The Hidden Pitfalls of Postop Enhancement P. 32 Meeting the Expectations of Older Cataract Patients P

BREAKING NEW GROUND IN MEIBOGRAPHY P. 14 • WILLS RESIDENT CASE SERIES P. 78 REPORTS FROM THE U.S. SMILE STUDY P. 65 • USING VISUAL FIELDS TO PREDICT PROGRESSION P. 57 eiwo ptamlg o.X,N.7• uy21 Ctrc ugr su Patc n aaatSrey• h iflso otpEhneet Older Cataract Patients The Pitfalls of Postop Enhancements • Plastics and Cataract Surgery • Cataract Surgery Issue • July 2013 • Review of Ophthalmology Vol. XX, No. 7 • DISTINGUISHING INFECTION POST-ANTI-VEGF INJECTION P. 42 • ARVO VISITS THE EMERALD CITY P. 50

Part 1 of 2

JulyJuly 2013 •revo revophth.comphth.com

The Hidden Pitfalls of Postop Enhancement P. 32 Meeting the Expectations of Older Cataract Patients P. 38

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RP0713_Abbott.indd 1 6/12/13 3:32 PM REVIEW NEWS Volume XX • No. 7 • July 2013 Nottingham Researchers Suggest A New Layer in the Cornea

Scientists at the University of Notting- of air were injected into the cornea greatly expand gene therapy to help ham, UK, have discovered a previously to gently separate the different layers. restore sight to patients with blinding undetected layer in the cornea. The The scientists then subjected the sepa- diseases ranging from inherited breakthrough, announced in a study rated layers to electron microscopy, defects like retinitis pigmentosa to published in Ophthalmology, could allowing them to study them at many degenerative illnesses of old age, such help surgeons to dramatically improve thousand times their actual size. as macular degeneration. outcomes for patients undergoing Understanding the properties and Unlike current treatments, the new corneal grafts and transplants. location of the new Dua’s layer could procedure—which takes as little as 15 The new layer has been dubbed the help surgeons to better identify where minutes—is surgically non-invasive, Dua’s Layer after the academic Profes- in the cornea these bubbles are occur- and it delivers normal genes to diffi - sor Harminder Dua who discovered it. ring and take appropriate measures cult-to-reach cells throughout the en- Professor Dua, a professor of oph- during the operation. If they are able tire retina. thalmology and visual sciences, said: to inject a bubble next to the Dua’s Over the last six years, several groups “This is a major discovery that will layer, its strength means that it is less have successfully treated people with a mean that ophthalmology textbooks prone to tearing, meaning a better out- rare inherited eye disease by injecting will literally need to be re-written. come for the patient. a virus with a normal gene directly into Having identifi ed this new and distinct The discovery will have an impact the retina of an eye with a defective layer deep in the tissue of the cornea, on advancing understanding of a num- gene. Despite the invasive process, we can now exploit its presence to ber of diseases of the cornea, includ- the virus with the normal gene was not make operations much safer and sim- ing acute hydrops, Descematocele and capable of reaching all the retinal cells pler for patients. pre-Descemet’s dystrophies. that need fi xing. “From a clinical perspective, there The scientists now believe that cor- “Sticking a needle through the reti- are many diseases that affect the back neal hydrops, a bulging of the cornea na and injecting the engineered virus of the cornea which clinicians across caused by fl uid build up that occurs in behind the retina is a risky surgical the world are already beginning to re- patients with keratoconus, is caused by procedure,” said David Schaffer, PhD, late to the presence, absence or tear in a tear in the Dua layer, through which professor of chemical and biomolecu- this layer.” water from inside the eye rushes in lar engineering and director of the The newly discovered layer is be- and causes waterlogging. Berkeley Stem Cell Center at the Uni- tween the corneal stroma and Des- versity of California, Berkeley. “But cemet’s membrane. Although it is just doctors have no choice because none 15 µm thick, it is incredibly tough and of the gene-delivery viruses can travel is strong enough to be able to with- Better Gene all the way through the back of the eye stand one and a half to two bars of to reach the photoreceptors—the light pressure. Delivery from sensitive cells that need the therapeu- The scientists proved the existence tic gene. of the layer by simulating human “Building upon 14 years of research, corneal transplants and grafts on Cal Scientists we have now created a virus that you eyes donated for research purposes Researchers at the University of Califor- just inject into the liquid vitreous to eye banks located in Bristol and nia, Berkeley, have developed an humor inside the eye and it delivers Manchester. easier and more effective method for genes to a very diffi cult-to-reach pop- During this surgery, tiny bubbles inserting genes into eye cells that could ulation of delicate cells in a way that

July 2013 | Revophth.com | 3

003_rp0713_news.indd 3 6/20/13 3:14 PM REVIEW News

is surgically non-invasive and safe. It’s variants of AAV—each carrying slightly More Responsibly—examines six ar- a 15-minute procedure, and you can different proteins on its coat—from eas that contribute to unnecessary likely go home that day.” which he and his colleagues selected costs: medication nonadherence, de- The engineered virus works far bet- fi ve that were effective in penetrating layed evidence-based treatment prac- ter than current therapies in rodent the retina. They then used the best tice, misuse of antibiotics, medication models of two human degenerative of these (7m8) to transport genes to errors, suboptimal use of generics and eye diseases, and can penetrate photo- cure two types of hereditary blindness mismanaged polypharmacy in older receptor cells in the eyes of monkeys, for which there are mouse models: X- adults. Together, these areas lead to which are like those of humans. linked retinoschisis, which strikes only unnecessary utilization of health-care Dr. Schaffer and his team are now boys and makes their retinas look like resources involving an estimated 10 collaborating with physicians to iden- Swiss cheese; and Leber’s congenital million hospital admissions, 78 million tify the patients most likely to benefi t amaurosis. In each case, when injected outpatient treatments, 246 million pre- from this gene-delivery technique and, into the vitreous humor, the AAV de- scriptions and four million emergency after some preclinical development, livered the corrective gene to all areas room visits annually. The study found hope soon to head into clinical trials, of the retina and restored retinal cells signifi cant opportunities for improve- he said. nearly to normal. ment—to ensure that patients receive The study was published on June When injected into the eye of a nor- the right medicines at the right time, 12 in the journal Science Translational mal monkey, the virus penetrated cells and take them in the right way. Medicine. spottily across the retina but almost “As our study makes clear, drugs are Three groups of researchers have completely in the fovea. Current virus- often not used optimally, resulting in successfully restored some sight to es do not penetrate foveal cells at all. signifi cant unnecessary health system more than a dozen people with Leber’s Dr. Schaffer predicts that the virus spending and patient burdens,” said congenital amaurosis, which leads to can be used not only to insert genes Murray Aitken, executive director, complete loss of vision in early adult- that restore function to non-working IMS Institute for Healthcare Infor- hood. They achieved this by inserting a genes, but can knock out genes or halt matics. “Those avoidable costs could corrective gene into adeno-associated processes that are actively killing retina pay for the health care of more than viruses (AAV), a common but benign cells, which may be the case in age- 24 million currently uninsured U.S. respiratory virus, and injecting the vi- related macular degeneration. citizens.” ruses directly into the retina. The pho- The report fi nds that progress is be- toreceptor cells take up the virus and ing made to address some of the chal- incorporate the functional gene into Study Tabs Cost lenges that drive wasteful spending their chromosomes to make a critical in many parts of the U.S. health-care protein that the defective gene could Of Inefficient Drug system. Medication adherence among not, rescuing the photoreceptors and large populations of patients with hy- restoring sight. Use at $200 Billion pertension, hyperlipidemia and diabe- Unfortunately, the technique cannot Avoidable costs of more than $200 tes has improved 3 to 4 percent since be applied to most blinding diseases billion are incurred each year in 2009. In addition, the proportion of because the needle often causes reti- the U.S. health-care system as a patients diagnosed with a cold or the nal detachment, making the situation result of medicines not being used fl u who inappropriately received anti- worse. Yet the standard AAV used in responsibly by patients and health-care biotic prescriptions has fallen from 20 eye and other types of gene therapy professionals, according to a new study percent to 6 percent since 2007. And, can’t penetrate into tissue to reach the by the IMS Institute for Healthcare patients are now receiving lower-cost photoreceptors and other cells, such as Informatics. This represents 8 percent generic alternatives to branded medi- retinal pigment epithelium, that need of the country’s total annual health-care cations, when available, 95 percent of to be fi xed. The retina is about 100,000 expenditures and amounts to millions the time. times thicker than an AAV, which is of avoidable hospital admissions, The report’s key fi ndings include: about 20 nanometers across. outpatient treatments, pharmaceutical • Medication nonadherence drives Years ago, Dr. Schaffer set out to prescriptions and emergency room the largest avoidable cost. Patients not fi nd a way to “evolve” AAV to pene- visits for patients. adhering to their doctors’ medication trate tissues, including eye and liver, as The report—Avoidable Costs in guidance experienced complications a way to deliver genes to specifi c cells. U.S. Healthcare: The $200 Billion that led to an estimated $105 billion To date he has generated 100 million Opportunity from Using Medicines in annual avoidable health-care costs.

4 | Review of Ophthalmology | July 2013

003_rp0713_news.indd 4 6/20/13 3:14 PM While the underlying reasons for nonadherence are varied and longstand- ing, the growing use of analytics and collaboration among providers, pharmacists and patients appear to be ad- Nasal & Temporal vancing both the understanding and effectiveness of intervention programs. Speculums • Delays in applying evidence-based less ain treatment to patients lead to $40 billion , St um cul in annual avoidable costs. The study pe st S Po le analyzed four disease areas where pa- rip T n* tients either are not diagnosed early w ro B : 4 or treatment is not initiated promptly. 6 1 8 -0 The largest avoidable impact is seen in 8 0 ss le diabetes, where such delays increased in ta S outpatient visits and hospitalizations. l, sa a N A reduction in this source of avoidable , m um lu i u costs is possible if insurance coverage an c it e T p , S is expanded, and at-risk patients are m t lu s m cu o u e P i able to receive appropriate screening p e n S l a t st ip i r T o and diagnostic testing. P T , l le * a ip n s • Some signs of improvement are r w a T o N r * , n B - evident in the responsible use of anti- w * m o * u r t l B r u biotics. The misuse of antibiotics con- : e c n e 5 i p 0 e t S 1 tributes to antimicrobial resistance and S t 7 - : s 5 S o 0 - P an estimated $34 billion each year in 4 e 6 l 1 p avoidable inpatient care costs. An ad- 8 i r 0 T - 8 * ditional $1 billion is spent on about 31 0 n

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* scriptions that are dispensed each year, 1 * e t r r u e typically for viral infections. There are ig n F i e

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ber of prescriptions for the common 0 2 cold and ﬂ u–viral infections that do not re gu respond to antibiotics. Fi • Efforts are under way to address Special Fenestrated the underlying causes of avoidable Blades Improve spending and to improve medication Exposure And Access To Superior Surgical use, with initiatives advancing across Approaches By Supporting the health-care landscape, including & Elevating The Middle Of The novel interventions, critical assess- Lids As Seen In The Following: ments of established solutions and Figure 1, Temporal Blades With Drape. pioneering models of stakeholder co- Figure 2, Temporal Blades With Out Drape. operation. Many of these initiatives involve a greater role for pharmacists, an integrated approach to addressing pa- Call 727-209-2244 For More Information. tient issues, alignment of ﬁ nancial incentives, and greater use of health-care informatics to guide decision-making and monitor progress. 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 s4EL s&AX %MAIL)NFO 2HEIN-EDICALCOMs7EBSITEWWW2HEIN-EDICALCOM $EVELOPED)N#OORDINATIONWITH2EAY("ROWN -$ $EVELOPED)N#OORDINATION7ITH2OGER&3TEINERT -$ 1339 Rev.A ,EONARDO$A6INCI 5NNAMED ADBC

003_rp0713_news.indd 5 6/20/13 3:15 PM Editorial

REVIEW Board

BUSINESS OFFICES 11 CAMPUS BOULEVARD, SUITE 100 NEWTOWN SQUARE, PA 19073 ONTRIBUTORS SUBSCRIPTION INQUIRIES (877) 529-1746 C (USA ONLY); OUTSIDE USA, CALL (847) 763-9630 CHIEF MEDICAL EDITOR PLASTIC POINTERS BUSINESS STAFF Mark H. Blecher, MD Ann P. Murchison, MD, MPH SALES MANAGER, NORTHEAST, MID ATLANTIC, OHIO BOTTOM LINE REFRACTIVE SURGERY JAMES HENNE Dennis D. Sheppard, MD Arturo S. Chayet, MD (610) 492-1017 [email protected]

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6 | Review of Ophthalmology | July 2013

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RO0513_Accutome.indd 1 4/18/13 1:40 PM July 2013 • Volume XX No. 7 | revophth.com Cover Focus 20 | Cataract Surgery: The Oculoplastic Factor By Christopher Kent, Senior Editor Many conditions affecting the eyelid and orbit can increase the risks associated with cataract surgery. Here’s help managing them.

32 | The Hidden Pitfalls of Postop Enhancements By Walter Bethke, Managing Editor How to manage patient expectations, choose a refractive target and improve vision.

38 | Meeting Expectations in Older Cataract Patients By Michelle Stephenson, Contributing Editor The latest generation of cataract patients shows that postop expectations are less about age, and more about attitude.

July 2013 | Revophth.com | 9

009_rp0713_toc.indd 9 6/20/13 3:15 PM Departments

45 3 | Review News

13 | Editor’s Page 14 | Technology Update Breaking New Ground In Meibography New options are making it easy to visualize the condition of a patient’s meibomian glands.

45 | Retinal Insider Distinguishing Infection After Anti-VEGF Intravitreal Injection The widespread use of anti-VEGF intravitreal injections makes early detection and treatment of postop complications crucial. 57 50 | Therapeutic Topics ARVO Goes to the Emerald City Highlights from the papers and posters of ARVO’s first foray outside of Florida.

57 | Glaucoma Management Using Visual Fields to Predict Progression Knowing which patients are at greatest risk is crucial to effective treatment. This new approach may help make that a reality.

65 | Refractive Surgery Reports from the U.S. SMILE Study A look at the U.S. trial for the new, 78 all-femtosecond-laser refractive procedure.

69 | Research Review Supplements Improve Macular Pigmentation

72 | Product News

74 | Classified Ads

77 | Advertising Index

78 | Wills Eye Resident Case Series

10 | Review of Ophthalmology | July 2013

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RP0513_Keeler Kowa.indd 1 4/10/13 1:53 PM ® 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 Plastics Demand Up, Walter C. Bethke (610) 492-1024 [email protected] Along With Scrutiny Senior Editor Christopher Kent (814) 861-5559 With all of the focus in recent years group play a role in the surge. But it [email protected] on the younger cataract patient, it adds that “Surgeons who bill Medicare would be easy to lose sight of what’s for large numbers of eyelid surgeries Associate Editor going on with the more conventional, dot a map of the United States. Yet 11 Kelly Hills (610) 492-1025 “standard-age” cataract patient of— of the 20 highest billers in 2008 were in [email protected] pick a number—70 or more years of Florida, which is both an elderly mec- age. We decided to address that with ca and the country’s foremost magnet Chief Medical Editor a specifi c article this month (p. 38) on for questionable Medicare billing.” Mark H. Blecher, MD meeting the needs of these patients, One top biller in South Florida, ac- and with our cover story (p. 20). The cording to the data, “billed Medicare Senior Director, Art/Production latter deals with the oculoplastic more than $800,000 in 2008 for about Joe Morris (610) 492-1027 considerations and potential compli- 2,200 eyelid lifts,” for an average of six [email protected] cations in the elderly cataract patient. a day, including weekends. This same It’s no revelation that elderly pa- doctor was also a top biller in 2006 and Art Director tients tend to have more issues with 2007. Jared Araujo their lids, their lashes, their tear ducts The other shoe fell this week and it’s (610) 492-1023 and other extraocular problems that something all surgeons who partici- [email protected] may need to be addressed in conjunc- pate in Medicare need to know about. Graphic Designer tion with their cataracts. What might In order to obtain the data that served Alicia Cairns be a revelation to some, though, is the as the basis for the report, the Center’s (610) 492-1029 increasing degree of Medicare billing reporters had to agree to maintain [email protected] for lid surgery. A report in late May the anonymity of any individual sur- by the Center for Public Integrity, a geons about whose billing practices International coordinator, Japan nonprofi t investigative news organi- they would report. A federal judge Mitz Kaminuma zation, fi nds that from 2001 to 2011, this week struck down a decades-old [email protected] eyelid lifts charged to Medicare more injunction barring public access to a Business Offi ces than tripled to 136,000 annually, with confi dential database of Medicare in- 11 Campus Boulevard, Suite 100 billing in the period quadrupling to surance claims, essentially removing Newtown Square, PA 19073 $80 million a year, and the number of that cloak of anonymity. The AMA has (610) 492-1000 physicians performing the surgeries suggested that it will appeal the de- Fax: (610) 492-1039 doubling. cision, and it’s uncertain how far the Subscription inquiries: At issue is medical necessity. As ruling extends but the implications for United States — (877) 529-1746 Medicare does not cover purely cos- surgeons’ privacy could be substantial. Outside U.S. — (847) 763-9630 metic, elective procedures, the case Again, no one has suggested any E-mail: must be made that the patient is suf- widespread gaming of the system by [email protected] fering a functional visual defi cit be- plastic or ophthalmic surgeons. But Website: www.revophth.com cause of the condition. those who might be just lost some The report takes pains to point cover. Professional Publications Group out that factors such as rising patient Jobson Medical Information LLC awareness of plastic surgery options thanks to reality television, and changing demands of patients in this age

July 2013 | Revophth.com | 13

013_rp0713_edit.indd 13 6/21/13 10:06 AM Technology Update

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

Breaking New Ground In Meibography New options are making it easy to visualize the condition of a patient’s meibomian glands, with no patient discomfort. Christopher Kent, Senior Editor

s interest in the causes and probe is not necessary, making it more the chin rest, such as infants or inpa- Atreatment of dry eye continues patient-friendly,” he explains. “The tients with severe systemic diseases.” to grow, interest in the meibomian structure of the meibomian glands Most of the limitations of the slit- glands—which secrete lipids that help can easily be observed in both the lamp system have now been elim- prevent excessive evaporation from upper and lower eyelids of patients inated with their latest iteration: a the tear fi lm—has grown as well. Re- without causing patient discomfort. portable, handheld, pen-shaped mei- cently, several new developments in “Using this system we’ve reported bography device, manufactured by meibography have made it easier to some new fi ndings,” he continues, “in- Topcon. “Our mobile, pen-shaped evaluate and monitor the condition of cluding the shortening of meibomian device comprises an infrared LED the glands. glands in contact lens wearers, meibo- light source (wavelength 940 nm), a “Meibomian gland dysfunction is a mian gland duct distortion in patients highly sensitive video camera for the major cause of dry eye,” notes Reiko with perennial allergic conjunctivitis, acquisition of a clear image, and com- Arita, MD, PhD, clinical researcher and the dropout of meibomian glands puter imaging software,” he says. “It’s in the department of ophthalmology in patients with obstructive meibo- connected to a monitor or a personal at the University of Tokyo School of mian gland dysfunction. The system computer. It provides a panoramic Medicine, and an associate professor is also useful for differentiating aque- view of all of the meibomian glands at Keio University. “However, con- ous-defi ciency dry eye from lipid-lay- along the upper or lower eyelid. To ventional meibography is performed er-defi ciency dry eye. Moreover, we avoid catoptric [refl ected] light, the in a limited number of clinics, prob- found meibomian gland dropout in body of the pen-shaped device is held ably because of the necessity for ex- patients who have used anti-glaucoma vertically toward the eyelid. None of aminer expertise, as well as patient eye drops for more than six months.” the subjects have reported glare, dis- discomfort induced by the direct ap- comfort or pain during the meibogra- plication of a transilluminating light Taking the Next Step phy procedure. probe to the eyelid.” “Using this mobile pen-shaped To create a less-invasive option, Dr. Despite its advantages, the slit-lamp meibography device, we can observe Arita’s team has developed two non- system has some downsides. “Because meibomian glands in patients who contact meibography systems. The there are many kinds of slit lamps all can’t sit up,” he continues. “We can fi rst, designed to attach to a slit lamp, over the world, this system can’t be visit a home for the aged and diag- includes an infrared fi lter and an in- used in all facilities,” he notes. “Also, nose meibomian-related diseases. We frared charge-coupled video camera. it can’t be used to examine the meibo- can also monitor the changes in the “In this system, a transilluminating mian glands of patients who can’t use meibomian glands of both healthy

14 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

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RP0213_Alcon Wavelight.indd 1 1/22/13 11:01 AM 52.9% at 3 months); visual fluctuations (32.1% at baseline versus 43.0% at 3 months); rise with increase of >5 mmHg or any reading above 25 mmHg; retinal detachment and halos (37.0% at baseline versus 42.3% at 3 months). Long term risks of LASIK for or retinal vascular accident; and decrease in BSCVA of >10 letters not due to irregular mixed astigmatism beyond 6 months have not been studied. astigmatism as shown by hard contact lens refraction. Clinical Data Wavefront-guided Treatment of Myopia: The WaveLight® The following complications occurred 3 months after LASIK during this clinical trial: ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System used in 0.8% (7/844) of eyes had a corneal epithelial defect; 0.1% (1/844) had any epithelium conjunction with the WaveLight® ALLEGRO Analyzer® device. The device uses a 6.5 mm in the interface; 0.1% (1/844) had foreign body sensation; 0.2% (2/844) had pain; and Health Care Professional Information Sheet-All WaveLight® ALLEGRETTO WAVE® optical zone, a 9.0 mm ablation/treatment zone, and is indicated for wavefront-guided 0.7% (6/844) had ghosting or double images in the operative eye. EX500 System Indications LASIK: 1) for the reduction or elimination of up to -7.0 D of spherical equivalent myopia The following complications did NOT occur 3 months following LASIK in this clinical The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System or myopia with astigmatism, with up to -7.0 D of spherical component and up to 3.0 D trial: corneal edema and need for lifting and/or reseating the flap/cap. CAUTION: Federal (USA) law restricts this device to sale by, or on the order of astigmatic component at the spectacle plane; 2) in patients who are 18 years of age Adverse Events and Complications for Hyperopia: Certain adverse events and of a physician. or older; and 3) in patients with documentation of a stable manifest refraction defined as ≤0.50 D of preoperative spherical equivalent shift over one year prior to surgery was complications occurred after the LASIK surgery. Only one adverse event occurred during Statements regarding the potential benefits of wavefront-guided and Wavefront the clinical study: one eye (0.4%) had a retinal detachment or retinal vascular accident Optimized® laser-assisted in-situ keratomileusis (LASIK) are based upon the results studied in a randomized clinical trial in the United States with 374 eyes treated; 188 ® reported at the 3 month examination. of clinical trials. These results are indicative of not only the WaveLight® ALLEGRETTO with wavefront-guided LASIK (Study Cohort) and 186 with Wavefront Optimized LASIK The following adverse events did NOT occur: corneal infiltrate or ulcer requiring WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System treatment but also the care (Control Cohort). 178 of the Study Cohort and 180 of the Control Cohort were eligible to treatment; lost, misplaced, or misaligned flap, or any flap/cap problems requiring of the clinical physicians, the control of the surgical environment by those physicians, be followed at 6 months. In the Study Cohort, accountability at 1 month was 96.8%, at surgical intervention beyond 1 month; corneal edema at 1 month or later visible in the the clinical trials’ treatment parameters and the clinical trials’ patient inclusion and 3 months was 96.8%, and at 6 months was 93.3%. In the Control Cohort, accountability slit lamp exam; any complication leading to intraocular surgery; melting of the flap of exclusion criteria. Although many clinical trial patients after the wavefront-guided at 1 month was 94.6%, at 3 months was 94.6%, and at 6 months was 92.2%. > 1 mm2; epithelium of > 1 mm2 in the interface with loss of 2 lines or more of BSCVA; and Wavefront Optimized® procedure saw 20/20 or better and/or had or reported The studies found that of the 180 eyes eligible for the UCVA analysis of effectiveness uncontrolled IOP rise with increase of > 5 mmHg or any reading above 25 mmHg and having better vision during the day and at night, compared to their vision with at the 6-month stability time point in the Study Cohort, 99.4% were corrected to decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard glasses or contact lenses before the procedure, individual results may vary. You can 20/40 or better, and 93.4% were corrected to 20/20 or better without spectacles or contact lens refraction. find information about the clinical trials below and in the Procudure Manuals for the contact lenses. In the Control Cohort, of the 176 eyes eligible for the UCVA analysis WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System. of effectiveness at the 6-month stability time point, 99.4% were corrected to 20/40 The following complications occurred 6 months after LASIK during this clinical trial: 0.8% (2/262) of eyes had a corneal epithelial defect and 0.8% (2/262) had any As with any surgical procedure, there are risks associated with the wavefront-guided or better, and 92.8% were corrected to 20/20 or better without spectacles or contact epithelium in the interface. and Wavefront Optimized® treatment. Before treating patients with these procedures, lenses. you should carefully review the Procedure Manuals, complete the Physician WaveLight® The clinical trials showed that the following subjective patient adverse events were The following complications did NOT occur 6 months following LASIK in this clinical System Certification Course, provide your patients with the Patient Information Booklet, reported as moderate to severe at a level at least 1% higher than baseline of the trial: corneal edema; foreign body sensation; pain, ghosting or double images; and and discuss the risks associated with this procedure and questions about the procedure subjects at 3 months post-treatment in the Study Cohort: light sensitivity (37.2% at need for lifting and/or reseating of the flap/cap. with your patients. baseline versus 47.8% at 3 months); and visual fluctuations (13.8% at baseline versus Adverse Events and Complications for Mixed Astigmatism: Certain adverse INDICATIONS: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer 20.0% at 3 months). In the Control Cohort: halos (36.6% at baseline versus 45.4% at 3 events and complications occurred after the LASIK surgery. No protocol defined adverse Laser System is indicated to perform LASIK treatments in patients with documented months); and visual fluctuations (18.3% at baseline versus 21.9% at 3 months). Long events occurred during the clinical study. However, two events occurred which were evidence of a stable manifest refraction defined as less than or equal to 0.50 diopters term risks of wavefront-guided LASIK for myopia with and without astigmatism beyond reported to the FDA as Adverse Events. 6 months have not been studied. (D) of preoperative spherical equivalent shift over one year prior to surgery, exclusive The first event involved a patient who postoperatively was subject to blunt trauma to of changes due to unmasking latent hyperopia in patients 18 years of age or older: for CONTRAINDICATIONS: LASIK treatments using the WaveLight® ALLEGRETTO WAVE® the treatment eye 6 days after surgery. The patient was found to have an intact globe the reduction or elimination of myopic refractive errors up to -12.0 D of sphere with and / ALLEGRETTO WAVE® Eye-Q Excimer Laser System are contraindicated if any of the with no rupture, inflammation or any dislodgement of the flap. The second event without astigmatic refractive errors up to following conditions exist. Potential contraindications are not limited to those included involved the treatment of an incorrect axis of astigmatism which required retreatment. in this list: pregnant or nursing women; patients with a diagnosed collagen vascular, -6.0 D; for the reduction or elimination of hyperopic refractive errors up to +6.0 D of The following adverse events did NOT occur: corneal infiltrate or ulcer requiring autoimmune or immunodeficiency disease; patients with diagnosed keratoconus or sphere with and without astigmatic refractive errors up to 5.0 D at the spectacle plane, treatment; corneal epithelial defect involving the keratectomy at 1 month or later; any clinical pictures suggestive of keratoconus; and patients who are taking one or both with a maximum manifest refraction spherical equivalent (MRSE) of +6.0 D; and in corneal edema at 1 month or later visible in the slit lamp exam; epithelium of > 1 mm2 of the following medications: isotretinoin (Accutane®1), amiodarone hydrochloride patients 21 years of age or older for the reduction or elimination of naturally occurring in the interface with loss of 2 lines or more of BSCVA; lost, misplaced, or misaligned (Cordarone®2). mixed astigmatism of up to 6.0 D at the spectacle plane. flap, or any flap/cap problems requiring surgical intervention beyond 1 month; ® ® LASIK is an elective procedure with the alternatives including but not limited to WARNINGS: Any LASIK treatment with the WaveLight ALLEGRETTO WAVE / decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard ® eyeglasses, contact lenses, photorefractive keratectomy (PRK), and other refractive ALLEGRETTO WAVE Eye-Q Excimer Laser System is not recommended in patients contact lens refraction; any complication leading to intraocular surgery; melting of surgeries. Only practitioners who are experienced in the medical management and who have: systemic diseases likely to affect wound healing, such as connective tissue the flap of > 1 mm2; uncontrolled IOP rise and retinal detachment or retinal vascular surgical treatment of the cornea, who have been trained in laser refractive surgery disease, insulin dependent diabetes, severe atopic disease or an immunocompromised accident. status; a history of Herpes simplex or Herpes zoster keratitis; significant dry eye that including laser system calibration and operation, may use the device as approved. None of the following complications occurred at 3 months after LASIK during this is unresponsive to treatment; severe allergies; and unreliable preoperative wavefront Prospective patients, as soon as they express an interest in an indicated LASIK procedure clinical trial: corneal edema; corneal epithelial defect; any epithelium in the interface; ® examination that precludes wavefront-guided treatment. The wavefront-guided LASIK and prior to undergoing surgery, must be given the WaveLight System Patient foreign body sensation, pain, ghosting or double images; and need for lifting and/or procedure requires accurate and reliable data from the wavefront examination. Every Information Booklet and must be informed of the alternatives for refractive correction reseating of the flap/cap. including eyeglasses, contact lenses, PRK, and other refractive surgeries. step of every wavefront measurement that may be used as the basis for a wavefront- guided LASIK procedure must be validated by the user. Inaccurate or unreliable data Subjects were asked to complete a patient questionnaire preoperatively and at ® ® ® Clinical Data Myopia: The WaveLight ALLEGRETTO WAVE / ALLEGRETTO WAVE Eye-Q from the wavefront examination will lead to an inaccurate treatment. 3-months, 6-months, and 1-year postoperatively. Excimer Laser System for LASIK treatments of myopic refractive errors up to -12.0 D of ® ® Adverse Events and Complications for Wavefront - guided Myopia: Certain sphere with and without astigmatic refractive errors up to -6.0 D at the spectacle plane PRECAUTIONS: Safety and effectiveness of the WaveLight ALLEGRETTO WAVE / ® adverse events and complications occurred after the wavefront-guided LASIK surgery. was studied in clinical trials in the United States with 901 eyes treated, of which 813 of ALLEGRETTO WAVE Eye-Q Excimer Laser System have not been established for patients No adverse event occurred during wavefront-guided treatments during this clinical 866 eligible eyes were followed for 12 months. Accountability at 3 months was 93.8%, with: progressive myopia, hyperopia, astigmatism and/or mixed astigmatism; ocular study. at 6 months was 91.9%, and at 12 months was 93.9%. disease; previous corneal or intraocular surgery, or trauma in the ablation zone; corneal abnormalities including, but not limited to, scars, irregular astigmatism and corneal The following adverse events did NOT occur: corneal infiltrate or ulcer requiring The studies found that of the 844 eyes eligible for the uncorrected visual acuity (UCVA) warpage; residual corneal thickness after ablation of less than 250 microns increasing treatment; lost, misplaced or misaligned flap or any flap/cap problems requiring analysis of effectiveness at the 3-month stability time point, 98.0% were corrected to the risk for corneal ectasia; pupil size below 7.0 mm after mydriatics where applied for surgical intervention beyond 1 month; corneal edema at 1 month or later visible in the 20/40 or better, and 84.4% were corrected to 20/20 or better without spectacles or wavefront-guided ablation planning; history of glaucoma or ocular hypertension of slit lamp exam; any complication leading to intraocular surgery; melting of the flap of contact lenses. > 23 mmHg; taking the medication sumatriptan succinate (Imitrex®3); under 18 years > 1 mm2; epithelium of > 1 mm² in the interface with loss of 2 lines or more of BSCVA; The clinical trials showed that the following subjective patient adverse events were (21 years for mixed astigmatism) of age; over the long term (more than 12 months uncontrolled IOP rise with increase of > 5 mmHg or any reading above 25 mmHg; and reported as moderate to severe at a level at least 1% higher than baseline of the after surgery); corneal, lens and/or vitreous opacities including, but not limited to, decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard subjects at 3 months post-treatment: visual fluctuations (12.8% at baseline versus cataract; iris problems including, but not limited to, coloboma and previous iris surgery contact lens refraction. 28.6% at 3 months). Long term risks of LASIK for myopia with and without astigmatism compromising proper eyetracking; taking medications likely to affect wound healing The following complications occurred 3 months after wavefront-guided LASIK during beyond 12 months have not been studied. including, but not limited to, antimetabolites; treatments with an optical zone below this clinical trial: corneal epithelial defect (0.6%); foreign body sensation (0.6%); and Clinical Data Hyperopia: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® 6.0 mm or above 6.5 mm in diameter; treatment targets different from emmetropia pain (0.6%). Eye-Q Excimer Laser System for LASIK treatments of hyperopic refractive errors up (plano) in which the wavefront-calculated defocus (spherical term) has been adjusted; The following complications did NOT occur 3 months following wavefront-guided LASIK to +6.0 D of sphere with and without astigmatic refractive errors up to 5.0 D with myopia greater than – 12.0 D or astigmatism greater than 6 D; hyperopia greater than in this clinical trial: corneal edema; any epithelium in the interface; ghosting or double a maximum MRSE of +6.0 D has been studied in clinical trials in the United States + 6.0 D or astigmatism greater than 5.0 D; mixed astigmatism greater than + 6.0 D; images; and need for lifting and/or reseating of the flap/cap. with 290 eyes treated, of which 100 of 290 eligible eyes were followed for 12 months. and in cylinder amounts > 4.0 to < 6.0 D. Accountability at 3 months was 95.2%, at 6 months was 93.9%, and at 12 months Due to the lack of large numbers of patients in the general population, there are few ATTENTION: The safety and effectiveness of LASIK surgery has ONLY been established was 69.9%. subjects with cylinder amounts in this range to be studied. Not all complications, with an optical zone of 6.0 – 6.5 mm and an ablation zone of 9.0 mm. The studies found that of the 212 eyes eligible for the UCVA analysis of effectiveness at adverse events, and levels of effectiveness may have been determined. Reference the Directions for Use labeling for a complete listing of indications, warnings the 6-month stability time point, 95.3% were corrected to 20/40 or better, and 67.5% Pupil sizes should be evaluated under mesopic illumination conditions. Effects of and precautions. were corrected to 20/20 or better without spectacles or contact lenses. treatment on vision under poor illumination cannot be predicted prior to surgery. Some The study showed that the following subjective patient adverse events were reported patients may find it more difficult to see in such conditions as very dim light, rain, fog, 1. Accutane ® is a registered trademark of as much worse by at least 1% of the subjects (in order of increasing frequency) at snow and glare from bright lights. This has been shown to occur more frequently in the Hoffmann-La Roche Inc. presence of residual refractive error and perhaps in patients with pupil sizes larger than 6 months post final treatment: glare from bright lights (3.0%); night driving glare 2. Cordarone ® is a registered trademark of the optical zone size. (4.2%); light sensitivity (4.9%); visual fluctuations (6.1%); and halos (6.4%). Long Sanofi S.A. term risks of LASIK for hyperopia with and without astigmatism beyond 12 months The refraction is determined in the spectacle plane, but treated in the corneal plane. 3. Imitrex ® is a registered trademark of have not been studied. In order to determine the right treatment program to achieve the right correction, Glaxo Group Limited Clinical Data Mixed Astigmatism: The WaveLight® ALLEGRETTO WAVE®/ ALLEGRETTO assessment of the vertex distance during refraction testing is recommended. WAVE® Eye-Q Excimer Laser System for LASIK treatments of naturally occurring mixed Preoperative evaluation for dry eyes should be performed. Patients should be advised astigmatism of up to 6.0 D at the spectacle plane has been studied in clinical trials in of the potential for dry eyes post LASIK and post wavefront-guided LASIK surgery. This the United States with 162 eyes treated, of which 111 were eligible to be followed at treatment can only be provided by a licensed healthcare professional. 6 months. Accountability at 1 month was 99.4%, at 3 months was 96.0%, and at 6 Adverse Events and Complications for Myopia: Certain adverse events and months was 100.0%. complications occurred after the LASIK surgery. Two adverse events occurred during The studies found that of the 142 eyes eligible for the UCVA analysis of effectiveness at the postoperative period of the clinical study: 0.2% (2/876) had a lost, misplaced, or the 3-month stability time point, 95.8% achieved acuity of 20/40 or better, and 67.6% misaligned flap reported at the 1 month examination. achieved acuity of 20/20 or better without spectacles or contact lenses. The following adverse events did NOT occur: corneal infiltrate or ulcer requiring The clinical trials showed that the following subjective patient adverse events were treatment, corneal edema at 1 month or later visible in the slit lamp exam; any reported as moderate to severe at a level at least 1% higher than baseline of the complication leading to intraocular surgery; melting of the flap of >1 mm2; epithelium subjects at 3 months post-treatment: sensitivity to light (43.3% at baseline versus of >1 mm2 in the interface with loss of 2 lines or more of BSCVA; uncontrolled IOP © 2013 Novartis 1/13 ALL13006JADUS-PI

RP0213_Alcon Wavelight PI.indd 1 1/22/13 10:59 AM Technology

REVIEW Update Reiko Arita, MD, PhD infants and those with con- low clinicians to take a se- genital diseases such as con- ries of pictures over time, genital ectodermal dysplasia to determine whether the and congenital insensitivity glands are changing. to pain with anhidrosis.” “Using the current Oc- In a recent study, Dr. ulus keratograph is very Arita’s group compared the simple,” she continues. new handheld device to the “Patients rest their head on slit-lamp system they had the chin rest, and you use previously developed.1 “We a cotton tip applicator to used both systems to visu- gently evert the lower or A new handheld, pen-shaped, non-contact meibography device alize the upper and lower developed in Japan allows acquisition of clear, panoramic images upper lid. You click on the eyelids of healthy volunteers and video without patient discomfort. The device can be connected meibography option, and and patients with meibomian to a monitor or personal computer for viewing or recording images. that opens up a window gland dysfunction, contact- onscreen. Sometimes you lens wearers with dryness and pa- plains that it has multiple capabilities. may need an assistant to hold the lid tients with allergic conjunctivitis,” he “The device was primarily designed to in place, but if you’re an experienced says. “The quality of images using the get a topographical map of the cornea, user, you can probably do it yourself. mobile meibography device was simi- but it also allows pupillometry, tear Then it’s as simple as clicking a button lar to those captured using the slit- film scans, measuring tear breakup to capture a photo or video.” lamp meibography system.” time and tear meniscus height,” she Dr. Srinivasan says the instru- The handheld device currently says. “The Oculus K4 didn’t have a ment isn’t currently able to per- costs about $3,000 and is available for dedicated meibography option, so we form digital analysis and quantifi- import, but has not been approved by used the infrared illumination that was cation of images, but this can be the Food and Drug Administration. available for pupilometry to capture done using other software. “There infrared meibography images.” Her are numerous subjective grading Other New Options group used the K4 to conduct their scales for this purpose,” she ex- initial meibography study, published plains. “But we can use a program “We need to have new ways to per- in 2012.2 The study demonstrated the like ImageJ to outline the areas form meibography,” agrees Sruthi feasibility and effectiveness of this of gland loss and then calculate the Srinivasan PhD, BS Optom, FAAO, tool for in-clinic meibography. gland loss as a percentage of the research assistant professor at the “The new model [K5M] includes total area of the lid, which is more Centre for Contact Lens Research at dedicated meibography software, al- objective.” She admits that digital the University of Waterloo in Ontario. lowing us to take meibography images quantifi cation is probably more than Her group has been conducting mei- more easily,” she says. “Also, the work- is needed for clinical use. “But if you bomian gland research, fi rst using the ing distance has been increased to want a precise quantifi cation of per- Oculus Keratograph 4 and more re- enlarge the fi eld of view; the infrared centage loss,” she says, “it is possible cently the newer Oculus K5M. “Some diodes have been rearranged; and the to achieve.” of the older meibography methods images are optimized for clarity and were more research-oriented, and not much easier to obtain. In addition, Dr. Arita is an advisor to Topcon. clinician-friendly,” she notes. “They this instrument gives you a variety of The Centre for Contact Lens Research tended to involve bulky equipment tools in a single platform. That’s why has conducted funded research studies and be time-consuming, and there we fi nd it more benefi cial than other on behalf of Oculus during the past was some discomfort for the patient. stand-alone meibography tools.” three years, but Dr. Srinivasan per- Video processing was difficult as Dr. Srinivasan notes that a clini- sonally does not have a fi nancial rela- well—we never got a full picture of cian-friendly meibography device tionship to Oculus or the instruments the lid in one shot, so we had to stitch will help both patients and clinicians. described.

them together. The new devices take “Clinicians can explain the condition 1. Arita R, Itoh K, Maeda S, et al. A Newly Developed Noninvasive a full picture of the lid in one shot.” more easily to patients if they have and Mobile Pen-Shaped Meibography System. Cornea Asked why they initially chose to a picture,” she says. “They can cor- 2013;32:3:242-247. 2. Srinivasan S, Menzies K, Sorbara L, Jones L. Infrared imaging pursue meibography using the Ocu- relate the signs and symptoms to the of meibomian gland structure using a novel keratograph. Optom lus Keratograph 4, Dr. Srinivasan ex- patient’s experience. It will also al- Vis Sci 2012;89:5:788-94.

July 2013 | Revophth.com | 17

014_rp0713_tech update.indd 17 6/20/13 2:10 PM ADVERTORIAL In the Spotlight: Bacitracin Ophthalmic Ointment USP Learn about the presurgical use of this antibiotic and ﬁ nd out why one renowned ophthalmologist insists on it for endophthalmitis prophylaxis.

hink what you will about people who are particular about doing things a certain way and only that way, but paying extreme attention to detail just might be a key to avoiding one of the most dreaded surgical complications: endophthalmitis. Robert H. Osher, TMD, a Cincinnati-based cataract surgeon, has had only one run-in with this sight-threatening condition in 35 years. Here, he shares his disciplined approach to cataract surgery, which he attributes to his tremendous track record. “I pay meticulous attention to the lids and lashes; use appropriate lid hygiene and medications, which include Bacitracin Ophthalmic Ointment USP on the lashes; carefully sterilize the ﬁ eld during surgery; pay careful attention to incision construction; and never underestimate the tragic severity of endophthalmitis,” he says. And he has been very satisﬁ ed with his regimen, which we will learn more about later.

Bacitracin: Tried and True Thanks to Bacitracin’s unsurpassed safety profi le, allergenic- In cataract surgery, preoperative regimens, which ity and side reactions are practically non-existent.1 typically consist of doses of antibiotics, are necessary for preventing intraocular infection. It is indicated for the treat- Bacitracin’s Key Role in Cataract Surgery ment of superfi cial infections involving the conjunctiva and/ Bacitracin is typically used preoperatively to prevent or cornea caused by Bacitracin-susceptible organisms and bacterial infections of the eye and/or surgical site by either should not be used in patients who have a history of hyper- killing susceptible bacteria or inhibiting their growth. sensitivity to Bacitracin. Following is a look at how this medication fi ts into Dr. The ointment can be applied to the conjunctiva or lid mar- Osher’s complete cataract surgery routine, starting with gins. It has proven therapeutic utility in a variety of superfi cial his preoperative regimen. ocular infections, including blepharitis and conjunctivitis.1 Furthermore, it has profound activity against common “[Bacitracin] has an excellent resistance Gram-positive pathogens.1–3 What makes this product even more attractive is its convenient dosing (one to three times profi le and is highly eff ective against daily)1 and the fact that it qualifi es as a tier-1 co-pay on most Gram-positive pathogens.” insurance plans.4 Although it has been available for decades (in topical Preoperative. “When I fi rst evaluate patients,” Dr. Osher form since the early 70s), it has never been administered begins, “I pay careful attention to the lids, lashes and lacrimal as a routine systemic antibiotic. Says Dr. Osher, “I may apparatus.” In his experience, he has found that virtually 90% be one of a few ophthalmologists who use Bacitracin, of patients have some evidence of blepharitis (e.g., secretions but I think it’s an outstanding drug against Gram-positive on the lashes or vascularized lids/lashes with meibomian bacteria.” In fact, its limited use has kept the drug’s secretions). So, the fi rst thing he does preoperatively is explain susceptibility profile relatively unchanged, making it an to the patient at the initial evaluation that the lids and lashes effective option, especially when treating Gram-positive are in the neighborhood next to the eye and that everyone pathogens such as Staphylococcus and Streptococcus. has their own secretions that they can’t see in the mirror but Dr. Osher has been using Bacitracin for 35 years and that he can see under a microscope. “And we have to control backs this statement up. Drawing on his own experience, the normal bacteria to avoid any chance of infecting the eye he notes that “It has an excellent resistance profile and during surgery,” he continues. “I initiate a hygienic cleans- is highly effective against Gram-positive pathogens, ing regimen in which the patient mechanically debrides and particularly the most common ones (e.g., Staphylococcus cleanses his lashes and lid margins with baby shampoo (and aureus primarily, but also Streptococcus and methicillin- rinse well) every day while in the shower.” resistance S. aureus).” Fast-forward to the day before surgery, when Dr. Osher He also believes that it’s a great drug and is very safe. gives the patient a fourth-generation fl uoroquinolone in the

0613_Fera_kr6ja.indd 2 6/4/13 2:22 PM ADVERTORIAL

eye for prophylaxis. The evening before surgery, he has each Dr. Osher instills the fl uoroquinolone in the patient’s eye patient apply Bacitracin ointment to the lashes and lid margins. and has him continue the antibiotic for fi ve more days. Baci- “I’ve been using this approach since 1978,” he says. “I believed, tracin is just one of the components that comprise the whole even then, that by coating the lashes with Bacitracin, we would system that he uses. “I believe that this disciplined have an excellent chance of weakening—if not killing—the approach works,” he says. “And when you have a winning bacteria present on every operating fi eld.” Simply put, “the lid team, you don’t change the lineup.” hygiene reduces the bacteria present, which are then pulver- ized by the Bacitracin,” Dr. Osher reasons. The Best Laid Plans … The day of surgery, he pulses the fl uoroquinolone and transi- All surgeons want to perform a perfect operation, but tions the patient to the operating room for a careful povidone- even if all goes well, there’s still a small chance of a postop iodine prep, followed by meticulous coverage and isolation of complication occurring. The primary source of intraocular the lids and lashes with eye drapes that he originally designed infection is often caused by bacteria from the patient’s own in the early 1980s for this purpose. Then he takes it one step ocular surface. Thus, meticulous preparation of the patient for further. “We place a drain in the lacrimal lake between the upper surgery—including prophylactic measures such as lid hygiene and lower lid and the medial canthus where fl uid pools,” he and the use of drugs like Bacitracin—is one of the most explains, noting that he never allows fl uid to come back over the important factors in reducing the risk of endophthalmitis. Take eye. Instead, any fl uid is wicked out of the sterile fi eld and into the it from a cataract surgeon whose 35 years of “amazing luck” drainage bag. Then, Dr. Osher takes it yet another step further. speaks for itself. ■ Using Steri-Strips (3M), he covers any lids and lashes that are exposed at the lateral canthal angle so that neither skin tissue References 1. Bacitracin Ophthalmic Ointment [Package Insert]. Locust Valley, NY, Fera nor lashes are ever touched by any instrument, injector, etc. Pharmaceuticals LLC, 2009. What about his intraoperative approach? It’s equally 2. Kowalski RP, Karenchak LM, Romanowski EG. Infectious disease: changing obsessive-compulsive, he admits. antibiotic susceptibility. Ophthalmol Clin N Am. 2003;16:1–9. “The surgery itself is every bit as important 3. Freidlin J, Acharya N, Lietman TM, et al. Spectrum of eye disease Intraoperative. caused by methicillin-resistant Staphylococcus aureus. Am J Ophthalmol. as the prophylaxis and preparation,” says Dr. Osher, emphasiz- 2007;144:313–315. ing that you have to have meticulous incision construction. He 4. http:www.fi ngertipformulary.com/drugs/Bacitracinopthalmicointment/ still believes in a three-plane, near clear, 2.2-mm fl ared incision Dr. Osher is Professor of Ophthalmology at the College using knives and blades that he designed. The last steps Dr. of Medicine of the University of Cincinnati and is Medical Osher performs include exchanging the fl uid in the anterior Director Emeritus of the Cincinnati Eye Institute. He has chamber with sterile fl uid using an irrigating and aspirating tip. received the Lifetime Achievement Award and the Kel- This way, “whatever is left in the eye is sterile,” he explains. “I man Award from the AAO, as well as the Binkhorst Award always carefully confi rm the watertightness of the incision.” Ad- and the Innovators Award from the ASCRS. He has no ditionally, he leaves the eye with a normal intraocular pressure financial relationship with Fera Pharmaceuticals. so there is no gradient to allow fl uid into the eye. Supported by Postoperative. Immediately following the procedure,

One Encounter Too Many Endophthalmitis is a rare but serious postoperative complication of cataract surgery and can have devastating eff ects on a patient’s vision. In 35 years of performing cataract surgery with his current system, Dr. Osher has only had one case of “The morbidity of endophthalmitis. endophthalmitis is The patient, who had ocular cicatricial pemphigoid, had cataract surgery performed in Boston, and lost his ﬁ rst eye. In 1990, after six months of immuno- enough to make you suppression at Harvard, he was referred to Dr. Osher for surgery in the second eye. never want to see it He says the surgery was unique “because I did a clear corneal incision to avoid touch- ing the conjunctiva, which can be lethal in cicatricial pemphigoid.” He recalls that the ever again.” patient’s vision was 20/40 the ﬁ rst day after surgery and 20/20 at the one-week visit. In the second week, the patient arrived in Cincinnati with an endophthalmitis due to Streptococcus viridans. This one case made a lasting impression on the surgeon. “The morbidity of endophthalmitis is enough to make you never want to see it ever again,” he says with emotion.

0613_Fera_kr6ja.indd 3 6/4/13 2:22 PM Cataract REVIEW Cover Focus Cataract Surgery: The Oculoplastic Factor Christopher Kent, Senior Editor

Many conditions hen examining a potential have limited benefi t if your lid is still cataract patient, most cata- in the way of your vision afterwards. affecting the eyelid Wract surgeons focus on the So if the patient has signifi cant ptosis, condition of the lens, cornea and reti- it probably ought to be fi xed before and orbit can na—and rightly so. But other factors, the cataract surgery.” such as the condition of the lids and Julie Ann Woodward, MD, associ- increase the risks tear ducts, can also affect the outcome ate professor of ophthalmology and associated with of cataract surgery. dermatology and chief of the Oculo- With that in mind, four surgeons plastic and Reconstructive Surgery cataract surgery. with extensive oculoplastic experience Service at Duke University School share their thoughts on which oculo- of Medicine in Durham, N.C., notes Here’s help plastic issues are most likely to impact another issue of concern. “A patient cataract surgery, and what a surgeon may have dermatochalasis, where the managing them. should do when they arise. redundant upper eyelid skin is heavy and lying on top of the eyelashes,” she Upper Eyelid Concerns says. “This can create conditions favorable for blepharitis because there’s Generally, ptosis doesn’t increase a warm, sticky environment that’s con- the risk of cataract surgery; in fact, ducive to bacterial growth underneath there is some argument for waiting the fl ap of skin. until after the cataract surgery to deal “In that situation, the cataract sur- with it. However, in severe cases it geon should refer the patient for a may need to be repaired fi rst. blepharoplasty to have the hooded Jonathan Dutton, MD, PhD, tissue removed,” she says. “This often FACS, professor and vice chair of improves the blepharitis so that the ophthalmology at the University of chance of infection after cataract sur- North Carolina at Chapel Hill, notes gery is decreased.” that if ptosis is mild and primarily a One factor that needs to be consid- cosmetic issue, most cataract surgeons ered before correcting ptosis is the won’t choose to do anything about it. patient’s dry-eye status. “If a surgeon “However, many patients who are go- refers a patient to us for ptosis re- ing to have cataract surgery are sent pair and the patient has very dry eye, to me to bring the lid up because it’s sometimes we’ll recommend either no so low that it’s blocking their vision,” ptosis surgery at all or a very conserva- he says. “Doing cataract surgery will tive ptosis repair,” says Dr. Woodward.

20 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

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RP0213_BL Lotemax.indd 1 1/10/13 2:27 PM USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C. Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day Brief Summary: Based on full prescribing information. (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/ To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb at kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) and 1-800-323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). INDICATIONS AND USAGE Treatment of rats with 0.5 mg/kg/day (6 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol LOTEMAX is a corticosteroid indicated for the treatment of post-operative etabonate was maternally toxic (significantly reduced body weight gain during inflammation and pain following ocular surgery. treatment) when administered to pregnant rats during organogenesis at doses DOSAGE AND ADMINISTRATION of ≥5 mg/kg/day. Invert closed bottle and shake once to fill tip before instilling drops. Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from Apply one to two drops of LOTEMAX into the conjunctival sac of the affected the start of the fetal period through the end of lactation, a maternally toxic eye four times daily beginning the day after surgery and continuing treatment regimen (significantly decreased body weight gain), gave rise to throughout the first 2 weeks of the post-operative period. decreased growth and survival, and retarded development in the offspring CONTRAINDICATIONS during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in etabonate had no effect on the duration of gestation or parturition when most viral diseases of the cornea and conjunctiva including epithelial herpes administered orally to pregnant rats at doses up to 50 mg/kg/day during the simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in fetal period. mycobacterial infection of the eye and fungal diseases of ocular structures. There are no adequate and well controlled studies in pregnant women. WARNINGS AND PRECAUTIONS LOTEMAX should be used during pregnancy only if the potential benefit Intraocular Pressure (IOP) Increase justifies the potential risk to the fetus. Prolonged use of corticosteroids may result in glaucoma with damage to the Nursing Mothers optic nerve, defects in visual acuity and fields of vision. Steroids should be It is not known whether topical ophthalmic administration of corticosteroids used with caution in the presence of glaucoma. If this product is used for 10 could result in sufficient systemic absorption to produce detectable quantities days or longer, intraocular pressure should be monitored. in human milk. Systemic steroids appear in human milk and could suppress Cataracts growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LOTEMAX is administered Use of corticosteroids may result in posterior subcapsular cataract formation. to a nursing woman. Delayed Healing Pediatric Use The use of steroids after cataract surgery may delay healing and increase the Safety and effectiveness in pediatric patients have not been established. incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical Geriatric Use steroids. The initial prescription and renewal of the medication order should No overall differences in safety and effectiveness have been observed be made by a physician only after examination of the patient with the aid between elderly and younger patients. of magnification such as slit lamp biomicroscopy and, where appropriate, NONCLINICAL TOXICOLOGY fluorescein staining. Carcinogenesis, Mutagenesis, Impairment Of Fertility Bacterial Infections Long-term animal studies have not been conducted to evaluate the Prolonged use of corticosteroids may suppress the host response and carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was thus increase the hazard of secondary ocular infections. In acute purulent not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in conditions of the eye, steroids may mask infection or enhance existing a chromosome aberration test in human lymphocytes, or in vivo in the single infection. dose mouse micronucleus assay. Treatment of male and female rats with up to Viral Infections 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (600 Employment of a corticosteroid medication in the treatment of patients with and 300 times the maximum clinical dose, respectively) prior to and during a history of herpes simplex requires great caution. Use of ocular steroids may mating did not impair fertility in either gender. prolong the course and may exacerbate the severity of many viral infections PATIENT COUNSELING INFORMATION of the eye (including herpes simplex). Administration Fungal Infections Invert closed bottle and shake once to fill tip before instilling drops. Fungal infections of the cornea are particularly prone to develop coincidentally Risk of Contamination with long-term local steroid application. Fungus invasion must be considered Patients should be advised not to allow the dropper tip to touch any surface, in any persistent corneal ulceration where a steroid has been used or is in as this may contaminate the gel. use. Fungal cultures should be taken when appropriate. Contact Lens Wear Contact Lens Wear Patients should be advised not to wear contact lenses when using LOTEMAX. Patients should not wear contact lenses during their course of therapy with Risk of Secondary Infection LOTEMAX. If pain develops, redness, itching or inflammation becomes aggravated, the ADVERSE REACTIONS patient should be advised to consult a physician. Adverse reactions associated with ophthalmic steroids include elevated FOR MORE DETAILED INFORMATION, PLEASE READ THE PRESCRIBING intraocular pressure, which may be associated with infrequent optic nerve INFORMATION. damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from Bausch & Lomb Incorporated pathogens including herpes simplex, and perforation of the globe where there Tampa, Florida 33637 USA is thinning of the cornea or sclera. US Patent No. 5,800,807 ©Bausch & Lomb Incorporated The most common adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%). ®/™ are trademarks of Bausch & Lomb Incorporated or its affiliates.

9303400

RP0213_BL Lotemax PI.indd 1 1/10/13 2:28 PM Cover Cataract

REVIEW Focus All images: Julie Ann Woodward, MD “We’ll explain to the patient that we can only lift the eyelid 1 or 1.5 mm to avoid worsening the dry eye. The more we correct the ptosis in this situation, the worse the patient’s dry eye will become.” Dr. Dutton concurs. “The more you open the palpebral ﬁ ssure by correcting the ptosis, the more dryness the patient will have,” he says. “That’s why some oculoplastic surgeons do a Schirmer’s test on every patient over 40 or 50. It’s not a great test, but it gives you some idea of tear function. In any case, if I see a patient with any kind of dry-eye issue and I’m planning ptosis surgery, I’m very conserva- tive. I’ll lift the lid up just enough to clear the pupil so the patient can see. You don’t want to make these patients bright-eyed and bushy-tailed the way you might a younger patient, because you could be throwing the patient into a much more symptomatic dry-eye situation.”

Making the Droop Worse

“One thing I see all the time—and this is fairly well-documented—is up- Surgery to correct ptosis and ectropion (above: before and after corrective surgery) can per lid ptosis a month or two, some- result in a change of K-reading and refraction. Nevertheless, surgery to repair ptosis is times a year after the cataract surgery,” often postponed until after cataract surgery because the cataract surgery may cause an notes Dr. Dutton. “In the literature increase in the ptosis in some patients. there have been debates about whether the cataract surgery is responsible Beverly Hills, Calif. “Some believe the the cataract surgery, requiring a sec- for the ptosis; the consensus is that it mechanical stretching of the lid dur- ond ptosis surgery.” probably is. During cataract surgery ing surgery may cause a little droop Dr. Woodward agrees. “Cataract you put a speculum in and rotate the afterwards. Years ago, when cataract surgery has about a 1-percent chance eye down to get at the superior limbus. surgeons gave a lot of numbing injec- of worsening eyelid ptosis,” she says. There are adhesions between the su- tions around the eye, they thought a “If patients need ptosis surgery, we perior rectus and the levator muscle in toxic reaction to the medication might usually recommend that they get their the orbit; when you pull one of them be causing the muscle to malfunction cataract surgery first. Of course, in in one direction and the other in the a little bit. It could simply be that the some cases the ptosis is so severe that other direction, you can theoretically patient’s improved vision allows her the surgeon fi nds it diffi cult to make damage those adhesions, causing pto- to observe a subtle droop she didn’t certain measurements. In those cases sis. Because of the nature of cataract notice before. we may go ahead and do the ptosis surgery, there’s not a lot we can do to “In any case, if a patient comes in for surgery fi rst.” prevent it.” cataract surgery with a few millimeters “There are many theories as to of ptosis, I wouldn’t repair it until after Lower Lids and Exposure why this may happen,” adds Guy G. the cataract is done,” he says. “If you Massry, MD, who practices at Beverly fi x it to make the lids equal, the patient “Another issue to think about is Hills Ophthalmic Plastic Surgery in could develop a little droop again after lower lid ectropion, where the lower

July 2013 | Revophth.com | 23

020_rp0713_f1.indd 23 6/21/13 10:10 AM Cover Cataract

REVIEW Focus

eyelid is very lax and the patient has ber of different reasons,” notes Dr. sclera showing between the cornea Woodward. “First, the eye can water and lower lid margin,” says Dr. Wood- because it’s inherently dry. The dry- ward. “Patients with this issue can be ness could be the result of not making more prone to exposure-related dry proper mucus or oils for the hydro- eye and infections. If there’s a lot of phobic layers that lie above and below sclera showing inferiorly, the cataract the aqueous layer in the tear fi lm; the surgeon may suggest having the lower eye tries to protect itself by refl exively lid tightened so it better approximates producing extra aqueous fluid from the lower edge of the cornea prior to the lacrimal gland. surgery. Normally, the lower eyelid “A second reason eyes can water is should touch the inferior edge of the malposition of the punctum, which cornea or limbus and the upper eyelid can happen with an ectropion,” she should cover about 2 mm of the supe- continues. “An ectropion can be re- rior cornea. paired using a number of different “Ectropion is very common,” she approaches. If the problem is just lid adds, “especially in cases of sleep ap- laxity, a tarsal strip can be performed; nea. Patients with sleep apnea tend if the punctum itself is everted, we to have fl oppy eyelids along with their may perform a medial spindle opera- Floppy eyelids can make patients more floppy palette. They are also more prone to dry eye and infections. If a patient tion. Sometimes a skin graft is needed likely to be eye-rubbers and have a lot has diffi culty closing his eyes or has to reposition the puncta. of mucus in the eyes; the eyelids can exposure symptoms, this should probably “The third reason an eye can wa- fl ip inside-out on the pillow. Such pa- be addressed prior to performing cataract ter is blockage in the nasolacrimal tients should be referred to oculoplas- surgery. duct,” she says. “If fl uid doesn’t fl ow tic surgeons for lid tightening prior to freely through the nose, bacteria may any cataract surgery.” Massry. “When tears well up and sit sit in a stagnant area and then flow “If you’re doing cataract surgery on on the eye, it’s like water in a bathtub; retrograde back out onto the eye, po- a patient who has any diffi culty closing after a while the tears can become tentially contaminating the cataract his eyes, or has exposure symptoms, murky and infected. If you’re doing wound. For that reason, if the patient that should probably be addressed be- cataract surgery, that’s the last thing has an eye-watering issue, he needs to fore the cataract surgery,” agrees Dr. you want.” be evaluated to make sure there’s no Massry. “Unlike ptosis, ectropion and John S. Jarstad, MD, medical di- nasolacrimal duct obstruction, espe- entropion predispose the patient to rector of Evergreen Eye Centers in cially if there’s any evidence that the irritation and infections after surgery. Federal Way, Wash., and an adjunct patient may have had dacryocystitis Furthermore, the individual may be professor at Pacifi c Northwest Univer- in the past. If there is a problem, we asymptomatic and complication-free sity College of Osteopathic Medicine, might resolve it either by inserting before surgery but start to have prob- in Yakima, Wash., agrees that address- a Crawford tube or by performing a lems with dry eye or scratchiness af- ing issues such as a blocked tear duct dacryocystorhinostomy.” terwards. You never know how surgery with excessive eye watering prior to In terms of deciding when tearing is will change the balance in the eye. So cataract surgery is crucial. (Dr. Jarstad suffi cient to warrant intervention, Dr. it’s worth addressing this beforehand, does numerous cataract surgeries ev- Jarstad says the medical history is a in part because any exposure may in- ery week, but has also done thousands big part of the answer. “Also, I ask the crease the risk associated with cataract of oculoplastic procedures over the patient, ‘Do you have tears running surgery, but also because you don’t course of his career and continues to down your cheek?’ If they say yes, I’m want the patient to blame related post- do them whenever circumstances per- concerned,” he says. “I also examine op problems on the cataract surgery.” mit.) “A blocked tear duct is a setup the tear film, staining the eye with for infection,” he notes. “In those cas- vital dyes like rose bengal or lissamine Too Many Tears es, we’d like to see a dacryocystorhi- green, and do fl uorescein testing.” nostomy performed or tubes placed “Anyone with excessive tearing into the tear ducts to allow adequate Additional Concerns should probably have that addressed drainage.” before cataract surgery,” says Dr. “Patients’ eyes can tear for a num- Cataract surgeons may encounter

24 | Review of Ophthalmology | July 2013

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REVIEW Focus

lifestyle a little bit, but it’s not a matter of vision loss or risking death. A tumor might be.” • Trichiasis. “If the eye is irritated because of the lashes coming back against the eye, the patient is going to have excess tearing,” notes Dr. Dut- ton. “I see a lot of these patients and their corneas are abraded, which is going to affect their visual acuity. If you take out the cataract but the cornea is in that condition, the patient isn’t going to be thrilled with the resulting vision. I think it makes sense to deal with this before proceeding with cataract surgery. “One way to deal with this is to simply pluck out the offending lashes,” he notes. “Sometimes the lashes will grow back in the correct position, but in most cases they’ll grow back in the incorrect position, so this won’t be sufﬁ cient. We prefer to use a radio- frequency tool to remove the lashes permanently. I’d do this before the cataract surgery.”

When Should You Refer? An example of dermatochalasis, where the redundant upper eyelid skin is heavy and lying on top of the eyelashes (before and after correction). This can create conditions Dr. Woodward notes that whether or favorable for blepharitis because there’s a warm, sticky environment conducive to not a cataract surgeon refers patients to bacterial growth underneath the ﬂ ap of skin. A blepharoplasty to correct this before a specialist for correction of oculoplastic cataract surgery may decrease the risk of postop infection. concerns really depends on the comfort level of the surgeon. “Years ago, doc- other issues as well: pecially if it’s elevated, if it’s ulcerated, tors were jacks-of-all-trades,” she says. • Tumors. “I see a lot of malignan- if there’s loss of lashes … those are all “Many cataract surgeons felt comfort- cies involving the eyelids,” says Dr. tip-offs that you may be dealing with a able taking care of ptosis and ectropion Dutton. “They’ve often been misdiag- malignancy. Refer the patient to some- themselves. Today, ophthalmologists nosed as inﬂ ammation or blepharitis. body who can make that diagnosis, if have become very subspecialized, and Blepharitis doesn’t occur in one loca- you can’t do it yourself.” they’re more apt to refer patients to an tion, on one lid, but general practitio- Dr. Massry agrees. “If a cataract sur- oculoplastic specialist. ners sometimes make that mistake. geon notices any abnormal growth, “However, this may depend partly Would an incorrectly diagnosed ma- whether it’s on the eyelid or the eye it- on your location,” she adds. “In some lignant tumor affect cataract surgery? self, it should be addressed before the cities, surgeons tend to stay subspe- The cataract surgeon is putting in a cataract surgery,” he says. “Potentially cialized; in other cities, surgeons are speculum and rubbing all over the lids; it’s a malignancy, and a malignancy, in more comfortable doing oculoplastic I don’t know whether that could dis- some circumstances, can be associ- procedures themselves. Here at Duke lodge tumor cells. ated with tremendous morbidity. It University we have so many subspe- “I think any ophthalmologist who can affect vision and it can potentially cialized ophthalmologists available sees a lesion on the lid should question spread. Cataract surgery is an elective that there’s no reason for surgeons to the patient,” he continues. “How long procedure; whether or not you do it try to do these all of these oculoplastic has it been there? Does it bleed? Es- right now may affect your vision and procedures themselves.”

26 | Review of Ophthalmology | July 2013

020_rp0713_f1.indd 26 6/21/13 10:10 AM RP0713_Biotissue.indd 1 6/19/13 11:43 AM Cover Cataract

REVIEW Focus

Dr. Massry agrees. “If you’re talk- pay little attention to cataracts or ing about an eyelid problem like the retina, so this is not a problem an entropion, ectropion or ptosis, unique to cataract surgeons.” it’s all about the comfort zone and • Don’t assume oculoplastic expertise of the physician,” he says. issues can be addressed after the “Many ophthalmologists have been cataract surgery. “I think there’s around for a while and are com- a tendency to assume you can take fortable doing basic eyelid work. care of these issues after cataract However, if you’re a surgeon who A cataract surgeon is in a unique position to surgery, because that’s how many just does high-volume cataract all uncover subtle but serious problems—if the focus plastics problems are addressed,” day, it may not make sense for you is on the entire eye, not just the cataract. Left: This says Dr. Jarstad. “Some issues like to do the eyelid surgery; your risk of patient’s makeup made it diffi cult to notice a basal ptosis can be affected by the cata- cell carcinoma along the lower eyelid. Right: The having a complication is going to be ract surgery, so it makes sense to same eye after Mohs surgery, prior to greater than it would be for some- reconstruction. Noticing subtle abnormalities such address those later. But other issues one who does oculoplastic work all as this can prolong a cataract patient’s life. really need to be addressed before day. And plenty of specialists are the cataract surgery to avoid putting available; 550 oculoplastic surgeons in tion before we start, and checking the the patient at risk.” this country are certifi ed by the Amer- retina to make sure there won’t be any • Alert a patient of existing pto- ican Society of Ophthalmic Plastic and surprises due to macular degeneration sis. “If a patient of yours is going to Reconstructive Surgery. It’s really up or some other retinal disease. But we have cataract surgery and already has to the surgeon to decide. sometimes overlook the eyelids. In a droopy lid, you need to point this “On the other hand,” he continues, particular, signifi cant laxity or a block- out beforehand so the patient doesn’t “if the patient has tear duct blockage age in the nasolacrimal system really blame it on your surgery,” says Dr. or a tumor, the surgery is a little more should be addressed before cataract Massry. advanced and should probably be re- surgery. Managing these concerns will • If the upper eyelashes point ferred to a specialist. Ectropion, en- give the patient a better outcome and straight down, ask the spouse whe- tropion and ptosis are bread-and-but- lower the risk of infection or a pro- ther the patient snores. “Upper eye- ter eyelid surgeries that many general longed recovery.” lid lash ptosis is one of the signs of ophthalmologists have been trained to Dr. Woodward agrees. “Of course, fl oppy eyelid syndrome,” Dr. Wood- do, and if the surgery doesn’t work out if a condition is severe, most cataract ward explains. “Floppy eyelid syn- it can probably be corrected. That’s surgeons will notice it and address it, drome is on the spectrum of floppy not the case with tumors or tear duct but sometimes they overlook it if it’s palate, and these individuals frequent- blockages, which most general oph- mild,” she says. “As a result, patients ly have sleep apnea. So if you observe thalmologists don’t treat routinely. In don’t get treated for dermatochalasis, that the lashes point straight down, it’s those cases, I would err on the side of ectropion or ptosis, even when the important to ask the patient and even being cautious and refer to an oculo- patient might benefi t and the cataract the spouse whether the patient snores. plastic colleague.” surgery would be safer.” The spouse will often say, ‘Yes, like a “Cataract surgeons can get so busy freight train,’ or, ‘Yes, he has a CPAP Strategies for Success looking at the cataract that they for- machine.’ Sometimes the patient is get the lids, conjunctiva, tear ducts already being treated for sleep apnea, When examining a potential cat- and so forth,” says Dr. Dutton. “For but sometimes patients haven’t been aract patient, these suggestions can example, I’d say that 40 to 50 percent treated before. In that case it’s real- help avoid increased surgical risk: of the patients I see who have skin ly important for us to refer them for • Don’t overlook the eyelids. “I cancer aren’t even aware of it. Some- sleep studies, because treating sleep think it’s important to pay attention body has to point it out to them; they apnea can potentially prolong the pa- to the ocular adnexa and look at the just thought the lesion was a little sore tient’s life.” lid position,” says Dr. Jarstad. “It’s or something and paid no attention to • If appropriate, try the snap- easy to overlook these. We’re usually it. The cataract surgeon is in a posi- back test. “Occasionally you’ll en- very focused on looking at the eyeball, tion to fi nd those things at the initial counter a patient with involutional ec- checking the cornea for corneal dys- examination. tropion, where the eyelids are very lax trophy, checking to make sure there’s “To be fair,” he adds, “I have to ad- and don’t approximate the globe well,” no zonular weakness or pseudoexfolia- mit that many oculoplastic surgeons notes Dr. Jarstad. “Those patients are

28 | Review of Ophthalmology | July 2013

020_rp0713_f1.indd 28 6/21/13 10:11 AM DUREZOL® Emulsion now has head-to-head data vs prednisolone acetate in patients with endogenous anterior uveitis.1

Scan the QR code with your smartphone or log on to www.infl ammationhappens.com to see the results for yourself.

INDICATIONS AND USAGE: DUREZOL® Emulsion is a topical corticosteroid t#BDUFSJBMJOGFDUJPOTo1SPMPOHFEVTFPGDPSUJDPTUFSPJETNBZTVQQSFTT that is indicated for the treatment of endogenous anterior uveitis. the host response and thus increase the hazard of secondary ocular Dosage and Administration JOGFDUJPOT*OBDVUFQVSVMFOUDPOEJUJPOT TUFSPJETNBZNBTLJOGFDUJPO PSFOIBODFFYJTUJOHJOGFDUJPO*GTJHOTBOETZNQUPNTGBJMUPJNQSPWF For the treatment of endogenous anterior uveitis, instill one drop into the after 2 days, the patient should be re-evaluated. conjunctival sac of the affected eye 4 times daily for 14 days followed by tapering as clinically indicated. t7JSBMJOGFDUJPOTo&NQMPZNFOUPGBDPSUJDPTUFSPJENFEJDBUJPOJOUIF treatment of patients with a history of herpes simplex requires great IMPORTANT SAFETY INFORMATION caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including Contraindications: DUREZOL® Emulsion, as with other ophthalmic herpes simplex). corticosteroids, is contraindicated in most active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis t'VOHBMJOGFDUJPOTo'VOHBMJOGFDUJPOTPGUIFDPSOFBBSFQBSUJDVMBSMZ (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial prone to develop coincidentally with long-term local steroid application. infection of the eye and fungal diseases of ocular structures. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Warnings and Precautions t$POUBDUMFOTXFBSo%63&;0-® Emulsion should not be instilled while t*OUSBPDVMBSQSFTTVSF *01 JODSFBTFo1SPMPOHFEVTFPGDPSUJDPTUFSPJETNBZ wearing contact lenses. result in glaucoma with damage to the optic nerve, defects in visual acuity BOEGJFMETPGWJTJPO*GUIJTQSPEVDUJTVTFEGPSEBZTPSMPOHFS *01TIPVME Adverse Reactions be monitored. *OUIFFOEPHFOPVTBOUFSJPSVWFJUJTTUVEJFT UIFNPTUDPNNPOBEWFSTF t$BUBSBDUTo6TFPGDPSUJDPTUFSPJETNBZSFTVMUJOQPTUFSJPSTVCDBQTVMBS SFBDUJPOTPDDVSSJOHJOPGTVCKFDUTJODMVEFECMVSSFEWJTJPO FZF cataract formation. JSSJUBUJPO FZFQBJO IFBEBDIF JODSFBTFE*01 JSJUJT MJNCBMBOEDPOKVODUJWBM hyperemia, punctate keratitis, and uveitis. t%FMBZFEIFBMJOHo5IFVTFPGTUFSPJETBGUFSDBUBSBDUTVSHFSZNBZEFMBZ IFBMJOHBOEJODSFBTFUIFJODJEFODFPGCMFCGPSNBUJPO*OUIPTFEJTFBTFT For additional information about DUREZOL® Emulsion please refer causing thinning of the cornea or sclera, perforations have been known to PDDVSXJUIUIFVTFPGUPQJDBMTUFSPJET5IFJOJUJBMQSFTDSJQUJPOBOESFOFXBM to the brief summary of prescribing information on adjacent page. of the medication order beyond 28 days should be made by a physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

Reference: 1. DUREZOL® Emulsion Package Insert.

RP0313_Alcon Durezol.indd 1 2/7/13 10:34 AM been used or is in use. Fungal culture should be taken Nursing Mothers when appropriate. It is not known whether topical ophthalmic administration of corticosteroids could result in Topical Ophthalmic Use Only sufficient systemic absorption to produce detectable DUREZOL® Emulsion is not indicated for intraocular quantities in breast milk. Systemically administered BRIEF SUMMARY OF PRESCRIBING INFORMATION administration. corticosteroids appear in human milk and could INDICATIONS AND USAGE Contact Lens Wear suppress growth, interfere with endogenous Ocular Surgery DUREZOL® Emulsion should not be instilled while corticosteroid production, or cause other untoward DUREZOL® (difluprednate ophthalmic emulsion) wearing contact lenses. Remove contact lenses prior effects. Caution should be exercised when DUREZOL® 0.05%, a topical corticosteroid, is indicated for the to instillation of DUREZOL® Emulsion. The preservative Emulsion is administered to a nursing woman. in DUREZOL® Emulsion may be absorbed by soft treatment of inflammation and pain associated with Pediatric Use contact lenses. Lenses may be reinserted after 10 ocular surgery. Safety and effectiveness in pediatric patients have not minutes following administration of DUREZOL® Endogenous Anterior Uveitis been established. DUREZOL® Emulsion is also indicated for the treatment Emulsion. of endogenous anterior uveitis. Geriatric Use ADVERSE REACTIONS No overall differences in safety or effectiveness have Adverse reactions associated with ophthalmic steroids DOSAGE AND ADMINISTRATION been observed between elderly and younger patients. Ocular Surgery include elevated intraocular pressure, which may be Instill one drop into the conjunctival sac of the associated with optic nerve damage, visual acuity and Nonclinical Toxicology affected eye 4 times daily beginning 24 hours after field defects; posterior subcapsular cataract formation; Carcinogenesis, Mutagenesis, and Impairment of surgery and continuing throughout the first 2 weeks secondary ocular infection from pathogens including Fertility of the postoperative period, followed by 2 times daily herpes simplex, and perforation of the globe where Difluprednate was not genotoxicin vitro in the for a week and then a taper based on the response. there is thinning of the cornea or sclera. Ames test, and in cultured mammalian cells CHL/ IU (a fibroblastic cell line derived from the lungs Ocular Surgery Endogenous Anterior Uveitis of newborn female Chinese hamsters). An in vivo Ocular adverse reactions occurring in 5-15% of Instill one drop into the conjunctival sac of the micronucleus test of difluprednate in mice was also subjects in clinical studies with DUREZOL® Emulsion affected eye 4 times daily for 14 days followed by negative. Treatment of male and female rats with included corneal edema, ciliary and conjunctival tapering as clinically indicated. subcutaneous difluprednate up to 10 mcg/kg/day hyperemia, eye pain, photophobia, posterior capsule prior to and during mating did not impair fertility DOSAGE FORMS AND STRENGTHS opacification, anterior chamber cells, anterior chamber ® in either gender. Long term studies have not been DUREZOL Emulsion contains 0.05% difluprednate as flare, conjunctival edema, and blepharitis. Other conducted to evaluate the carcinogenic potential of a sterile preserved emulsion for topical ophthalmic ocular adverse reactions occurring in 1-5% of subjects difluprednate. administration. included reduced visual acuity, punctate keratitis, CONTRAINDICATIONS eye inflammation, and iritis. Ocular adverse reactions Animal Toxicology and/or Pharmacology The use of DUREZOL® Emulsion, as with other occurring in < 1% of subjects included application In multiple studies performed in rodents and ophthalmic corticosteroids, is contraindicated in most site discomfort or irritation, corneal pigmentation non-rodents, subchronic and chronic toxicity tests active viral diseases of the cornea and conjunctiva and striae, episcleritis, eye pruritis, eyelid irritation of difluprednate showed systemic effects such including epithelial herpes simplex keratitis and crusting, foreign body sensation, increased as suppression of body weight gain; a decrease (dendritic keratitis), vaccinia, and varicella, and also in lacrimation, macular edema, sclera hyperemia, and in lymphocyte count; atrophy of the lymphatic mycobacterial infection of the eye and fungal disease uveitis. Most of these reactions may have been the glands and adrenal gland; and for local effects, of ocular structures. consequence of the surgical procedure. thinning of the skin; all of which were due to the pharmacologic action of the molecule and are well Endogenous Anterior Uveitis WARNINGS AND PRECAUTIONS known glucocorticosteroid effects. Most, if not all of A total of 200 subjects participated in the clinical IOP Increase these effects were reversible after drug withdrawal. trials for endogenous anterior uveitis, of which 106 Prolonged use of corticosteroids may result in The NOEL for the subchronic and chronic toxicity tests were exposed to DUREZOL® Emulsion. The most glaucoma with damage to the optic nerve, defects were consistent between species and ranged from common adverse reactions of those exposed to in visual acuity and fields of vision. Steroids should 1–1.25 mcg/kg/day. be used with caution in the presence of glaucoma. If DUREZOL® Emulsion occurring in 5-10% of subjects this product is used for 10 days or longer, intraocular included blurred vision, eye irritation, eye pain, PATIENT COUNSELING INFORMATION pressure should be monitored. headache, increased IOP, iritis, limbal and conjunctival Risk of Contamination hyperemia, punctate keratitis, and uveitis. Adverse This product is sterile when packaged. Patients should Cataracts reactions occurring in 2-5% of subjects included be advised not to allow the dropper tip to touch any Use of corticosteroids may result in posterior anterior chamber flare, corneal edema, dry eye, surface, as this may contaminate the emulsion. subcapsular cataract formation. iridocyclitis, photophobia, and reduced visual acuity. Use of the same bottle for both eyes is not recommended with topical eye drops that are used in Delayed Healing USE IN SPECIFIC POPULATIONS association with surgery. The use of steroids after cataract surgery may delay Pregnancy healing and increase the incidence of bleb formation. Teratogenic Effects Risk of Secondary Infection In those diseases causing thinning of the cornea or Pregnancy Category C. Difluprednate has been If pain develops, or if redness, itching, or inflammation sclera, perforations have been known to occur with shown to be embryotoxic (decrease in embryonic becomes aggravated, the patient should be advised to the use of topical steroids. The initial prescription body weight and a delay in embryonic ossification) consult a physician. and renewal of the medication order beyond 28 days and teratogenic (cleft palate and skeletal) anomalies Contact Lens Wear should be made by a physician only after examination when administered subcutaneously to rabbits during DUREZOL® Emulsion should not be instilled while of the patient with the aid of magnification such as organogenesis at a dose of 1–10 mcg/kg/day. The wearing contact lenses. Patients should be advised slit lamp biomicroscopy and, where appropriate, no-observed-effect-level (NOEL) for these effects was to remove contact lenses prior to instillation of fluorescein staining. 1 mcg/kg/day, and 10 mcg/kg/day was considered to DUREZOL® Emulsion. The preservative in DUREZOL® be a teratogenic dose that was concurrently found in Bacterial Infections Emulsion may be absorbed by soft contact lenses. the toxic dose range for fetuses and pregnant females. Prolonged use of corticosteroids may suppress Lenses may be reinserted after 10 minutes following Treatment of rats with 10 mcg/kg/day subcutaneously the host response and thus increase the hazard administration of DUREZOL® Emulsion. of secondary ocular infections. In acute purulent during organogenesis did not result in any reproductive toxicity, nor was it maternally toxic. At conditions, steroids may mask infection or enhance Revised: June 2012 100 mcg/kg/day after subcutaneous administration existing infection. If signs and symptoms fail to U.S. Patent 6,114,319 improve after 2 days, the patient should be re- in rats, there was a decrease in fetal weights and evaluated. delay in ossification, and effects on weight gain in the pregnant females. It is difficult to extrapolate Viral Infections these doses of difluprednate to maximum daily Manufactured For Employment of a corticosteroid medication in the human doses of DUREZOL® Emulsion, since DUREZOL® treatment of patients with a history of herpes simplex Emulsion is administered topically with minimal requires great caution. Use of ocular steroids may systemic absorption, and difluprednate blood levels Alcon Laboratories, Inc. prolong the course and may exacerbate the severity were not measured in the reproductive animal studies. 6201 South Freeway of many viral infections of the eye (including herpes However, since use of difluprednate during human Fort Worth, Texas 76134 USA simplex). pregnancy has not been evaluated and cannot rule 1-800-757-9195 ® [email protected] Fungal Infections out the possibility of harm, DUREZOL Emulsion should Manufactured By: Fungal infections of the cornea are particularly prone be used during pregnancy only if the potential benefit justifies the potential risk to the embryo or fetus. Catalent Pharma Solutions to develop coincidentally with long-term local steroid Woodstock, IL 60098 application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has ©2012 Novartis 6/12 DUR12020JAD

RP0313_Alcon Durezol PI.indd 1 2/7/13 10:32 AM Cover Cataract

REVIEW Focus

at risk for exposure and infection after work in a particular specialty for years, “That puts us in a little bit of a bind surgery. In that situation I was taught you learn to notice and identify subtle because we have to make sure that to do the snap-back test, where you problems that would escape the notice they’re not at risk of infection. In this pinch the lower eyelid and pull it away of anyone else. situation we treat them with antibiotic from the globe and let it spring back. “Also, always take the patient at his eye drops for a couple of weeks be- If it takes more than a second or two word,” he adds. “If he has a complaint fore surgery and then go ahead. In our to spring back and approximate the but you don’t fi nd anything, assume experience that has worked, but it’s eyeball, the patient may require some he’s right; something is going on. Usu- defi nitely more risky. We’ve had to do eyelid tightening with a tarsal strip ally if you spend the time and search this several times in the past 27 years, procedure or a wedge resection before carefully, you’ll fi nd the problem. If and so far we have not seen infections surgery.” not, refer the patient. Don’t let it drop or other issues.” • If the patient is tearing exces- just because you can’t fi nd the prob- • Don’t be afraid to refer. “The sively, determine the cause. “If the lem yourself.” majority of patients we see are great cause is mechanical, such as lid laxity • If a patient refuses corrective candidates for cataract surgery,” notes or punctal stenosis, that shouldn’t af- surgery, inform the patient of the Dr. Jarstad. “But nowadays almost ev- fect the cataract surgery,” notes Dr. consequences and then reconsid- eryone has the option of referring a Dutton. “But if the tearing is due to er. Dr. Massry notes that occasion- patient to an oculoplastic specialist or blepharitis or a possible nasolacrimal ally a patient won’t want to undergo someone with experience in oculo- duct infection, I’d get that fi xed before the oculoplastic surgery. “Whether a plastics. If you don’t feel you can deal cataract surgery. And if the patient is corrective surgery is necessary for a with a problem, I wouldn’t hesitate to tearing but the cause isn’t obvious, you given patient is always a judgment call refer the patient.” might want to refer the patient just on the part of the cataract surgeon,” to make sure that the lacrimal drain he says. “If the surgeon feels that the How Much Risk is Acceptable? system is OK.” problem is minor or inconsequential, • If something doesn’t seem quite or the patient’s a lot older and wouldn’t Undoubtedly, many cataract pa- right, don’t let it drop. Dr. Massry agree to go through the extra proce- tients who might have benefi tted from notes that sometimes a problem isn’t dure anyway, then the surgeon has to having oculoplastic issues addressed obvious, so it behooves the cataract decide whether or not it’s safe to do before cataract surgery have not, ei- surgeon to be alert for something that the cataract surgery given the patient’s ther because the condition went un- just doesn’t seem right. When that’s condition. It’s really all about the judg- noticed, or because the surgeon felt the case, he advises considering a re- ment of the treating physician. that addressing the problem wasn’t ferral. “For example, suppose a patient has necessary. In most cases, the patients “For example,” he says, “a general had a little bit of ectropion for 20 years probably didn’t suffer any vision loss ophthalmologist referred a patient to and doesn’t want to have surgery to as a result. me who had droopy, puffy lids. The fix it because he’s been doing fine,” Nevertheless, whether proceed- patient said that the puffiness had he continues. “It’s possible that after ing in a borderline situation is ideal is been progressive, and was noticeably you do the cataract surgery it will get open to question. “If I were doing cat- worse in one eye. When I examined worse and he won’t be ‘just fi ne’ any aract surgery, I wouldn’t want to take him, I realized that a lot of the heavi- more. So you have to let the patient any risk whatsoever, no matter how ness on the upper lid in the worse know that it could get worse. small,” says Dr. Dutton. “I’d get ev- eye was not standard droopiness; the “In this situation, all you can do is erything about the eye in good shape globe was a little more prominent and inform patients in an ethical manner,” before doing the surgery. There’s no slightly inferiorly displaced. It was he adds. “You can’t tell them what to reason to do cataract surgery if the pa- very subtle, but I ordered a CAT scan; do; they have to make their own de- tient is going to complain afterwards it revealed a tumor in the orbit. cision. If they won’t agree to the ex- that he can’t see or that his eye hurts “There are several lessons worth tra surgery, then you have to decide all the time. noting here,” he continues. “First, if whether you’re willing to proceed.” “Patients are always going to blame something doesn’t seem right, don’t Dr. Jarstad has encountered this you if they have any problems after let it drop. And if it potentially involves as well. “I’ve had some patients who you’ve done surgery on them, whether an area you don’t work with on a daily felt they could not endure a dacryo- the problem was there beforehand or basis, refer to someone who manag- cystorhinostomy, but they still want not,” he adds. “So, you might as well es those issues every day. When you the cataract surgery done,” he says. take care of those issues fi rst.”

July 2013 | Revophth.com | 31

020_rp0713_f1.indd 31 6/21/13 10:11 AM Cataract REVIEW Cover Focus The Hidden Pitfalls of Postop Enhancements Walter Bethke, Managing Editor

How to espite the best biometry, main procedure and that these are there will be the occasional simple ‘touch-up’ cases to make his manage patient Dcataract procedure that re- vision a little better. However, these sults in a refraction that misses the situations can get very complex, and expectations, mark. Though some monofocal in- these enhancements are far more dif- traocular lens patients can just wear fi cult than PRK or LASIK on a virgin choose a spectacles for small errors, there will eye, for a host of reasons. If you didn’t refractive target be patients with larger errors, or mul- do the original cataract surgery and tifocal IOL patients whose refractions this isn’t your patient, by agreeing to and improve need to be extremely accurate, who enhance him you’ll be suddenly adopt- will need some sort of postop inter- ing all the issues and concerns of the vision. vention to get them where they need patient who had a less-than-ideal out- to be. Here, experts used to dealing come, and he’ll become your problem. with these patients explain why they In such a situation, ask yourself if it’s aren’t as straightforward as they ap- something you want to get involved pear, and share methods to get pain.” tients seeing well again. • Complications and/or ocular pathology. One of the factors that Preoperative Considerations can make these cases more complex is a complication from the cataract pro- Chicago surgeon Louis Probst says cedure. “Though IOL surgery is very that there are aspects to correcting re- effective, it does have a complication sidual refractive error that the surgeon rate,” says Dr. Probst. “If the patient may not have considered. Here are had a complication during his cataract several issues Dr. Probst says are worth procedure, this could affect his fi nal thinking about: outcome from his postop enhance- • Who was the original surgeon? ment. He may not have the potential “The cases differ depending on who to see 20/20, yet his expectation for did the initial cataract surgery,” Dr. the enhancement is that he will see Probst says. “If it’s your patient, it’s very well, if not perfectly, so this sets your responsibility to make him happy the bar high. However, talking to him and follow through as you see fi t. But about this before surgery can be tricky if it’s not your patient, be aware that because of the lofty image of laser vi- there’s a kind of false assumption out sion correction and LASIK in society, there that the patient already had his which leads many to believe they will

32 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

032_rp0713_f2.indd 32 6/20/13 2:34 PM Introducing an advanced formulation of BROMDAY® (bromfenac ophthalmic solution) 0.09% PROLENSA™ POWERED FOR PENETRATION

PROLENSA™ delivers potency and penetration with QD efﬁ cacy1,2 Advanced formulation delivers corneal penetration1-3 Proven efﬁ cacy at a lower concentration1

Available in 1.6-mL and 3-mL bottle sizes

IMPORTANT RISK INFORMATION ABOUT PROLENSA™ Indications and Usage Warnings and Precautions PROLENSA™ (bromfenac ophthalmic solution) 0.07% is a nonsteroidal anti- æ6XOĆWHDOOHUJLFUHDFWLRQV æ,QFUHDVHGEOHHGLQJRIRFXODUWLVVXHV infl ammatory drug (NSAID) indicated for the treatment of postoperative infl ammation æ6ORZRUGHOD\HGKHDOLQJ æ&RUQHDOHIIHFWVLQFOXGLQJNHUDWLWLV and reduction of ocular pain in patients who have undergone cataract surgery. æ3RWHQWLDOIRUFURVVVHQVLWLYLW\ æ&RQWDFWOHQVZHDU Dosage and Administration Adverse Reactions Instill one drop into the affected eye once daily beginning 1 day prior to surgery, The most commonly reported adverse reactions in 3%-8% of patients continued on the day of surgery, and through the fi rst 14 days post surgery. were anterior chamber infl ammation, foreign body sensation, eye pain, photophobia, and blurred vision. Please see brief summary of full Prescribing Information on adjacent page. References: 1. PROLENSA™ Prescribing Information, April 2013. 2.'DWDRQĆOH%DXVFK /RPE,QFRUSRUDWHG3.%DNOD\DQ*$ 3DWWHUVRQ+06RQJ&.*RZ-$0F1DPDUD75KRXUHYDOXDWLRQRIWKHRFXODUGLVWULEXWLRQRI14&ODEHOHGEURPIHQDFIROORZLQJWRSLFDO instillation into the eyes of New Zealand White rabbits. J Ocul Pharmacol Ther. 2008;24(4):392-398. píDUHWUDGHPDUNVRI%DXVFK /RPE,QFRUSRUDWHGRULWVDIĆOLDWHV k%DXVFK /RPE,QFRUSRUDWHG3ULQWHGLQ86$8635$

RP0713_BL Prolensa.indd 1 6/17/13 9:28 AM PROLENSATM (bromfenac ophthalmic solution) 0.07% Brief Summary INDICATIONS AND USAGE PROLENSA following cataract surgery include: anterior chamber PROLENSA (bromfenac ophthalmic solution) 0.07% is indicated for the inflammation, foreign body sensation, eye pain, photophobia and vision treatment of postoperative inflammation and reduction of ocular pain in blurred. These reactions were reported in 3 to 8% of patients. patients who have undergone cataract surgery. USE IN SPECIFIC POPULATIONS DOSAGE AND ADMINISTRATION Pregnancy Recommended Dosing Treatment of rats at oral doses up to 0.9 mg/kg/day (systemic One drop of PROLENSA ophthalmic solution should be applied to exposure 90 times the systemic exposure predicted from the the affected eye once daily beginning 1 day prior to cataract surgery, recommended human ophthalmic dose [RHOD] assuming the human continued on the day of surgery, and through the first 14 days of the systemic concentration is at the limit of quantification) and rabbits postoperative period. at oral doses up to 7.5 mg/kg/day (150 times the predicted human Use with Other Topical Ophthalmic Medications systemic exposure) produced no treatment-related malformations in PROLENSA ophthalmic solution may be administered in conjunction reproduction studies. However, embryo-fetal lethality and maternal with other topical ophthalmic medications such as alpha-agonists, beta- toxicity were produced in rats and rabbits at 0.9 mg/kg/day and blockers, carbonic anhydrase inhibitors, cycloplegics, and mydriatics. 7.5 mg/kg/day, respectively. In rats, bromfenac treatment caused Drops should be administered at least 5 minutes apart. delayed parturition at 0.3 mg/kg/day (30 times the predicted human exposure), and caused dystocia, increased neonatal mortality and CONTRAINDICATIONS reduced postnatal growth at 0.9 mg/kg/day. None There are no adequate and well-controlled studies in pregnant WARNINGS AND PRECAUTIONS women. Because animal reproduction studies are not always Sulfite Allergic Reactions predictive of human response, this drug should be used during Contains sodium sulfite, a sulfite that may cause allergic-type reactions pregnancy only if the potential benefit justifies the potential risk to including anaphylactic symptoms and life-threatening or less severe the fetus. asthmatic episodes in certain susceptible people. The overall prevalence Because of the known effects of prostaglandin biosynthesis- of sulfite sensitivity in the general population is unknown and probably inhibiting drugs on the fetal cardiovascular system (closure of ductus low. Sulfite sensitivity is seen more frequently in asthmatic than in non- arteriosus), the use of PROLENSA ophthalmic solution during late asthmatic people. pregnancy should be avoided. Slow or Delayed Healing Nursing Mothers All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including Caution should be exercised when PROLENSA is administered to a bromfenac, may slow or delay healing. Topical corticosteroids are also nursing woman. known to slow or delay healing. Concomitant use of topical NSAIDs and Pediatric Use topical steroids may increase the potential for healing problems. Safety and efficacy in pediatric patients below the age of 18 have not Potential for Cross-Sensitivity been established. There is the potential for cross-sensitivity to acetylsalicylic acid, Geriatric Use phenylacetic acid derivatives, and other NSAIDs, including bromfenac. There is no evidence that the efficacy or safety profiles for Therefore, caution should be used when treating individuals who have PROLENSA differ in patients 70 years of age and older compared to previously exhibited sensitivities to these drugs. younger adult patients. Increased Bleeding Time With some NSAIDs, including bromfenac, there exists the potential for NONCLINICAL TOXICOLOGY increased bleeding time due to interference with platelet aggregation. Carcinogenesis, Mutagenesis and Impairment of Fertility There have been reports that ocularly applied NSAIDs may cause Long-term carcinogenicity studies in rats and mice given oral increased bleeding of ocular tissues (including hyphemas) in conjunction doses of bromfenac up to 0.6 mg/kg/day (systemic exposure 30 with ocular surgery. times the systemic exposure predicted from the recommended It is recommended that PROLENSA ophthalmic solution be used with human ophthalmic dose [RHOD] assuming the human systemic caution in patients with known bleeding tendencies or who are receiving concentration is at the limit of quantification) and 5 mg/kg/day (340 other medications which may prolong bleeding time. times the predicted human systemic exposure), respectively, revealed Keratitis and Corneal Reactions no significant increases in tumor incidence. Use of topical NSAIDs may result in keratitis. In some susceptible Bromfenac did not show mutagenic potential in various mutagenicity patients, continued use of topical NSAIDs may result in epithelial studies, including the reverse mutation, chromosomal aberration, and breakdown, corneal thinning, corneal erosion, corneal ulceration or micronucleus tests. corneal perforation. These events may be sight threatening. Patients with Bromfenac did not impair fertility when administered orally to male evidence of corneal epithelial breakdown should immediately discontinue and female rats at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, use of topical NSAIDs, including bromfenac, and should be closely respectively (systemic exposure 90 and 30 times the predicted human monitored for corneal health. exposure, respectively). Post-marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial PATIENT COUNSELING INFORMATION defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), Slowed or Delayed Healing rheumatoid arthritis, or repeat ocular surgeries within a short period Advise patients of the possibility that slow or delayed healing may of time may be at increased risk for corneal adverse events which may occur while using NSAIDs. become sight threatening. Topical NSAIDs should be used with caution Sterility of Dropper Tip in these patients. Advise patients to replace bottle cap after using and to not touch Post-marketing experience with topical NSAIDs also suggests that use dropper tip to any surface, as this may contaminate the contents. more than 24 hours prior to surgery or use beyond 14 days post-surgery Advise patients that a single bottle of PROLENSA, be used to treat may increase patient risk for the occurrence and severity of corneal only one eye. adverse events. Concomitant Use of Contact Lenses Contact Lens Wear Advise patients to remove contact lenses prior to instillation of PROLENSA should not be instilled while wearing contact lenses. PROLENSA. The preservative in PROLENSA, benzalkonium Remove contact lenses prior to instillation of PROLENSA. The chloride, may be absorbed by soft contact lenses. Lenses may be preservative in PROLENSA, benzalkonium chloride may be absorbed by reinserted after 10 minutes following administration of PROLENSA. soft contact lenses. Lenses may be reinserted after 10 minutes following Concomitant Topical Ocular Therapy administration of PROLENSA. If more than one topical ophthalmic medication is being used, the medicines should be administered at least 5 minutes apart ADVERSE REACTIONS Rx Only Clinical Trial Experience Manufactured by: Bausch & Lomb Incorporated, Tampa, FL 33637 Because clinical trials are conducted under widely varying conditions, Under license from: adverse reaction rates observed in the clinical trials of a drug cannot be Senju Pharmaceuticals Co., Ltd. directly compared to rates in the clinical trials of another drug and may Osaka, Japan 541-0046 not reflect the rates observed in clinical practice. Prolensa is a trademark of Bausch & Lomb Incorporated or its affiliates. The most commonly reported adverse reactions following use of © Bausch & Lomb Incorporated. 9317600

RP0713_BL Prolensa PI.indd 1 6/17/13 9:29 AM Cover Cataract

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see very well. You can try to counsel Refractive Surgery in Virgin vs. Multifocal IOL Eyes him otherwise, but he will still have the hope that he’s going to see very well.” 35-year-old virgin eye Older, post-multifocal eye The same goes for situations where Postop target Plano Varies. Some surgeons alter it based on the the patient has ocular pathology that refraction location of the lens’s near point (e.g., ReSTOR: prevents her from reaching 20/20. “For plano/plano; Tecnis MF: plano dominant example,” says Dr. Probst, “if some- eye/+0.5 D non-dominant). Some base it on a one’s uncorrected vision is 20/40 after patient’s activities. IOL surgery, but a retinal exam re- PRK or LASIK? LASIK for most eyes PRK avoids dry eye in this older, drier veals that at least half of that decreased and PRK for thin and/ population, but may have delayed healing uncorrected vision is probably due to or steep corneas issues. LASIK heals fast but risks DLK, fl ap some macular pathology, and her fi nal complications and worsening of dry eye. best-corrected vision might be 20/30, Correct higher- Yes No, HOAs are part of a multifocal lens’s you don’t want to do an LVC proce- order aberrations mechanism of action—use conventional LVC. dure to improve vision by just one line with custom? in the best case, while undergoing all Surgical skill General requirements Higher level; must be able to deal with the risks of another procedure.” needed for a LASIK surgeon multifocal vision pre- and postop • YAG laser. The possible effect Quality of vision Good Depends; the IOL creates multifocality at the of a YAG capsulotomy needs to be cost of some contrast sensitivity accounted for, say surgeons. “Once Residual refractive Some error is Multifocal IOL won’t function adequately until someone’s had an IOL procedure, one error tolerated, especially refractive errors are managed. of the reasons his vision is decreased low myopia might be because he has an opacifi ed posterior capsule,” says Dr. Probst. “If 0.75 D hyperopic or 0.75 D myopic, “A multifocal patient doesn’t have that’s the case, it might be more ap- and can’t stand it, is a candidate. The a firm target,” says Dr. Probst. “He propriate to have the YAG performed lens won’t work as intended and he’s has multifocal vision with distance and fi rst before doing any refractive pro- unhappy, and he’s spent a lot of money near targets, so picking an endpoint be- cedure to determine whether that can to get that multifocality.” comes a delicate matter. The patients improve the patient’s vision.” Of course, surgeons say that the themselves are also more challenging irony is that even though the multi- because they have more complex ex- Premium IOL Patients focal patient can be helped the most pectations than a single-vision patient. by sharpening his vision, he’s also the They’re looking for distance and near Though surgeons say it’s possible for most challenging because his vision is vision, so you have the opportunity to monofocal IOL patients to be unhappy now multifocal. fail at both. Multifocal patients require enough to warrant some sort of post- “You’ll see a higher frequency of extensive discussion about what their op touch-up, in reality many already patients needing refractive touch-ups expectations are for the enhancement: expect to wear glasses for some as- from the multifocal group,” says Nash- emphasis on reading or on distance?” pect of their vision postop. Instead, it is ville, Tenn., surgeon Ming Wang. “For To help zero in on the endpoint, sur- the premium IOL patient, who paid a instance, if you don’t clean up a -1 D geons use the tools usually associated good deal of money for his lenses and/ error in a multifocal patient, not only with preop refractive surgery: manifest or doesn’t want to wear glasses, who will he be nearsighted due to the error, refractions; anterior and posterior cor- often wants and needs to have even but the myopia will prevent the lens neal topography and wavefront imag- relatively small amounts of postop er- from working as it’s intended. Once ing. They say to discount wavefront a ror corrected. Here are tips for manag- you correct the refractive error, some- bit, however, since the multifocality of ing these unique patients. thing new comes out of the lens that the lens may render it less than per- • Multifocal and accommodative isn’t present in a monofocal patient: fectly accurate. lenses. “I think the multifocal IOL pa- the intrinsic multifocality.” Dr. Probst says the process involves tient with an error is the best indication So, surgeons agree that multifocal a lot of discussion of the patient’s activi- for laser refractive surgery postop,” IOL patients with postop refractive er- ties and expectations. “Let’s say we do says Tucson, Ariz., surgeon William ror need correction, but this gives rise a WaveScan on a patient with a multi- Fishkind. “A multifocal patient who to another question: What refractive focal lens and it reads a refraction of comes out a little off, maybe 0.5 to target do you aim for? -1.5 D,” he says. “Then, we do a mani-

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fest refraction and find that the pa- situations, such as leisure, work and vision is the same as ReSTOR, tient gets his best distance and near sports,” explains Dr. Probst. “He can but the near point is a little too vision with -0.75 D. This makes it a then identify the areas where it was close for most patients, sitting at little tricky determining what the tar- good and not so good and you can ad- about 25 cm, or 4 D. So for Tecnis get should be. It’s through the trial just the target. One of the great things I intentionally target a little plus lenses and having him look at distance about this is he’s participated in the in the non-dominant eye, making and at near that you determine which decision, which he’ll appreciate. Also, it around +0.5 D, the goal being correction is ideally suited to that pa- if the postop vision isn’t 100 percent to move this 25-cm focal length tient’s expectations. This could take crystal clear, he’ll also realize he shares slightly out nearer to 33 cm. multiple visits to sort through. What some of the responsibility for it, which “For Crystalens, it’s different also bears some discussion with the can be helpful at times.” still,” he adds. “When the Crystalens patient is that the multifocal lens has As an alternate approach, Dr. eventually settles into position, we’ve already induced some loss in quality of Wang says he’s found that multifo- found it comes forward a little bit vision, so the patient will be starting a cal lenses and the Crystalens actual- due to capsular contraction, so if you step or two behind the virgin refractive ly need slightly different refractive aim at plano you’ll probably end up surgery eye. If you don’t explain this to targets for postop laser enhance- slightly minus. We’ve found the av- him, he may attribute a loss of quality ments. “For ReSTOR, we’ve found erage accommodation in these in his ﬁ nal vision to the enhancement it’s best to target plano in both the patients is about +0.75 D, but for rather than the original IOL surgery.” dominant and non-dominant eyes,” people to use a computer, which is If possible, some surgeons like to he says. “This truly gives two fo- sort of in the intermediate distance, do a contact lens trial. “If the patient cal points for each eye, one at dis- they need maybe +1.25 D. So, in the will do it, a contact lens trial for a week tance and one at about 33 cm. For dominant eye, I aim for +0.25 D, or two allows him to try the corrected Tecnis, however, we’ve found that and in the non-dominant eye I’ll aim for vision at distance and near in different it’s slightly different. The distance -0.5 D due to the 0.75 D average

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032_rp0713_f2.indd 36 6/20/13 2:33 PM amount of accommodation enhancing a multifocal IOL pa- the lens gives.” tient, it’s probably best to avoid • Toric IOLs. Errors af- custom ablations and perform a

ter toric lens implantation are MD Ming Wang, conventional procedure instead. somewhat less involved than “By their very design, multifo- after multifocal procedures, cal IOLs are supposed to cause but still involve some diagnos- some higher-order aberrations,” tic work. Dr. Fishkind says a says Dr. Wang. “The lenses list of pertinent questions can intentionally generate some help home in on the problem. spherical aberration to cause “Did the lens rotate or not?” axial dispersion, or the existence he says. “What’s the effective of two images, one of which lens position? Where is the fi nal An eye with a multifocal IOL will demonstrate many is focused closer to the retina astigmatic refractive axis? How aberrations on wavefront analysis that are actually and one away from the retina. much is the astigmatic error? necessary for the lens to function properly, surgeons say. Though, classically, ophthalmol- Can it be corrected with a limbal ogy has always tried to reduce relaxing incision or a laser or does the days, PRK heals in weeks. However, spherical aberration and axial disper- lens need to be re-rotated back into the post-cataract patient is older than sion, they are the essence of the mul- position?” the typical refractive surgery patient, tifocality of the IOL. Also, these lenses When facing a toric lens enhance- so their eyes are drier to begin with, are almost always slightly decentered a ment, Dr. Probst first compares the and I don’t want to induce more dry little bit which, because of their rings, preop and postop cylinder. “If there eye by doing LASIK.” will cause a little higher-order aberra- was a change in axis but there is still a Other surgeons, such as Dr. Probst, tion, too. If we do a custom treatment signifi cant amount of astigmatism, that think LASIK is better. “If you have in these cases, it will erase some of suggests that perhaps the lens wasn’t the choice, and are comfortable with the multifocality of the lens by erasing implanted in the correct axis or it ro- LASIK, I believe it’s the better option,” some of the higher-order aberrations. tated,” he says. “Then, a lens rotation he says. “This is not just because of the Also, the cornea is regular in these pa- might be more appropriate. But, if it’s rapid healing, which the patient will tients, so we shouldn’t make it irregular a toric patient with little residual astig- appreciate, but also for another reason by putting reverse aberrations on it to matism who’s now myopic, then LVC that’s not often appreciated by sur- compensate for minor ones generated on the cornea would be appropriate.” geons: It’s possible for PRK to not go by the lens.” too well in older patients. These older Ultimately, Dr. Probst says that, no Choosing a Procedure patients often have delayed re-epithe- matter how you approach these cases, lialization and may run into problems they will still be challenging. “I’m a Once you and the patient have de- with healing post-PRK. Sometimes, 100-percent corneal refractive sur- termined that an enhancement is nec- non-healing epithelial defects occur geon,” he says. “But I really try not essary, surgeons advise trying to wait in these older patients and take weeks to do too many of these cases. Many at least 90 days before performing it, to heal, which is aggravating for the surgeons have come to me with the to allow any postop infl ammation and patient and the doctor, and puts the idea that these cases are a great op- residual astigmatism to resolve, and to patient at risk for infection. In the 2011 portunity to do more LASIK but, in ensure you know the exact amount of ASCRS survey on infections after re- fact, this is a very complex area that’s error you’re dealing with. At that point, fractive surgery, the infection rate after riddled with potential pitfalls. I’m not surgeons say the procedure you choose PRK was six times higher than that af- saying you shouldn’t do these cases, depends on which potential complica- ter femtosecond LASIK and 2.5 times particularly if they’re your own pa- tions you’d rather avoid. higher than microkeratome LASIK,1 tients and you feel that you could help Some surgeons, like Dr. Wang, pre- and I speculate that it might be even them see better, but be warned that fer PRK. “I typically do PRK because higher in this older group because of they can turn out to be far more com- it avoids LASIK’s issues with diffuse la- delayed re-epithelialization. The as- plex than they fi rst appear.” mellar keratitis, dry eye and fl ap com- sumption that PRK is automatically plications,” he says. “It’s an overall bet- safer isn’t necessarily valid.” 1. Solomon R, Donnenfeld ED, Holland EJ, et al. Microbial keratitis trends following refractive surgery: Results of the ASCRS infectious ter procedure except in one category: Whichever procedure is chosen, keratitis survey. J Cataract Refract Surg 2011;37:7:1343-50. doi: delayed gratifi cation. LASIK heals in surgeons say that, when faced with 10.1016/j.jcrs.2011.05.006.

July 2013 | Revophth.com | 37

032_rp0713_f2.indd 37 6/20/13 2:35 PM Cataract REVIEW Cover Focus Meeting Expectations in Older Cataract Patients Michelle Stephenson, Contributing Editor

It’s less about age, he elderly population today is College, and a consultant specialist diverse. Some elderly patients in cataract and refractive surgery in and more about Tare very mobile and are still Palm Beach Gardens, Fla. driving and playing golf, while other He sees today’s 80-year-olds as yes- attitude. elderly patients spend their time in- terday’s 60-year-olds. They are active, doors reading or doing other seden- healthier and living longer than previ- tary activities. ous generations. As the baby boom “The older population is one that generation moves into the retirement we can really serve and make the years, its expectations may be higher biggest difference,” says Robert M. than today’s elderly patients. “There Kershner, MD, MS, FACS. “The are about 78 million of them,” says majority of our cataract patients are Dr. Kershner. “This is the generation in their sixth, seventh and eighth de- that has always wanted everything cades of life. Their level of satisfaction and needed it right now. They are for our efforts is among the highest. demanding. They believe they know Thirty years ago, we waited to do sur- what’s best, they know what they want gery until it was absolutely necessary and they usually get it. That’s quite a and there was no other alternative. contrast from the retirement genera- The generation of surgeons prior to tion of a decade ago. A few years ago, mine waited until the cataract was we were performing 2.2 to 2.4 mil- ripe. Our criteria for surgical inter- lion procedures annually. The latest vention have changed over the years, numbers are 3.1 to 3.2 million. These and today’s threshold for surgery is numbers are not because people are more dependent upon the patient’s developing cataracts at an acceler- lifestyle than an arbitrary line on an eye ated rate. It is because our technolo- chart. The criteria for proceeding with gies and our outcomes have improved surgery in a patient who doesn’t drive dramatically and the population that and sits at home all day watching TV can beneﬁ t is expanding.” are obviously going to be considerably different from those of the 40-year-old Understanding Your Patient who works late, travels and is having night vision problems.” Dr. Kershner The ﬁ rst step in managing expec- is a professor and chairman of the tations in the older cataract patient Department of Ophthalmic Medi- is to get to know him as an indi- cal Technology at Palm Beach State vidual. If the patient is retired, it is

38 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

038_rp0713_f3.indd 38 6/20/13 2:18 PM Cover Cataract

REVIEW Focus

important to ﬁ nd out what For some patients, a pre- he did as an occupation be- mium lens may not be the fore retirement. best solution. For example, if While many elderly pa- a patient plays golf, a multifo- tients are still active, some cal lens may not be a good are not. It is important to choice if the patient wants sit down with each individ- the best distance acuity. ual patient and ask about “Monovision is not particu- his needs and lifestyle. “Sur- larly good for golfers because geons have to make a con- of the depth of field and certed effort to explore what stereovision needed on the their patients’ lives are like, green,” says Dr. Kershner. what their day-to-day needs “On the other hand, if the are, and what they want to person mostly reads on a lap- accomplish by undergo- top or Kindle and drives in- ing eye surgery,” Dr. Kershner says. “The whole concept frequently at night, then she will need “Surgeons often don’t take the time the best vision in the intermediate to to do that. Older surgeons think they of ‘converting’ people near range. Many surgeons feel they know this group (after all, we are from standard to can do good surgery, and neuroadapta- all in the same boat), but they are tion will intervene to make up the dif- wrong. Young surgeons don’t take premium I think is a ference between a clear, well-centered the time to look up from their EHR terrible disservice to intraocular lens and dysphotopsias. screens to see who they are talking But, adaptation can take months if it to. So much of today’s exam is del- ophthalmologists as occurs at all. It is always better to front- egated to ancillary personnel.” well as to patients. load the patient time. It pays for itself He notes that, while a proper pre- down the road.” operative interview may add only We should really be Lisa B. Arbisser, MD, agrees that two or three minutes to the exam looking for what is premium lenses are not for all patients. for each patient, the time required “When patients are asked to step out to convince an unhappy patient that right for an individual of the paradigm that Medicare has she made the right decision can take patient according to created and pay themselves, their ex- days, weeks or months. Perhaps the pectations really skyrocket,” she says. most important question you can what his or her goals “That’s part of why we should never be ask a patient is what her typical day actually are.” upselling people for that which they is like. don’t understand and don’t need or —Lisa B. Arbisser, MD want, because then they are likely to be Premium Lenses? unhappy. The whole concept of ‘converting’ people from standard to pre- Dr. Kershner says that he sees the valuable lesson here is to listen to every mium I think is a terrible disservice to same mistakes being made over and patient, ask the right questions and ophthalmologists as well as to patients. over again when he consults with prac- hear what each patient’s needs are. As We should really be looking for what is tices. “Many patients end up getting the professional in the equation, we right for an individual patient accord- premium lenses when their needs are need to inquire as to their day-to-day ing to what his or her goals actually not going to be met by those lenses,” and light-to-dark visual needs. It may are.” Dr. Arbisser is in private practice he says. “They are being talked into be difﬁ cult to take the extra time to do at Eye Surgeons Associates in Iowa doing something just because they the preop interview properly, but it is and Illinois and an adjunct associate think they should or because the doc- time well spent, not just because it can professor at the Moran Eye Center at tor sounds convincing. This is a for- land you in court if you don’t take the the University of Utah. mula for failure. If the patient’s needs time, but because unhappy patients do She notes that there is no perfect are not addressed or their concerns not refer. With today’s social network- implant, so patients will either be given discussed, your patient will seek out ing, they can share their unhappiness blended vision or bilateral multifocal another physician or an attorney. The with the world.” diffractive lenses. “Nothing is going to

40 | Review of Ophthalmology | July 2013

038_rp0713_f3.indd 40 6/20/13 2:18 PM make them like they are 15 again so we or glaucoma and so will enjoy their time when doctors made house calls, have to manage their expectations as a spectacle-free bilateral multifocality and they may prefer to spend more result and make sure that it’s very clear indefi nitely.” time with the doctor than with ancil- what the trade-offs are, that they are She only implants multifocal IOLs lary staff. not widgets, and that we are not God. in 9 to 10 percent of her patients, “I take a more traditional approach Only then we can meet expectations but she implants premium lenses in with everyone, but especially with most of the time,” she says. well over 30 percent because she be- the older demographic,” says Rob- lieves that neutralizing astigmatism ert Arleo, MD, in private practice Age Versus Attitude is a huge boon to all patients. “Even in Ithaca, N.Y. “They want the MD people who think they want to wear to do more and the optometrist to Dr. Arbisser notes that managing glasses and look better in glasses are do less, and I think they need a little patient expectations is often less about well-served not to require them for bit of education to work through the age and more about patient rigidity. “I function,” she says. “For this reason, I reality of how things are structured think there are rigid people at age 50 have done peripheral astigmatic kera- now. They view the doctor/patient and malleable people at age 85, so totomy since [Florida surgeon James relationship in a more traditional way it’s less about age and more about at- Gills] described it years ago, have em- where the doctor makes the treat- titude,” she says. “I always ask how pa- braced toric lenses since their incep- ment decisions,” he adds. tients feel about glasses. Would they tion, and enjoy trading fi nicky manual Dr. Arleo notes that it is important be happy to have readers? Will they AK for the femto laser version today.” to determine the patient’s primary be willing to have prescription glasses She notes that blended vision has complaint and focus on improving they wear occasionally? Some people a much wider audience than multi- that complaint. This population can think glasses age them or are uncom- focals, and she has been using this also be more diffi cult to manage be- fortable, and they are willing to do strategy for almost half of her mono- cause many of them have other eye whatever they can to get rid of them, focal patients for decades. “I never conditions in addition to the cataract. while others think they hide their bags aim for more than 1.5 D difference For example, many older patients and they wouldn’t be recognizable between the two eyes,” she says. “I have dry eyes, glaucoma or macular without them. I offer all the choices think, above this disparity, there is degeneration. Any of these associ- to 80-year-olds that I offer to 55-year- enough aniseikonia and decrease in ated conditions can limit vision to olds. There are still 85-year-olds on depth perception to cause poor ad- some degree. the tennis court, at least in Iowa. I am aptation and function. My blended “Many patients think that cataract hesitant to recommend multifocals vision patients are still encouraged to surgery is going to solve everything, except to those people for whom it is get glasses for fi ne near tasks or chal- which is not the case for most peo- so critical to be rid of glasses.” lenging night driving, but many wear ple,” he says. “I tend to shy away from She explains that patients must them rarely. Lately, I have been us- multifocal lenses in this demograph- understand that there is a trade-off ing a bi-aspheric hydrophilic implant, ic. If they have been nearsighted, in general vision quality with multi- which confers more depth of focus I really encourage them to remain focality, though it’s the only way the than my standard acrylic implant for at a functional level of nearsighted- vast majority of patients can be truly patients who choose blended vision ness unless there is a very specific independent of glasses for all daily as a premium option. These allow me reason to change that because they activities. Many people can deal well to aim for just -0.75 D or -1 D at the have lived with it for so long. I have with this reality. “Naturally, we care- most for the near eye, giving wonder- had more people unhappy becoming fully choose only patients with healthy ful binocular results. I am mindful of emmetropic when they were near- eyes and visual systems for these im- the higher YAG rate inherent in the sighted than leaving them somewhat plants,” says Dr. Arbisser. “Because hydrophilic material and other poten- nearsighted. I’m sensitive to that in we can’t predict the future, when im- tial unknowns.” everyone, but with the older popula- planting a diffractive lens in a younger tion, it’s even more important not to person I’m mindful of the future risk Take Extra Time rock the boat too much.” of disease development. So, in fact, In his practice, the main complaint I’m more confi dent to offer multifo- Although today’s seniors may be in the older age group is difficulty cals to older patients who, once they more technology-savvy than previous driving. “So, we focus on making that are 80 or 85 and healthy, are unlike- generations, they are still traditional ly to ever get macular degeneration in many areas. They remember a (continued on page 73)

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

Distinguishing Infection Post-Intravitreal Injection The widespread use of anti-VEGF intravitreal injections makes early detection and treatment of postop complications crucial. By Daniel B. Roth, MD, Kunjal K. Modi, New Brunswick, N.J.; Harry W. Flynn Jr, MD, Miami

ue to the current widespread use plications of intravitreal injections.2-4 tion Treatments Trial (CATT), the rate Dof intravitreal injections in clinical With the increasing rates of intravitreal of endophthalmitis was 0.7 percent practice, with annual injection rates injections since their approval for use, for ranibizumab and 1.2 percent for more than 160 times higher than in the incidence of infectious endophthal- bevacizumab.7 1991 and more than 1 million injections mitis has been extensively studied. Re- Noninfectious endophthalmitis performed in 2008,1 it has become in- cent retrospective case series have re- (post-injection sterile infl ammation, in creasingly important to identify poten- ported post-injection endophthalmitis which evidence of an infectious etiol- tial post-injection complications. Both rates between 0.022 percent and 0.16 ogy was lacking and the milder clini- noninfectious and infectious inflam- percent.5,6 However, in the Compari- cal presentation seemed most consis- mation have been reported as com- son of Age-related Macular Degenera- tent with sterile inflammation), has been reported after intravitreal bev- azicumab at a rate of 0.09 percent to 1.1 percent and was reported at a rate of 0.2 percent in CATT.5-10 Noninfec- tious inflammation may occur more often in patients with prior history of uveitis, pseudophakia and history of vitrectomy. Several reports of noninfectious endophthalmitis after intravitreal bevacizumab injections have been documented, describing an infl ammatory reaction that is often painless and recovers slowly but without perma- nent damage.11,12 The American Soci- ety of Retina Specialists Therapeutic Surveillance Subcommittee surveyed retina specialists’ experience during a two-month period and identified 15 eyes treated with intravitreal afl ibercept that presented with sterile infl am- Figure 1. Infectious endophthalmitis demonstrating hypopyon and fi brin in the anterior mation after the injection; however chamber. some of these eyes were treated with

42 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

042_rp0713_rtinsider.indd 42 6/20/13 2:29 PM NEW For the treatment of elevated IOP UNLOCK NEW TREATMENT POSSIBILITIES

SIMBRINZA™ Suspension provided additional 1-3 mm Hg IOP lowering compared to the individual components1

■ IOP measured at 8 AM, 10 AM, 3 PM, and 5 PM was reduced by 21-35% at Month 32-4 ■ Efﬁ cacy proven in two pivotal Phase 3 randomized, multicenter, double-masked, parallel-group, 3-month, 3-arm, contribution-of-elements studies2,3 ■ The most frequently reported adverse reactions (3-5%) were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy1 ■ Only available beta-blocker-free ﬁ xed combination2,3

INDICATIONS AND USAGE Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA™ SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) Suspension has not been specifi cally studied in these patients and 1%/0.2% is a fi xed combination indicated in the reduction of elevated is not recommended. intraocular pressure (IOP) in patients with open-angle glaucoma or Adverse Reactions ocular hypertension. In two clinical trials of 3 months’ duration with SIMBRINZA™ Suspension, Dosage and Administration the most frequent reactions associated with its use occurring in The recommended dose is one drop of SIMBRINZA™ Suspension approximately 3-5% of patients in descending order of incidence included: in the affected eye(s) three times daily. Shake well before use. blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. ™ SIMBRINZA™ Suspension may be used concomitantly with other topical Adverse reaction rates with SIMBRINZA Suspension were comparable to ophthalmic drug products to lower intraocular pressure. If more than one those of the individual components. Treatment discontinuation, mainly due to topical ophthalmic drug is being used, the drugs should be administered adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. at least fi ve (5) minutes apart. Drug Interactions—Consider the following when prescribing SIMBRINZA™ Suspension: IMPORTANT SAFETY INFORMATION Concomitant administration with oral carbonic anhydrase inhibitors is not Contraindications recommended due to the potential additive effect. Use with high-dose SIMBRINZA™ Suspension is contraindicated in patients who are salicylate may result in acid-base and electrolyte alterations. Use with hypersensitive to any component of this product and neonates and CNS depressants may result in an additive or potentiating effect. Use with infants under the age of 2 years. antihypertensives/cardiac glycosides may result in additive or potentiating Warnings and Precautions effect on lowering blood pressure. Use with tricyclic antidepressants may Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, blunt the hypotensive effect of systemic clonidine and it is unknown if use and although administered topically, is absorbed systemically. Sulfonamide with this class of drugs interferes with IOP lowering. Use with monoamine attributable adverse reactions may occur. Fatalities have occurred due oxidase inhibitors may result in increased hypotension. to severe reactions to sulfonamides. Sensitization may recur when a ™ sulfonamide is readministered irrespective of the route of administration. For additional information about SIMBRINZA Suspension, If signs of serious reactions or hypersensitivity occur, discontinue the use please see Brief Summary of full Prescribing Information on of this preparation. adjacent page. Corneal Endothelium—There is an increased potential for developing corneal edema in patients with low endothelial cell counts.

References: 1. SIMBRINZA™ Suspension Package Insert. 2. Katz G, DuBiner H, Samples J, et al. Three-month randomized trial of fi xed-combination brinzolamide, 1%, and brimonidine, 0.2% [published online ahead of print April 11, 2013]. JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2013.188. 3. Nguyen QH, McMenemy MG, Realini T, et al. Phase 3 randomized 3-month trial with an ongoing 3-month safety extension of fi xed-combination brinzolamide 1%/brimonidine 0.2%. J Ocul Pharmacol Ther. 2013;29(3): 290-297. 4. Data on fi le, 2013.

RP0613_Alcon Simbrinza.indd 1 5/20/13 10:07 AM BRIEF SUMMARY OF PRESCRIBING INFORMATION Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic tration of 14C-brinzolamide to pregnant rats, radioactivity was found INDICATIONS AND USAGE suspension 1%, the most frequently reported adverse reactions to cross the placenta and was present in the fetal tissues and blood. SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic reported in 5 to 10% of patients were blurred vision and bitter, Developmental toxicity studies performed in rats with oral doses of suspension) 1%/0.2% is a fixed combination of a carbonic anhydrase sour or unusual taste. Adverse reactions occurring in 1 to 5% of 0.66 mg brimonidine base/kg revealed no evidence of harm to the inhibitor and an alpha 2 adrenergic receptor agonist indicated for patients were blepharitis, dermatitis, dry eye, foreign body sensation, fetus. Dosing at this level resulted in a plasma drug concentration the reduction of elevated intraocular pressure (IOP) in patients with headache, hyperemia, ocular discharge, ocular discomfort, ocular approximately 100 times higher than that seen in humans at the open-angle glaucoma or ocular hypertension. keratitis, ocular pain, ocular pruritus and rhinitis. recommended human ophthalmic dose. In animal studies, brimoni- The following adverse reactions were reported at an incidence dine crossed the placenta and entered into the fetal circulation to a DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, limited extent. in the affected eye(s) three times daily. Shake well before use. SIM- diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye There are no adequate and well-controlled studies in pregnant wom- fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, BRINZA™ Suspension may be used concomitantly with other topical en. SIMBRINZA™ Suspension should be used during pregnancy ophthalmic drug products to lower intraocular pressure. If more lid margin crusting or sticky sensation, nausea, pharyngitis, tearing only if the potential benefit justifies the potential risk to the fetus. than one topical ophthalmic drug is being used, the drugs should be and urticaria. Nursing Mothers - In a study of brinzolamide in lactating rats, administered at least five (5) minutes apart. Brimonidine Tartrate 0.2% - In clinical studies of brimonidine decreases in body weight gain in offspring at an oral dose of 15 mg/ tartrate 0.2%, adverse reactions occurring in approximately 10 to kg/day (150 times the recommended human ophthalmic dose) were DOSAGE FORMS AND STRENGTHS 30% of the subjects, in descending order of incidence, included oral Suspension containing 10 mg/mL brinzolamide and 2 mg/mL observed during lactation. No other effects were observed. However, dryness, ocular hyperemia, burning and stinging, headache, blurring, brimonidine tartrate. following oral administration of 14C-brinzolamide to lactating rats, foreign body sensation, fatigue/drowsiness, conjunctival follicles, radioactivity was found in milk at concentrations below those in the CONTRAINDICATIONS ocular allergic reactions, and ocular pruritus. SIMBRINZA™ Suspension is contraindicated in blood and plasma. In animal studies, brimonidine was excreted in Hypersensitivity - Reactions occurring in approximately 3 to 9% of the subjects, in patients who are hypersensitive to any component of this product. breast milk. descending order included corneal staining/erosion, photophobia, It is not known whether brinzolamide and brimonidine tartrate are Neonates and Infants (under the age of 2 years) - SIMBRINZA™ eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper Suspension is contraindicated in neonates and infants (under the age excreted in human milk following topical ocular administration. respiratory symptoms, eyelid edema, conjunctival edema, dizziness, Because many drugs are excreted in human milk and because of the of 2 years ) see Use in Specific Populations blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, potential for serious adverse reactions in nursing infants from SIM- WARNINGS AND PRECAUTIONS conjunctival blanching, abnormal vision and muscular pain. BRINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ The following adverse reactions were reported in less than 3% of 1%/0.2%, a decision should be made whether to discontinue nursing Suspension contains brinzolamide, a sulfonamide, and although the patients: lid crusting, conjunctival hemorrhage, abnormal taste, or to discontinue the drug, taking into account the importance of the administered topically is absorbed systemically. Therefore, the same insomnia, conjunctival discharge, depression, hypertension, anxiety, drug to the mother. types of adverse reactions that are attributable to sulfonamides palpitations/arrhythmias, nasal dryness and syncope. The individual component, brinzolamide, has been may occur with topical administration of SIMBRINZA™ Suspension. Pediatric Use - The following reactions have studied in pediatric glaucoma patients 4 weeks to 5 years of age. The Fatalities have occurred due to severe reactions to sulfonamides Postmarketing Experience - been identified during postmarketing use of brimonidine tartrate individual component, brimonidine tartrate, has been studied in pedi- including Stevens-Johnson syndrome, toxic epidermal necrolysis, ophthalmic solutions in clinical practice. Because they are reported atric patients 2 to 7 years old. Somnolence (50-83%) and decreased fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and voluntarily from a population of unknown size, estimates of frequency alertness was seen in patients 2 to 6 years old. SIMBRINZA™ other blood dyscrasias. Sensitization may recur when a sulfonamide cannot be made. The reactions, which have been chosen for Suspension is contraindicated in children under the age of 2 years is re-administered irrespective of the route of administration. If signs inclusion due to either their seriousness, frequency of reporting, . of serious reactions or hypersensitivity occur, discontinue the use of [see Contraindications] possible causal connection to brimonidine tartrate ophthalmic No overall differences in safety or effectiveness have this preparation [see Patient Counseling Information] solutions, or a combination of these factors, include: bradycardia, Geriatric Use - been observed between elderly and adult patients. Corneal Endothelium - Carbonic anhydrase activity has been hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin observed in both the cytoplasm and around the plasma membranes reactions (including erythema, eyelid pruritus, rash, and vasodilation), OVERDOSAGE of the corneal endothelium. There is an increased potential for de- and tachycardia. Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system veloping corneal edema in patients with low endothelial cell counts. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, effects may occur following an oral overdose of brinzolamide. Serum Caution should be used when prescribing SIMBRINZA™ Suspension lethargy, pallor, respiratory depression, and somnolence have electrolyte levels (particularly potassium) and blood pH levels should to this group of patients. been reported in infants receiving brimonidine tartrate ophthalmic be monitored. Severe Renal Impairment - SIMBRINZA™ Suspension has not been solutions [see Contraindications]. specifically studied in patients with severe renal impairment (CrCl Very limited information exists on accidental ingestion of brimonidine DRUG INTERACTIONS in adults; the only adverse event reported to date has been hypo- < 30 mL/min). Since brinzolamide and its metabolite are excreted There is a potential for an Oral Carbonic Anhydrase Inhibitors - tension. Symptoms of brimonidine overdose have been reported in predominantly by the kidney, SIMBRINZA™ Suspension is not recom- additive effect on the known systemic effects of carbonic anhydrase neonates, infants, and children receiving brimonidine as part of med- mended in such patients. inhibition in patients receiving an oral carbonic anhydrase inhibitor ical treatment of congenital glaucoma or by accidental oral ingestion. The management of patients with and brinzolamide ophthalmic suspension 1%, a component of Acute Angle-Closure Glaucoma - Treatment of an oral overdose includes supportive and symptomatic acute angle-closure glaucoma requires therapeutic interventions in SIMBRINZA™ Suspension. The concomitant administration of therapy; a patent airway should be maintained. addition to ocular hypotensive agents. SIMBRINZA™ Suspension has SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not been studied in patients with acute angle-closure glaucoma. not recommended. PATIENT COUNSELING INFORMATION Advise patients that if serious or unusual The preservative in SIMBRINZA™, benzalkoni- Carbonic anhydrase inhibitors Sulfonamide Reactions - Contact Lens Wear - High-Dose Salicylate Therapy - ocular or systemic reactions or signs of hypersensitivity occur, they um chloride, may be absorbed by soft contact lenses. Contact lenses may produce acid-base and electrolyte alterations. These alterations should discontinue the use of the product and consult their physician. should be removed during instillation of SIMBRINZA™ Suspension were not reported in the clinical trials with brinzolamide ophthalmic but may be reinserted 15 minutes after instillation [see Patient suspension 1%. However, in patients treated with oral carbonic Temporary Blurred Vision - Vision may be temporarily blurred Counseling Information]. anhydrase inhibitors, rare instances of acid-base alterations have following dosing with SIMBRINZA™ Suspension. Care should be occurred with high-dose salicylate therapy. Therefore, the potential exercised in operating machinery or driving a motor vehicle. Severe Cardiovascular Disease - Brimonidine tartrate, a component for such drug interactions should be considered in patients receiving of SIMBRINZATM Suspension, has a less than 5% mean decrease in Effect on Ability to Drive and Use Machinery - As with other drugs blood pressure 2 hours after dosing in clinical studies; caution should SIMBRINZA™ Suspension. in this class, SIMBRINZA™ Suspension may cause fatigue and/or be exercised in treating patients with severe cardiovascular disease. CNS Depressants - Although specific drug interaction studies have drowsiness in some patients. Caution patients who engage in haz- ™, the possibility of an additive ardous activities of the potential for a decrease in mental alertness. Because brimonidine tartrate, a not been conducted with SIMBRINZA Severe Hepatic Impairment - or potentiating effect with CNS depressants (alcohol, opiates, barbitu- component of SIMBRINZA™ Suspension, has not been studied in Avoiding Contamination of the Product - Instruct patients that rates, sedatives, or anesthetics) should be considered. patients with hepatic impairment, caution should be exercised in ocular solutions, if handled improperly or if the tip of the dispensing such patients. Antihypertensives/Cardiac Glycosides - Because brimonidine tar- container contacts the eye or surrounding structures, can become trate, a component of SIMBRINZA™ Suspension, may reduce blood contaminated by common bacteria known to cause ocular infections. Brimonidine tartrate, a Potentiation of Vascular Insufficiency - pressure, caution in using drugs such as antihypertensives and/or Serious damage to the eye and subsequent loss of vision may result component of SIMBRINZATM Suspension, may potentiate syndromes cardiac glycosides with SIMBRINZA™ Suspension is advised. from using contaminated solutions [see Warnings and Precau- associated with vascular insufficiency. SIMBRINZA™ Suspension . Always replace the cap after using. If solution changes color Tricyclic antidepressants have been tions ] should be used with caution in patients with depression, cerebral or Tricyclic Antidepressants - or becomes cloudy, do not use. Do not use the product after the reported to blunt the hypotensive effect of systemic clonidine. It is not coronary insufficiency, Raynaud’s phenomenon, orthostatic hypoten- expiration date marked on the bottle. sion, or thromboangitis obliterans. known whether the concurrent use of these agents with SIMBRINZA™ Suspension in humans can lead to resulting interference with the Intercurrent Ocular Conditions - Advise patients that if they have There Contamination of Topical Ophthalmic Products After Use - IOP lowering effect. Caution is advised in patients taking tricyclic ocular surgery or develop an intercurrent ocular condition (e.g., trau- have been reports of bacterial keratitis associated with the use antidepressants which can affect the metabolism and uptake of ma or infection), they should immediately seek their physician’s ad- of multiple-dose containers of topical ophthalmic products. These circulating amines. vice concerning the continued use of the present multidose container. containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhib- Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at ocular epithelial surface [see Patient Counseling Information]. itors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect least five minutes apart. ADVERSE REACTIONS such as hypotension. Caution is advised in patients taking MAO Because clinical studies are conduct- Contact Lens Wear - The preservative in SIMBRINZA™, benzalkoni- Clinical Studies Experience - inhibitors which can affect the metabolism and uptake of circulating ed under widely varying conditions, adverse reaction rates observed um chloride, may be absorbed by soft contact lenses. Contact lenses amines. in the clinical studies of a drug cannot be directly compared to the should be removed during instillation of SIMBRINZA™ Suspension, rates in the clinical studies of another drug and may not reflect the USE IN SPECIFIC POPULATIONS but may be reinserted 15 minutes after instillation. rates observed in practice. Pregnancy - Pregnancy Category C: Developmental toxicity ©2013 Novartis studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ U.S. Patent No: SIMBRINZA™ Suspension - In two clinical trials of 3 months kg/day (20, 60, and 120 times the recommended human ophthalmic 6,316,441 duration 435 patients were treated with SIMBRINZA™ Suspension, dose) produced maternal toxicity at 6 mg/kg/day and a significant and 915 were treated with the two individual components. The most increase in the number of fetal variations, such as accessory skull ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA frequently reported adverse reactions in patients treated with SIM- bones, which was only slightly higher than the historic value at 1 and 1-800-757-9195 BRINZA™ Suspension occurring in approximately 3 to 5% of patients 6 mg/kg. In rats, statistically decreased body weights of fetuses from in descending order of incidence were blurred vision, eye irritation, dams receiving oral doses of 18 mg/kg/day (180 times the recom- [email protected] dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse mended human ophthalmic dose) during gestation were proportional reactions reported with the individual components were comparable. to the reduced maternal weight gain, with no statistically significant Treatment discontinuation, mainly due to adverse reactions, was effects on organ or tissue development. Increases in unossified reported in 11% of SIMBRINZA™ Suspension patients. sternebrae, reduced ossification of the skull, and unossified hyoid Other adverse reactions that have been reported with the individual that occurred at 6 and 18 mg/kg were not statistically significant. No components during clinical trials are listed below. treatment-related malformations were seen. Following oral adminis- © 2013 Novartis 4/13 MG13003JAD

RP0613_Alcon Simbrinza PI.indd 1 5/20/13 10:09 AM intravitreal antibiotics as a precau- Table 1. Characteristics Differentiating Infectious from tion for possible infectious endo- Noninfectious Endophthalmitis phthalmitis.13 As these sterile infl ammatory condi- More Common Features Infectious Noninfectious tions lack an infecting organism, they are typically treated with steroids and Pain Moderate to severe pain Usually mild pain observation, as opposed to topical and intravitreal antibiotics. In a recent Vision loss Severe Mild to moderate study, eyes receiving afl ibercept expe- Fibrin Always present Rare rienced at least some mild form of intraocular infl ammation in 0.28 percent of injections (Roth DB, et al. The Inci- Hypopyon Very common Usually absent dence of Noninfectious Intraocular In- fl ammation after Intravitreal Afl iber- Vitreous opacity Usually prominent Usually mild cept Injection. Verbal communication, presented at the American Society of Conjunctival/vascular Very common Often absent Retinal Specialists annual meeting, Las congestion Vegas, Nev., August 27, 2012). Infectious endophthalmitis is de- Less Common Features Infectious Noninfectious fi ned by the presence of an infecting organism within the eye and can occur Retinal infi ltrates Occasionally present Absent following any intraocular procedure, Intraretinal hemorrhages Common Rare including intravitreal injection, surgery and trauma. Furthermore, con- Whitening of retinal vessels May be present Absent tamination of medication batches can lead to clusters of endophthalmitis, Clinical Course Rapidly progressive Slow improvement which can have devastating visual effects. An outbreak in southern Florida occurred where 12 patients presented highlights the importance of adhering early to avoid potential progressive with symptoms of infectious endo- ing to the highest standards for sterile vision loss from infectious endophthal- phthalmitis following intravitreal be- preparation of medications and injec- mitis.16,18 vacizumab injection. In 10 of the 12 tion technique, accurately identifying Even in cases of infectious endoph- patients, Streptococcus was isolated an infectious endophthalmitis versus a thalmitis, it is not always possible to from vitreous fl uid.14 Each of these pa- noninfectious infl ammation, and treat- identify the organism, either due to tients was injected with an inadequate sample bevacizumab prepared of ocular fluids, poor by the same private specimen handling or compounding phar- difficulty in culturing macy, with all but one the specific organism. eye resulting in count Therefore, a “culture- fi ngers or worse visual negative” case of en- acuity at four months of dophthalmitis may follow up. actually be infectious. Recently, a Georgia In 25 to 30 percent compounding phar- of endophthalmitis macy recalled 40 lots cases, one is unable to of its bevacizumab sy- identify an organism ringes after reports of via culture. Infectious endophthalmitis due to and noninfectious en- presumed contamina- dophthalmitis can oc- tion.15 This report, as Figure 2. Infectious endophthalmitis after treatment with intravitreal antibiotics, casionally present in a well as many others, showing retracting fi brin in the pupil and reduction in the hypopyon. similar manner in the

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REVIEW Insider

marked vision loss, shown in the End- ophthalmitis Vitrectomy Study (EVS) to be present in 94 percent of postoperative endophthalmitis cases.20 Blurred vision is not as common in noninfectious endophthalmitis, but is typical in infectious cases. Vision loss ABcan range from moderate to profound, depending on the virulence of the or- Figure 3. A. B-scan ultrasonography showing dense opacities and membranous debris in ganism in infectious cases,21 and vision the setting of infectious endophthalmitis. B. Mild vitreous opacities in the setting of loss is less marked in noninfectious noninfectious endophthalmitis. cases, if signifi cant vitritis is present. A sudden decrease in visual acuity after post-injection patient, and thus, this of the fi brin (See Figure 2) after treat- injection should be another early warn- article aims to differentiate between ment is an important sign that the an- ing sign for infectious endophthalmi- infectious versus noninfectious infl am- tibiotic therapy is effective. If an eye tis. Clinicians should maintain a low mation after anti-VEGF agents, based presents with hypopyon and fibrin, threshold for follow-up for patients upon signs, symptoms and clinical fea- one must assume an infectious etiology complaining of subjective post-injec- tures. until proven otherwise. tion pain or loss of vision, as they are Certain features during post-injec- often the fi rst symptoms apparent to tion follow-up can be a clue to the cli- Pain patients as a warning sign.18,20 nician to an infectious cause: These features include presence of fi brin and Commonly reported in these pa- Less Common Clincal Features hypopyon, marked anterior chamber tients, pain is an early warning sign of cells and/or vitritis, decreased visual infectious etiology. Some discomfort Several identifiable features are acuity, and conjunctival or scleral con- often occurs after intravitreal injec- commonly seen in infectious endo- gested vessels. Additional, less-com- tion, but typically resolves within 24 phthalmitis. Echography can measure mon features that can occasionally be hours. Ocular surface irritation may the degree of vitreous opacities in these helpful include presence of retinal last longer, especially in the presence patients. Endophthalmitis in general is hemorrhages, retinal infi ltrates or cot- of corneal epithelial breakdown or po- characterized by dense opacities, indi- ton-wool spots and periphlebitis. vidone-iodine induced dryness or ex- cating the purulent infectious process. ternal infl ammation after the injection Noninfectious inflammation usually Hypopyon and Fibrin procedure. Noninfectious infl amma- has less dense or minimal opacities. tion can cause mild discomfort; how- Another suggestive feature of infection Hypopyon has been reported as a ever, more intense pain and deep ache is the presence of intraretinal hemor- presenting feature of infectious end- after injection may suggest infectious rhages, which are likely secondary to ophthalmitis in 78 percent of patients endophthalmitis. retinitis or localized venous occlusive in one study (See Figure 1).5 Anterior Pain associated with infectious dis- disease. Retinal periphlebitis has been chamber fibrin is uncommon in the ease is often described by patients shown in clinical reports and animal setting of noninfectious endophthal- as deep and more intense, but these models to occur early in the process mitis, but is very common in infectious subjective symptoms are often highly of infectious endophthalmitis.22 Intra- endophthalmitis. Thus, hypopyon and/ variable. Nevertheless, 75 percent of retinal hemorrhages are rarely seen as or fibrin are very strong predictors infectious cases in one study presented a feature in noninfectious endophthal- of an infectious process. With the in- with the symptom of pain.18 Symptoms mitis, thus their presence has posi- fl ammation associated with infectious usually begin within one week of injec- tive predictive value for an infectious endophthalmitis, there is an infl ux of tion, with an average onset 2.8 days af- source. Retinal infi ltrates suggest an polymorphonuclear leukocytes, aque- ter anti-VEGF injection in one study.19 infectious source and are commonly ous fl are from an infl ux of protein, and composed of inflammatory cells and a conversion of intraocular fi brinogen Vision Loss debris from the infl ammatory process. into fi brin. Fibrin in the anterior cham- Noninfectious endophthalmitis after ber is an important fi nding in patients Along with pain in the eye, another intravitreal injection is a self-limited with endophthalmitis, and retraction very common presenting feature is process, and resolves spontaneously

46 | Review of Ophthalmology | July 2013

042_rp0713_rtinsider.indd 46 6/20/13 2:32 PM Toric outcomes: The evidence is overwhelming

Conﬁdence in Keratometry

Toric IOL outcomes must measure up to today’s surgical standards. The IOLMaster® has been used extensively in peer-reviewed, published studies of toric IOL implantation1. In these studies, excellent surgical outcomes were reported using IOLMaster keratometry measurements.

Visit www.IOLMaster.info/toricstudies to review the summary of studies with reported refractive outcomes for toric IOLs.

With evidence-based outcomes like this, it’s no wonder the IOLMaster is the preferred method of keratometry for toric IOL calculations.2

1 Bullimore MA, The IOLMaster and Determining Toric IOL Power, 2013 2 Leaming DV, 2012 Practice Styles and Preferences of the U.S. ASCRS Members Survey

047_rp0713_zeissIOL.indd 1 6/21/13 4:21 PM Retinal

REVIEW Insider

after a short period of ob- displacement of the con- servation. This entity is junctiva, use of gloves or well-recognized to occur type of intravitreal agent after intravitreal triam- administered.21 cinolone injections, with The consequences of an incidence as high as delay in treating infec- 0.5 percent to 2 percent tious endophthalmitis of injections,23-25 and often can be devastating.16,17 presents with a quiet ocu- Therefore, in borderline lar surface, no fi brin and a patients, it may be best hypopyon. This hypopyon to treat empirically with may be true inflamma- intravitreal antibiotics. tory cells or alternatively, In milder cases evalu- mostly a collection of set- ated early in the course, tling triamcinolone crys- treatment with frequent tals, also termed a pseudo- topical steroids can be hypopyon.23 considered, and the pa- In noninfectious infl am- tient can be examined mation after anti-VEGF Figure 4. Intraretinal hemorrhages in the setting of infectious several hours later until agents, a hypopyon is typi- endophthalmitis. the diagnosis becomes cally absent and the in- more well-defi ned. Ulti- flammatory reaction is usually mild to two weeks. mately, careful clinical examination to moderate.19 Although a vitreous Since it is sometimes diffi cult to dis- and attention to subtle clinical fea- cellular reaction may be present, it tinguish these two conditions, clinical tures will guide the clinician to prop- usually does not obscure the view of judgment is the most practical source erly manage patients with early in- fundus details, and it is never a dense of delineation. As described in Table fl ammation after injection and treat vitritis. The B-scan echography can 1, certain pertinent features can help them appropriately. aid in distinguishing the level of vitritis the clinician decide whether to use in- and helping to guide the clinician to travitreal antibiotics for infectious en- Dr. Roth is an associate professor determine the nature of the vitreous dophthalmitis, or reassure the patient of ophthalmology at Robert Wood opacifi cation. Infl ammation after anti- of a benign inflammatory response. Johnson Medical School, in associa- VEGF agents may be an immune re- The onset of symptoms in infectious tion with New Jersey Retina. He may action to the drug itself, to breakdown endophthalmitis typically correlates be reached at [email protected], products in the injected material, or to with the virulence of the causative or- or at the Retina Vitreous Center, an unknown contaminant.24 In cases ganism. The most common infective 10 Plum St., New Brunswick, N.J. of noninfectious endophthalmitis, the organism following intravitreal injec- 08901, (732)-220-1600. Mr. Modi is a infl ammatory reaction usually resolves tion is Staphylococcus epidermidis, third-year medical student at Robert spontaneously, typically without del- which has been identifi ed in one study Wood Johnson Medical School. Dr. eterious visual sequelae.27 Neverthe- in approximately 65 percent of end- Flynn is a professor of ophthalmol- less, topical steroids may aid in a more ophthalmitis isolates after anti-VEGF ogy at the Bascom Palmer Eye Insti- rapid resolution of intraocular infl am- injection.28 However, Streptococcal tute at the University of Miami. mation, ocular discomfort and visual species have been reported as well, Dr. Roth is a consultant to Aller- loss. One report suggests that with possibly due to needle contamination gan, Forsight Labs, Regeneron and multiple injections with anti-VEGF from oral fl ora at the time of injection. ThromboGenics. Dr. Flynn receives agents, there is a greater likelihood for Rates of endophthalmitis after in- support from Santen and Vindico. generating an infl ammatory response, travitreal injection can be decreased This work was supported in part by as anti-VEGF agents are humanized by following aseptic technique proto- the National Institutes of Health, antibodies.11 The four patients in that col for the injection, reduced talking Bethesda, Md., grant NIH P30- series had primarily vitreous and an- during the injection procedure27,30 and EY014801, and an unrestricted grant terior chamber cells without fi brin or use of a lid speculum.5 However no to the University of Miami from Re- hypopyon, and the infl ammation re- difference was seen in infection rates search to Prevent Blindness, New solved with topical steroids within one with use of a bladed lid speculum, York, N.Y.

48 | Review of Ophthalmology | July 2013

042_rp0713_rtinsider.indd 48 6/20/13 2:30 PM 1. Ramulu PY, Do DV, Corcoran KJ, et al. Use of retinal of bevacizumab for treatment of neovascular age-related immediate vitrectomy and of intravenous antibiotics for the procedures in Medicare benefi ciaries from 1997 to 2007. macular degeneration. Ophthalmology 2008;115(11):1911. treatment of postoperative bacterial endophthalmitis. Arch Arch Ophthalmol 2010;128:1335-40. e1–1915.e1. Ophthalmol 1995;113:1479-1496. 2. Moshfeghi A, Rosenfeld PJ, Flynn HW Jr, et al. 11. Bakri SJ, Larson, TA, Edwards AO. Intraocular infl ammation 21. Johnson MW, Doft BH, Kelsey SF, et al. The Endophthalmitis Endophthalmitis after intravitreal anti-vascular endothelial following intravitreal injection of bevacizumab. Graefe’s Arch Vitrectomy Study. Relationship between clinical presentation growth factor antagonists: A six-year experience at a Clin Exp Ophthalmol 2008;246:779-81. and microbiologic spectrum. Ophthalmology 1997;104:261. university referral center. Retina 2011;31:662-668. 12. Kay CN, Tarantola RM, Gehrs KM, et al. Uveitis following 22. Jeng, BH, Kaiser, PK, Lowder, CY. Retinal vasculitis and 3. Day S, Acquah K, Mruthyunjaya P, et al. Ocular intravitreal bevacizumab: a non-infectious cluster. Ophthalmic posterior pole ‘hypopyons’ as early signs of acute bacterial complications after anti-vascular endothelial growth factor Surg Lasers Imaging 2011; 42:292-296. endophthalmitis. Am J Ophthalmol 2001;131:800-802. therapy in Medicare patients with age-related macular 13. Hahn P, Kim JE, Stinnett S, et al. Afl ibercept-related sterile 23. Roth DB, Flynn HW Jr. Distinguishing between infectious degeneration. Am J Ophthalmol 2011;152:266–272. infl ammation. Ophthalmology 2013;120:1100-1101. and noninfectious endophthalmitis after intravitreal 4. Chong DY, Anand R, Williams PD, et al. Characterization of 14. Goldberg RA, Flynn HW Jr, Isom RF, et al. An Outbreak of triamcinolone injection. Am J Ophthalmol 2008;146:346-347. sterile intraocular infl ammatory responses after intravitreal Streptococcus Endophthalmitis After Intravitreal Injection of 24. Roth DB, Lee SS, Flynn HW Jr. Infl ammatory reactions bevacizumab injection. Retina 2010;30:1432-1440. Bevacizumab. Am J Ophth 2012;153:204-08. after intravitreal triamcinolone acetonide: Possible 5. Fintak DR, Shah GK, Blinder KJ, et al. Incidence 15. FDA Medwatch. Avastin Unit Dose Syringes by mechanisms and therapeutic options. Expert Rev Ophthalmol of endophthalmitis related to intravitreal injection of Clinical Specialties: Recall—Potential For Serious 2010;5(3):273-76. bevacizumab and ranibizumab. Retina 2008;28:1395–9. Eye Infection. FDA Medwatch online 2013, http:// 25. Nelson ML, Tennant MT, Sivalingam A, et al. Infectious and 6. Wu L, Martinez-Castellanos MA, Quiroz-Mercado H, et al. www.fda.gov/Safety/MedWatch/SafetyInformation/ presumed noninfectious endophthalmitis after intravitreal Twelve-month safety of intravitreal injections of bevacizumab SafetyAlertsforHumanMedicalProducts/ucm344664. triamcinolone acetonide injection. Retina 2003;23:686-91. (Avastin): Results of the Pan-American Collaborative Retina htm?source=govdelivery. 26. Johnson D, Hollands H, Hollands S, et al. Incidence Study Group (PACORES). Graefe’s Arch Clin Exp Ophthalmol 16. López-Cabezas C, Muner DS, Massa MR. Antibiotics and characteristics of acute intraocular infl ammation after 2008;46:81-87. in endophthalmitis: Microbiological and pharmacokinetic intravitreal injection of bevacizumab: A retrospective cohort 7. Comparison of Age-related Macular Degeneration considerations. Curr Clin Pharmacol 2010;5(1):47-54. study. Can J Ophthalmol 2010;45(3)239-42. Treatments Trials (CATT) Research Group. Ranibizumab 17. Lemley CA, Han DP. Endophthalmitis: a review of current 27. McCannel CA. Meta-analysis of endophthalmitis after and bevacizumab for treatment of neovascular age-related evaluation and management. Retina 2007;27:662-80. intravitreal injection of anti-vascular endothelial growth macular degeneration: Two-year results. Ophthalmology 18. Wisniewski SR, Capone A, Kelsey SF, et al. Characteristics factor agents: Causative organisms and possible prevention 2012;119:1388-98. after cataract extraction or secondary lens implantation strategies. Retina 2011;31:654-61. 8. Artunay O, Yuzbasioglu E, Rasier R, et al. Incidence and among patients screened for the Endophthalmitis Vitrectomy 28. Sakamoto T, Ishibashi T, Ogura Y, et al. Survey of management of acute endophthalmitis after intravitreal Study. Ophthalmology 2000;107:1274. triamcinolone-related non-infectious endophthalmitis. Nihon bevacizumab (Avastin) injection. Eye 2009;23(12):2187-93. 19. Hoevenaars NED, Gans D, Missotten T, et al. Suspected Ganka Gakkai Zasshi 2011;115(6):523-8. 9. Georgopoulos M, Polak K, Prager F, et al. Characteristics of bacterial endophthalmitis following intravitreal anti-VEGF 29. Ta CN. Minimizing the risk of endophthalmitis following severe intraocular infl ammation following intravitreal injection injection: Case series and literature review. Ophthalmologica intravitreous injections. Retina 2004;24:699-705. of bevacizumab (Avastin) Br J Ophthalmol 2009;93:457-462. 2012;228:143-147. 30. Schimel AM, Scott IU, Flynn HW Jr. Endophthalmitis After 10. Wickremasinghe SS, Michalova K, Gilhotra J, et al. 20. Endophthalmitis Vitrectomy Study Group. Results of the Intravitreal Injections: Should the Use of Face Masks Be the Acute intraocular infl ammation after intravitreous injections Endophthalmitis Vitrectomy Study. A randomized trial of Standard of Care? Arch Ophthalmol 2011;129:1607-1609.

042_rp0713_rtinsider.indd 49 6/20/13 2:31 PM Therapeutic Topics REVIEW

ARVO Goes to The Emerald City Highlights from the papers and posters of ARVO’s ﬁ rst foray outside of the balmy borders of Florida. Mark B. Abelson, MD, CM, FRCSC, FARVO, and Ora Staff, Andover, Mass.

n a dramatic change from a de- a valuable preventative approach for also noted that this replacement of I cades-long tradition, ARVO con- patients at risk for age-related macu- beta carotene in the original formula- vened its annual meeting this May in lar degeneration. This fi ve-year study tion with lutein + zeaxanthin reduced a place other than Florida, as ophthal- included 4,203 participants random- the risk for lung cancer in ex-smokers. mologists and vision scientists headed ized to receive: 1) 10 mg lutein + 2 mg to the Pacific Northwest for ARVO zeaxanthin; 2) 350 mg DHA + 650 mg Models, Methods, Endpoints 2013. While many attendees may EPA; 3) lutein + zeaxanthin and DHA have felt some trepidation about the + EPA or 4) placebo. All participants A key aspect of therapeutic de- change, by the end of the week most also took either the original AREDS velopment is the refinement and agreed that sunny Seattle was a ter- formulation or were randomized to optimization of methods for patient rifi c choice. The relaxed atmosphere AREDS variations (no beta carotene, inclusion in studies and disease as- of the city provided a pleasant setting reduced zinc or both). sessment. Ocular infl ammation is an for scientifi c discourse and socializing There were no significant differ- area of active effort, and many pre- with colleagues old and new. Plus, ences in disease progression in the senters reported on their attempts to it wasn’t hard to find a good sand- four major treatment groups. The improve protocol design, symptom wich shop, café or restaurant close by, probability of progression to advanced evaluation or both. which is always a bonus. AMD was 31 percent in the place- Investigators from our research This month, we’ll review the high- bo group, 29 percent in the lutein + fi rm, Ora, used modifi cations to the lights of the meeting in various areas zeaxanthin group, 31 percent in the traditional conjunctival allergen chal- of vision research. (Unless otherwise DHA + EPA group and 30 percent in lenge protocol to elicit a more chron- specifi ed, all of the abstract citations the lutein + zeaxanthin and DHA + ic, inflammatory conjunctivitis that are from this year: IOVS 2013;54.) EPA group. There was also no signifi - may be a means for developing treat- cant difference between the two zinc ments for chronic allergy. (Gomes P, AREDS2 concentrations tested. One subgroup, et al. ARVO E-Abstract 2555) Other consisting of patients receiving lutein refinements included updated pro- The scientifi c headliner of this year’s + zeaxanthin and no beta-carotene, tocols for fl uorophotometry and con- meeting was the AREDS2 trial,1 the saw an 18-percent reduction in the junctival staining. (Heckley C, et al. second part of the Age-related Eye risk of progression to advanced AMD ARVO E-Abstract 6043; Lane K, et Disease Study. AREDS2 examined when compared to those who took al. ARVO E-Abstract 6045) The op- modifi cations to the vitamin formula- AREDS with beta-carotene (and no timization of fl uorometric measures tion that AREDS had established as lutein + zeaxanthin). Study authors of tear turnover was particularly in-

50 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

050_rp0713_ttops.indd 50 6/20/13 3:48 PM Video capture of blink behavior and patterns has allowed for a more comprehensive assessment of the role of blink in ocular surface disease. (Lafond A, et al. ARVO E-Abstract 962)

triguing, because the authors were going forward. MUC16 values increase. (Watson M, able to show a signifi cant correlation Biomarker assessment was not lim- et al. ARVO E-Abstract 4309) An- between this sign of dry-eye disease ited to cytokine studies, and other other study used a polymerase chain and the Ocular Surface Disease Index presentations described quantifica- reaction-based measure of MUC5A symptomatology scale, a noteworthy tion of other potential indicators or expression to screen for goblet cells accomplishment for clinical studies of predictors of ocular disease. One in patients with limbal cell defi ciency. this disease. study provided evidence that several The goal of this study was to correlate Advances in ocular surface micros- micro RNAs associated with retinal loss of this key cell type with disease copy was a dominant topic, as well. degeneration can be detected in sys- severity. (Suarez-Cortes TM, et al. Studies of corneal nerve morphol- temic circulation, and so may ulti- ARVO E-Abstract 547) ogy by in vivo confocal microscopy mately function as biomarkers for Ora presented novel data on the use demonstrated the utility of enhanced retinal disease. (Peng Q, et al. ARVO of software analysis for the evaluation ocular surface imaging, both as a po- E-Abstract 1947) These short-chain of corneal superfi cial punctate kerati- tential diagnostic tool and as a poten- nucleic acid molecules function as tis, an important primary endpoint for tial therapeutic endpoint. (Sanchez regulators of gene transcription in a dry-eye trials. (Rodriguez J, et al. AR- Dalmau BF, et al. ARVO E-Abstract tissue-specifi c manner. The potential VO-E Abstract 4341) Clinical grad- 530; You JY, et al. ARVO E-Abstract importance of miRNAs (particular- ing, typically based on a 0-to-4 point 531) Other presentations focused ly miRNA-96 and miRNA-124) was scale, poses many challenges, such as on IVCM-based advances in limbal confi rmed in other presentations ex- inefficiencies in reproducibility, ac- morphology and on infl ammatory cell amining the role of these molecules in curacy, subjectivity and sensitivity. In infiltration of the conjunctival vas- retinal degeneration. (Langmann T, et a population of 665 dry-eye subjects, culature. (Baclagon ER, et al. ARVO al. ARVO E-Abstract 4517) the software-based approach gener- E-Abstract 537; Angeli E, et al. ARVO There were a number of presenta- ated accurate, effi cient quantifi cation E-Abstract 2557) tions that provided new insights on of corneal desiccation. An automated A big topic in clinical methodology the measures used to assess blink rates approach is useful in standardizing for ocular infl ammation was the mea- and the importance of considering lid the SPK evaluation process and allows surement of biomarkers of disease contact time to differentiate between for clear identification of improve- with a focus on those found in tears. A normal and dry-eye subjects. (John- ment due to therapeutic intervention. number of groups reported efforts to ston P, et al. ARVO E-Abstract 967; Automation may not be applicable in identify both normal and pathological Lafond A, et al. ARVO E-Abstract every situation, however. In another values for cytokines in tears. (Hagan 962) Other presenters examined the study, comparison of software-based S, et al. ARVO E-Abstract 955; En- relationship between tear meniscus analysis of hyperemia grading showed riquez-De-Salamanca A, et al. ARVO dimensions and other disease mea- that while this approach may be use- E-Abstract 2072; Dionne K et al. sures in subcategories of dry eye and ful for dry-eye studies, confounding ARVO E-Abstract 4324; Lakshman N found that in patients with aqueous factors in allergic hyperemia (such as et al. ARVO E-Abstract 4325) While tear deficient dry eye and autoim- chemosis) preclude the use of auto- there were some disagreements on mune disease, lower tear volume is mated redness analyzers. (Raval Y, et the quantitative aspects of these stud- associated with worse corneal epi- al. ARVO E-Abstract 2553) ies, it’s clear that the technology to ac- thelial disease. (Tung CI, et al. ARVO Dry eye is a disease that involves a curately measure picogram quantities E-Abstract 970) range of functional tests of tear fi lm of signaling molecules including IL-2, Mucin function in dry eye was also stability, but despite this it’s still not IL-6 and IL-8 is here, and such mea- the subject of multiple presenta- clear which tests are best. One group surements will become an increas- tions. One presentation found that as sought to address this topic by cal- ingly important aspect of diagnosis the signs of dry eye worsen, soluble culating the correlations of dry-eye

July 2013 | Revophth.com | 51

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a treatment effect lasted longer than four months off-treatment. There was also a robust response in the 3.2-mg dose group of at least three months off-treatment in all subjects. A demonstrated mean best-corrected acuity improvement of eight letters as mea- Digitization and pseudocolor enhancement can allow for automated quantifi cation of sured by ETDRS in this group cor- superfi cial punctate keratitis. The original image is on the left, the enhanced one on the responded to a 30-percent decrease right. (Rodriguez J, et al. ARVO E-Abstract 4341) in central macular thickness and improvement in retinal architecture. signs to signs, symptoms to symp- tein tyrosine phosphatase. The VE- Monday’s retina posters included toms, and both signs and symptoms PTP enzyme, also known as human a meta analysis of ranibizumab safety to objective tests of tear-fi lm stability. protein phosphatase β or HPTBβ, is a data in patients with AMD, retinal vein Contrary to many other reports, the negative regulator of the Tie2 recep- occlusion or DME. (Avery RL, et al. authors reported that many signs and tor, which is expressed on vascular ARVO E-Abstract 1535) The analysis symptoms correlate with quality-of- endothelial cells and plays a key role pooled 22 Phase II, III and IIIb stud- life variables. In addition, they found in stabilizing blood vessels. Inhibition ies and included 10,300 patients with a a stronger correlation between tear of VE-PTP restores Tie2 signaling, mean follow-up time of 15.9 months. turnover rate and symptoms than that reducing vascular leak and pathologic In the analysis, patients with DME seen between Schirmer’s tests and neovascularization. In the study, the showed higher mortality rates and a symptomatology. Lid variables, how- researchers note that, in vitro, “AKB- greater rate of wound healing compli- ever, correlated in unexpected ways, 9778 promoted phosphorylation of cations than those with either AMD and the authors suggest that com- Tie2, enhanced angiopoietin (Ang)-1 or RVO. No other patterns of systemic pensatory mechanisms may underlie induced Tie2 phosphorylation, and disease emerged from the study. these fi ndings. (Saigal S, et al. ARVO stimulated phosphorylation of signal- As our experience with therapeu- E-Abstract 4361) ing molecules in the Tie2 pathway.” tic responses to either ranibizumab In vivo, AKB-9778 also induced phos- or bevacizumab is extended, it’s im- Retina, Glaucoma and Dry Eye phorylation of Tie2. While AKB-9778 portant to examine the distinctions is initially being developed for dia- in therapeutic responses observed In addition to the preclinical pre- betic macular edema, vascular stabili- to these and other anti-VEGF based sentations, ARVO always presents a zation may also provide benefi ts for a therapies. This was addressed in a good opportunity to see what may be wide variety of disease states. Aerpio retrospective study of afl ibercept ef- in the pipeline of new therapeutics. initiated a Phase Ib/IIa trial of AKB- fi cacy in patients who had previously We came across a number of inter- 9778 for the treatment of DME in received treatment with either ranibi- esting posters throughout the week, September 2012.2 zumab or bevacizumab. (Yonekawa Y, including some on Thursday, the last The agent ALG-1001 is being in- et al. ARVO E-Abstract 1938) Mean day of the meeting. Just in case you vestigated in several vascular eye dis- central macular thickness, visual acu- weren’t able to stick around through eases including wet AMD, DME and ity and treatment history were col- the end of the week, we’ll provide a symptomatic vitreomacular adhesion. lected from 94 patients (104 eyes) in recap here, as a number of the “best- ALG-1001 is a new small-molecule two treatment centers. Although the in-show” posters were presented on oligopeptide that targets multiple follow-up was modest (average of 18 ARVO’s fi nal day. integrin receptor sites that play key weeks), signifi cant reduction in CMT A group of investigators, one of roles in cell signaling and regulating was observed in two patient popula- whom is an employee for Aerpio cellular shape, motility and the cell tions: patients who were refractory Therapeutics (Cincinnati, Ohio) pro- cycle. Interim data on the Phase Ib/ to ranibizumab or bevacizumab and vided in vitro and in vivo data on the IIa dose-ranging, monotherapy study those who received afl ibercept after company’s drug AKB-9778. (Shen J, of the drug in wet AMD was present- a recurrence of disease progression. et al. ARVO E-Abstract 6094) The re- ed at this year’s ARVO.3 (Kaiser P, et Both groups also showed a stabili- searchers confi rmed its bioactivity as al. ARVO-E Abstract 2177) In the fi rst zation of VA following aflibercept. a potent and selective small molecule human study of the agent, the drug Thus, despite similar mechanisms inhibitor of vascular endothelial-pro- appeared safe and well-tolerated and of action, afl ibercept appears to be a

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useful therapeutic option in patients with Y-39983. Additionally, hyperemia traocular pressure. (Tomohiro K, et previously treated with other VEGF was observed with Y-39983 at all con- al. ARVO E-Abstract 766; Karakawa antagonists. centrations, whereas only mild hyper- T, et al. ARVO E-Abstract 1998) In The treatment landscape for vitreo- emia was observed with the highest dogs and monkeys, the IOP-lowering macular adhesions changed when ocri- concentration (0.4%) of AMA0076. effects of ONO-9054 were more po- plasmin (Jetrea; Thrombogenics NV, Looking ahead, Amakem initiated a tent and longer-lasting than the effects Leuven, Belgium) was approved by Phase IIa proof-of-concept, placebo- produced by an FP receptor agonist the FDA in 2012.3 This recombinant controlled, dose-escalation study of (latanoprost), a beta-adrenergic re- protease targets vitreous proteins, re- topical AMA0076 in September 2012. ceptor antagonist (timolol) and a fi xed sulting in degradation and enzymatic combination of the two. (Nagai K, et al. vitrectomy. A Phase III study sub-anal- ARVO E-Abstract 1986) In a double- ysis examined the effi cacy of ocriplas- masked study of 48 healthy volunteers, min in patients designated as clinical Data implicating ONO-9054 was well-tolerated and candidates for traditional vitrectomy. B-Amyloid in the there were no apparent dose-related (Kuppermann BD. ARVO E-Abstract responses in any systemic or local tol- 1942) Patients were evaluated for pathology of glaucoma, erability parameters. (Rowe-Rendle- VMA resolution 28 days after injection as analyzed via levels man C, et al. ARVO E-Abstract 440) of either ocriplasmin or placebo. In pa- Mimetogen (Montréal, Québec) tients with full-thickness macular hole, of B-Amyloid in presented post-hoc data from a com- closure was also assessed at 28 days. glaucomatous retinas pleted trial of MIM-D3 Ophthal- Overall, 33.2 percent of eyes treated mic Solution. Patients with greater with ocriplasmin achieved VMA reso- compared to healthy or more rapid exacerbation of signs lution as compared with 11.5 percent subjects, set the stage and symptoms from Ora’s CAE were (p=0.001) of those treated with place- more responsive to MIM-D3, which bo; in patients with a baseline FTMH, for MRZ-99030, a targets mucin-protective compensa- these rates were 50 percent and 25.5 B-Amyloid aggregation tory mechanisms. (Ousler G, et al. percent (p=0.006), respectively. In ad- ARVO E-Abstract 4343) Addition- dition, the study doctors report that modulator. ally, the post-hoc analysis supports FTMH closures were seen in 40.6 per- an association between the duration cent of the ocriplasmin-treated group of dry eye and the response to treat- as compared to 10.1 percent in the Data implicating β-Amyloid in the ment for the reduction in both signs placebo group. pathology of glaucoma, as analyzed and symptoms. (Meerovich K, et al. Building off data presented at via levels of β-Amyloid in human ARVO E-Abstract 4340) Patients who last year’s ARVO (Van de Velde S, glaucomatous retinas in comparison reported having dry eye for fi ve to 10 et al. IOVS 2012;53:ARVO E-Ab- to healthy subjects, set the stage for years saw a significant reduction in stract 1977; Sijnave D, et al. IOVS MRZ-99030 (Merz Pharmaceuticals; fl uorescein staining and experienced 2012;53:ARVO E-Abstract 2522; Hol- Frankfurt, Germany), a β-Amyloid ag- improvements in their dry-eye symp- landers K, et al. IOVS 2012;53:ARVO gregation modulator. (von Thun und toms, as opposed to those patients E-Abstract 1974), Amakem Therapeu- Hohenstein-Blaul N, et al. ARVO E- who reported having dry-eye disease tics (Diepenbeek, Belgium) presented Abstract 1139) Merz researchers found for durations of one to fi ve years or new preclinical data on its lead drug that the topically administered drug greater than 10 years. candidate, the locally acting Rho ki- signifi cantly reduced retinal ganglion Also targeted to treat ocular sur- nase (ROCK) inhibitor AMA0076. cell apoptosis in a rodent model of glau- face orders such as dry eye, EBI-005 In Dutch Belted rabbits, once-daily coma compared to vehicle control in a is a potent IL-1R1 inhibitor. Eleven treatment with AMA0076 resulted in dose-dependent manner. (Gravius A, Biotherapeutics (Cambridge, Mass.) IOP reduction that was more sustained et al. ARVO E-Abstract 2625) presented clinical data from a Phase than Y-39983, a non-local ROCK in- Multiple abstracts from Japan’s Ono I safety study demonstrating that hibitor. (Van de Velde S, et al. ARVO Pharmaceuticals highlighted ONO- EBI-005 was safe and well-tolerated E-Abstract 5631) The data demon- 9054, an isopropyl ester derivative of in normal volunteers at two dose lev- strated that AMA0076 elicited a sus- the free acid ONO-AG-367 classifi ed els when administered three times tained, 24-hour effect on lowering in- as a dual FP/EP3 receptor agonist daily. (Goldstein M, et al. ARVO E- traocular pressure, an effect not seen that may be effective in lowering in- Abstract 4319) The positive results

54 | Review of Ophthalmology | July 2013

050_rp0713_ttops.indd 54 6/20/13 3:49 PM of the Phase 1a study prompted a Phase 1b study in patients with dry eye. Eleven also presented preclinical toxicology data demonstrating that EBI-005 was well-tolerated in both mouse and rabbit. (Furfi ne E, et al. ARVO E-Abstract 4320) Preclinical data on a new topically administered anti-infl ammatory, cis- Urocanic acid, demonstrated a significant reduction in corneal staining using a murine model of dry eye in a study from Ora. (Whitlock A, et al. ARVO E-Abstract 902) The same compound also showed promise in an Ora preclinical study of allergic conjunctivitis, so we’re likely to see additional studies of cis-UCA in the future. (McLaughlin J, et al. ARVO E-Abstract 2554) An interesting wrinkle in the therapeutic development paradigm was described by two poster presentations on the effi cacy of low-dose brimonidine as an eye-whitener. (Chapin MJ et al. ARVO E-Abstract 2556; Horn G et al. ARVO E-Abstract 5451) (One of the presenters is the patent holder for this use of brimonidine.) The re-purposing of this anti-glaucoma agent provides a great example of how clinicians may be the best untapped resource in the drug development landscape. It also reminds us why we like the ARVO meeting: It represents a unique opportunity for clinicians and scientists to rub elbows, share ideas and move ocular therapeutics forward.

Dr. Abelson is a clinical professor of ophthalmology at Harvard Medical School.

1. Age-Related Eye Disease Study 2. Lutein + Zeaxanthin and Omega-3 Fatty Acids for Age-Related Macular Degeneration. JAMA 2013;309:19:2005-2015. 2. Safety and Pilot Efﬁ cacy of AKB-9778 in Subjects With Diabetic Macular Edema. http://clinicaltrials.gov/ct2/show/ NCT01702441?term=AKB-9778&rank=1. Accessed May 29, 2013. 3. A Safety And Efﬁ cacy Study Of ALG-1001 In Human Subjects With Wet Age-Related Macular Degeneration. http://clinicaltrials. gov/ct2/show/NCT01749891?term=ALG-1001&rank=1. Accessed May 15, 2013. 4. Approval letter for Jetrea (ocriplasmin) Intravitreal Injection. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2012 /125422Orig1s000ltr.pdf. Accessed May 29, 2013.

050_rp0713_ttops.indd 55 6/21/13 10:17 AM Course Director: William F. Mieler, MD Chicago,g, IL Faculty: Jay S. Duker, MD William Rich, MD University of Illinois at Chicago (UIC) Faculty: Boston, MA Washington DC Jennifer I. Lim, MD Pravin U. Dugel, MD David Sarraf, MD Larry Ulanski, MD Phoenix, AZ Los Angeles, CA Felix Y. Chau, MD Yannek Leiderman, MD Peter K. Kaiser, MD Paul Sternberg, MD Cleveland, OH Additional Chicago-area Nashville, TN Vitreoretinal Specialists Kirk H. Packo, MD George A. Williams, MD Jennifer J. Kang-Mieler, PhD Chicago, IL Royal Oak, MI Swissôtel 323 EAST WACKER DRIVE, CHICAGO, IL 60601 • RESERVATIONS: 888-737-9477

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000_rp0613AlcAVTT.indd 57 5/22/13 3:17 PM Glaucoma Management

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

Using Visual Fields to Predict Progression Knowing which patients are at greatest risk is crucial to effective treatment. This new approach may help make that a reality. By Joseph Caprioli, MD, Los Angeles

think most glaucoma specialists do well without any treatment at all. gression by studying visual fields I would agree that many glaucoma If a 70-year-old patient has a very slow usually focus primarily on the patients today are overtreated or rate of progression, he’s not going to parts of the field that seem to be undertreated. This is not a refl ection go blind within the next 30 years. You getting worse. That makes sense, of our competence, but of our limita- can leave him alone, saving him the because non-uniform progression tions when it comes to identifying cost and morbidity of treatment. On is the nature of glaucoma damage; which glaucoma patients are most the other hand, a young patient who different portions of the visual fi eld likely to lose vision—and how quickly. is getting worse fast is likely to lose his behave differently. The damage from In an ideal world, we might be vision if left untreated. That’s not only glaucoma is relatively localized and able to constantly monitor all of our a bad situation for the individual, but tends to appear in typical patterns. patients and respond to changes comes with a great cost to our society Perhaps most important, the portion in their condition the moment the (as numerous studies have shown). of the visual field that’s damaged is changes appear, but this is not an ideal These patients need more aggressive likely to get worse much faster than world. Furthermore, our constraints treatment. other parts of the fi eld that have been are likely to increase because we’re The point is that we need to get the relatively spared by the disease. In going to have even more limited right level of treatment to the right fact, the latter areas may not change resources for medical care in the patients at the right time. Without at all; that’s just the nature of the future; fewer doctors will be treating having reasonably accurate estimates pathophysiology of glaucoma. So, if a growing number of patients, while of progression rates, we really don’t you want to know whether a patient is dealing with decreasing health-care know which patients need intensive progressing rapidly or slowly, it makes funding. To make the best of this treatment and which don’t. sense to focus on the parts of the situation we’re going to have to focus visual fi eld that are damaged, rather on treating those patients who are at Separating Fast and Slow than on the fi eld as a whole. the greatest risk of losing vision. With that in mind, we recently de- To do that, we need to be able To date, most of the statistical veloped a software system that can to identify those patients who are approaches for estimating the speed analyze a sequence of visual fields, progressing quickly. The reality is that of glaucoma progression have used identify locations that are progressing not everybody with glaucoma is going indices that were relatively global, at faster rates than the remainder to go blind. Depending on their age taking the entire visual field into of the fi eld, and then predict future and other factors, many patients who account. However, experienced prac- deterioration of the fi eld based on this have a slow rate of progression may titioners who are estimating pro- information. In essence, the system

This article has no commercial sponsorship. July 2013 | Revophth.com | 57

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epo_housead.indd 1 10/22/12 4:38 PM Glaucoma

REVIEW Management

30dß 0 to 2.5% 25dß 2.5 to 5% 5% to 10% 20dß 10% to 20% 10dß 20% to 30% 5dß 30% to 40% 0dß 40% and up Fast rate: 26% Initial VF Final VF in series Progression rates Slow rate: 3% An example of using the rate of visual fi eld decline to predict probable future outcomes in a glaucomatous eye (barring intervention). Above, left to right: grayscale of the initial visual fi eld; grayscale of the fi nal visual fi eld in the series; grayscale showing the percentage rate of decay per year at each location; visual fi eld partitioned into locations progressing more slowly (green) and faster (red). Directly below: average decay rates for slow and fast components given by the red and green dots, respectively. The black dots indicate the average rate of decay across the whole fi eld, while the black line shows mean deviation (MD). Bottom of page: grayscale predictions for thresholds at fi nal follow-up, at three confi dence intervals.

mimics what an experienced glaucoma subtracts that amount specialist would do, but because it’s of deterioration digital, it can do it far more accurately. from the entire fi eld, One of the fundamental problems leaving a net rate of of visual fi elds is that they’re highly progression that can variable, so it’s often difficult for a be attributed solely human brain to pick out the signal to the disease. In from the noise. But software is able fact, in most eyes Visual Field to do it very quickly and reproducibly. the magnitude of % of Normal the slow component Using the Data compared to the fast component is actually The reason that it’s helpful to pay pretty small, so when less attention to the parts of the visual you subtract it out, it field that are progressing slowly (if doesn’t make a very Years at all) is that much of the slower big difference. In degradation in the visual fi eld is the result of aging or cataract formation Eighth Year Predicted from First Four Years rather than glaucoma. Our system keeps that from confounding the issue by removing that gradual shift from consideration. First, the software divides the fi eld into areas that are getting worse relatively quickly and those that are 10th percentile getting worse relatively slowly, based on the preceding series of visual prediction fields, using point-wise exponential regression (PER) analysis of threshold sensitivities. The rate of change seen in the slower areas may, to a small 50th percentile extent, represent glaucomatous dam- prediction age, but for the most part it can be explained by the other causes. That means the deterioration seen in those 90th percentile areas is probably happening across prediction the entire visual fi eld, so the software

July 2013 | Revophth.com | 59

057_rp0713_gm.indd 59 6/21/13 10:18 AM SAVE THE DATE 2013 CALENDAR CONTINUING PROFESSIONAL EDUCATION The Continuing Professional Education (CPE) Ophthalmology programs are CME activities designed to complement third-year ophthalmology residency medical education as well as Glaucoma fellows programs. These CME programs take place in a comfortable arena for residents and fellows to exchange ideas with their peers. Faculty for these educational programs are comprised of physicians from both university programs and private practices. The format of the programs consists of presentations of illustrative and unusual cases, panel discussions, and didactic lectures as well as a state-of- the-art, hands-on wet lab experience. It is our hope that you will encourage selected residents and fellows to attend these educational programs, which are all accredited to ensure fair balance.

August 2-3, 2013 August 9-10, 2013 Fort Worth, TX Fort Worth, TX Course Director: Course Director: Tommy Korn, MD James Katz, MD Attending Ophthalmologist, Midwest Center for Sight Sharp Rees-Stealy Medical Group, Des Plaines, IL Sharp Memorial Hospital, San Diego, CA

GLAUCOMA FELLOWS September 27-28, 2013 October 18-19, 2013 Fort Worth, TX Fort Worth, TX Course Director: Course Director: Mitchell A. Jackson, MD Kuldev Singh, MD Founder/Medical Director, Jacksoneye Professor of Ophthalmology and Director of Chicago, IL Glaucoma Service at the Stanford University School of Medicine, California

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Supported by an independent Jointly sponsored by: medical educational grant from:

076_rp0613CPEcal.indd 86 5/22/13 3:47 PM Glaucoma

REVIEW Management

30dß 0 to 2.5% 25dß 2.5 to 5% 20dß 5% to 10% 10% to 20% 10dß 20% to 30% 5dß 30% to 40% 0dß 40% and up Initial VF Final VF in series Progression rates Fast rate: 25% Slow rate: 5% Another example of using the rate of visual ﬁ eld decline to predict probable future outcomes in a glaucomatous eye (barring intervention). This eye has a better prognosis than the previous example on p. 59. (For a detailed explanation of the charts, see the charts and caption on p. 59.)

some eyes, if the patient isn’t too old 12 visual field exams (389 eyes of among the glaucoma patients than or has already had cataract surgery, 309 patients). Forecasts made by among the cataract patients (19 ±10 the rate of change in the slow areas the system correlated approaches zero. well with the actual Next, the software uses this data measured outcomes to make predictions for what the (p<0.001). visual fi eld will likely look like in, say, Two independent fi ve years if nothing changes (i.e., no cohorts were also change in treatment is undertaken). used to determine the In other words, it projects into the software’s ability to future assuming that the future rate differentiate areas of Visual Field will be similar to the past rate. With glaucomatous damage % of Normal statistical analysis, it produces a worst- from reduced vision case scenario, a best-case scenario caused by cataract; the and a most-likely scenario. difference in rate of In addition to giving the physician decay between faster valuable information, this is also and slower segments something you can show to the patient. of the visual fi eld were Years If the patient is getting worse fast, that significantly greater will be reflected in a much worse- looking visual fi eld in the future, even Eighth Year Predicted from First Four Years in the best-case outcome prediction; the worst case might show the patient becoming blind. (This could help reduce the problem of patient non- compliance.)

Validating the System 10th percentile prediction We’ve conducted two studies to validate this system as a means to separate the fast progressors from the slow progressors. The initial study 50th percentile involved fairly advanced patients with a lot of visual ﬁ eld damage from prediction glaucoma1; it was based primarily on data collected during the Advanced Glaucoma Intervention Study. We 90th percentile included individuals with six or prediction more years of follow-up and at least

July 2013 | Revophth.com | 61

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2013_cme_housead_ad.indd 1 5/22/13 12:08 PM Glaucoma

REVIEW Management

percent vs. 5 ±5 percent, (p<0.001). in some eyes.) treatment to those patients who need After we completed that study, It’s worth noting some limitations to it and helping to prevent unneeded our next concern was whether the what these studies show. We required treatment side effects and problems system would work as well in patients a minimum of fi ve test locations in a in patients who don’t. The software is with less damage. Some of the more visual fi eld in each rate component in not part of any commercial product globally based visual fi eld progression order to avoid mistaken identifi cation at present (which may be partly be- analyzers have low sensitivity when of deterioration when none was pre- cause it can be seen as a competing testing patients with early damage, sent. How well the system would work approach to existing analysis tools). and produce highly variable results with fewer deteriorating locations in a However, there’s nothing secret about when used with patients who have visual fi eld cannot be determined from it and we don’t have any proprietary advanced damage. So we wanted to these trials. Also, it’s possible that a interest in it. We’ve already published be sure that our system would work small subgroup of patients might have the technique, so anybody can create well across the full range of visual fi eld slow, diffuse glaucomatous damage, similar software; there’s enough detail sensitivity. which may be refl ected in the “slow” in the published articles to tell you The second group of patients we component. exactly how to do it. Furthermore, tested, 409 eyes of 279 open-angle anyone who has the skills and interest glaucoma patients from the database can tweak what we’ve developed. at the University of California, Los At this point we’re still working on Angeles, had much less glaucoma Not only do our a Web-based version of the concept, damage.2 Their data were also studies support the and we expect to be ready to share combined with the data from the it pretty soon. Once we feel that it’s fi rst study to see how well the system validity of the software perfected, anyone is welcome to use worked over a broad range of damage program, they support it. In the meantime, as the system levels. For comparison, predictive proves its value, we expect that manu- forecasts were calculated using both the concept that facturers will eventually choose to the mean deviation and visual field accurate prediction incorporate it into their products. index forecasting systems; comparison For now, I think it’s important to of the prediction errors of the three of future progression note that not only do our studies approaches favored our system’s depends largely on support the validity of the software forecasts (p<0.001). Overall, the new program, they support the concept system was successful at identifying paying attention to the that accurate prediction of future high-risk rapid progressors across a damaged areas of the progression depends largely on paying broad range of disease severity. attention to the damaged areas of the We have another study, currently visual fi eld, not just visual fi eld, not just global analyses. in press, in which we looked at 83 global analyses. So until software for this purpose is patients who underwent glaucoma available, I encourage clinicians to surgery to see what effect the sur- remember to focus on those areas gery had on their progression rates. when trying to decide which patients In brief, the data showed that the Nevertheless, the system appears need intensive treatment. surgery produced a significant re- to work well over the entire range duction in the rate of progression in of visual field damage. It’s more Dr. Caprioli is the David May II the fast-progressing parts of the visual sensitive with early glaucoma patients Professor of Ophthalmology, chief of field, but essentially no change in than existing predictive systems, and the glaucoma division and director the rate of the slower-changing parts more specifi c when testing those with of the Glaucoma Basic Science and of the field. This suggests that the advanced glaucoma. Clinical Laboratories at the Jules slower change is likely not a result of Stein Eye Institute in Los Angeles. glaucomatous damage. (In fact, some What’s Next? 1. Caprioli J, Mock D, Bitrian E, et al. A method to measure and eyes showed a slightly increased rate predict rates of regional visual fi eld decay in glaucoma. Invest of progression in the slower areas Once our system is thoroughly Ophthalmol Vis Sci 2001;52;7;4765-73. after trabeculectomy; that makes tested, its use should help clinicians 2. Azarbod P, Mock D, Bitrian E, et al. Validation of point- wise exponential regression to measure the decay rates of sense, since trabeculectomy is known distinguish between fast and slow glaucomatous visual fi elds. Invest Ophthalmol Vis Sci 2012;53: to accelerate the formation of cataract progressors, directing more aggressive 5403-5409.

July 2013 | Revophth.com | 63

057_rp0713_gm.indd 63 6/20/13 2:17 PM Save the Date Aug. 23-25, 2013

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Accreditation Statement This activity has been planned and implemented Provided by in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Institute for the Advancement of Human Behavior (IAHB) and Review of Ophthalmology®/ ® Jobson Medical Information LLC. The IAHB is accredited by the ACCME to provide continuing medical education for physicians. COPE approval pending Credit Designation Statement This activity has been approved for AMA PRA Category 1 CreditTM. The Administrator’s Program is approved by the National Board for the Partially supported by an Certifi cation of Ophthalmic Executives for 7 Category A Credits, Certifi ed educational grant from Ophthalmic Executive Designation. Jointly sponsored by

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0413SanAnt_ascrsAd.indd 1 5/24/13 2:12 PM Refractive Surgery

REVIEW Edited by Arturo Chayet, MD

Reports from the U.S. SMILE Study A look at the U.S. trial for the new, all-femtosecond-laser refractive procedure performed with the Visumax laser. Walter Bethke, Managing Editor

.S. refractive surgeons would creating a three-dimensional lenticule approximately 6.5 mm in diameter, U no doubt enjoy a procedure with that we extract through this small in- and the outer dimension of the pocket the rapid healing profile of LASIK cision. The removal of this lenticule that’s created is 8 mm. but which only required one piece of induces central fl attening in the cor- “At the conclusion of the case, we equipment. They came a step closer nea that treats the myopia. In that remove the lenticule and spread it out to this goal with the submission of the way, it’s somewhat analogous to the on the anterior surface of the cornea fi rst set of data for Carl Zeiss Med- procedure automated lamellar kera- to make sure there aren’t any missing itec’s all-femtosecond, small-incision toplasty, in which the surgeon made pieces,” Dr. Doane explains. “If there lenticule extraction procedure to two passes with the microkeratome are any, your only option at that point the Food and Drug Administration. and removed a lenticule of tissue.” is to create a flap and look for the Here’s a look at the procedure and The incision that’s used to remove the missing pieces, because you wouldn’t how it’s faring in its fi rst U.S. trial. lenticule is angled anywhere from 60 be able to see them otherwise.” The to 90 degrees. The lenticule itself is postop regimen is similar to LASIK’s, The SMILE Procedure MRSE Predictability (Diopters) at Three Months The SMILE procedure uses the Visumax femtosecond laser to create 8 an intrastromal refractive change in 7 the cornea. “In SMILE, the surgeon uses the 6 Visumax to create a posterior refrac- 5 tive pass,” explains John Doan, MD, of St. Louis, one of the study’s princi- 4

pal investigators. “He then makes an Achieved 3 anterior intrastromal pass that’s planar to the corneal surface. The posterior 2 cut is a lenticular refractive cut and 1 the anterior is simply the front surface of the lenticule, which has no refrac- 0 1 2 3 4 5 6 7 8 tive power. So, instead of vaporizing Attempted quarter-micron pieces of tissue, we’re

This article has no commercial sponsorship. July 2013 | Revophth.com | 65

065_rp0713_rs.indd 65 6/20/13 3:47 PM RETINA ONLINE E-NEWSLETTER

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0411_Retina Online house Ad.indd 1 1/22/13 2:44 PM Refractive

REVIEW Surgery

SMILE Patients’ Uncorrected Vision Results with typical corneal refractive surgery,” he says. “There have been 100 no infections and no epi- 90 thelial ingrowth. There have been cases of mild 80 diffuse lamellar keratitis 70 One day in a few eyes as surgeons 60 Seven days got used to the new 50 One month technique, but nothing 40 that’s led to lost lines of

Percent of eyes Percent 30 Three months best-corrected vision. 20 There can be an epithe- 10 lial defect, which I’ve 0 seen myself, but we also 20/40 or better 20/25 or better 20/20 or better see that with LASIK.” At this point, though SMILE proponents consisting of steroid and antibiotic achieved refractions, in the SMILE would like to think the fi eld is mov- drops for a week, with regular follow- study at three months the R2 value ing toward all-femtosecond proce- up visits. was 0.99. “What was interesting is dures, if an enhancement is neces- that the predictability for 1 to 3 D sary after SMILE, it’s acknowledged The Results treatments is just as good as LASIK,” that you still need an excimer to do Dr. Doane says. “However, for treat- it. “Right now, it appears that en- Though Carl Zeiss Meditec isn’t ments of 6 to 8 D, LASIK’s predict- hancement rates will be lower than sharing all of the data on the full 100 ability isn’t as good as it is for 1 to 3 with LASIK since it appears that patients that have been submitted D, so there’s a drop-off in how accu- SMILE is more predictable across to the FDA from the SMILE study, rate we can be with the excimer. But the range of corrections,” says Dr. Dr. Doane is able to discuss the out- this wasn’t the case with the SMILE Doane, referring to the tight R2 val- comes of his 64 study patients. procedure. So far its refractive pre- ue. “But if you had to do an enhance- In the trial, patients had SMILE in dictability has been just as good with ment, the options are to do a PRK, so one eye and LASIK in the other. In 6- to 8-D corrections as it is with the you go back to an excimer, or creat- Dr. Doane’s 64 patients, the average 1- to 3-D treatments. ing a fl ap and doing an ablation in the sphere was -4.39 D (r: -1.5 to -7.5) “The patients have essentially been stromal bed, which also involves an and the average cylinder was -0.14 exactly where we want them to be in excimer. There’s also the possibility, D (r: zero to -0.5 D). The average terms of refraction,” Dr. Doane con- though it’s just in the concept stage spherical equivalent refraction was tinues. “Unlike the excimer, which at this point, of doing layers of photo- -4.46 D (r: -1.63 to -7.75 D). In the needs to travel through the air before disruptive pulses in the stroma with 53 patients available for follow-up at it hits the cornea and can therefore the femtosecond to resolve whatever a month, the average SE was -0.11 be affected by volatile substances minimal refractive error is there. (r: -0.75 to +0.38 D), with the aver- such as particulates in the air or per- This approach hasn’t been done yet, age sphere being zero and average fume, with the femtosecond we’re though.” astigmatism -0.21 D. For the 37 pa- docked with the cornea, so it’s a com- Looking down the road, Dr. Do- tients available at three months, the pletely closed system. The system ane says Carl Zeiss Meditec is await- average SE was -0.06 D. All of the is closed tighter still with SMILE ing FDA approval to begin the fi nal patients see 20/25 or better uncor- because you’re doing the photodis- Phase III study of the device, and rected postoperatively. ruption within the cornea.” that the eventual approval may also Dr. Doane says the treatment In terms of safety, Dr. Doane says involve compound myopic astigma- proved to be highly predictable. Us- none of the eyes lost two lines of vi- tism in addition to just simple myopia. ing regression analysis, where an R2 sion. “There is nothing new or out “Then we’ll have to see if we can treat value of 1 would mean perfect pre- of the ordinary in terms of the inci- mixed astigmatism and if we want to dictability between attempted and dence of complications associated treat hyperopia,” he says.

66 | Review of Ophthalmology | July 2013

065_rp0713_rs.indd 66 6/24/13 1:59 PM Refractive

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July 2013 | Revophth.com | 67

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Supplements Improve Macular Pigmentation

fter a 12-month intervention, Ger- Visual Outcome of Cataract ative complications were the strongest Aman researchers concluded that a Surgery from the ERQOCRS influences on the visual outcomes, supplement containing a fixed com- ifteen European cataract surgery but surgical complications and ocular bination of xanthophylls (lutein and Fclinics participated in a database changes requiring complex surgery zeaxanthin) and ω-3 long-chain poly- study to analyze visual outcomes af- also had a negative infl uence. Dete- unsaturated fatty acids (LC-PUFA) ter cataract surgery; the data sup- rioration of visual acuity after the sur- signifi cantly improved plasma antioxi- ports excellent outcomes. A majority gery (n=6,112 [1.7 percent of cases]) dant capacity, circulating macular xan- of patients (61.3 percent) achieved was most common in patients with a thophyll levels and the optical density a corrected distance visual acuity good preoperative visual acuity. The of macular pigment in patients with of 1.0 (20/20) or better. While age researchers also note that a weakness nonexudative AMD, and sex influenced outcomes, the of the study could be the self-reported A total of 145 individuals with non- greatest infl uences were short-term nature of some data to the registry. exudative AMD were randomly di- postoperative complications, ocular J Cataract Refract Surg vided as follows: placebo group; group comorbidity, surgical complications 2013;39:673-679. 1 (a daily capsule containing lutein 10 and complex surgery. Lundström M, Barry P, Henry Y, Rosen P, et al. mg, zeaxanthin 1 mg, docosahexaeno- Data were drawn from case series ic acid 100 mg and eicosapentaenoic of cataract extractions reported to Corneal Thickness as Predictor acid 30 mg); and group 2 (double the the European Registry of Quality Of Corneal Transplant Outcome dose of substances used in group 1). Outcomes for Cataract and Refrac- new report from the Cornea Do- After a month of intervention, the tive Surgery database; 368,256 cata- A nor Study shows that in the fi rst concentrations of the administered ract extractions were available for five years after penetrating kerato- carotenoids in plasma as well as the analysis. Case series data was entered plasty, corneal thickness can serve as optical density of the macular pig- into the database by surgeons, by a predictor of corneal graft survival. ment increased significantly in the transfer from existing national regis- However, CT is not a substitute for groups randomized to receive supple- tries or by electronic medical record cell density measurement because mentary macular xanthophylls and systems. The database contains indi- both measures are independently pre- ω-3 LC-PUFAs; these concentrations vidual anonymous data on preopera- dictive of graft failure. remained stable though the end of tive, intraoperative and postoperative A total of 887 patients with a cor- the study. Use of the double dose of measures. neal transplant for a moderate-risk xanthophyll and LC-PUFA supple- The best visual outcomes were condition (principally Fuchs’ dystro- ments in group 2 resulted in a benefi - achieved in age groups 40 to 74 years, phy or pseudophakic corneal edema) cial alteration of the fatty acid profi le with men showing a higher percent- had postoperative CT measurements in the plasma of patients with AMD age of excellent vision (1.0 [20/20] or throughout a fi ve-year follow-up time. in comparison with group 1. The lipo- better). A corrected distance visual Relationships between baseline (re- philic antioxidant capacity in plasma acuity of 0.5 (20/40) or better and of cipient, donor and operative) factors was also signifi cantly elevated. 1.0 (20/20) or better was achieved in and CT were explored. Proportional JAMA Ophthalmol 2013;131:564-572. 94.3 percent and 61.3 percent of cas- hazards models were used to assess Arnold C, Winter L, Fröhlich K, Jentsch S, et al. es. Ocular comorbidity and postoper- the association between CT and graft

This article has no commercial sponsorship. July 2013 | Revophth.com | 69

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failure. Relationship between CT and paired Student t test, with the statisti- the presence of a glaucoma tube (5/5), cell density was assessed with a longi- cal signifi cance set at p<0.05. previous graft failure (4/5) and ante- tudinal repeated measures model and The mean age of the 50 Xeomin pa- rior synechiae (2/5). Spearman correlation estimates. tients was 64.9 years; 39 (78 percent) Cornea 2013;32:745-750. Higher longitudinal CT measure- were women and 11 (22 percent) were Martinez J, Galor A, Perez V, Karp C, et al. ments were associated with the fol- men. In all, 26 (52 percent) preferred lowing: diagnosis of pseudophakic or Xeomin and 24 (48 percent) preferred Antibiotic-resistant Ocular aphakic corneal edema (p<0.001); Botox. Those who preferred Xeomin Surface Flora After IVT Injection intraocular pressure >25 mmHg believed that it was “more effective” epeated use of topical moxifl oxa- during the fi rst postoperative month (n=10; 29 percent), while those who Rcin after intravitreal injection ap- (p=0.003); white (non-Hispanic) preferred Botox concluded that it had pears to increase antibiotic resistance donor race (p=0.002); and respira- a “longer duration” (n=11; 37 per- in ocular surface flora. Because of tory causes of donor death (p<0.001). cent). The mean treatment interval this, researchers recommend that Among those without graft failure was 13 weeks (SD=6.39) in those who routine use of prophylactic antibiotics within the first postoperative year, preferred Botox, whereas it was 10.2 after IVT injection be discouraged. the five-year cumulative incidence weeks (SD=2.15) in those who pre- Patients 65 years and older with of graft failure (±95 percent CI) was ferred Xeomin (p=0.017). There was newly diagnosed age-related macular 5 percent ±5 percent in those with a no statistical difference when com- degeneration were recruited by seven one-year CT ≤500 µm; 5 percent ±3 paring mean disease duration, num- retinal specialists from July 1, 2010 percent for CT 501 to 550 µm; and ber of total treatments and number through December 31, 2011. The 20 percent ±11 percent for CT >600 of units/treatment between the two study group (n=84) received topical µm. In a multivariate analysis, both preference groups. moxifl oxacin hydrochloride for three one-year CT and cell density were as- Ophthal Plast Reconstr Surg days after each monthly IVT injec- sociated with subsequent graft failure 2013;29:205-207. tion, while the control group (n=94) (p=0.002 and 0.009). CT increase was Chundury R, Couch S, Holds J. received no topical antibiotics after modestly associated with endothelial injection. Researchers measured the cell loss during follow-up (r= -0.29). Endothelial Graft Failure After resistance to moxifl oxacin and ceftazi- Cornea 2013;32:729-736. Contralateral APK dime in cultured isolates at baseline Verdier D, Sugar A, Baratz K, Beck R, et al. ascom Palmer Eye Institute and and monthly for three months in both Bthe Miami Veterans Affairs Hospi- groups, studying the changes in the Patient Preferences Between tal are the fi rst to describe graft failure minimal inhibitory concentration of Botox and Xeomin in BEB because of slow endothelial attenu- culture isolates. ccording to doctors in Missouri, ation after contralateral autologous In the study group, the baseline Apatients with benign essential corneal transplantation (APK). adjusted MIC increased from 1.04 to blepharospasm treated with both Five patients received a contralater- 1.25 µg/mL (p=0.01), the MIC for 50

onabotulinumtoxinA (Botox) and in- al APK and a simultaneous allogeneic percent of isolates (MIC50) increased cobotulinumtoxinA (Xeomin) who penetrating keratoplasty in the donor from 0.64 to 1.00 µg/mL and the MIC

prefer Xeomin over Botox had a sta- eye at the Bascom Palmer Eye Insti- for 90 percent of isolates (MIC90) in- tistically signifi cant shorter treatment tute and the Miami Veterans Affairs creased from 0.94 to 4 µg/mL. In both interval. In addition, those who pre- Hospital. Median patient age at the groups, the culture-positive rate did ferred Xeomin thought it was more time of surgery was 67 years (r: 58 to not change signifi cantly when adjust- effective; patients who preferred Bo- 88 years); four patients were male and ed for baseline. No signifi cant change tox thought it had a longer duration one female; one patient was white and was found in the MIC level, culture-

of effect. four were black. The surgeries were positive rate, MIC50 level or MIC90 Fifty patients with BEB being uneventful and no operative or imme- level in the control group. Subgroup treated with Botox were switched to diate postoperative complications oc- analysis found diabetes mellitus to be Xeomin. At a scheduled follow up, curred in either eye. During follow-up noncontributory to both the MIC and patients decided to either continue (r: 18 to 54 months; mean: 35 months; culture-positive rate. with the Xeomin or switch back to Bo- median: 34 months), four autologous JAMA Ophthalmol 2013;131:456-461. tox, and preferences regarding treat- grafts failed because of endothelial Published online February 21, 2013. ment were recorded. The preference attenuation. Identiﬁ ed risk factors for doi:10.1001/jamaophthal- groups were then analyzed using un- failure in the autologous eyes included mol.2013.2379.

July 2013 | Revophth.com | 71

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72 | Review of Ophthalmology | July 2013 This article has no commercial sponsorship.

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(continued from page 41) you make them emmetropic. You Snowbirds who spend part of the may need to have different goals year in Florida or Arizona or those better and not trying to make the for them. When we do change their who relocate to more temperate ar- patient 30-years-old again,” he visual acuity, we have to really be eas are often engaged in more out- says. In his practice, many patients clear about how it will affect their door activities than those in other are retired professors, so they of- lifestyle. If a person is myopic but areas of the country, so they may ten have very high expectations. likes hiking, you may want to make value distance vision more than el- However, he says that, while the him or her emmetropic. It takes derly patients in colder climates. baby boom generation believes that a little more counseling than with Dr. Arleo notes that surgeons medicine ﬁ xes everything, the old- someone who is 45 or 50.” need to be a little bit more careful er population is more cognizant of Surgeons in different parts of the about instructions with older pa- the fact that they are older and are country may encounter different tients. “Many of these people have not going to have vision like they patient expectations. For example, hearing issues. Some might be hav- had 30 years ago. Dr. Arleo practices in a small city ing some dementia,” he says. “We He recommends delivering more with two universities. “We have a are very careful about giving them and promising less. “You have to be disproportionate number of very specific instructions and making careful about what you are promis- educated elderly people. They are sure they understand everything. ing about what they are going to just as tech savvy as far as research- Many of them are juggling multiple get,” says Dr. Arleo. “If I have an ing the docs as the younger people medications, and they have multiple engineering professor who is -6, around here. However, that may be doctors. I think they need a little you’re going to really have to twist different in other parts of the coun- more TLC with the logistics of ev- my arm to not leave him a -3. Many try. I think it’s very speciﬁ c to your erything. Fix the problem, but don’t of those people will be unhappy if location,” he says. try to go for it too much.”

July 2013 | Revophth.com | 73

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ROPH0713.indd 75 6/13/13 6:43 PM 076_rp0713_wills.indd 76 ceptor loss,poorretinallamination retinal thinning,photore- revealed raphy wereperformed.TheOCT mography testandelectroretinog- esthesia, anopticalcoherenceto- pia lentis, and four of the children had pia lentis,andfourofthechildrenhad sations. Sixofthechildrenhadecto- atrophy andfi brillar vitreous conden- prominent choroidalvessels,macular ation, whichconsistedofRPEatrophy, and adistinctivevitreo-retinaldegener- smooth cryptlessirides,highmyopia bloch syndrome.Alleightchildrenhad genetically confirmed diagnosisof Kno- in acaseseriesofeightpatientswith Arif Khan,MD,andcoworkersin2012 of thisdisorderwascharacterizedby ing mutationontheotherallele. tion ononealleleandanoveltruncat- previously reportedtruncatingmuta- to beacompoundheterozygotewith in oculartissues.Ourpatientwasfound throughout thebody, butparticularly endothelial basementmembranes expressed inhumanepithelialand which isanonfi coding forcollagen18A1(COL18A1), caused byamutationinthegeneen- to 30secondsinthemicrowave will rejuvenates itselfnaturally. Twenty that doesnotrequirehydrating and microwavable moist-heatcompress Discussion Diagnosis, Workup andTreatment Before readingon, pleaseseep. 78forpresentingcomplaint, andexamination. history 76 T MGD, BlepharitisandChalazions Eye, Hydrating CompressforDry (continued fromp.73) Product News While thepatientwasunderan-

The distinct ophthalmic phenotype The distinctophthalmicphenotype Knobloch syndromeisknowntobe REVIEW | press, featuringMediBeads,isa he BruderEyeHydratingCom- ReviewofOphthalmology Resident CaseSeries Resident CaseSeries bril-forming collagen collagen bril-forming | July2013 one eyeonly. Compresses areavailableto cover air-dried andused continually. Stye in water, washedwithamildsoap, press thatcanbetotallysubmerged the onlymicrowavableeyecom- for years,thecompanysays.Itis the compressoverandagain for theeyes,andusercanapply give 10minutesofgoodmoistheat sound. byultra- of26.25mm axial length The patientwasnotedtohavean with bothrodandconedysfunction. was mildlyabnormalinbotheyes, and macularhypoplasia.TheERG tions thatresultinKnoblochSyn- tears ordetachmentandectopialentis. include closemonitoringforretinal ity andnystagmus.Goalsoftreatment cle correctionimprovedhisvisualacu- idence ofdevelopmentaldelay. Specta- which wasnormalanddidnothaveev- evaluation, includingrenalultrasound, lagen 18present. there isanyfunctionalisoformofcol- is alsodependentuponwhetherornot of retinaldetachment.Theprognosis temic involvementandincreasedrisk the extentofCNSmalformation,sys- bloch syndromeisgreatlyaffectedby tient), cutisaplasiaorencephalocele. a patchofalopecia(asseeninourpa- may beabsent,abnormalitiesinclude hypoplasia. Althoughoccipitaldefects delay, renalanomaliesandpulmonary associations includedevelopmental posterior perinuclearopacity. Systemic Identification ofadditionalmuta- asystemic underwent Our patient The prognosisofchildrenwithKno- bruderophthalmic.com. ophthalmic.com 827-8337, ext.218,visit bruder Surgical instruments,call1(888) ucts, includingBruderOphthalmic line ofBruderOphthalmicprod- the completeand learnmoreabout mediately. To receive afreesample doctors’ offices, andisavailableim- recessive developmentaldisorder. bloch syndrome,arareautosomal hypoplasia wassuspiciousforKno- tic retinalappearanceandmidface an occipitallesion,acharacteris- rare geneticentity. of knowledgewecurrentlyhaveonthis portant contributiontothesmallfund new mutationscontinuestobeanim- eye development.Thediscoveryof molecular mechanismsthatcontrol drome hasthepotentialtorevealnovel 2001,71:1320-9. genetic herterogeneityinKnoblochsyndrome Am JHumGenet reveals novelmutations, presenceofathirdisoform, andpossible 5. SuzukiO, Sertie A. et al. XVIII Molecularanalysisofcollagen 2009;15:801-9. and skinbiopsyanalysisinKnoblochsyndrome. Molecular Vision 4. SuzukiO, E, Kague K, Bagatini etal. mutations Novelpathogenic phenotype. An Acad BrasCienc2006;78:123–31. 18A1andtheirrelevancetothehuman incollagen Mutations 3. Passos-Bueno MR, SuzukiOT, Armelin-Correa LM, etal. 1994;52(2):170-3. tion ofautosomalrecessiveinheritance. Am JMedGenet syndrome inalargeBrazilianconsanguinousfamily: Confi rma- 2. Passos-Bueno MR, MarieSK, MonteiroM, etal. Knobloch Ophthalmol 2012,96:890-5. ophthalmic phenotypeofKnoblochsyndromeinchildren. BrJ 1. Khan AO, Aldahmesh MA, MohamedJY, etal. The distinct with thepreparationofthiscase. Ocular Geneticsfortheirassistance ment ofPediatricOphthalmologyand MD oftheWills EyeInstituteDepart- Levin, MDandWadakarn Wuthisiri, The compressissoldonlythrough The combinationofhighmyopia, The authorwouldliketothankAlex or e-maileyes@ 6/20/13 2:08 PM Advertising

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076_rp0713_wills.indd 77 6/24/13 2:02 PM Resident Case Series Wills Eye Edited by Matthew Dykhuizen, MD REVIEW

High myopia and nystagmus in a young child prompt a referral to the Wills Pediatric Ophthalmology and Ocular Genetics Department.

Alessandra Intili, MD

Presentation

A 2-year-old Caucasian male was referred to the Wills Eye Institute Department of Pediatric Ophthalmology and Ocular Genetics by an outside physician for evaluation of high myopia and the presence of nystagmus. The onset of nystagmus occurred at 2 months of age. He had been wearing spectacles since he was 7 months, with improvement of both his visual acuity and nystagmus.

Medical History

The pregnancy was uneventful and he was born full-term by spontaneous vaginal delivery. The patient had no prior surgeries, no hospital admissions and no serious injuries. Notably, a cystic area on the occiput of the skull was discovered on fetal ultrasound. A postnatal CT was performed and no communication was found between the intracranial vault and the elevated occipital lesion. Family history and pedigree revealed no evidence of parental consanguinity or a constricted gene pool. A maternal uncle reportedly had very fair skin, an inability to tan and high myopia without nystagmus. A maternal great aunt had severe developmental delay.

Examination

General examination of the patient revealed a fair-skinned, blue-eyed child with blond hair, mild mid-facial hypoplasia, and an elevated area of alopecia at the occiput (See Figure 1). Ophthalmic examination revealed a cycloplegic refraction of -21.50 +3.00 X 90 in the right eye, and -23.50 +2.00 X 75 in the left. The pupils were equal, round and reactive, without a relative afferent pupillary defect. Extraocular muscle motility was full, with horizontal, symmetrical, pendular nystagmus and an additional latent component in each eye. There was a preference for a 5 to 10 degree chin down position, with a right head tilt. There was also an exotropia of 18 prism diopters at distance, and 20 diopters at near. Intraocular pressure was 11 mmHg in the right eye and 14 mmHg in the left eye. Slit-lamp examination of the anterior segment was signifi cant for cryptless irides with radial furrows and no transillumination defects (See Figure 2). Dilated fundus examination (See Figure 3) of the right eye revealed abnormal fi brillar condensations in the vitreous, anomalous optic nerves, bilateral poor foveal refl exes, and diffuse retinal attenuation with a prominent cho- roidal pattern. There was a geographic area of macular atrophy. Pigmentary mottling was present 360 de- Figure 1. Posterior aspect of Figure 2. External photo of left Figure 3. Color fundus photo of grees around the midperiph- the patient’s scalp, with a central eye revealing a smooth, cryptless right eye, revealing macular ery. There was no evidence area of alopecia overlying the iris. hypoplasia and pigmentary of retinal breaks, retinal tears putative cyst. mottling. or lattice degeneration.

What is your differential diagnosis? What further workup would you pursue? Please turn to p. 76

78 | Review of Ophthalmology | July 2013

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