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Is There Tachyphylaxis to IntravitrealAnti-Vascular Endothelial Growth FactorPharmacotherapy in Age-Related MacularDegeneration?
Shlomit Schaal, MD, PhD, Henry J. Kaplan, MD, Tongalp H. Tezel, MD
Purpose: To determine whether repetitive injections of intravitreal bevacizumab and/or triamcinolone ace-tate in patients with exudative age-related macular degeneration (AMD) results in a decrease in biologicalresponse.
Design: Retrospective comparative case series.Participants: Forty-three eyes of 43 patients with exudative AMD.Methods: Pre- and postinjection optical coherence tomography (OCT) sections of 43 patients with AMD
were analyzed to determine the change in the biologic response after each subsequent injection of intravitrealbevacizumab (2.5 mg/100 �L), preservative-free triamcinolone acetonide (pfTA) (4.0 mg/100 �L), or a combina-tion of bevacizumab (1.25 mg/50 �L) and pfTA (2.0 mg/50 �L). The retinal thickness of each OCT sector wasdetermined and expressed as volume. Standardized volumetric change index (SVCI) was determined to identifya statistically significant change. Pre- and postinjection (6 weeks) SVCI differences were plotted as a function oftime to determine the biological response after each intravitreal treatment.
Main Outcome Measures: Change in SVCI after intravitreal injections and the number of injections requiredto decrease the biological response by 50% (INJ50).
Results: There was no difference in the age, gender, and preinjection thickness of the retina in each of the3 groups. The SVCI after intravitreal bevacizumab injections decreased, indicating a possible tachyphylacticresponse to bevacizumab. This decrease in biological response was partially alleviated with the addition of pfTA.Combination of pfTA and bevacizumab increased the INJ50 from 2.9 with bevacizumab alone to 5.1 injections.A biphasic biologic response was observed with pfTA characterized by a rapid increase in efficacy with thesecond injection, peaking at the third injection and gradually decreasing afterward.
Conclusions: Repeated intravitreal injections of bevacizumab in exudative AMD seemed to be associatedwith decreased bioefficacy. However, combined pharmacotherapy with triamcinolone acetate lessened thiseffect. Thus, multitargeted pharmacotherapy in exudative AMD may have a therapeutic benefit.
Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.
Ophthalmology 2008;115:2199–2205 © 2008 by the American Academy of Ophthalmology.Age-related macular degeneration (AMD) remains the lead-ing cause of irreversible vision loss among the elderlypopulation in the United States and Western Europe.1 As the“baby boomer” generation ages within the next decade,AMD will affect the sight of more than 6 million people.2
The use of intravitreal pharmacotherapy has recentlyrevolutionized the treatment of exudative AMD. The firstgeneration of such agents targets vascular endothelialgrowth factor (VEGF) because of its central role in thedevelopment of subretinal choroidal neovascularization. AnRNA-based aptamer (pegaptanib) and 2 antibody fragments(ranibizumab and bevacizumab)3,4 have been introduced forclinical use, and several others are in preparation. Theseagents decrease the plasma leak through incompetent neo-vasculature and result in a temporary increase in vision.They often require frequent intravitreal injections, which
carry the risks of retinal tear and endophthalmitis.5 The© 2008 by the American Academy of OphthalmologyPublished by Elsevier Inc.
short-term response to these drugs is often favorable; how-ever, their safety and efficacy in the long-term are stillquestionable.5 Early studies revealed a favorable trendfor continuous VEGF neutralization in preserving centralvision.6,7
For medications taken chronically, diminution of a bio-logic effect is a major concern that can limit long-termefficacy. This phenomenon has been termed tachyphylaxis,referring to a progressive decrease in therapeutic responseafter repetitive administration of a pharmacologically activesubstance.8 The present study was undertaken to investigatewhether repeated intravitreal injection of bevacizumab caninduce a decrease in biological response. We used OCT toanalyze the retinal morphometric changes induced by in-creased intraretinal fluid. OCT is noninvasive, fast, andmore accurate in determining the anatomic changes induced
by intraretinal fluid egress compared with fluorescein an-2199ISSN 0161-6420/08/$–see front matterdoi:10.1016/j.ophtha.2008.07.007
Ophthalmology Volume 115, Number 12, December 2008
giography, which may not accurately indicate net fluidtransport at areas of leakage.9
Furthermore, we used the retinal volume changes in-duced by bevacizumab as an outcome measure in a stan-dardized and controlled fashion. The use of an objectivemorphometric parameter as an outcome measure allowed usto avoid confounding effects that may affect visual acuity,such as the lesion location, composition, size, duration,effect of previous treatments, and development of mediaopacities during the course of therapy.10–12
Materials and Methods
This retrospective interventional case study was approved andmonitored by the Institutional Review Board of the University ofLouisville, School of Medicine and conducted according to theprinciples of the Declaration of Helsinki. This study involvedpatients with exudative AMD seen from October of 2003 toJanuary of 2007.
Eligibility criteria included age �65 years; the presence ofcharacteristic age-related maculopathy changes (e.g., drusen, reti-nal pigment epithelium atrophy, retinal pigment epithelium hyper-pigmentation, and/or geographic atrophy), along with clinicaland fluorescein angiographic evidence of subfoveal choroidal neo-vascularization in 1 eye; and at least 1 year of intravitreal phar-macotherapy, without interruption in treatment or follow-up. Inclu-sion criteria were independent of lesion size and composition, becausewe studied the change in biological response for the same patientthroughout the course of intravitreal therapy. Patients with othercauses of subretinal neovascularization (e.g., presumed ocular his-toplasmosis syndrome, high myopia, angioid streaks), ocular or sys-temic diseases associated with macular edema or ischemia, or traumaor media opacities were excluded. Patients receiving pharmacother-apy in the fellow eye were excluded to avoid the confounding effectof the systemic absorption of intravitreal medication from the othereye. Patients with symptomatic coronary artery disease (e.g., angina,shortness of breath) or at high risk of stroke (e.g., uncontrolledsystemic hypertension, diabetes, or recent history of transient isch-
Figure 1. Standard 9 zones in OCT. The area of each zone is used to conv
N � nasal; OD � right eye; OS � left eye; S � superior; SVCI � Standardiz2200
emic attacks) were not given bevacizumab to avoid any possiblearterial thrombosis. Eligible patients received 1 of 3 different treat-ments: (1) intravitreal injection of 2.5 mg/100 �L bevacizumab(Avastin, Genentech, Inc., San Francisco, CA); (2) intravitreal injec-tion of 4 mg/100 �L preservative-free triamcinolone acetonide(pfTA) (New England Compounding Center, Framingham, MA); or(3) combined intravitreal injection of 1.25 mg/50 �L bevacizumaband 2 mg/50 �L pfTA. Intravitreal injections were repeated at3-month intervals for at least 3 successive times.
All patients received a full clinical examination, which in-cluded best-corrected Snellen visual acuity, applanation tonome-try, slit-lamp biomicroscopy, and stereoscopic posterior segmentevaluation by one of the participating retina specialists after fulldilation with 1.0% tropicamide and 2.5% phenylephrine. Opticalcoherence tomography (OCT) was performed with a Zeiss StratusOCT Model 3000 (Carl Zeiss Meditec, Inc., Dublin, CA) usingscan acquisitions of 6 radial lines, each 6 mm in length, at 30-degree intervals, manually centered on the patient’s fovea. Astandard scan acquisition protocol was used, with 512 A-scans perline with 400 A-scans per second. Automatic boundary locationwas manually verified for all scans and corrected when necessaryusing Stratus OCT software (Version 4.0). Use of OCT in a similarfashion has been shown to result in highly reproducible quantita-tive measurements in the setting of neovascular AMD.13
Treatment choice was based on the preference of the physicianand patient. Follow-up examinations coupled with OCT analysiswere done at the sixth week postinjection, which was previouslydetermined to be the most effective biologic time for the thera-peutic effect of bevacizumab (Tezel TH, Barr CC, Kaplan HJ. In-travitreally injected anti-VEGF drugs exert a biological effect inthe fellow eye. Paper presented at the 24th Annual Meeting of theAmerican Society of Retina Specialists. Cannes, France, 2006).
Morphometric Analysis
Figure 1 defines each of the 9 OCT zones used to evaluatethickness and volumetric changes. The concentric circles have adiameter of 1, 3, and 6 mm. The thickness of each sector wascalculated for each patient visit. Intraindividual and interindividualvariation of the thickness of each sector was determined in a cohort
e unidimensional thickness data to SVCI. C � central zone; I � inferior;
ert th ed Volumetric Change Index; T � temporal.
Schaal et al � Tachyphylaxis to Intravitreal AMD Pharmacotherapy
of untreated patients with exudative AMD, and the distribution ofthe change in thickness of each sector was fit to a Gaussian curve(data not shown). Two standard deviations of the variation for eachsector in untreated exudative patients was accepted as a statisti-cally significant change in thickness. This prerequisite eliminatesany retinal thickness variation error and only accepts change thatfalls into 2.4% of the distribution curve as a significant change.
The biologic effectiveness of treatment for each retinal sector, ateach time point, was determined by calculating a standardized volu-metric change index (SVCI) based on OCT measurement of the changein retinal thickness and the area of each sector. SVCI was defined as
�n � C�T2 �Te � To
2 SD � AS
where SD represents the standard deviation of thickness for anOCT sector; C-T2 represents each OCT sector; and As representsthe area of each OCT sector. To and Te are the initial and postinjection(sixth week) thickness measurements, respectively. The SVCI
Figure 2. The relative efficacy of bevacizumab decreases with subsequentefficacy [%] � 99.3–45.1 ln [number of injections]). The number of injecto be 2.9 injections. Combining bevacizumab with pfTA slowed downSimilarly, the relative efficacy plot for combined bevacizumab and pfTA iefficacy (%) � 98.4–29.7 ln (number of injections) (r � �0.95, P�0.0008
Table 1. Demographic Characteristics of Patients
No. ofPatients
MeanAge
PercentMale/
FemalePercent
Caucasian
AverageNo. of
Injectionsper
Patient
Group 1Bevacizumab
15 82�6 40/60 100 5.1�1.4
Group 2 pfTA 11 77�6 44/54 100 4.6�1.5Group 3
Bevacizumab �pfTA
17 78�7 27/76 100 3.7�0.7
pfTA � preservative-free triamcinolone acetonide.
at the third injection (P � 0.005) and continued afterward. pfTA � preservat
measurements at 6 weeks postinjection were used as the referencefor all subsequent changes in retinal thickness for the reasonpreviously mentioned. SVCIs of subsequent injections were stan-dardized to the initial SVCI, which was accepted as 100%. Thus,all SVCIs for subsequent intravitreal injections were calculated asa proportion of 100% and expressed as the relative efficacy of theinjected drug.
Statistical Analysis
All quantitative data were expressed as mean � standard devia-tion. The age of the patients, number of intravitreal injections indifferent treatment groups, and retinal thicknesses of OCT zonesbefore each injection were compared with Kruskal-Wallis one-wayanalysis of variance on ranks because of the nonparametric natureof the data. Dunn’s method was used for pairwise multiple com-parison procedure.14 A confidence level of P�0.05 was consideredto be statistically significant. Standardized volumetric change wasplotted against the number of injections, and best-fit curves werederived to determine the biologic response to the intravitrealpharmaceutical. By using this curve, the number of injections thatcoincided to a 50% reduction in the initial biological response(INJ50) was estimated for each drug.
Results
This study included 43 eyes of 43 patients. Fifteen eyes receivedonly bevacizumab, 11 eyes received only pfTA, and 17 eyesreceived combined bevacizumab and pfTA. The mean age of thepatients was 79�7 years (range, 68–89 years; Table 1); there wasno significant age difference among the treatment groups (82�6
ions. This trend fit well into a 2-parameter logarithmic equation (relativerequired to decrease the biological response by 50% (INJ50) is calculatedchyphylaxis to bevacizumab and prolonged the INJ50 to 5.1 injections.
ions fits well to a 2-parameter logarithmic equation in the form of retinale difference in relative efficacies between 2 treatments became significant
injecttionsthe tanject). Th
ive-free triamcinolone acetonide; RE � relative efficacy.
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years for bevacizumab, 77�6 years for pfTA; 78�7 years forcombined bevacizumab and pfTA; P � .07); the majority of thepatients were female (n � 28, 65%). A total of 192 intravitrealinjections were given (76 bevacizumab, 37 pfTA, and 79 com-bined bevacizumab and pfTA). A total of 384 retinal volumetricchange analyses were done using OCT during the follow-up periodof 54�17 weeks. The average number of intravitreal injectionswas comparable between bevacizumab (5.1�1.4) and combinedpfTA/bevacizumab (4.6�1.5) (P�0.05); however, fewer injec-tions of pfTA alone were given (3.7�0.7, P � 0.004). No signif-icant differences were observed between the average thicknessesof the retina before each injection (P�0.05).
Repeated injections of bevacizumab suggested a decrease inbiological response in all eyes, as measured by decreased rel-ative efficacy, over time (Figures 2 and 3). Approximately 3injections were required for the efficacy to decrease to 50% ofthe initial response. Combining bevacizumab with pfTA par-tially alleviated the efficacy decrease observed with bevaci-zumab alone (Figures 2 and 4) and increased the number ofinjections needed to reach 50% relative efficacy to 5.08. Therelative efficacy differences between combined injections ofbevacizumab/pfTA and bevacizumab alone reached a statisti-cally significant level at the third injection and remained thesame afterward (P � 0.005).
Figure 3. Vertical OCT sections of an 81-year-old woman with subfoveal c
intravitreal injections of bevacizumab. An initial robust response diminishes in2202
A biphasic efficacy response was observed after pfTA in-jections that peaked at the third injection and gradually de-creased in subsequent injections (Figures 5 and 6). However,the efficacy of subsequent pfTA injections never decreasedbelow the first injection level. Accordingly, 5 of 9 patients(45.5%) exhibited maximum decrease in retinal thickness afterthe second and third injections of pfTA. No comparable retinalthickness reduction was observed with subsequent injections.Combining pfTA with bevacizumab abolished the peak biologiceffect of pfTA seen after the second and third injections. Therelative efficacy of pfTA showed a marked interindividualvariation for pfTA (i.e., average � 102.1%�52.1%) comparedwith bevacizumab (61.1%�17.1%) and combined bevaci-zumab/pfTA (47.5%�22.2%, P � 0.05).
Discussion
Our results suggest that repetitive administration of bevaci-zumab in patients with choroidal neovascularization sec-ondary to AMD seems to result in a progressive decrease inthe biological response. Such a decrease in the bioefficacyof pharmaceuticals may be attributed to tachyphylaxis.8 The
dal neovascularization in the right eye. The patient received 7 consecutive
horoi subsequent injections because of tachyphylaxis to bevacizumab.
with pfTA. The initial response continues throughout the subsequent injectio
pfTA � preservative-free triamcinolone acetonide; RE � relative efficacy.
Schaal et al � Tachyphylaxis to Intravitreal AMD Pharmacotherapy
pattern of tachyphylaxis, in general, varies according toseveral parameters, such as the administration frequency,dose, receptor expression patterns on the target, and pres-ence of antagonists.15,16 No similar decrease in efficacy wasnoted with the injection of pfTA. Also, the combination ofbevacizumab with pfTA partially alleviated the efficacydecrease, suggesting that the progressive decrease in effi-cacy may be prevented by using pharmaceuticals with dif-ferent modes of action.
Initial clinical trails with VEGF-neutralizing drugs indi-cated the benefit of continuous treatment over “as needed”treatment.6,7 A major problem for the chronic administration ofa pharmaceutical is the desensitization of the target tissue tothe drug itself. This may become a major issue in the caseof exudative AMD pharmacotherapy because current ther-apeutic strategy is aimed at mono-targets. For example, inaddition to anti-VEGF neutralizing agents, other drugs beingdeveloped for the treatment of choroidal neovascularization aredirected at hypoxia-inducible factor, integrins, angiopoetins,erythropoietin, and pigment epithelium-derived growth factor.9
o received 7 consecutive intraocular injections of bevacizumab combinedns with minimal residual fluid accumulation only in the late injections.
Figure 4. Vertical optical sections of the right eye of an 87-year-old woman wh
Figure 5. Intravitreal pfTA injections are characterized by an augmentedinitial response that peaks at the third injection and subsequently dimin-ishes in magnitude. Another striking characteristic of the pfTA injectionsis the wide range of interindividual variation in the biological response.
One possible solution to avoid a decrease in biologic effect
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would be to combine drugs with different modes of action, asevidenced by the combination of bevacizumab with pfTA.
Theoretically, there could be several factors playing arole in the desensitization of choroidal neovascularization toinhibition of VEGF. For example, several other angiogenicsignaling pathways may compensate for the blocked activityof VEGF when using bevacizumab. A good example isfibroblast growth factor, which acts on the protein kinase Cand mitogen-activated protein kinase (MAPK) pathwaysthrough growth factor receptor-bound protein 2 (Grb2) andSOS (son of sevenless [signalling molecule]) adaptors. Thelatter can mimic the actions of VEGF by activating tyrosinekinase Src and PI3 kinase.17 In the case of pegaptanib, thelack of the specificity to block all VEGF isoforms mayresult in decreased efficacy, because it is known that severalsignal transduction pathways can influence alternative splic-ing in response to environmental cues (e.g., cellular stress,cytokines, growth factors, and hormones) and feed intoalternative splicing.18
Our study revealed a wide interindividual variation in theresponse of choroidal neovascularization to pfTA. Interin-dividual variations in local metabolism to inactivate triam-cinolone and/or dissociate it from its binding proteins maybe an underlying cause.19 This may simply be because ofinterindividual differences in 11-� hydroxysteroid dehydro-genase type-2 activity. This unidirectional dehydrogenaseinactivates biologically active glucocorticoids and is knownto be abundant in the eye.20 Interindividual differences inthe availability of glucocorticoid receptors on the choroidalneovascular epithelia and the access of pfTA to these re-ceptors are other factors that may play a role.
We observed a biphasic efficacy for pfTA with an in-crease in its effect after the second injection, peaking at thethird injection and gradually becoming less effective after-ward. Similar biphasic effects of corticosteroids have beenreported on cell proliferation.21,22 The antiangiogenic prop-erties of pfTA are mediated through its action on the glu-cocorticoid receptor.23 Thus, it is possible that the biphasic
Figure 6. Vertical OCT sections of the left eye of an 83-year-old womanof retinal dehydration persisted throughout the subsequent injections.
response to pfTA is mediated at the receptor level. pfTA
2204
initially activates the glucocorticoid receptors by increasingthe transformation of 10 S oligomeric cytosolic glucocorti-coid receptors to 4-5 S nuclear receptors, thus increasing thesensitivity of the choroidal neovascular epithelia to initialpfTA injections. Subsequent desensitization may be relatedto a pfTA-mediated decrease in receptor half-life.24
Because of the retrospective nature of our study, theresults need to be accepted cautiously. There may beseveral uncontrolled confounding factors and selectionbiases. However, our observations suggest a decrease inbiologic effect to repeated intravitreal bevacizumab in-jections used to neutralize VEGF and inhibit choroidalneovascularization. Recognition of this possible effectwith monotherapy in exudative AMD may be importantin the long-term management of patients with choroidalneovascularization. Awareness of this possibility shouldhelp in the planning, development, and evaluation ofpharmacotherapeutics for AMD.
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1985;260:418 –27.Footnotes and Financial Disclosures
Originally received: October 30, 2007.Final revision: June 5, 2008.Accepted: July 15, 2008.Available online: October 18, 2008. Manuscript no. 2007-1412.
Department of Ophthalmology and Visual Sciences, Kentucky LionsEye Center, University of Louisville School of Medicine, Louisville,Kentucky.
Presented in part at: the Annual Meeting of the American Academy ofOphthalmology, New Orleans, November 2007 and chosen as the “Best
Financial Disclosure(s):The author(s) have made the following disclosure(s): Tongalp H. Tezel,MD, was supported in part by a Career Development Award from Researchto Prevent Blindness, Inc., New York.
Commercial relations: None.
Conflict of Interest statement: The authors declare that no conflictingrelationship exists for any author.
Correspondence:Tongalp H. Tezel, MD, Kentucky Lions Eye Center, Department of Oph-thalmology and Visual Sciences, University of Louisville School of Med-icine, 301 E. Muhammad Ali Blvd, Louisville, KY 40202. E-mail:
[email protected]2205
