Review of Ophthalmology Vol XIX, No • July 2012 • Topography-guided Ablation • Intrastromal Refractive Surgery • Presbyopia Surgery Options • Genetic Testing for AMD CATCHING DIABETIC MACULAR EDEMA EARLY P 16 • A CLOSER LOOK AT A NEW EXCIMER LASER P 61 GENETIC TESTING FOR AMD P 56 • A LOOK BACK AT ARVO HIGHLIGHTS P 44 WILLS RESIDENT CASE SERIES P 74 • NOT YOUR FATHER’S TRABECULECTOMY P 51 Part of July Ju uly 20 22012 12 • rrevophth.com evo voph phth ph th.c ccom o Topography-guided Ablation: Pros and Cons P 20 Refractive Surgery Goes Intrastromal P 32 Presbyopia Surgery: Beyond Multifocal IOLs P 38 fc_rp0712.2.indd AN CI I N R CH FO E N T IC ATIO LM UC DIT A TH G ED CRE H P N O : O NUI AHP E I D SI NT JC IN CO 6/22/12 9:39 AM Get there at the speed of WaveLight ® { The cheetah’s aerodynamic body and flexible spine allow it to reach speeds of up to 75 miles an hour Only the WaveLight® Workstation can keep up with today’s rapidly changing technology needs Designed to accommodate your refractive technology goals now and into the future, the WaveLight® Workstation is the fastest way to get where you want to go Ū The 200 kHz FS200 Femtosecond Laser creates custom flaps in only seconds* Ū The 400 Hz ALLEGRETTO WAVE® Eye-Q Laser enables treatment times of only 1.7 seconds per diopter* Ū Provides a broad range of customized, patient-specific treatments Ū Its advanced platform offers expanding technologies for more streamlined procedures ® To see how the WaveLight Workstation can get you there faster, visit AlconSurgical.com © 2011 Novartis 11/11 WaveLight® FS200 Femtosecond Laser ALLEGRETTO WAVE® Eye-Q Excimer Laser ALL11498JAD *Treatment times are approximate For Important Safety Information and Full Directions for Use, Please Reference the WaveLight® ALLEGRETTO WAVE® Laser System Full Directions for Use on Adjacent Pages RP0212_Alcon Wavelight.indd 1/12/12 2:28 PM Health Care Professional Information Sheet-All WaveLight® Allegretto Wave® System Indications The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System CAUTION: Federal (USA) law restricts this device to sale by, or on the order of a physician Statements regarding the potential benefits of wavefront-guided and Wavefront Optimized® laserassisted in-situ keratomileusis (LASIK) are based upon the results of clinical trials These results are indicative of not ony the WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System treatment but also the care of the clinical physicians, the control of the surgical environment by those physicians, the clinical trials’ treatment parameters and the clinical trials’ patient inclusion and exclusion criteria Although many clinical trial patients after the wavefront-guided and Wavefront Optimized® procedure saw 20/20 or better and/or had or reported having better vision during the day and at night, compared to their vision with glasses or contact lenses before the procedure, individual results may vary You can find information about the clinical trials below and in the Procudure Manuals for the WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System As with any surgical procedure, there are risks associated with the wavefront-guided and Wavefront Optimized® treatment Before treating patients with these procedures, you should carefully review the Procedure Manuals, complete the Physician WaveLight® System Certification Course, provide your patients with the Patient Information Booklet, and discuss the risks associated with this procedure and questions about the procedure with your patients INDICATIONS: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System is indicated to perform LASIK treatments in patients with documented evidence of a stable manifest refraction defined as less than or equal to 0.50 diopters (D) of preoperative spherical equivalent shift over one year prior to surgery, exclusive of changes due to unmasking latent hyperopia in patients 18 years of age or older: for the reduction or elimination of myopic refractive errors up to -12.0 D of sphere with and without astigmatic refractive errors up to -6.0 D; for the reduction or elimination of hyperopic refractive errors up to +6.0 D of sphere with and without astigmatic refractive errors up to 5.0 D at the spectacle plane, with a maximum manifest refraction spherical equivalent (MRSE) of +6.0 D; and in patients 21 years of age or older for the reduction or elimination of naturally occurring mixed astigmatism of up to 6.0 D at the spectacle plane LASIK is an elective procedure with the alternatives including but not limited to eyeglasses, contact lenses, photorefractive keratectomy (PRK), and other refractive surgeries Only practitioners who are experienced in the medical management and surgical treatment of the cornea, who have been trained in laser refractive surgery including laser system calibration and operation, may use the device as approved Prospective patients, as soon as they express an interest in an indicated LASIK procedure and prior to undergoing surgery, must be given the WaveLight® System Patient Information Booklet and must be informed of the alternatives for refractive correction including eyeglasses, contact lenses, PRK, and other refractive surgeries RP0212_Alcon Wavelight PI.indd Clinical Data Myopia: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System for LASIK treatments of myopic refractive errors up to -12.0 D of sphere with and without astigmatic refractive errors up to -6.0 D at the spectacle plane was studied in clinical trials in the United States with 901 eyes treated, of which 813 of 866 eligible eyes were followed for 12 months Accountability at months was 93.8%, at months was 91.9%, and at 12 months was 93.9% The studies found that of the 844 eyes eligible for the uncorrected visual acuity (UCVA) analysis of effectiveness at the 3-month stability time point, 98.0% were corrected to 20/40 or better, and 84.4% were corrected to 20/20 or better without spectacles or contact lenses The clinical trials showed that the following subjective patient adverse events were reported as moderate to severe at a level at least 1% higher than baseline of the subjects at months post-treatment: visual fluctuations (12.8% at baseline versus 28.6% at months) Long term risks of LASIK for myopia with and without astigmatism beyond 12 months have not been studied Clinical Data Hyperopia: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System for LASIK treatments of hyperopic refractive errors up to +6.0 D of sphere with and without astigmatic refractive errors up to 5.0 D with a maximum MRSE of +6.0 D has been studied in clinical trials in the United States with 290 eyes treated, of which 100 of 290 eligible eyes were followed for 12 months Accountability at months was 95.2%, at months was 93.9%, and at 12 months was 69.9% The studies found that of the 212 eyes eligible for the UCVA analysis of effectiveness at the 6-month stability time point, 95.3% were corrected to 20/40 or better, and 67.5% were corrected to 20/20 or better without spectacles or contact lenses The study showed that the following subjective patient adverse events were reported as much worse by at least 1% of the subjects (in order of increasing frequency) at months post final treatment: glare from bright lights (3.0%); night driving glare (4.2%); light sensitivity (4.9%); visual fluctuations (6.1%); and halos (6.4%) Long term risks of LASIK for hyperopia with and without astigmatism beyond 12 months have not been studied Clinical Data Mixed Astigmatism: The WaveLight® ALLEGRETTO WAVE®/ ALLEGRETTO WAVE® Eye-Q Excimer Laser System for LASIK treatments of naturally occurring mixed astigmatism of up to 6.0 D at the spectacle plane has been studied in clinical trials in the United States with 162 eyes treated, of which 111 were eligible to be followed at months Accountability at month was 99.4%, at months was 96.0%, and at months was 100.0% The studies found that of the 142 eyes eligible for the UCVA analysis of effectiveness at the 3-month stability time point, 95.8% achieved acuity of 20/40 or better, and 67.6% achieved acuity of 20/20 or better without spectacles or contact lenses The clinical trials showed that the following subjective patient adverse events were reported as moderate to severe at a level at least 1% higher than baseline of the subjects at months post-treatment: sensitivity to light (43.3% at baseline versus 52.9% at months); visual fluctuations (32.1% at baseline versus 43.0% at months); and halos (37.0% at baseline versus 42.3% at months) Long term risks of LASIK for mixed astigmatism beyond months have not been studied Clinical Data Wavefront-guided Treatment of Myopia: The WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System used in conjunction with the WaveLight® ALLEGRO Analyzer® device The device uses a 6.5 mm optical zone, a 9.0 mm ablation/ treatment zone, and is indicated for wavefront-guided LASIK: 1) for the reduction or elimination of up to -7.0 D of spherical equivalent myopia or myopia with astigmatism, with up to -7.0 D of spherical component and up to 3.0 D of astigmatic component at the spectacle plane; 2) in patients who are 18 years of age or older; and 3) in patients with documentation of a stable manifest refraction defined as ≤0.50 D of preoperative spherical equivalent shift over one year prior to surgery was studied in a randomized clinical trial in the United States with 374 eyes treated; 188 with wavefront-guided LASIK (Study Cohort) and 186 with Wavefront Optimized® LASIK (Control Cohort) 178 of the Study Cohort and 180 of the Control Cohort were eligible to be followed at months In the Study Cohort, accountability at month was 96.8%, at months was 96.8%, and at months was 93.3% In the Control Cohort, accountability at month was 94.6%, at months was 94.6%, and at months was 92.2% The studies found that of the 180 eyes eligible for the UCVA analysis of effectiveness at the 6-month stability time point in the Study Cohort, 99.4% were corrected to 20/40 or better, and 93.4% were corrected to 20/20 or better without spectacles or contact lenses In the Control Cohort, of the 176 eyes eligible for the UCVA analysis of effectiveness at the 6-month stability time point, 99.4% were corrected to 20/40 or better, and 92.8% were corrected to 20/20 or better without spectacles or contact lenses The clinical trials showed that the following subjective patient adverse events were reported as moderate to severe at a level at least 1% higher than baseline of the subjects at months post-treatment in the Study Cohort: light sensitivity (37.2% at baseline versus 47.8% at months); and visual fluctuations (13.8% at baseline versus 20.0% at months) In the Control Cohort: halos (36.6% at baseline versus 45.4% at months); and visual fluctuations (18.3% at baseline versus 21.9% at months) Long term risks of wavefront-guided LASIK for myopia with and without astigmatism beyond months have not been studied CONTRAINDICATIONS: LASIK treatments using the WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System are contraindicated if any of the following conditions exist Potential contraindications are not limited to those included in this list: pregnant or nursing women; patients with a diagnosed collagen vascular, autoimmune or immunodeficiency disease; patients with diagnosed keratoconus or any clinical pictures suggestive of keratoconus; and patients who are taking one or both of the following medications: isotretinoin (Accutane®1), amiodarone hydrochloride (Cordarone®2) WARNINGS: Any LASIK treatment with the WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System is not recommended in patients who have: systemic diseases likely to affect wound healing, such as connective tissue disease, insulin dependent diabetes, severe atopic disease or an immunocompromised status; a history of Herpes simplex or Herpes zoster keratitis; significant dry eye that is unresponsive to treatment; severe allergies; and unreliable preoperative wavefront examination that precludes wavefront-guided treatment The wavefrontguided LASIK procedure requires accurate and reliable data from the wavefront examination Every step of every wavefront measurement that may be used as the basis for a wavefront-guided LASIK procedure must be validated by the user Inaccurate or unreliable data from 1/12/12 2:30 PM the wavefront examination will lead to an inaccurate treatment PRECAUTIONS: Safety and effectiveness of the WaveLight® ALLEGRETTO WAVE® / ALLEGRETTO WAVE® Eye-Q Excimer Laser System have not been established for patients with: progressive myopia, hyperopia, astigmatism and/or mixed astigmatism; ocular disease; previous corneal or intraocular surgery, or trauma in the ablation zone; corneal abnormalities including, but not limited to, scars, irregular astigmatism and corneal warpage; residual corneal thickness after ablation of less than 250 microns increasing the risk for corneal ectasia; pupil size below 7.0 mm after mydriatics where applied for wavefront-guided ablation planning; history of glaucoma or ocular hypertension of > 23 mmHg; taking the medication sumatriptan succinate (Imitrex®3); under 18 years (21 years for mixed astigmatism) of age; over the long term (more than 12 months after surgery); corneal, lens and/ or vitreous opacities including, but not limited to, cataract; iris problems including, but not limited to, coloboma and previous iris surgery compromising proper eyetracking; taking medications likely to affect wound healing including, but not limited to, antimetabolites; treatments with an optical zone below 6.0 mm or above 6.5 mm in diameter; treatment targets different from emmetropia (plano) in which the wavefront-calculated defocus (spherical term) has been adjusted; myopia greater than – 12.0 D or astigmatism greater than D; hyperopia greater than + 6.0 D or astigmatism greater than 5.0 D; mixed astigmatism greater than + 6.0 D; and in cylinder amounts > 4.0 to < 6.0 D Due to the lack of large numbers of patients in the general population, there are few subjects with cylinder amounts in this range to be studied Not all complications, adverse events, and levels of effectiveness may have been determined Pupil sizes should be evaluated under mesopic illumination conditions Effects of treatment on vision under poor illumination cannot be predicted prior to surgery Some patients may find it more difficult to see in such conditions as very dim light, rain, fog, snow and glare from bright lights This has been shown to occur more frequently in the presence of residual refractive error and perhaps in patients with pupil sizes larger than the optical zone size The refraction is determined in the spectacle plane, but treated in the corneal plane In order to determine the right treatment program to achieve the right correction, assessment of the vertex distance during refraction testing is recommended Preoperative evaluation for dry eyes should be performed Patients should be advised of the potential for dry eyes post LASIK and post wavefront-guided LASIK surgery This treatment can only be provided by a licensed healthcare professional Adverse Events and Complications for Myopia: Certain adverse events and complications occurred after the LASIK surgery Two adverse events occurred during the postoperative period of the clinical study: 0.2% (2/876) had a lost, misplaced, or misaligned flap reported at the month examination The following adverse events did NOT occur: corneal infiltrate or ulcer requiring treatment, RP0212_Alcon Wavelight PI r.indd corneal edema at month or later visible in the slit lamp exam; any complication leading to intraocular surgery; melting of the flap of >1 mm2; epithelium of >1 mm2 in the interface with loss of lines or more of BSCVA; uncontrolled IOP rise with increase of >5 mmHg or any reading above 25 mmHg; retinal detachment or retinal vascular accident; and decrease in BSCVA of >10 letters not due to irregular astigmatism as shown by hard contact lens refraction The following complications occurred months after LASIK during this clinical trial: 0.8% (7/844) of eyes had a corneal epithelial defect; 0.1% (1/844) had any epithelium in the interface; 0.1% (1/844) had foreign body sensation; 0.2% (2/844) had pain; and 0.7% (6/844) had ghosting or double images in the operative eye The following complications did NOT occur months following LASIK in this clinical trial: corneal edema and need for lifting and/or reseating the flap/cap Adverse Events and Complications for Hyperopia: Certain adverse events and complications occurred after the LASIK surgery Only one adverse event occurred during the clinical study: one eye (0.4%) had a retinal detachment or retinal vascular accident reported at the 3 month examination The following adverse events did NOT occur: corneal infiltrate or ulcer requiring treatment; lost, misplaced, or misaligned flap, or any flap/cap problems requiring surgical intervention beyond 1 month; corneal edema at 1 month or later visible in the slit lamp exam; any complication leading to intraocular surgery; melting of the flap of > 1 mm2; epithelium of > 1 mm2 in the interface with loss of lines or more of BSCVA; uncontrolled IOP rise with increase of > 5 mmHg or any reading above 25 mmHg and decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard contact lens refraction The following complications occurred 6 months after LASIK during this clinical trial: 0.8% (2/262) of eyes had a corneal epithelial defect and 0.8% (2/262) had any epithelium in the interface The following complications did NOT occur 6 months following LASIK in this clinical trial: corneal edema; foreign body sensation; pain, ghosting or double images; and need for lifting and/or reseating of the flap/cap Adverse Events and Complications for Mixed Astigmatism: Certain adverse events and complications occurred after the LASIK surgery No protocol defined adverse events occurred during the clinical study However, two events occurred which were reported to the FDA as Adverse Events The first event involved a patient who postoperatively was subject to blunt trauma to the treatment eye 6 days after surgery The patient was found to have an intact globe with no rupture, inflammation or any dislodgement of the flap The second event involved the treatment of an incorrect axis of astigmatism which required retreatment The following adverse events did NOT occur: corneal infiltrate or ulcer requiring treatment; corneal epithelial defect involving the keratectomy at 1 month or later; corneal edema at 1 month or later visible in the slit lamp exam; epithelium of > 1 mm2 in the interface with loss of 2 lines or more of BSCVA; lost, misplaced, or misaligned flap, or any flap/cap problems requiring surgical intervention beyond 1 month; decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard contact lens refraction; any complication leading to intraocular surgery; melting of the flap of > 1 mm2; uncontrolled IOP rise and retinal detachment or retinal vascular accident None of the following complications occurred at 3 months after LASIK during this clinical trial: corneal edema; corneal epithelial defect; any epithelium in the interface; foreign body sensation, pain, ghosting or double images; and need for lifting and/or reseating of the flap/cap Subjects were asked to complete a patient questionnaire preoperatively and at 3-months, 6-months, and 1-year postoperatively Adverse Events and Complications for Wavefront - guided Myopia: Certain adverse events and complications occurred after the wavefront-guided LASIK surgery No adverse event occurred during wavefront-guided treatments during this clinical study The following adverse events did NOT occur: corneal infiltrate or ulcer requiring treatment; lost, misplaced or misaligned flap or any flap/cap problems requiring surgical intervention beyond 1 month; corneal edema at 1 month or later visible in the slit lamp exam; any complication leading to intraocular surgery; melting of the flap of > 1 mm2; epithelium of > 1 mm² in the interface with loss of 2 lines or more of BSCVA; uncontrolled IOP rise with increase of > 5 mmHg or any reading above 25 mmHg; and decrease in BSCVA of > 10 letters not due to irregular astigmatism as shown by hard contact lens refraction The following complications occurred 3 months after wavefront-guided LASIK during this clinical trial: corneal epithelial defect (0.6%); foreign body sensation (0.6%); and pain (0.6%) The following complications did NOT occur 3 months following wavefront-guided LASIK in this clinical trial: corneal edema; any epithelium in the interface; ghosting or double images; and need for lifting and/ or reseating of the flap/cap ATTENTION: The safety and effectiveness of LASIK surgery has ONLY been established with an optical zone of 6.0 – 6.5 mm and an ablation zone of 9.0 mm Reference the Directions for Use labeling for a complete listing of indications, warnings and precautions Accutane® is a registered trademark of Hoffmann-La Roche Inc Cordarone® is a registered trademark of Sanofi S.A Imitrex® is a registered trademark of Glaxo Group Limited © 2011 Novartis 11/11 ALL11498JAD-PI 1/12/12 2:32 PM REVIEW NEWS Volume XIX • No • July 2012 Ocular Pulse Testing May Offer a Method of Detecting Stroke Risk A simple eye test may someday offer an effective way to identify patients who are at high risk for stroke, say researchers at the University of Zurich They showed that a test called ocular pulse amplitude (OPA) can reliably detect carotid artery stenosis (CAS), a known risk factor for stroke The OPA test could be performed by ophthalmologists during routine exams The study, published in the June Ophthalmology, confirmed that patients who had the lowest OPA scores also had the most seriously blocked arteries Each year, approximately 795,000 Americans suffer a new or recurrent stroke, and more than 137,000 of these people die as a result People with severe CAS are much more likely to suffer stroke Physicians would like to catch and treat CAS before that can happen, but because CAS has no symptoms and an efficient test is not currently available, the disease often goes undetected The Swiss research team used a device called the dynamic contour tonometer to check the OPA of 67 patients who were assumed to have CAS The OPA score is calculated by finding the difference between the intraocular pressure levels during the systolic and diastolic phases of the heartbeat The tonometer measures the two pressure levels, then instantly computes the patient’s OPA score When blood flow to the eye is blocked by CAS, there is not much difference between the two pressure levels, so the OPA score is low The study confirmed that patients with the lowest OPA scores also had the most seriously blocked arteries The researchers used ultrasound exams to corroborate that each study participant had CAS and to detail the severity of the blockage “Our results show that ocular pulse amplitude is a reliable, safe screening test for carotid artery stenosis,” said lead researcher Pascal Bruno Knecht, MD “We recommend further study to confirm the value of using OPA to detect and assess the severity of CAS and to define its use in stroke prevention.” A research review performed for the U.S Preventive Services Task Force indicated that if an efficient screening test for CAS were available, the incidence of stroke and fatalities due to stroke could be substantially reduced The review stated that the test should be able to detect clinically significant CAS, defined as 60 percent to 99 percent blockage of the carotid arteries Some hightech tests, such as magnetic resonance angiography and color duplex ultrasound, already meet this standard, but they are expensive and not widely available Their primary use is in diagnosing patients who already have symptoms of stroke It could be efficient to perform the OPA test during a standard eye exam, if the ophthalmologist is already using the dynamic contour tonometer to screen for glaucoma This type of tonometer is not widely used in the United States, although it is in Europe The researchers say that other than CAS, very few diseases could cause low OPA scores, and that an ophthalmologist could easily rule out these other diseases during an eye exam Lenses May Slow Myopia Progress in Children Research at the University of Houston College of Optometry suggests that optical treatments warrant further study for their potential to slow the progression of nearsightedness in children Conducted by UH assistant professor David Berntsen, OD, PhD, and his colleagues from Ohio State University, the study compared the effects of wearing and then not wearing progressive addition lenses in children who are nearsighted The study examined 85 children from to 11 years old over the course of two years The results were published in Investigative Ophthalmology and Visual Science Selected according to their eye alignment and accuracy of focusing on near objects, the myopic children were fitted with either normal singlevision lenses or no-line bifocals to correct their nearsightedness In addition to observing and testing the children, the doctors obtained feedback from parents and guardians of both the children’s outdoor activities July 2012 | Revophth.com | 005_rp0712_news.indd 6/21/12 3:45 PM REVIEW News and near-work tasks, such as reading and computer use Previous research suggested that nearsighted children who not focus accurately when reading books or doing other near work may benefit more from wearing no-line bifocal glasses than nearsighted children who focus more accurately Dr Berntsen’s study found a small, yet statistically significant, slowing of myopia progression in children wearing the bifocals compared to those who simply wore singlevision lenses Dr Berntsen asserts, however, that the results not suggest that children be fitted with no-line bifocal lenses solely for the purpose of slowing the progression of myopia “While the small effect found in the group of children wearing bifocal spectacles does not warrant a change in clinical practice, we found the beneficial effect was still present for at least one year after children stopped wearing no-line bifocal lenses,” Dr Berntsen said “This is promising if other optical lens designs can be developed that an even better job of slowing how fast myopia increases in children.” By understanding why different types of lenses result in the slowing of myopia progression, Dr Berntsen says researchers will be better able to design lenses that may be more effective in slowing the increase of nearsightedness in children “Single-vision lenses are normally prescribed when a child gets a pair of glasses, but glasses with progressive addition lenses were shown to slightly reduce myopic progression in our study,” he said “For any treatment that reduces myopia progression in children to be useful, the effect of the spectacles or contact lenses must persist after children stop wearing them The fact that the small treatment effect from our study was still present one year after discontinuing the treatment is promising The results suggest that if newer optical designs currently being investigated a better job of slowing myopia progression, the effects may be expected to persist and decrease how nearsighted the child ultimately becomes.” Dr Berntsen says the study results and evidence from other studies suggest that lenses specifically designed to change blur in the eye’s peripheral vision may be able to slow the increase of nearsightedness “There is support for continuing to investigate new lenses specially designed to change the blur profile on the back of the eye in order to reduce the increase of myopia in children,” he said “There is still further research to be done, but our work is an important step in discovering the methods needed to slow the progression of nearsightedness.” Stem Cells Able to Form Optic Cup Human-derived stem cells can spontane- ously form an optic cup, according to a study published in Cell Stem Cell Transplantation of this 3D tissue in the future could help patients with visual impairments see clearly “This is an important milestone for a new generation of regenerative medicine,” says senior study author Yoshiki Sasai, MD, PhD, of the RIKEN Center for Developmental Biology, in Kobe, Japan “Our approach opens a new avenue to the use of human stem cell-derived complex tissues for therapy, as well as for other medical studies related to pathogenesis and drug discovery.” In the study, the optic cup spontaneously emerged from human embryonic stem cells (hESCs)—cells derived from human embryos that are capable of developing into a variety of tissues— thanks to the cell culture methods op- A human embryonic stem cell-derived optic cup generated in culture Bright green, neural retina; off green, pigment epithelium; blue, nuclei; red, active myosin (strong in the inner surface of pigment epithelium) timized by Dr Sasai and his team The hESC-derived cells formed the correct 3D shape and the two layers of the optic cup, including a layer containing a large number of light-responsive photoreceptor cells Because retinal degeneration primarily results from damage to these cells, the hESCderived tissue could be ideal transplantation material Beyond the clinical implications, the study will likely accelerate the acquisition of knowledge in the field of developmental biology For instance, the hESC-derived optic cup is much larger than the optic cup that Dr Sasai and collaborators previously derived from mouse embryonic stem cells, suggesting that these cells contain innate species-specific instructions for building this eye structure “This study opens the door to understanding human-specific aspects of eye development that researchers were not able to investigate before,” Dr Sasai says HSV Infection Tied to AMD A team of researchers reports that hu- man cytomegalovirus, a type of herpes virus, is associated with neovascular | Review of Ophthalmology | July 2012 005_rp0712_news.indd 6/21/12 3:45 PM age-related macular degeneration They report that human cytomegalovirus causes the production of vascular endothelial growth factor, a signal protein that regulates the formation of new blood vessels The results were published in PLoS Pathogens “Prior to this work, cofactors for the development of AMD included genetics, a high-fat diet and smoking Now, we are adding an infectious agent as another cofactor,” said Richard D Dix, professor at the Georgia State Viral Immunology Center’s Ocular Virology and Immunology Laboratory Affiliated research institutions include the Duke University Eye Center, the Bascom Palmer Eye Institute of the University of Miami Miller School of Medicine, the Viral Immunology Center at Georgia State, and the Department of Ophthalmology at the Emory University School of Medicine Human cytomegalovirus is a common herpes virus, said Dr Dix About 80 percent of the population is estimated to have antibodies for the virus, and it is often acquired during childhood In a normal, healthy immune system, the virus becomes latent in the cells of bone marrow and blood But in the elderly, the immune system’s function is reduced, the virus proliferates and the production of VEGF increases Identifying human cytomegalovirus as a cofactor in the development of AMD opens up new paths for the treatment of AMD, Dr Dix said One route could include reducing the viral load—the amount of the human cytomegalovirus in the blood stream—by treatment with an antiviral drug known as ganciclovir Additional research paths include looking at the genetics involved in the upregulation of VEGF by human cytomegalovirus “If we can knock down a certain gene or genes of the virus that stimulates VEGF production, we might be able to decrease its production and minimize AMD,” Dr Dix said Rhein Fire & Ice Mask Product #85-9005 s &OR(EAT4HERAPY0LACE)T)N!-ICROWAVE &OR3ECONDS 7ARM2ELIEF,ASTS-INUTES s &OR#OLD4HERAPY!FTER0LACING)N4HE&REEZER (OURS #OOL2ELIEF,ASTS-INUTES s )NCLUDES#LOTH3LEEVE&OR!DDITIONAL,ID 0ROTECTION s %ASY4O5SE !ND#AN"E#LEANED!ND2EUSED -ULTIPLE4IMES s !VAILABLE5NITS0ER"OX &OR-ORE)NFORMATION#ALL RHEIN CODE VIDEO CODE 3360 Scherer Drive, Suite B, St Petersburg, FL 33716 s4EL s&AX %MAIL)NFO 2HEIN-EDICALCOM7EBSITEWWW2HEIN-EDICALCOM 7OMAN7EARING$RY%YE(EAT-ASK RHEIN CODE 1301 Rev.C 005_rp0712_news.indd VIDEO CODE ACBB 6/21/12 3:45 PM REVIEW Retinal Insider Edited by Carl Regillo, MD and Emmett T Cunningham Jr., MD, PhD, MPH Genetic Testing for AMD Inches Forward A look at the status of current technology and where it fits in the management of patients with age-related macular degeneration Ivana K Kim, MD, Boston ver the past six years, we have made great progress in understanding the complex genetics underlying age-related macular degeneration At this point more than 25 genes have been reported to influence AMD risk, and the identification of the major genetic risk factors has elucidated new therapeutic targets, such as the alternative complement pathway.1 This knowledge, combined with advances in technology allowing for rapid and precise genotyping, make it now possible to profile an individual’s genetic risk for AMD O Genetic Tests for AMD Risk There already are several commercially available tests for determining an individual’s genetic risk for AMD as listed in Table The various tests differ in the numbers of genetic markers and methods used for calculating risk The two main tests currently directed to ophthalmic providers for patient risk stratification are Macula Risk (ArcticDx) and RetnaGene (Sequenom) The Macula Risk test uses markers in four genes as well as smoking history to predict an individual’s risk of advanced 56 | Review of Ophthalmology | July 2012 056_rp0712_rtinsider.indd 56 AMD and categorizes patients into five risk groups (one to five, with five representing highest risk) Sequenom’s RetnaGene test employs an independently validated model using 13 single nucleotide polymorphisms in the major AMD-associated genes and is geared specifically for predicting risk of the neovascular form of AMD A risk score is generated and the patient is categorized into three risk groups: low; medium; or high DeCODE genetics offers AMD risk screening as part of its Complete scan which analyzes genetic risk factors for 50 conditions and must be ordered through a physician The 23andMe test is a retail product available directly to the general population The ACCE Model Now that these tests are available, it is necessary to determine whether it is worthwhile to perform genetic testing The Centers for Disease Control and Prevention sponsored the development of the ACCE model for evaluating scientific data on emerging genetic tests This model considers four components: 1) analytic validity; 2) clinical validity; 3) clinical utility; and 4) ethical/legal/social implications.2 Analytic Validity The criterion of analytic validity refers to the technical accuracy of the test Current technology makes genotyping very accurate Therefore, determining whether an individual has the high-risk or low-risk allele at a specific single nucleotide polymorphism is performed quite reliably The main source of error with the current tests available would be likely due to problems with sample handling Clinical Validity The measure of clinical validity asks how well a test can actually discriminate between high- and low-risk groups A method for calculating this discriminative ability is plotting true positives vs false positives, which is called a receiver operating curve (ROC) (See Figure 1) The area under this curve (AUC) is a measure of discriminative ability, with a perfect test giving an AUC of one The recommended AUC of a model for screening a population at increased risk of disease is >0.75.3 This article has no commercial sponsorship 6/20/12 4:11 PM Figure Genetic Risk Models 1.0 0.8 TPF 0.6 Three gene model CFH + LOC model CFH model LOC model C2 model Null model 0.4 0.2 0.0 0.0 0.2 0.4 0.6 FPF 0.8 1.0 Figure Examples of receiver operating curves (ROC) for AMD models using differing numbers of genetic variants The grey line represents “chance.” The farther away a curve is from the chance line, the better the predictive value of the model and the closer the area under the curve (AUC) is to In this plot, the AUC=0.79 for the three-gene model TPF=True Positive Frequency, FPF=False Positive Frequency (See endnotes for source.) Current models for predicting AMD risk that include various combinations of epidemiologic, clinical and genetic factors give AUC’s of approximately 0.8.4,5,6 Therefore, these models appear to have sufficient accuracy for predicting advanced AMD in those already at increased risk based on age or evidence of early AMD How much does genotyping add to our ability to predict advanced AMD? A previous analysis by Johanna Seddon, MD, and colleagues demonstrated that a model of AMD risk including age, gender, education, baseline AMD grade, smoking and body mass index had an AUC of 0.757.6 The addition of genetic factors (SNPs in CFH, ARMS2, C2, CFB and C3) increased the AUC to 0.821 In these models, the baseline grade of AMD was the strongest predictor of risk of progression to advanced AMD More recently, work by Michael Klein, MD, et al confirmed that an individual’s macular phenotype, represented by the AREDS Simple Scale score (See Figure An eye with large drusen and pigmentary abnormalities This eye would receive two points on the AREDS Simple Scale, as described in Table If the other eye had similar findings or advanced AMD, it would also receive two points and the total score for the patient would be four Table and Figure 2), has the greatest predictive value.7 The predictive models in this analysis included age, family history, smoking, the AREDS Simple Scale score, the presence of very large drusen, the presence of advanced AMD in one eye, and two polymorphisms in CFH and ARMS2 strongly associated with risk of AMD The AUC was 0.872 with genetic factors included and 0.865 without These data indicate that it is possible to provide accurate assessment of risk of advanced AMD without necessarily doing genetic testing The authors have made their risk calculator available online at caseyamdcalc.ohsu.edu One other measure of clinical validity is positive predictive value (PPV) or the percentage of individuals identified as high-risk who will actually develop advanced disease This value correlates with disease prevalence With regard to the AMD scenario, the PPV of any genetic test will be better if applied to elderly individuals with early stages of AMD rather than young, unaffected individuals Clinical Utility The measure of clinical utility considers how the test results will affect clinical management of the individual What can we for those individuals whose genetic testing indicates that they are at high risk for vision loss from AMD? Currently, we not have preventive measures other than high-dose antioxidant and zinc supplements as demonstrated by the Age-Related Eye Disease Study.8 Experience from genetic testing for Alzheimer’s disease revealed that those who knew that they carried the risk variant in the ApoE gene reported that they were more likely to use dietary supplements as a preventive measure against the development of the disease.9 The same might hold true for those determined to be at high-risk for advanced AMD However, some evidence suggests that July 2012 | Revophth.com | 57 056_rp0712_rtinsider.indd 57 6/20/12 4:11 PM REVIEW Retinal Insider Table Genetic Tests for AMD Test Markers Sample Macula Risk CFH, ARMS2, C3, ND2, Smoking Cheek swab RetnaGene (CNV risk) CFH/CFHR region, C2, CFB, ARMS2, C3 Cheek swab or blood deCode Complete Scan CFH, ARMS2/HTRA1, C2, CFB, C3 (East Asians: ARMS2/HTRA1 only) Cheek swab ARUP Laboratories CFH, ARMS2 Blood 23andMe CFH, ARMS2, C2 Saliva those with the CFH Y402H risk allele might have a reduced benefit from taking the AREDS supplements.10 We might also suggest more frequent monitoring for high-risk patients and possibly recommend home monitoring devices Preferential hyperacuity perimetry has been demonstrated to detect early neovascular AMD with high sensitivity and specificity.11,12 This technology has been developed for home monitoring, and other applications are being developed for smartphones and computers The impact of recommending such monitoring for high-risk patients will need to be assessed What about using genetics to guide therapy? So far, there have been no consistent associations between response to anti-VEGF therapy and genotype.13-15 However, associations may new diagnosis However, the impact of being predicted to be at high-risk of vision loss from AMD should not be underestimated and options for counseling should be available, as recommended for all other genetic testing Where We Stand Today emerge in the future as new therapeutic pathways are targeted, for example the complement pathway Also, the studies to date have been performed to a limited number of polymorphisms As genotyping technology continues to improve and becomes more affordable, more extensive analyses may be performed revealing new associations Ethical/Legal/Social Implications Currently there not appear to be any particular ethical or social issues associated with genetic testing for AMD As noted previously, genetic testing for AMD should only be considered for patients with earlystage disease and not for young, presymptomatic individuals Therefore, the results of this testing should not necessarily label individuals with a Table AREDS Simplified Severity Scale Severity Score Rate of Advanced AMD (five-year) 0.5 percent percent 12 percent 25 percent 50 percent Severity score determined by presence of large drusen (1 point) and pigment changes (1 point) in each eye Ferris FL, Davis MD, Clemons TE, Lee LY, Chew EY, Lindblad AS, Milton RC, Bressler SB, Klein R; Age-Related Eye Disease Study (AREDS) Research Group A simplified severity scale for age-related macular degeneration: AREDS Report No 18 Arch Ophthalmol 2005 Nov;123(11):1570-4 Should we offer genetic testing in routine clinical practice? In terms of the ACCE paradigm, the analytic validity of AMD genetic tests is good, meaning there are no technical difficulties in genotyping the major risk variants Clinical validity is also good in terms of being able to accurately identify high-risk patients However, we must keep in mind that the accuracy is highest if we apply these tests to those with early-stage disease rather than the general population In terms of clinical utility, we are still exploring how the results of testing will be applied to the management of patients with AMD At the present time, there not appear to be significant ethical, legal and social implications of genetic testing for AMD, but these issues should be reassessed as utilization increases The most significant impact of the identification of genetic risk factors for AMD has been the insight provided regarding potential therapeutic targets as a result of the elucidation of pathways involved in disease pathogenesis Genotyping will remain a critical element of ongoing and future clinical trials as more information regarding genetics and specific disease manifestations (genotype-phenotype correlations) as well as genetics and response to therapy (pharmacogenetics) remains to be discovered Outside of the trial setting, given the growing availability of commercial genetic tests for AMD, clinicians will require some knowledge about these tests in order to have an informed discussion with patients who are interested in knowing their genetic profile 58 | Review of Ophthalmology | July 2012 056_rp0712_rtinsider.indd 58 6/20/12 4:11 PM REVIEW Dr Kim is an associate professor of ophthalmology at the Harvard Medical School and on the Retina Service at Massachusetts Eye and Ear Infirmary Contact her at (617) 573-3367; fax: (617) 573-3678 or ivana_kim@meei harvard.edu Figure adapted from Jakobsdottir J et al PLoS Genet Feb;5(2):e1000337 Epub 2009 Feb doi:10.1371/journal pgen.1000337.g003 Calendar JULY 21 - 25 BERLIN The 20th Biennial Meeting of the International Society for Eye Research will present clinicians and vision researchers from all over the world with the latest scientific achievements and research in the field For more information, visit kenes.com/iser AUGUST - 11 CANCUN, MEXICO The 18th International Course on Cornea and Refractive Surgery, a joint meeting of the World Keratoconus Society and the Pan-American Cornea Society, will be held in Cancun Topical issues will include technological developments, advances in surgical techniques and international multicenter studies in the field of cornea and external diseases For more information, visit convention-center.net/cornea2012 SEPTEMBER DeAngelis MM, Silveira AC, Carr EA, Kim IK Genetics of age-related macular degeneration: current concepts, future directions Semin Ophthalmol 2011 May;26(3):77-93 Centers for Disease Control and Prevention ACCE http:// www.cdc.gov/genomics/gtesting/ACCE/FBR/index.htm Janssens AC, Moonesinghe R, Yang Q, Steyerberg EW, et al The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases Genet Med 2007;9:528-535 Jakobsdottir J, Gorin MB, Conley YP, Ferrell RE, Weeks DE Interpretation of genetic association studies: Markers with replicated highly significant odds ratios may be poor classifiers PLoS Genet 2009 Feb;5(2):e1000337 Epub 2009 Feb Hageman GS, Gehrs K, Lejnine S, et al Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration Human Genomics 2011 July;5(5):1-21 Seddon JM, Reynolds R, Maller J, Fagerness JA, et al Prediction model for prevalence and incidence of advanced agerelated macular degeneration based on genetic, demographic, and environmental variables Invest Ophthalmol Vis Sci 2009 May;50(5):2044-53 Klein ML, Francis PJ, Ferris FL 3rd, Hamon SC, Clemons TE Risk assessment model for development of advanced age-related macular degeneration Arch Ophthalmol 2011 Dec;129(12):1543-50 Epub 2011 Aug 8 Age-Related Eye Disease Study Research Group A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no Arch Ophthalmol 2001;119:1417-36 Green RC, Roberts JS, Cupples LA, Relkin NR, et al; REVEAL Study Group Disclosure of APOE genotype for risk of Alzheimer’s disease N Engl J Med 2009 Jul 16;361(3):245-54 10 Klein M, Francis P, Rosner B, et al CFH and LOC387715/ ARMS2 Genotypes and Treatment with Antioxidants and Zinc for Age-Re-lated Macular Degeneration Ophthalmology 2008;115:1019-1025 11 Alster Y, Bressler NM, Bressler SB, Brimacombe JA, et al; Preferential Hyperacuity Perimetry Research Group Preferential Hyperacuity Perimeter (PreView PHP) for detecting choroidal neovascularization study Ophthalmology 2005112:1758-65 12 Lai Y, Grattan J, Shi Y, Young G, Muldrew A, Chakravarthy U Functional and morphologic benefits in early detection of neovascular age-related macular degeneration using the preferential hyperacuity perimeter Retina 2011;31:1620-6 13 Lee AY, Raya AK, Kymes SM, Shiels A, Brantley MA Jr Pharmacogenetics of complement factor H (Y402H) and treatment of exudative age-related macular degeneration with ranibizumab Br J Ophthalmol 2009 May;93(5):610-3 14 Kloeckener-Gruissem B, Barthelmes D, Labs S, Schindler C, Kurz-Levin M, Michels S, Fleischhauer J, Berger W, Sutter F, Menghini M Genetic association with response to intravitreal ranibizumab (Lucentis) in neovascular AMD patients Invest Ophthalmol Vis Sci 2011 Jul 1;52(7):4694-702 15 McKibbin M, Ali M, Bansal S, Baxter PD, West K, Williams G, Cassidy F, Inglehearn CF CFH, VEGF and HTRA1 promoter genotype may influence the response to intravitreal ranibizumab therapy for neovascular age-related macular degeneration Br J Ophthalmol 2012 Feb;96(2):208-12 5-8 WÜRZBURG, GERMANY The Glaucoma Research Society annual meeting will foster discussion and interaction between leading glaucoma clinicians and researchers to synthesize new and existing knowledge and to identify strategies for future clinical, translational or basic research For more information, visit glaucomasociety.org/2012 12 - 15 ST LOUIS Envision Conference 2012, the largest multi-disciplinary low-vision rehabilitation and research conference in the United States, takes place at the Hilton St Louis at the Ballpark This one-of-a-kind conference will feature clinical education, workshops and research presentations by top experts in low-vision rehabilitation CME credits will be available For more information, or to register, visit envisionconference.org OCTOBER 4-6 BUENOS AIRES, ARGENTINA The biannual meeting of the Latin American Society of Cataract and Refractive Surgeons will meet for three days in Buenos Aires There will be sessions, paper presentations and surgical technique training, as well as courses for managers and technicians For more information, please visit congresos-rohr.info/alaccsa-r2012/index.php, alaccsa-r.com or email alaccsar2012@congresos-rohr.com 10 - 13 NICE, FRANCE The European Association for Vision and Eye Research is the leading ophthalmological research association in Europe, covering all areas of ophthalmology and the visual sciences EVER currently has over 750 members from 67 countries all over the world and represented by 11 scientific sections, ranging from epidemiology to optics, the cornea to the retina and immunology to genetics Central conference events will include keynote lectures, special interest symposia, courses, workshops and plenary lectures Accreditation is offered by the European Accreditation Council for Continuing Medical Education (EACCME) For more information, visit ever.be NOVEMBER 8-9 CHICAGO The 43rd Annual Fall Science Symposium of the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) will be held at the Swissôtel in Chicago This meeting will provide a forum for the presentation of new concepts, techniques and clinical experiences in orbital disease and surgery; aesthetic surgery; and oculofacial, orbital, and lacrimal surgery Forum space will also be available to discuss practice management, access to care and physician advocacy CME credits will be available For more information, visit asoprs.org 10 - 13 CHICAGO The American Academy of Ophthalmology’s Annual Meeting will take place in Chicago, at McCormick Place West Convention Center This will be a joint meeting with the Asia-Pacific Academy of Ophthalmology APAO is a federation of national societies whose mission is to preserve and protect the vision of the people in the Asia-Pacific region APAO will have 45 hours of its own programming, focusing on the current challenges facing Asia-Pacific ophthalmologists The annual meeting will be preceded by Subspecialty Days on the 9th and 10th CME hours will be available For more information, visit aao.org 27 - 29 MANILA, PHILIPPINES The Asia Cornea Society 3rd Biennial Scientific Meeting, held immediately prior to the Philippine Academy of Ophthalmology annual meeting, will bring together some of the foremost leaders, innovators and visionaries in the field of cornea, external disease, refractive surgery and eye banking from all over the world, as well as hundreds of participants especially from the dynamic Asia Pacific Region For more information, visit asiacorneasociety2012manila.com/index.php July 2012 | Revophth.com | 59 056_rp0712_rtinsider.indd 59 6/20/12 4:12 PM RETINA ONLINE E-NEWSLETTER Once a month, Medical Editor Philip Rosenfeld, MD, PhD, and our editors provide you with timely information and easily accessible reports that keep you up to date on important information affecting the care of patients with vitreoretinal disease EASY WAYS TO SUBSCRIBE! http://www.jobson.com/globalemail/ Fax: 610 610.492.1039 0.492.1039 o orr C Call: all: 610.492.1027 10.492 0411_Retina Online house Ad.indd 11/18/11 4:19 PM REVIEW Refractive Surgery Edited by Arturo Chayet, MD A Closer Look at the New EX500 Laser The new excimer from Alcon/WaveLight has features to enhance connectivity and decrease procedure times Walter Bethke, Managing Editor t’s not often that a new excimer laser gets approved for laser vision correction, so when it happens, surgeons take notice Recently, refractive surgeons were given a new excimer option with the Food and Drug Administration approval of the Alcon/ WaveLight EX500 laser, which brings some new features and increased speed to the table Here’s a look at the new laser and how it might fit into a refractive practice I ment ranges into higher ones, as well as with mixed astigmatism and hyperopes, speed becomes a factor, since desiccation becomes important with regard to outcomes.” For comparison, Dr Stonecipher cites a study that compared the results of the 200-Hz Allegretto Wave to those of the 400-Hz device in 206 eyes of 121 patients with -6 to -12 D of error with up to D of cylinder.1 At the three- and six-month visits in the 200-Hz group, 77 percent (109/141) and 86 percent (121/141) of eyes, respectively, were within ±0.50 D of the intended correction In the 400-Hz group, 98.5 percent (64/65) and 100 percent (65/65) of eyes were within ±0.50 D of the intended correction at three and six months postoperatively Treatment Speed One of the key features of the device is its ablation speed, running at 500 Hz, vs the speed of the previous model, the Allegretto Wave IQ 400 Hz “Granted, it’s incrementally faster,” says Greensboro, N.C., surgeon Karl Stonecipher “However, it matters With a speed of 400 Hz, the laser ablated at a rate of two seconds per diopter With 500 Hz, though, it’s speed is 1.4 seconds per diopter.” Dr Stonecipher says it’s been his experience that up to about -7 D, the outcomes between the 400-Hz and the 500-Hz lasers are somewhat similar “But when they get out of those treat- The EX500 can be networked via a wireless connection to other Alcon instruments in the operating room, cutting down on the number of times patient data needs to be input This article has no commercial sponsorship 061_rp0712_rs.indd 61 July 2012 | Revophth.com | 61 6/21/12 9:37 AM EVERY MONDAY Have you been receiving and reading custom e-blasts from Review of Ophthalmology? If not, you’re missing out on valuable information! You’re a busy practitioner and not surprisingly, your e-mail inbox is often full Fortunately, when you scan through the sender list, determining which messages to delete and which to save or read, you can feel confident knowing that e-blasts from Review of Ophthalmology, a Jobson Medical Information, LLC publication, contain the most current and comprehensive information available in the field to keep you on the cutting edge Review of Ophthalmology’s online stable of products includes editorial newsletters and promotional information about new products, treatments and surgical techniques, as well as alerts on continuing education courses for ophthalmologists • Our FREE weekly e-newsletter, Review of Ophthalmology Online, brings you the latest in ophthalmic research, as well as industry news In an effort to keep eyecare professionals informed, this resource is waiting in your inbox every Monday morning • Retina Online, our free monthly e-newsletter, is for retina specialists and general ophthalmologists interested in enhancing their knowledge on the topics of retina and related disease diagnosis and treatment, as well as the latest in surgical procedures Your time is valuable — and so is your practice These e-products are the most effective way for you to receive updates on breaking news and research — all just a click away Don’t miss out! 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 REVIEW Refractive Surgery In the 200-Hz group, at the threeand six-month follow-up 84 percent (119/141) and 77 percent (109/141) of eyes, respectively, saw 20/20 or better uncorrected By contrast, in the 400-Hz group 80 percent (52/65) and 92 percent (60/65) of eyes had 20/20 or better uncorrected vision at three and six months, respectively At the six-month follow-up, Dr Stonecipher and his colleagues found that refractive predictability and visual acuity were statistically significantly superior in eyes in the 400-Hz group (p