Purpose
To examine the hypothesis that surgical intraocular pressure (IOP) reduction leads to enhancement of visual field (VF) sensitivity in glaucomatous eyes.
Design
Prospective case-control study.
Methods
Patients with uncontrolled IOP requiring trabeculectomy or aqueous drainage device were enrolled. Controls consisted of medically treated glaucoma patients with stable IOP and no change in medical therapy during follow-up. Two baseline preoperative VFs and 3 follow-up VF examinations at 1, 2, and 3 months postoperatively were used for analysis. The same number of VF examinations measured within an 18-month interval was used for control eyes. VF locations with significant change were defined as exceeding 95% test-retest confidence limits based upon the mean sensitivity using the 2 baseline VF exams. The number of significantly changing locations per eye and changes in mean and pattern standard deviation (PSD) from the mean baseline fields were compared between groups using a Poisson generalized estimating equation model.
Results
Thirty eyes of 30 surgically treated glaucoma patients and 41 eyes of 28 stable controls were enrolled. Postoperative IOP was decreased at follow-up 3 compared with baseline ( P < .001) in the surgical eyes, but was similar in control eyes ( P = .92). At follow-up 3, the number of test locations improving in central ( P = .014) and peripheral ( P = .019) VF locations was significantly greater in the surgical eyes. The number of eyes with improved PSD at follow-up 3 was significantly greater in the surgical eyes compared with controls ( P = .02).
Conclusions
Short-term enhancement of central and peripheral VF sensitivity occurs after surgical reduction of IOP in glaucomatous eyes and may represent a potential biomarker for retinal ganglion cell response to therapeutic interventions in glaucoma.
Glaucoma is a progressive optic neuropathy characterized by progressive structural and functional abnormalities of the optic nerve. Intraocular pressure (IOP) is the most important modifiable risk factor for disease onset and progression. Multicenter, prospective clinical trials have confirmed the value of reducing IOP in patients with ocular hypertension, open-angle glaucoma with elevated IOP, and low-tension glaucoma, in preventing or delaying visual field (VF) progression.
Several studies have described structural changes in the optic nerve following IOP reduction. Reversal of optic disc cupping following glaucoma surgery has been reported to occur in both children and adults. The mechanism by which this occurs may in part be related to changes in the translaminar pressure gradient, resulting in anterior movement of the lamina cribrosa. Increased postoperative thickness in the peripapillary retinal nerve fiber layer (RNFL) has similarly been described as measured using optical coherence tomography.
In spite of these discoveries, functional visual improvement as a consequence of IOP reduction has remained controversial and poorly understood. Improvement in VF sensitivity after IOP lowering was originally proposed by Spaeth, who suggested that improved retinal ganglion cell (RGC) function may occur. Reversal of RGC dysfunction after pharmacologic and surgical IOP reduction as measured using the pattern electroretinogram (PERG) was subsequently described. Further validation to support this concept has been demonstrated recently in the Collaborative Initial Glaucoma Treatment Study (CIGTS), which showed lower IOP to be an important predictor of improvement in VF mean deviation (MD) in eyes with surgically treated glaucoma. The purpose of the present study was (1) to prospectively examine the hypothesis that surgical IOP reduction may lead to localized enhancement of VF sensitivity in glaucomatous eyes, and (2) to explore factors associated with enhancement in postoperative VF sensitivity.
Patients and Methods
This prospective cohort study was approved by the Institutional Review Board for Human Research at the University of Miami and followed the tenets of the Declaration of Helsinki. Case subjects made up of glaucoma patients who met eligibility criteria with uncontrolled IOP on maximal medical therapy requiring trabeculectomy or aqueous drainage device implantation, who gave informed consent to participate, were enrolled. Control subjects were medically treated glaucoma patients with stable IOP and no inter-current change in IOP-lowering therapy during serial follow-up.
Glaucomatous optic neuropathy was defined as notching, excavation, or RNFL defect. Glaucomatous eyes had repeatable 24-2 standard automated perimetry (SITA-standard, Humphrey Field Analyzer; Carl Zeiss Meditec, Inc, Dublin, California, USA) abnormality, defined as abnormal Glaucoma Hemifield Test and pattern standard deviation (PSD) outside 95% normal limits. Control subjects matched for age and VF MD were selected from a group of medically treated glaucoma patients enrolled in a prospective longitudinal glaucoma monitoring study who had no change in IOP-lowering therapy throughout the study period. Eyes with visual acuity below 20/30, corneal or retinal pathology, or unreliable VF examinations (>33% rate of fixation losses, false positives, or false negatives) were excluded.
All patients underwent a complete ophthalmic examination, including refraction, visual acuity measurement, slit-lamp biomicroscopy, dilated stereoscopic fundus examination, photography of the optic disc, gonioscopy, Goldmann applanation tonometry, and ultrasound pachymetry (DGH 55 Pachmate; DGH Technology, Inc, Exton, Pennsylvania, USA) at baseline.
Visual Field Data
The VF series in the glaucoma group consisted of 2 baseline preoperative and 3 follow-up postoperative VF measurements on month 1 (follow-up 1), 2 (follow-up 2), and 3 (follow-up 3). The VF series in the control group consisted of 2 baseline VF measurements performed 1 month apart, and 3 consecutive VF measurements at 6-month intervals (follow-up 1, follow-up 2, and follow-up 3, respectively). Individual sensitivity values were extracted for each VF examination.
Statistical Analysis
Statistical analysis was performed using the commercially available R Language software (R Core Team, 2013. Vienna, Austria) and JMP software version 8.0.2 (SAS Inc, Cary, North Carolina, USA).
The variance of the VF sensitivity values at each test location was calculated using the absolute difference between the 2 baseline measurements of sensitivity values at each test location, incorporating 30 glaucoma and 41 control eyes. The test locations were grouped, using (1) all test locations, (2) central 16 locations, and (3) peripheral 36 locations. Linear regression was applied to predict this difference for a given sensitivity. Any change beyond 1.96 × the predicted standard deviation (SD) of the test-retest variability for a given starting sensitivity value was considered significant. Similarly, significant change in MD and PSD was defined as any change beyond 1.96 × SD of the test-retest variability for that starting value, using the mean MD and PSD values of the 2 baseline VF examinations. Postoperative VF examinations were not included in the variability estimate to avoid increased variance frequently observed in eyes recovering from surgery. The number of significantly improved locations per eye was compared between groups (mean of 2 baseline VFs compared with follow-up 3) using a Poisson generalized estimating equation model. Analysis of VF examinations performed at follow-up 1 and follow-up 2 were not used for comparison to avoid biasing VF sensitivity introduced by the confounding effects of postoperative inflammation, medication use including cycloplegia, and change in central visual acuity. Significant changes in MD and PSD from mean baseline fields were compared between groups using a linear generalized estimating equation model. Further generalized estimating equation models were used to explore whether the magnitude of IOP change between the mean of the baseline readings and follow-up 3 predicted the magnitude of VF change.
Results
The study population consisted of 30 eyes of 30 surgically treated glaucoma patients (age 68.3 ± 18.4 years) and 41 eyes of 28 controls (age 67.4 ± 7.3 years). The baseline MD values in the surgical group (−7.6 ± 4.9 dB) and the control group (−5.6 ± 4.2 dB) were similar ( P > .05). The mean time interval between the baseline and follow-up 3 examination was greater ( P < .001) in control eyes (18.3 ± 2.91 months) compared to surgical eyes (4.9 ± 1.96 months). The population demographics and clinical characteristics are shown in Table 1 . The mean postoperative IOP (9.9 ± 4.7 mm Hg) was significantly decreased ( P < .001) at follow-up 3 compared with baseline (18.0 ± 6.7 mm Hg) in the surgical group, while control eyes had similar IOP at follow-up 3 and baseline (13.7 ± 3.2 mm Hg vs 13.7 ± 2.6 mm Hg, P = .92) ( Figure 1 ).
| Mean ± SD (Range) | Control Group (n = 41) | Surgical Group (n = 30) | P Value |
|---|---|---|---|
| Age (y) | 66.8 ± 7.3 (22.5–70.2) | 68.3 ± 18.4 (37.9–67.9) | <.65 a |
| Sex | |||
| Male | 7 (11 eyes) | 7 (7 eyes) | .9 b |
| Female | 21 (30 eyes) | 23 (23 eyes) | |
| Ethnicity | |||
| White | 26 | 26 | |
| Black | 1 | 1 | .4 b |
| Hispanic | 0 | 2 | |
| Other | 1 | 1 | |
| Ocular laterality | |||
| Right | 23 | 19 | |
| Left | 18 | 11 | .7 b |
| Glaucoma diagnosis | |||
| POAG | 30 | 10 | |
| LTG | 0 | 11 | |
| XFG | 1 | 1 | <.001 b |
| PG | 8 | 2 | |
| Inflammatory | 0 | 2 | |
| CACG | 2 | 4 | |
| Surgical procedure | – | ||
| Trabeculectomy | N/A | 23 | |
| Drainage implant | N/A | 7 | |
| Time between baseline and follow-up 3 visit (mo) | 18.3 ± 2.91 | 4.9 ± 1.96 | <.001 a |
| Lens status | |||
| Phakic | 33 | 16 | .03 b |
| Pseudophakic | 8 | 14 | |
| Spherical equivalent refractive error (D) | −0.744 ± 2.37 (−31.8 to 0.6) | −0.634 ± 1.98 (−31.7 to −0.19) | .84 a |
| Visual acuity (logMAR) | |||
| Baseline | −0.03 ± 0.11 | −0.06 ± 0.08 | <.001 a |
| Follow-up 3 | −0.02 ± 0.13 | −0.07 ± 0.10 | .018 a |
| Intraocular pressure (mm Hg) | |||
| Baseline | 13.7 ± 3.15 | 18.0 ± 6.66 | <.001 a |
| Follow-up 3 | 13.7 ± 3.19 | 9.93 ± 4.68 | <.001 a |
| Glaucoma medication (n) | |||
| Baseline | 1.88 ± 0.98 | 2.97 ± 1.10 | <.001 a |
| Follow-up 3 | 1.88 ± 0.98 | 0.667 ± 1.09 | .018 a |
| Visual field (dB) | |||
| Baseline mean deviation | −5.56 ± 4.20 | −7.61 ± 4.90 | .063 a |
| Baseline PSD | 6.77 ± 4.16 | 7.67 ± 3.99 | .36 a |
| Mean ocular perfusion pressure | |||
| Baseline | N/A | 46.8 ± 10.5 | N/A |
| Follow-up 3 | 44.9 ± 6.5 | 53.0 ± 6.8 | <.001 |
Localized changes in VF sensitivity values at the follow-up 3 visit were compared with the baseline sensitivity values in the surgical and control groups to identify test locations that were significantly improved or deteriorated using all test locations ( Table 2 ), 16 central locations ( Table 3 ), and 36 peripheral locations ( Table 4 ). Surgically treated eyes had significantly more VF test locations with improved sensitivity at follow-up 3 compared with controls (mean 6.14 ± 6.31 vs 3.24 ± 2.90, P = .010) using all VF test locations. As illustrated in Figure 2 , surgically treated eyes had a significantly greater number of central VF test locations with improved sensitivity (mean 1.83 ± 2.3 vs 0.85 ± 1.2, P = .014) and peripheral VF test locations (4.21 ± 4.6 vs 2.24 ± 2.6, P = .019) as compared with controls. The number of locations with deteriorating VF sensitivity at follow-up 3 were similar between the surgical and the control group using all, central, and peripheral VF test locations ( P > .05).
| All Test Locations Included at Follow-up 3 | Outside the 95% CI for Test-Retest | ||
|---|---|---|---|
| Control (n = 41) | Surgery (n = 30) | P Value | |
| Mean number of locations improving | 3.24 ± 2.90 | 6.14 ± 6.31 | .010 |
| Mean number of locations deteriorating | 4.78 ± 4.42 | 6.41 ± 5.83 | .433 |
| Number of eyes ≥1 location improving | 88% (36) | 87% (26) | 1.000 |
| Number of eyes ≥1 location deteriorating | 95% (39) | 87% (26) | .233 |
| Number of eyes with ≥1 location improving repeated on 3 follow-up visits | 34% (14) | 33% (10) | 1.000 |
| Number of eyes with ≥1 location deteriorating repeated on 3 follow-up visits | 34% (14) | 33% (10) | 1.000 |
| 16 Central Test Locations Included at Follow-up 3 | Outside the 95% CI for Test-Retest | ||
|---|---|---|---|
| Control (n = 41) | Surgery (n = 30) | P Value | |
| Mean number of locations improving | 0.85 ± 1.17 | 1.83 ± 2.25 | .019 |
| Mean number of locations deteriorating | 1.63 ± 2.08 | 1.86 ± 2.36 | .851 |
| Number of eyes ≥1 location improving | 46% (19) | 60% (18) | .196 |
| Number of eyes ≥1 location deteriorating | 73% (30) | 63% (19) | .492 |
| Number of eyes with ≥1 location improving repeated on 3 follow-up visits | 15% (6) | 17% (5) | 1.000 |
| Number of eyes with ≥1 location deteriorating repeated on 3 follow-up visits | 10% (4) | 20% (6) | .304 |
| 36 Peripheral Test Locations Included at Follow-up 3 | Outside the 95% CI for Test-Retest | ||
|---|---|---|---|
| Control (n = 41) | Surgery (n = 30) | P Value | |
| Mean number of locations improving | 2.24 ± 2.62 | 4.21 ± 4.58 | .02 |
| Mean number of locations deteriorating | 3.17 ± 3.09 | 4.35 ± 3.72 | .165 |
| Number of eyes ≥1 location improving | 78% (32) | 70% (21) | .589 |
| Number of eyes ≥1 location deteriorating | 85% (35) | 87% (26) | .599 |
| Number of eyes with ≥1 location improving repeated on 3 follow-up visits | 22% (9) | 27% (8) | .780 |
| Number of eyes with ≥1 location deteriorating repeated on 3 follow-up visits | 17% (7) | 37% (11) | .096 |
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