Mean (± SD) diurnal intraocular pressure (IOP) levels over time by treatment group.
Mean diurnal intraocular pressure(IOP) levels at 8 AM, 10 AM, and 4 PM at week 26 by treatment group.
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Higginbotham EJ, Feldman R, Stiles M, Dubiner H, Fixed Combination Investigative Group. Latanoprost and Timolol Combination Therapy vs MonotherapyOne-Year Randomized Trial. Arch Ophthalmol. 2002;120(7):915–922. doi:10.1001/archopht.120.7.915
Copyright 2002 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2002
To compare the efficacy and safety of a fixed combination of 0.005% latanoprost and 0.5% timolol maleate administered once daily vs monotherapy with either 0.005% latanoprost once daily or 0.5% timolol twice daily.
Patients with either primary or secondary open-angle glaucoma or ocular hypertension participated in a 6-month, randomized, double-masked, multicenter study with 3 parallel treatment groups. The double-masked period was preceded by a 2- to 4-week "run-in" treatment with timolol. Subjects could receive fixed combination therapy during a 6-month open-label extension.
Main Outcome Measure
The difference between groups in mean diurnal intraocular pressure reduction in study eye(s) from baseline through 6 months of treatment.
Overall, 418 patients were enrolled in the study; 332 completed the open-label phase. Diurnal intraocular pressure levels were similar at baseline, but at week 26, they were 19.9 ± 3.4 mm Hg in the fixed combination therapy group, 20.8 ± 4.6 mm Hg in latanoprost-treated patients, and 23.4 ± 5.4 mm Hg in timolol-treated patients (data are given as mean± SD). The mean change from baseline was greater among patients receiving fixed combination therapy compared with each monotherapy group (P<.01). Fixed combination therapy effectively lowered intraocular pressure levels for up to 1 year. All treatments were well tolerated.
The combination of 0.005% latanoprost and 0.5% timolol administered once daily is effective and well tolerated for up to 12 months.
GLAUCOMA IS a leading cause of irreversible blindness.1 The only effective and clinically proved means of managing the condition is to reduce the intraocular pressure (IOP), primarily with ocular-hypotensive medications.2,3 Given that medical management is the first line of treatment, compliance is an ongoing important issue for physicians and patients. More complex medication regimens have been associated with reduced compliance in patients with ocular hypertension and glaucoma.4,5 Combining 2 IOP-reducing medications in one bottle may help patients adhere to therapeutic regimens by reducing the number of medication containers used and the total number of doses administered. Before recommending a combination therapy, however, its long-term efficacy must be determined.
Small short-term studies6,7 have suggested that the combination of latanoprost and timolol may be more effective in reducing IOP than either therapy alone. The present research compared the long-term efficacy and safety of a fixed combination of 0.005% latanoprost and 0.5% timolol maleate administered once daily vs monotherapy with either 0.5% timolol twice daily or 0.005% latanoprost once daily in a large sample of patients.
This randomized, prospective, double-masked study with an open-label extension was conducted at 38 centers. Approval by the Institutional Review Board of each investigator's institution was obtained before the first patient was included from that site. Eligible patients were 18 years or older; were diagnosed as having unilateral or bilateral primary open-angle, pigmentary, or pseudoexfoliative glaucoma or ocular hypertension; had a best-corrected visual acuity measuring better than 20/200; and provided written informed consent. Patients were eligible for inclusion if their prestudy IOP was 30 mm Hg or higher without IOP-reducing medication or 25 mm Hg or higher with prior therapy. Previous timolol or latanoprost therapy was permitted.
Exclusion criteria included a history of acute angle closure or occludable angles; use of contact lenses; ocular surgery, argon laser trabeculoplasty, or ocular inflammation or infection within 3 months of the prestudy visit; hypersensitivity to benzalkonium chloride; or any other abnormal ocular condition or symptom that the investigator determined precluded study enrollment. The presence of concomitant diseases that contraindicate adrenergic antagonist use excluded patients. Nursing mothers, pregnant women, and women who were of childbearing potential and not using adequate contraception for at least the previous 3 months were excluded. Patients also were ineligible if they could not adhere to the treatment or visit plan or had participated in another clinical study within 1 month of the prestudy visit.
Patients were assessed for eligibility at the prestudy visit, which took place within the 4 weeks before the baseline visit (Figure 1). During the double-masked treatment period, scheduled visits were performed at baseline and at weeks 2, 6, 13, and 26; the open-label extension included visits at weeks 28, 39, and 52. A deviation of ±1 week from baseline was permitted for all subsequent visits. At the baseline visit, patients were allocated to 1 of 3 treatment groups according to a computer-generated randomization code list. A single blocked randomization list was generated for the entire study. Study medication was shipped to the individual study sites in sets such that each set was a multiple of the block size used in generating the randomization. Drug was issued according to patient numbers that were given in consecutive order at baseline. This method of randomization and drug assignment provided for a stratified randomization schedule, with study site as the stratification factor.
Intraocular pressure measurements were conducted with a calibrated Goldmann applanation tonometer at 8 AM, 10 AM, and 4 PM at the baseline visit and at weeks 2, 13, 26, and 52. At weeks 6, 28, and 39, the IOP was measured only at 8 AM. Two IOP measurements were performed at least 1 hour apart at the prestudy visit. During each visit, except the prestudy visit, IOP measurements were performed in triplicate in each eye. An automated visual field examination was performed at baseline (unless a documented test had been performed in the prior 3 months) and at weeks 13, 26, and 52. Visual acuity was assessed and eyelid and slitlamp biomicroscopy was performed at every visit. Medical and ocular histories were obtained, and gonioscopy and refraction were performed, at the prestudy visit. Ophthalmoscopy was performed at the prestudy visit and at weeks 26 and 52. Any changes in concomitant use of medication or in ocular findings were noted at every visit.
Adverse events, defined as any undesirable medical event regardless of whether it was treatment related, were monitored throughout the study and were coded using World Health Organization terminology. Serious adverse events included overdoses; those considered to be life threatening, sight threatening, or disabling; those that required or prolonged hospitalization; or those that were associated with cancer or a congenital anomaly.
Using standard magnifications and 2 flashes, instant (Polaroid) color photographs of the whole anterior surface of the iris of each study eye and of each patient's face were taken between the prestudy and baseline visits and at weeks 26 and 52. Two masked readers compared the first set of photographs with those taken at the end of the double-masked and open-label phases to evaluate the presence or absence of increased iris pigmentation. One masked reader used the same procedure to evaluate darkening, thickening, or lengthening of the eyelashes.
After the prestudy visit and before treatment with study medication, eligible patients discontinued therapy with other ocular hypotensive agents and underwent 2 to 4 weeks of "run-in" treatment with 1 drop of 0.5% timolol twice daily to ensure safety. No washout was required, and the last dose of timolol run-in treatment was administered at the investigator's site on the morning of the baseline visit immediately after the first IOP measurement. During the 6-month double-masked phase, patients were instructed to administer 1 drop of study medication twice a day, at approximately 8 AM and 8 PM, according to the regimen outlined in Figure 1. Patients in the fixed combination therapy and in the latanoprost groups administered medication at 8 AM and placebo at 8 PM; those in the timolol group administered medication at 8 AM and 8 PM. On the days of visits to the investigator site, the morning dose was administered immediately after the 8 AM IOP measurements. Medications were provided in identical coded bottles. Patients were instructed to apply the first dose in the evening of the day of the baseline visit and the last dose in the morning of the week 26 visit immediately after the 8 AM IOP measurement. All study participants were offered the opportunity to receive fixed combination therapy during the 6-month open-label extension.
Throughout the study, both eyes were considered study eyes in patients with bilateral glaucoma when all inclusion criteria were fulfilled and no exclusion criteria existed. In cases of bilateral disease in which only 1 eye met all eligibility criteria (study eye), the contralateral eye could also be treated with the study drug provided that there were no exclusion criteria for this eye. Patients with unilateral disease were treated only in the affected eye.
The primary efficacy outcome was the difference between the fixed combination therapy and the 2 monotherapy groups in mean diurnal IOP reduction in study eye(s) from baseline through 6 months of treatment. Intraocular pressure time point values for each eye were the mean of the replicate IOP measurements taken. Diurnal IOP was calculated as the average of the 8 AM, 10 AM, and 4 PM IOP time point values taken during each full-day visit. In patients with 2 study eyes, the mean IOP at each time point across eyes was used in diurnal IOP calculations.
Secondary efficacy outcomes were the differences between the fixed combination therapy and monotherapy groups for the percentages of patients reaching target IOP levels and the differences among groups in the consistency of IOP reduction up to 1 year. Treatment failures were patients in whom the diurnal IOP (or the mean IOP if noted at week 6) was increased at least 10% from baseline and was 23 mm Hg or higher and in whom such pressure elevation was sustained on a second examination conducted within 2 weeks. Open-label fixed combination therapy was started in patients in whom treatment was considered to have failed; if the IOP remained uncontrolled, they were withdrawn from the study.
Intent-to-treat efficacy analyses during the 6-month double-masked phase included all patients who received at least 1 drop of study medication. Missing data were handled as follows: in analyses of diurnal IOP values, the last available IOP measurement was carried forward; for patients in whom treatment had failed, the IOP measurement at the time of failure was carried forward; if IOP data were missing at weeks 2 and 13, week 26 measurements were carried backward; if IOP data were missing at week 2, the week 13 measurement was carried backward; diurnal IOP was based on measurements available for that day; and baseline IOP measurements were carried forward only for patients with no subsequent treatment IOP measurements. Intent-to-treat efficacy analyses during the open-label phase included all patients who received at least 1 drop of study medication during the open-label phase and for whom IOP data were available at weeks 26 and 52. In each phase, subanalyses were performed for response to medication based on age, race, and sex. Adverse event analyses in both study phases were based on all randomized patients who received at least 1 drop of study medication.
Differences in the mean diurnal IOP reduction between groups during 6 months of therapy were estimated (least square mean differences) using a repeated-measures analysis of covariance with baseline IOP as a covariate; patient, treatment, visit, and center as main factors; and treatment group–by–visit and treatment group–by–center interaction factors. The 95% confidence intervals (CIs) were calculated. Pearson χ2 tests compared proportions of patients in each group reaching target diurnal IOP levels between groups at week 26. Paired t tests were used to calculate 90% CIs for differences in the mean diurnal IOP levels at weeks 26 and 52; if the CI was within ±1.5 mm Hg, the diurnal IOP was considered to be maintained. Before the study, a sample size of 112 patients per treatment group was calculated as sufficient to detect an IOP reduction of 1.2 mm Hg from baseline at a single visit with a significance level of .05 and a power of 0.80. An SD for diurnal IOP change from baseline of 3.2 mm Hg was anticipated. To allow for withdrawals, 130 to 140 patients were included in each treatment group. Data are given as mean (± SD) unless otherwise indicated.
In all, 418 patients were included in the 6-month double-masked phase of the study: 138 in the fixed combination therapy group, 140 in the timolol group, and 140 in the latanoprost group (Figure 2). Between 1 and 30 patients were recruited in each of the 38 centers; 8 centers contributed 5 patients or fewer each. Of the 418 patients randomized, 345 completed 6 months of assigned therapy. Investigators switched 29 patients in whom treatment had failed to open-label treatment with fixed combination therapy (17 from the timolol group, 10 from the latanoprost group, and 2 from the fixed combination therapy group); 52 patients (including 8 in whom treatment had failed and who had been switched to fixed combination therapy) were withdrawn from the study (24 from the timolol group, 15 from the latanoprost group, and 13 from the fixed combination therapy group). The most common reasons for withdrawal were uncontrolled IOP (n = 20), other adverse events (n = 9), closure of a study center (n = 8), protocol violation (n = 6), and inadequate follow-up (n = 5).
Treatment groups were similar at baseline (Table 1), although the male-female ratio was somewhat higher in the timolol group and more patients in the fixed combination therapy group had a homogeneously blue, gray, or green iris. Primary open-angle glaucoma and ocular hypertension were the most common diagnoses. Most patients (84%) had received IOP-reducing medications within 3 months before enrolling in the study.
Diurnal IOP levels were similar at baseline: 23.1 ± 3.8 mm Hg in the fixed combination therapy group, 22.9 ± 4.1 mm Hg in the latanoprost group, and 23.7 ± 4.1 mm Hg in the timolol group (Figure 3). At week 26, the diurnal IOP levels were 19.9 ± 3.4 mm Hg in the fixed combination therapy group, 20.8 ± 4.6 mm Hg in the latanoprost-treated patients, and 23.4 ± 5.4 mm Hg in the timolol-treated patients. The mean change from baseline across weeks 2 to 26 was statistically significantly greater among patients receiving fixed combination therapy compared with those in each monotherapy group. The least square mean difference between fixed combination therapy– and latanoprost-treated patients was −1.0 mm Hg (95% CI, −1.7 to −0.3 mm Hg; P= .005) and between fixed combination therapy– and timolol-treated patients was −2.9 mm Hg (95% CI, −3.5 to −2.3 mm Hg; P<.001). There was no statistically significant difference in response to the fixed combination vs latanoprost or vs timolol based on age (P = .79 and .99, respectively), race (P = .66 and .11, respectively), or sex (P= .29 and .08, respectively). The mean IOP reductions were fairly consistent across measurement times in all treatment groups at week 26 (Figure 4).
Compared with timolol-treated patients, more patients receiving fixed combination therapy achieved IOP levels lower than 18 mm Hg and lower than 21 mm Hg (Table 2). Differences between latanoprost-treated patients and those receiving fixed combination therapy were not statistically significant at any target IOP level.
Of the 418 randomized patients, 258 reported adverse events. Table 3 lists adverse events that occurred in 1% or more of the patients. The most common complaint was irritation of the eye (in 46 of the 418 subjects). Investigators noted hyperemia involving the bulbar conjunctiva in 9 patients in the fixed combination therapy group and in 18 in the latanoprost group. Four patients reported hypertrichosis(2 each in the fixed combination therapy and latanoprost groups). Two latanoprost-treated patients and 2 patients receiving fixed combination therapy reported increased iris pigmentation. The single patient with iritis in the latanoprost group continued receiving study medication, and the event resolved. Two cases of macular edema occurred (1 each in the fixed combination therapy and latanoprost groups); both patients had diabetes mellitus and were treated with focal laser therapy. Headache (in 16 of the 418 patients) and upper respiratory tract infection (in 30 of the 418 patients) were the most commonly noted systemic adverse events. Four patients had clinically significant changes in either blood pressure or heart rate (2 in the fixed combination therapy group and 1 each in the other treatment groups), and 2 receiving fixed combination therapy exhibited bradycardia.
Eye photographs were available for 318 patients. The 2 readers noted iris changes in 8 of 120 and 9 of 113 patients undergoing fixed combination therapy and in 9 of 112 and 11 of 106 latanoprost-treated patients. Incidences of eyelash changes were as follows: fixed combination therapy, 29 of 114 patients; and latanoprost therapy, 21 of 106 patients. An additional 4 of 20 patients who switched from either timolol or latanoprost to fixed combination therapy demonstrated eyelash changes.
In all, 332 patients completed the 6-month open-label extension phase of the study and received fixed combination therapy (Figure 1). Of these patients, 113 were originally assigned to the fixed combination therapy group, 106 to the latanoprost group, and 94 to the timolol group. In addition, 19 of 29 patients who were switched to open-label fixed combination therapy during the double-masked phase achieved IOP control(12 of 17 from the timolol group, 7 of 10 from the latanoprost group, and 0 of 2 from the fixed combination therapy group) and were included in the analyses. Thirty-two patients were withdrawn from this phase of the study; the most common reasons for withdrawal were closure of a study center (n = 16), uncontrolled IOP (n = 8), and other adverse events (n = 3).
The diurnal IOP levels at weeks 26 and 52 for the patients originally receiving fixed combination therapy were 19.4 ± 3.0 and 18.9 ± 3.2 mm Hg, respectively (P>.05). At weeks 26 and 52, the diurnal IOP levels in the group that originally received latanoprost therapy were 20.1 ± 3.8 and 20.1 ± 3.4 mm Hg, respectively (P>.05); they were 21.6 ± 3.7 and 19.3 ± 3.5 mm Hg, respectively (P<.001) in the group that originally received timolol. There was no statistically significant difference in response based on age, race, or sex.
Overall, 186 patients reported an adverse event during the open-label extension phase of the trial (Table 4). Common ocular adverse events included eye irritation (burning, stinging, and itching), errors of refraction, and corneal disorders (punctate epithelial erosions and cataract). Most adverse events were considered mild. Upper respiratory tract infections were the most common systemic adverse event. Compared with baseline, 5 patients exhibited clinically significant changes in blood pressure or heart rate. Five cases of hypertension or aggravated hypertension, 1 of cardiac failure, and 2 of tachycardia were reported.
At week 52, photographs were available for 302 patients. Among those originally receiving timolol, increased iris pigmentation was noted in 17 of 86 patients by one reader and in 9 of 90 patients by the other. The 2 readers noted iris changes in 13 of 103 and 7 of 109 patients receiving fixed combination therapy and in 17 of 103 and 11 of 103 latanoprost-treated patients. Irides that were green and brown or blue or gray with brown were the most prone to darkening. Eyelash changes were noted in 18 of 89 patients originally treated with timolol, 32 of 105 in the original fixed combination therapy group, and 27 of 99 originally treated with latanoprost.
The results of the present research demonstrate that the fixed combination of 0.005% latanoprost and 0.5% timolol is more effective in reducing IOP levels than either therapy alone, with a greater difference in efficacy between fixed combination therapy and timolol than between fixed combination therapy and latanoprost. Because timolol reduces aqueous humor production and latanoprost increases uveoscleral outflow, the hypotensive actions of the medications are expected to be at least partially additive, and, in fact, small short-term studies6,7 have shown additional 13% to 36% reductions in IOP in patients receiving latanoprost and timolol compared with monotherapy. Data from the present sample of 418 patients followed up for up to 1 year confirm the additive hypotensive effect of latanoprost and timolol and support the findings of a study8 that included 139 patients in whom the difference in the IOP-lowering effect of fixed combination therapy vs timolol was greater than that between fixed combination therapy vs latanoprost. We found that the fixed combination therapy effectively lowered the IOP for up to 1 year, an important observation because timolol has been shown to lose efficacy in some patients after long-term use.9
Although the results of the double-masked phase of the study showed statistically significant differences in efficacy among treatment groups, some might argue that they are less significant clinically. However, the research included patients who were not only refractory to their ocular hypotensive agents but who also had baseline IOP levels while receiving timolol that were lower than levels that are typical in studies that include patients in whom all of the IOP-reducing medications have been washed out. Either of these factors could have depressed differences in IOP reductions between patients receiving fixed combination therapy and those receiving monotherapy.
Two additional features of the study design also may have influenced results. First, fixed combination therapy was administered in the morning, but latanoprost monotherapy was given in the evening. While there is some evidence that the prostaglandin analogue has greater efficacy on daytime IOP if it is administered in the evening,10 others11,12 have reported no difference in response to therapy in patients administered latanoprost in the morning vs in the evening. Although the present design may have favored the evening administration of latanoprost, clinicians may want to advise some patients to instill the fixed combination in the morning. McCannel et al13 noted that aqueous humor production is not affected during sleep by a β-blocker administered in the evening. In addition, the morning administration of fixed combination therapy may enhance patient compliance and reduce the risk of nocturnal arterial hypotension that is sometimes associated with the nighttime use of β-blockers such as timolol.14
Second, most patients had used antiglaucoma medications within the 3 months leading up to the study and, by inclusion criteria, had prestudy IOP levels of 25 mm Hg or higher. It is likely that many of these patients responded differently from those who had not previously been treated with antiglaucoma medication, a factor that may partly explain the wide range of IOP reductions reported. In general, the effect of such design factors is difficult to estimate in studies that focus on the efficacy of antiglaucoma medications in either glaucomatous or hypertensive eyes.
Although not studied herein, the relative therapeutic simplicity of fixed combination therapy may increase patient compliance. Kass et al4 compared compliance in patients prescribed timolol twice daily vs pilocarpine hydrochloride 4 times daily and found increased compliance with the twice-daily regimen (84.3% ± 14.0% vs 77.7% ± 18.7%; P = .01). Gurwitz et al5 evaluated medication compliance in 2440 elderly patients with glaucoma during a 1-year period; nearly one quarter of the patients did not refill a prescription when expected, and medications requiring more than twice-daily administration more frequently went unfilled. Further research concerning the potential influence of fixed combination therapy on medication compliance is needed.
The fixed combination regimen was generally safe and well tolerated. The higher rate of conjunctival hyperemia in patients receiving fixed combination and latanoprost therapies may be related to differences in concentrations of the preservative, benzalkonium chloride, which irritates the conjunctiva and the cornea.15 Concentrations of benzalkonium chloride were 0.1 mg/mL in the fixed combination therapy solution, 0.2 mg/mL in the latanoprost solution, 0.1 mg/mL in the timolol solution, and 0.1 mg/mL in the placebo, which was administered once daily to patients in the fixed combination therapy and latanoprost groups. Thus, patients in the latanoprost group received the greatest amount of benzalkonium chloride daily and evidenced the highest frequency of conjunctival hyperemia. Because patients receiving fixed combination therapy had the second highest rate of conjunctival hyperemia, the condition may also be related to prostaglandin use rather than to the preservative.
Rates of increased iris pigmentation assessed from photographs were somewhat higher in the present study than those reported in US trials,16,17 but were similar to the 10% rate reported in a trial conducted in the United Kingdom.18 Differences in patient demographics and the difficulty of evaluating differences in rating criteria across studies may account for discrepant findings. To our knowledge, this is the first large study to prospectively measure changes in eyelashes after this specific prostaglandin analogue therapy for glaucoma, although other investigators19,20 have reported this adverse effect. While it is difficult to assess subtle eyelash changes clinically, it is important that practitioners be aware of such observations so that patients can be appropriately informed. Thus far, changes in iris color and lashes seem to be cosmetic, but these unique adverse effects continue to require close observation.
In summary, the fixed combination of 0.005% latanoprost and 0.5% timolol administered once daily in the morning for 26 weeks was more effective in controlling IOP than monotherapy with either timolol or latanoprost. The efficacy of the fixed combination therapy was maintained for up to 52 weeks and was as well tolerated as the individual therapies alone. Although clinicians must screen patients to ensure that use of a β-blocker is not contraindicated, for many patients with open-angle glaucoma or ocular hypertension, the treatment offers a convenient combination of 2 medications administered once daily—a dosing schedule that may enhance patient compliance while effectively lowering IOP levels.
Submitted for publication August 10, 2001; final revision received January 31, 2002; accepted February 12, 2002.
This study was supported by Pharmacia & Upjohn, Inc, Kalamazoo, Mich; and in part by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY (Dr Higginbotham).
Baltimore, Md: Eve J. Higginbotham, MD (principal investigator). Richmond, Va: Robert Allen, MD. Sacramento, Calif: Barbara Arnold, MD; Richard Lewis, MD. Providence, RI: Robert Bahr, MD. Atlanta, Ga: Reay Brown, MD; Douglas Day, MD. Tampa, Fla: Moira Burke, MD. Reading, Pa: Moiz Carim, MD. Anaheim, Calif: Arthur Charap, MD. Tacoma, Wash: Kevin Chismire, MD. Portland, Ore: George Cioffi, MD; John Samples, MD. Morrow, Ga: Harvey Dubiner, MD. Houston, Tex: Robert Feldman, MD. Dallas, Tex: Ronald Fellman, MD. Wheaton, Ill: David Gieser, MD.Madison, Wis: Gregg Heatley, MD. Concord, NH: Andre d'Hemecourt, MD. Louisville, Ky: David Karp, MD. Boulder, Colo: Donald Kellum, MD. Austin, Tex: Robert Laibovitz, MD. Kansas City, Mo: Charles Lederer, MD; Michael Stiles, MD.Memphis, Tenn: Alan Mandell, MD.South Bend, Ind: Steven Meyer, MD. Denver, Colo: Andrew Michael, MD; Robert Shields, MD. Charlotte, NC: Thomas Mundorf, MD; Michael Rotberg, MD. Galveston, Tex: Katherine Ochsner, MD. Minneapolis, Minn: Charles Ostrov, MD. Charlottesville, Va: Bruce Prum, MD. Boston, Mass: Joel Schuman, MD. New Port Richey, Fla: Jeffrey Schwartz, MD. Mount Pleasant, SC: Elizabeth Sharpe, MD.South Plainfield, NJ: Franklin Spirn, MD. Iowa City, Iowa: John Stamler, MD. San Francisco, Calif: Robert Stamper, MD. Charleston, SC: William Stewart, MD. San Antonio, Tex: Martha Walton, MD. Chicago, Ill: Jacob Wilenski, MD.
Corresponding author and reprints: Eve J. Higginbotham, MD, Department of Ophthalmology, University of Maryland School of Medicine, 419 W Redwood St, Suite 580, Baltimore, MD 21201 (e-mail: FCWEJH6786@aol.com).