intraocular pressurewith medications You alsoshouldaggressivelymanage steroids foratleasttwotothreedays. gal therapyandavoidtopicalor oral continue theoralortopicalantifun- etration orendophthalmitis.Postop, leave abarriertofurther fungal pen- in orderto the beginningsofacataract, leave thepatientphakic,evenifhehas the graft,ifnecessary. Also,youwantto ination, andbepreparedtodecenter to 1.5-mmclearmarginwiththetreph- says. “You shouldprovideatleasta1- and notallowthesecondarygraft,”she want thatareatobecomevascularized ary opticalgraftlater, andyoudon’t it’s likelythatyou’llneedasecond- the graftassmallpossible,because that shekeepsinmind.“Try tokeep Halfpenny hasseveralconsiderations these grafts,herearetheexperts’tips. corneal specialistundertakingoneof tic keratoplastyisnecessary. Forthe cases. treatment failsin15to36percentof Arch Ophthalmol2010;128:6:672-78. offungalkeratitis. andvoriconazoleforthetreatment natamycin 3. PrajnaNV, MascarenhasJ, Krishnan T, etal. Comparisonof [article inFrench]. Ann BiolClin(Paris) 2010;68:4:441-47. Tunis: Epidemiologicaldata, modalities andtherapeutic diagnostic 2. Anane S, Ben Ayed N, MalekI, etal. intheareaof Keratomycosis voriconazole. JAMAOphthalmol2013;131:4:422-29. trial:treatment vs.A randomizedtrialcomparingnatamycin 1.NV, Prajna Krishnan T, MascarenhasJ,al. et The mycoticulcer Withan ocular thedauntingcourse When approachingthegraft,Dr. cant advancesinthefi eld willbe 2,3 Whenthisoccurs,atherapeu- cient- 9/20/13 11:48 AM 800.787.5426 haag-streit-usa.com

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RP1013_Haag Twinkle.indd 1 9/12/13 3:13 PM 048_rp1013_f3.indd 48 Boost YourBoost Bottom Line? Can Treating Eye Dry Michelle Stephenson, ContributingEditor 48 REVIEW |

Review ofOphthalmology Cover Focus Cover chair timerequired New technologies between theextra and extraprofi ts. and theproper tip thebalance approach may | October2013 Data intablescourtesyofBruceMaller, BSMConsulting. I providing themostadvancedtechnol- preoperatively,to helpthesepatients “Having anestablisheddry-eyeclinic Institute inToronto, Ontario,Canada. tor andco-founderoftheHerzigEye direc- Sheldon Herzig,MD,medical gland dysfunctionanddryeyes,”says correction becauseoftheirmeibomian patients whomaynotqualifyforlaser a refractivesurgerypractice,thereare “In candidates. tosurgical candidates vices isthatitcanconvertnonsurgical their dry-eyepatientpopulation. diagnosis andtreatmentoptionsto (1) MedicareRates Assumes 2012National Chief Complaint: Blurry VisionChief Complaint:Blurry Table 1. Patient’s ExampleofDry-Eye Visits/Charges Four Plugs (1st eye$146, 2ndeye$73) Punctal Plugs(2) Other Potential Treatment Dry-Eye Revenue: Total Annual RevenuePerPatient Twelve MonthFollow-up Exam(99213) Three MonthFollow-up Exam(99213) One MonthFollow-up Exam(99213) New Patient, ComprehensiveExam(92004) Description One benefi t ofofferingdry-eyeser- fi bottom line,somesurgeonsare to boosttheirpractice’sn aneffort nding successbyexpandingthe

Dry Eye Dry This articlehasnocommercial sponsorship. everywhere, and there are booklets everywhere, andtherearebooklets practice. “Thereissignageaboutit a dry-eyecenterofexcellenceinher York,land inNew hasincorporated Ophthalmic ConsultantsofLongIs- running moreefﬁ but willalsohelpkeepthepractice with dry-eyediseasemoreefﬁ staffed andequippedwillnotonlydeal ed dry-eyeclinicthatisappropriately in abusypractice,sohavingdedicat- tients canconsumealotofchairtime tive surgery.” to onewhodoesverywellwithrefrac- function, canconvertanon-candidate restorenormaltear ogies toperhaps Marguerite McDonald, MD, from Marguerite McDonald,MD,from Dr. Herzignotesthatdry-eyepa- Estimated Revenue ciently. $370 $219 $354 $144 $70 $70 $70 ciently ciently (1) 9/20/13 11:20 AM SOME SURFACES ARE WORTH PROTECTING

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References 1. Christensen MT, Blackie CA, Korb DR, et al. An evaluation of the performance of a novel lubricant eye drop. Poster D692 presented at: The Association for Research in Vision and Ophthalmology Annual Meeting; May 2-6, 2010; Fort Lauderdale, FL. 2. Davitt WF, Bloomenstein M, Christensen M, et al. Efﬁcacy in patients with dry eye after treatment with a new lubricant eye drop formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 3. Data on ﬁle, Alcon. 4. Wojtowica JC., et al. Pilot, Prospective, Randomized, Double-masked, Placebo-controlled Clinical Trial of an Omega-3 Supplement for Dry Eye. Cornea 2011:30(3) 308-314. 5. Geerling G., et al. The International Workshop on Meibomian Gland Dysfunction: Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction. IOVS 2011:52(4).

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REVIEW Focus

and leafl ets in every single room,” she Table 2. Revenue and Net Income Opportunity says. “We try hard to stay on time, but most patients have time to scan at least Dry-Eye Patient Population one brochure while they are waiting Dry Eye Cataract Glaucoma Plug Patients Total Value for the doctor to come in. Even if they Patients from Patients from from Dry Eye from Dry Eye haven’t heard of us being a dry-eye Dry Eye Dry Eye center of excellence, they will leave Number of 1,500 105 23 150 Patients 7%(1) 1.5%(2) knowing that we are, and they often Revenue Rate tell their friends. There is a lot of word- Per Patient(3) $354 $1,600 $500 $219 $743,350 of-mouth referral in a dry-eye practice. Gross $531,000 $168,000 $11,500 $32,850 If you make an unhappy middle-aged Revenue (1) Assumes 50 percent capture of cataract prevalence from 2005 Gallup Study dry-eye patient happy after she has (2) Assumes 50 percent capture of glaucoma prevalence from 2005 Gallup Study been to fi ve or six doctors, the halo ef- (3) Revenue rates per patient are determined as follows: • Dry Eye assumes $354 per patient per year with various offi ce procedures fect is incredible. You are much more • (92004 = $144, three exams – 99213 = @ $70 each). • Cataract assumes bilateral cataract surgery. Revenue rate includes surgery, exam and diagnostic testing. likely to get her daughter’s LASIK and • Glaucoma assumes revenue rate per patient with POAG and no systemic disease. her father’s cataract surgery.” • Plug assumes fi rst eye = $146, second eye = $73. All patients seen in the practice take a very short questionnaire. It takes complete this regimen, Dr. McDonald LipiFlow treatment is not covered by them less than 30 seconds to check off offers LipiFlow. insurance, so—for the average prac- whether or not they have symptoms tice with the average LipiFlow pricing of dry eye and the frequency of those LipiFlow, LipiView and IPL structure—the margins are usually at symptoms. Tear osmolarity testing is least as good as if the surgeon per- ordered on any patient who checks off Adding LipiView, LipiFlow and informed a LASIK procedure. Another ocular surface symptoms on the ques- tense pulsed light therapy to a practice advantage to the LipiFlow treatment is tionnaire and on most patients who are is one way to boost revenue. “Dry eye that there is just about no medicolegal 40 or older, because the incidence of is becoming a more attractive market liability with it; I have never heard of a dry-eye spikes in this age group. “Ad- now because there are more objective LipiFlow lawsuit because it is so non- ditionally, I order tear osmolarity on diagnostic tools and in-offi ce therapeu- invasive.” anyone presenting for any kind of oph- tic treatments that have expanded our Jay Pepose, MD, PhD, medical di- thalmic surgery and on anyone with armamentarium,” says Elizabeth Yeu, rector of Pepose Vision Institute and a history of dry eyes. Honestly, there MD, an assistant professor at Eastern president of the Lifelong Vision Insti- aren’t very many people in a cornea Virginia Medical School and corneal tute in St. Louis, notes that LipiFlow specialist’s practice who don’t get a tear specialist at Virginia Eye Consultants should not just be considered as a last- osmolarity test as part of their exam,” in Norfolk, VA. resort treatment option. “The patients she says. LipiView is a diagnostic tool that, to who are trying LipiFlow as a last re- Dr. McDonald uses the results of the a certain degree, quantifi es the mei- sort are the most motivated, but you tear osmolarity test to guide therapy. A bum and helps objectively gauge how have to be careful with them because if normal score is 290 to 295 mOsm/L. patients may respond to a LipiFlow you have someone with no meibomian At this score, the tears are in homeo- treatment, she adds. “LipiView pro- gland function, those patients are so stasis with the blood, which is normal vides a numerical measurement of the end-stage that they may not respond and healthy. For every point above this thickness of the lipid layer within the to the treatment. It is always better to score, the eyes are drier. If a patient is tear fi lm, with value ranges that corre- catch people before end-stage, while between 295 and 310 mOsm/L, she is late this to posterior lid margin disease they still have some functional glands,” asked to use artifi cial tears four times severity,” says Dr. Yeu. he says. a day. In severe cases, patients are on LipiFlow and intense pulsed light Another procedure used to treat dry lid scrubs twice a day and erythromy- are the newest treatment options for eye is intense pulsed light, or IPL. “I cin ointment at night, low-dose doxy- dry eye. Dr. McDonald says that Lipi- like the concept but there is very little cycline by mouth, artifi cial tears four Flow has a high conversion rate in her published about it compared to how to eight times a day, and nutritional practice. “It is a 12-minute computer- much is published about other treat- supplements. This can be overwhelm- controlled pulsating thermal lid mas- ments, such as LipiFlow,” Dr. McDon- ing for many patients. In these cases or sage treatment that is highly effective ald says. “There is a little more liability in cases where the patient is unable to in treating dry eye,” she says. “The with IPL, so you have to be careful:

50 | Review of Ophthalmology | October 2013

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RP1013_Reliance.indd 1 9/12/13 3:15 PM Cover Dry Eye

REVIEW Focus

Patients who are more darkly pigment- Table 3. Osmolarity Testing Scenario ed can get scarring, and one has to remember to insert the eye shields or Number of patients 1,500 there can be ocular damage.” Number of eyes tested 2 Adding new treatment options can Number of visits 4 disrupt patient fl ow, so you may want Number of osmolarity tests 12,000 Reimbursement per eye $23.40 $280,800 to consider grouping dry-eye patient visits. “When we fi rst started offering Cost of TearLab Osmolarity System $0 LipiFlow, when a patient said he or (Free use of system with Test Card Commitment) she wanted it, we were doing it right Cost of Test Cards $10 $120,000 that very moment,” Dr. McDonald says. “However, this made patient fl ow Net revenue of TearLab Osmolarity Testing $160,000 a bit chaotic. Because it is a 12-minute (Does not include revenue for offi ce visits, punctal plugs or supplement sales) procedure, we decided to have ‘Dry- eye Fridays.’ We do LipiFlow treat- so it takes away the subjectivity of stag- your referring ophthalmologists and ments all day on Fridays. We have now ing ‘redness.’ ” optometrists the option of bringing trained our optometrists to perform Additionally, it determines the thick- their patients over and allowing them LipiFlow procedures, but we did them ness of the lipid layer using interferom- to perform their own treatments.” ourselves until we felt we had done etry, provides automatic measurement Dr. Yeu believes that the use of Lipi- enough to be totally comfortable with of the tear meniscus height, and tracks Flow to treat dry eye is on the rise. these treatments.” the movement of particles in the tear “Although it’s still a relatively newer fi lm to determine tear viscosity. “The therapy and there is not as much out The Bottom Line practice can invoice for these photo- there in evidence-based literature to graphs using the external photography support this yet, we believe that the Other ways to increase income in- CPT code, and the average reimburse- LipiFlow will likely grow in its indi- clude tear osmolarity testing and tak- ment for these photos is $40,” Dr. Mc- cations,” she says. “I would not be ing anterior segment images. “The Donald says. surprised to see this being utilized in Keratograph 5M by Oculus has—in To develop a dry-eye center of excel- all realms of mild to moderate dry- addition to a Placido-based topogra- lence, Dr. McDonald recommends eye disease, not just for the obvious pher—five new images that assist in starting with tear osmolarity fi rst. “Get evaporative ones. In-offi ce meibomian the diagnosis of dry eye and meibo- the doctors and staff comfortable with gland expression is going to be more mian gland disease and the response how to do it and when to do it. Once and more widely utilized. It is like any to treatment,” Dr. McDonald says. you have that under your belt, you other chronic disease in that there is “For instance, it has an automated tear should quickly move on to acquiring no single modality therapy that is a breakup time, which is notoriously dif- LipiFlow technology and the Kerato- cure-all. I think LipiFlow is a great fi cult to measure by clinical observa- graph 5M,” she says. adjunctive professional therapy that tion only. Not only does it tell you what However, be prepared for a big price will continue to grow and gain greater the tear breakup time is, but it shows tag. “The Keratograph 5M is approxi- momentum in the next few years and is you what part of the cornea broke up mately $25,000 to $28,000. The Lipi- certainly not a fad treatment.” fi rst. It will give you the average break- Flow/LipiView package from Tear- Even if you are not interested in up time in seconds and will classify the Science is around $100,000,” she says. getting in this deep and purchasing level of dry eye. It also has meibogra- To defray these costs, Dr. Yeu says expensive equipment, your practice phy, so the glands can be seen and the she has heard of practices that are col- can still capitalize by simply expanding gland-containing area of the lid can lectively purchasing the fairly portable your dry-eye patient base and follow- be calculated, as well as demonstrat- unit and are sharing the LipiFlow like ing them. These added patients will ing gland tortuosity and documenting a “timeshare,” where the unit travels also expand your surgical population where on the lid the dropout is oc- between the practices on a rotating as they later require cataract surgery or curring. It also has a way to categorize schedule. “The machine can go to one glaucoma treatment. conjunctival erythema by calculating practice one week and then to anoth- Bruce Maller, an ophthalmic busi- the ratio of blood vessels to sclera. It er practice the next week,” she says. ness consultant, has developed a con- will accurately and automatically stage “Another great idea to help cover the servative dry-eye fi nancial model (See conjunctival erythema for the clinician, overhead may be to consider offering Tables 1 & 2). First, he provides an

52 | Review of Ophthalmology | October 2013

048_rp1013_f3.indd 52 9/20/13 11:21 AM example of a dry-eye patient’s visits/ 1,500 dry-eye patients. He assumed we have an optical, and the optical charges for one year if a patient had that the ophthalmologist will only carries fi sh oil and different artifi cial the chief complaint of blurry vision. be able to keep half of them in the tears,” he says. “We try to carry some Visits alone would bring in $354 per practice. Though Bruce used modest that you can’t get too easily at the patient per year. Additionally, if two estimates in every instance, as well as pharmacy. We want to have a good, punctal plugs were implanted, the 2012 Medicare reimbursement rates, non-preserved tear and a good, oil- revenue would be $219 per patient, it was staggering how profi table this containing tear. This also gets people and the revenue for four plugs is effort—an emphasis on treating dry into the optical, where they may make $370 per patient. eye—was to the average practice. an additional purchase. Some prac- Then, he calculates the revenue You don’t have to stop treating cata- tices are also initiating allergy skin and net income opportunity for a racts or glaucoma or anything else; testing, so we are looking into that be- practice that was able to bring in your volume of these cases will actu- cause there is a lot of overlap in these 1,500 dry-eye patients, which is a ally increase.” patients between dry eye and allergy.” conservative estimate according to When tear osmolarity testing is Dr. McDonald believes that it is Dr. McDonald. “Bruce assumes that added to the model, an additional the perfect time to get into this fi eld with very modest marketing, it would $160,800 of net revenue is possible. because of the demographic shift in be fairly easy for any practice to get (See Table 3). the population. In addition, there are 1,500 new dry-eye patients to come better diagnostics, better drugs and in over the course of a year,” she Other Innovative Ideas better procedures for ocular surface says. “Based on several recent Gal- disease. “We can do more for these lup polls, Bruce was able to calculate For additional income, Dr. Pepose’s patients than ever before, and with how many cataract, glaucoma and practice also sells some dry-eye prod- virtually no medicolegal exposure,” retina cases would be found in those ucts. “It is not terribly profi table but she notes.

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RP1013_Medflow Secret.indd 1 9/19/13 9:53 AM Retinal Insider

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

Gene Therapy for Retinal Diseases The eye represents a unique target organ for gene therapy. Here’s a look at some of the current avenues of research. J. Peter Campbell, MD, MPH, and J. Timothy Stout, MD, PhD, MBA, Portland, Ore.

lmost as long as we have known for Leber’s congenital amaurosis type transduce the appropriate cells; d) a Aabout our genetic makeup, scien- 2 (LCA2).4-6 These pivotal trials paved suffi cient potential patient pool to at- tists have dreamed of harnessing the the road for a number of other early tract pharmaceutical support; and e) power of gene expression to treat hu- clinical trials for retinal disease and the the underlying diseased retina having man disease.1 It has taken many years fi rst Phase III study for gene therapy the potential for restoration of function to realize those dreams, however the involving the eye. A full review of gene with gene replacement and not being past 10 years have led to some very therapy techniques and preclinical irreparably diseased. promising advances.2 Gene therapy, research is beyond the scope of this Leber’s congenital amaurosis is a in its current form, employs the host’s article, and we would refer the read- heterogeneous group of autosomal re- gene expression machinery to tran- er to additional references.2,7 In this cessive diseases characterized by early- scribe and translate therapeutic ge- brief review we would like to provide onset rod-cone dystrophy and severe netic information that has been deliv- a broad overview of current avenues of vision loss. There are a variety of genes ered to target cells through the use of research, focusing on those in or near that produce the LCA phenotype of genetically modifi ed viral vectors. One clinical trials. varying severity, but certain defects in challenge of gene therapy has been RPE65 produce LCA2 with early-on- our ability to design vectors able to Inherited Retinal Degenerations set blindness but delayed photorecep- introduce the therapeutic genes into tor degeneration. This led investiga- host cells and achieve long-term gene From the beginning, the idea of tors to hypothesize that restoration of expression without local toxicity or im- targeting inherited retinal degenera- function of RPE65, which is involved mune reaction.3 tions has been tantalizing. It is simple in photoreceptor cell cycling, might The eye represents a unique target in theory to imagine how, in diseases prevent progression of degeneration organ for gene therapy due to the im- where the gene defect is known, the and may allow restoration of visual mune privilege afforded by the blood- wild-type gene could be introduced function.3 ocular barrier, the ability to directly with a viral vector and the functional After encouraging preclinical animal visualize, access and locally treat the gene product would restore function studies, approval was obtained for hu- target tissue and, with regards to clini- and/or prevent cell death. However, man trials in 2008, and three separate cal trials, the simultaneous control pro- translating the theory into reality de- Phase I trials demonstrated the safety vided by the other eye. Perhaps it is pends at least upon: a) the causative and efficacy of RPE65 delivered via not surprising, then, that one of the gene being known; b) the therapeutic an adeno-associated virus vector by most publicized advances in the fi eld gene being cloned into a viral vector; subretinal injection, with functional in the last decade was a series of trials c) the vector being safe and able to improvement beyond two years.4-6,8

56 | Review of Ophthalmology | October 2013 This article has no commercial sponsorship.

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RO0913_S4Optik.indd 1 8/26/13 11:22 AM Retinal

REVIEW Insider

Gene Therapy Trials Clinicaltrials.gov Disease Gene Vector Mode Phase Sponsor Identiﬁ er Locations Leber’s congenital CBSB-RPE65 AAV2 Subretinal I University of NCT00481546 Children’s Hospital of Philadelphia amaurosis type II Pennsylvania University of Florida

Leber’s congenital RPE65 AAV2 Subretinal I/II Nantes University NCT01496040 Nantes University Hospital amaurosis type II Hospital Leber’s congenital CB-RPE65 AAV2 Subretinal I/II Applied Genetics NCT00749957 Casey Eye Institute, Oregon Health & amaurosis type II Technologies Corp Science University University of Massachusetts Leber’s congenital RPE65 AAV2 Subretinal I/II Children’s Hospital NCT01208389 Children’s Hospital of Philadelphia amaurosis type II of Philadelphia Leber’s congenital RPE65 AAV2 Subretinal III Children’s Hospital NCT00999609 Children’s Hospital of Philadelphia amaurosis type II of Philadelphia University of Iowa

MERTK-associated VMD2- AAV2 Subretinal I King Khaled NCT01482195 King Khaled Eye Specialist Hospital retinitis pigmentosa MERTK Eye Specialist Hospital, Riyadh, Saudi Arabia Neovascular age- Endostatin & LV Subretinal I Oxford Biomedica NCT01301443 Wilmer Eye Insitute, Johns Hopkins related macular Angiostatin Hospital degeneration Casey Eye Institute, Oregon Health & Science University Neovascular age- SFLT01 AAV2 Intravitreal I Genzyme NCT01024998 Johns Hopkins Hospital related macular Retina Consultants of Arizona degeneration Ophthalmic Consultants of Boston University of Massachusetts

Neovascular age- SFLT-1 AAV2 Intravitreal I/II Lions Eye NCT01494805 Lions Eye Institute, Perth, Australia related macular Institute, Perth degeneration Avalanche Biotechnologies Choroideremia REP1 AAV2 Subretinal I/II University of NCT01461213 Moorﬁ elds Eye Hospital Oxford St Mary’s Hospital, Central Manchester University Hospitals NHS Foundation Trust Oxford Radcliffe Hospitals NHS Trust Eye Unit, Southampton University Hospitals NHS Trust Stargardt’s disease ABCR LV Subretinal I/II Oxford BioMedica NCT01367444 Casey Eye Institute, Oregon Health & Science University Centre Hospitalier Nationale d’Ophthalmologie des Quinze-Vingts Usher type IB MYO7A LV Subretinal I/II Oxford BioMedica NCT01505062 Casey Eye Institute, Oregon Health & Science University

There are several ongoing Phase I, II ing several years, there is evidence that the need for long-term clinical studies and III studies in the United States the underlying retinal degenerative of these therapies, and for ongoing and Europe for LCA2 using a variety process in LCA2 may not be slowed research aimed at slowing the kinetics of vectors and protocols to treat LCA2, by the delivery of RPE65. Artur of the underlying degeneration, which and many believe Food and Drug Ad- Cideciyan, PhD, and colleagues re- may be perpetuated by “downstream” ministration approval is possible.9 cently demonstrated continued pho- processes unaffected by delivery of the Though the initial clinical results toreceptor degeneration after therapy gene product.11 have been encouraging and have led to at a rate consistent with the natural Several other inherited retinal de- improvements in visual function last- history of LCA2.10 These results afﬁ rm generations are in early-phase clinical

58 | Review of Ophthalmology | October 2013

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RP1013_Vmax.indd 1 9/20/13 10:26 AM Retinal

REVIEW Insider

trials using a number of different occlusions, represents another viral vectors, including choroider- large target population with nu- emia, autosomal recessive retinitis merous molecular targets for gene pigmentosa, Stargardt’s, and Usher therapy. As in AMD, VEGF in- syndrome (type IB), with many hibition with monthly intravitreal others in preclinical animal stud- injection has become the mainstay ies. Most of the clinical work in- of treatment for macular edema volves transduction with AAV or due to diabetes and vein occlusion, lentiviral vectors. Currently, the and clinical trials are under way long-term LCA animal model data For a brief video of gene therapy delivery to the retina, exploring the role of VEGF inhi- suggests ongoing production of please visit revophth.com/video/gene/. bition in retinal neovasculariza- RPE65, but there is no regulation tion in proliferative diabetic reti- of the kinetics of the gene production. required injections is burdensome and nopathy. In both AMD and diabetic For LCA2, this may not matter, but for expensive. Myriad preclinical studies macular edema, monthly injections other disease states, retinal function have explored other growth factors are often required for months to years, may be more sensitive to the “thera- involved in the pathogenesis of neovas- and lapses in treatment can lead to fur- peutic index” of the gene product. cular AMD and other delivery models, ther vision loss. There are currently no including subretinal injection, subcon- clinical trials for gene therapy in retinal Broader Applications junctival injection, intravitreal injec- vascular disease. tion of longer-acting molecules and While the success of the LCA2 trials intraocular delivery devices.12,13 Future Directions demonstrated proof of principle that Peter Campochiaro, MD, and col- a defi cient single gene could be deliv- leagues demonstrated safety in a Phase There are prospects for commercial- ered to the eye and restore function, I study of pigment epithelial derived ly available gene therapies for retinal and brought hope to many patients factor (PEDF) in an adenoviral vec- disease in the near future, but much with inherited retinal disease for whom tor with intravitreal injection. They work remains to be done. In the fi eld there has been no available treat- demonstrated a dose-dependent clini- of inherited retinal degenerations, the ment, designing gene therapy vectors cal response with tolerable local side next step will be to expand the indi- for monogenetic recessive conditions effects.14 Another Phase I trial using cations available for treatment, and requires a large amount of resources an AAV vector to express a soluble initiate treatment earlier in the disease for a relatively small potential patient VEGF receptor is currently enrolling process, which will require excellent population. Bringing the cost of this patients.15 safety and effi cacy data in the current technology down enough to encourage Besides VEGF, PEDF and placental and future clinical trials. exploration into rarer inherited retinal growth factor, other molecules such Similarly, in AMD and retinal vas- degenerations may require a broader as endostatin and angiostatin modu- cular disease, where we have increas- potential market overall. It is exciting late the permeability of the retinal and ingly effective therapies, the safety of to explore how this technology could choroidal vasculature and represent long-term, viral-vector-mediated gene be used to help restore or preserve vi- intriguing targets for gene therapy. transduction will need to be demon- sion for more common conditions. A Phase I study of subretinal injec- strated. Especially for conditions that Age-related macular degeneration tion of a lentiviral vector-expressing have existing therapies, the cost of is a leading cause of irreversible blind- endostatin and angiostatin is currently gene therapy will need to be justifi ed. ness in the United States and is in- enrolling patients with advanced neo- In a culture of ever-increasing health- creasing in prevalence. Though the vascular AMD.14 Another trial involves care costs, the novelty and intrigue of pathophysiology of AMD is complex the use of an AAV vector to deliver new technology must be balanced with and multifactorial, the mainstay of a soluble form of the VEGF recep- thoughtful cost-effectiveness analysis. treatment for the neovascular form tor into the eyes of similar patients.15 Finally, it remains to be seen wheth- is vascular endothelial growth factor These are landmark trials of drugs that er gene therapy may be used in con- inhibition, which currently requires may ultimately replace monthly thera- junction with, in place of, or will be monthly evaluation and repeat intra- peutic injections for patients with neo- replaced by cell-based regenerative vitreal injections. Though this repre- vascular disease. therapies on the horizon.16 One thing sented a breakthrough in the treat- Retinal vascular disease, including is certain: For thousands of patients ment of this disease, the frequency of diabetic retinopathy and retinal vein (continued on page 81)

60 | Review of Ophthalmology | October 2013

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RP0913_Keeler Indirects.indd 1 8/12/13 12:05 PM Therapeutic Topics REVIEW

The Modern Wisdom Of Clinical Models How models of disease, carried out in the clinic, can yield useful information about an ailment and treatments for it. Mark B. Abelson, MD, CM, FRCSC, FARVO, and Lisa M. Smith, Andover, Mass.

he perceptive thinker Hip- The modern approach to drug other allergy symptoms, including T pocrates famously declared, “Vita discovery rests on the foundation of tearing and swelling, have subjective brevis, Ars longa, Occasio praeceps, randomized, double-masked clinical components that are halfway between Experimentum periculosum, Iudi- trials in predefined disease popula- a sign and symptom.1 In contrast, dry- cium diffi cile,” or, “Life is short, art tions, yet the nature of certain diseas- eye disease has a plethora of symp- long, opportunity fl eeting, experiment es sometimes makes defi ning a drug toms related to us by the patient: dry- perilous, judgment diffi cult.” When effect extremely difficult. In these ness; scratchiness; grittiness; burning; you think about it, this could be aptly cases, a clinical model that mimics the stinging; itching; ocular fatigue; and, applied to nearly all circumstances in disease may provide a superior plat- rarely, photophobia. How can a cli- medicine. In our short lifespan, we form for investigating the activity of nician accurately measure the daily are physicians with a craft, a skill that drugs in a clinical setting. Those dis- incidence and severity of these sub- takes a lifetime to acquire and hone, eases that are best served by a model jective symptoms? The subject diary and despite our training and experi- include conditions with: 1) a strong has been the conventional method ence we face diffi cult diagnostic and subjective component with regard of collecting subjective data outside treatment decisions on a daily basis. to symptoms; 2) inherent temporal, of the clinic, but it is fraught with in- How would this aphorism stand up locational and behavioral variability, consistencies and, when it is com- to the study of therapeutics and their both between and within subjects; pleted, is often done so cursorily in development? Just as well. While the and 3) signifi cant placebo effi cacy. In the parking lot just before the doctor’s history of medicine is full of perilous ophthalmology, two such diseases are visit. The elegance of a disease model trial-and-error discoveries of thera- ocular allergy and dry eye. in this setting lies in the fostering of pies, in the 20th century and beyond symptoms’ appearance directly in the our approach has been more selec- Moving Targets presence of the clinician, who no lon- tive, more precise, and more able to ger has to jog the patient’s memory to predict a response at onset of treat- To describe the utility of modeling, retrieve an accurate recapitulation of ment as well as monitor the duration let’s fi rst drill down on the characteris- the disease process. This is a reverse of its action. To do this, drug develop- tics of each of these diseases. With the case of “now you have it, now you ment methods need to distill the dis- exquisitely sensitive cornea to reckon don’t,” in which consistent, reproduc- ease to its essence in a discrete time with, ocular surface diseases are all ible, real-time subject grading pro- frame where clinically and statistically defi ned by ocular pain or discomfort. vides invaluable data on how a drug signifi cant effects can be compared to Itching is the pathognomonic symp- can alter disease symptoms. an active or negative control. tom of allergic conjunctivitis, while The second disease characteristic

62 | Review of Ophthalmology | October 2013 This article has no commercial sponsorship.

062_rp1013_ttops.indd 62 9/20/13 12:20 PM that benefits from a modeling ap- Locational variability is far more proach is variability. Allergic sensitivi- diffi cult to control in a clinical setting, ty is highly variable between individu- however. A person in today’s world als: Patients may experience anything typically moves between four or more from mild itching or rhinorrhea to distinct environmental settings: the off-the-chart IgE levels and risk of home; public or private transporta- anaphylaxis. Similarly, dry-eye disease tion; the workplace; and various out- can run the gamut from mild irritation door or public spaces between the due to prolonged visual tasking (such others. Each of these environments as a day in front of a computer screen) has its own level of pollutants, pollen to a debilitating level of corneal abra- and other potential allergens, and its sion, pain and photophobia. With own characteristic relative humidity, such diversity in the patient popula- temperature, ventilation and lighting. tion, it’s likely that responses to a po- All of these factors can affect the signs tential therapeutic will also be varied. and symptoms of dry eye or ocular Using a clinical model it’s possible allergy. Similarly, the drastic changes to identify a potential study group in environment and location that may with disease severity that’s not so mild occur on weekends can also greatly or so severe that a drug effect cannot alter a person’s disease, be it freedom be readily observed. In addition, sub- Traditional diagnostics such as tear-fi lm from reading, writing and staring at jects with a similar, moderate severity breakup can be automated for use in a computer eight hours a day for a of disease are more likely to display clinical trials. dry-eye sufferer, or outdoor activities a clinically significant magnitude of like hiking or cycling for the pollen response to an effective therapy. In noting and controlling for the time allergy sufferer. This behavioral varia- this way models allow us to reduce the of offi ce appointments when doing a tion adds an additional layer to the noise inherent in a variable disease clinical trial, as a dry-eye subject will complexity of tracking ocular surface and provide a true measure of a treat- be much more naturally symptomatic disease process and treatment. ment’s clinical value.2-4 at an evening appointment. A second It’s important to remember that Temporal variability is also a com- form of temporal variability involves all these types of variability are un- mon feature of many diseases. Is the the seasons: Is the disease character- controlled and uncontrollable not disease worse or better in the morning ized by seasonal fluctuations? Pol- only across subjects (inter-subject or evening? Does it subside at night? len allergies are an obvious example variability), but also within subjects In the case of allergy, two possibilities of this, but the worsening of dry-eye (intra-subject variability), creating a are common. Allergy sufferers who symptoms in the low humidity of in- situation of waxing and waning signs are sensitive only to airborne pollens door winter environments is another and symptoms without consistency, a will be less symptomatic in the eve- seasonal accent to this complex dis- highly variable signal that can make nings while in bed (with eyes closed) ease. the identifi cation of a drug effect dif- away from exposure. This is also true The third type of disease variability fi cult or impossible. for dry-eye sufferers with their lids is locational. Geographic differences closed, allowing the ocular surface in ocular surface disease incidence The Placebo Effect time to reset tear-fi lm imbalances and or severity are typically due to dif- avoid the high cost of tear evapora- ferences in climate: Arid regions are The difficulty in conducting reli- tion. In contrast, a subject with mite worse for dry eye while temperate able clinical trials is impeded further allergies might fi nd bedtime to be his climates and long growing seasons can when signs and symptoms respond worst nightmare when it comes to al- exacerbate pollen sensitivities. There’s to placebo treatment. In some condi- lergic symptoms. also growing evidence that urban pol- tions, the placebo in a topical drug The dry-eye patient generally feels lution contributes to both chronic dry trial may be similar to the current good in the morning, after the ocular eye and allergic infl ammation.6-8 On treatments used by trial subjects. For surface has been protected through- the opposite end of the spectrum, the dry-eye treatment trials, the major- out the night, and progressively wors- absence of dust mites at higher eleva- ity of subjects are already using tear ens with time awake.5 This obser- tions can provide a needed respite to substitutes ad lib, and while they may vation highlights the importance of both allergy and asthma sufferers. only provide transient symptomatic

October 2013 | Revophth.com | 63

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REVIEW Topics

relief they are, for many patients, the to the eye has been performed for able conditions. In this way, variabil- best available therapy. Nevertheless, a decades to study allergic disease, the ity originating from inherent differ- negative control is needed to compare fine control that has evolved in ev- ences in allergic sensitivity, time of effi cacy across double-masked, ran- ery aspect of this protocol has led to day, season, location and behavior are domized, placebo-controlled trials. the approval of 19 anti-allergic drugs all minimized. With these variables This is usually provided by the drug since its acceptance as a validated taken care of, the benefi cial effects of vehicle, whose comfort, particularly method for drug development in placebo are reduced and a true drug in the case of dry eye, is maximized 1990.10 effect can be accurately defi ned.11 in terms of osmolarity and wettability. In the CAC, pre-selected subjects It is highly predictable, then, that this with a history of ocular allergy and The CAE Model vehicle will provide signifi cant benefi t a positive skin test are administered to dry-eye sufferers used to treating baseline challenges on two separate The ocular surface is exquisitely their disease with tear substitutes. visits with the allergen to which they in tune with its environmental con- Placebo effects also impact ocular are sensitized, establishing a repro- ditions, and manipulation of factors allergy trials, although their effect is a ducible, and consistent, bilateral such as temperature, wind or relative bit more complex. Tear substitutes or response of moderate severity to a humidity can provide a means to in- vehicle placebo can provide multiple pre-determined dose. The step-wise duce tear-fi lm instability and a desic- benefits to the allergy sufferer and increases in allergen also bring all cating stress on the ocular surface. In thus confound clinical trial fi ndings. subjects to approximately the same the controlled adverse environment, They wash away environmental al- reaction, avoiding the large fl uctua- subject responses to an adverse envi- lergens, minimizing their contact with tions caused by differences in sensi- ronment challenge while performing surface antibodies and mast cells. tivity. Subjects can then be adminis- a visual task are used as a baseline, They also dilute the in-place media- tered drug in the prescribed dosage and aid in identifying a defi ned popu- tors released by previous exposure, regimen in a double-masked, ran- lation of subjects with comparable including histamine, prostaglandins, domized, placebo-controlled fashion. disease signs and symptoms. Like the leukotrienes, chemokines and cyto- While this might appear to be pre- CAC, the CAE can also be used to as- kines. Finally, the wettability effects vention rather than treatment of an sess test-agent effi cacy by measuring of topical placebos provide comfort allergic response, the Food and Drug changes in the dry-eye status of sub- and relief from ocular surface dam- Administration accepts this method jects from baseline to post-challenge age and inflammation, even in the since it reflects the nature of aller- through slit lamp evaluations, validat- absence of the well-known comorbid- gic disease, which is actually episodic ed scoring of dry-eye redness by the ity of allergy and dry eye,6 leading to bursts of mediator release in response investigator and by computer,12 stain- decreased symptomology.9 With these to exposure, and whose treatment ing with fluorescein and lissamine, obstacles to overcome, it’s a wonder can be seen as a temporary breach in tear-fi lm breakup times13 and Schirm- that any drug has been approved these episodes. After drug treatment, er’s testing. The subject’s symptomol- based on environmental studies. the subject is again challenged and ogy is graded individually and with a Of course, use of models in ocular signs and symptoms are graded with variety of validated grading systems, surface drug development is a subject scales developed in the past 25 years again in a clinical setting and in real we’ve been involved in for quite some that are tailored to the nuances of time, preventing the vagaries of diary time.10 Now that we’ve described itching, redness and swelling specifi c completion and with no hindrance some of the general factors involved to allergy. The itching scale in particu- from subjective memory. Finally, pre- in the decision to use a model-based lar allows the subject to grade his or cise methods have been developed protocol to test drug effi cacy, let’s take her symptoms in front of the clinician to assess blink behavior,14,15 tear-fi lm a closer look at the specific aspects with confi dence that data are being dynamics (OPI)16 and visual function of two models that we have designed collected in real time.9-11 during tasking (IVAD),17 all of which and refined to respond to each of This challenge method identifies can be combined with CAE challenge these impediments to well-founded effects at onset, and also the duration in a before-and-after protocol. Often, and reproducible clinical science. of effect, which is almost impossible CAE challenge-based studies are con- to ascertain under natural conditions. ducted in concert with environmental Conjunctival Allergen Challenge Thus, the CAC model creates a dis- collection of data, since treatment crete allergic reaction in all subjects with active dry-eye molecules typi- While the instillation of allergen in-office, under clinically observ- cally requires treatment durations of

64 | Review of Ophthalmology | October 2013

062_rp1013_ttops.indd 64 9/20/13 12:21 PM one month or more. Like the CAC model, the CAE model minimizes the inter- and intra-subject variability of inherent disease, environment and behavior. This dampening of background noise again aids in minimizing the benefi cial effects of placebo when evaluating a drug.2-4,9-11 Overall, models allow us to focus on the potential effi cacy of test compounds in shorter, more defi ned time frames. This allows for a streamlining of the development process with benefi ts to both the developers and consumers alike. Even when there is a desire for large-scale trials using more traditional protocols, disease models can provide vital proof-of-concept fi ndings to speed the best therapeutics to the patients. Though it’s true “life is short and art long,” is it possible that clinical models have let us sidestep the ancient wisdom, the idea of advancements in medicine evolving in incremental steps over time? Or have we simply seized the fl eeting opportunity to test clinical science with the tools available today, based on a foundation of knowledge built over centuries? Medicine and clinical science have unquestionably benefited from disease models, which provide the opportunity for the experiment and judgment of Hippocrates with the velocity and precision that today’s fast-paced society requires.

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School. Ms. Smith is a medical writer at Ora Inc.

1. Leonardi A, Bogacka E, Fauquert JL, et al. Ocular allergy: Recognizing and diagnosing hypersensitivity disorders of the ocular surface. Eur J Allergy Clin Immunol 2012;67:1327-1337. 2. Ousler GW III, Gomes PJ, Welch D, Abelson MB. Methodologies for the study of ocular surface disease. Ocul Surf 2005;3:3:143. 3. Abelson MB, Knight E. Dry eye therapy: Evaluation of current directions and clinical trials. Adv Exp Med Biol 1994;350:431-6. 4. Abelson MB, Ousler GW III, Nally LA, Emory TB. Dry eye syndromes: Diagnosis, clinical trials and pharmaceutical treatment-‘improving clinical trials’. Adv Exp Med Biol 2002;506(B):1079-86. 5. Walker PM, Lane KJ, Ousler GW III, Abelson MB. Diurnal variation of visual function and the signs and symptoms of dry eye. Cornea 2010;29:6:607-12. 6. Gomes PJ, Ousler GW III, Welch DL, Smith LM, Coderre J, Abelson MB. Exacerbation of signs and symptoms of allergic conjunctivitis by a controlled adverse environment challenge in subjects with a history of dry eye and ocular allergy. Clin Ophthalmol 2013;7:157-65. 7. Barnes CS, Alexis NE, Bernstein JA, et al. Climate change and our environment: The effect on respiratory and allergic diseases. J Allergy Clin Immunol Pract 2012;1:2:137-141. 8. Warm K, Lindberg A, Lundback B, Ronmark E. Increase in sensitization to common airborne allergens among adults: Two population-based studies 15 years apart. Allergy Asthma Clin Imunol 2013;9:1:20. 9. Abelson MB, Loefﬂ er O. Conjunctival allergen challenge: Models in the investigation of ocular allergy. Curr Allergy Asthma Rep 2003;3:4:363-8. 10. Abelson MB, Chamber WA, Smith LM. Conjunctival allergen challenge. A clinical approach to studying allergic conjunctivitis. Arch Ophthalmol 1990;108:1:84-8. 11. Abelson MB. Comparison of the conjunctival allergen challenge model with the environmental model of allergic conjunctivitis. Acta Ophthalmol Scand Suppl 1999;228:38-42. 12. Rodriguez JD, Johnston PR, Ousler GW 3rd, Smith LM, Abelson B. Automated grading system for the evaluation of ocular redness associated with dry eye. Clin Ophthalmol 2013;7:1197-1204. 13. Abelson MB, Ousler GW 3rd, Nally LA, Welch D, Krenzer K. Alternative reference values for tear ﬁ lm break up time in normal and dry eye populations. Adv Exp Med Biol 2002;506(B):1121-5. 14. Johnston PR, Rodriguez J, Lane KJ, Ousler G, Abelson MB. The interblink interval in normal and dry eye subjects. Clin Ophthalmol 2013;7:253-9. 15. Rodriguez JD, Ousler GW III, Johnston PR, Lane K, Abelson MB. Investigation of extended blinks and interblink intervals in subjects with and without dry eye. Clin Ophthalmol 2013;7:337. 16. Ousler GW III, Hagberg KW, Schindelar M, Welch D, Abelson MB. The Ocular Protection Index. Cornea 2008;27:5:509-13. 17. Torkildsen G. The effects of lubricant eye drops on visual function as measured by the Interblink Interval Visual Acuity Decay test. Clin Ophthalmol 2009;3:501-506.

062_rp1013_ttops.indd 65 9/20/13 12:21 PM Glaucoma Management

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

The Forgotten Piece in The Compliance Puzzle Getting your glaucoma patients to come in as recommended may be just as important as proper medication use. Shan C. Lin, MD, San Leandro, Calif., and Kuldev Singh, MD, MPH, Stanford, Calif.

very doctor managing glaucoma cation refill and follow-up data on Our most recent study was done E knows that compliance is a sig- the same patients for whom disease in two parts. The fi rst author of both nificant factor in how well patients progression has been monitored at reports was Cindy Ung, a medical respond to treatment. However, two San Francisco General Hospital. We student at Stanford University types of compliance can affect the hypothesized that how well glaucoma who performed a cross-sectional outcome: compliance with medication patients do over time might not analysis on patients at San Francisco use—the type of compliance that has simply be a question of whether or General Hospital. To determine been the focus of much work and not they are taking their medications, subjects’ level of disease we used discussion—and compliance with but also how closely they are being classifications of glaucoma severity recommended follow-up visits. monitored. Regular follow-up allows based on the American Academy of Hundreds of papers about medi- determination of disease course with Ophthalmology’s Preferred Practice cation compliance have been pub- adjustment of medications, as well Patterns. For purposes of determining lished. In contrast, little has been as consideration of laser and surgical compliance with medication use, we written about the impact of appro- options for those who are doing poorly examined the patient’s refill history priate surveillance on disease out- with current therapy. using a previously validated method. comes. Recent data, however, shows While taking appropriate medi- The fi rst paper looked at medication that patient compliance with follow- cations as prescribed likely improves adherence among glaucoma patients.1 up—returning for exams at the times outcomes, such therapy has its limi- It found that patients who had more prescribed by the doctor—may be at tations; not all compliant patients severe glaucoma were more compliant least as important as how faithfully the are destined to do well. Making the with medical therapy than those with patient uses prescribed medications. assumption that medication com- mild or moderate stages of disease, as Here, we’d like to share some of pliance insures good outcomes, indicated by a greater propensity to the surprising fi ndings recent studies and placing insufficient emphasis refi ll their prescriptions (See Table 1). have uncovered, and discuss the im- on appropriate follow-up, can lead (These results contradict a previous plications for clinicians striving to to disaster. Given that glaucoma is study that found that patients who achieve the best possible outcomes. often an asymptomatic disease until were more diseased were less com- late in the disease course, patients pliant with their medications.2) The Power of Follow-up who forget to return to your offi ce— One possible explanation for these perhaps assuming that simply taking fi ndings is that people who have more Our group has been fortunate the medications is enough—might be severe disease probably receive more enough to have access to both medi- getting worse without knowing it. counseling and are more aware of

66 | Review of Ophthalmology | October 2013 This article has no commercial sponsorship.

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0000_topcon_blast/ad_v2.indd 1 9/6/13 11:13 AM Glaucoma

REVIEW Management

their visual defi cit than those with less- Table 1. Multivariable Logistic Regression Analysis of Factors severe disease. That awareness might 1 explain why they were more likely to for Poor Medication Adherence in Glaucoma Patients (n=126) use their medications as directed. Variable Adjusted Odds Ratio P Value Our second study looked for correlations between disease severity, Age (per year) 1.03 (0.99-1.07) 0.22 medication use and compliance with Gender 1.07 (0.50-2.29) 0.87 3 follow-up visits. After adjusting for Race (Asian vs. non-Asian) 0.61 (0.27-1.39) 0.24 confounding factors, the data revealed that being less adherent to Education (less than high school vs. more) 0.77 (0.34-1.74) 0.53 the recommended follow-up schedule Glaucoma diagnosis (POAG vs. other) 0.85 (0.40-1.81) 0.67 was associated with more severe glau- No. of medications (1 vs. ≥2) 0.66 (0.28-1.57) 0.35 comatous disease (See Table 2). Pa- tients who had only mild or moder- Years of having glaucoma (per year) 1.00 (0.93-1.08) 0.92 ate glaucoma were more compli- Disease severity (mild/moderate vs. severe) 1.54 (1.03-2.31) 0.04 ant with keeping appointments as In contrast to a previous study, this data indicated that patients with more severe disease recommended than those with more were more compliant with medication use, not less. severe disease. Given the cross-sectional nature of the study, we were (due to some other cause) leading to greater disease severity and poor unable to address the issue of causa- a worsening of the disease? follow-up compliance suggest that tion—i.e., did more regular follow- Unfortunately, we can’t fully answer compliance with follow-up may be up result in better outcomes? Never- that question in a cross-sectional a complex and underappreciated theless, the findings are a basis for study, and performing a prospective parameter that influences the well- exploring this hypothesis further in a randomized trial to address the issue being of glaucoma patients. These prospective study. would require closer surveillance data are a reminder: Using your medi- of one group of glaucoma subjects cations properly is important, but Making Sense of the Data versus another with equally severe it’s not a substitute for appropriate disease, a study design that may not recommended follow-up to maximize How can we account for the fi nding be considered ethical. your chances of a good outcome. that patients who were more likely to Interestingly, we found no racial or use their medications as prescribed ethnic correlations to the likelihood Clinical Implications were less likely to return for follow-up of returning for follow-up visits in the visits? It’s possible that these patients study. The only factors that correlated Given this new data, clinicians were thinking, “Well, I’m fi ne. I don’t with poor follow-up were disease may want to put more emphasis need to go see the doctor so often severity and glaucoma medication on conveying to their patients the because if I’m taking my medications, usage. In contrast, some previous importance of adherence to recom- the disease must be under control.” studies of other cohort populations mended follow-up. Using medications In contrast, those who were not have found associations between as prescribed is still important, but taking their medications regularly factors such as race and ethnicity without timely, regular examinations may have been more fearful of the and inconsistent follow-up.4 And, to check the patient’s status and adjust adverse consequences of medication of course, some patient populations the medications as necessary—as noncompliance and felt a greater might face fewer practical obstacles well as offer non-medical therapeutic need for regular surveillance. to returning for follow-up visits than options when appropriate—patients Another question is whether the was the case with our population. may be at greater risk of vision loss. association between disease severity There may also be differences in As noted, our studies did not fi nd and follow-up inconsistency refl ects appreciating the need to return for an association between ethnicity some kind of causal link. If patients checkups amongst different patient or race and follow-up compliance, with worse disease are less reliable populations, so our results don’t ne- but other studies have. So along about returning for follow-up visits, cessarily refl ect the situation in every with emphasizing the importance is the worse condition of the eyes ophthalmology practice. of follow-up, clinicians may want to partially interfering with the patients’ Nevertheless, the associations we make an extra effort to address the return? Or is the failure to return found between medication usage, needs of specific patient groups to

October 2013 | Revophth.com | 69

066_rp1013_gm.indd 69 9/20/13 11:53 AM RP1013_Tomey.indd 1 9/20/13 10:20 AM Glaucoma

REVIEW Management

increase the likelihood of them re- Table 2. Multivariable Logistic Regression Analysis of Factors turning in a timely manner. If your 3 glaucoma patient population includes for Poor Follow-up Adherence in Glaucoma Patients (n=206) patients whose first language is Variable Adjusted Odds Ratio P Value not English, for example, you may Age (per year) 1.00 (0.96-1.03) 0.81 consider providing information and Gender 0.60 (0.32-1.12) 0.11 instructions in multiple languages. Race (Asian vs. non-Asian) 0.78 (0.41-1.47) 0.46 Studies have also found that poor Education (more than high school vs. less) 1.10 (0.58-2.08) 0.68 follow-up compliance is associated Years of having glaucoma (per year) 1.03 (0.97-1.09) 0.36 with unfamiliarity with the necessary treatment duration, lack of knowledge Glaucoma surgery (yes or no) 0.73 (0.30-1.74) 0.39 about the permanency of glaucoma- Medications (yes or no) 3.29 (1.41-7.65) 0.01 induced vision loss and the perception Disease severity (severe vs. mild/moderate) 1.89 (1.21-2.94) 0.01 that it isn’t important to attend follow- Expected no. of follow-up visits (mild: two visits; 1.55 (0.60-3.98) 0.37 up visits. Making sure your patients moderate/severe: three visits) don’t fall into any of these categories This study found that patients with severe disease were less likely to return for follow-up could go a long way toward changing exams as recommended than those with less-severe disease. their behavior, in terms of coming back for follow-up visits. Electronic by the practice. This might also be make sure our patients do understand health records may be able to help another area in which electronic the nature of the disease and the in this regard. Currently, some sys- medical records could help. If a importance of returning for follow- tems have the ability to print out an patient fails to return at the scheduled up visits—especially in light of this information sheet for each patient time, the system could contact the new data. We have more available at checkout; it should be possible to patient by phone or automated treatment options for glaucoma have such a sheet available in multiple email, perhaps based on the patient’s than ever before; keeping patients languages. preference, while also alerting staff if under appropriate surveillance, and In an ideal world, one way to deal the patient fails to reschedule. thereby maximizing their likelihood with poor follow-up compliance of receiving the right treatment at the would be to treat the glaucoma in Spreading the Word right time, may be the single most a manner that doesn’t require fre- important factor in optimizing the quent follow-up. Unfortunately, such Unfortunately, among doctors odds of vision preservation. an option doesn’t currently exist. treating glaucoma it’s not uncommon That’s a message worth Laser trabeculoplasty is helpful to have the occasional patient come spreading. in some situations in which people in having lost a signiﬁ cant amount of have difﬁ culty returning for follow- vision in one eye—a patient that we Dr. Lin is a professor of clinical up, perhaps in developing coun- may have seen years ago who then ophthalmology and director of the tries; but in general the pressure dropped off the radar. At the outset, Glaucoma Service at the University reduction achieved is moderate and of course, glaucoma may not be as- of California at San Francisco. Dr. the magnitude and length of the sociated with any symptomatology; Singh is a professor of ophthalmology effect is variable, making appropriate patients may lose much of their vision and director of the Glaucoma Service follow-up a necessity. Surgery is an before realizing that something is at Stanford University School of option we sometimes resort to in really wrong. At the same time, we all Medicine.

order to address an individual’s poor have a lot going on in our lives, so it’s not 1. Ung C, Zhang E, Alfaro T, Murakami Y, Zhang M, Seider MI, Lin compliance with using medication; hard to imagine how someone could SC, Singh K. Glaucoma severity and medication adherence in a county hospital population. Ophthalmology 2013;120:6:1150-7. but again, follow-up may be even postpone coming in for a checkup— 2. Sleath B, Blalock S, Covert D, et al. The relationship between more important in these situations. especially if the patient doesn’t fully glaucoma medication adherence, eye drop technique, and visual ﬁ eld defect severity. Ophthalmology 2011;118:2398-402. (Certainly when trabeculectomy is grasp the seriousness of the situation. 3. Ung C, Murakami Y, Zhang E, Alfaro T, Zhang M, Seider MI, performed, follow-up is crucial.) Sadly, by the time patients have lost Singh K, Lin SC. The Association Between Compliance With Recommended Follow-up and Glaucomatous Disease Severity in One possibility for getting patients vision from glaucoma, the effects are a County Hospital Population. Am J Ophthalmol 2013;156:2:362-9. to follow-up in a timely manner is generally irreversible. 4. Murakami Y, Lee BW, Duncan M, Kao A, Huang JY, Singh K, Lin SC. Racial and ethnic disparities in adherence to glaucoma to coordinate their care with the Either way, as the caregivers, it’s follow-up visits in a county hospital population. Arch Ophthalmol assistance of someone designated our job to do everything possible to 2011;129:7:872-8.

October 2013 | Revophth.com | 71

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000_rp1213AlcChiOS.indd 86 9/23/13 12:15 PM Refractive Surgery

REVIEW Edited by Arturo Chayet, MD

The Dos and Don’ts of Phakic Lens Implants These lenses can give excellent results in selected patients, but there’s both an art and a science to their implantation. Walter Bethke, Managing Editor

or patients who aren’t ideal can- high-frequency ultrasound, we have a • Peripheral iridotomies. Dr. F didates for corneal refractive sur- better idea of what that measurement Moshirfar says that in some cases the gery, surgeons say it can be useful is behind the iris, but, despite that, you Visian may float around a bit, mak- to have phakic lenses in your arma- can’t control the amount of separa- ing two preop iridotomies imperative. mentarium. However, performing an tion that will exist between the Visian “With the Visian, you need to make intraocular procedure, especially with and the anterior lens capsule, which your YAG PIs before the surgery, pref- the crystalline lens still present, pres- should be a vault of between 250 and erably one to three weeks prior,” says ents a number of challenges different 500 µm. In some cases, you may fi nd Dr. Moshirfar. “You need to make two from those associated with LASIK that the vault is good in the beginning PIs and make them peripheral enough and PRK. Here, several experts adept but gradually decreases, or you may be so patients don’t have aberrations as a at implanting these lenses tell how surprised that the vault is a lot less than result of them, because in some cases you can enjoy safer, better outcomes. you anticipated. There are only four patients can see the iridotomies as well sizes of the Visian so, as a result, not as light distortions in the periphery, The Visian ICL every patient will fi t perfectly into one especially if they have large palpebral of them, meaning you can’t control the fissures and don’t have the superior For the Staar Visian, surgeons say lens vault.” brow or lid covering the superior iris. there are several stages of the lens Dr. Moshirfar says there are a vari- It’s very important that you put the measurement and implantation that ety of ways to measure the sulcus-to- PIs around the 10 o’clock or 11 o’clock are crucial. sulcus diameter, but he recommends positions, or at 1 o’clock and 2 o’clock. • Preop measurements. “The en- ultrasound biomicroscopy if at all pos- Try to avoid the 2:30, 3 o’clock, and dothelial cell count is important for sible, and even has a certifi ed ultraso- 9 o’clock positions, which will cause both [the Visian and the Verisyse],” nographer who does the measurement patients to defi nitely see the PIs and says Majid Moshirfar, MD, director of in each case to minimize variability. “If the light coming through them. Some- refractive surgery and cornea for the my patient’s anterior chamber is very times, you even have to take the patient Moran Eye Center at the University deep—from 3.6 to 4 mm—and if I into the operating room and tattoo the of Utah. “So the surgeon needs a good have a good sulcus-to-sulcus measure- cornea in those areas so they don’t see anterior chamber depth measurement. ment, the Visian is a good option,” Dr. the light coming through the PIs.” With the Visian, it is still a challenge to Moshirfar says. “But if I don’t have a Minneapolis surgeon Sherman get an exact measurement of the sul- solid sulcus-to-sulcus measurement Reeves says that doing the PI ahead cus-to-sulcus diameter, which is a key I think the Verisyse would be a good of time has a couple of benefits. “If to its implantation. With the advent of choice.” I haven’t obtained a UBM, I can do

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REVIEW Surgery

it at that visit, too,” he says. “Also, step in the groove,” says Dr. Piracha. “I though it’s uncommon, you can get put one slipknot suture in the center of some bleeding with an intraoperative the wound after I put the lens in, which surgical PI, so I like to keep the actual maintains the chamber so I can better surgery as quiet as possible.” work in it. This is important because • Folding and implantation. Dr. these myopes often have fl oppy eyes Moshirfar recommends using Ocu- and you worry about chamber collapse Coat in conjunction with the Visian. and the lens touching endothelium. I “Mix the OcuCoat 50/50 with saline then perform enclavation [discussed solution in the lens cartridge,” he says. Using a needle to enclavate the iris into the below] and then pass the next two su- “Make sure the lens is symmetrically clips on either side of the Verisyse can be tures and, before tying them, remove folded and not torqued in the car- challenging, surgeons say. all the viscoelastic from the anterior tridge. And don’t put too much Ocu- chamber.” For viscoelastic, Dr. Pira- Coat into the anterior chamber—use ences at the University of Louisville. cha recommends a cohesive visco that just enough so you can put your lens “A nice feature of the Pentacam HR is comes out easier than a dispersive. “I inside and behind the iris. As the lens an Artisan/Verisyse preop calculation, don’t like a dispersive because it stays unfolds in the chamber, be patient and that lets you make sure the eye has the in the eye, is more diffi cult to remove inject it slowly so the fi rst set of wings normal anatomy for a Verisyse implant. and can cause pressure spikes.” of the ICL can gradually open. Then, The device shows a virtual image of • Enclavation. This is a maneuver slowly tuck them beneath the nasal the Verisyse in the patient’s anterior unique to the Verisyse that fi xates it in iris. As the lens unfolds, you can get chamber, demonstrating whether or place on the iris. To do it, the surgeon the other two ends of the ICL under not there’s enough space for the lens. It uses a special needle to bunch up bits the temporal iris. Making sure that the will also show what the patient’s cham- of iris into small clips on either end of patient is well-dilated is very helpful. ber will look like in 20 or 30 years, since the lens. “If I do a superior incision, I “Later, when doing I/A, don’t be as we age the natural lens thickens and do my nasal enclavation fi rst because overly aggressive,” Dr. Moshirfar adds. the chamber gets narrower.” there’s less space on that side because “This can create turbulence in the an- • Incision.While the Visian is fold- the pupil tends to be more nasal, as terior chamber that can create tran- able and goes through a temporal clear well as superior,” says Dr. Piracha. sient anterior subcapsular vacuoles, cornea incision, the Verisyse requires “Then I do the temporal enclavation and can cause some swelling in the a 5.5 to 6 mm incision that’s not com- because I have more space. If I’m us- anterior lens capsule’s epithelial cells, pletely corneal: surgeons recommend ing a temporal incision—in cases of which could cause issues later.” limbal-corneal or scleral-limbal. Be- against-the-rule astigmatism—I do the cause the incision’s large, many sur- superior enclavation fi rst.” The Verisyse geons prefer making it superiorly. Dr. Moshirfar says it pays to encla- “Most of these high myopes who re- vate correctly the fi rst time. “You re- The AMO Verisyse goes into the ceive the Verisyse have with-the-rule ally shouldn’t try to enclavate each side anterior chamber, so surgeons say its astigmatism or oblique astigmatism, more than twice,” he says. “Even if the considerations differ from the poste- so it makes sense to make a superior lens isn’t perfectly centered, don’t keep rior chamber Visian. wound,” says Dr. Moshirfar. “That way, trying, because you’ll reach a point • Anterior chamber depth. Un- afterward when there is conjunctival- where the iris is traumatized and you like the Visian, which relies on the ization of the cornea in that area, the won’t have enough iris for the enclava- sulcus-to-sulcus measurement, the vessels don’t look so red and patients tion. The best advice I can give is to anterior chamber depth and its vault don’t have the look of episcleral infl am- mark the center of the pupil on the size for proper results, surgeons say mation. The upper lid covers it up and corneal surface and then place two tiny that the Verisyse is mainly dependent it heals nicely.” Surgeons also recom- ink marks on the cornea corresponding on the anterior chamber depth. “The mend a nerve block in Verisyse pa- to the spots on the iris where you will key is you have to have an anterior tients to avoid issues from squeezing. want to enclavate. This way, you can chamber depth of at least 3.2 mm,” Managing sutures is also a part of the gauge your centration once you’re in says Asim Piracha, MD, associate pro- Verisyse surgery. “I make a limbal inci- the eye because, by that time, the pupil fessor in ophthalmology and visual sci- sion, make a groove, then create a nice may be a different shape.”

October 2013 | Revophth.com | 75

073_rp1013_rs.indd 75 9/20/13 11:09 AM REVIEW Classiﬁ eds

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ROPH1013.indd 77 9/12/13 8:27 PM REVIEW Classiﬁ eds

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78 | Review of Ophthalmology | October 2013

ROPH1013.indd 78 9/12/13 8:27 PM Resident Case Series Wills Eye Edited by David Perlmutter, MD REVIEW

A contact lens wearer develops a corneal ulcer that is nonresponsive to multiple therapies.

Margaret Greven, MD

Presentation

A 55-year-old man with a history of soft contact lens wear presented to the Wills Eye Cornea Service for evaluation of six weeks of pain and blurry vision in the right eye. The patient initially presented to an outside optometrist who diagnosed a corneal abrasion in the right eye. Two weeks later he presented to an outside ophthalmologist with worsening symptoms in his right eye, was diagnosed with a corneal ulcer, and was initiated on moxifl oxacin 0.5% four times per day. He continued to worsen, and three days later he was started on fortifi ed vancomycin drops every hour while awake, oral valacyclovir 500 mg three times per day, and topical trifl uridine nine times per day, and corneal cultures were obtained. Cultures were negative for bacteria and fungi. Three weeks later the patient presented to the Wills Eye Cornea Service due to persistence of his symptoms. Prior to presenting to Wills, the patient had at one time been on the following treatments: loteprednol 0.5%; moxifl oxacin 0.5%; fortifi ed vancomycin; trifl uridine; tobramycin/dexamethasone; valacyclovir; doxycycline; and artifi cial tears.

Medical History

At his initial visit to Wills Eye, the patient denied contact lens overwear, sleeping in lenses, showering or swimming in lenses. His ocular history was otherwise negative. His past medical history was signiﬁ cant only for hyperlipidemia. His only systemic medication was a statin.

Examination

The patient’s visual acuity with correction was 20/100 in the right eye and 20/20 in the left eye. His pupils were equal and reactive with no afferent pupillary defect. His motility was full, and intraocular pressures were 8 mmHg bilaterally. On slit-lamp examination, the right eye revealed 1+ injection and a 3.75 mm x 4 mm inﬁ ltrate with an overlying epithelial defect (See Figure 1). The left eye had trace injection, scattered peripheral subepithelial corneal inﬁ ltrates, and a pseudo- dendritic epithelial staining pattern (See Figures 2 & 3).

Figure 1. Slit-lamp photo of the right eye Figure 2. Slit-lamp photo of the left eye on Figure 3. Slit-lamp photo of the left eye on on presentation showing central presentation with peripheral subepithelial presentation with pseudo-dendritic staining inﬁ ltrate with overlying epithelial defect. inﬁ ltrates. pattern.

What is your differential diagnosis? What further workup would you pursue? Please turn to p. 80

October 2013 | Revophth.com | 79

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Before reading on, please see p. 79 for presenting complaint, history and examination.

Diagnosis, Workup and Treatment

After examination of the right eye tive for Acanthamoeba in both eyes four-month course of treatment in the the patient was thought to have a bac- (See Figure 4). Corneal cultures and left eye. Visual acuity in the right eye terial ulcer with a component of medi- contact lens case cultures were nega- after treatment remained 20/200 due camentosa from his multiple topical tive. The patient was started on dual to central corneal scarring, while in the treatments. However, once the pseu- therapy with polyhexamethylene bi- left eye, visual acuity after treatment do-dendritic staining and subepithelial guanide (PHMB) and propamidine was 20/20. infiltrates were noted in the asymp- (Brolene) drops every hour tomatic left eye, suspicion was raised around the clock in both for Acanthamoeba keratitis. Both eyes eyes. were re-cultured for bacteria and fun- The patient had a slow gi, corneal scrapings from both eyes improvement on this treat- were sent for pathology, and the pa- ment regimen (See Figures tient’s contact lens case was sent for 5 & 6). The medications cultures. Polymyxin/bacitracin oph- were gradually tapered thalmic ointment every two hours was and the patient received a started in the right eye. Two days later ﬁ ve-month course of treat- pathology results were reported posi- ment in the right eye and a

Figure 5. Slit-lamp photo of the right eye improving after two months of treatment; vision 20/200.

Figure 6. Slit-lamp photo of the left eye after two months of treatment; vision 20/20, subepithelial inﬁ ltrates and Figure 4. Acanthamoeba cysts seen in corneal scrapings from both eyes. pseudo-dendritic staining resolved.

Discussion

Acanthamoeba keratitis is an in- known and strongest risk factor for tors that disrupt the normal epithelial fection of the cornea caused by cyst- Acanthamoeba keratitis is contact lens barrier of the cornea include minor forming protozoans ubiquitous in the wear, as well as inadequate lens dis- corneal trauma and epithelial base- environment.1 The condition was ﬁ rst infection.1-3 Additional risk factors in ment membrane dystrophy; dry eye described in the early 1970s but an contact lens wearers include swimming may also predispose to disease.1-3 increase in incidence occurred in the in lenses, overnight wear of lenses and Acanthamoeba keratitis is often 1980s associated with an increase in exposure of lenses to contaminated initially misdiagnosed as herpetic or soft contact lens wear.2 The most well- water and well water.4 Other risk fac- bacterial disease, leading to delay in

80 | Review of Ophthalmology | October 2013

079_rp1013_wills.indd 80 9/20/13 11:26 AM Retinal

REVIEW Insider

initiation of appropriate treatment.4,5 ites and cysts resulting in cell death.1 (continued from page 60) Clinical features of Acanthamoeba The diamidines include propamidine keratitis include pain out of propor- (Brolene) 0.1% and hexamidine 0.1% with inherited retinal degenerations tion to clinical signs, photophobia and and also work through increasing potentially amenable to treatment with tearing.1 Absence of pain does not, membrane permeability in both tro- this technology, the future is brighter however, preclude the diagnosis. Early phozoites and cysts.1 Treatment may than it was before. in the course of the disease, a pseudo- be initiated with either a biguanide dendritic epitheliopathy, subepithelial alone or a biguanide in addition to a Dr. Campbell is a vitreoretinal fel- infi ltrates and radial keratoneuritis may diamidine and is typically prescribed low at the Casey Eye Institute, Oregon be noted.1,4 Our patient in this case every hour around the clock for the Health & Science University. Follow- demonstrated the early Acanthamoeba first few days of treatment. Practice ing fellowship, he will return to the keratitis paradigm in his asymptom- patterns vary by provider as there are Wilmer Eye Institute to serve as the atic left eye. Of note, although this no studies demonstrating efficacy of Stephen J. Ryan Assistant Chief of Ser- eye was clearly involved, the patient dual therapy over monotherapy.7 Our vice. Dr. Stout is vice-president and a was without pain in his left eye. Later patient was initially started on dual professor of ophthalmology at OHSU. disease is characterized by ring infi l- therapy with PHMB and propamidine Contact Dr. Stout at [email protected]. trates, ulceration, keratic precipitates but due to propamidine toxicity fin- 1. Friedmann T. A brief history of gene therapy. Nature Genetics and sometimes hypopyon formation, ished out his course on PHMB alone. 1992;2(2):93-98. doi:10.1038/ng1092-93. demonstrated by our patient’s symp- His overall course of five months in 2. Liu MM, Tuo J, Chan C-C. Gene therapy for ocular diseases. Br J 1,4 Ophthalmol 2011;95(5):604-612. doi:10.1136/bjo.2009.174912. tomatic right eye. Prompt diagnosis one eye and four months in the other 3. Chung DC, Lee V, Maguire AM. Recent advances in ocular gene and treatment initiation is important in eye is typical, as most patients require therapy. Curr Opin Ophthalmol 2009;20(5):377-381. doi:10.1097/ ICU.0b013e32832f802a. Acanthamoeba keratitis because early several months of treatment prior to 4. Maguire AM, Simonelli F, Pierce EA, et al. Safety and Effi cacy treatment leads to better visual out- resolution.2 of Gene Transfer for Leber’s Congenital Amaurosis. N Engl J Med 4,5 2008;358(21):2240-2248. doi:10.1056/NEJMoa0802315. comes. Acanthamoeba keratitis is a chal- 5. Bainbridge JWB, Smith AJ, Barker SS, et al. Effect of Gene Definitive diagnosis of Acantha- lenging disease to diagnose and to Therapy on Visual Function in Leber’s Congenital Amaurosis. N Engl J Med 2008;358(21):2231-2239. doi:10.1056/NEJMoa0802268. moeba keratitis can be made only with treat. As early diagnosis and treatment 6. Cideciyan AV, Aleman TS, Boye SL, et al. Human gene therapy cultures or histology of corneal scrap- portends a better visual prognosis, for RPE65 isomerase defi ciency activates the retinoid cycle of 2 vision but with slow rod kinetics. Proc Natl Acad Sci USA 2008 ings as in our case. Confocal micros- Acanthamoeba must be considered in Sep 30;105(39):15112-7. doi: 10.1073/pnas.0807027105. Epub copy is used in some centers to aid in any patient thought to have herpetic 2008 Sep 22. 7. McClements ME, Maclaren RE. Gene therapy for retinal disease. diagnosis, with reported sensitivity in epithelial disease, contact lens-related Transl Res 2013. doi:10.1016/j.trsl.2012.12.007. one study of 90.6 percent and specifi c- subepithelial infi ltrates or a corneal ul- 8. Maguire AM, High KA, Auricchio A, et al. Age-dependent effects 6 of RPE65 gene therapy for Leber’s congenital amaurosis: A phase ity of 100 percent. If clinical suspicion cer unresponsive to treatment. 1 dose-escalation trial. Lancet 2009;374(9701):1597-1605. for Acanthamoeba keratitis warrants, doi:10.1016/S0140-6736(09)61836-5. 9. Mullard A. Gene therapies advance towards fi nish line. Nat Rev however, treatment should not be de- The author would like to thank Drug Discov 2011 Sep 30;10(10):719-20. doi: 10.1038/nrd3572. layed pending defi nitive diagnosis. Christopher Rapuano, MD, and Ralph 10. Cideciyan AV, Jacobson SG, Beltran WA, et al. Human retinal gene therapy for Leber congenital amaurosis shows advancing Treatment of Acanthamoeba kera- Eagle Jr., MD, for their assistance in retinal degeneration despite enduring visual improvement. titis is aimed at killing the cystic, or preparing this case. Proc Natl Acad Sci USA 2013;110(6):E517-25. doi:10.1073/ pnas.1218933110. dormant, form of the organism, which 11. Cepko C, Vandenberghe LH. Retinal Gene Therapy Coming of 1. Dart JK, Saw VP, Kilvington S. Acanthamoeba keratitis: Diag- Age. Hum Gene Ther 2013. doi:10.1089/hum.2013.050. is highly resistant to most treatments nosis and treatment update 2009. Am J Ophthalmol 2009;148: 1,2 12. Campochiaro PA. Gene Transfer for Neovascular Age-Related and can persist for months to years. 487-499. Macular Degeneration. Hum Gene Ther 2011;22(5):523-529. Two classes of medication have activ- 2. Hammersmith KM. Diagnosis and management of Acanthamoe- doi:10.1089/hum.2011.050. ba keratitis. Curr Opin Ophthalmol 2006 Aug; 17(4): 327-31. 13. Kauper K, McGovern C, Sherman S, et al. Two-year intraocular ity against Acanthamoeba cysts: bigu- 3. Page MA, Mathers WD. Acanthamoeba keratitis: A 12-year delivery of ciliary neurotrophic factor by encapsulated cell technol- anides and diamidines. These medica- experience covering a wide spectrum of presentations, diagnoses, ogy implants in patients with chronic retinal degenerative diseases. and outcomes. J Ophthalmol. 2013 Published online 2013 Jun 12. Invest Ophthalmol Vis Sci 2012;53(12):7484-7491. doi:10.1167/ tions are not commercially available in 4. Thebpatiphat N, Hammersmith KM, Rocha FN, Rapuano CJ, iovs.12-9970. the United States and can only be ob- Ayres BD, Laibson PR, Eagle RC Jr., Cohen EJ. Acanthamoeba 14. Campochiaro PA, Nguyen QD, Shah SM, et al. Adenoviral vector- Keratitis: A Parasite on the Rise. Cornea 2007;26:701-706. delivered pigment epithelium-derived factor for neovascular age- tained from compounding pharmacies 5. Chew HF, Yildiz EH, Hammersmith KM, Eagle RC Jr, Rapuano related macular degeneration: results of a phase I clinical trial. Hum CJ, Laibson PR, Ayres BD, Jin YP, Cohen EJ. Clinical Outcomes Gene Ther 2006;17(2):167-176. doi:10.1089/hum.2006.17.167. or from overseas. The two biguanides and Prognostic Factors Associated With Acanthamoeba Keratitis. 15. Safety and Tolerability Study of AAV2-sFLT01 in Patients With currently in use are polyhexameth- Cornea 2011;30:435-441. Neovascular Age-Related Macular Degeneration (AMD)–Full Text 6. Tu EY, Joslin CE, Sugar J et al. The relative value of confocal View–ClinicalTrials.gov. clinicaltrials.gov. Available at: http://clinical- ylene biguanide (PHMB) 0.02% and microscopy compared to superfi cial corneal scrapings in the trials.gov/ct2/show/NCT01024998. Accessed January 18, 2013. chlorhexidine 0.02%. These agents act diagnosis of acanthamoeba keratitis. Cornea 2008;27:764-767. 16. Singh MS, Charbel Issa P, Butler R, et al. Reversal of end-stage 7. Oldenburg CE, Acharya NR, Tu EY, et al. Practice patterns and retinal degeneration and restoration of visual function by photore- by disrupting the cytoplasmic mem- opinions in the treatment of acanthamoeba keratitis. Cornea ceptor transplantation. Proc Natl Acad Sci USA 2013;110(3):1101- brane of Acanthamoeba trophozo- 2011;30:1363-8. 1106. doi:10.1073/pnas.1119416110.

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