THE FLUID WAVE: EVALUATING CANAL SURGERY P. 56 • SEALANTS AND GLUES IN REVIEW P. 14
eiwo ptamlg o.XI o Ags 04• ie l eia mgn Otmzn niVG ramn Vi clso pin Pseudoexfoliation Syndrome Vein Occlusion Options • Optimizing Anti-VEGF Widefi Treatment • • eld Retinal Imaging August 2014 • Review of Ophthalmology Vol. XXI, No. 8 • ICD-10 POSTPONED: NOW WHAT? P. 18 • THE KEYS TO MULTIFOCAL IOL CENTRATION P. 65 MULTIMODAL RETINAL IMAGING IN PLAQUENIL TOXICITY P. 44 • WHAT’S BEHIND PXS P. 52
August 2014 • revophth.com
ANNUAL RETINA ISSUE TheTh DDevil’s il’ iin the h DiDistant DDetails il P2P. 266 Maximizing the Benefi ts of Anti-VEGF P. 30 Increasing Options to Treat Vein Occlusion P. 40
Also Inside: The Critical Driver of Success: Physician Time P. 22
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RP0814_Regeneron.indd 1 7/21/14 1:10 PM REVIEW NEWS Volume XXI • No. 8 • August 2014 Researchers: First Tissue Grown From Adult Human Stem Cell K Lathrop, B Ksander, M Frank and N Frank. Boston researchers have identified a way known examples of constructing a tis- to enhance regrowth of human cor- sue from an adult-derived human stem neal tissue to restore vision, using a cell. molecule known as ABCB5 that acts as Limbal stem cells help maintain a marker for hard-to-fi nd limbal stem and regenerate corneal tissue. Their cells. This work, a collaboration be- loss due to injury or disease is one of tween the Massachusetts Eye and Ear/ the leading causes of blindness. In the Schepens Eye Research Institute, Bos- past, tissue or cell transplants have ton Children’s Hospital, Brigham and been used to help the cornea regener- Women’s Hospital and the VA Boston ate, but it was unknown whether there Healthcare System, provides promise were actual limbal stem cells in the to burn victims, victims of chemical grafts, or how many, and the outcomes A restored functional cornea following injury and others with damaging eye were not consistent. transplantation of human ABCB5-positive diseases. The research, published this In this study, researchers were able limbal stem cells to limbal stem cell- week in Nature, is also one of the fi rst to use antibodies detecting ABCB5 to defi cient mice. Transplants consisting of human ABCB5-positive limbal stem cells resulted in restoration and long-term FDA Approval for Ozurdex 0.7 mg for Select DME Cases maintenance of a normal clear cornea, whereas control mice that received either The Food and Drug Administration approved Allergan’s Ozurdex (dexamethasone intra- no cells or ABCB5-negative cells failed to vitreal implant) as a new treatment option for diabetic macular edema in adult patients restore the cornea. who have an artifi cial lens implant or who are scheduled for cataract surgery. Ozurdex is a sustained-release biodegradable steroid implant that demonstrated long-term effi cacy zero in on the stem cells in tissue from without the need for monthly injections. deceased human donors and use them DME currently impacts more than 560,000 Americans. The Ozurdex implant uses the pro- to regrow anatomically correct, fully prietary and innovative Novadur solid polymer delivery system—a biodegradable implant functional human corneas in mice. that releases medicine over an extended period of time—to suppress infl ammation, which “Limbal stem cells are very rare, plays a key role in the development of DME. The FDA approval of Ozurdex for this indication is based on the MEAD (Macular Edema: and successful transplants are depen- Assessment of Implantable Dexamethasone in Diabetes) study. MEAD includes two dent on these rare cells,” says Bruce multicenter, three-year, sham-controlled, masked, randomized clinical studies assessing Ksander, PhD, of Mass Eye and Ear, the proportion of patients with 15 or more letters improvement in best-corrected visual co-lead author on the study with post- acuity from baseline. The most common adverse events in the studies included cataracts doctoral fellow Paraskevi Kolovou, and elevated intraocular pressure. An increase in mean IOP was seen with each treatment MD. “This fi nding will now make it cycle, and the mean IOP generally returned to baseline between treatment cycles. much easier to restore the corneal sur- “DME is a complicated disease to treat,” said Pravin Dugel, MD, clinical associate face. It’s a very good example of basic professor of ophthalmology at the Keck School of Medicine at the University of Southern research moving quickly to a transla- California, managing partner of Retinal Consultants of Arizona, and clinical investigator in the MEAD clinical trial. “Ozurdex provides long-term improvement of DME without the tional application.” need for monthly injections, which helps these patients who are also managing the other ABCB5 was originally discovered conditions common with diabetes.” in the lab of Markus Frank, MD, of The Ozurdex implant is already indicated for the treatment of macular edema following Boston Children’s Hospital, and Na- branch retinal vein occlusion or central retinal vein occlusion and for the treatment of non- tasha Frank, MD, of the VA Boston infectious uveitis affecting the posterior segment of the eye. Healthcare System and Brigham and
August 2014 | Revophth.com | 3
003_rp0814_news.indd 3 7/25/14 11:28 AM REVIEW News
Women’s Hospital, co-senior investiga- Cataract Surgery for example, can provide benefi ts in a tors on the study, as being produced variety of ways—for people with Al- in tissue precursor cells in human skin Pays Dividends in zheimer’s and also for their caregivers and intestine. In the new work, using a from whom unnecessary burden can mouse model developed by the Frank Alzheimer’s Patients be lifted,” Dr. Carrillo said. lab, they found that ABCB5 also occurs Cataract surgery for people with Alzhei- At AAIC 2014, Alan J. Lerner, MD, in limbal stem cells and is required for mer’s disease and other dementias not of Case Western Reserve University their maintenance and survival, and for only improves vision but can slow de- and University Hospitals Case Medi- corneal development and repair. Mice cline in cognition and improve quality cal Center and colleagues reported lacking a functional ABCB5 gene lost of life for both people with the disease interim results from an ongoing clini- their populations of limbal stem cells, and their caregivers, according to clini- cal trial to determine the effects of and their corneas healed poorly after cal trial results reported in July at the cataract removal on several measures injury. Alzheimer’s Association International of visual ability, cognitive measures, “ABCB5 allows limbal stem cells to Conference 2014 in Copenhagen, and quality of life in people with survive, protecting them from apop- Denmark. dementia. Study participants are re- tosis [programmed cell death],” said “This study supports the Alzheimer’s cruited from dementia and ophthal- Markus Frank. “The mouse model Association view that people with de- mology clinics at University Hospitals allowed us for the fi rst time to under- mentia retain, and benefi t from, full Case Medical Center and Metro- stand the role of ABCB5 in normal de- health-care treatment,” said Maria Health Medical Center in Cleveland, velopment, and should be very impor- Carrillo, PhD, Alzheimer’s Association and are divided into two groups: tant to the stem cell fi eld in general,” vice president of medical and scientifi c 1) immediate surgery following re- said Natasha Frank. relations. “Too common attitudes such cruitment and; 2) delayed or refused Markus Frank is working with the as, ‘There’s no need for extra care’ or surgery. Vision and cognitive status, biopharmaceutical industry to devel- ‘Why put them through all of that’ are mood and capability to complete dai- op a clinical-grade ABCB5 antibody not justifi ed and are bad medical prac- ly activities are evaluated at baseline that would meet U.S. regulatory ap- tice.” and six months after recruitment, or provals. “A single lab cannot do a “Appropriate thoughtfulness and re- six months after surgery. study like this,” said Natasha Frank, straint are necessary when considering Preliminary analysis of results from also affi liated with the Harvard Stem surgery or other procedures for people 20 surgical and eight non-surgical Cell Institute. “It integrates genetics, with Alzheimer’s or another dementia. participants showed that the surgi- knockout mice, antibodies, transplan- However, we should not assume that cal group had signifi cantly improved tation—a lot of technical expertise medical procedures cannot be pur- visual acuity and quality of life, re- that we were lucky came together in sued or are too risky. As these new re- duced decline in memory and execu- a very nice way.” sults show, improving sensory abilities, tive functioning, and improvements in behavioral measures compared with Expanded Approval for B + L Victus the non-surgical group. Levels of per- Bausch + Lomb has received 510(k) Institute, Bloomington, Minn. “In lower ceived burden for caregivers of peo- clearance from the FDA for the Victus Fem- grade cataracts, we have seen up to a ple in the surgical group also showed tosecond Laser Platform for laser-assisted 50-percent reduction in the phaco energy improvement. lens fragmentation during cataract surgery. required to remove the lens following lens “These preliminary results indi- The fragmentation procedure, which fragmentation with the laser, compared cate that improved vision can have follows a capsulotomy, uses the femtosec- with standard phaco.” a variety of benefi ts for people with ond laser to split the cataractous lens into B + L has been installing Victus platforms dementia and their loved ones, both sections. This is followed by phacoemul- in leading surgery centers globally since visual and non-visual,” said Dr. Lern- sifi cation for cataract removal. he Victus it received CE mark in November 2011 platform offers a number of different lens and the FDA clearances in July 2012. It is er. “Our fi ndings need to be verifi ed fragmentation patterns depending on the now one of the only femtosecond lasers in a larger study, but they suggest cataract grade and user preference. in the U.S. with clearance for the creation the need to aggressively address de- “Academic research has shown that of a corneal fl ap in patients undergoing mentia co-morbidities such as vision- cataracts pre-treated with lens fragmenta- LASIK surgery, anterior capsulotomy during impairing cataracts, while balancing tion can require less phacoemulsifi cation cataract surgery, penetrating arcuate cuts/ safety and medical risks.” energy for removal,” said Y. Ralph Chu, incisions in the cornea and laser-assisted “If the results hold up, it will signifi - MD, founder and director of the Chu Vision lens fragmentation during cataract surgery. cantly affect how we treat cataracts in
4 | Review of Ophthalmology | August 2014
003_rp0814_news.indd 4 7/25/14 11:28 AM individuals with dementia. Other in- terventions to offset sensory loss—in- cluding vision and hearing—may help improve quality of life for people with dementia and their caregivers,” Dr. 4HE 3TEINERT /LIVER Lerner added. According to the Alzheimer’s As- 3MART 0HONE sociation, a person with dementia has the right to any medical treat- ment available. People with the dis- -ARKER ease may require longer courses of 0RODUCT some treatments such as rehabilita- tive therapies compared to people with intact cognition. Therapies that may be of benefi t should not be dis- continued because a person with Al- zheimer’s has failed to make progress as the same rate as someone without the disease.
LS IA AD TAL 2 “If the results hold up, $IS it will signifi cantly affect how we treat cataracts in individuals with
K dementia.” C *A E — Alan J. Lerner, MD ON RPH 0LUG )NTO %A 3MART 0HONE .OT )NCLUDED
Making medical decisions about s %LEGANT $ESIGN 4HAT %ASILY 0LUGS )NTO !NY 3MART treatment remains the right of the per- 0HONE %ARPHONE *ACK son with Alzheimer’s until he or she no longer has the cognitive capacity to s #OMPATIBLE 7ITH !NY 3MART 0HONE h,EVELv !PP &OR understand the decision. At that time, 0ERFECT (ORIZONTAL 2ADIAL -ARKS !T /CLOCK /R !T 4HE $ESIRED &INAL !XIS 0RECISELY 'UIDED "Y 4HE 3MART 0HONE h,EVELv medical decisions are made by the per- !PP MM )$ MM /$ son’s surrogate. The Alzheimer’s Asso- ciation recommends that preferences s %ASY 4O 5SE -ADE )N 4HE 53! 'UARANTEED &OR ,IFE about medical treatment and decisions 2EUSABLE !UTOCLAVABLE !ND !VAILABLE &OR ! $AY should be addressed early in the dis- 3URGICAL %VALUATION 7ITHOUT /BLIGATION ease process through the execution of advance directives. Absent an advance #ALL &OR -ORE )NFORMATION directive, the surrogate decision maker should be guided by the values and any
expressed wishes of the person with 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 s 4EL s &AX Alzheimer’s disease. %MAIL )NFO 2HEIN-EDICALCOM s 7EBSITE WWW2HEIN-EDICALCOM $EVELOPED )N #OORDINATION 7ITH 2OGER & 3TEINERT -$ !LEJANDRO /LIVER -$
1350 Rev.A 3TYLIZED %YE 2HEIN -EDICAL ABBE
003_rp0814_news.indd 5 7/25/14 11:28 AM Editorial
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6 | Review of Ophthalmology | August 2014
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RP0814_Optos.indd 1 7/14/14 3:10 PM August 2014 • Volume XXI No. 8 | revophth.com Cover Focus 26 | The Devil’s in the Distant Details By Walter Bethke, Managing Editor Widefield angiography systems can help catch peripheral ischemic areas that portend worsening disease.
30 | Maximizing the Benefits of Anti-VEGF By Christopher Kent, Senior Editor Experts discuss how the options compare, how they can most effectively be used and what’s in the pipeline. 40 | Increasing Options to Treat Vein Occlusion By Michelle Stephenson, Contributing Editor First-line treatment is typically an anti-VEGF agent. If that is inadequate, steroids can be initiated, either in combination with the anti-VEGF agent or alone.
Feature Article 22 | The Critical Driver of Practice Success: Physician Time By Charles P. Kroll Balance sheets and income statements are yesterday’s tools, says this ophthalmic practice veteran.
Cover images: Michael Singer, MD, Jarrod Wehmeier, and Szilárd Kiss, MD August 2014 | Revophth.com | 9
009_rp0814_toc.indd 9 7/25/14 11:30 AM Departments
44 3 | Review News
13 | Editor’s Page 14 | Technology Update Sealants and Glues in Review A look at the current glues and sealants, tips for their use and new ideas surgeons are trying.
18 | Medicare Q&A A Delay for ICD-10—Now What?
44 | Retinal Insider Multimodal Imaging in Hydroxychloroquine Toxicity 65 Advanced imaging techniques may lead to timely diagnosis and more effective treatment of Plaquenil-related toxicity.
52 | Therapeutic Topics Inside Pseudoexfoliation Syndrome PXS can not only cause cataract and glaucoma but can lead to other surgical complications.
56 | Glaucoma Management The Fluid Wave: Evaluating Canal Surgery Creating an episcleral venous fluid wave during canal surgery can help surgeons predict the likelihood of success. 71 65 | Refractive Surgery The Keys to Multifocal Centration The best way to center these intraocular lenses is up for debate. A review of the arguments.
67 | Advertising Index
68 | Classified Ads
71 | Wills Eye Resident Case Series
10 | Review of Ophthalmology | August 2014
009_rp0814_toc.indd 10 7/25/14 11:31 AM RETINA ONLINE E-NEWSLETTER
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RP0814_Essilor.indd 1 7/14/14 1:41 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 New Tech, New Patients Walter C. Bethke (610) 492-1024 [email protected] Drive Systemic Change Senior Editor Christopher Kent (814) 861-5559 We’re reaching the point where real- graduates to become assistant physi- [email protected] world effects of the 2010’s Affordable cians, with no residency, to practice Care Act, Obamacare, can start to be primary care and prescribe drugs Associate Editor documented. In the months since it in underserved or rural areas of the Kelly Hills (610) 492-1025 began to kick in, the ACA is starting state, with oversight of a licensed [email protected] to produce some real evidence of its physician. impact. • An Annals of Internal Medicine Chief Medical Editor This month the New England Jour- study this month offers an expanded Mark H. Blecher, MD nal of Medicine reported that 10.3 role for nurse practitioners (includ- million Americans gained health cov- ing writing and changing prescrip- Senior Director, Art/Production erage this year, and that the percent- tions) in managing chronic diseases Joe Morris (610) 492-1027 age of uninsured patients fell from 21 as an effective solution to the short- [email protected] percent in September 2013 to 16.3 age of primary-care physicians. A percent in April 2014. What appears new law this month in Kentucky for Art Director not to have materialized yet is the in- the fi rst time allows similar indepen- Jared Araujo undation of the health-care system by dent privileges to nurse practitio- (610) 492-1023 the newly insured that many experts ners, following an established col- [email protected] had foreseen. laboration with a physician. Graphic Designer But the system is still preparing for • Illinois enacted legislation Matt Egger it in a variety of ways, such as expand- aimed at bringing doctors and nurses (610) 492-1029 ed use of technology and expanding out of retirement to help as volun- [email protected] treatment privileges, that represent teers in free medical clinics. The law major changes from traditional care. allows retired health professionals to International coordinator, Japan • The Federation of State Medi- get volunteer licenses at no cost. The Mitz Kaminuma cal boards has drafted a model law law waives fees for the fi rst 500 vol- [email protected] that would ease the way to multiple- unteer licenses and then allows for a Business Offi ces state licensure, enabling treatment fee waiver or reduction. The law also 11 Campus Boulevard, Suite 100 by videoconference and online. applies to dentists, physician assis- Newtown Square, PA 19073 • CMS rulemakers have proposed tants and optometrists. (610) 492-1000 a new telemedicine payment policy As the pressure points and de- Fax: (610) 492-1039 to extend Medicare reimbursement mands of increased medical cover- Subscription inquiries: to wellness and behavioral health age become apparent, the system is United States — (877) 529-1746 visits. changing in ways that not so long ago Outside U.S. — (847) 763-9630 • Medical insurers WellPoint and would not have been imagined. E-mail: Aetna this month began offering [email protected] patients, by next year as many as 8 Website: www.revophth.com to 10 million of them, the ability to have “e-visits” with doctors, virtual Professional Publications Group visits in which the physicians may Jobson Medical Information LLC prescribe drugs, in some states. • Missouri enacted legislation this month that allows medical school
August 2014 | Revophth.com | 13
013_rp0814_edit.indd 13 7/25/14 3:13 PM Technology Update
REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD
Ocular Sealants and Glues in Review A look at the ways ophthalmologists use sealants and glues, and where the newly approved ReSure sealant fi ts in. Walter Bethke, Managing Editor
he use of synthetic glues and bio- that it’s not FDA-approved but it’s a adhere to soft contact lenses. How- Tadhesives has made life simpler standard treatment.” ever, you almost always have to cover for a lot of surgeons, allowing them to Dr. Rapuano says that, when work- the polymerized cyanoacrylate with a secure ocular tissues or protect tissues ing with cyanoacrylate, controlling soft contact lens because the surface from further damage from such pa- moisture in the area of operation is is very rough and you don’t want to thologies as corneal perforations. Re- key. “Cyanoacrylate polymerizes as cause the patient discomfort or have cently, ophthalmologists got another soon as it touches something like wa- the lids poke at it with each blink and option in the sealant realm with the ter, aqueous or saline,” he explains. risk dislodging it.” approval of ReSure Sealant (Ocular “So, if you have a perforation and Dr. Rapuano says it works very well Therapeutix). Here’s a review of the aqueous is coming out, as soon as for sterile perforations, but in infec- current glues and sealants, tips for cyanoacrylate hits the aqueous it will tions it can be more challenging. “In their use, and new uses surgeons have solidify. This is good and bad. In the infected perforations, the tissue tends been trying with them. presence of moisture, it’s good in that to be mushier and the cyanoacry- • Cyanoacrylate. Though not of- it will solidify pretty instantly. But if late doesn’t stick that well,” he says. fi cially approved for use on the eye, you have a dry divot and put down the “Sometimes for sterile perforations it cyanoacrylate has been used by oph- glue, it will remain as a liquid for sev- stays on for many months. In those thalmologists for more than 30 years. eral minutes until the moisture around cases you just have to keep changing “The main indication for cyanoacry- the glue polymerizes it. The danger is the contact lens and following the pa- late is the management of perforated that, if it hasn’t polymerized and you tients. Once the cornea heals, the glue corneal ulcers, both sterile and infec- touch it with something like a Weck- will pop off.” tious,” says Christopher Rapuano, Cel, it will start to polymerize as you’re • Fibrin glue. This is a biologically MD, director of the cornea service touching it, and you’ll get this wick derived tissue sealant (as opposed to at Philadelphia’s Wills Eye Institute. that comes off the glue. So, you have the synthetic cyanoacrylate) that’s in- “It works well for that indication. We to be really patient and not touch any dicated for use in controlling bleeding. also use it for ulcers where the cornea wet glue with either an instrument or Like cyanoacrylate, even though it’s is very thin and might perforate in the a Weck-Cel. So, when I’m 95-percent not specifi cally approved for ophthal- next couple of days or weeks; we just sure it’s polymerized, I’ll fl ood it with mic surgeries, ophthalmologists have fi ll it with glue and let it heal before saline or proparacaine so I’m sure it’s found several uses for it. “Fibrin glues it perforates. Since it’s not FDA-ap- polymerized. Also, you don’t want to such as Evicel, Tisseel and Artiss are proved, I have patients sign a consent put a contact lens on it when it’s in used to secure tissue to the surface form that states what we’re doing and its liquid state because I’ve seen glue of the eye,” says Dr. Rapuano. “Spe-
14 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
014_rp0814_tech update.indd 14 7/25/14 11:35 AM ILEVRO™ Suspension Designed to put potency precisely where you need it 1,2
ONCE-DAILY POST-OP
One drop should be applied once daily beginning 1 day prior to surgery through 14 days post-surgery, with an additional drop administered 30 to 120 minutes prior to surgery 3 Use of ILEVRO™ Suspension more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events3
INDICATIONS AND USAGE ILEVRO™ Suspension is a nonsteroidal, anti-infl ammatory prodrug indicated Patients with complicated ocular surgeries, corneal denervation, corneal for the treatment of pain and infl ammation associated with cataract surgery. epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye Dosage and Administration syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which ™ One drop of ILEVRO Suspension should be applied to the affected eye may become sight threatening. Topical NSAIDs should be used with one-time-daily beginning 1 day prior to cataract surgery, continued on the caution in these patients. day of surgery and through the fi rst 2 weeks of the postoperative period. An additional drop should be administered 30 to 120 minutes prior to surgery. Use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events. IMPORTANT SAFETY INFORMATION • Contact Lens Wear – ILEVRO™ Suspension should not be administered while using contact lenses. Contraindications Adverse Reactions ILEVRO™ Suspension is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula The most frequently reported ocular adverse reactions following cataract or to other NSAIDs. surgery occurring in approximately 5 to 10% of patients were capsular opacity, decreased visual acuity, foreign body sensation, increased Warnings and Precautions intraocular pressure, and sticky sensation. • Increased Bleeding Time – With some nonsteroidal anti-infl ammatory For additional information about ILEVRO™ Suspension, please refer to the drugs including ILEVRO™ Suspension there exists the potential for brief summary of prescribing information on adjacent page. increased bleeding time. Ocularly applied nonsteroidal anti-infl ammatory drugs may cause increased bleeding of ocular tissues (including hyphema) References: 1. Ke T-L, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug in conjunction with ocular surgery. with potential utility in the treatment of trauma-induced ocular infl ammation, II: In vitro bioactivation • Delayed Healing – Topical nonsteroidal anti-infl ammatory drugs (NSAIDs) and permeation of external ocular barriers. Infl ammation. 2000;24(4):371-384. 2. Data on fi le. including ILEVRO™ Suspension may slow or delay healing. Concomitant 3. ILEVRO™ Suspension package insert. use of topical NSAIDs and topical steroids may increase the potential for healing problems. • Corneal Effects – Use of topical NSAIDs may result in keratitis. In some patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use.
©2013 Novartis 2/13 ILV13030JAD
RP0114_Alcon Ilevro.indd 1 12/16/13 11:21 AM Non‐Ocular Adverse Reactions Non‐ocular adverse reactions reported at an incidence of 1 to 4% included headache, hypertension, nausea/vomiting, and sinusitis. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects. Pregnancy Category C: Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of ma- ternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 70 and 630 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 20 and 180 times human plasma exposure for rabbits, respectively. In rats, maternally BRIEF SUMMARY OF PRESCRIBING INFORMATION toxic doses ≥10 mg/kg were associated with dystocia, increased post- implantation loss, reduced fetal weights and growth, and reduced fetal INDICATIONS AND USAGE survival. ILEVRO™ Suspension is indicated for the treatment of pain and inflammation associated with cataract surgery. Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well‐controlled studies in pregnant women. Because DOSAGE AND ADMINISTRATION animal reproduction studies are not always predictive of human response, Recommended Dosing ILEVRO™ Suspension should be used during pregnancy only if the potential One drop of ILEVRO™ Suspension should be applied to the affected eye one- benefit justifies the potential risk to the fetus. time-daily beginning 1 day prior to cataract surgery, continued on the day of surgery and through the first 2 weeks of the postoperative period. An Non‐teratogenic Effects. additional drop should be administered 30 to 120 minutes prior to surgery. Because of the known effects of prostaglandin biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the Use with Other Topical Ophthalmic Medications use of ILEVRO™ Suspension during late pregnancy should be avoided. ILEVRO™ Suspension may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibi- Nursing Mothers tors, alpha-agonists, cycloplegics, and mydriatics. If more than one topical ILEVRO™ Suspension is excreted in the milk of lactating rats. It is not ophthalmic medication is being used, the medicines must be administered known whether this drug is excreted in human milk. Because many drugs at least 5 minutes apart. are excreted in human milk, caution should be exercised when ILEVRO™ Suspension is administered to a nursing woman. CONTRAINDICATIONS ILEVRO™ Suspension is contraindicated in patients with previously demon- Pediatric Use strated hypersensitivity to any of the ingredients in the formula or to other The safety and effectiveness of ILEVRO™ Suspension in pediatric patients NSAIDs. below the age of 10 years have not been established. WARNINGS AND PRECAUTIONS Geriatric Use Increased Bleeding Time No overall differences in safety and effectiveness have been observed With some nonsteroidal anti-inflammatory drugs including ILEVRO™ Suspen- between elderly and younger patients. sion, there exists the potential for increased bleeding time due to interfer- NONCLINICAL TOXICOLOGY ence with thrombocyte aggregation. There have been reports that ocularly Carcinogenesis, Mutagenesis, Impairment of Fertility applied nonsteroidal anti-inflammatory drugs may cause increased bleeding Nepafenac has not been evaluated in long‐term carcinogenicity studies. of ocular tissues (including hyphemas) in conjunction with ocular surgery. It Increased chromosomal aberrations were observed in Chinese hamster is recommended that ILEVRO™ Suspension be used with caution in patients ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not with known bleeding tendencies or who are receiving other medications mutagenic in the Ames assay or in the mouse lymphoma forward mutation which may prolong bleeding time. assay. Oral doses up to 5,000 mg/kg did not result in an increase in the for- Delayed Healing mation of micronucleated polychromatic erythrocytes in vivo in the mouse Topical nonsteroidal anti-inflammatory drugs (NSAIDs) including ILEVRO™ micronucleus assay in the bone marrow of mice. Nepafenac did not impair Suspension, may slow or delay healing. Topical corticosteroids are also fertility when administered orally to male and female rats at 3 mg/kg. known to slow or delay healing. Concomitant use of topical NSAIDs and PATIENT COUNSELING INFORMATION topical steroids may increase the potential for healing problems. Slow or Delayed Healing Corneal Effects Patients should be informed of the possibility that slow or delayed healing Use of topical NSAIDs may result in keratitis. In some susceptible patients, may occur while using nonsteroidal anti‐inflammatory drugs (NSAIDs). continued use of topical NSAIDs may result in epithelial breakdown, corneal Avoiding Contamination of the Product thinning, corneal erosion, corneal ulceration or corneal perforation. These Patients should be instructed to avoid allowing the tip of the dispensing events may be sight threatening. Patients with evidence of corneal epithelial container to contact the eye or surrounding structures because this could breakdown should immediately discontinue use of topical NSAIDs including cause the tip to become contaminated by common bacteria known to cause ILEVRO™ Suspension and should be closely monitored for corneal health. ocular infections. Serious damage to the eye and subsequent loss of vision Postmarketing experience with topical NSAIDs suggests that patients may result from using contaminated solutions. with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), Use of the same bottle for both eyes is not recommended with topical eye rheumatoid arthritis, or repeat ocular surgeries within a short period of time drops that are used in association with surgery. may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these Contact Lens Wear patients. ILEVRO™ Suspension should not be administered while wearing contact lenses. Postmarketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post surgery may Intercurrent Ocular Conditions increase patient risk and severity of corneal adverse events. Patients should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should Contact Lens Wear immediately seek their physician’s advice concerning the continued use of ILEVRO™ Suspension should not be administered while using contact lenses. the multi‐dose container. ADVERSE REACTIONS Concomitant Topical Ocular Therapy Because clinical studies are conducted under widely varying conditions, If more than one topical ophthalmic medication is being used, the medi- adverse reaction rates observed in the clinical studies of a drug cannot be cines must be administered at least 5 minutes apart. directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. Shake Well Before Use Patients should be instructed to shake well before each use. U.S. Patent Ocular Adverse Reactions Nos. 5,475,034; 6,403,609; and 7,169,767. The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sen- sation, increased intraocular pressure, and sticky sensation. These events occurred in approximately 5 to 10% of patients. Other ocular adverse reactions occurring at an incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment. Some of these events may be the consequence of the cataract surgical ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA procedure. © 2013 Novartis 2/13 ILV13030JAD
RP0114_Alcon Ilevro PI.indd 1 12/16/13 11:24 AM Technology
REVIEW Update
cifi cally, this takes the form of securing portant to note because when most conjunctival tissue during pterygium people work with it, they’re a little slow surgery with conjunctival auto-grafts, their fi rst time. The sealant comes in a and securing amniotic membrane tis- tray with a blue solution and a more sue in pterygium surgery or another particulate white component that you surgery where amniotic membrane mix together. There will be a tempta- Christopher Rapuano, MD Christopher Rapuano, is used to cover some abnormality or tion to get all the white dissolved be- conjunctival defect.” fore you apply the sealant. The truth An interesting evolving technique is, however, if you take all that time to using fibrin glue was developed by Cyanoacrylate placed over a corneal get it dissolved, your window for work- Chennai, India, surgeon Amar perforation can give the tissue time to heal, ing with it has closed. Be quick. Agarwal. In complicated cases in surgeons say. “Another thing I’d recommend do- which an intraocular lens can’t be fi x- ing is mix it under the operating mi- ated normally, Dr. Agarwal has built is used to apply the mixture to the eye. croscope right next to the incision you upon ideas fi rst proposed by German Fairfield, Conn., surgeon Robert want to seal,” Dr. Noecker continues. surgeon Gábor Scharioth, MD, PhD. Noecker has used ReSure for both “This way, when it’s ready, the distance In Dr. Agarwal’s glued-haptic tech- on- and off-label uses, and has got- you have to move it is only a centi- nique, the surgeon first creates two ten to know its idiosyncrasies. “This meter. Also, I’d tell surgeons to make partial-thickness, limbal-based scleral is a sealant, and is a derivative of the sure the eye is dry. If there’s an active flaps 180 degrees apart. Then, the product DuraSeal, which is used by leak or the surface is too wet, ReSure surgeon performs an anterior vitrec- neuro-surgeons to seal the dura dur- will tend to stick to itself rather than tomy. With the help of an assistant, ing cerebrospinal leaks,” he says. “The to the tissue you want to seal. The the surgeon externalizes the haptics key difference between a sealant and a other thing is that it’s best to get the through the sclerotomies, then tucks glue is that the former is meant to go application surface of the eye oriented the ends of the haptics into a Scharioth into a crevice and seal it, and it doesn’t in a horizontal plane, which may mean intralamellar tunnel he creates with a necessarily hold tissue together. Once turning the patient’s head a bit just so 26-ga. needle at the location of the ex- the sealant is set in place, it takes on the sealant doesn’t tend to fl ow away ternalization. The surgeon then closes this rubber consistency and is very from where you’re applying it. Since the scleral fl aps over the externalized durable. It will stick around for at least this will most likely be a temporal clear haptics with fi brin glue.1 a few days, and its advantage is it mini- corneal incision you’re sealing, you’ll “Fibrin glue solidifi es at a different mizes the use of sutures. want the head oriented a little hori- rate than cyanoacrylate,” explains Dr. “I’ve used it for clear corneal zontally, or the patient looking a little Rapuano, “so you have to get used wounds, and for instances in which toward his nose. It only takes a few to knowing how quickly you have to I’ve removed a glaucoma tube shunt seconds to set it in place, but you don’t move before it’s attaching things. Fi- or there’s a scleral defect and I wanted want it to run away from the incision.” brin glue will begin to secure things to seal the area,” Dr. Noecker adds. Since ReSure costs somewhat more after about 30 seconds to a minute. “If you want to create a situation on than a suture, Dr. Noecker says it’s Though it takes 10 minutes before it’s the sclera where there’s no fl ow or you not something a surgeon will use in totally secure, it starts to polymerize want to seal up a hole you no longer everyone. “It’s more expensive than a pretty quickly.” need, it can be very useful. However, if suture, so you have to take that into ac- • ReSure sealant. ReSure is the situation has a vigorous fl ow rate, it count,” he says. “As a skilled surgeon, made of a polyethylene glycol hydro- probably won’t work that well. But, if will I use it on every case? No. But I gel, which is a different material from you can get the area temporarily dry, it will use it on premium cases such as cyanoacrylate or fi brin glue, and is ap- will seal scleral defects.” Dr. Noecker femtosecond cataract. Fortunately, proved for the sealing of clear corneal says he’ll often use it to seal wounds the risk of problems is low for cataract incisions used in cataract removal/ in cases where he’s corrected astigma- surgery, but there are cases in which I IOL implantation. It actually comes as tism with a toric lens or incisions. want to drive that chance of a problem two separate materials, a polyethylene Dr. Noecker says working with down even lower by using the sealant glycol solution and a trilysine amine ReSure has taught him some things. in a particular patient.” solution, which, when mixed together “The key is to be prepared to act 1. Agarwal A, Jacob S, Kumar DA, Narasimhan S. Handshake technique for glued intrascleral haptic fi xation of a posterior by the user, form the sealant. An ap- quickly,” he says. “You have about a chamber intraocular lens. J Cataract Refract Surg. 2013;39:3:317- plicator that comes in the ReSure kit fi ve-second working time. This is im- 22.
August 2014 | Revophth.com | 17
014_rp0814_tech update.indd 17 7/25/14 11:35 AM 018_rp0814_mqa.indd 18 more diagnosiscodesandincreases spaceforreportingtains additional as ofApril1,2014.Thenewform con- on January1,2014,withrequireduse pare despitethedelay. stay thecourseandcontinuetopre- Association encouragedphysiciansto and theAmericanHealthInformation ican AcademyofProceduralCoders rently affectingphysicians.TheAmer- the numerousregulatoryburdenscur- ciation applaudedthedecision, citing reviews. TheAmericanMedicalAsso- 2015. Thedelaywasmetwithmixed not adoptICD-10priortoOctober1, of HealthandHumanServicesmay acted, whichsaidthattheSecretary 2014 (Pub.L.No.113-93)wasen- A A “space” for ICD-10 codes? form that provides increased & Medicaid 1500 Services Medicare for Centers new 10 implementation? Q questions fordoctorsandhealth-careorganizations. A one-yeardelayinICD-10implementationbringsupmany What? Now A Delay for ICD-10– 18 Q REVIEW | ReviewofOphthalmology Donna McCune, CCS-P, COE, CPMA Medicare Q&A 1500 formreplacedversion08/05 No; version02/12oftheCMS ing AccesstoMedicareActof On April1,2014,theProtect- in implementing the adelay also Was there ICD- in delay the announce When did Congress | August2014 following: affected. TheCMSpostingstates the 10; itnotesthatICD-9will alsobe on acodeset“partialfreeze”forICD- CMS recentlypublishedinformation posted ontheCMSwebsite. ICD-9 andICD-10fi les arealso html. Inaddition,the2015 ICD-10-CM-and-GEMs. Coding/ICD10/2015- cms.gov/Medicare/ on theCMSwebsiteat fi A A its website? Q found atnucc.org/. tion onthenewformcanbe Box 17.Additionalinforma- and supervisingphysiciansin “qualifiers” forordering,referring for ICD-10.Thenewformalsoadds seven digits,whichwillberequired the spacefordiagnosiscodesofupto Q les are currently available les arecurrentlyavailable
tober 1 of eachyear.tober 1 However, ICD updatesareeffectiveOc- Equivalence Mapping Yes. 2015General The to be created? Will new codes continue update ICD-10 fi to continue CMS Will les on This articlehasnocommercial sponsorship. ICD-10-CM codesfor2015. will benonew, deletedorrevised the ICD-9-CMandICD-10code be onlylimitedcodeupdatestoboth testing? Q OnOctober1,2014therewill • additional front-end Will CMS conduct sets. Thisistocapture ing, CMS stated that there ing, CMSstatedthatthere new technologiesand diseases asrequiredby section 503(a)ofPub. covered entities. reporting toHIPAA- L. 108-173. longer be used for longer beusedfor 2015, againthere 2016, oneyearafter 9-CM, asitwillno In aseparatepost- OnOctober1, • will beupdatesonly OnOctober1, • the new scheduled the newscheduled updates toICD- There willbeno as notedabove. implementation will begin. of ICD-10,reg- ular updates to ICD-10 to ICD-10 7/25/14 1:15 PM Yes. CMS had planned a test- er-level understanding of ophthalmol- in both eyes, is coded with one code A ing week in July 2014. This test- ogy for proper code selection. in ICD-10, H40.11x2. ing was cancelled due to the delayed Technicians and scribes can im- Physicians currently not docu- implementation of ICD-10. CMS ex- prove their documentation, especially menting the stage of glaucoma pects to conduct end-to-end testing with history taking. A fair amount of should begin to stage the glaucoma in 2015; watch the CMS website and information required for proper ICD- now so that it is not a burden when your local Medicare contractor web- 10 code selection will come from the ICD-10 coding begins. sites for further details. patient’s history. What other documentation Was the March 2014 end- Is there any value in Q changes should we Q to-end testing successful? Q practicing our ability to consider making? select an ICD-10 code? It was. CMS reports that testers Because ICD-10 codes are more A submitted more than 127,000 Yes. By beginning to dual-code A specific than ICD-9, there are claims with ICD-10 codes to the A some encounters with ICD-10 many changes you can begin to imple- Medicare fee-for-service claims sys- codes, you will reveal vulnerabilities ment. tem and received electronic acknowl- in your chart documentation that 1. Are your assessments as spe- edgement that their claims were ac- make code selection diffi cult or im- cifi c as possible? For example, if you cepted. Nationally, CMS showed an possible. In addition, the more famil- note a corneal ulcer in your impres- 89-percent acceptance rate for ICD- iar you and your staff become with the sion, are you indicating whether it is 10 codes, which they considered a manual, the less intimidating it will be a central corneal ulcer, or a marginal successful result. CMS also noted in October 2015. ulcer or a perforated corneal ulcer? that some claims were purposely sub- 2. Are your assessments specifi c to mitted with errors to test that errors Are some ophthalmic which eye or eyelid? For example, would be identifi ed. Q diseases coded differently do you note in the impression if the in ICD-10 than ICD-9, and will patient has a chalazion on the left Is it a worthwhile exercise this necessitate a change in my lower or left upper lid as opposed to Q to familiarize myself current documentation? just noting chalazion? Is the patient’s with the existing ICD-10-CM nuclear sclerotic cataract in her right Manual? Yes, there are several. Glaucoma eye, left eye or both eyes? A is a good example of a disease 3. For patients with a systemic dis- Defi nitely. There are many new that is coded differently. Many physi- ease and an ocular manifestation, are A concepts presented in ICD-10. cians are lax with documenting the you indicating both the disease and The ICD-10-CM Manual contains stage of glaucoma in a patient’s medi- the manifestation in the impression? four more chapters than ICD-9 and cal record. Currently, few payers, if Improved documentation in the the number of code choices increases any, will deny a claim that does not impression will facilitate more ef- from 14,000 to 69,000. The guide- contain the ICD-9 stage code. With ficient selection of ICD-10 codes. lines published in the beginning of ICD-10, your ability to select a code It is not too soon to begin to make the manual are extremely instructive for glaucoma will require that the dis- these changes in your current medi- and provide a review of ICD-9 guide- ease stage be documented. cal records. lines as well as introduce some subtle For example, when coding appro- changes to coding with ICD-10. priately for glaucoma with ICD-9 Should we wait on ICD-10 codes, the type of glaucoma is one Q and begin to prepare for Should I continue to train ICD-9 code and the stage of glau- ICD-11? Q my staff during this delay? coma is a second ICD-9 code. A patient with primary open-angle No. ICD-11 only exists in draft This is a great opportunity to glaucoma, moderate stage, is coded A form and is not expected until A better prepare them for ICD- as 365.11 for the POAG and 365.72 2020 or 2025. 10. Non-clinical staff will benefi t with to describe the moderate stage. In additional training on medical termi- ICD-10, the stage is added to the Ms. McCune is vice pres ident of the nology and anatomy of the eye. The ICD-10 code for POAG as a sev- Cor coran Con sult ing Group. Con tact specifi city of ICD-10 requires a high- enth digit. POAG, moderate stage her at [email protected].
August 2014 | Revophth.com | 19
018_rp0814_mqa.indd 19 7/25/14 1:15 PM Testing performed exclusively by: No test is perfect. The RetnaGene™ AMD and RetnaGene™ LR laboratory-developed tests are highly accurate, genetic tests. However, erroneous results may occur in rare cases.
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RP0814_Nicox.indd 3 7/14/14 3:22 PM Practice Management REVIEW Feature The Critical Driver of Success: Physician Time Charles P. Kroll, Chicago
Balance sheets op Quiz: What were you doing cial reports fueled by the PC revo- during the financial presenta- lution: key performance indicators; and income Ption at your last board meeting? benchmarking; retrospective RVU A. Texting your spouse analysis to make Henry Ford proud; statements are B. Checking e-mail and the most recent iteration, EHR C. Stepping out to make a call dashboards designed by software en- yesterday’s D. All of the above gineers. Although providing number- tools, says this Traditional fi nancial reports of a bal- centric feedback, this data tsunami ance sheet and income statement were drowns out the essence of your prac- ophthalmic conceived 150 years ago during the tice’s financial success and most im- Industrial Revolution to portant asset: physician practice veteran. facilitate railroad fi- time. nancing. Although In this article, their intent is to I’ll lay out three communicate steps that wed the financial the concept of health of a physician time business, the with financial reports are management, spoken in the promoting language of ac- physician un- counting, a lan- derstanding and guage foreign to ownership of fi nan- many physicians. cial performance. Historical by defi nition, the statements are often Step 1: Doctor Days presented weeks, if not months, after the fact. Build the foundation of your prac- Much like driving while looking in tice’s fi nancial management, budgets the rearview mirror, it’s no wonder no and projections on physician and op- one is paying attention. tometrist time, or “doctor days,” rather than relying on accounting department To address this comprehension void edicts or RVU-based budgets. Simply and time lag, many medical practices put, calendar out doctor days (or half rely on an assortment of ad hoc fi nan- days) by type of service: clinic; ASC;
22 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
022_rp0814_f1.indd 22 7/25/14 1:16 PM 99/100 doctors prefer fundus imaging with a built-in inverter.
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RP0814_Haag Eibos.indd 1 7/16/14 3:11 PM Feature Practice Management REVIEW
and hospital. This process links, in an tive, 1 percent of 200 doctor days per port templates can be updated and easy to understand manner, fi nancial year is two days, or about 1.3 hours per maintained by current staff utilizing performance with the investment of month (20 minutes per week, 4 min- Word, Excel and existing practice physician time, while de-emphasizing utes per day) assuming 100 percent management software, bypassing cum- esoteric accounting reports. government payer mix. bersome Sharepoint altogether. Fi- Applying estimated gross charges nally, the best kept secret in the EHR and net revenue by doctor day by type Step 2: Real-Time Reports industry: pre-loaded and license-free of service closes the loop, producing Internet browser reporting tools are accurate and predictive budgets in the While the argument has been made available for EHRs running on Micro- aggregate, and by individual physician that profi t margins on many surgical soft’s SQL server platform. and OD type of service and location. procedures render real-time fi nancial Although these simple steps won’t One payoff is the ability to evaluate the reporting unnecessary for medical render traditional fi nancial reports ob- ratio of doctor time to various fi nancial practices, common sense and the cur- solete, taking mind-numbing numbers, and patient-care metrics. For example, rent health-care reimbursement en- meaningless minutiae and disjointed 19 percent of total doctor clinic time is vironment suggest otherwise. Lack of data off the table removes the psycho- invested at a particular location provid- timely, actionable information masks logical barriers to fi nancial comprehen- ing 11 percent of patient visits. and enables a multitude of sins: payer sion, encouraging healthy physician Implementation of the doctor day and contracting issues; clinic workfl ow and management dialogue regarding model transforms your sclerotic an- and appointment scheduling; front both short-term clinic operation objec- nual budget—typically approved and desk proficiency and business office tives and long-term strategic fi nancial forgotten hours before the annual effectiveness; and yes, unscheduled planning. holiday party—into a living document physician time off. You can now relax guilt-free and text capable of capturing the financial Focus on these three words and fol- your spouse, check e-mail and make impact of changes in budgeted doc- low their corresponding rules: simple; calls during the HR director’s presen- tor days, e.g., new physician or OD time; and visual. tation! hire. Married to actual year-to-date • Rule #1. Simple. Keep reports Stop driving by the rearview mirror numbers, “fl ex” your budget based on simple and relevant: production; cash using Industrial Age fi nancial manage- anticipated doctor days, and avoid the collections; a few key patient-care ba- ment and reporting tools, and embrace 8th Deadly Sin: negative physician rometers, e.g., visits, cataracts and re- the Information Age. You already know compensation and taxable income fractive where you’ve been. Keep your eyes on news after year-end. • Rule #2. Time. Present data in the road, your hands upon the wheel: Divorced from procedure volume terms of time, e.g., cash collections are Know where you are today (Steps 2 and RVU-driven mock-ups, the doctor 1.2 days behind month-to-date budget and 3) and where you’re going (Step day model is an effective tool to evalu- • Rule #3. Visual. Present infor- 1). ate and negotiate value-based contract mation visually with intuitive charts, Focus on your most important as- proposals from payers. Historical fee- rather than raw numbers or text expla- set—physician time—and strength- for-service data, converted to doctor nations. en and grow your practice’s fi nancial days, can be developed to determine health by responding to changing cir- an acceptable return on the invest- Step 3: On-Line Access cumstances in the here and now, built ment of physician time for anticipated on the foundation and communicated covered lives and patient encounters, Establish a secure one page In- in the language of time. the cornerstone of any successful risk- tranet for one-click access to real-time sharing contract negotiations. Level and historical fi nancial reports from a Mr. Kroll has 20 years of health- the playing fi eld against health plan ac- smartphone, tablet or laptop. Notifi ca- care experience, including 11 years tuaries, and negotiate with confi dence. tion of time-sensitive updates can be with Minnesota Eye Consultants, Finally, aside from patient-care and pushed out via e-mail or private Twitter P.A., providing financial manage- outcomes considerations, make in- feed. Granted, while most physicians ment and consulting CFO services to formed decisions to opt in or out of prefer to “just practice medicine,” this independent and hospital-affi liated government incentive programs based step democratizes the fi nancial report- specialty and primary-care medi- on incremental doctor days required ing process and fosters a culture of cal clinics. Contact him at cpkroll@ to offset penalties in the event you opt transparency and accountability. gmail.com or on Twitter at https:// out. For example, from a time perspec- Both the Intranet and real-time re- twitter.com/CharlesPKroll.
24 | Review of Ophthalmology | August 2014
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RP0414_Santen.indd 1 3/21/14 9:40 AM Retina REVIEW Cover Focus The Devil’s in The Distant Details Walter Bethke, Managing Editor
Wide-fi eld here’s an old saying that goes, look in certain directions as the test “What gets measured, gets proceeds, the system can add to the angiography Tdone.” In the world of reti- fi eld of view. “Its wide-fi eld setting is nal care, it could be paraphrased as, 102 degrees,” says Jarrod Wehmeier, systems can help “What gets seen, gets treated,” since ophthalmic photographer at the Reti- a retinal specialist can’t address issues na Institute in St. Louis. “However, I catch peripheral he can’t see, and might even catego- think you can add 20 to 30 degrees in ischemic areas rize a patient’s disease differently if he each direction by having the patient saw retinal features that didn’t appear look around in different directions.” that portend on conventional angiography. This The Retina Institute’s Gaurav Shah, is especially true in cases of diabetic MD, who consults for Heidelberg, worsening retinopathy and retinal vein occlu- says one advantage to him was that the sion, where peripheral retinal features wide-fi eld viewing was just an add-on disease. might have an impact on the patient’s for an instrument he already owned, condition. Here, experts explain why rather than a new capital equipment they’ve found value in examining the purchase in the six-figure realm. “It far periphery with very wide-fi eld reti- didn’t make sense to spend the extra nal systems, and offer tips for getting money vs. just getting an add-on lens the best images. that costs about $20,000,” he says. Some users say that just hitting The Systems the “acquire” button on the HRA2 or Spectralis with the wide-screen For angiography of the typical di- module might not produce the best abetic retinopathy or vein occlusion resolution images in some cases, and patient, there are three main systems that’s why the machine offers an image that clinicians routinely use. averaging feature called automatic real • Heidelberg wide-fi eld viewing time image stabilization, or ART. “I’d module. This is an add-on, non-con- suggest using the ART button with tact lens for the Heidelberg Retinal single frames to greatly increase your Angiograph-2 or the Spectralis OCT resolution,” says Mr. Wehmeier. “This that allows the user to select an angle locks onto the retina and takes 10 of view of 51 degrees, 68 degrees or frames and overlaps them to increase 102 degrees when doing fl uorescein the resolution of the image.” angiography. Users say that, with some • Optos 200Tx. The non-contact “steering” of the patient to get him to Optomap 200Tx allows clinicians to
26 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
026_rp0814_f2.indd 26 7/25/14 1:17 PM acquire angiographic data on the retina found that patients’ disease severity with a 200-degree fi eld of view. As with may be different depending on where the Heidelberg wide-angle viewing the lesions are located,1 and he found
system, the user can steer the Opto- MD Kiss, Szilárd that a third of the lesions were outside map patient, yielding an even larger the standard viewing fi elds. If you’ve area for examination. “Sometimes got more lesions in the periphery, a people forget you can steer the patient patient may progress faster. Knowing with the Optos,” says Szilárd Kiss, MD, details such as these will infl uence how director of clinical research and associ- In this patient, the posterior pole looked often you follow-up with a patient and ate professor of ophthalmology at Weill essentially normal, but an Optos ultra wide- perhaps even when he’s going to need Cornell Medical College in New York fi eld view showed extensive disease. treatment based on the condition of City. “If the photographer sees some- his peripheral retina.” thing he wants to focus on, he can still patient fl ow of his practice better. “We Dr. Shah says that he also appreci- steer the patient’s gaze.” fi nd it diffi cult to use a contact system ates the extra information he acquires, When a user views Optomap im- with the volume of patients we see,” even if the exact relevance to treatment ages, Dr. Kiss says there are some as- he explains. “Even though it may give is still a matter of debate. “It gives us pects he’ll need to get used to. “There better images, sometimes you have to the views we need of the periphery to are some trade-offs that are inherent in make sure you can do a test effi ciently.” look for areas of ischemia, especially in all wide-fi eld imaging systems as well It’s worth noting that though the cases of retinal vascular disease such as the ellipsoid mirror used by Optos,” contact RetCam system does wide- as vein occlusions and diabetic reti- he says. “When one views a spherical field imaging, it’s almost exclusively nopathy,” he says. “There are still con- surface on a fl at monitor, the periphery used for diagnosing and managing reti- fl icting reports regarding whether or will not have the same representation nopathy of prematurity. not treating ischemic retina makes a as the posterior pole. This is akin to difference in persistent macular ede- the same issues faced by mapmakers Putting the Systems to Use ma. However, I think that in patients in which their maps make Greenland who have ischemia the VEGF load is appear several times the size of the Users of wide-fi eld systems say that, greater than in non-ischemic eyes, so U.S., when in fact, it is about one third when you use them properly, they may detecting it may give us an opportunity the size.” Dr. Kiss points out that there provide information that you might to supplement or augment our other are software fi xes that are now being have otherwise missed. Here are the therapies such as anti-VEGF and ste- worked on to correct for this periph- potential benefi ts of wide-fi eld imag- roid injections or laser. It also gives eral non-linearity. ing, and tips on how to achieve them. you a way to identify people who will “Some have talked about the Op- • Extra information. Before wide- probably keep experiencing disease tos losing some resolution in the pos- fi eld imaging systems, clinicians relied recurrences. In addition, we know that terior pole,” Dr. Kiss adds. “But this on the seven standard fields, which ischemic eyes have a worse prognosis. is unfounded. I always challenge my involved the use of traditional lenses Ultimately, I think having information colleagues to show me something on aimed at different areas of the retina on ischemic areas in the periphery al- conventional imaging in the posterior to form a composite image that pro- lows a physician to tailor his therapy to pole that you couldn’t see on wide-fi eld vided approximately a 75-degree fi eld the patient or modify existing therapy, imaging. You can see everything in the of view. “The seven standard fields as well as providing a way to monitor posterior pole that you need to see used to be the gold standard in view- the patient during follow-up.” with the Optos ultra wide-fi eld image.” ing conditions such as diabetes,” re- The nature of angiography itself may • Staurenghi lens. This is a contact- marks Dr. Kiss, who adds that retina make wide-fi eld imaging’s information lens based viewing system that attaches specialists have always been interested more useful than just creating a mon- to a scanning laser ophthalmoscope in seeing more of the retina, but were tage of single images from a traditional such as the HRA2. It can provide a just limited. “Now, examining the pe- lens. “If you’re using a traditional-sized 150-degree viewing field, with the riphery as Lloyd Paul Aiello, MD, and lens to shoot fi ve or six photos around drawback that it needs to make direct our group have done in some of our the globe to get the peripheral retina, contact with the patient’s cornea in or- studies has made us realize that the you may be off by one or two minutes der to make this view possible. Though classifi cation of a patient’s disease can compared to the dye circulating in the it yields good images, Dr. Shah says actually change based on peripheral eye,” notes Dr. Kiss. “By the time the a non-contact system often suits the features,” Dr. Kiss says. “Dr. Aiello patient resets and then you reset, you
August 2014 | Revophth.com | 27
026_rp0814_f2.indd 27 7/25/14 1:17 PM Cover Retina
REVIEW Focus
may not get the pathology. Also, with a uses the entire 5-cc injection. “I usually montage it helps to know what you’re try to use 5 cc in fi ve seconds,” he ex- looking for. If you’ve got a patient with plains. “You’re going to need as much
a pathology in the superotemporal Jarrod Wehmeier dye as possible in as short a time as quadrant of the far periphery, it’s easy possible in order to get a high-contrast to tell the photographer to focus on image. If you only inject 3 cc, you’ll that. But if you have a patient in whom notice there’s not enough dye to fi ll the you’re not sure where the pathology is, images and you’ll lose quality.” the wide-fi eld imaging will get it all.” In addition to using the ART feature Dr. Kiss says there’s preliminary data described earlier to average the Hei- from single-site studies that laser treat- delberg’s images, Mr. Wehmeier also ment based on peripheral retinal data says adjusting the device’s gain, or the might reduce the treatment burden overall brightness of the image, can in the future. “First, a caveat: This all help. “I try to adjust the gain so it’s up remains to be proven in larger, mul- as high as possible fi rst,” he says. “This ticenter trials, but there’s some indi- will make for a grainy image at fi rst but, cation that, in patients who have an once the dye hits the eye—when you incomplete response to anti-VEGF start to see choroidal fl ush—I turn the therapy—as well as the so-called gain all the way down and let the dye ‘VEGF-addicts’—you could perhaps fi ll in and do its work.” laser the peripheral ischemia and re- Dr. Kiss says that, with the Opto- duce the amount of anti-VEGF treat- map, there’s a learning curve in deal- ment you need. ing with the patient’s lids and lashes. “In vein occlusion,” Dr. Kiss con- Experts say that using a montage “The patient is pressed up against the tinues, “if you look at the posterior composed of several individual images device, so you have to make sure the pole, you’ll see a small vein occlusion. (top) may not be as effective as one wide- lids are out of the way,” he says. “You “But when you look in the periphery fi eld image (bottom, same patient). have to make sure he’s in the best po- with ultra wide-fi eld imaging, you get sition to get an optimal image in the a sense of the extent of the disease Heidelberg’s wide-angle viewing sys- superior and inferior quadrants. Some and the disease burden. That might tem, it can help to make some adjust- colleagues use a Q-Tip to get the lids be why a patient needs a lot of anti- ments before the angiography study out of the way, but we’ve found the VEGF injections or multiple Ozur- begins. “When you bring the patient photographer’s finger works just as dex treatments. So, instead of lasering into the chinrest, since the size of the well. Occasionally, the patient can hold the macula, one could imagine an ap- lens is quite large you have to have the up his upper lid to get rid of that lash proach where you laser the periph- patient turn his head to a 45-degree artifact.” ery and maybe decrease the ischemic angle,” he explains. “This isn’t a tilt Dr. Kiss says getting peripheral drive that way. The same thing might of the head, just a turn. This is so the retinal details is a relatively recent also be true in diabetes. We and oth- lens doesn’t hit his nose and he can development but not a new concept. ers have published that the areas of look straight ahead. It gives you a nice “The idea that the peripheral retina non-perfusion in the periphery are cor- viewing area. Also, if possible, have is important isn’t something new,” Dr. related with the presence or absence of another person hold the lids open to Kiss says. “Looking back at the origi- diabetic macular edema.2 Though that make the imaging easier for you and nal discussions of diabetic retinopathy doesn’t imply causality, once again one avoid lash artifacts. I’ve been able to do by the giants in retina, they acknowl- cannot only imagine using this to quan- it usually with a Q-Tip and have gotten edged the importance of the periph- tify the disease burden but perhaps great images but, if you really want to ery, but couldn’t image it efficiently. also treating those peripheral areas to document something in the periphery, Now we can.” help preserve the posterior pole and it can be helpful to have someone else 1. Silva PS1, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, maintain a patient’s vision rather than on-hand. This is especially true for the Aiello LP. Peripheral lesions identifi ed by mydriatic ultrawide fi eld lasering the posterior pole and possibly fi rst couple of times you’re doing it just imaging: Distribution and potential impact on diabetic retinopathy severity. Ophthalmology 2013;120:12:2587-95. compromising vision.” to get used to the machine’s opera- 2. Wessel MM1, Nair N, Aaker GD, Ehrlich JR, D’Amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultra-widefi eld • Tips and techniques.Mr. Weh- tion.” Mr. Wehmeier says he injects the fl uorescein angiography, is associated with diabetic macular meier says that, when working with the fl uorescein as quickly as possible, and oedema. Br J Ophthalmol 2012;96:5.
28 | Review of Ophthalmology | August 2014
026_rp0814_f2.indd 28 7/25/14 1:18 PM RP0814_Diopsys.indd 1 7/14/14 1:35 PM Retina REVIEW Cover Focus Maximizing the Benefi ts of Anti-VEGF Christopher Kent, Senior Editor
Experts dis cuss he advent of anti-VEGF drugs Medicine. “A number of studies have has caused a revolution in the compared the drugs head-to-head. It how the options Ttreatment of diseases such as appears that Lucentis does a little bit wet age-related macular degeneration better job of getting the macula dry compare, how and diabetic retinopathy. Today, the and keeping it that way. In the CATT field continues to move forward as study, for example, more eyes had they can most researchers and manufacturers work fl uid with Avastin than with Lucentis, effectively be used to improve the outcomes produced by and patients who were treated only drugs such as Avastin (bevacizumab), when they had fl uid required fewer and what’s in the Lucentis (ranibizumab) and Eylea (af- injections with Lucentis than Avastin.” libercept), and try to fi nd ways to re- Dr. Freund notes that the differ- pipeline. duce the number of intraocular injec- ences between Avastin and Lucentis tions required for effective treatment. are more obvious when addressing Here, three experts in the fi eld dis- conditions other than macular degen- cuss the current developments in this eration. “In wet macular degeneration area, and offer their thoughts about there’s not a whole lot of VEGF being what may lie ahead. expressed that needs to be inhibited,” he points out. “In contrast, in acute Avastin vs. Lucentis central retinal vein occlusion there are extremely high levels of VEGF The difference in price between expression, so we tend to see more Avastin and Lucentis has been a piv- of the differences between the drugs otal factor in the popularity of Avastin, when treating this condition. That’s but differences in effectiveness and also true in some patients with diabet- safety are still being debated. “Both ic retinopathy. In my experience, the Avastin and Lucentis are potent, commercial drugs work better than highly effective molecules—at least Avastin in these situations, so I prefer for wet macular degeneration—and to use them.” they’ve been shown to produce simi- Peter K. Kaiser, MD, the Chaney lar visual outcomes,” says K. Bailey Family Endowed Chair in Ophthal- Freund, MD, a retina specialist who mology Research at the Cleveland practices at Vitreous-Retina-Macu- Clinic Lerner College of Medicine, la Consultants of New York and is a and professor of ophthalmology at clinical professor of ophthalmology the Cole Eye Institute, agrees that at the New York University School of vein occlusions may call for a different
30 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
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RO0314_S4optik.indd 1 2/28/14 9:03 AM Cover Retina
REVIEW Focus
Comparison of Clinical Trial Results and Costs of Anti-VEGF Drugs
Ranibizumab 0.5 mg Bevacizumab 1.25 mg Afl ibercept 2 mg* Main randomized clinical trials ANCHOR (n=423) MARINA (n=716) CATT (n=1,185) VIEW 1 (n=1,217) CATT (n=1,185) VIEW (n=2,457) VIEW 2 (n=1,240) Patients avoiding a loss of 15 ANCHOR: 89% (monthly arm) CATT: 88.4% (PRN arm); VIEW: 92% (monthly arm); letters at two years CATT: 92.8% (PRN arm); 93.3% (monthly arm) 92.2% (monthly arm) 92% (q8 arm) VIEW: 92% (monthly arm) Patients who gained 15 letters ANCHOR: 41% (monthly arm) CATT: 28.3% (PRN arm); VIEW: 31% (monthly arm); at two years CATT: 30.7% (PRN arm); 32.8% (monthly arm) 31.8% (monthly arm) 33% (q8 arm) VIEW: 32% (monthly arm) Mean change in visual acuity ANCHOR: +10.7 (monthly arm) CATT: +5 (PRN arm); VIEW: +7.6 (monthly arm); at two years (letters) CATT: +6.7 (PRN arm); +8.8 (monthly arm) +7.8 (monthly arm) +7.6 (q8 arm) VIEW: +7.9 (monthly arm) Mean number of treatments at ANCHOR: 21.3 (monthly arm) CATT: 14.1 (PRN arm); VIEW: 16 (monthly arm); two years CATT: 12.6 (PRN arm); 22.4 (monthly arm) 23.4 (monthly arm) 11.2 (q8 arm) VIEW: 16.5 (monthly arm) USFDA approval June 2006 Off-label use November 2011 Approximate cost of drug $1,991.55 $23.48 $1,961 Reimbursement per injection** $118 $118 $118 PRN=as needed. q8=every eight weeks. All drugs given as intravitreal injections with three initial monthly injections. Table based on Freund KB, et al., 2013.3 * VIEW data integrated from VEW 1 and VIEW 2. **Reimbursement by Medicare part B in 2013 in New York State.
approach. “Macular degeneration is pounded,” he says. “But beyond those to produce the desired result.” not really a VEGF-driven problem, kinds of concerns, the CATT trial did “Overall, the Avastin vs. Lucentis whereas retinal vein occlusion and show that there was a small, statisti- debate has become a hotly contested diabetic macular edema are,” he says. cally significant difference between area,” adds Dr. Freund. “Some people “Because of that, clinically we are see- Avastin and Lucentis in terms of sys- fi rmly believe that Avastin is as good as ing a bigger difference in effi cacy be- temic safety, although it wasn’t one the other options in every way, at least tween drugs, although we don’t have a particular systemic adverse effect; it for treating macular degeneration, comparison study yet to demonstrate was distributed over many things. The while others point out the somewhat that one drug is superior to the others. difference was in favor of Lucentis, small but potentially real differences.” We will have results from a study com- but it was a small difference, and many paring Lucentis, Avastin and Eylea for people have discounted it because A Third Option treating diabetic macular edema later it didn’t make a whole lot of sense. this year. But for CRVO, we currently The systemic safety problems weren’t With the Food and Drug Adminis- have no guidance until the SCORE 2 necessarily linked to the mechanism tration approval of Eylea in Novem- study is fi nished. of action of the drug. Also, the other ber 2011, surgeons had two approved “I think with all of these diseases, studies didn’t fi nd that difference.” anti-VEGF drugs to choose from, in many of us start with Avastin and only Dr. Kaiser feels the evidence of addition to the off-label use of Avas- switch to a different drug when the safety differences doesn’t warrant a tin. This further enlivened the debate patient doesn’t do as well as we expect. change in protocol. “From a stand- regarding which—if any—is superior. There’s really no reason to start with point of safety—outside of the com- Dr. Kaiser notes that the VIEW the more expensive drug.” pounding issue, which is still a big con- study in macular degeneration found Dr. Freund notes that the obvious cern—there’s no compelling evidence Eylea to be similar in effi cacy to Lu- issues with Avastin are potential con- that Avastin has any additional safety centis, while requiring fewer injec- cerns of safety; in particular, the is- issues,” he says. “For most of us, that tions. “In this study, patients were sue of compounding pharmacies. “In gives us the green light to use Avastin able to go longer between treatments rare situations the drug has become more frequently. Certainly many prac- with Eylea than Lucentis,” he says. contaminated, and in other countries tices have turned to using Avastin fi rst “Whether that difference remains in such as China there have been issues in all patients. They only switch the clinical practice remains to be seen. with counterfeit Avastin being com- patient to another drug if Avastin fails We are fi nding that many of our pa-
32 | Review of Ophthalmology | August 2014
032_rp0814_f3.indd 32 7/25/14 2:16 PM RP0414_lombart.indd 1 3/26/14 4:57 PM Cover Retina
REVIEW Focus
tients who fail to respond to Avastin or Lucentis do better when we switch Scheduling Intravitreal Injections them to Eylea, and several case series have found the same thing. So in my One key issue with the intravitreal injection of anti-VEGF drugs is fi nding ways to practice, I often start patients with avoid giving more injections than are truly necessary. “For the most part I use a treat- Avastin. If they don’t respond to Avas- and-extend treatment regimen,” says Peter K. Kaiser, MD, the Chaney Family Endowed tin, I switch them to Eylea because of Chair in Ophthalmology Research at the Cleveland Clinic Lerner College of Medicine. the longer duration, similar efficacy “I try to treat until the patient is dry and then extend the time interval between the and lower cost compared to Lucen- injections. We now have good evidence from the LUCAS study showing that this works tis. The exception would be diabetic very well. As-needed scheduling has been shown to be less effi cacious than monthly macular edema, for which Eylea is not treatment, but by only a few letters. So I think it’s perfectly fi ne to not use fi xed dosing. approved. In that situation I’ll switch Of course, it’s not wrong to use fi xed dosing—in fact, it’s the gold standard—but it’s too to Lucentis if Avastin fails.” much of a burden on the patient to come in every month for treatments.” “Eylea is very effective,” agrees Dr. K. Bailey Freund, MD, a retina specialist and clinical professor of ophthalmology at the Freund. “Our group and others have New York University School of Medicine, is the originator of the treat-and-extend pro- shown that some patients do seem to tocol. “Treat-and-extend has become the most widely used treatment regimen, despite respond somewhat better anatomical- the fact that there’s minimal randomized clinical trial evidence showing that it works ly—in particular, those who have prov- as well as monthly dosing or the Eylea regimen or OCT-guided therapy,” he says. “Only en resistant to the alternatives. Switch- one prospective, randomized trial, the LUCAS trial, showed impressive results for the ing them may allow for less-frequent treat-and-extend regimen. But despite the limited data, retina specialists have gravitated dosing. It’s labeled for eight-week dos- towards it; if you look at the annual survey of the American Society of Retina Specialists, ing after the fi rst three monthly treat- the preferred treatment regimen has gradually moved toward treat-and-extend.” ments, which is quite different from “Some surgeons still do p.r.n. scheduling,” notes David M. Brown, MD, FACS, who the Lucentis label.” practices at Retina Consultants of Houston and runs the Greater Houston Retina David M. Brown, MD, FACS, who Research Center. “I think that’s wrong because I don’t think it’s ever a good thing to have practices at Retina Consultants of recurring edema. Some physicians do the injections monthly, but I’d say the majority of Houston and runs the Greater Hous- higher-volume surgeons—probably 90 percent—use treat-and-extend.” ton Retina Research Center, has writ- “Patients differ widely in terms of how often they need injections,” Dr. Freund adds. ten extensively about the use of the “When you do treat-and-extend you’re individualizing the treatment, fi nding those different anti-VEGF options in macu- patients who need more injections and those who need fewer, so patients come in when lar degeneration, diabetes and retinal they actually need the injection, not just every month rigidly.” vein occlusion, and their comparative —CK effi cacy. “In terms of durability—get- ting the retina dry and keeping it that tensively know that Avastin is less po- diabetes,” he adds. “That could re- way longer—I think Lucentis and Ey- tent than the others,” he adds. “Even ally change diabetes management, de- lea are definitely better for treating in the CATT trial, Avastin didn’t win in pending on the outcome of the direct diabetic macular edema, and I think any category. Usually if you have drugs head-to-head comparison of Lucentis, those drugs are better for at least half that really are equal, one drug will win Avastin and Eylea for diabetes that’s in of all macular degeneration patients. in one category and the other will win progress right now. The data should be If you look at the data from the CATT in another category. Avastin didn’t win out in January. My guess is that Eylea trial, monthly Avastin dried out about in any category. People keep saying will turn out to be more durable, but 30 percent of patients, while monthly that Lucentis and Avastin are equal, we won’t know until we see the data. Lucentis dried out about 50 percent. but if it’s my eye or my dad’s eye that’s If it shows that Avastin is absolutely In Regeneron’s VIEW 1 and VIEW in trouble, I’m using Lucentis or Ey- equal in every way, then I think every 2 trials, Lucentis dried out about 50 lea if I have a choice. However, as I insurer will say you need to use Avas- percent of eyes, similar to the CATT said earlier, if you succeed in drying tin, and that’s fi ne. If it shows that Ey- results, and Eylea dried out about 70 the retina out, it doesn’t matter which lea or Lucentis (or both) are superior, percent. That suggests that you’ll get drug you used. So, I think it’s very rea- then we’ll be in the same situation we more effective drying with Eylea than sonable to start with the cheaper drug. are with macular degeneration.” with Lucentis or Avastin. “The biggest thing happening with Dr. Freund points out that Eylea “I believe that most people who Eylea is that they have a pending in- was tested in two strengths: 0.5 mg have worked with all of these drugs ex- vestigational new drug approval for and 2 mg. “It’s the 2-mg formulation
34 | Review of Ophthalmology | August 2014
032_rp0814_f3.indd 34 7/25/14 2:16 PM that was approved, so we’re giving a in part on the insurers,” notes Dr. fairly large dose of drug,” he notes. Brown. “More and more insurers are “Whether the drug itself is truly more either doing a step edit, where they potent than the others or we’re just want you to use Avastin fi rst, or they’re giving more of an equally potent drug simply using a passive-aggressive strat- is still debated. But I think most reti- egy to avoid dealing with surgeons nal specialists have the impression that who use the expensive drugs. Medi- Eylea is somewhat more potent. care advantage plans are not supposed “Increased potency sounds really to restrict drugs any more than Medi- good,” he continues, “but there’s a care—they’re supposed to provide the concern that comes from the CATT same thing Medicare does. So they and IVAN studies, the latter being say you can use any drug you want, the U.K. head-to-head comparison of and then they drop providers who use Lucentis and Avastin. In both studies the more expensive drugs. They say it was seen that patients who got more they’re making their provider pool injections developed more geographic smaller or consolidating, but if you atrophy. That’s a big problem, because look at the pool, the only people they that’s often how patients end up los- keep on are doctors who never use ing vision over the long term; retinal Lucentis or Eylea. I’ve been kicked off cells die. So, a drug that’s more potent of, or not selected for, most Medicare might reduce the number of injections Advantage plans and HMOs in our needed but cause more geographic market because I use Lucentis and atrophy. It’s a theoretical concern at Eylea in recalcitrant patients. this point, but some people like myself “Of course, this would never hap- are watching this very carefully. In our pen except in such an unusual situ- zeal to get maculas completely dry we ation,” he adds. “There’s no place could potentially be accelerating the else in medicine where you have a dry aspect of the disease. $50 drug competing with a $1,300 or “If this is true,” he adds, “it will be $2,000 drug. And we’re in such a small hard to prove. It’s possible that if we field that they can kick us off their analyze some of the data from recent panels and it saves them money.” trials we may be able to tell whether Dr. Brown points out that many in- higher doses cause more geographic surers won’t even allow a step edit. “I atrophy. But geographic atrophy is wish the insurance companies would part of the natural course of the dis- allow that, even though the Centers ease, so it will be hard to tease apart for Medicare & Medicaid Services has what the drug might be doing vs. the said that step edits aren’t appropriate,” disease itself.” he says. “As a result, in our practice Dr. Brown says he uses whichever we have to take the patient’s insurance drug keeps the retina dry. “If Avas- into consideration. We know which tin keeps the retina dry, whether it’s insurers want us to use Avastin, even macular degeneration or retinal vein though they don’t say it. Patients with occlusion or diabetes, that’s fi ne,” he that insurance only get Avastin. With notes. “If however, you’re giving a pa- other patients we can do what we tient a shot of Avastin every month think is the best for the patient.” and he still has persistent fl uid, I think Although Dr. Brown believes it’s the patient would be better served by reasonable to start a macular degen- trying Lucentis or Eylea.” eration patient on Avastin, he notes that occasionally a patient won’t agree. The Insurance Factor “Patients,” he says, “sometimes make this argument: ‘I’ve got great insur- “The drug a surgeon uses depends ance and I’ve been paying for it for
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REVIEW Focus
a long time. Why are you making me coverage. So the irony is that if you none of the combination trials has yet start with a drug that’s not made to have a Medicare advantage plan that matched the visual results achieved go into the eye and has a risk of en- says ‘Yes, we cover Lucentis,’ you’re with anti-VEGF monotherapy. dophthalmitis from a compounding not eligible for the free drug. At the “The exception may be combining pharmacy issue?’ In the fi nal analysis, same time, you’re not really eligible anti-VEGF with another sophisticated if a patient has good insurance, I start for the insurance-covered drug, be- pharmacological agent,” he continues. him on an approved drug—Lucentis cause your surgeon may be fi red from “There’s a drug called Fovista, cur- or Eylea. If the patient is cash-pay or the insurer’s panel if he uses it.” rently undergoing a Phase III trial in underinsured, I start him on Avastin. combination with Lucentis; the com- If that patient has lots of fl uid, then I Combination Treatments bination is being evaluated in compar- fi ght the insurance company to try to ison with Lucentis monotherapy. Fo- get one of the other drugs. For a number of reasons, one popu- vista targets platelet-derived growth “Another option is to get the pa- lar approach to trying to improve on factor, which is involved in the devel- tient into one of the Access programs,” the current drugs has been to look for opment of the pericytes that help in he notes. “The Access programs are new drugs and other procedures that the maturation of neovascular vessels. pretty good at getting free drugs for might combine with the current drugs In other words, Fovista inhibits the patients who can’t afford them. These and produce even better outcomes. pericytes.” are charities originally developed by “Studies have looked at combining Dr. Kaiser believes that in terms the pharmaceutical companies to pro- anti-VEGF drugs with photodynamic of combining drugs, using a PDGF vide access to chemotherapy for can- therapy, steroids and radiation,” notes inhibitor is at the top of the list. “Fo- cer. If you make less than $100,000, Dr. Freund. “The problem is that vista is the first out of the gate,” he you can get free Lucentis or Eylea— these combinations sometimes reduce says. “The Phase II study showed very but only if you don’t have insurance the number of injections needed, but good results in comparison to anti-
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032_rp0814_f3.indd 36 7/25/14 2:15 PM VEGF alone, resulting in a signifi cant impossible for anyone other than a big improvement in vision. If that’s repli- pharmaceutical company to conduct cated in Phase III, they’ll have a hit on a trial like this, because only they can their hands because we’ll have a treat- provide the anti-VEGF drug without ment that actually improves vision having to buy it. In any case, these over our current anti-VEGF therapies. options are three to seven years away, Of course, this means patients would assuming they pan out. In the near undergo two injections, but they won’t future, however, there is a proposed care as long as they’re getting better Phase III trial of an Alcon anti-VEGF results. My patients would be willing drug that looks encouraging.” to do three or more injections every Dr. Freund adds that the reason month if it would improve their vision, many of these are combination trials is especially since they would be done at that it would be unethical to do a trial the same visit.” of a drug vs. placebo. “This way the “Regeneron and Bayer have also subjects in both groups get a proven announced that they’re working on an therapy, and maybe the group get- anti-PDGF agent,” Dr. Freund notes. ting the new drug won’t need as many “The potential benefi t of their formu- injections,” he explains. “In the case lation is that it could be co-formulated of squalamine lactate, I also believe it with Eylea. In contrast, in the Fovista would be a bit of a reach to think that trial the patients have to get two injec- any drug used topically as monother- tions back-to-back; you can’t mix the apy could compete with a drug being two drugs. So if the strategy of using injected intravitreally.” Fovista in combination with one of the existing drugs gets FDA approv- Anti-VEGF and Radiation? al, it will have to be given the same way. That’s a drawback, so the trial In terms of combining anti-VEGF will need to show a fairly substantial with radiation, Dr. Freund says stud- benefi t over Lucentis alone to make ies have not borne out the Neovista it something that doctors and patients approach. “The Neovista approach would want to do. But it’s certainly involved doing a vitrectomy and in- possible. Also, if you did this a number serting a probe into the eye,” he says. of times it might result in fewer injec- “Now there’s an offi ce-based IRay ra- tions being needed down the road, but diation system that uses external beam we don’t know if that will be the case.” radiation that’s in clinical trials. But I Dr. Freund says another potential am skeptical that radiation is really go- combination drug worth noting is ing to be an effective treatment. It has squalamine lactate, a topical therapy. a fairly narrow therapeutic window. If “That’s being used in combination you give too much you’ll cause radia- with anti-VEGF in hopes of reducing tion retinopathy; if you give too little, the treatment burden,” he explains. it may not impact the disease you’re “It’s currently in clinical trial. It’s felt to trying to treat.” be a fairly potent antiangiogenic mol- “Radiation in combination with anti- ecule that can reach therapeutic levels VEGF therapy is still being looked at,” in the retina with topical dosing.” notes Dr. Kaiser. “It’s gotten farther in Dr. Brown notes that there are Europe than in the United States. The some Phase I trials combining other INTREPID study for Oraya’s IRay antiangiogenic agents with an anti- system has shown a decrease in the VEGF drug. “One that’s combined number of injections, with similar vi- with Lucentis is coming from Roche; sual results, when used in combination another that combines with Eylea is with anti-VEGF. It’s only approved in from Regeneron,” he says. “It’s nearly Europe, but we’re hoping for a Phase
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REVIEW Focus
III study in the United States.” mostly Avastin with patients who have are trying to create more oversight,” Dr. Brown believes combining anti- that insurance. notes Dr. Brown. “That’s a great idea; VEGF drugs with radiation is unlikely “Sequestration has also made it we want to give safer Avastin to our to be widely adopted. “The data shows harder to use Lucentis and Eylea by patients. But the downside of the in- that doing this doesn’t produce im- cutting the margin from 6 percent to 4 creased oversight is that some phar- proved visual acuity,” he points out. percent,” he adds. “That makes it even macies are now requiring individual “I present at meetings every month tougher to manage these drugs.” prescriptions. We can’t provide an in- and talk about anti-VEGF trials where • Pay attention to your com- dividual prescription for every patient patients gained two or three lines, so pounding pharmacy. Dr. Freund to get the drug; it would simply be too an alternative that doesn’t lead to im- notes that managing compounding diffi cult. The FDA’s role is to protect proved vision, to me, is not viable.” pharmacy concerns is tough. “You at- the U.S. population, so it makes sense tempt to evaluate your pharmacy as to have these new regulations. How- Staying Out of Trouble much as possible, but you can’t know ever, they may end up limiting the use for sure what procedures are being of Avastin and increasing Lucentis and These strategies can help prevent followed in actuality,” he says. “I’ve Eylea use—which the insurance com- problems from arising: had the unfortunate experience that panies won’t like. • When treating diabetic macu- three of the compounding pharma- “I do think surgeons should opt for lar edema, don’t wait to start the cies I’ve used over the course of my the certified pharmacies,” he adds. injections. “The data shows that if career—all except the one I’m cur- “Hopefully, the practical concerns you wait a year, you never get the gains rently using—were shut down by the being raised by the new laws can be you would have gotten,” Dr. Brown FDA because of serious concerns. resolved. In any case, every practice points out. “No matter which drug Years ago I ordered some drug from should do a lot of due diligence, check- you’re using, start injecting these pa- the New England Compounding ing carefully to fi nd out what the phar- tients sooner rather than later. No- Pharmacy; that was the one that had macy you’re using is doing. Does it test body holds off injecting patients with the fungal contamination of steroids the compounded drug for toxins? For macular degeneration, because ev- that killed patients with encephalitis. bacterial contaminants? How many erybody knows that the eye will be Franks Pharmacy, in Pensacola Fla., times has it had problems? If a phar- far worse off in a couple of months if was shut down for fungal contamina- macy starts to require prescriptions you don’t treat. With diabetes, it’s a tion of drugs. And the pharmacy that we’ll switch to a different pharmacy, lot easier to postpone starting while I was using up until recently failed but we’ll do a lot of careful checking to you’re managing other things such as to tell doctors that one of its batches make sure the drugs are safe.” blood pressure control and systemic had failed the sterility test, so they Dr. Kaiser agrees. “I think the key concerns. But the longer you wait to had their license suspended. Some is to make sure that the pharmacy that start injections, the less chance you of the best institutions in the country you’re buying your Avastin from is cer- have of robust gains.” were using these pharmacies. While tifi ed,” he says. “Then, make sure you • Be especially careful about situations like this are rare, it’s a real periodically double-check the phar- managing your cash fl ow relating concern. macy’s status. Finally, make sure your to Lucentis and Eylea. “More and “Of course, if you look at the num- pharmacy checks the sterility of every more we’re seeing some secondary in- ber of patients who have lost vision batch. Pharmacies don’t necessarily do surers dragging their feet about paying due to problems with compounded this, but they should.” their portion of the coverage,” says Dr. Avastin, it’s a tiny number compared • Inspect the drug package when Brown. “If you’re using anything other to the number of patients who have it arrives from the compounding than Avastin and 10 percent of your been treated with Avastin,” he adds. pharmacy. “If the package looks like secondaries are delaying payments for “None of my patients were ever it went through a freeze-thaw cycle, a while, stretching them out to 90 days harmed in any of these situations, but send it back,” says Dr. Kaiser. “You or more, you might not notice it at fi rst it goes to show that there are issues wouldn’t want to use that batch. If it because some money is coming in. But with compounding pharmacies that looks like the packaging is all wet, as if the delay in reimbursement can add we do have to take seriously. You want the ice melted, that’s a big tipoff.” up and really hurt your practice. You to ensure, to the best of your ability, need to fi gure out which insurers are that your pharmacy is adhering to the In the Pipeline delaying payments, and then either guidelines.” talk to those insurers or consider using “The compounding pharmacy laws Naturally, more anti-VEGF drugs
38 | Review of Ophthalmology | August 2014
032_rp0814_f3.indd 38 7/25/14 2:16 PM are on the horizon. “Another drug opment will be Lucentis and Avas- with potential is ALG-1001, an in- tin going off patent a few years from tegrin antagonist from Allegro,” says now. “In 2019 Lucentis and Avastin Dr. Kaiser. “Integrin antagonists use go off patent, so if you’re doing the a different approach to angiogenesis. numbers on whether to go through ALG-1001 is interesting because not a drug-approval process you have to only does it seem to work as mono- look forward,” says Dr. Brown. “It therapy, it also appears to work in takes three to fi ve years to go through combination with anti-VEGF. Right that process, and you’re probably go- now the big question is, should the ing to be competing with other cheap- initial testing be done as combination er agents at that point—biosimilar Lu- therapy or monotherapy? It seems to centis and Avastin drugs.” work by itself and have a long-lasting The other key factor is creating a effect, but it takes a little time to get drug that can produce better results going. Using it in combination with than the current drugs, which is not an an anti-VEGF drug may be benefi cial easy thing to do. “We all hope some- because you’ll get both the immediate thing will be the next big blockbuster, wow factor and the long-lasting effect but it’s really hard to surpass the data from the new drug.” from the previous trials,” Dr. Brown “Another anti-VEGF agent that’s points out. gotten a lot of attention is Allergan’s drug, previously known as Darpin, Taking Action now called Abicipar,” notes Dr. Freund. “They had some issues with Dr. Freund notes that all of the cur- infl ammation, but they’re reformulat- rent options are viable, so the main ing. That’s thought to potentially be a issue is getting treated in time. “Com- very potent anti-VEGF agent.” prehensive ophthalmologists who New delivery methods are also aren’t treating with intravitreal injec- promising, in particular because they tions should be aware that we now may eliminate the need for repeat have some really good therapies and injections. “In wet macular degen- multiple choices,” he says. “The key eration, the next big thing may be sus- thing is to identify these patients and tained-release anti-VEGF treatment, get them to a physician who can treat allowing us to do one treatment that them properly. As a retina specialist, lasts a lot longer,” notes Dr. Kaiser. there are pros and cons to each drug, “One approach to this is gene ther- but you can’t really go too far wrong apy, which would cause anti-VEGF with any of the three current drugs for to be released indefinitely. Another treating macular degeneration. They approach is the Neurotech method, all work well.” in which you surgically implant ge- netically altered RPE cells in a little Dr. Freund is a consultant for Ge- cylinder. They release the anti-VEGF nentech, Bayer and Regeneron. Drs. drug for as long as the implant is in Kaiser and Brown are consultants for the eye. The latter approach seems all of the companies whose products safer to me, since when the treatment are mentioned. is done you can remove the cylinder. 1. Papadoloulos N, Martin J, Ruan Q, et al. Binding and You can’t turn off the gene therapy, neutralization of vascular endothelial growth factor (VEGF) and which is a little concerning. Testing of related ligands by VEGF Trapm ranibizumab and bevacizumab. Angiogenesis 2012;15:2:171-85. the Neurotech system is just starting, 2. Vinores SA. Technology evaluation: Pegaptanib, Eyetech/Pfi zer. though, so we probably won’t have it Curr Opin Mol Ther 2003;5:6:673-79. 3. Freund KB, Mrejen S, Gallego-Pinazo R. An update on for a few years.” the pharmacotherapy of neovascular age-related macular One key factor in new drug devel- degeneration. Expert Opin Pharmacother 2013;14:8:1017-28.
032_rp0814_f3.indd 39 7/25/14 2:44 PM Retina REVIEW Cover Focus Increasing Options to Treat Vein Occlusion Michelle Stephenson, Contributing Editor
First-line treatment hen treating branch or cen- jerk refl ex nowadays is to go with an tral retinal vein occlusion, anti-VEGF agent fi rst. If that doesn’t is typically an anti- Wthe standard of care is phar- work at all, switch to a steroid. If it macologic therapy with either an an- works partially, the general practice VEGF agent. If ti-VEGF agent or steroid alone or is to switch to another anti-VEGF in combination. “For branch retinal agent, seeking a better response in a that is inadequate, vein occlusion, people are mainly us- given individual. After that, we’ll try steroids can be ing Avastin off-label or Lucentis on- steroids either alone or in combina- label,” says Antonio Capone Jr., MD, tion.” initiated, either in a surgeon from Royal Oak, Mich. Both Lucentis and Avastin have “For central retinal vein occlusion, been shown to effectively treat reti- combination with we are using those same two drugs nal vein occlusion and have similar plus Eylea and Ozurdex. In patients visual and anatomic outcomes. A re- the anti-VEGF who would benefit from a steroid, cent retrospective study included 81 but cost is a consideration, some use patients with retinal vein occlusion agent or alone. triamcinolone off-label instead of us- and macular edema who were naïve ing Ozurdex.” to anti-VEGF therapy.1 Twenty-six Chicago-based surgeon Seenu eyes were treated with ranibizumab Hariprasad, MD, points out that only (Lucentis), 33 eyes were treated with two pharmacologics are Food and bevacizumab (Avastin), and 22 eyes Drug Administration-approved for were treated with bevacizumab and use to treat all retinal vein occlusions: then switched to ranibizumab. The Ozurdex (dexamethasone intravit- main outcome measure was change real implant) and Lucentis. Eylea in visual acuity at three months, six (afl ibercept intravitreal injection) is months and at the fi nal visit. also FDA-approved, but only for the The mean visual acuity improved treatment of central retinal vein oc- from 20/80 to 20/40 in the ranibi- clusion. zumab group and from 20/125 to Dr. Capone says deciding on a drug 20/60 in the bevacizumab group. is done empirically: “You try one class The mean change in central subfi eld of drug to see if it works. If it doesn’t, thickness was -186 µm and -212 µm, you try the other. If it only works respectively. The mean time between partially, you combine them. There injections was 94 ±21.1 days in the is considerable individual variability ranibizumab group and 103.8 ±10.5 with regard to response. The knee- days in the bevacizumab group. In
40 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
040_rp0814_f4.indd 40 7/25/14 2:21 PM All images: Michael Singer, MD the group that switched than bevacizumab therapy from bevacizumab to ra- alone and required fewer nibizumab, mean initial vi- bevacizumab injections in sual acuity was 20/125. Vi- cases of both branch and sual acuity reached 20/60 at central retinal vein occlu- crossover and remained at sion.3 20/60 through the remain- The study included 30 der of the study. eyes that were randomly Dexamethasone intravit- assigned to receive either real implants have also been combination therapy or shown to be a safe and ef- monotherapy with be- fective treatment option. A vacizumab. All patients recent study evaluated the received intravitreal be- safety and efficacy of one vacizumab at baseline, fol- or two treatments over 12 lowed one week later by months in eyes with macu- Figure 1. Fundus photo of branch retinal vein occlusion. dexamethasone implants lar edema related to branch or sham injections. Month- or central retinal vein oc- ly bevacizumab injections clusion.2 were given if the central This study included 1,256 subfi eld thickness was less patients with vision loss than 250 µm, and the com- caused by macular edema bined group received a associated with retinal vein second implant after four occlusion. At baseline, 421 or fi ve months if the cen- patients received a dexa- tral subfi eld thickness was methasone 0.7-mg implant, less than 250 µm. 412 received a dexametha- At six months, patients sone 0.35-mg implant, and receiving combined ther- 423 received a sham im- apy required fewer be- plant. At day 180, patients vacizumab re-injections could receive a dexametha- compared to those receiv- sone 0.7-mg implant if their ing monotherapy (two ver- best-corrected visual acuity Figure 2. Red-free image of branch retinal vein occlusion. sus three). The combined was less than 84 letters or therapy group also expe- if their retinal thickness was greater visual acuity of 15 letters or more rienced greater mean reductions in than 250 µm, and 997 patients re- from baseline was achieved by 30 central subfield thickness (-56 µm ceived this implant. Except for cata- percent of patients 60 days after the versus +45 µm) and were more likely ract, the incidence of ocular adverse fi rst dexamethasone implant and by to have resolved all edema, which events was similar in patients who 32 percent of patients 60 days after was considered a central subfield received their fi rst or second dexa- the second dexamethasone implant. thickness less than 250 µm (seven of methasone implant. Over 12 months, Dr. Hariprasad believes combin- 11 eyes versus two of 14 eyes). Mean cataract progression occurred in 90 ing pharmaceuticals is very advanta- visual acuity changes from baseline of 302 phakic eyes (29.8 percent) that geous. “There are some patients in were similar between groups. received two dexamethasone implant whom I go straight to a combination Dr. Capone notes that many oph- 0.7-mg injections compared with fi ve approach, and there are other pa- thalmologists stick with anti-VEGF of 88 sham-treated phakic eyes (5.7 tients who are suboptimal respond- monotherapy longer than they percent). Cataract surgery was per- ers in whom we will try combination should. Typically, patients’ response formed in four of the 302 (1.3 per- therapy,” Dr. Hariprasad says. to anti-VEGF injections is evident cent) phakic eyes that received two A recent study found that bevaci- early in the course of treatment. “Pa- implants and one of 88 (1.1 percent) zumab combined with dexametha- tients who are going to have a good eyes that received the sham implant. sone implants produced greater response to anti-VEGF will typically An improvement in best-corrected improvements in macular thickness do so within the fi rst three injections,”
August 2014 | Revophth.com | 41
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REVIEW Focus
he says. “In fact, I think you can tell largely unresponsive,” Dr. Capone This retrospective study includ- after the fi rst injection whether the says. ed 64 patients with retinal vein oc- patient will be a marginal responder Los Angeles-based surgeon Da- clusions. Half received injections or a nonresponder. There is a ten- vid Boyer, MD, agrees. “If patients of bevacizumab, and half received dency to keep whipping the horse don’t have the response that I would injections of ranibizumab. Central three or six times before deciding to like, I add the steroids very early,” he macular thickness and best-corrected make the switch. This is not in the says. “Other ophthalmologists like to visual acuity were obtained at base- patient’s best interest. The longer the wait until after four, fi ve or six injec- line, at two weeks (just prior to the edema is present, the worse the fi nal tions. If I’m not seeing the response dexamethasone intravitreal implant), visual outcome.” I want after a couple of injections and at six weeks. At the two-week He believes that a better approach of anti-VEGF and I add a steroid, examination, the bevacizumab group is to use an anti-VEGF agent and it doesn’t mean I’m not going to use had a mean central macular thick- promptly gauge by the presence and anti-VEGF after that, but I can add a ness reduction of 26.2 ±3.4 percent magnitude of a response whether the steroid for a better response.” compared with a 47 ±3.5 percent patient should be treated exclusively Michael Singer, MD, from San reduction with ranibizumab. At six with an anti-VEGF or whether a ste- Antonio, Texas, typically initiates weeks, there was a 31.6 ±3.2 percent roid should be brought in. “A deci- treatment with Lucentis in cases of central macular thickness reduction sion can be made earlier in the game branch retinal vein occlusion because with bevacizumab versus 52 percent than is conventional practice as to he conducted a study that found ±3.2 percent with ranibizumab. At whether an adjunctive or alternative that ranibizumab appears to have a two weeks, 15 (9 percent) bevaci- therapeutic agent would be appropri- greater effect than bevacizumab in zumab patients and 25 (78.1 percent) ate for a patient with vein occlusion the short-term of decreasing macular ranibizumab patients achieved a cen- that is only partially responsive or edema.4 tral macular thickness of less than
040_rp0814_f4.indd 42 7/25/14 2:20 PM 300 µm, and at six weeks, 18 (56.3 percent) bevacizumab patients compared to 30 (93.8 percent) ranibizumab pa- tients achieved a central macular thickness less than 300 µm. Visual acuity was not signifi cantly different between the two groups at any time interval. “I like the results of this study because vein occlusion patients are a lot younger than macular degeneration patients as a general rule, and they need better vision sooner,” Dr. Singer says. “With central retinal vein oc- clusion, it gets a little more complicated. If it’s more ischemic, I’m much more likely to use Eylea, because the GALILEO and COPERNICUS studies included central retinal vein occlusions in their study design, so aflibercept’s effectiveness has been shown.5,6 The CRUISE study7 excluded these patients based on the inclusion criteria for the study, so ranibizumab’s effec- tiveness has not been demonstrated in a clinical trial setting,” Dr. Singer adds. According to Dr. Boyer, triamcinolone has been ICARE shown to be helpful in central retinal vein occlusions, and Ozurdex has been shown to be helpful in both cen- SUMMER tral retinal vein and branch retinal vein occlusion. “We usually start with an anti-VEGF drug, and if I get a great response, meaning that it dries out and vision improves, SPECIALS then I probably would continue the anti-VEGF, hoping that I could eventually get to a treatment and extend protocol and eventually not need to treat the patient,” ORDER YOUR ICARE TODAY he says. Your Patients Will Surgical Treatments Thank You For It
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(continued on page 62)
040_rp0814_f4.indd 43 7/25/14 2:21 PM Retinal Insider
REVIEW Edited by Carl Regillo, MD and Emmett T. Cunningham Jr., MD, PhD, MPH
Multimodal Imaging in Plaquenil Toxicity Advanced imaging techniques may lead to timely diagnosis and more effective treatment of hydroxychloroquine-related toxicity. Ehsan Rahimy, MD, and James Vander, MD, Philadelphia
ydroxychloroquine, sold under the various autoimmune diseases, includ- tients are on long-term therapy with Hbrand name Plaquenil (Sanofi- ing systemic lupus erythematosus this medication in America alone.2 Aventis), is an antimalarial drug that and rheumatoid arthritis.1 By some Retinal toxicity associated with HCQ has gained widespread use in treating estimates, more than 150,000 pa- use is relatively rare, estimated at 1 percent after five years and ris- ing with continued therapy.3 How- ever, the retinopathy, described as a bull’s-eye, is untreatable and tends to progress even after cessation of the drug. Accordingly, in recent years there has been an increased em- phasis on more effective screening measures utilizing multimodal imag- ing techniques to elicit early signs of toxicity before the characteristic advanced changes manifest clinically. This review summarizes the clinical presentation of HCQ retinopathy, current American Academy of Oph- thalmology recommended screening guidelines and contribution of ancil- lary imaging studies in establishing a timely diagnosis.
Clinical Presentation & Exam
In the earliest stages of HCQ tox- Figure 1. Fundus photos (top) demonstrate extensive paracentral depigmentation of the icity, patients are often asymptom- retinal pigment epithelium sparing the central fovea bilaterally, consistent with bull’s-eye atic with preservation of visual acuity. maculopathy. Fluorescein angiography (bottom) shows parafoveal granular However, perceptive individuals may hyperfl uorescence correlating to patchy RPE disruption with subsequent window defect. report difficulty with night vision,
44 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
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glare or paracentral scotomas that in- examination and automated thresh- terfere with reading.4-6 The scotoma old Humphrey visual field testing typically becomes apparent to the with a white 10-2 pattern (which patient well before changes are seen should be interpreted with a low on examination. While recognition threshold for abnormality and with of subtle foveal depigmentation has repeat testing if irregularities are been described in some cases of early noted), at least one of the follow- toxicity, this was only after corrobora- ing supplemental objective imaging tion with ancillary imaging studies.7 studies is recommended: 1) spectral- On the other hand, visible bull’s- domain optical coherence tomogra- eye retinopathy, characterized by a phy; 2) fundus autofl uorescence; or ring of retinal pigment epithelium 3) multifocal electroretinography, at degeneration often sparing the fo- baseline and annually at each visit veal center, is a late fi nding indicative after five years of HCQ use.4 No- of advanced damage (See Figure 1). tably absent, fluorescein angiogra- Thus, ophthalmoscopy alone is not phy was not recommended in these suffi cient to screen for HCQ toxic- guidelines. While FA can reveal the Figure 2. Spectral-domain optical coherence 7,8 tomography demonstrating advanced ity. That being said, a detailed ante- bull’s-eye pattern of granular hyper- hydroxychloroquine retinopathy with rior and posterior segment examina- fl uorescence and may be able to elu- parafoveal loss of the external limiting tion to assess for corneal verticillata cidate subtle RPE defects, it has not membrane, disruption of the outer ellipsoid as well as concurrent macular disease been proven to be as sensitive as the zone, thinning of the outer nuclear layer and (i.e., age-related macular degenera- aforementioned tests and comes with disruption to the underlying retinal pigment tion), remains important in monitor- added morbidity due to its invasive- epithelial layer (A). The relative sparing of ing these patients long term. ness.4 the subfoveal structures results in the characteristic “fl ying saucer” sign of 11 Screening Guidelines Spectral-Domain OCT advanced toxicity (B).
In 2002, the AAO published its By generating high-resolution, outer retinal structures contrasting initial Preferred Practice Patterns for cross-sectional images of the retina in to the adjacent perifoveal loss of the HCQ retinopathy screening in re- vivo, SD-OCT may detect signifi cant photoreceptor ellipsoid band and sponse to the diverse regimens be- structural alterations prior to devel- ONL atrophy (See Figure 2).11 ing advocated at the time.9 These opment of visible HCQ retinopathy. While much of the literature has recommendations were revised in Previously described OCT fi ndings focused on the changes to the out- 2011 to refl ect the increased sensi- in HCQ toxicity include loss of the er retina in HCQ retinopathy, the tivity of newer diagnostic imaging external limiting membrane, disrup- earliest SD-OCT findings of toxic- techniques.4 tion of the outer ellipsoid zone, para- ity may actually localize to the inner If a patient was deemed a low risk foveal thinning of the outer nuclear retina. Sirichai Pasadhika, MD, and for retinopathy, follow-up examina- layer and RPE damage.6,7,10 Despite colleagues observed selective thin- tions were recommended begin- these various changes, numerous ning of the perifoveal inner retina on ning at five years of therapy after studies have supported the notion SD-OCT, especially the inner plexi- the initial baseline. If a patient was that relative “foveal resistance” is form and ganglion cell layers, in pa- high risk, annual follow-up was rec- common in HCQ toxicity, as demon- tients treated with long-term HCQ ommended. High risk was defined strated by preservation of the subfo- (more than fi ve years) in the absence as someone with duration of HCQ veal outer retinal layers, accounting of structural changes to the outer use more than fi ve years, more than for the intact central visual acuity retinal/RPE or other clinically evi- 1,000 grams of cumulative consump- that can be seen even in advanced dent toxicity.12 Interestingly, thinning tion, more than 6.5 mg/kg/d daily disease states.6 This foveal sparing of the retinal nerve fi ber layer was dosing, increased age (no cut-point serves as the basis for the “fl ying sau- not found in these patients, which specifi ed), concomitant hepatic/renal cer” sign of HCQ retinopathy de- the authors proposed only happens disease or pre-existing maculopathy scribed by Eric Chen, MD, and col- once signifi cant retinal ganglion cell of another etiology.4 leagues, where an ovoid appearance degeneration has occurred. In a In addition to an ophthalmologic is created by the intact central foveal separate study designed to compare
August 2014 | Revophth.com | 47
044_rp0814_rtinsider.indd 47 7/25/14 2:23 PM ENRICH YOUR PRACTICE
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2014_rp_tsrad.indd 90 7/21/14 2:56 PM Retinal
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chronically treated patients with and less reliable as a primary screening without ophthalmoscopic evidence tool. of toxicity, signifi cant thinning of the More important than screening, inner, outer and full thickness retina the true value of FAF lies in its ca- was observed in patients with clini- pability to monitor progression in cally apparent retinal toxicity, where- known cases of HCQ retinopathy, as only selective thinning of the in- such as when a patient has been ner retina was detected in the group discontinued from the medication, without fundus changes.13 Once but still requires periodic follow-up again, RNFL thinning was absent in examinations. In this context, FAF patients with chronic HCQ exposure provides a sensitive indicator of RPE and no fundus changes; however, the degeneration as toxicity progresses, group with fundus changes related particularly in advanced stages. As to drug toxicity demonstrated peri- the RPE atrophies, the FAF intensity papillary RNFL thinning. Recently, in the pericentral macula changes to Ulviye Yigit and coauthors corrobo- a mottled, or speckled appearance, rated these findings by measuring and eventually coalesces into dark signifi cant thinning of the inner ret- areas of absence of FAF signal once ina during HCQ therapy, especially the cells have died (See Figure 3). in para- and perifoveal areas, in the Figure 3. Fundus autofl uorescence patterns in These dark regions may be bordered various stages of hydroxychloroquine absence of clinical fundus changes.14 by a rim of increased autofluores- retinopathy. Classic bull’s-eye maculopathy Unique to their study was the inclu- appearance (A). As the RPE atrophies, the FAF cence, portending which RPE cells 17 sion of the patients receiving HCQ intensity in the pericentral macula changes to a will undergo degeneration next. It treatment for less than fi ve years (av- mottled, or speckled appearance (B), and bears noting that not all cases associ- erage duration: 2.5 years). eventually coalesces into dark areas of ated with advanced retinal atrophy as More investigations involving larg- absence of FAF signal once the cells have confi rmed by other techniques (i.e., er numbers of patients need to be died (C). These dark regions may be bordered SD-OCT) have a marked appearance performed to better determine what by a rim of increased autofl uorescence (A-C), on FAF. This fi nding highlights the SD-OCT-based indices may be reli- portending which RPE cells will undergo importance of the AAO’s guidelines degeneration next. ably assessed in early HCQ toxicity. to use more than one imaging mo- However, given its rapid image ac- dality when identifying HCQ toxic quisition time, noninvasive nature on the other hand, indicates RPE effects. and wide availability in many clinics, cell death.17 the majority of practitioners contin- The early fi nding of a pericentral Multifocal Electroretinography ue to favor SD-OCT as the primary ring of increased FAF intensity, ap- adjunct to visual fi eld testing in HCQ pearing as a hyperfl uorescent glow, Traditional full-field electroreti- screening. may be seen in HCQ toxicity be- nography represents a test of global fore RPE degeneration develops, retinal function in response to photic Fundus Autofl uorescence and is thought to represent areas of stimulation. As it is not sensitive to early photoreceptor damage from functional changes localized to the Imaging with FAF may help elu- accumulation of outer segment de- macula, cases of HCQ toxicity would cidate toxic alterations to the under- bris.4,18,19 However, this can be quite demonstrate abnormalities only af- lying RPE due to long-term HCQ subtle and may be easily missed by ter diffuse retinal damage has al- therapy. An increased FAF signal the untrained reviewer. When ob- ready occurred, limiting its utility in typically indicates accumulation of served, coexisting mfERG or SD- screening programs.4,9 lipofuscin, in particular the A2E fl uo- OCT abnormalities have also been Conversely, multifocal ERG, with rophore, within the RPE either from concomitantly detected, suggesting its ability to record localized cen- abnormal metabolism with increased a pathophysiologic basis for the FAF tral retinal defects, has gained ac- phagocytosis of photoreceptor outer finding.7,18 Despite this, evidence ceptance as an excellent candidate segments or an inherited/acquired supporting the usefulness of FAF in for detecting subtle changes in the defect of the phagocytotic process- detecting early subclinical toxicity is early stages of toxicity.20 Raj Maturi, es.15,16 An extinguished FAF signal, still lacking overall, thus making it MD, and colleagues fi rst reported a
August 2014 | Revophth.com | 49
044_rp0814_rtinsider.indd 49 7/25/14 2:24 PM Retinal
REVIEW Insider
and the central macular area is usual- ly spared until late in the disease pro- cess, these patients typically demon- strate a larger ring ratio than would be expected (above the 99 percent limits of accepted normals created from a subset of healthy subjects).20 While mfERG testing has shown great promise as an objective mea- sure for detecting early HCQ toxicity as well as tracking the progression of macular changes in known disease, Figure 4. The ring ratio method of multifocal electroretinogram interpretation. it is limited by its dependence on The diagram of the 61-hexagon stimulus pattern system on the left shows the hexagons patient cooperation, specialized staff belonging to each ring. Ring-averaged waveforms from a normal patient are on the right. training for administration and inter- (See endnotes for image credit.) pretation, and overall cost. Perhaps most importantly, it is not as readily marked reduction in the central 16˚ 2) peripheral loss; and 3) general- available or easy to reliably perform mfERG amplitude in a patient with ized loss.24 Their system for classify- as SD-OCT or FAF, thus limiting its manifest HCQ retinopathy in the ing patterns of mfERG changes has widespread use to date. setting of a normal full-fi eld ERG.21 since been corroborated by other Similar results have been obtained groups.20,22 No Single ‘Best Test’ by subsequent studies characteriz- In an effort to increase the sensi- ing HCQ users. Timothy Y.Y. Lai, tivity over standard mfERG inter- Despite the increased integra- MMedSc, MRCS, and colleagues ob- pretation in detecting early HCQ tion of these imaging systems into served a longitudinal decline in the toxicity, Jonathan S. Lyons, MD, and both research and clinical practice retinal function of patients receiv- Matthew L. Severns, PhD, devel- forums, there remains no consensus ing long-term HCQ, and proposed oped a novel algorithm for tabulating which test is the gold standard for that serial mfERG may help detect mfERG data, termed the “ring ratio detecting early HCQ toxicity. The early retinal changes associated with method” (See Figure 4).20,25 Given discord is evident throughout the lit- toxicity.22 In a follow-up study, they that the amplitude of any single ad- erature, as various proponents have showed that mfERG responses cor- ministered mfERG can vary by up to argued in favor of visual fi elds, FAF, related with the HVF 10-2 mean de- 30 percent from a subsequent test- mfERG or SD-OCT as the most viation values, and thus could supple- ing,26 the ring ratio was designed to sensitive/specific method. In a re- ment visual fi eld testing by providing decrease this background noise and cent retrospective, private-practice an objective measurement of retinal create more normative values to aid based study of 219 patients, David J. function in patients using HCQ.23 in clinical decision making. For this, Browning, MD, PhD, concluded that The most specifi c waveform pat- the data from a 61-hexagon mfERG the revised guidelines emphasizing tern seen in patients with HCQ tox- is structured into fi ve zones of con- ancillary FAF, SD-OCT or mfERG, icity is paracentral amplitude loss, centric rings (R1-R5). have actually raised screening cost indicative of decreased retinal func- The ring ratios of the mfERG are without improving case detection of tion in the susceptible perifovea. In defi ned as the ratios of the central toxicity.27 another study, Dr. Maturi and col- ring amplitude (R1) to each of the Meanwhile, others have suggest- leagues proposed that prolonged im- peripheral ring amplitudes, resulting ed that certain patients may differ plicit time, when seen in conjunction in fi ve measurements for each eye: in their apparent sensitivity to dif- with the paracentral loss of ampli- R1, R1/R2, R1/R3, R1/R4, and R1/ ferent tests, and therefore careful tude, may be a more specific fea- R5. Because R1 has the highest ring screening with multiple modalities ture of HCQ toxicity.24 Furthermore, amplitude in the normal eye, normal is likely to increase the diagnostic they demonstrated three additional ring ratios are more than 1.0; how- yield in detecting toxicity prior to configurations, besides paracentral ever, since the areas of depressed the onset of irreversible structural/ loss, of abnormal mfERG ampli- mfERG amplitude in HCQ toxicity functional loss.7 Michael Marmor, tude changes: 1) central foveal loss; are typically pericentral ring-shaped, MD, and Ronald Melles, MD, re-
50 | Review of Ophthalmology | August 2014
044_rp0814_rtinsider.indd 50 7/25/14 3:11 PM cently illustrated the need for this malities that precede objective visual ity. Subtle abnormalities detected us- multifaceted approach in a subset of field loss. Larger scale studies are ing one modality warrant additional 11 patients representing 10 percent required to validate these fi ndings. follow-up testing to confi rm or refute of their patients with known HCQ Recently, two groups have de- these fi ndings, with the ultimate goal toxicity. This cohort demonstrated scribed the use of microperimetry of early diagnosis before irreversible pathognomonic 10-2 fi eld loss with systems to evaluate for early HCQ visual loss. prominent parafoveal ring scoto- toxicity.35,36 By testing perimetry un- mas that were strongly indicative of der simultaneous fundus visualiza- Figure 4 reproduced with permis- retinopathy; however, they did not tion, a precise anatomic correlate to sion from: Lyons JS, Severns ML. display any evidence of structural a functional aberration can be ob- Detection of early hydroxychloro- damage on SD-OCT imaging.28 The tained.35 Lucia Martinez-Costa and quine retinal toxicity enhanced by authors emphasized the need to take colleagues observed signifi cant dif- ring ratio analysis of multifocal elec- a broad approach when dealing with ferences in microperimetry retinal troretinography. Am J Ophthalmol HCQ screening, not to rely solely on sensitivity measurements between 2007. May;143(5):801-809. any single procedure, and follow-up 209 patients taking either HCQ or Dr. Rahimy is a second-year fellow any equivocal results with additional chloroquine compared with 204 con- at Wills Eye Hospital and a clini- confi rmatory testing. trol subjects.36 Renu Jivrajka, MD, cal instructor of ophthalmology at and colleagues detailed their fi ndings Thomas Jefferson University School Future Directions in a cohort of 16 patients on HCQ of Medicine. Dr. Vander is an attend- therapy for more than fi ve years with ing surgeon of the Retina Service at The advent of adaptive optics im- no signs of toxicity by conventional Wills Eye Hospital and professor of aging has enabled visualization of the 10-2 HVF, SD-OCT, FAF or mfERG ophthalmology at Thomas Jefferson cone photoreceptor mosaic in vivo testing; however, with microperim- University School of Medicine. Dr. to resolutions of ≤ 2 µm by compen- etry they noted a signifi cant overall Rahimy may be contacted at era sating for aberrations in ocular op- reduction in mean retinal sensitiv- [email protected]. Dr. Vander may tics.29-31 Using this technology, pho- ity between patients and age-similar be contacted at jvander@midatlantic toreceptor abnormalities have been controls.35 An additional advantage retina.com. uncovered in various retinal diseases of the particular microperimetry sys- 1. Tehrani R, Ostrowski RA, Hariman R, Jay WM. Ocular toxicity that were not otherwise discernible tem utilized was its ability to obtain of hydroxychloroquine. Semin Ophthalmol 2008;23(3):201-209. with SD-OCT imaging.32,33 simultaneous SD-OCT images and 2. Semmer AE, Lee MS, Harrison AR, Olsen TW. Hydroxychlo- roquine retinopathy screening. Br J Ophthalmol 2008;92(12): The use of adaptive optics in HCQ superimpose retinal sensitivity and 1653-1655. retinopathy is relatively new. Kim- thickness values, further reinforcing 3. Wolfe F, Marmor MF. Rates and predictors of hydroxychloro- quine retinal toxicity in patients with rheumatoid arthritis and berly E. Stepien, MD, and colleagues the notion of correlating functional systemic lupus erythematosus. Arthritis Care Res (Hoboken) demonstrated disruption of the cone response to an anatomic structure. 2010;62(6):775-784. 4. Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF. Revised photoreceptor mosaic in areas cor- Future prospective longitudinal recommendations on screening for chloroquine and hydroxy- chloroquine retinopathy. Ophthalmology 2011;118:415-422. responding to HVF 10-2 defects and studies are needed, with serial mi- 5. Michaelides M, Stover NB, Francis PJ, Weleber RG. Retinal SD-OCT ellipsoid zone abnormal- croperimetry testing, in order to bet- toxicity associated with hydroxychloroquine and chloroquine: Risk factors, screening, and progression despite cessation of ities in two patients on long-term ter determine whether the reduced therapy. Arch Ophthalmol 2011;129:30-39. HCQ therapy.33 Similarly, Korean re- retinal sensitivities actually represent 6. Mititelu M, Wong BJ, Brenner M, Bryar PJ, Jampol LM, Fawzi AA. Progression of hydroxychloroquine toxic effects after drug searchers observed a disrupted cone early subclinical HCQ toxicity. therapy cessation: New evidence from multimodal imaging. mosaic pattern with individual cones Hydroxychloroquine is a valuable JAMA Ophthalmol 2013;131:1187-1197. 7. Marmor MF. Comparison of screening procedures in hydroxy- having irregular shapes and sizes in a drug with an overall low side-effect chloroquine toxicity. Arch Ophthalmol 2012;130:461-469. patient with bull’s-eye maculopathy.34 profi le. While ocular toxic effects are 8. Elder M, Rahman AM, McLay J. Early paracentral visual fi eld loss in patients taking hydroxychloroquine. Arch Ophthalmol Additionally, overall measured cone infrequent, they may be associated 2006;124:1729-1733. densities were diminished in all pre- with signifi cant and irreversible pa- 9. Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF. Recommendations on screening for chloroquine and hydroxy- determined test points at various dis- tient morbidity. Early detection of chloroquine retinopathy: A report by the American Academy of Ophthalmology. Ophthalmology 2002;109:1377-1382. tances from the foveal center. Taken toxicity during subclinical stages with 10. Kellner S, Weinitz S, Kellner U. Spectral domain optical together, both groups proposed AO discontinuation of the medication coherence tomography detects early stages of chloroquine retinopathy similar to multifocal electroretinography, fundus provides a non-invasive, quantitative, may help prevent further structur- autofl uorescence and near-infrared autofl uorescence. Br J high-resolution modality for imaging al and functional deterioration. As Ophthalmol 2009;93(11):1444-1447. HCQ retinopathy patients, and may such, clinicians should maintain a low allow detection of subclinical abnor- threshold for suspecting HCQ toxic- (continued on page 55)
August 2014 | Revophth.com | 51
044_rp0814_rtinsider.indd 51 7/25/14 2:24 PM Therapeutic Topics REVIEW
A Close Look at Pseudoexfoliation This disease is linked to vision loss, hearing loss and cataract. Learning more about it may help lead to better treatments. Mark B. Abelson, MD, CM, FRCSC, FARVO, and James McLaughlin, PhD, Andover, Mass.
edicinal nomenclature is a cu- pears in the anterior chamber and can coma, it was clear from earliest stud- M rious thing: The systematic logic lead to cataract, glaucoma and com- ies that patients developed glaucoma of Latin-based anatomical identifi ca- plications with intraocular surgery. from PXS as the exfoliative material tion contrasts with the haphazard ter- Here, we take a wide-ranging look at built up in and around the trabecular minology used in the naming of dis- what the latest research reveals about meshwork, slowed aqueous humor eases. So we call conditions “primary” PXS diagnosis, etiology, and genetics. outflow and caused an elevation in or “essential” if their underlying cause We also compare PXS with related intraocular pressure.3 While all of this is unknown, even though “idiopathic” disorders and discuss ideas for treat- is true, recent studies of the genetic would seem a more appropriate de- ment strategies. and physiologic mechanisms at work scriptor. Other diseases take on the in PXS, together with other glaucoma names of those who first described What’s in a Name research efforts, may provide clues them, such as Paget’s disease or Cush- leading to real progress in breaking ing’s syndrome, labels that say more The exfoliation syndrome associ- the mechanistic code for POAG. about the condition’s history than its ated with glaucoma that was fi rst de- etiology. Then there is the wholesale scribed in 1917 was later referred to Diagnosis of PXS use of the prefi x “pseudo,” telling us as pseudoexfoliation to distinguish it “looks like this disease, but it’s not.” it from an occupational condition of The central fi nding in a diagnosis of Ultimately, we end up with names like “true exfoliation,” a delamination of PXS is the presence of white or light pseudopseudohypoparathyroidism, the lens capsule common in glass- fl akes in the anterior chamber of the a bone disorder far simpler than its blowers.1 In the medical literature of eye, whose resemblance to epithelial name would imply. These pseudo- the early 20th century it was some- debris gave rise to the description as portmanteaus provide vague clues times called senile exfoliation, and exfoliation. Studies on the nature of to the underlying condition, but still was considered a relatively rare form the material suggest that it consists of leave us wishing for a more descrip- of secondary glaucoma restricted to connective tissues (elastin, collagen) tive, less verbose designation. those of advanced years and Nordic together with adhered enzymes.4,5 In ophthalmology, all of these ele- heritage. Even as recently as 2000, Histologically, exfoliation material ments contribute to pseudoexfoliative PXS was described as “a disease pri- stains with periodic acid-Schiff re- syndrome, a condition whose name is marily of people of Scandinavian de- agents, indicating the presence of car- at the same time descriptive, histori- scent, with some features that suggest bohydrates or proteoglycans. These cal and yet still a bit misleading. PXS a genetic component.”2 Unlike the properties led to the suggestion that is a systemic condition that fi rst ap- black box of primary open-angle glau- the debris included amyloid proteins,
52 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
052_rp0814_ttops.indd 52 7/25/14 2:26 PM and that it could be related to the cen- tral nervous system amyloid deposi- tion that occurs in Alzheimer’s disease. It turns out there is no association between the two disorders (although PXS is linked to several systemic con- All images: Ike Ahmed, MD Ahmed, Ike All images: ditions; see below).6,7 While PXS is anecdotally associated with the Scan- dinavian population, the syndrome accounts for a greater percentage of open-angle glaucomas than primary disease in other ethnic populations, particularly Arabic, Mediterranean and Japanese patients.4,8,9 Worldwide, it is the most common cause of sec- ondary glaucoma, and represents 5 to 18 percent of all open-angle disease. Fibrillar material on the patient’s anterior lens capsule is a hallmark sign of It’s estimated that, globally, 30 per- pseudoexfoliation syndrome. cent of people over age 60 have some form of anterior exfoliative deposits.2 nective tissue dysregulation is natu- generative neurological disorder, but Exfoliation syndrome goes beyond rally more readily identifi able in the several studies have established that the build up of anterior segment de- setting of the anterior segment. How- no linkage between the two disor- bris. Changes in the lens capsule and ever, systemic manifestations of PXS ders exists.6,7 Interestingly, a recent iris are also seen in PXS.1-3 Reduced have been investigated in both small- report suggested that deposition of dilation function due to build up of scale, retrospective studies and large- β-amyloid in the lens may be the fi rst PXS materials and degeneration of cohort, population-based research.10 reliable test for AD.14 both sphincter and dilator muscles As a disorder of connective tissues, The association of PXS with con- is often observed. In addition, focal particular interest has focused on the nective tissue dysregulation in the eye membrane disruption in melanin- potential impact of the disease on suggests that it may exert similar ef- containing epithelial cells yields a cardiovascular function. Despite this fects in other tissues, but for obvious pattern of peripupillary atrophy de- interest, the first prospective, case- reasons these effects are more readily scribed as “moth eaten.”2,4 controlled studies have only been identifi able in the setting of the ante- Collectively, PXS effects in the an- published in the past two to three rior segment. Case studies have sug- terior segment lead to ocular hyper- years. These studies confi rm that pa- gested associations between PXS and tension and open-angle glaucoma. tients with PXS exhibit higher risk of skin disorders, pulmonary disease and PXS is also associated with increases several common forms of vascular dis- additional renal conditions. Progress in angle closure, cataract and lens ease, including renal artery stenosis in identifying the genetic loci for PXS subluxation. Lens capsule atrophy in and abdominal aortic aneurysm.11,12 is likely to advance investigations into combination with poor mydriasis can Several other conditions have been these and other systemic diseases.15 make for challenging cataract surgery associated with PXS. An association in PXS patients.2,4 While the combina- with sensorineural hearing loss was Genetics of PXS and Glaucoma tion of IOP-lowering medications and shown in a study that compared au- surgical approaches used to treat PXS ditory function in PXS patients with Most of the genes linked to PXS is the same as that used for POAG, it’s age-matched controls.13 The study have been identified with genome- possible that a better understanding examined both frequency range and wide association studies.16,17 One of this glaucoma variant may lead to threshold sensitivities. In contrast, of the first such genes encodes one more fundamental progress in our the suggested association between member of a ubiquitous family of knowledge of all forms of the disease. PXS and Alzheimer’s disease has been enzymes involved in connective tis- discounted by a number of stud- sue metabolism, the lysyl oxidases. PXS: A Systemic Disease ies. Interest in this potential linkage The LOXL1 gene product induces stemmed from a desire to identify crosslinks between different sites on The association of PXS with con- reliable predictive markers for the de- extracellular matrix proteins, and it’s
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REVIEW Topics
the daunting Putting PXS Pieces Together question of why Another intriguing piece of this some develop puzzle is the phenomenon of normal- glaucoma while tension glaucoma, patients who ex- others do not. hibit the optic nerve head degenera- While lowering tion of glaucoma without an elevation IOP remains the in IOP. A growing body of evidence single best pre- implicates a mismatch in trans-lamina dictor of treat- cribrosa pressures in NTG.22,23 For ment success, some patients, normal ocular pressure patients with could still yield differential pressures normal-tension across the LC similar to those in pa- glaucoma show tients with elevated IOP, if these pa- that there’s tients had unusually low intracranial more to it than pressures. One condition in which that. this pressure difference at the LC Focal membrane disruption of melanin-containing cells can give the Research has may be an issue is idiopathic intra- iris a moth-eaten look in pseudoexfoliation. found that the cranial hypertension, a diagnosis as- common de- sociated with morbid obesity that is thought that polymorphisms in the nominator in all glaucoma-linked increasing worldwide.24 For patients gene associated with PXS encode an genes is an association with extracel- with IIH, severe headache and op- altered enzyme resulting in too many lular matrix and trabecular function, tic disc swelling are the primary di- crosslinks or inappropriate crosslinks, but these same genes may also be par- agnostic features. These individuals and ultimately a brittle, more easily ticipants in homeostasis of the lamina have cerebrospinal fluid pressures damaged matrix. cribrosa matrix. A unifying link, then, that exceed normal IOP values. In GWAS have identifi ed the LOXL1 is a common effect on the extracel- severe cases, patients may require locus as a PXS-associated gene in lular matrix at both the front and the CSF shunting to reduce intracranial subjects from diverse genetic back- back of the eye.19,20 fl uid pressures, but these devices typi- grounds, further strengthening the Changes in the signaling pathway cally yield extremely low intracranial case for the gene as a key factor in regulated by TGFβ is another aspect fl uid pressures, effectively “fl ipping” PXS disease. Despite this, other loci of glaucoma pathophysiology seen the trans-LC pressure differential. including genes for the extracellular in pseudoexfoliation and in all other Patients with long-term in-dwelling matrix protein, clusterin, the enzyme forms of the disease. Patients with shunts are at increased risk for glau- glutathione transferase and the sig- glaucoma of any etiology exhibit el- coma, and there is a recent prospec- naling peptide TNF-α have also been evated aqueous humor TGFβ, a cyto- tive study showing that NTG patients implicated in PXS disease.8 Other fac- kine that both regulates matrix forma- have significantly lower CSF pres- tors, including unilateral presentation tion and causes increases in IOP.20, 21 sures than either controls or high-IOP and variability in onset suggest that Consistent with this role of TGFβ are glaucoma patients.25 PXS etiology results from the com- two genetic disorders: Marfan syn- One explanation for these observa- bined effects of genetic predisposition drome and congenital scleroderma. tions is that factors such as elevated coupled with one or more environ- Both of these conditions are due to a TGFβ are responses to the pressure mental factors. mutation of the microfi bril-associated differentials sensed at the level of the Genetics of POAG are complex, and gene FBN1, both exhibit elevated LC, the trabecular meshwork or both. identifi cation of glaucoma-associated TGFβ and both include glaucoma as Elevation of matrix regulatory stimuli genes such as myocilin or optineurin part of the spectrum of their pheno- may initiate a positive feedback cycle has provided some insight without types. A recurring question in all of in which remodeling could promote yielding breakthroughs in either the these observations regards cause and or facilitate cupping, nerve damage etiology or treatment of the disease.18 effect: Are elevated cytokines and el- and further remodeling. While spec- While identifi cation of genes involved evated intraocular pressure responses ulative, this idea is consistent with in PXS may provide a clearer patho- to altered matrix dynamics, or are current therapeutic standards that physiology for the exfoliative aspects they somehow the initiators of these primarily slow the process down. An of the syndrome, we are still left with responses? interesting idea might be to test a dual
54 | Review of Ophthalmology | August 2014
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REVIEW Insider
5. Sein J, Galor A, Sheth A, et al. Exfoliation syndrome: New (continued from page 51) therapy of IOP-lowering agents in genetic and pathophysiologic insights. Curr Opin Ophthalmol combination with antagonists of ma- 2013;24:2:167-74. 11. Chen E, Brown DM, Benz MS, et al. Spectral domain optical β 6. Ekström C, Kilander L. Pseudoexfoliation and Alzheimer’s coherence tomography as an effective screening test for hydroxy- trix remodeling factors such as TGF disease: A population-based 30-year follow-up study. Acta chloroquine retinopathy (the “fl ying saucer” sign). Clin Ophthalmol or connective tissue growth factor.26 Ophthalmol 2014;92:355-8. 2010;4:1151-1158. 7. Abramsson A, Landgren S, Zetterberg M, et al. No association 12. Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning This combination could, in theory, of LOXL1 gene polymorphisms with Alzheimer’s disease. of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond) 2010;24(5):756-762; quiz 763. Neuromolecular Med 2011;13:2:160-6. halt the remodeling cycle, reducing 13. Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxy- the effects of the TGFβ signaling 8. Elhawy E, Kamthan G, Dong CQ, Danias J. Pseudoexfoliation chloroquine or chloroquine on inner retinal structures. Eye (Lond) syndrome, a systemic disorder with ocular manifestations. 2010;24(2):340-346. pathway at both the front and the Human Genomics 2012;6:22. 14. Ulviye Y, Betul T, Nur TH, Selda C. Spectral domain optical coher- back of the eye. 9. Olawoye OO, Pasquale LR, Ritch R. Exfoliation syndrome in ence tomography for early detection of retinal alterations in patients sub-Saharan Africa. Int Ophthalmol 2014 May 21. [Epub ahead using hydroxychloroquine. Indian J Ophthalmol 2013;61(4):168-171. This allows us to return to one of of print] 15. Kennedy CJ, Rakoczy PE, Constable IJ. Lipofuscin of the retinal those inappropriately named diseases 10. Cedrone C, Mancino R, Ricci F, et al. The 12-year incidence pigment epithelium: A review. Eye (Lond) 1995;9 ( Pt 6)):763-771. 16. Okubo A, Rosa RH, Jr., Bunce CV, et al. The relationships of age of glaucoma and glaucoma-related visual fi eld loss in Italy: The that we touched on earlier in this dis- changes in retinal pigment epithelium and Bruch’s membrane. Invest Ponza eye study. J Glaucoma 2012;21:1:1-6. Ophthalmol Vis Sci 1999;40(2):443-449. cussion, Marfan syndrome. Marfan 11. Gonen KA, T Gonen T, Gumus B. Renal artery stenosis and 17. Holz FG, Bellman C, Staudt S, Schutt F, Volcker HE. Fundus auto- is an autosomal dominant disorder abdominal aorta aneurysm in patients with pseudoexfoliation fl uorescence and development of geographic atrophy in age-related syndrome. Eye 2013;27:735–741. macular degeneration. Invest Ophthalmol Vis Sci 2001;42(5):1051- caused by dysregulation of the gene 12. Djordjevic-Jocic J, Jovanovic P, Bozic M, et al. Prevalence 1056. for fibrillin 1, a connective tissue and early detection of abdominal aortic aneurysm in 18. Kellner U, Renner AB, Tillack H. Fundus autofl uorescence and mfERG for early detection of retinal alterations in patients us- pseudoexfoliation syndrome and pseudoexfoliation glaucoma. protein. Although it is still in the in- ing chloroquine/hydroxychloroquine. Invest Ophthalmol Vis Sci Curr Eye Res 2012;37:617-23. 2006;47(8):3531-3538. vestigational stage, early clinical data 13. Singham NV, Zahari M, Peyman M, et al. Association between 19. Marmor MF. Fundus autofl uorescence is not the best early screen suggest that a family of drugs called ocular pseudoexfoliation and sensorineural hearing loss. J for hydroxychloroquine toxicity. JAMA Ophthalmol 2013;131:1487- Ophthalmol 2014;2014:825936. Epub 2014 Apr 17. 1488. sartans (such as losartan) that are clas- 14. Kerbage C, Sadowsky CH, Tariot PN, et al. Detection of 20. Lyons JS, Severns ML. Detection of early hydroxychloroquine sifi ed as angiotensin antagonists may amyloid β signature in the lens and its correlation in the brain to retinal toxicity enhanced by ring ratio analysis of multifocal electro- aid in the diagnosis of Alzheimer’s disease. Am J Alzheimers Dis retinography. Am J Ophthalmol 2007;143:801-809. be effective in reducing risk of aortic 21. Maturi RK, Folk JC, Nichols B, Oetting TT, Kardon RH. Hydroxy- Other Demen.2014 Feb 14. [Epub ahead of print] aneurysm, the major risk in patients chloroquine retinopathy. Arch Ophthalmol 1999;117:1262-1263. 15. Schlötzer-Schrehardt U. Molecular pathology of 22. Lai TY, Chan WM, Li H, Lai RY, Lam DS. Multifocal electroretino- 27 with this syndrome. In addition to pseudoexfoliation syndrome/glaucoma – new insights from graphic changes in patients receiving hydroxychloroquine therapy. LOXL1 gene associations. Exp Eye Res;88:776-785. Am J Ophthalmol 2005;140:794-807. their action on the Renin-Angiotensin 16. Lemmela S, Forsman E, Sistonen P, Eriksson A, Forsius H, 23. Lai TY, Ngai JW, Chan WM, Lam DS. Visual fi eld and multifocal system, these drugs also act as physi- Jarvela I. Genome-wide scan of exfoliation syndrome. Invest electroretinography and their correlations in patients on hydroxychlo- β Ophthalmol Vis Sci. 2007; 48:4136–4142. roquine therapy. Doc Ophthalmol 2006;112(3):177-187. ological antagonists of TGF . For 24. Maturi RK, Yu M, Weleber RG. Multifocal electroretinographic 17. Thorleifsson G, Magnusson KP, Sulem P, et al. Common Marfan patients, the drug presumably evaluation of long-term hydroxychloroquine users. Arch Ophthalmol sequence variants in the LOXL1 gene confer susceptibility to 2004;122:973-981. attenuates excessive matrix synthe- exfoliation glaucoma. Science 2007;317:1397-1400. 25. Lyons JS, Severns ML. Using multifocal ERG ring ratios to detect 18. Fingert JH. Primary open angle glaucoma genes. Eye (Lond) and follow Plaquenil retinal toxicity: a review : Review of mfERG ring sis in the walls of the great arteries. 2011;25:587-95. ratios in Plaquenil toxicity. Doc Ophthalmol 2009;118(1):29-36. Patients with PXS, as well as those 19. Schlötzer-Schrehardt U, Hammer CM, Krysta AW, et al. LOXL1 26. Tzekov RT, Gerth C, Werner JS. Senescence of human multifocal with POAG, might receive benefit defi ciency in the lamina cribrosa as candidate susceptibility electroretinogram components: A localized approach. Graefes Arch factor for a pseudoexfoliation-specifi c risk of glaucoma. Clin Exp Ophthalmol 2004;242(7):549-560. 27. Browning DJ. Impact of the revised american academy of oph- from similar potential actions at the Ophthalmology 2012;119:9:1832-43. thalmology guidelines regarding hydroxychloroquine screening on TM and LC. Perhaps calling sartans 20. Kuchtey J, Kuchtey RW. The microfi bril hypothesis of actual practice. Am J Ophthalmol 2013;155:418-428.e411. angiotensin inhibitors is yet another glaucoma: Implications for treatment of elevated intraocular 28. Marmor MF, Melles RB. Disparity between Visual Fields and Opti- pressure. J Ocul Pharm Ther 2014;30:170-180. cal Coherence Tomography in Hydroxychloroquine Retinopathy. Oph- example of where an inaccurate name 21. Fuchshofer R. The pathogenic role of transforming growth thalmology 2014;121:1257-62. actually leaves out the most impor- factor- 2 in glaucomatous damage to the optic nerve head. Exp 29. Roorda A, Romero-Borja F, Donnelly Iii W, Queener H, Hebert T, Eye Res 2011;93:2:165-9. Campbell M. Adaptive optics scanning laser ophthalmoscopy. Opt Express 2002;10(9):405-412. tant, and most intriguing, characteris- 22. Fleischman D, Allingham RR. The role of cerebrospinal fl uid 30. Park SP, Chung JK, Greenstein V, Tsang SH, Chang S. A study of tics of the drug. pressure in glaucoma and other ophthalmic diseases. Saudi J of factors affecting the human cone photoreceptor density measured Ophthalmol 2013;27:97–106. by adaptive optics scanning laser ophthalmoscope. Exp Eye Res 23. Jonas JB, Wang N, Wang YX, et al. Ocular hypertension: General 2013;108:1-9. Dr. Abelson is a clinical professor characteristics and estimated cerebrospinal fl uid pressure. The 31. Kim JE, Chung M. Adaptive optics for retinal imaging: Current of ophthalmology at Harvard Medical Beijing eye study 2011. PLoS One 2014;9:7:e100533. status. Retina 2013;33:1483-1486. 24. Wakerly BR, Tan MH, Ting EY. Idiopathic Intracranial 32. Carroll J, Neitz M, Hofer H, Neitz J, Williams DR. Functional pho- School. Dr. McLaughlin is a medical hypertension. Cephalalgia. 20 May 2014. pii: 0333102414534329. toreceptor loss revealed with adaptive optics: An alternate cause of color blindness. Proc Natl Acad Sci U S A 2004;101(22):8461-8466. [Epub ahead of print]. writer at Ora Inc. in Andover. 33. Stepien KE, Martinez WM, Dubis AM, Cooper RF, Dubra A, Carroll 25. Ren R, Jonas JB, Tian G, et al. Cerebrospinal fl uid pressure in J. Subclinical photoreceptor disruption in response to severe head 1. Johnson DH. The exfoliation syndrome: A continuing challenge. glaucoma: A prospective study. Ophthalmology 2010;117:2:259- trauma. Arch Ophthalmol 2012;130:400-402. In: Albert DM and Jakobiec FA, ed. Principles and Practices of 66. 34. Bae EJ, Kim KR, Tsang SH, Park SP, Chang S. Retinal damage in chloroquine maculopathy, revealed by high resolution imaging: A Ophthalmology, 2nd ed. Philadelphia: WB Saunders, 2000:2718- 26. Wallace DM1, Clark AF, Lipson KE, Andrews D, Crean JK, case report utilizing adaptive optics scanning laser ophthalmoscopy. 2730. O’Brien CJ. Anti-connective tissue growth factor antibody treatment reduces extracellular matrix production in trabecular Korean J Ophthalmol 2014;28(1):100-107. 2. Ritch R, Schlötzer-Schrehardt U. Exfoliation syndrome. Surv 35. Jivrajka RV, Genead MA, McAnany JJ, Chow CC, Mieler WF. Micro- meshwork and lamina cribrosa cells. Invest Ophthalmol Vis Sci Ophthalmol 2001;45:265-315. perimetric sensitivity in patients on hydroxychloroquine (Plaquenil) 3. Davis RE, Schuman JS. Pseudoexfoliation Syndrome: Don’t 2013;54:13:7836-48. therapy. Eye (Lond) 2013;27(9):1044-1052. brush it off. Br J Ophthalmol.2013;97:1091-1092. 27. Matt P, Eckstein F. Novel pharmacological strategies to 36. Martinez-Costa L, Victoria Ibanez M, Murcia-Bello C, et al. Use 4. Schlötzer-Schrehardt U, Naumann GO. Ocular and systemic prevent aortic complications in Marfan syndrome. J Geriatr of microperimetry to evaluate hydroxychloroquine and chloroquine pseudoexfoliation syndrome. Am J Ophthal 2006;141:921-937. Cardiol 2011;8:4:254-7. retinal toxicity. Can J Ophthalmol 2013;48(5):400-405.
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REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD
The Fluid Wave: Evaluating Canal Surgery Creating an episcleral venous fl uid wave during canal surgery can help surgeons predict the likelihood of success. Ronald L. Fellman, MD, and Davinder S. Grover, MD, MPH, Dallas
n open-angle glaucoma, the existing drainage system. Instead of IOP could be lowered to the level of I eye’s natural outfl ow channels fail abandoning the compromised outfl ow their episcleral venous pressure. to adequately drain aqueous humor. system, the surgeon and patient choose Despite the advantages of canal This increased resistance to outfl ow to try and enhance fl ow through the surgery, it has a few drawbacks. One causes chronic elevation of intraocular native collector system. This bleb-less major challenge is that it’s diffi cult to pressure with eventual nerve fiber option is used especially for patients predict the success of the procedure. layer damage and corresponding fi eld with mild to moderate disease, before Here, we describe a strategy we’ve loss, the hallmarks of open-angle their natural collector channels have developed that can be used during the glaucoma. collapsed or atrophied. surgery to give the surgeon a sense of For many decades, surgeons The beauty of this type of micro- whether or not the minimally invasive lowered IOP by circumventing the invasive canal-based surgery is that glaucoma procedure is likely to lead to abnormal resistance of the eye’s in- it improves flow into the patient’s a favorable outcome. herent drainage system by performing own natural drainage system, instead trabeculectomy and creating a new of creating an artificial one. (When Collector Channels Revisited outlet. This surgeon-made artificial explained appropriately, most patients outflow track abandoned the eye’s understand the concept of improving There are two major aqueous natural drain by shunting aqueous to flow into their natural drain that’s outflow pathways in the eye: con- the subconjunctival space, forming been damaged by glaucoma.) This ventional and nonconventional. Con- a bleb. The potential problems asso- elegant microinvasive surgery also ventional outflow is the trabecular ciated with bleb-forming surgery are combines well with cataract surgery, meshwork-Schlemm’s canal-collector well known to all ophthalmologists; making it possible to achieve two goals channel path that empties into the they include hypotony maculopathy; with one surgery, without substantially episcleral veins; nonconventional out- scarring; dysesthesia; leaks; blebitis; increasing the surgical risk. flow is via the uveoscleral pathway and choroidal hemorrhage. Creating a limbal fistula to drain (i.e., suprachoroidal). Understanding In recent years, thanks to advances aqueous, as when implanting a fi lter, the anatomy of these outflow path- in technology and the relentless pur- typically lowers IOP more than a ways is key to understanding how the suit of a better procedure, glaucoma canal-based procedure, but not every newer glaucoma surgeries work (See surgeons are shifting away from bleb- glaucoma patient has advanced dis- Figure 1). forming procedures and moving ease that requires a subnormal IOP. Many surgeons are not well-ac- toward more physiologic operations A signifi cant number of patients could quainted with the conventional col- that enhance fl ow through the eye’s have their glaucoma stabilized if their lector channels, probably for a couple
56 | Review of Ophthalmology | August 2014 This article has no commercial sponsorship.
056_rp0814_gm.indd 56 7/25/14 3:11 PM of reasons. For one thing, to better understand you can’t easily visualize the why the procedure was collectors at the slit lamp successful or failed. If one during a clinical exam. Also, visualizes a diffuse bleb because canal surgery hasn’t and it correlates with a been a common approach low IOP, it makes sense. to treating glaucoma for If the IOP is elevated many decades, there has and a bleb is not present, been less need to pay one understands why the attention to the collector procedure failed. With channels. In the 1960s, the canal-based surgery, the advent of trabeculotomy only marker we have is created excitement about the postoperative pres- angle surgery and spurred sure; if the pressure extensive research and dis- is low, we assume the cussion. However, seg- collectors are working, Figure 1. The trabecular meshwork-Schlemm’s canal-aqueous mental trabeculotomy with episcleral venous outfl ow pathway is illustrated on the right; the but we don’t have any way a metal trabeculotome, as uveoscleral or suprachoroidal outfl ow pathway is illustrated on the to know for sure. That’s invented by H. Mermann left. Microinvasive canal surgery is dependent on the integrity of the especially true when we Burian, MD, and Lee Allen, trabecular meshwork, collector channels and downstream venous do phacoemulsifi cation at MD, didn’t produce favor- network for favorable outcomes. the same time, because able long-term outcomes, so it’s conceivable that the interest and excitement waned. The focus on minimally invasive glaucoma lowered pressure was a consequence technology simply wasn’t as good as surgery will provide greater insight of the cataract surgery. what we have today. into the canal and distal collector If canal surgery fails, granted the Ultimately, interest in the natural systems. above limitations, there are several drainage channels plummeted when possible reasons: trabeculectomy was invented. This What Can Go Wrong • The stent you placed didn’t end new surgery allowed surgeons to make up next to a functioning collector a hole in the eye and create a new, The purpose of canal surgery is to channel. Unfortunately, the fl ow of nonphysiologic drainage channel, optimize the traditional conventional aqueous around Schlemm’s canal is abandoning the patient’s natural outflow pathway by shunting fluid limited. That means we can’t expect collectors. After creating an external into the collector channels and out to lower IOP simply by getting more new drainage pathway, it was not as through the episcleral veins. One fl uid into the canal; we have to get it important to focus on the episcleral problem with this approach has into the canal at points where there veins or collector channels. As a been that it’s very diffi cult to assess are nearby viable collector channels. result, much of the science relating the preoperative, intraoperative That’s still a challenge because we to the collector channels ground to a or postoperative condition of the don’t have any easy or definitive standstill, and their role in glaucoma collector channels and episcleral way to determine the location of the therapy was slowly de-emphasized veins. (For example, Matthias C. collectors. and eventually forgotten. Grieshaber, MD, evaluated the • The collector channels have Today, however, canal-based sur- collector channels with dye during atrophied. One of the things that geries are experiencing a renaissance. canaloplasty and found that the can go wrong in the eye’s natural As a result, the collector channels degree of dye dispersion into the veins drainage system is loss of the collector have become a topic of interest correlated with a lower postoperative channels. This might happen, for again. However, our understanding of IOP.1) Generally, if the surgery fails to example, if ongoing high IOP caused Schlemm’s canal, the distal collector produce the desired outcome, we’ve the trabecular meshwork to be con- system and wound healing in the angle had to resort to guessing what the stantly pushed against the back lag far behind our understanding of reason might be. wall of Schlemm’s canal where the trabeculectomy, glaucoma drainage In contrast, with trabeculectomy collectors are located, shutting them tubes and wound modulation with there is a visible outcome marker: off, resulting in downstream channel anti-metabolites. Hopefully, this new the bleb, which enables the surgeon atrophy. If you were to place an
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REVIEW Management
iStent next to atrophied canal procedures are collector channels, the performed in the nasal result would likely be quadrant using a tem- disappointing. Even if poral approach. the surgery itself went The collector channel perfectly, the fluid system is intricate and would have nowhere to difficult to evaluate. It go and the IOP would runs through what is remain elevated. called the scleral plexus, In an ideal world, which is fairly complex we’d have some way to and contains several evaluate the patency layers that aqueous must and capacity of the pass through to reach collector channels be- the episcleral veins; the fore deciding to do exception is a major canal surgery, but at vein of Ascher, which the moment no such Figure 2. This diagram depicts the route of aqueous humor once it leaves has a direct route from method exists. Schlemm’s canal. Aqueous must pass through the collector channels to the the canal to the epi- • The stent is mal-deep scleral plexus (blue), then to the mid plexus (brown), fi nally arriving at scleral vein (See Figure positioned. There is the episcleral plexus (red). We are currently unable to visualize this 2). The layer on the a learning curve for pathway preoperatively. However, we can see episcleral fl ow during bottom is called the all ophthalmic pro- surgery (assuming the intrascleral pathway is intact) by visualizing the deep scleral plexus; the episcleral venous wave. Note: The large laminated red vein—an cedures. After insertion aqueous vein of Ascher—originates from the canal and bypasses the entire one in the middle is the of a device, it may be intrascleral network (deep and mid). This large vein can often be seen mid-scleral plexus; and malpositioned and postoperatively at the slit lamp and usually correlates with low IOP. the one on the top is the therefore not function- episcleral plexus. At the ing correctly. However, it can be That’s where the episcleral venous slit lamp you can see the channels in difficult to determine whether the fluid wave comes in; observing this the episcleral plexus because they’re device is properly placed. wave near the end of surgery may close to the surface, but you can’t see • Scarring has blocked the ow.fl provide real information about the others because they’re deeper in If the IOP drops after the surgery whether the device is properly the sclera. Because we’re not able to and then climbs back up a few weeks located (or the Trabectome has visualize the majority of the collector or months later, the issue is most been performed correctly) and the system, it’s very diffi cult to study and likely wound healing. Unfortunately, anatomic condition of nearby ac- evaluate. the reality is that we’re not able cessed collector channels, via the clock One exception to this is the pre- to modulate wound healing in the hours and the extent of the wave. The viously mentioned aqueous veins canal at this point in time. This is characteristics of the episcleral fl uid of Ascher, larger drainage collector partly because we can’t see what’s wave may help predict the outcome channels fi rst discovered in the 1950s happening; we don’t know if the col- of the procedure, and may suggest the by Norman Ascher, MD. While it’s lectors are closing down. And it’s not reason for success or failure. not possible to see aqueous moving necessarily a simple thing to do; it through most veins in the sclera, it is took about 60 years to understand Collector System Anatomy possible to see aqueous mixing with how to modulate wound healing blood in vivo at the slit lamp in the with trabeculectomy so it didn’t scar The human eye has 25 to 35 cir- larger aqueous veins of Ascher. And down—and in some cases it still does cumferential collector channels. Ap- if you were able to place a stent next anyway. We’re in our infancy trying proximately six of these collectors to one of these channels, it’s likely to understand wound healing in the are connected to large venous emis- the surgery would produce more canal and collector channels, and that saries: the aqueous veins of Ascher. favorable results. puts us at a disadvantage. The majority of these larger veins The overall problem for us as sur- are located nasally and inferiorly, The Fluid Wave Explained geons is that all of these issues are especially inferonasally. That lo- diffi cult, if not impossible, to evaluate. cation is fortuitous, because most The episcleral venous fl uid wave is
58 | Review of Ophthalmology | August 2014
056_rp0814_gm.indd 58 7/25/14 3:11 PM a transient blanching of the episcleral vessels adjacent to a canal-based surgical site, seen during irrigation and aspiration, fi rst described by us during a phacotrabectome surgery.2 Creation of the episcleral venous fluid wave is all about generating pressure differentials. Normally, the pressure in the episcleral veins is around 15 mmHg. If one stops the infusion of balanced salt solution during irrigation and aspiration, the intracameral pressure drops to about 2 or 3 mmHg. The resulting pressure Figure 3. Top: A phacotrabectome case displaying a marked episcleral venous fl uid wave. differential encourages blood to re- Top left: Baseline view of episcleral veins, no I/A, foot position zero, low IOP. Top right: View flux from the collector system into of the same episcleral veins with I/A, high infusion, foot position two and high IOP. The high the anterior chamber through the IOP reverses the pressure gradient; BSS fl ows through the adjacent cleaved meshwork into canal, specifically in areas where the veins, washing out the blood. Note how the small veins near numbers 1 and 3, and the the trabecular meshwork has been large vein near number 2, are far less visible on the right. This case was graded a four-plus bypassed or ablated. If the infusion of wave, suggesting a functioning trabecular outfl ow system. Bottom: a minimal episcleral venous fl uid wave. Left: baseline view. Right: view during episcleral venous fl uid wave. BSS is then restarted, there’s a rapid Small differences can be seen near numbers 1 and 2, but nothing like the case above. reversal of the pressure gradient; This episcleral venous fl uid wave is graded one-plus, suggesting limited function of the BSS will flow out through the path trabecular outfl ow system and the likelihood of a poor outcome for canal-based surgery. of least resistance, which is usually the collector channels underlying the (Of course, if you tried to generate the for evaluating episcleral fl ow, much area of trabecular meshwork that has wave during a phacoemulsification like during the famed outfl ow cadaver been cleaved or stented. This surge procedure without canal surgery, you studies of Paul Chandler and W. of BSS washes the blood into the wouldn’t see anything, because an Morton Grant. Sure enough, we did. downstream collector system and intact canal will not let BSS into the We quickly discovered that when you creates a blanching of the episcleral collector channels. The exchange of open up a section of the canal with venous plexus (See Figure 3, above). fluids in the veins doesn’t happen the Trabectome you typically see the When the veins fill with BSS, they unless you’ve stented or opened the episcleral venous fl uid wave at those either become invisible, or one is able canal to the anterior chamber.) same clock hours.2 to appreciate a train-track appearance Using the episcleral venous fluid This has been true for all the canal of blood lining the inner-wall of the wave to evaluate the condition of surgeries we’ve tried. If we implanted episcleral veins, representing laminar the collector system first occurred an iStent, we’d see one to two clock fl ow. to us during viscocanalostomy. We hours of fl ow into the adjacent veins. This visual change in the presence noted that during viscocanalostomy, If we implanted a Hydrus shunt, of the episcleral venous fluid wave in which you unroof the canal ab which covers three to four clock hours tells the surgeon that there is externo, it was possible to inject BSS of the canal, we’d see an equivalent communication between the anterior into the canal and see fl ow into the area of fl ow. We recently published chamber and the downstream nearby episcleral veins. That was very a technique we developed called collector system. That means the exciting, because for the fi rst time we gonioscopy-assisted transluminal collector channels are probably patent, had intraoperative evidence of the trabeculotomy, or GATT, in which even at the levels we cannot see; after patency of the conventional collector we open up 360 degrees of the canal all, the fl uid has to go through those system. Sometimes we would see a using a microcatheter.3 This resulted levels to make it to the visible veins. great deal of fl ow, sometimes minimal in seeing the fl ow all the way around A good visible fl uid wave is a strong fl ow. The same thing happened with the sclera. piece of evidence that the collector canaloplasty. When the Trabectome Of course, this is only true under channel system is at least anatomically came along, we wondered if we optimal circumstances. There are functional, although there is no could see the same phenomenon ab cases in which the fl ow through the evidence of its physiologic function. interno, a more self-contained model collector channels is minimal. That
August 2014 | Revophth.com | 59
056_rp0814_gm.indd 59 7/25/14 3:11 PM Dear Third Year Residency Program Director,
We would like to invite you to review the upcoming 3rd Year Residency Program for 2014. This program offers a unique educational opportunity for third-year residents by providing the chance to meet and exchange ideas with some of the most respected thought leaders in ophthalmology. The program is designed to provide your residents with a state-of-the-art didactic and wet lab experience. The program also serves as an opportunity for your residents to network with residents from other programs.
After reviewing the material, it is our hope that you will select and encourage your residents to attend this educational program.
Best regards, Postgraduate Healthcare Education Third-Year Residency Program 2014:
September 12-13 Fort Worth, TX Program Chair: Anthony Arnold, MD
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2014_CSE_dir_september.indd 86 7/15/14 1:48 PM Glaucoma
REVIEW Management
may mean one of several things: the during the wave, not just the larger not the pressure-lowering part of the distal collectors may be atrophic; in veins. You’ll often see a network of procedure will work. the case of a shunt, the device may tiny veins between the larger veins, We think one day we’ll have an be in the wrong location; possibly the which have a reticulated network optical coherence tomographer back pressure in the veins is excessive; appearance. If the fl ow is good, the or some other technology that will or more likely, there’s some other fluid will also push the blood down allow us to visualize and evaluate the problem we don’t yet understand. these veins, making the whole area collector channels. When we have that, One likely reason the wave has not briefl y turn white. Of course, if your we’ll be able to improve our results been appreciated until recently is that surgery opens the path into one of with canal-based surgery. We’ll be when we’re operating we’re always the three to six veins of Ascher, which able to tell a patient that her collector looking at what’s going on through likely connect directly to the canal, channels can be salvaged. Or, we’ll the pupil or in the anterior chamber. you may see a large surge of BSS into be able to say that the patient’s distal During cataract surgery you’re not the vein of Ascher. collectors are atrophic and probably looking at the sclera. To observe the We think a four-plus wave is a not functional, so we’ll do some presence or absence of an episcleral sign that the patient is going to do other procedure, perhaps designed venous fl uid wave, you not only have well—or at least better than a patient to increase fl ow into the uveoscleral to perform the test, you also have to who doesn’t have a wave. (We’re pathway. If that doesn’t work, we’ll make a point of looking at the adjacent currently evaluating this.) Seeing a still be able to fall back on trabec- episclera. surge of fluid running down those ulectomy. Unfortunately, the tech- veins means they are anatomically nology that will let us evaluate the Real-World Use patent. Unfortunately, we can’t say collector system is probably fi ve or 10 with certainty that they’re functional, years away. We now use the fl uid wave to test because functional means the aqueous Microinvasive canal surgery is in the patency of the collector channels will fl ow through there under normal its infancy, especially compared to as part of every canal procedure. physiologic conditions. Forcing fl uid trabeculectomy. Over time we’ll work Currently, for example, we frequently through them in the OR is not very out the best way to increase flow combine a Trabectome procedure physiologic, but it’s all we have. We into the canal and the best way to with phacoemulsification. We start can’t see the collectors preoperatively modulate wound healing. It took a the procedure with the Trabectome, or postoperatively with any regularity, long time to improve trabeculectomy, then do the cataract surgery. During but by using the episcleral venous and it will take a long time to improve the irrigation/aspiration portion, fl uid wave we can at least see them in canal surgery. But we think the odds while removing viscoelastic, assuming the operating room. of us improving canal surgery are everything is coming along nicely, the much greater today because of our limbus and sclera are visualized to see Riding the Wave technology—and because small- the veins. incision cataract surgery works so well Next, we carry out the maneuver to As canal surgery becomes more in conjunction with this type of canal elicit the episcleral venous fl uid wave. popular, the episcleral venous fluid procedure. We go to foot position zero and let the wave can help us identify potential pressure drop, hopefully producing problems and give us a sense of Drs. Fellman and Grover are a reflux of blood from the veins. whether the surgery is likely to be attending surgeons and clinicians (The refl ux spot is the best location successful. It provides some infor- at Glaucoma Associates of Texas in to initially look for the wave.) Then mation about the patency of the col- Dallas. we access foot position two, creating lector channels before we complete 1. Grieshaber MC, Pienaar A, Olivier J, Stegmann R. Clinical a surge of fluid into the anterior the surgery. evaluation of the aqueous outfl ow system in primary open- chamber. (We raise the BSS bottle In addition, seeing the wave (or not angle glaucoma for canaloplasty. Invest Ophthalmol Vis Sci height for this part.) The degree, loca- seeing it) can also help the surgeon 2010;51:3:1498-504. doi: 10.1167/iovs.09-4327. Epub 2009 Nov 20. tion and extent of the wave are re- set appropriate patient expectations. 2. Fellman RL, Grover DS. Episcleral Venous Fluid Wave: corded. This adds a couple of minutes You can tell the patient that you saw a Intraoperative Evidence for Patency of the Conventional Outfl ow System. J Glaucoma 2012 Dec 31. [Epub ahead of print] to the case. (If you need to, you can lot of fl ow going through his collector 3. Grover DS, Godfrey DG, Smith O, Feuer WJ, Montes de Oca elicit the wave multiple times.) channels, and that’s a good sign; or I, Fellman RL. Gonioscopy-assisted transluminal trabeculotomy, ab interno trabeculotomy: Technique report and preliminary If the flow is four-plus, an entire you might say you didn’t see a lot of results. Ophthalmology 2014;121:4:855-61. doi: 10.1016/j. section of the sclera may blanch flow, so you don’t know whether or ophtha.2013.11.001. Epub 2014 Jan 10.
August 2014 | Revophth.com | 61
056_rp0814_gm.indd 61 7/25/14 3:12 PM Cover Retina
REVIEW Focus
(continued from page 43) sured in all patients with mac- ular edema before initiating occlusion is short-duration PAS- treatment with an intravitreal CAL macular photocoagulation, anti-VEGF agent. which appears to be safe and provide anatomical improve- Future ment.6 “Right now, surgery is rarely According to Dr. Hariprasad, used and is reserved for people the future of treating retinal vein who, with chronic treatment occlusion looks bright. “There over a long period of time, don’t are other sustained-delivery ste- respond,” Dr. Boyer says. “If we roid devices that are being in- can duplicate the surgery, mean- vestigated, and sustained deliv- ing that a study could be done Figure 3. Early-phase fl uorescein of branch retinal vein ery of steroids and anti-VEGF that shows the benefi t of surgery occlusion. agents will be a godsend for over anti-VEGF therapy, then I these patients. We are also look- think more people would utilize ing at wide-fi eld angiography to it, but there are risks involved see if peripheral nonperfusion with surgery and no standard- has a role in the management of ization of the treatment. If sur- this disease,” he explains. gery could be standardized and more reliable with a low com- 1. Yuan A, Ahmad BU, Xu D, et al. Comparison of intravitreal ranibizumab and bevacizumab for the treatment of plication rate, I defi nitely think macular edema secondary to retinal vein occlusion. Int J it would be something that we Ophthalmol 2014;7(1):86-91. 2. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone would have to consider.” intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results. Ophthalmology 2011;118:2453-2460. Systemic Treatments 3. Maturi RK, Chen V, Raghinaru D, Bleau L, Stewart MW. A 6-month, subject-masked, randomized controlled study Interestingly, systemic treat- to assess effi cacy of dexamethasone as an adjunct to bevacizumab compared with bevacizumab alone in ment may play a role in resolv- Figure 4. Late-phase fl uorescein of branch retinal vein the treatment of patients with macular edema due to ing macular edema. Three re- occlusion. central or branch retinal vein occlusion. Clin Ophthalmol cent cases of macular edema 2014;8:1057-1064. 4. Singer MA, Cohen SR, Groth SL, Porbandarwalla S. associated with retinal vein occlusion pertension, the macular edema as- Comparing bevacizumab and ranibizumab for initial reduction of improved after successful treatment sociated with retinal vein occlusion central macular thickness in patients with retinal vein occlusions. 7 Clin Ophthalmol 2013;7:1377-1383. of systemic hypertension alone. had decreased and her VA improved 5. Korobelnik JF, Holz FG, Roider J, et al; GALILEO Study Group. The first case was a 72-year-old to 20/20. Intravitreal afl ibercept injection for macular edema resulting from woman with a central retinal vein The third case was a 71-year-old central retinal vein occlusion: One-year results of the Phase 3 GALILEO Study. Ophthalmology 2014;121:202-208. occlusion who had macular edema in man with branch retinal vein occlu- 6. Heier JS, Clark WL, Boyer DS, et al. Intravitreal afl ibercept her left eye and visual acuity of 20/50. sion. His visual acuity was 20/50, injection for macular edema due to central retinal vein occlusion: Two-year results from the COPERNICUS Study. Ophthalmology Her blood pressure was 169/96 and his blood pressure was 165/87 2014;121:1414-1420. mmHg, and she was prescribed a mmHg. One month after initiation 7. Brown DM, Campochiaro PA, Singh RP, et al; CRUISE calcium blocker. One month after of treatment for systemic hyperten- Investigators. Ranibizumab for macular edema following central retinal vein occlusion: Six-month primary end point results of a the initiation of treatment, her blood sion, his macular edema had disap- phase III study. Ophthalmology 2010;117:1124-1133. pressure was decreased, macular peared and his visual acuity improved 8. Pichi F, Specchia C, Vitale L, et al. Combination therapy with dexamethasone intravitreal implant and macular grid laser in edema was reduced and her visual to 20/20. patients with branch retinal vein occlusion. Am J Ophthalmol acuity improved to 20/20. All of these cases had non-ischemic 2014;157:607-615. The second case was a 62-year-old retinal vein occlusion by fl uorescein 9. Pitcher JD 3rd, Liu T, Prasad PS, Schwartz SD, Hubschman JP. Short-duration focal pattern grid photocoagulation for macular woman with branch retinal vein oc- angiography, and none developed edema secondary to branch retinal vein occlusion. Semin clusion. Her visual acuity was 20/40, ischemic changes for at least one Ophthalmol 2012;27(3-4):69-72. 10. Kida T, Morishita S, Kakurai K, Suzuki H, Oku H, Ikeda T. and her blood pressure was 165/97 year. Treatment of systemic hypertension is important for improvement mmHg. After six weeks of taking The authors of this study recom- of macular edema associated with retinal vein occlusion. Clin medication to treat her systemic hy- mend that blood pressure be mea- Ophthalmol 2014;8:955-958.
62 | Review of Ophthalmology | August 2014
040_rp0814_f4.indd 62 7/25/14 2:22 PM GLAUCOMA FELLOWS SAVE THE DATE CONTINUING SPECIALIZED EDUCATION
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063_rp0711Reviews_Platter.indd 1 6/14/11 9:35 AM Refractive Surgery
REVIEW Edited by Arturo Chayet, MD
The Keys to Multifocal IOL Centration How surgeons are meeting the challenge of obtaining the sharpest vision for their multifocal lens patients. Walter Bethke, Managing Editor
hough diffractive multifocal for centering that lens in most people. T intraocular lenses can be very But, if it doesn’t look perfect, I’ll rotate successful in some patients, allowing the haptics to a different location.”
them to see both near and far, sur- MD Daniel Chang, Bakersfi eld, Calif., surgeon Daniel geons say you’ll never achieve such Chang has been working with Charles- remarkable results unless you get the ton, S.C., ophthalmologist George lens properly centered. The best way Waring IV on the concept that an ef- to center these IOLs, though, is up for fective centration point would be what debate, with various surgeons advo- they term the subject-fi xated, coaxially cating different approaches to getting sighted, corneal light refl ex. them positioned properly. Here are a “A fundamental problem that we couple of approaches to the problem, Bakersfi eld, Calif., surgeon Daniel Chang face when addressing the centration and their possible pros and cons. says that if you use an instrument with a of IOL implantation procedures is that fi xation light that’s coaxial to your view, we lack consistent nomenclature and and the patient fi xates on it (represented a coordinate system with which to dis- Thoughts on Centration here as PI, or the 1st Purkinje image, shown along with the 3rd and 4th Purkinje cuss the problem,” Dr. Chang says. Surgeons center their multifocal images), that will be the best place to “We use various terms like visual axis, IOLs based on a variety of factors, center a multifocal lens. line-of-sight, pupillary axis and opti- ultimately falling back on the process cal axis with little regard to their true that works best for them. limeter on the bench. Having said that, defi nitions. Just the term visual axis has Des Moines, Iowa, ophthalmologist I’ll try to center the lens so that it looks multiple usages in the literature. Even James Davison bases his centration right to me with respect to the dilated if we were to choose a singular defi ni- approach on the pupil and the cap- pupil at the time of surgery and the tion such as ‘the line from the fi xation sulorhexis. “I don’t think you can use capsulorhexis that we made so that it’s point to the entrance nodal point to any one factor and hope that you’ll overlapped completely. I’ll rotate the the exit nodal point to the fovea,’ how get it perfect,” he says. “And I’m not lens so that it sits properly and most of does that help me during surgery? The sure that it really matters to get it per- the time I end up leaving [the haptics] pupillary axis and line-of-sight both fect. The manufacturers have built in superior-temporal and inferior-nasal, are related to the pupil center, but the a tolerance so the modulation transfer with the AcrySof single-piece IOL, pupil center shifts when it dilates. Also, function of the lens isn’t affected even at least. I have no data for that at all; the Purkinje refl exes don’t always line if it’s decentered almost up to a mil- it’s just that seems to be a good spot up, making the optical axis diffi cult to
This article has no commercial sponsorship. August 2014 | Revophth.com | 65
065_rp0814_rs.indd 65 7/25/14 4:07 PM Refractive
REVIEW Surgery
apply when centering a lens. Dr. Chang says. “With other topogra- ly. However, when the IOL naturally “Recently, I co-authored a paper phers, the manufacturer can verify if centers in-the-bag and is aligned with with George Waring IV that’s now ac- their fi xation light is coaxial with their the cornea on the optical axis, both are cepted for publication,” Dr. Chang particular topographer’s camera. This tilted about 5.2 degrees, called angle continues. “And in it we advocate that would be your preop/postop reference alpha, and decentered 0.6 mm tempo- the surgeon consider what we call the point.” Intraoperatively, certain surgi- ral to the visual axis and 0.3 mm from subject-fi xated, coaxially sighted cor- cal microscopes have coaxial lighting, the pupil center. This means the lens neal light refl ex. That’s a mouthful to such as the Zeiss Lumera. “It has three will always be tilted about 5 degrees say, but here’s how to understand it: lights, with the two smaller lights coax- relative to the visual axis, so the chief The surgeon looks at the patient’s eye ial with the surgeon’s eyes,” Dr. Chang ray coming through the cornea that through a light such that the surgeon’s says. “So if you tell the patient to fi xate hits the center of the IOL is never per- view is coaxial with the beam path of on one of the two stereo coaxial lights, pendicular and the pencil of light rays the fi xation light. Then, if the patient’s and you look through the ocular on never symmetrically converge from eye is fi xated on that same light source, the same side as that light, you have a the cornea. Because these rays aren’t the surgeon sees the refl ection of the patient-fi xated, coaxially sighted, cor- symmetrical and the chief ray isn’t per- fi xation light as the subject-fi xated, co- neal light reflex. Then, you have an pendicular, they strike the microscopic axially sighted corneal light reflex— optical arrangement illuminating the diffractive edges of the IOL at angles everything is lined up. It’s a unique eye in the exact same configuration for which they weren’t designed. The lighting situation, and can be seen in that you did preop and postop; so you result is additional light scatter that the various devices already in our prac- have a marker you can correlate preop, patient describes as ‘waxy’ vision with tices. The SF-CSCLR is reproducible intraop and postop.” Dr. Chang says it’s glare and haloes. If you really wanted because it is related to the anterior worth checking with your microscope’s to line up the lens so that the central corneal surface, and it doesn’t move manufacturer to see if the fi xation light rays were perpendicular to the lens, around with implant position. Also, and your viewing axis are truly coaxial. you’d have to move the lens nasally— though this refl ex is actually visualized The next step involves giving sur- almost 0.6 mm nasally—from the cen- at the iris/IOL plane, which eliminates geons more opportunities to use this ter of the bag over to the fi rst Purkinje- parallax, the tricky part is having the centration method, says Dr. Chang. Sanson image, or PS1. patient fi xate and using a light that’s “I’m trying to promote this concept to “The problem with moving the lens coaxial with your viewing axis.” industry, so we can have more devices that far nasally, however, is it violates At his practice, Dr. Chang did a that make it easier for surgeons to uti- the second requirement of multifocal small retrospective study of 117 Tecnis lize it,” he says. lenses,” Dr. Holladay continues. “The Multifocal IOL cases centered on the second requirement for diffractive op- SF-CSCLR with an average follow-up The Other Half of the Story tics is that the lens has to be concen- of 100 days. “I looked at the uncor- tric with the aperture, the pupil. The rected and best-corrected vision cor- Houston IOL and optics expert Jack bifocal or trifocal diffractive optics are related to centering on the SF-CSCLR Holladay, MD, MSEE, FACS, says only balanced, or symmetrical, when vs. centering on the pupil. Though that centering on something such as a the incoming pencil of rays, or wave- there were trends that showed better corneal light refl ex can be helpful with front, are symmetrical with respect to vision from SF-CSCLR centration, a multifocal lens, but leaves out an im- the diffractive rings. This only occurs there were too many other variables portant second criterion for getting the when the diffractive rings are concen- and factors for the results to reach sta- sharpest vision. tric with the pupil. The imbalance of tistical signifi cance. Early uncorrected “For a diffractive multifocal lens to the resulting diffractive pattern also vision, though, suggested better vision work properly, it requires two things, causes additional light scatter and is trended with centering on the light which usually produces a paradox,” additive to the first cause described refl ex.” explains Dr. Holladay. “First, it has to above. So, unfortunately, it’s not pos- If a surgeon is interested in trying be lined up so the rays from the cor- sible to satisfy both criteria with the this method of centration, Dr. Chang nea are converging so the central ray human eye, because the fi rst Purkinje says the instrument most surgeons that comes through the cornea goes image is almost never centered on the have that may let them do it is a placido through the center of, and is perpen- pupil. It’s a paradox. The separation disc corneal topographer. “I use the dicular to, the lens. In other words, between the center of the pupil and Atlas topographer, which has a coaxial picture two lenses along a common the fi rst Purkinje image is called angle fi xation light in the center of the rings,” optical axis—they are lined up perfect- kappa, and the best you can do is put
66 | Review of Ophthalmology | August 2014
065_rp0814_rs.indd 66 7/25/14 4:08 PM Advertising
REVIEW Index
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Diopsys Regeneron Pharmaceuticals, Inc. 29 2 Phone (973) 244-0622 Phone (914) 847-7000 [email protected] www.regeneron.com OC = the optical center of the cornea; PC = the pupillary center; www.diopsys.com VA = Purkinje-Sanson I image and visual axis. Houston Rhein Medical ophthalmologist Jack Holladay says the ideal place to center a Essilor of America 5 multifocal IOL is between PC and VA. 12 Phone (800) 637-4346 www.essilorusa.com Fax (727) 341-8123 the lens somewhere between these two points to minimize the additional light scatter and reduce complaints of haloes, glare and waxy vision.” Haag-Streit S4OPTIK Dr. Holladay says that clinical studies analyzing multifo- 23 31 cal IOL results in patients with varying sizes of angle kappa Phone (800) 627-6286 Phone (888) 224-6012 and decentration of the IOL relative to the pupil have Fax (603) 742-7217 confi rmed these concepts clinically. “An article by Amar Santen Inc. USA Agarwal and co-workers suggested that patients with large Icare USA 25 angle kappas—where the center of the pupil and the light 43 Phone (415) 268-9100 refl ex are far apart—actually end up with worse perfor- Phone (888) 389-4022 Fax (510) 655-5682 mance with diffractive multifocal lenses than patients with www.icare-usa.com www.santeninc.com smaller angle kappas.1 A second article confi rmed that large angle kappa and decentration of the IOL temporal to the Keeler Instruments US Ophthalmics pupil (and farther from the visual axis) were associated with the highest risk of poor outcomes with multifocal IOLs.”2 7, 75 35, 37, 39 For the most successful outcomes with diffractive multifo- Phone (800) 523-5620 Phone (305) 503-2729 cal IOLs, Dr. Holladay recommends that at surgery the IOL Fax (610) 353-7814 www.usophthalmic.com be nudged nasally so the diffractive rings are located just [email protected] nasal to being concentric with the pupil, between the pupil Lombart Instruments center and the Purkinje light refl ex (if coaxial). Secondly, 33 he recommends avoiding patients with large angle kappas Phone (800) 446-8092 (> 0.4 mm or 2.8 degrees when using a penlight or >5.2 de- Fax (757) 855-1232 grees on the Orbscan II, which measures about two times 3 larger values). “Following these two rules will avoid the NicOx, Inc. majority of diffractive multifocal patients who are unhappy 20-21 due to unnecessary glare,” Dr. Holladay says. Phone (214) 346-2913 1. Prakash G, Prakash DR, Agarwal A, Kumar DA, Agarwal A, Jacob S. Predictive factor and kappa www.nicox.com angle analysis for visual satisfaction in patients with multifocal IOL implantation. Eye (Lond) 2011;25:9:1187-93. 2. Karhanová M, Marešová K, Pluhácek F, Mlcák P, Vlácil O, Sín M. The importance of angle kappa for centration of multifocal intraocular lenses. Cesk Slov Oftalmol 2013;69:2:64-8. [Article in Czech] This advertiser index is published as a convenience and not as part of the 3. Basmak H, Sahin A, Yildirim N, Papakostas TD, Kanellopoulos AJ. Measurement of angle kappa advertising contract. Every care will be taken to index correctly. No allowance with synoptophore and Orbscan II in a normal population. J Refract Surg 2007;23:456–460. will be made for errors due to spelling, incorrect page number, or failure to insert.
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Unfamiliar with our products? Visit www.revophth.com and check out our newsletter archives. Go to www.jobson.com/globalEmail/default.aspx to sign up for the e-newsletters that interest you. 071_rp0814_wills.indd 71 produced someright-sidedhyperglobus,andKrimskytestingconfirmed nohypertropia(SeeFigure1). the rightand25mmonleftwithabaseof107mm.Afi rm masswaspalpablealongtherightinferiororbitalrimthat left side.Althoughswellingwasevidentalongtherightcheekandlowereyelid,Hertelexophthalmometry25mm on tion fields andcolorplateswerefullinbotheyes.Additionally, theintraocularpressurewasnormalonbothrightand 20/30 inthelefteye.Pupilswereequalandreactivewithoutanafferentpupillarydefect.Extraocularmotility, confronta- Examination Liberia totheUnitedStates20yearsprior. Heworkedasacounselorincitygrouphome. in thepast.Hetooknochronicmedications,andhisfamilyhistorywasnoncontributory. Thepatienthadmovedfrom Medical History chills orrecentweightloss. rent tearingbutdeniedanychangeinvision,diplopia,ocularpain,headacheorconstitutionalsymptomsincludingfever, ing andmildtendernessoftherightcheekafteraccidentaltraumasixweeksprior. Hedescribedmoderateconcur- Presentation N.Brynn Wajda, MD swelling andtendernessinhischeekconcurrenttearing. Not longafteraminoraccident,youngmanpresentswith right inferiororbitalrimcausinghyperglobus. swelling alongtherightcheek andamassalongthe photographdemonstratingFigure 1.External What isyourdifferentialdiagnosis? Whatfurtherworkupwouldyoupursue?Please turntop. 72
Vital signswerestableandwithinnormallimits.Ocularexaminationrevealedvisualacuityof20/25intherighteye Medical historywassignifi cant onlyforseasonalallergieswhichhehadreceivedallergydesensitizationinjections A 32-year-old African-Americanmalepresented toanophthalmologyoffice withachiefcomplaintofpersistentswell- REVIEW Wills Eye Wills Eye Resident CaseSeries Edited by Alessandra Intili, MD August 2014 | Revophth.com |
71 7/25/14 3:13 PM 071_rp0814_wills.indd 72 osteolytic lesioninvolvingtherightzygomaandorbitalspace. Figure 2.Side-by-side CTcoronal imageswhich demonstrate anexpansile soft-tissueand 72 botyroid variantofembryonal; alveo- and identifying features: embryonal; types, eachwithitsowncharacteristic four distincthistopathologicalsub- sifi generalized HornandEnterlineclas- adopted muscle. Basedonthewidely pacity todifferentiateintostriated mesenchymal cellsthathavetheca- that developsfromundifferentiated Discussion
drafted. Thisincludedbenignpro- bone-lesion differentialdiagnosiswas ings, amorecompleteandextensive quisition oftheseradiographicfi right zygoma(SeeFigure2).With ac- and osteolyticlesioninvolvingthe and showedanexpansile,moth-eaten related lesionsordistantmetastases. secondary neoplasmsincludingsinus- liferative orvasculardisorders,and (benign ormalignant),lymphopro- such ascellulitis,primarybonelesions infectious andneoplasticdisorders differential diagnosisalsoincluded idiopathic orbitalinfl lesterol granuloma;histiocytosis;and eurysmal bonecyst;giantcellorcho- conditions suchasahematoma;an- cluded inflammatoryorreactive exam, thedifferentialdiagnosisin- Diagnosis, Workup andTreatment REVIEW cation system,thereareclassically Rhabdomyosarcoma isaneoplasm | ReviewofOphthalmology A CToftheorbitswasperformed Based ontheclinicalhistoryand Resident CaseSeries ammation. The ammation. | August2014 nd- 1,2 common, withafrequency of 50to patient outcome. cation systemthatwouldbetterpredict tute withthegoalofcreatingaclassifi including theNationalCancerInsti- adapted byinvestigatingorganizations this schemehasbeenmodifiedand myosarcoma Studies,inrecentyears in theoriginalIntergroupRhabdo- pleomorphic. Althoughused lar; and AE1/AE3 andCAM5.2. were positivefordesmin,myogenin, ure 3).Immunohistochemistrystains scattered mitoticfigures reminiscent ofrhabdomyoblastsand abundant eosinophiliccytoplasm sheets ofnumerousstrapcellswith biopsy. Resultingpathologyshowed ma andbonehemangioma. cell histiocytosis,non-ossifyingfi plasia, osteomyelitis,Langherhans’ or unicameralbonecysts,fibrous dys- vascular lesionsincludinganeurysmal choristoma; andreactive,fi metastasis, myeloma,lymphomaand chondrosarcoma, Ewing’s sarcoma), a primarysarcoma(i.e., osteosarcoma, blastoma; malignantprocessessuchas teoblastoma, enchondroma,chondro- cesses suchasosteoidosteoma,os- The embryonal subtype is the most The embryonalsubtypeisthe most The patientwasdiagnosedwithor- an orbitalThe patientunderwent 3 1,2 (See Fig- brous or brous bro- - and mitoticfi cells withabundanteosinophiliccytoplasm demonstrating extensive sheetsofstrap Figure 3.Histopathology photograph arises inthesuperonasalorbit and thus bryonal rhabdomyosarcoma usually nosis andlongersurvivalrates. Em- subtypes duetotheirsuperiorprog- are deemedfavorablehistopathologic appearance) andspindlecellvariants like conjunctivaandgrapelikeclinical association withamucousmembrane- category, thebotyroid(namedforits of 94percent. Within theembryonal 60 percentandafive-yearsurvival return foranyfurthervisits. therapy andfailedto fused further tioned departments,thepatientre- visit ineachofthepreviously men- bulking. Unfortunately, afteronlyone followed bylocalradiation±localde- adriamycin, andcyclophosphamide) adjuvant chemotherapy(vincristine, localized therapyintheformofneo- sue acombinationofsystemicand the final recommendationwastopur- debulking/resection werediscussed, motherapy, radiotherapyandsurgical options, includingobservation,che- localized totherightorbit.Whileall A PET/CTshowedthatdiseasewas Hematology/Oncology departments. versity HospitalOtolaryngologyand well astheThomasJeffersonUni- Hospital OcularOncologyserviceas and wasreferredtotheWills Eye bital spindlecellrhabdomyosarcoma gures. 7/25/14 3:14 PM produces inferolateral globe displace- Table 1. IRSG Surgical-Pathologic Grouping System ment. This is contrasted with the alve- olar subtype, which histopathologically Group Defi nition I Localized tumor, completely removed with pathologically clear margins and no regional resembles pulmonary tissue due to lymph node involvement branching, fi brous septae that enclose II Localized tumor, grossly removed with (a) microscopically involved margins, (b) involved the tumor cells and create pseudo- grossly resected regional lymph nodes, or (c) both alveoli. The alveolar subtype has an III Localized tumor with gross residual disease after grossly incomplete removal, or biopsy only IV Distant metastases present at diagnosis approximate frequency of 30 percent, a fi ve-year survival rate of 74 percent, Table 1, outlining the intergroup rhabdomyosarcoma post-surgical staging system. and usually arises in the inferior or- (Adapted from: Raney RB, et al.10) bit. Additionally, around 75 percent of alveolar cases have a characteristic Specifi cally, 76 percent were located in but can occur in patients of any age. genetic translocation involving chro- the orbit, but the conjunctiva, eyelid, Four distinct histopathological sub- mosome 1 or 2 and chromosome 13 and uveal tract were also found to be types have different frequency rates [t(1;13) or t(2;13)]. These genetic varia- primary sites of disease. and prognoses. Fortunately, due to tions have prognostic signifi cance, with In terms of staging, categories are advances in chemotherapy and radio- the t(1;13) mutation having a much classically defined based on the In- therapy over the past fi fty years, sur- more favorable survival rate. Finally, tergroup Rhabdomyosarcoma Study vival rates have markedly improved the classic pleomorphic variant is now post-biopsy system (See Figure 4).11 and disfi guring procedures such as ex- a subset within the anaplastic rhabdo- Favorable prognostic factors include enteration are no longer the standard myosarcoma category used in modern an orbital location, younger age (1 to of care. classifi cation systems. It represents less 10 years), female sex, embryonal his- than 1 percent of rhabdomyosarco- tology, and low tumor burden (size <5 The author would like to thank Rob- mas and occurs almost exclusively in cm diameter).4-6,12 ert Penne, MD, and Michael Rabinow- adults.3-8 In addition to histopathol- Treatment approaches usually cor- itz, MD, members of the Wills Eye Hos- ogy, immunohistochemistry is criti- relate with the stage of disease. Spe- pital Oculoplastic and Orbital Surgery cally important in making the diagnosis cifi cally, patients with stage I disease Service, for their time and assistance in of rhabdomyosarcoma. Some of the usually receive chemotherapy with preparing this case report. most common markers include des- either vincristine or actinomycin. For 1. Heggeness MH, et al. Orthopedic Surgery. In: Brunicardi FC, ed. min; myo-D1; myoglobin; myogenin; those with stage II or III disease, some Schwartz’s Principles of Surgery. 9th ed. New York, NY: McGraw- muscle-specifi c actin; skeletal muscle combination of chemotherapy (typical Hill, 2010. 4,8,9,10 2. Srinivasan RC, Tolhurst SR, Vanderhave K. Orthopaedics. In: myosin; and vimentin. agents being vincristine, actinomycin Doherty GM (ed): Current Surgical Diagnosis and Treatment, ed. Orbital rhabdomyosarcoma is most and cyclophoshamide) and radiother- 13. New York, NY: McGraw-Hill Medical, 2009:1006-1091. 3. Newton, WA, et al. Classifi cation of rhabdomyosarcomas and commonly a disease of pediatric pa- apy is the standard. Finally, for those related sarcomas. Cancer 1995;76(6):1073-85. tients who usually present with symp- with metastatic or stage IV involve- 4. Jurdy L, et al. Orbital rhabdomyosarcomas: A review. Saudi J Ophthalmol 2013;27:167-75. toms before the age of 10 years. It ment, an intensive chemotherapy and 5. Karcioglu ZA, et al. Orbital rhabdomyosarcoma. Cancer Control represents approximately 4 percent of radiation regimen is used, along with 2004;11.5:328-33. 6. Shields CL, et al. Primary ophthalmic rhabdomyosarcoma in 33 pediatric malignancies and is the most intrathecal chemotherapy for patients patients. Trans Am Ophthalmol Soc 2001;99:133-144. common soft-tissue sarcoma of the with intracranial involvement. With 7. Sorensen PHB, et al. PAX3-FKHR and PAX7-FKHR Gene Fusions Are Prognostic Indicators in Alveolar Rhabdomyosarcoma: A head and neck in this patient popula- advances in chemotherapy and radio- Report From the Children’s Oncology Group. J Clinical Oncology tion. Initial presenting symptoms usu- therapy over the past 50 years, surgical 2002; 20(11):2672-79. 8. Eagle RC, Jr. Eye Pathology: An Atlas and Text. 2nd ed. Philadel- ally include rapidly developing propto- treatment is no longer the standard phia: Lippincott Williams & Willkins, 2011. sis, globe displacement, eyelid edema, of care, and survival rates have mark- 9. Xian-li S, et al. Orbital rhabdomyosarcoma: Immunoshistochem- ical studies of seven cases. Chin Med J 1990;103(6):485-88. and ptosis. In contrast, adult cases such edly improved from 30 percent to 90 10. Furlong MA, Mentzel T, Fanburg-Smith JC. Pleomorphic as ours are much more rare. In fact, no percent. In fact, while surgical excision rhabdomyosarcoma in adults: A clinicopathologic study of 38 cases with emphasis on morphologic variants and recent skeletal more than 20 documented adult cases and exenteration used to be the pri- muscle-specifi c markers. Mod Pathol 2001;14(6):595-603. were found during a literature review mary treatment, these approaches are 11. Raney RB, et al. The intergroup rhabdomyosarcoma study group (IRSG): Major lessons from the IRS-I through IRS-IV studies spanning a 50-year time period after often reserved for cases with recurrent as background for the current IRS-V treatment protocols. Sarcoma 1965.iv,v,vi While the orbital location disease.4,11,13 2001;5:9-15. 12 Bagdonaite L, et al. Multidisciplinary management of adult is most common, Carol Shields, MD, In summary, rhabdomyosarcoma orbital rhabdomyosarcoma. Orbit 2013;32(3): 208-10. found various ophthalmic sites of dis- is the most common primary orbital 13. Crist W, et al. The third intergroup rhabdomyosarcoma study. J ease in a 25-year period case review. and soft tissue malignancy in children, Clin Oncol 1995;13(3):610-30.
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