Effectiveness of Single-Digit IOP Targets on Decreasing Global And

ORIGINAL STUDY

Effectiveness of Single-Digit IOP Targets on Decreasing Global and Localized Visual Field Progression After Filtration Surgery in Eyes With Progressive Normal-Tension Glaucoma

Shawn M. Iverson, DO, Scott K. Schultz, MD, Wei Shi, MS, William J. Feuer, MS, and David S. Greenﬁeld, MD

progression,4–8 glaucoma can exist even among individuals Purpose: To examine the effectiveness of achieving single-digit for whom IOP measurements are within the statistically intraocular pressure (IOP) targets with filtration surgery on defined “normal range.”9–12 Although an artificial con- decreasing global and localized visual field (VF) progression in eyes struct, normal-tension glaucoma (NTG) is a widely used with progressive normal-tension glaucoma (NTG). term to classify the disease in patients with glaucomatous Methods: A retrospective chart review was conducted to identify optic neuropathy with or without visual field (VF) loss NTG patients who underwent trabeculectomy with mitomycin C whose pressures are within the 95th percentile of the normal between 2006 and 2010 for progressive VF loss with preoperative distribution of IOP measurements in the healthy population IOPr15 mm Hg during the 12 months before surgery. All eyes had (IOP < 22 mm Hg using Goldmann applanation tonom- glaucomatous optic neuropathy and progressive VF loss, uncon- etry).1–2 NTG is a common disorder and accounts for trolled IOP on maximum therapy, and a minimum of 2 baseline approximately 20% to 30% of open-angle glaucoma cases preoperative and 4 postoperative VF examinations. VF progression in the United States1–4 and a significantly higher proportion was assessed using Guided Progression Analysis (GPA) and Pro- 13 gressor software. in other parts of the world, particularly Korea (77%) and Japan (92%).5 Results: Fifteen eyes of 14 patients (mean age 71.8 ± 7.5 y) were The beneficial effect of reducing IOP by 30% in eyes enrolled with mean follow-up of 71 ± 26 months. Mean post- with NTG has been demonstrated.7–11 Most patients ach- operative IOP (8.5 ± 3.5 mm Hg) was significantly (P < 0.001) ieve this therapeutic target using nonsurgical therapy reduced compared with preoperatively (13.1 ± 1.5 mm Hg). The including antiglaucomatous medication and laser trabecu- probability of achieving an IOP goal r10 mm Hg was 66% at 4 years’ follow-up. The overall rate of postoperative VF progression loplasty. The treatment of progressive NTG that fails to using any method was 13.3% (1 eye using Progressor; 1 eye using respond to medical therapy represents a therapeutic chal- GPA and Progressor). Average postoperative slope of MD lenge, particularly in eyes in which progression has occur- (0.25 ± 0.86 dB/y) and pattern SD (0.49 ± 0.83 dB/y) were red at low IOP levels. Glaucoma filtration surgery in NTG improved (P = 0.05 and 0.07) compared with the preoperative eyes has been well described.9,12,14–16 Aoyama et al12 dem- slopes (1.05 ± 0.66 and 1.21 ± 0.71 dB/y). onstrated that VF progression in NTG patients was halted Conclusions: Achieving single-digit IOP targets with filtration sur- in a large proportion of patients after trabeculectomy when gery has a beneficial effect on reducing global and localized rates of IOP was reduced by at least 20%, with better efficacy if VF progression in NTG eyes with progression at low IOP. lowered by 30%. Eyes with progressive VF loss at very low preoperative Key Words: normal-tension glaucoma, filtration surgery, intra- IOP have a therapeutic window that is considerably more ocular pressure, visual field, progression narrow and represent a unique challenge. The risk-to-ben- (J Glaucoma 2016;25:408–414) efit ratio must be carefully considered given that trabeculectomy in eyes with NTG carries an increased risk of hypotony, hypotony maculopathy, and choroidal effu- sion.15–17 To avoid such complications, many clinicians will laucoma is a progressive disorder characterized by avoid surgical intervention in these patients despite pro- Gstructural and functional abnormalities of the optic 1–3 gressive VF loss. We have recently reported that trabecu- nerve. Even though intraocular pressure (IOP) is the lectomy with antifibrosis therapy is a safe and effective most important modifiable risk factor for disease onset and strategy for achieving long-term IOP reduction of 20% to 40% in NTG eyes with VF progression at very low pre- Received for publication August 4, 2014; accepted January 9, 2015. operative IOP levels.18 In the present study, we examined From the Bascom Palmer Eye Institute, University of Miami Miller the effectiveness of achieving single-digit IOP targets with School of Medicine, Miami, FL. Supported by University of Miami Core Grant (P30-EY014801), glaucoma filtration surgery on decreasing global and Bethesda, MD; an unrestricted grant from Research to Prevent localized VF progression in eyes with progressive NTG. Blindness, New York, NY; a grant from the Department of Defense (W81XWH-09-1-0675); The Maltz Family Endowment for Glau- coma Research, Cleveland, OH. METHODS Disclosure: The authors declare no conflict of interest. Reprints: David S. Greenfield, MD, Bascom Palmer Eye Institute, Study Population University of Miami Miller School of Medicine, 7101 Fairway After Institutional Review Board approval was Drive, Palm Beach Gardens, Miami, FL 33418 (e-mail: dgreenfi[email protected]). obtained from the University of Miami Miller School of Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Medicine Clinical Research Ethics Board, a retrospective DOI: 10.1097/IJG.0000000000000240 chart review was conducted. Consecutive open-angle

408 | www.glaucomajournal.com J Glaucoma Volume 25, Number 5, May 2016 Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. J Glaucoma Volume 25, Number 5, May 2016 Single-Digit IOP Targets glaucoma patients who had undergone trabeculectomy by a absence of VF progression using event-based and trend- single surgeon (D.S.G.) at Bascom Palmer Eye Institute, based methods. For event-based progression analysis, we Palm Beach Gardens, Florida between February 1, 2006 used GPA, a method that uses statistical criteria designed and October 31, 2010 were identified. Patients with NTG for the Early Manifest Glaucoma Trial19 and compares the had glaucomatous optic neuropathy consisting of neuro- locations on pattern deviation change probability map of retinal rim narrowing, progressive VF loss, and initial follow-up VFs to the average of 2 baseline examinations. untreated IOP < 21 mm Hg, with no single reading An automated analysis identifies test locations that show >22 mm Hg. The baseline IOP of each patient was change greater than the expected variability in pattern reported as the average of consecutive IOP measurements deviation at the 95% significance level. Progression was during the 12-month period before surgery. Patients with defined as a significant change detected in Z3 points, and mean preoperative IOPr15 mm Hg during the 12-month repeated in the same locations on 3 consecutive tests, and period before surgery were enrolled. Exclusion criteria categorized by the GPA software as “Likely Progression.” consisted of age 18 years and below, recorded IOP > 22 The trend-based analysis method used automated pointwise mm Hg on any visit, ocular disease other than glaucoma, linear regression (PLR) analysis of VF sensitivity values prior incisional surgery except uncomplicated cataract extraction, follow-up period of <12 months, <2 preoperative or 4 postoperative VF examinations using a TABLE 1. Baseline Clinical Characteristics of the Study Swedish Interactive Threshold Algorithm (SITA) standard Population (n = 15) 24-2 strategy (Humphrey Field Analyzer II; Carl Zeiss Clinical Variables No. Patients (%) Meditec, Dublin, CA), or VFs other than standard white- on-white using a size III stimulus. Only reliable VF results Age (y) consisting of <15% fixation losses and <30% false neg- Mean (±SD) 71.8 ± 7.5 Median (range) 71 (54-85) ative or false positives were included. Sex All patients had preoperative glaucomatous pro- Male 4 (27) gression evaluated using the Humphrey Field Analyzer Female 11 (73) Guided Progression Analysis (GPA, software version 4.2; Race Carl Zeiss Meditec), defined as a significant decrease from White 13 (86) baseline (2 examinations) pattern deviation at Z3 of the Black 1 (7) same test points on 3 consecutive tests, or by serial review Hispanic 1 (7) of longitudinal VFs with confirmatory testing in referral Anticoagulation/antiplatelet 9 (60) patients. Intraocular pressure (mm Hg) Mean ± SD 13.1 ± 1.5 Glaucoma surgery was indicated in patients with VF Median (range) 12.5 (11.1-15.5) progression and in whom the IOP was considered unsat- BCVA (logMAR) isfactory for the extent of glaucomatous damage. Trabe- Mean ± SD 0.21 ± 0.28 culectomy was performed in a standardized manner. A Median (range) 0.1 (0-1) superior limbus-based or fornix-based flap was created, and 20/20-20/40 12 (80) a fluid-retaining sponge soaked with MMC (0.4 mg/mL) 20/50-20/80 2 (13) was applied to the superior sclera for 1 to 3.5 minutes. A 20/100-20/200 1 (7) single highly myopic patient received intraoperative 5-flu- Spherical equivalent orouracil (50 mg/mL, 5 min duration) at the time of trabe- Mean ± SD 1.97 ± 2.99 Median (range) 1.25 (7.25 to 1.5) culectomy. A partial-thickness scleral flap was dissected, Glaucoma medications and a paracentesis was made. A block of limbal tissue was Mean ± SD 2.53 ± 1.25 excised underneath the trabeculectomy flap. The scleral flap Median (range) 3 (0-4) was reapproximated to the scleral bed with interrupted 10-0 Prior surgery nylon sutures. The conjunctiva was closed, and Seidel Cataract extraction 4 (27) testing was performed at the conclusion of the case. Laser trabeculoplasty 7 (47) Surgical failure was defined as inadequate IOP Lens status* reduction (categorized as <30% reduction from the base- Phakic 11 (73) line IOP on 2 consecutive follow-up visits after 3 mo), Pseudophakic 4 (27) Visual field (dB) reoperation for glaucoma, or loss of light perception vision. MD [mean (±SD)] 9.53 ± 6.45 Eyes that had not failed and were not on supplemental Pattern standard deviation [mean (±SD)] 8.60 ± 3.67 medical therapy were considered complete successes. Eyes Conjunctival flap that had not failed but required supplemental medical Limbus based 14 (93) therapy were defined as qualified successes. IOP reduction Fornix based 1 (7) was calculated at postoperative month 3 and all follow-up Duration of MMC (0.4 mg/mL) (min) intervals thereafter. Final change in best-corrected visual Mean (±SD) 2.13 ± 1.37 acuity (BCVA), IOP, and number of IOP-lowering medi- Median (range) 2 (0.5-5) cations was calculated at last follow-up compared with Laser suture lysis 7 (47) Duration of follow-up (mo) baseline. Early postoperative complications were defined as Mean (±SD) 68.5 ± 27.8 surgical complications developing within the first month Range 35-110 after trabeculectomy; late postoperative complications occurred >1 month following surgery. All data are given as the n (%) of patients unless otherwise specified. Postoperative VF progression was defined using 2 *1 eye underwent combined CEIOL/trabeculectomy. BCVA indicates best-corrected visual acuity; logMAR, logarithm of analysis methods. Eyes were classified as postoperative minimum angle of resolution; MMC, mitomycin C. progressors or nonprogressors based upon the presence or

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RESULTS TABLE 2. Intraocular Pressure (IOP) and Medical Therapy at The charts of 274 patients were evaluated for enroll- Baseline and Follow-up ment. A total of 244 patients were excluded with pre- N IOP (mm Hg)* No. Glaucoma Meds* operative IOP means >15 mm Hg, inadequate follow-up, Baseline 15 13.1 ± 1.47 2.53 ± 1.25 secondary glaucoma, prior ocular surgery, or comorbid 6 mo 15 7.67 ± 4.68 0.07 ± 0.26 ocular disease. Fifteen additional eyes were excluded due to 12 mo 15 7.5 ± 4.25 0.27 ± 0.8 insufficient number of postoperative VF examinations. 18 mo 15 7.23 ± 3.25 0.08 ± 0.28 Fifteen eyes of 14 patients (mean age 71.8 ± 7.5 y) were 2 y 15 8.47 ± 4.02 0.53 ± 1.06 enrolled with a mean follow-up of 68.5 ± 27.8 months. 3 y 15 9.17 ± 3.97 0.60 ± 1.12 Baseline clinical characteristics are presented in Table 1. 4 y 12 7.79 ± 3.60 0.42 ± 1.16 The mean preoperative IOP during the year before surgery Last follow-up 15 8.47 ± 3.46w 0.80 ± 1.32w was 13.11 ± 1.47 mm Hg using a mean of 2.53 ± 1.25 IOP- *Mean ± SD. lowering medications. Eleven eyes (73%) were phakic at the wP < 0.001 compared with baseline. time of trabeculectomy; 6 eyes had worsening of cataract requiring subsequent cataract extraction. Compared with baseline, the change in vision among pseudophakic eyes using Progressor software (version 3.3; Medisoft Inc., (0.02 ± 0.26, logMAR) was similar (P = 0.29) to phakic Leeds, UK), which generates slopes to analyze the rate of eyes (0.10 ± 0.06, logMAR). global and local sensitivity change and the associated level 20 Mean postoperative IOP and number of IOP-lowering of statistical significance (P-values). PLR progression was medications at all follow-up time points are illustrated defined as Z2 adjacent test locations losing Z1.0 dB/y at in Table 2. The mean postoperative IOP at last follow-up Pr0.01 for inner locations or Z2.0 dB/y at Pr0.01 for 20,21 (8.47 ± 3.46 mm Hg) and number of IOP-lowering medi- edge locations. In addition, MD and pattern standard cations (0.80 ± 1.32) were significantly lower compared deviation (PSD) slopes were generated for eyes that had with baseline (13.1 ± 1.47 mm Hg and 2.53 ± 1.25, Z5 preoperative and Z5 postoperative VF examinations. respectively, P < 0.01). This represents a reduction in IOP Statistical analysis was performed using JMP software by a mean of 4.63 mm Hg (35%) from preoperative version 8.0 (SAS Inc., Cary, NC) and SPSS 18 (SPSS, Chi- levels. Figure 1 illustrates the Kaplan-Meier plot of the cago, IL). Kaplan-Meier survival curve was used to analyze cumulative probability of failure to achieve IOP reduction the cumulative probability of maintaining a postoperative Z30% below baseline, at various postoperative follow-up IOP reduction of <30% or Z30% from baseline. Clinical timepoints, with or without antiglaucomatous medications. characteristics of the study population were calculated using 2 A total of 5 eyes (33%) did not maintain at least 30% 2-sided Student t test for continuous variables and the w or reduction in IOP through last follow-up. We also examined the Fisher exact test for categorical variables. BCVA was the overall cumulative probability of achieving a single- converted to logMAR equivalent for statistical analysis. The digit IOP target goal during the follow-up period. Failure rates of MD and PSD loss over time were calculated using was defined as a postoperative IOP > 10 mm Hg on 2 linear regression analysis and paired Student t test. A P-value consecutive follow-up visits after 3 months. The probability of r0.05 was considered statistically significant for all of successfully achieving this numeric IOP goal was 87%, variables. 80%, 80%, 66% at 1, 2, 3, and 4 years, respectively. Early and late postoperative complications are presented in Table 3. There were no surgical failures based upon the need for reoperation for glaucoma or loss of light perception vision. A total of 9 eyes (60%) experienced at

TABLE 3. Postoperative Complications Among the Study Group (n = 15) No. Patients (%) Early postoperative complications* Choroidal eﬀusion 1 (7) Hyphema 2 (13) Hypotony 5 (33) Late postoperative complicationsw Hypotony 6 (40) Hypotony maculopathy 1 (7) Dysesthesia 1 (7) Cystoid macular edema 1 (7) Persistent diplopia 1 (7) Chronic or recurrent iritis 1 (7) Choroidal eﬀusion 0 Decreased visual acuity by >2 Snellen lines 0 Bleb leak 0 Endophthalmitis/blebitis 0

FIGURE 1. Kaplan-Meier plot of the cumulative probability of Hypotony was deﬁned as IOPr5 mm Hg on 2 consecutive failure to achieve IOP reduction Z30% below baseline, at postoperative visits. various postoperative follow-up timepoints, with or without *Onset r1 month after surgery. antiglaucomatous medications. wOnset was >1 month after surgery.

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FIGURE 2. (Continued) least 1 early or late postoperative complication. During the maculopathy based upon unchanged postoperative visual early postoperative period, 2 eyes (13.3%) developed tran- acuity compared with preoperative levels. One additional sient hyphema and 1 eye (6.7%) developed choroidal effu- eye with ocular hypotony and no macular folds required sion. Six eyes (40%) experienced hypotony (IOPr5mmHg bleb revision for reduced visual acuity associated with on 2 consecutive follow-up visits after 3 mo) during the irregular astigmatism. There was no significant difference postoperative period; 1 (6.7%) of which developed hypot- (P = 0.89) in postoperative BCVA (logMAR) between eyes ony maculopathy. Macular OCT imaging was performed in that developed hypotony (0.20 ± 0.24) compared with eyes all 6 eyes with postoperative hypotony, and demonstrated without hypotony (0.18 ± 0.32). Postoperative MD slopes chorioretinal folds in 1 patient. Baseline visual acuity in tended to be better (P = 0.09) in eyes that did not experi- hypotonous eyes ranged from 20/20 to 20/40 and post- ence hypotony (0.14 ± 0.63 dB/y) compared with those operative visual acuity was 20/20 to 20/60. No patient with hypotony (0.48 ± 0.67 dB/y). PSD slopes were sim- experienced decreased visual acuity by >2 Snellen lines. No ilar (P = 0.29) between those with and without hypotony surgical intervention was required in the eye with hypotony (0.13 ± 0.33 and 0.67 ± 1.74, respectively).

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FIGURE 2. Methods for visual field progression analysis. A, Guided Progression Analysis (GPA) of a single eye identified by the software as “Likely Progression” defined as a significant change detected in Z3 points on 3 consecutive tests. B, Pointwise linear regression analysis (Progressor) of sensitivity values in the same eye with progression defined as Z2 adjacent test locations losing Z1.0 dB/year at Pr0.01 for inner locations or Z2.0 dB/year at Pr0.01 for edge locations. Figure 2 can be viewed in color online at www.glaucomajournal.com

The mean number of VF examinations was VF progression; 1 eye using PLR analysis and 1 eye using 8.21 ± 5.11 preoperatively and 6.73 ± 3.49 postoperatively. both GPA and PLR (Fig. 2). Among the 2 eyes identified All patients had preoperative glaucomatous progression. with postoperative VF progression, one eye was pseudo- Seven eyes were judged to have “likely progression” using phakic and the other required cataract surgery 9 months GPA analysis. The remaining eyes that were not eligible for following filtering surgery. Mean IOP was lower in pro- GPA analysis had a mean 4.76 ± 4.65 preoperative fields gressing eyes compared with nonprogressing eyes (5.38 vs. from which the determination of progression was made by 9.54, respectively). The mean age of patients with pro- serial analysis with confirmatory testing. Postoperative gression (61 ± 9.9 y of age) was younger compared with fields were examined using GPA and PLR analyses on all those without progression (73 ± 6.0 y of age). eyes. Two eyes (13.3%) were judged to have postoperative To compare preoperative and postoperative VF characteristics, a subanalysis was conducted on 9 eyes with at least 5 preoperative and postoperative fields (Table 4). TABLE 4. Clinical and Visual Field Parameters Before and After Glaucoma Surgery (n = 9) Mean length of follow-up during the preoperative (91.53 ± 41.55 mo) and postoperative (64.9 ± 25.7 mo) Before After period was not significantly different (P = 0.22). Average w Parameters Surgery* Surgery* P postoperative slope of MD (0.25 ± 0.86 dB/y) and PSD No. meds 2.11 ± 1.17 0.67 ± 1.41 0.016 (0.49 ± 0.83 dB/y) were improved (P = 0.05 and 0.07) VA (logMAR) 0.14 ± 0.14 0.10 ± 0.17 0.27 compared with the preoperative slopes (1.05 ± 0.66 and Mean IOP (mm Hg) 13.28 ± 1.62 7.78 ± 3.83 0.001 1.21 ± 0.71 dB/y). No postoperative changes (P > 0.05) MD slope (dB/y) 1.05 ± 0.66 0.26 ± 0.86 0.05 were identified in the number of significantly progressing PSD slope (dB/y) 1.21 ± 0.71 0.49 ± 0.83 0.07 points, or in the postoperative slope of mean sensitivity of No. progressing pointsz 2.75 ± 5.47 2.22 ± 3.90 0.86 the central 16 or peripheral 36 VF test locations. Global rate of progressionz 0.53 ± 0.71 0.54 ± 0.90 0.82 (dB/y) Slope of mean sensitivity 0.76 ± 0.52 0.34 ± 0.51 0.11 central 16 points (dB/y) DISCUSSION Slope of mean sensitivity 0.75 ± 0.95 0.43 ± 0.75 0.36 NTG represents a subgroup of open-angle glaucoma peripheral 36 points with measured untreated IOP in the statistically normal (dB/y) range. Although most patients respond favorably to IOP Duration of follow-up 91.53 ± 41.55 64.91 ± 25.84 0.22 7 (mo) reduction of 30% below the untreated baseline, a subset of NTG eyes continue to progress despite achieving and *Values presented as mean ± SD. maintaining IOP control in the low teens. The management w Students t test. of such eyes represents a clinical challenge given that non- zValues determined by Progressor software. IOP indicates intraocular pressure; PSD, pattern standard deviation. surgical approaches typically cannot lower IOP below episcleral venous pressure, and a narrow therapeutic

412 | www.glaucomajournal.com Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved. J Glaucoma Volume 25, Number 5, May 2016 Single-Digit IOP Targets window exists in which further IOP lowering may be ach- intervention to achieve the IOP targets described herein are ieved while avoiding ocular hypotony. Glaucoma filtration not required in the majority of persons. Thus, our study surgery is often required in eyes with, or at high risk for, population consisted of a relatively small number of eyes. disease progression.9,12,14–16 We recently reported that tra- In addition, there is an inherent problem in retrospective beculectomy with antifibrosis therapy is a safe and effective series comparing VF slopes before and after surgery, as the strategy for achieving long-term IOP reduction of 20% to decision for surgery is often based on the worst VF in the 40% in NTG eyes with VF progression at very low pre- series. This situation is precisely the one that is susceptible operative IOP levels.18 Although studies have demonstrated to “regression to the mean” which could explain, at least in that surgical IOP reduction in NTG patients may slow the part, the changes in slopes we identified in this study. It is a rate of VF progression,10–12,22–25 to our knowledge VF standard practice at our institution to repeat and confirm outcomes in eyes specifically requiring single-digit target VF change, as the small risk of increased optic nerve IOP levels have not been described. damage or VF loss by waiting some number of weeks or We found that achieving single-digit IOP targets months outweighs the risk of proceeding to surgery. (mean 8.5 mm Hg) in eyes with progressing NTG at very Finally, it is possible that the presence of cataract or low preoperative levels (mean 13 mm Hg) had a beneficial hypotony may have had a confounding affect upon our effect on the rates of global and localized VF progression. ability to detect progression. This is of clinical importance as most surgeons hesitate to In conclusion, our results demonstrate that achieving perform surgical intervention in such eyes given the narrow single-digit IOP targets with filtration surgery with therapeutic window for success. Overall, 2 eyes (13%) were adjunctive antifibrosis therapy has a beneficial effect on identified with localized postoperative VF progression reducing global and localized rates of VF progression in using event-based and trend-based statistical analysis NTG eyes with progression at low IOP. Postoperative VF methods. Noteworthy is that these eyes had lower progression may continue to occur in some eyes. Ocular postoperative IOP (mean 5.4 mm Hg) compared with hypotony is a common postoperative complication, and nonprogressing eyes (mean 9.5 mm Hg). We are unable to careful selection of patients is recommended to avoid differentiate whether the postoperative VF changes were hypotony-related surgical complications. related in part to the influence of ocular hypotony, non- IOP-dependent factors, or a combination of both. Our REFERENCES results compare favorably to other studies looking at global10–12,24 and localized22–25 VF loss following IOP- 1. Levene RZ. Low tension glaucoma: a critical review and new lowering surgery for NTG that have reported postoperative material. Surv Ophthalmol. 1980;24:621–664. 2. Hitchings RA. Low tension glaucoma-its place in modern progression rates of approximately 20% to 48%. glaucoma practice. Br J Ophthalmol. 1992;76:494–496. Filtration surgery was also associated with a reduction 3. Klein BE, Klein R, Sponsel WE, et al. 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