Pars plana vitrectomy (PPV) is the third most commonly performed ocular surgery in the United States and indications are rapidly expanding.1 Despite its widespread and growing application, there is a paucity of high-quality studies assessing its long-term complications.
Although short-term intraocular pressure (IOP) elevations after vitrectomy are well-known,2 prevalence of IOP elevation and subsequent risk of open-angle glaucoma (OAG) are not firmly established. Previous studies reporting an increased risk of OAG after routine vitrectomy surgery have been entirely retrospective in nature, often without baseline assessment, and therefore unable to establish causality.1,3–7
IOP is a well-established risk factor for the development of OAG and the only treatable factor that can slow its progression. The Prospective Retinal and Optic Nerve Vitrectomy Evaluation (PROVE) study is a prospective, controlled longitudinal study designed to evaluate long-term changes in IOP following vitrectomy surgery. Herein we report the 3-year IOP data in our cohort of patients undergoing routine vitrectomy surgery.
Patients and Methods
The PROVE study was approved by the Vanderbilt University Medical Center Institutional Review Board, complied with the Health Insurance Portability and Accountability Act, and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All subjects gave informed consent before enrollment. The study is registered at Clinicaltrials.gov (identifier NCT01162356).
Details of enrollment, inclusion and exclusion criteria, and testing are published.8 In brief, 80 eyes of 40 patients undergoing unilateral vitrectomy surgery for epiretinal membrane (ERM), macular hole (MH), and vitreous opacities (VO) were consecutively enrolled at the Vanderbilt Eye Institute between April 2010 and February 2012. Inclusion criteria included patients who were 18 years of age or older, planned vitrectomy for visually significant unilateral ERM, MH, or vitreous opacities due to syneresis and/or complete posterior detachment, and the ability to comply with testing and long-term follow-up. Exclusion criteria included any media opacity that would interfere with imaging, history of glaucoma, uveitis, trauma, use of aqueous suppressants for ocular hypertension, history of advanced retinal disease (eg, exudative age-related macular degeneration, diabetic macular edema) that would interfere with retinal thickness measurements, and history of previous vitrectomy in either eye or postoperative complications requiring repeat vitrectomy surgery within 3 months. Patients with disease in the fellow control eye that, in the opinion of the investigator, was likely to warrant future vitrectomy surgery were also excluded.
All patients underwent comprehensive baseline testing of both their study (surgical) and fellow (control) eye within 4 weeks before their surgery. Testing consisted of a complete ocular examination by a fellowship-trained vitreoretinal surgeon and glaucoma evaluation by a fellowship-trained glaucoma specialist.
Details of the baseline glaucoma evaluation are published.8 In brief, the glaucoma evaluation was performed in masked fashion and included best-corrected visual acuity (BCVA), three IOP measurements by two independent methods (three separate measurements by Goldmann applanation and three separate measurements by Tono-Pen; Reichert, Depew, NY), gonioscopy, central corneal thickness measurement by pachymetry (DGH Technology, Exton, PA), and clinical assessment of cup-to-disc ratio. At each visit, patients also underwent visual field testing and optic nerve optical coherence tomography (OCT). Visual fields were assessed before dilation using a 24-2 static white-on-white Swedish interactive thresholding algorithm test program (SITA Fast, Humphrey visual field analyzer; Carl Zeiss Meditec, Dublin, CA). Spectral-domain OCT (Cirrus OCT; Carl Zeiss Meditec, Dublin, CA) using optic disc cube scan protocol was used to measure peripapillary retinal nerve fiber layer (pRNFL) thickness in a 6 × 6-mm2 area, consisting of 200 × 200 axial scans at the optic disc region. Follow-up evaluations were performed by the same glaucoma specialist who was masked to previous test results, and every effort was made to ensure that follow-up evaluations were performed at the same time of day.
All vitrectomy surgeries were performed by one of three fellowship-trained vitreoretinal surgeons using a 23- or 25-gauge three-port pars plana approach. All intraoperative procedures were at the discretion of the primary surgeon.
All testing, as described previously, was repeated at 3 months and then annually after surgery.
Sample Size Calculation
Assuming an approximately 15% and 5% rate of loss in mean pRNFL thickness (with standard deviation of 15%) among study and fellow (control) eyes, respectively, over 2 years, one-sided inference of mean analysis resulted in a sample size requirement of 36 patients to allow for adequate power with an “a” set at 0.05 and a “b” set at 0.80. Anticipating a 10% loss to follow-up, the enrollment goal was set for 40 patients.
The cohort was analyzed as a whole and was also stratified based on surgical indication and lens status. Statistical software was used to analyze the data and generate tables and figures (GraphPad, La Jolla, CA; and Excel; Microsoft, Redmond, WA). Snellen VA was converted to logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. Comparisons of continuous variables among subgroups were performed using Student's t-test and Wilcoxon signed-rank test. Contingency testing was performed using the Fisher exact test. Time-to-event analysis was performed to assess timing of cataract surgery after vitrectomy. One-way analysis of variance (ANOVA) was performed to compare two data sets (curves). Mean Goldmann applanation results were used for IOP analysis. P values less than .05 were considered to be of statistical significance.
Thirty-two of 40 patients (80%) completed 3-year follow-up. Two patients passed away and one patient moved to another state. Another patient's health declined due to advanced Parkinson's disease and was unable to return for the 3-year visit. Two other patients withdrew from the study, and two more patients missed their 3-year follow-up but were still enrolled. Surgical indications included 15 ERMs, 12 MHs, and five VOs.
There was no statistical difference in mean IOP between study and fellow eyes at any time point. Mean IOP measured at baseline by Goldmann applanation was 15.6 mm Hg ± 3.7 mm Hg in study eyes and 16.3 mm Hg ± 2.7 mm Hg in fellow eyes (P = .25). Mean IOP measured at 3-years after vitrectomy was 16.2 mm Hg ± 3.2 mm Hg in study eyes and 16.1 mm Hg ± 2.8 mm Hg in fellow eyes (P = .98).
A subgroup analysis was performed of study eyes that were pseudophakic at baseline (n = 16). Mean IOP in this subset progressively increased at each subsequent follow-up visit from baseline independent of surgical indication (Figure 1). At 3-years after vitrectomy, mean IOP was 16.8 mm Hg ± 3.2 mm Hg, which was significantly elevated from mean baseline IOP of 14.3 mm Hg ± 2.9 mm Hg (Figure 1; P < .029). In contrast, mean IOP in corresponding fellow eyes (12 of 16 were pseudophakic) did not significantly change at 3 years (P = .21). The IOP elevation became statistically significant at postoperative year 1, then stabilized over years 2 and 3. Change in mean IOP for pseudophakic study eyes was significantly greater at all follow-up visits compared to their corresponding fellow eyes (Figure 2; P < .05 for each postoperative time point). Matched analysis of change in IOP for each study eye with its corresponding fellow eye was also statistically different (P < .05 for each postoperative time point).
Mean change in intraocular pressure (IOP) in pseudophakic and phakic eyes post-vitrectomy. There is a significant increase in pseudophakic study eyes (n = 16) and a significant decrease in phakic eyes. These trends persist when stratifying study eyes according to surgical indication (ERM = epiretinal membrane; VO = vitreous opacities; MH = macular hole). Error bars represent 1 standard error of the mean.
Change in mean intraocular pressure (IOP) in pseudophakic study eyes from baseline. Study eyes that were pseudophakic at baseline showed a significant increase in IOP from baseline (P < .05 at 3 years). Corresponding fellow eyes did not change significantly from baseline. One-way analysis of variance testing of both curves was statistically different (P = .04). Error bars represent 1 standard error of the mean.
In contrast to an increase in mean IOP in pseudophakic study eyes after vitrectomy, mean IOP steadily decreased in study eyes that were phakic (n = 16) at baseline (Figure 3). In these eyes, IOP decreased after vitrectomy reaching the level of statistical significance (P = .02) at 2 years with mean IOP of 15.0 mm Hg ± 3.6 mm Hg, which was an approximate decrease of 2 mm Hg from baseline mean IOP of 17.0 mm Hg ± 4 mm Hg. However, at 3 years, IOP trended upwards, with mean IOP of 15.6 mm Hg ± 3.1 mm Hg and was no longer significantly different when compared to baseline IOP. IOP distribution during the study period in phakic and pseudophakic study eyes is seen in Figure 4.
Mean intraocular pressure (IOP) change in study eyes phakic at baseline (n = 16). There is a significant mean IOP reduction noted at the 2-year follow-up visit (P < .05), approximately 14 months after average time of cataract extraction. Error bars represent 1 standard error of the mean.
Intraocular pressure (IOP) distribution in pseudophakic and phakic study eyes. BL = baseline; mo = month; yr = year
At 3 years postoperatively, mean logMAR BCVA in surgical eyes was 0.10 (Snellen equivalent 20/25), which was significantly improved from baseline visual acuity (VA) of 0.39 (Snellen equivalent 20/50; P = .001). Fellow eye VA did not vary significantly during the course of the study. Fifteen of 16 phakic eyes (94%) underwent cataract surgery and, therefore, 31 of 32 post-vitrectomy eyes (97%) were pseudophakic by 3-year follow-up (Table 1).
Three-Year Clinical Outcomes for Study Eyes and Fellow Eyes
Time to event analysis demonstrated that 15 of the 16 (94%) study eyes phakic at baseline underwent cataract surgery by their 2-year follow-up, with the majority occurring within the first 10 months after vitrectomy surgery.
The 3-year results of PROVE demonstrate a progressive IOP increase in pseudophakic eyes following routine vitrectomy surgery. To our knowledge, this is the first prospective, controlled, longitudinal study to report this finding, which may be clinically important since IOP is a risk factor for the development of glaucoma. Furthermore, the results of PROVE show that although removal of the crystalline lens reduces IOP in the initial ensuing months following vitrectomy surgery, IOP may ultimately increase with longer follow-up. These findings have direct clinical implications because PPV is the third most common ocular surgery (after refractive and cataract surgery) performed in the United States and cataract removal is generally required in the majority of eyes within 2 years after surgery.
In 2006, Chang postulated that vitrectomy surgery resulted in an increased incidence of OAG, presumably due to an increase in oxygen tension and consequent production of free radical oxygen species.9 Experimental studies have since given credence to this theory. The vitreous gel appears to actively regulate reactive oxygen species within the eye by consuming oxygen.10 Ascorbate (vitamin C) exists in extremely high concentration in the vitreous when compared to plasma and reacts chemically with oxygen to produce water.10 In support of this, surgical removal results in higher intraocular oxygen tension that may account for the accelerated nuclear sclerosis (except in highly ischemic eyes) observed after vitrectomy surgery.11 The crystalline lens also consumes oxygen and serves as a barrier to diffusion of oxygen from the vitreous cavity to the anterior chamber.12 Its removal results in higher anterior chamber oxygen tension.13 In vitro studies demonstrate that higher oxygen tension results in progressive toxicity and death of trabecular endothelial cells (presumably due to exposure to free radical oxygen species), which could result in outflow resistance and subsequent elevation of IOP.14,15
Although there are accumulating experimental data demonstrating a plausible mechanism to explain an association between OAG and vitrectomy, published clinical studies reporting this association are limited to retrospective analysis.1,3–7 Furthermore, it is well-established that patients undergoing uneventful vitrectomy surgery can develop visual field defects,16,17 which confounds retrospective assessment of OAG, especially in the absence of rigorous baseline assessment. The 3-year results of PROVE are therefore the most compelling clinical evidence to date of a cause and effect association between the combination of vitrectomy and cataract extraction and increasing IOP. This observed association is further strengthened by the rigorous design of PROVE and consistency with published 1-year results.18 The linear relationship observed between IOP increase and elapsed time supports a pathophysiological mechanism dependent on progressive trabecular tissue injury due to prolonged free radical exposure. Importantly, there was no observed increase in IOP in fellow non-vitrectomized eyes in PROVE, which allows us to control for confounding factors such as aging and selection bias.
Despite progressive increase in IOP of pseudophakic eyes, the overall mean IOP in surgical eyes did not increase as IOP decreased in phakic eyes after cataract surgery. Our results are therefore consistent with prospective studies that report a reduction of IOP after cataract surgery.19–21 Although the exact mechanism of reduced IOP after cataract surgery is unknown, postulated mechanisms include reduction of lens-induced outflow resistance (a consequence of age-related increasing volume),22,23 low-grade inflammation resulting in either decreased aqueous production or increased uveal outflow,24 and high fluid flow and IOP (fluidics) during phacoemulsification increasing patency and decreasing resistance through the trabecular meshwork.22,25 A report by the American Academy of Ophthalmology concluded that the best available evidence indicates that phacoemulsification results in a measurable reduction in IOP in eyes with OAG,20 which has led some to suggest cataract surgery as a reasonable and safer option to lower IOP than traditional glaucoma surgery.26
In our series, however, although IOP initially decreases in vitrectomized eyes after cataract surgery, by year 3, IOP trends upwards. The adult lens is typically 9 mm to 10 mm in diameter and 4 mm to 5 mm in axial length and constitutes a relatively small volume (∼200 μL) of the posterior chamber when compared to vitreous (∼4 mL to 5 mL).27 Glucose is its primary energy source, and approximately 80% of glucose is metabolized via anaerobic metabolism. The lack of aerobic respiration suggests that the lens consumes relatively little oxygen directly and likely contributes minimally to oxygen regulation when in the presence of a much larger volume of vitreous. Instead, the lens probably plays a more important role as a relative barrier to diffusion of reactive oxygen species, and its removal therefore exacerbates but is not likely the direct cause of oxidative tissue damage. In support of this, large prospective series, to date, with up to 3 years of follow-up have not observed a rise in IOP after cataract surgery in non-vitrectomized eyes.19,21 Follow-up at years 4 and 5 in PROVE should provide greater clarity of the ultimate effects on IOP in vitrectomized eyes that subsequently undergo cataract surgery.
As with all prospective studies, our results should be interpreted with caution. Despite our robust results, a relatively small number of eyes were enrolled in PROVE overall and there was loss to follow-up. Nonetheless, our comparative analysis with matched fellow eyes allows us to control for these confounding factors and gives us sufficient power to detect small differences. A confirmatory larger prospective trial specifically looking at IOP changes in pseudophakic eyes following vitrectomy surgery would be beneficial. Despite the study's limitations, there are several singular strengths of PROVE, which include its rigorous design with baseline assessment and investigation of a timely and unaddressed topic.
In conclusion, the 3-year results of PROVE confirm and expand upon our published 1-year results.18 Pseudophakic eyes undergoing routine vitrectomy surgery experience a progressive increase in IOP. Although cataract surgery in phakic eyes after vitrectomy initially results in a decrease in IOP, our 3-year results suggest that IOP may ultimately increase. Longer term follow-up of this cohort may demonstrate whether these observations translate into a greater risk of developing OAG.
- Lalezary M, Kim SJ, Jiramongkolchai K, Recchia FM, Agarwal A, Sternberg P Jr, . Long-term trends in intraocular pressure after pars plana vitrectomy. Retina. 2011;31(4):679–685. doi:10.1097/IAE.0b013e3181ff0d5a [CrossRef]
- Han DP, Lewis H, Lambrou FH Jr., Mieler WF, Hartz A. Mechanisms of intraocular pressure elevation after pars plana vitrectomy. Ophthalmology. 1989;96(9):1357–1362. doi:10.1016/S0161-6420(89)32715-1 [CrossRef]
- Wu L, Berrocal MH, Rodriguez FJ, et al. Intraocular pressure elevation after uncomplicated pars plana vitrectomy: Results of the Pan American Collaborative Retina Study Group. Retina. 2014;34(10):1985–1989. doi:10.1097/IAE.0000000000000189 [CrossRef]
- Fujikawa M, Sawada O, Kakinoki M, Sawada T, Kawamura H, Ohji M. Long-term intraocular pressure changes after vitrectomy for epiretinal membrane and macular hole. Graefes Arch Clin Exp Ophthalmol. 2014;252(3):389–393. doi:10.1007/s00417-013-2475-4 [CrossRef]
- Yu AL, Brummeisl W, Schaumberger M, Kampik A, Welge-Lussen U. Vitrectomy does not increase the risk of open-angle glaucoma or ocular hypertension – a 5-year follow-up. Graefes Arch Clin Exp Ophthalmol. 2010;248(10):1407–1414. doi:10.1007/s00417-010-1409-7 [CrossRef]
- Luk FO, Kwok AK, Lai TY, Lam DS. Presence of crystalline lens as a protective factor for the late development of open angle glaucoma after vitrectomy. Retina. 2009;29(2):218–224. doi:10.1097/IAE.0b013e31818ba9ca [CrossRef]
- Koreen L, Yoshida N, Escariao P, et al. Incidence of, risk factors for, and combined mechanisms of late-onset open-angle glaucoma after vitrectomy. Retina. 2012;32(1):160–167. doi:10.1097/IAE.0b013e318217fffb [CrossRef]
- Reddy RK, Lalezary M, Kim SJ, et al. Prospective Retinal and Optic Nerve Vitrectomy Evaluation (PROVE) study: Findings at 3 months. Clin Ophthalmol. 2013;7:1761–1769.
- Chang S. LXII Edward Jackson lecture: Open angle glaucoma after vitrectomy. Am J Ophthalmol. 2006;141(6):1033–1043. doi:10.1016/j.ajo.2006.02.014 [CrossRef]
- Shui YB, Holekamp NM, Kramer BC, et al. The gel state of the vitreous and ascorbate-dependent oxygen consumption: Relationship to the etiology of nuclear cataracts. Arch Ophthalmol. 2009; 127(4):475–482. doi:10.1001/archophthalmol.2008.621 [CrossRef]
- Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens: A possible mechanism for nuclear cataract formation. Am J Ophthalmol. 2005;139(2):302–310. doi:10.1016/j.ajo.2004.09.046 [CrossRef]
- Shui YB, Fu JJ, Garcia C, et al. Oxygen distribution in the rabbit eye and oxygen consumption by the lens. Invest Ophthalmol Vis Sci. 2006;47(4):1571–1580. doi:10.1167/iovs.05-1475 [CrossRef]
- Siegfried CJ, Shui YB, Holekamp NM, Bai F, Beebe DC. Oxygen distribution in the human eye: Relevance to the etiology of open-angle glaucoma after vitrectomy. Invest Ophthalmol Vis Sci. 2010;51(11):5731–5738. doi:10.1167/iovs.10-5666 [CrossRef]
- Beebe DC, Holekamp NM, Shui YB. Oxidative damage and the prevention of age-related cataracts. Ophthalmic Res. 2010;44(3):155–165. doi:10.1159/000316481 [CrossRef]
- Sacca SC, Pascotto A, Camicione P, Capris P, Izzotti A. Oxidative DNA damage in the human trabecular meshwork: Clinical correlation in patients with primary open-angle glaucoma. Arch Ophthalmol. 2005;123(4):458–463. doi:10.1001/archopht.123.4.458 [CrossRef]
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- Taban M, Lewis H, Lee MS. Nonarteritic anterior ischemic optic neuropathy and ‘visual field defects’ following vitrectomy: Could they be related?Graefes Arch Clin Exp Ophthalmol. 2007;245(4):600–605. doi:10.1007/s00417-006-0420-5 [CrossRef]
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- Mansberger SL, Gordon MO, Jampel H, et al. Reduction in intraocular pressure after cataract extraction: The Ocular Hypertension Treatment Study. Ophthalmology. 2012;119(9):1826–1831. doi:10.1016/j.ophtha.2012.02.050 [CrossRef]
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Three-Year Clinical Outcomes for Study Eyes and Fellow Eyes
|Eye Group||Baseline||3 Month||1 Year||2 Year||3 Year|
|Mean logMAR VA (Snellen)||Study Eye||0.39* (20/50)||0.24+* (20/35)||0.23+* (20/34)||0.14+* (20/28)||0.10+* (20/25)|
|Fellow Eye||0.06 (20/23)||0.06 (20/23)||0.05 (20/22)||0.02 (20/21)||0.02 (20/21)|
|Phakic Eyes, n (%)||Study Eye||20 (50.0)||20 (50.0)||10 (26.3)||2 (5.9)||1 (3.1)|
|Fellow Eye||25 (62.5)||25 (62.5)||21 (55.3)||14 (41.2)||13 (40.6)|
|Pseudophakic Eyes, n (%)||Study Eye||20 (50.0)||20 (50.0)||28 (73.7)||32 (94.1)||31 (96.9)|
|Fellow Eye||15 (37.5)||15 (37.5)||17 (44.7)||20 (58.9)||19 (59.4)|
|Mean IOP in Phakic Study Eyes (mm Hg ± SD)||17.0 ± 4.0||16.3 ± 3.8||15.5 ± 3.4||15.0 ± 3.6||15.6 ± 3.1|
|Mean IOP in PseudoPhakic Study Eyes (mm Hg ± SD)||14.3 ± 2.9||15.0 ± 2.5||16.3 ± 2.8||16.4 ± 3.0||16.8 ± 3.2|