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LXII Edward Jackson Lecture: Open Angle Glaucoma After Vitrectomy

  • Stanley Chang
    Correspondence
    Inquiries to Stanley Chang, MD, Edward S. Harkness Eye Institute, 635 West 165th St, New York, NY 10032
    Affiliations
    Edward S. Harkness Eye Institute, Department of Ophthalmology, Columbia University, New York, New York
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Published:March 20, 2006DOI:https://doi.org/10.1016/j.ajo.2006.02.014

      Purpose

      To present data and an hypothesis for the late development of open angle glaucoma (OAG) after vitrectomy.

      Design

      A retrospective observational case series.

      Methods

      The records of 453 eyes that had undergone vitrectomy were reviewed for postoperative OAG. Eyes with confounding factors were excluded. Sixty-eight eyes of 65 patients that underwent routine vitrectomy were followed for a mean of 56.9 months (range, seven to 192 months). For the main outcome measures, patients were classified into three groups: patients with suspected glaucoma, patients in whom glaucoma developed after the operation, and patients with pre-existing glaucoma.

      Results

      In glaucoma suspects, the mean intraocular pressure was significantly higher in the operated eye compared with the fellow eye (P = .0001). In eyes with new onset glaucoma, 23 of 34 eyes (67.6%) had it in the vitrectomized eye only. In phakic eyes, the time interval between vitrectomy and the development of glaucoma (mean, 45.95 months) was significantly longer than eyes that were nonphakic at the time of vitrectomy (mean, 18.39 months; P = .0115). When the interval between cataract surgery in phakic eyes to the development of glaucoma was compared with the interval from vitrectomy to glaucoma diagnosis in the nonphakic group, the difference was not statistically significant. In eyes with glaucoma before the operation, the mean number of antiglaucoma medications that were required to control the intraocular pressure was significantly higher in the vitrectomized eye, compared with the fellow eye (2.9 medications ± 1.2 vs 2.0 medications ± 1.4; P = .0215; n = 14).

      Conclusion

      There is an increased risk of OAG after vitrectomy. The presence of the lens may be protective. In established OAG before the operation, the number of antiglaucoma medications may increase after surgery. Oxidative stress is hypothesized to have a role in the pathogenesis.
      I am most grateful to the American Academy of Ophthalmology and the American Journal of Ophthalmology for their invitation to give this lecture honoring the achievements of one of the “founding fathers” of American Ophthalmology, Dr Edward Jackson. Joining ranks with 61 of the most prominent leaders in ophthalmology who have given this lecture previously is a distinction that is both absolutely incredible but also humbling.
      • Liesegang T.J.
      • Hoskins H.D.
      • Jensen A.D.
      The significance of the Edward Jackson Lecture.
      It has been exactly 40 years since the last Jackson Memorial Lecture was given by an ophthalmologist from New York, Dr Irving Leopold. At that time, Dr Leopold had a faculty appointment at Columbia University before taking the chair at Mount Sinai School of Medicine the following year. Four other Columbia faculty members have given this distinguished lecture: John Dunnington, Algernon Reese, Ludwig Von Sallman, and George Smelser. I am very pleased to share this honor.
      Dr Jackson exhibited leadership and excellence in many facets of ophthalmology (Figure 1).
      • Crisp W.H.
      Edward Jackson, student and teacher.
      • Albert D.M.
      Edward Jackson in 1896: a man and his specialty at the crossroads: LXII Edward Jackson Memorial Lecture, part I.
      He was the quintessential clinician who was analytical and precise in applying his broad experience and knowledge to solving clinical problems. He was a prolific author who wrote >600 articles and many books on ophthalmology and refraction. He led the movement to elevate the standards for training ophthalmologists and medical students in eye disorders. He was greatly respected and admired by his peers and was a founder and first leader of professional organizations such as the Western Ophthalmologic, Otological, Laryngological, and Rhinological Association (later renamed the American Academy of Ophthalmology and Otolaryngology), the American Board of Ophthalmology, and first Editor-in-Chief of the American Journal of Ophthalmology. Above all, Edward Jackson was the ultimate teacher. He organized the first postgraduate course in ophthalmology in the United States and was always sought out by his residents and associates with their interesting patients. He was dedicated, kind, and generous with his time to his students. He is responsible for introducing the concept of instruction courses at the annual American Academy of Ophthalmology meeting, a program that started in 1921. Education is vital to the progress of ophthalmology. It is with this spirit that I would like to dedicate this lecture to the many teachers who have shared their knowledge, transferred their skills, and given guidance professionally and personally throughout my career. Their interest and mentorship have made me successful.
      Since the revolutionary introduction of vitrectomy in 1971 by Machemer and associates,
      • Machemer R.
      • Buettner H.M.
      • Norton E.W.
      • Parel J.M.
      Vitrectomy a pars plana approach.
      • Machemer R.
      • Parel J.M.
      • Norton E.W.
      Vitrectomy: a pars plana approach: technical improvements and further results.
      this procedure has become the third most frequently performed ophthalmic surgical operation, after cataract and excimer laser refractive surgery. It is estimated that approximately 225,000 vitrectomies are done in the United States each year. The known long-term complications of vitrectomy are relatively few. In the phakic eye, the lens develops a progressive increase in nuclear sclerosis, eventually requiring cataract surgery.
      • Margherio R.R.
      • Cox Jr, M.S.
      • Trese M.T.
      • Murphy P.L.
      • Johnson J.
      • Minor L.A.
      Removal of epimacular membranes.
      The pseudophakic eye that undergoes vitrectomy is more likely to need a posterior capsulotomy with YAG laser.
      • Chang M.A.
      • Parides M.K.
      • Chang S.
      • Braunstein R.E.
      Outcome of phacoemulsification after pars plana vitrectomy.
      In the posterior segment, there is a potential for late retinal detachment, often in the areas of the sclerotomy incisions, when tears develop in the vitreous base from vitreous incarceration at the sclerotomy sites.
      After vitrectomy, a rise in intraocular pressure (IOP) is not an uncommon event in the immediate postoperative period.
      • Weinberg R.S.
      • Peyman G.A.
      • Huamonte F.U.
      Elevation of intraocular pressure after pars plana vitrectomy.
      • Han D.P.
      • Lewis H.
      • Lambrou Jr, F.H.
      • Mieler W.F.
      • Hartz A.
      Mechanisms for intraocular pressure elevation after pars plana vitrectomy.
      • Thompson J.T.
      • Sjaarda R.N.
      • Glaser B.M.
      • Murphy R.P.
      Increased intraocular pressure after macular hole surgery.
      • Chen C.J.
      Glaucoma after macular hole surgery.
      • Chen P.P.
      • Thompson J.T.
      Risk factors for elevated intraocular pressure after the use of intraocular gases in vitreoretinal surgery.
      Often the pressure rise is related to the use of viscoelastics, an expanding gas bubble,
      • Chen P.P.
      • Thompson J.T.
      Risk factors for elevated intraocular pressure after the use of intraocular gases in vitreoretinal surgery.
      silicone oil tamponade, hemorrhage, inflammation, or corticosteroid response. Frequently, medical treatment is effective until the surgical healing response subsides. Infrequently, angle closure glaucoma occurs, sometimes resulting in a permanent glaucoma. In eyes with silicone oil, late glaucoma may develop from emulsification of the oil or from the sudden passage of oil into the anterior chamber that obstructs the passage of fluid into the trabecular meshwork.
      • Costarides A.P.
      • Alabata P.
      • Bergstrom C.
      Elevated intraocular pressure following vitreoretinal surgery.
      The development of new open angle glaucoma (OAG) as a late event after vitrectomy has had little attention.
      • Weinberg R.S.
      • Peyman G.A.
      • Huamonte F.U.
      Elevation of intraocular pressure after pars plana vitrectomy.
      • Tranos P.
      • Asaria R.
      • Aylward W.
      • Sullivan P.
      • Franks W.
      Long term outcome of secondary glaucoma following vitreoretinal surgery.
      In most case series studies of vitrectomy outcomes, there are little data that indicate that OAG is a late complication. The clinical courses of the following three patients illustrate the possibility that vitrectomy may predispose the eye to OAG.

      Case studies

       Patient 1

      A 57-year-old Caucasian man was referred in September 2000 for large retinal tears in the right eye. Four years earlier, he had had a 120-degree giant retinal tear with three inferior horseshoe tears in the left eye that were treated with laser photocoagulation. Three days before my examination, he noted floaters in the right eye, and an inferior shadow developed two days later. The visual acuity in the right eye was 20/20 with correction. There was mild vitreous debris and hemorrhage. A bullous retinal detachment was present from 10:30 to 2 o’clock, with two large horseshoe tears at 12 and 1:30 o’clock (FIGURE 2, FIGURE 3, Top). Two additional horseshoe tears were located equatorially at 6:00 and at 7:30 o’clock. In the left eye the retina was attached, and the tears were surrounded by laser photocoagulation scars. The IOPs were OD 17 mm Hg, OS 18 mm Hg.
      Figure thumbnail gr2
      FIGURE 2Preoperative fundus drawing of the right eye (Patient 1) with large posterior retinal tears and retinal detachment. The intraocular pressures were OD 17 mm Hg, OS 18 mm Hg.
      Figure thumbnail gr3
      FIGURE 3Pre- and postoperative photographs (Patient 1). (Top) A large posterior tear at 12 o’clock was treated with vitrectomy, perfluorocarbon liquid, endolaser, and gas tamponade. No scleral buckle was used. (Bottom) After the operation, the visual acuity was 20/25.
      Because of the large posterior tears, the retinal detachment in the right eye was managed by primary vitrectomy, perfluorocarbon liquid tamponade, endophotocoagulation, and perfluorocarbon gas injection. A scleral buckle was not done. Postoperatively, one month later, the retina was completely attached with reabsorption of the gas bubble and corrected visual acuity of 20/25. One year later and receiving no ocular medications, his corrected visual acuity was 20/40 in the right eye, and the IOP was normal. A nuclear cataract was noted in the right eye. The patient elected to proceed with uneventful phacoemulsification and intraocular lens implantation in the right eye in October 2001, thirteen months after vitrectomy. His IOP remained normal initially after the procedure, but eight months after cataract surgery IOP had increased to 24 mm Hg. Gonioscopy showed an open angle. Three months later, the IOP was 29 mm Hg, and timolol 0.5% was started. In January 2003 with timolol therapy, the IOP was 28 mm Hg, and Cosopt was started twice daily. One year later, the IOP increased to 30 mm Hg while he was receiving Cosopt; twice daily latanoprost 0.005% was added daily. The IOP in the left eye was normal throughout this period without any medications. At the last visit 55 months after vitrectomy, the visual acuity remains OD 20/25 + 2, OS 20/70 (Figure 3, Bottom). The IOPs were OD 19 mm Hg, OS 15 mm Hg. The medications are Cosopt twice daily, latanoprost hs (at bedtime), in the right eye only.

       Patient 2

      A 43-year-old African-American woman was first examined in January 1991 with symptoms of floaters in the right eye and was found to have visual acuity of 20/20. An operculated retinal hole was found at 8 o’clock at the equator with paravascular lattice degeneration from 11 to 12 o’clock. Both areas were surrounded with laser photocoagulation. In July 1997, the patient suddenly noted a visual field defect and dimming of vision in the right eye; a retinal detachment was found (Figure 4). The detachment was bullous from 10 o’clock clockwise to 5 o’clock and extended posteriorly close to the macula. The tears superiorly had coalesced into one large postequatorial retinal tear at 12 o’clock. A primary vitrectomy with perfluorocarbon liquid, endophotocoagulation, and perfluorocarbon gas injection were done. The retina was reattached with a 20/30 corrected visual acuity (Figure 5). In March 1998, nine months after vitrectomy, visual acuity decreased to 20/50, and the patient underwent uneventful phacoemulsification with intraocular lens implantation. The IOP remained normal in both eyes until March 2002, when the IOP was elevated in the right eye (OD 23 mm Hg, OS 17 mm Hg). She was followed as a glaucoma suspect in the right eye for twelve months, when the cup in the right optic disk appeared enlarged compared with the left and IOPs were OD 23 mm Hg, OS 17 mm Hg. Timolol 0.5% was started in the right eye only (Figure 6). On timolol therapy, five months later, the IOP increased to 24 mm Hg, and Cosopt twice daily was started. With Cosopt twice daily at last follow-up examination, 77 months after vitrectomy, the IOPs ranged between OU 13 to 14 mm Hg, with no medications in the left eye.
      Figure thumbnail gr4
      FIGURE 4Preoperative fundus drawing (Patient 2) with large posterior horseshoe tear that caused a macular-sparing retinal detachment. Vitrectomy, perfluorocarbon liquid, endolaser, and gas tamponade were done without scleral buckling. The intraocular pressures were normal throughout the perioperative period.
      Figure thumbnail gr5
      FIGURE 5Postoperative fundus montage of attached retina (Patient 2); laser photocoagulation was placed only around the retinal tears. The corrected visual acuity was 20/30.
      Figure thumbnail gr6
      FIGURE 6Patient 2. Four years after vitrectomy, the intraocular pressure was OD 23 mm Hg, OS 17 mm Hg. The patient was followed as a glaucoma suspect for 12 months until asymmetry of the optic cups was noted with enlargement in the right eye. Timolol 0.5% was started in the right eye only.

       Patient 3

      A 61-year-old Caucasian woman was seen in June 1988 with metamorphopsia in the left eye of one month duration. Her corrected visual acuity was OD 20/25, OS 20/20. Cellophane maculopathy was noted in the left eye. In September 1994, the visual acuity in the left eye was reduced to 20/60-2, and the macular pucker was diagnosed. The IOPs were 19 mm Hg OU. Vitrectomy with membrane peeling was recommended, but the patient decided to wait until July 1995 to undergo surgery when the vision worsened slightly. Vitrectomy was uncomplicated, and the recuperation was unremarkable. The IOPs were OD 18 mm Hg and OS 20 mm Hg. The patient was followed regularly, and a brunescent nuclear cataract developed in the operated left eye. In July 1998, the IOPs were measured at OD 20 mm Hg and OS 22 mm Hg at one month before cataract surgery. After phacoemulsification and intraocular lens implantation, the visual acuity improved from 20/60 to 20/30. The patient was followed regularly, and macular drusen were found in both eyes in September 2000. From the years 2000 to 2005, the IOPs were frequently higher by 3 to 4 mm Hg in the vitrectomized left eye. In March 2005, the IOP in that eye was found to be 26 mm Hg and later 34 mm Hg on repeat testing by her local ophthalmologist. Gonioscopy revealed an open angle. Latanoprost was started in the left eye only, and two weeks later the IOPs were OD 14 mm Hg, OS 22 mm Hg.
      This patient had unilateral OAG in the vitrectomized eye 116 months (nine years, eight months) after vitrectomy and 80 months (six years, eight months) after phacoemulsification and intraocular lens implantation. A graph of the IOPs over the clinical course of this patient is shown in Figure 7.
      Figure thumbnail gr7
      FIGURE 7Graph of intraocular pressure (IOP) over the clinical course of 17 years (Patient 3). IOP was normal and symmetric for many years before vitrectomy for macular pucker. The IOP increased in the vitrectomized left eye just before cataract surgery but did not require treatment until six years later. The IOP in the fellow eye was normal. BID = twice daily.
      In summary, all three patients underwent an uncomplicated vitrectomy with improvement of visual acuity, later followed by cataract surgery. After vitrectomy, the IOP returned to normal and was similar to that in the fellow eye after the operation. As expected, a nuclear cataract developed in each of the patients, and they underwent an uneventful phacoemulsification procedure with intraocular lens implantation (nine to 36 months after vitrectomy). At some period after cataract surgery (in one patient, >6 years), each patient had OAG in the operated eye only, with the unoperated fellow eye maintaining a normal IOP. Thus, I grew suspicious that the vitrectomy, and later the cataract surgery, contributed to the development of glaucoma.

      Methods

      With the assistance of my colleagues and fellows at Columbia, I embarked on a retrospective chart review of all patients who had undergone vitrectomy at the Edward Harkness Eye Institute since 1995. Approval for this review was obtained from the Columbia University Medical Center Institutional Review Board, with exemption of Informed Consent because of its retrospective nature. The study was compliant with Health Insurance Portability and Accountability Act (HIPAA) regulations.
      Nine eyes (13.2%) had one previous vitrectomy. All patients underwent conventional pars plana vitrectomy with a 20-gauge, three-port system in conjunction with a retrobulbar anesthetic block with a lidocaine 2% and bupivacaine 0.75% mixture with 1/200,000 epinephrine. Intraoperatively, perfluoro-n-octane (Perfluoron) was used as an adjunct in 12 eyes (17.6%), in 11 eyes for the management of retinal detachment, and in one eye to float a dislocated intraocular lens anteriorly. At the end of the surgical procedure, 35 eyes (51.5%) received an air tamponade, and 26 eyes (38.2%) received a nonexpanding concentration of fluorinated intraocular gas:air mixture (sulfur hexafluoride, perfluorohexane, perfluoropropane). Seven eyes (10.3%) received no internal tamponade. Ten eyes (14.7%) had previous or concomitant scleral buckling at the time of vitrectomy. After the operation, follow-up visits routinely included visual acuity and slit-lamp and fundus examinations. All IOPs were measured with Goldman applanation tonometry.
      A long follow-up period was required because of long latency for the development of OAG, and the charts of all vitrectomy patients with a follow-up period of >six months were examined. Of 1156 charts that were reviewed, 703 patients were excluded because of a follow-up period of ≤six months. Of the remaining 453 patients, patients were identified to include those with a higher IOP in the operated eye, OAG suspects, or OAG that required treatment. Some patients were excluded because of the possibility that the elevated IOP may have resulted from the ocular disease process, after multiple surgeries, or from other confounding factors such as intravitreal corticosteroids or silicone oil. These exclusion criteria are listed in Table 1. In all instances documented gonioscopic findings confirmed open angle status for inclusion in the study. In all, we identified 68 eyes in 65 patients and separated them into three categories as described below.
      TABLE 1Clinical Characteristics Potentially Confounding the Diagnosis of Open Angle Glaucoma After Vitrectomy and Excluded From the Study
      Patients with more than two vitrectomy operations
      Previous history of anterior inflammation (eg, uveitis, endophthalmitis)
      Rubeosis irides or proliferative diabetic retinopathy with severe ischemia or other retinal vascular disease associated with iris neovascularization
      Use of silicone oil, with or without emulsification
      Severe penetrating trauma with corneal opacification or ciliary body loss
      Angle closure glaucoma
      Patients receiving intravitreal triamcinolone
      Patients chronically using topical or periocular steroids
      Vitrectomy combined with a glaucoma surgical procedure (eg, endocyclophotocoagulation or pars plana tube shunt)

       Group 1: Glaucoma suspects

      In this group of patients (n = 10), the IOP in the vitrectomized eye was higher than the fellow eye by ≥4 mm Hg on three or more postoperative visits. The IOP could be normal or as high as 25 mm Hg in the operated eye. No visual field loss in the operated eye or asymmetry of optic cup size (>0.2) was present. These patients were not treated with antiglaucoma therapy. If both eyes had vitrectomy or the fellow eye had other significant eye disease that could affect IOP, the patients were not eligible for inclusion.

       Group 2: New onset glaucoma

      These patients (n = 43 eyes, 40 patients) were believed to have glaucoma and underwent treatment because of elevated IOP, optic disk changes, and visual field change that was compatible with the optic nerve appearance. The eyes that were included had IOP of ≥30 mm Hg. Also included were patients with elevated IOP and disk or visual field changes that were consistent with glaucoma. Another group that also was included were patients with normal tension glaucoma in which the optic disk cupping was asymmetric and discovered after the operation with high normal or slightly elevated IOP. Most of these patients were sent to a glaucoma subspecialist for an opinion. After July 2002, central corneal thickness was often measured with ultrasound pachymetry (Sonomed 300P PacScan, Lake Success, New York, USA) to assist in the assessment for normal tension glaucoma.

       Group 3: Pre-existing glaucoma

      This group (n = 15) included patients with pre-existing OAG that was treated with medication before vitrectomy. In this group of patients, the goal was to study the effect of vitrectomy on the progression of glaucoma in the operated eye.
      For all patients, the following parameters were recorded: age, gender, high myopia (≥7 diopters), lens status, indications for vitrectomy, length of time after vitrectomy to phacoemulsification, length of time after vitrectomy and cataract surgery to the development of OAG, glaucoma treatment before and after vitrectomy, the course of glaucoma progression (medications, progression of visual field loss, surgical therapy), and the length of follow-up time. Student t tests were done to compare variables among the groups.

      Results

      The mean age of the patients at the time of vitrectomy for each group is shown in Table 2. There were no statistically significant differences between the groups.
      TABLE 2Mean Age of the Patients with Postoperative Open Angle Glaucoma at the Time of Vitrectomy
      GroupYearsN
      1 Suspect57.7 ± 22.35 (range, 6–78)10
      2 New onset62.3 ± 11.96 (range, 26–88)40
      3 Preoperative open angle glaucoma67.3 ± 5.44 (range, 59–77)15
      The indications for vitrectomy for each of the groups are listed in Table 3. Macular pucker or macular hole accounted for 61.8% of all eyes, and the remaining eyes did not have complex problems.
      TABLE 3Indications for Vitrectomy in Patients With Postoperative Open Angle Glaucoma
      IndicationGroup 1Group 2Group 3Total
      Macular pucker4171132
      Macular hole46010
      Retinal detachment111113
      Vitreous hemorrhage0628
      Retained lens fragments0213
      Dislocated intraocular lens0101
      Serous detachment 2 degrees to optic pit1001
      The preoperative and postoperative lens status in all groups is noted in Table 4. Forty-one eyes were phakic (60.3%) before vitrectomy, and only two eyes (2.9%) were phakic at the last follow-up examination.
      TABLE 4Lens Status Before and After Vitrectomy in Eyes With Postoperative Open Angle Glaucoma
      GroupBefore VitrectomyAfter Vitrectomy
      PhakicPseudophakic/AphakicPhakicPseudophakic/Aphakic
      164/019/0
      22514/4138/4
      3105/0015/0
      The mean follow-up interval between the vitrectomy and last follow-up visit is given in Table 5 for all groups. There were no statistically significant differences between groups.
      TABLE 5Mean Follow-up Interval of Eyes With Open Angle Glaucoma After Vitrectomy
      GroupMonths
      155.2 ± 20.6 (range, 15–74)
      262.2 ± 47.1 (range, 7–192)
      342.8 ± 37.3 (range, 9–156)
      All patients56.9 ± 42.4
      In group 1, the glaucoma suspect group, the mean IOP of three consecutive follow-up visits was compared in the vitrectomized eye with the fellow unoperated eye. In this group, the mean IOP was 19.5 ± 2.7 mm Hg in the vitrectomized eye, compared with 14.3 ± 3.0 mm Hg in the fellow eye (P = .0001, paired t test).
      In group 2, eyes in which new onset glaucoma developed after vitrectomy, the time interval between vitrectomy and the diagnosis of glaucoma was significantly longer in phakic eyes compared with the interval between vitrectomy and glaucoma diagnosis in nonphakic eyes. In initially phakic eyes, the mean time interval was 45.95 ± 44.79 months (range, one to 174 months; n = 20), compared with 18.39 ± 13.76 months (range, three to 59 months; n = 23) in eyes that were nonphakic at the time of vitrectomy (P = .0115). When comparing the interval between cataract extraction to glaucoma diagnosis in initially phakic eyes (mean, 32.17 ± 30.86 months; n = 18) and the interval to glaucoma in nonphakic eyes (at the time of vitrectomy; mean, 18.39 ± 13.76 months; n = 23), the difference was no longer statistically significant (P = .0627). In a subset of group 2 patients, 34 patients had normal fellow eyes that did not have significant disease (except for cataract surgery) and could be used for comparison. The number of antiglaucoma medications that were taken in the vitrectomized eye (mean, 1.79 ± 0.95) was greater than used in the fellow eye (mean, 0.65 ± 1.0), and this was highly statistically significant (n = 34; P = .0001). Of these, 23 patients (67.6%) received treatment for glaucoma only in the vitrectomized eye.
      Group 3 eyes included patients who were treated for OAG before vitrectomy in one eye. In 14 patients, the fellow eye did not undergo vitrectomy and could be used for comparison. At the last follow-up visit, the mean number of glaucoma medications that were used in eyes that had vitrectomy was 2.9 ± 1.2 and, in the fellow eye, was 2.00 ± 1.4 (P = .0215). At the last follow-up visit, the mean IOP was 14.43 ± 2.0 mm Hg in vitrectomized eyes, compared with 14.36 ± 3.8 mm Hg in the fellow eye (P = .9265).
      In most patients, the glaucoma was well controlled and did not cause much change in visual function. One patient (group 2) underwent a glaucoma shunt procedure because of the progression of cupping on maximal medical therapy (Figure 8). In two other patients (both group 3), the visual field loss progressed centrally, but no further surgery was done because of macular disease (macular hole, macular pucker).
      Figure thumbnail gr8
      FIGURE 8In general, postvitrectomy open angle glaucoma was controlled successfully with medical therapy. However, a monocular patient who was treated for macular pucker with laser applied to inferior retinal tears required surgery. The cupping increased in the right optic disk, and a tube shunt implant was placed.

      Discussion

      We reviewed the literature that reported the clinical outcomes after vitrectomy for various retinal conditions to see whether OAG was reported as a late complication of vitrectomy. In a review of several reports of large surgical series for macular holes,
      • Ezra E.
      • Gregor Z.J.
      Surgery for idiopathic full-thickness macular hole: two-year results of a randomized clinical trial comparing natural history, vitrectomy, and vitrectomy plus autologous serum: Morfields Macular Hole Study Group report no. 1.
      • Leonard 2nd, R.E.
      • Smiddy W.E.
      • Flynn Jr, H.W.
      • Feuer W.J.
      Long-term visual outcomes in patients with successful macular hole surgery.
      • Scott I.U.
      • Moraczewski A.L.
      • Smiddy W.E.
      • Flynn Jr, H.W.
      • Feuer W.J.
      Long-term anatomic and visual acuity outcomes after initial anatomic success with macular hole surgery.
      epimacular membranes,
      • Margherio R.R.
      • Cox Jr, M.S.
      • Trese M.T.
      • Murphy P.L.
      • Johnson J.
      • Minor L.A.
      Removal of epimacular membranes.
      • Pesin S.R.
      • Olk R.J.
      • Grand M.G.
      • et al.
      Vitrectomy for premacular fibroplasia prognostic factors, long-term follow-up, and time course of visual improvement.
      • Michels R.G.
      Vitrectomy for macular pucker.
      • Margherio R.R.
      • Trese M.T.
      • Margherio A.R.
      • Cartright K.
      Surgical management of vitreomacular traction syndrome.
      and vitrectomy for retinal detachment,
      • Sharma Y.R.
      • Karunanithi S.
      • Azad R.V.
      • et al.
      Functional and anatomic outcome of scleral buckling versus primary vitrectomy in pseudophakic retinal detachment.
      • Ahmadieh H.
      • Moradian S.
      • Faghihi H.
      • et al.
      Pseudophakic and Aphakic Retinal Detachment (PARD) Study Group
      Anatomic and visual outcomes of scleral buckling versus primary vitrectomy in pseudophakic and aphakic retinal detachment: six-month follow-up results of a single operation: report no. 1.
      • Miki D.
      • Hida T.
      • Hotta K.
      • Shinoda K.
      • Hirakata A.
      Comparison of scleral buckling and vitrectomy for retinal detachment resulting from flap tears in superior quadrants.
      • Halberstadt M.
      • Chatterjee-Sanz N.
      • Brandenberg L.
      • Koerner-Stiefbold U.
      • Koerner F.
      • Garweg J.G.
      Primary retinal reattachment surgery anatomical and functional outcome in phakic and pseudophakic eyes.
      • Campo R.V.
      • Sipperley J.O.
      • Sneed S.R.
      • et al.
      Pars plana vitrectomy without scleral buckle for pseudophakic retinal detachments.
      • Devenyi R.G.
      • de Carvalho Nakamura H.
      Combined scleral buckle and pars plana vitrectomy as a primary procedure for pseudophakic retinal detachments.
      there was little information about the rates of glaucoma. In one series of 71 eyes with pseudophakic retinal detachment that was managed with vitrectomy or vitrectomy and scleral buckling, 14 eyes (19.7%) were noted to be on antiglaucoma therapy before the operation. At the nine month follow-up examination, 27 eyes (38%) were treated with topical medication for glaucoma.
      • Stangos A.N.
      • Petropoulos I.K.
      • Brozou C.G.
      • Kapetanios A.D.
      • Whatham A.
      • Pournaras C.J.
      Pars-plana vitrectomy alone vs. vitrectomy with scleral buckling for primary rhegmatogenous pseudophakic retinal detachment.
      The authors did not comment on the significance of this finding.
      The data from this study strongly suggest that vitrectomy increases the risk of the development of OAG in the operated eye. Most commonly, glaucoma was unilateral and developed in the eye that underwent vitrectomy and subsequent cataract surgery. The development of glaucoma may take ≥10 or more years. The specific indications for vitrectomy did not appear to be a risk factor. Because this is a retrospective chart review, it is difficult to determine the true incidence of OAG after vitrectomy because of the variability in follow-up periods and the large number of patients who were excluded because of short follow-up periods. We estimate that up to 15% to 20% of eyes may be at risk for the development of OAG after vitrectomy. This suggests that up to 30,000 new cases of glaucoma may develop annually in the United States after vitrectomy.
      The time from vitrectomy in phakic eyes to the development of OAG (mean, 45.9 months) compared with same interval in pseudophakic eyes (mean, 18.4 months) was statistically significant. In contrast, the time from cataract surgery to the development of OAG in phakic eyes was not statistically significant from eyes that were pseudophakic at the time of vitrectomy. This suggests that the presence of the lens may have a protective role and may delay the development of OAG. The progression of nuclear sclerosis in the lens of the vitrectomized eye is well-known. In a series of 75 patients, the cumulative incidence of progressive nuclear sclerosis was 72% in the operated eye and 15% in the fellow eye after twenty-four months.
      • de Bustros S.
      • Thompson J.T.
      • Michels R.G.
      • Enger C.
      • Rice T.A.
      • Glaser B.M.
      Nuclear sclerosis after vitrectomy for idiopathic epiretinal membranes.
      • Melberg N.S.
      • Thomas M.A.
      Nuclear sclerotic cataract after vitrectomy in patients younger than 50 years of age.
      The progression of nuclear sclerosis was more likely in older patients. After removal of the vitreous, the lens undergoes a myopic shift in the refractive state of the eye and develops a slow, but relentless, clouding of the nucleus in almost all eyes. When the vitreous is not removed, the lens does not develop cataract for up to five years.
      • Sawa M.
      • Ohji M.
      • Kusaka S.
      • et al.
      Nonvitrectomizing vitreous surgery for epiretinal membrane long-term follow up.
      Postvitrectomy cataract was managed with phacoemulsification and intraocular lens implantation in all eyes. The possibility that the cataract surgery increases the risk of OAG after the operation was considered. However, several case series that examined the effect of phacoemulsification on IOP in nonglaucomatous eyes reported that the IOP decreases after the operation.
      • Shingleton B.J.
      • Gamell L.S.
      • O’Donoghue M.W.
      • Baylus S.L.
      • King R.
      Long-term changes in intraocular pressure after clear corneal phacoemulsification normal patients versus glaucoma suspect and glaucoma patients.
      • Suzuki R.
      • Kuroki S.
      • Fujiwara N.
      Ten year follow up of intraocular pressure after phacoemulsification and aspiration with intraocular lens implantation performed by the same surgeon.
      • Pohjalainen T.
      • Vesti E.
      • Uusitalo R.J.
      • Laatikainen L.
      Intraocular pressure after phacoemulsification and intraocular lens implantation in nonglaucomatous eyes with and without exfoliation.
      In several series that reported the outcomes of patients with OAG who underwent phacoemulsification, the glaucoma was easier to manage. The number of medications that were required to control IOP was significantly reduced, and the IOP was lower than preoperative levels.
      • Mathalone N.
      • Hyams M.
      • Nieman S.
      • Buckman G.
      • Hod Y.
      • Geyer O.
      Long-term intraocular pressure control after clear corneal phacoemulsification in glaucoma patients.
      • Hayashi K.
      • Hayashi H.
      • Nakao F.
      • Hayashi F.
      Effect of cataract surgery on intraocular pressure control in glaucoma patients.
      • Pohjalainen T.
      • Vesti E.
      • Uusitalo R.J.
      • Laatikainen L.
      Phacoemulsification and intraocular lens implantation in eyes with open-angle glaucoma.
      • Hudovernik M.
      • Pahor D.
      Intraocular pressure after phacoemulsification with posterior chamber lens implantation in open-angle glaucoma.
      These effects persisted in eyes that were followed for a mean of 2.8 years.
      • Pohjalainen T.
      • Vesti E.
      • Uusitalo R.J.
      • Laatikainen L.
      Phacoemulsification and intraocular lens implantation in eyes with open-angle glaucoma.
      Thus, phacoemulsification does not appear to affect IOP in normal and glaucomatous eyes and may even reduce it after operation.
      In this study, we found that, in eyes with pre-existing glaucoma, the glaucoma frequently worsened in the vitrectomized eye, because the number of medications that were used to control the IOP increased after surgery. The factors that contributed to these findings are not clear, but there are several possible explanations. First, the surgical inflammation and debris could have reduced the aqueous outflow facility further. Another consideration is that the optic disk in the vitrectomized eye becomes more susceptible to damage after the operation. Last, it is possible that the removal of the vitreous body alters the biochemical environment in such a way that aqueous outflow becomes reduced.
      The delayed onset of glaucoma in the vitrectomized eye suggests that there is a diffusible factor in the vitreous that appears after the cortical vitreous is removed. This factor alters the trabecular meshwork over time and reduces aqueous outflow that results in elevated IOP and glaucoma. After the immediate postoperative period, there is usually no visible inflammation in the eye after uncomplicated surgery. It is my hypothesis that oxygen is the main factor and that oxidative stress affects the cells of the trabecular meshwork over time, causing a rise in IOP in some eyes. In the phakic eye, the lens is protective by metabolizing most of the oxygen; but after cataract surgery, the trabecular meshwork is subjected to oxidative damage by an increased oxygen level from the vitreous.
      Oxygen tension has been measured before and after vitrectomy in the normal rabbit eye.
      • Barbazetto I.A.
      • Liang J.
      • Chang S.
      • Zheng L.
      • Spector A.
      • Dillon J.P.
      Oxygen tension in the rabbit lens and vitreous before and after vitrectomy.
      Before vitrectomy, the oxygen tension is highest near the retinal surface and decreases in the anterior vitreous just posterior to the center of the lens (Figure 9). There is a further gradient within the lens, with the lowest oxygen tension in the center of the lens. After vitrectomy, the oxygen tension near the lens rises to two to three times the preoperative level, and the concentration gradient in the vitreous disappears. In humans, Holekamp and associates
      • Holekamp N.M.
      • Shui Y.B.
      • Beebe D.C.
      Vitrectomy surgery increases oxygen exposure to the lens a possible mechanism for nuclear cataract formation.
      measured the oxygen tension in the vitreous in patients who underwent vitrectomy. They reported the elevation of oxygen tension after vitrectomy and found in eight patients who underwent reoperation that a statistically significant elevation of oxygen tension persisted for many months after the initial surgery (three to twenty months; mean, ten months).
      Figure thumbnail gr9
      FIGURE 9In the nonvitrectomized phakic eye, the oxygen tension (pO2) is lower (arrow) in the center of the vitreous than in the vitreous near the retinal surface.
      In the phakic eye after vitrectomy, the elevated oxygen levels are modulated by antioxidant mechanisms in the vitreous and lens.
      • McNulty R.
      • Wang H.
      • Mathias R.T.
      • Ortwerth B.J.
      • Truscott R.J.
      • Bassnett S.
      Regulation of tissue oxygen levels in the mammalian lens.
      • Truscott R.J.
      Age-related nuclear cataract-oxidation is the key.
      For instance, in the presence of transition metals such as copper and iron, ascorbic acid may be oxidized with the result that hydrogen peroxide is produced. Glutathione and catalase then detoxify the hydrogen peroxide. Oxygen crosses cell membranes readily in the lens. Most of the oxygen is consumed by oxidative phosphorylation that takes place in the outer layers of the lens where mitochondria are most populous.
      • Truscott R.J.
      Age-related nuclear cataract-oxidation is the key.
      The lens nucleus has very low levels of oxygen; however, when ambient levels increase, protein oxidation begins in the center of the lens, and nuclear cataract develops (Figure 10). The lens also contains high levels of ascorbate that diffuse from the fluid that surrounds it. The ascorbate and glutathione within the lens also consume oxygen. The high rate of progression of nuclear sclerosis after vitrectomy is a sign that the lens does not have sufficient antioxidant capacity to deal completely with the prolonged elevation of oxygen levels. After cataract surgery, the increased levels of vitreous oxygen mix with the aqueous fluid and subsequently pass through the aqueous outflow channels (Figure 11).
      Figure thumbnail gr10
      FIGURE 10After vitrectomy, the gradient disappears, and oxygen tension (pO2) increases (arrow) in the central vitreous, surrounding the lens, eventually causing cataract.
      Figure thumbnail gr11
      FIGURE 11After cataract surgery, the increased level of oxygen in the vitreous no longer is metabolized by the lens and mixes with aqueous humor that passes through the trabecular meshwork (arrows). pO2 = oxygen tension.
      The pathologic mechanisms that cause glaucoma are multiple and complex.
      • Gabelt B.T.
      • Kaufman P.L.
      Changes in aqueous humor dynamics with age and glaucoma.
      However, there is good evidence that oxidative damage to cells in the trabecular meshwork alters its outflow capacity and may contribute to the pathogenesis of OAG. There are several pathways by which elevated levels of hydrogen peroxide and free radicals may cause damage to cells in the trabecular meshwork.
      • Nguyen K.P.
      • Chung M.L.
      • Anderson P.J.
      • Johnson M.
      • Epstein D.L.
      Hydrogen peroxide removal by the calf aqueous outflow pathway.
      • Kahn M.G.
      • Giblin F.J.
      • Epstein D.L.
      Glutathione in calf trabecular meshwork and its relation to aqueous humor outflow facility.
      Antioxidant mechanisms such as superoxide dismutase decrease in human trabecular meshwork cells with increasing age.
      • Freedman S.F.
      • Anderson P.J.
      • Epstein D.L.
      Superoxide dismutase and catalase of calf trabecular meshwork.
      Oxidative DNA damage was found to be increased in the trabecular meshwork of patients with OAG.
      • Chen J.Z.
      • Kadlubar F.F.
      A new clue to glaucoma pathogenesis.
      • Izzotti A.
      • Sacca S.C.
      • Cartiglia C.
      • De Flora S.
      Oxidative deoxyribonucleic acid damage in the eye of glaucoma patients.
      • Sacca S.C.
      • 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.
      Deletion of GSTM1 (encoding gene for glutathione S-transferases) gene predisposes individuals to more oxidative DNA damage and an increased risk of glaucoma.
      • Izzotti A.
      • Sacca S.C.
      • Cartiglia C.
      • De Flora S.
      Oxidative deoxyribonucleic acid damage in the eye of glaucoma patients.
      Oxidized proteins are degraded by the 20S proteasome, and this activity is reduced in the trabecular meshwork of patients with glaucoma.
      • Caballero M.
      • Liton P.B.
      • Epstein D.L.
      • Gonzalez P.
      Proteasome inhibition by chronic oxidative stress in human trabecular meshwork cells.
      • Wright G.
      • Terada K.
      • Yano M.
      • Sergeev I.
      • Mori M.
      The high levels of ascorbate in the aqueous convert oxygen, which provides a source for hydrogen peroxide. Human trabecular meshwork cells that are exposed briefly to H2O2 showed impaired adhesion to the extracellular matrix.
      • Zhou L.
      • Li Y.
      • Yue B.Y.
      Oxidative stress affects cytoskeletal structure and cell-matrix interactions in cells from an ocular tissue the trabecular meshwork.
      The loss of adhesiveness was believed to be related to the rearrangement of cytoskeletal structures. Continued exposure to H2O2 might lead to trabecular endothelial cell loss and compromised outflow.
      Figure 12 provides a diagram that gives a summary of the sequences of oxidative stress and its relationship to postvitrectomy cataract and glaucoma that are hypothesized.
      Figure thumbnail gr12
      FIGURE 12Flow diagram of the role of oxidative stress that is hypothesized to cause an increase in nuclear cataract and open angle glaucoma. The presence of a human lens delays the development of open angle glaucoma.
      The results found in this study have several important clinical implications. Most of these patients were followed for a number of years after vitrectomy. The glaucoma was usually diagnosed as part of routine follow-up examinations. In general, the disease was found at a relatively early stage and treated promptly with good clinical outcomes. Only one patient required a glaucoma surgery because of progression under maximal medical therapy. Because of the retrospective nature of this study, it is difficult to know the exact incidence of OAG after vitrectomy. Most patients were lost to follow up or returned to their referring physician. In the patients who did not receive follow up with an ophthalmologist, the consequences might be more serious because most likely the early changes of glaucoma would be relatively asymptomatic. Thus, it is extremely important to stress the importance of long-term follow-up examination to patients who undergo vitrectomy, especially in those eyes that have had the lens removed.
      This study excluded patients with OAG who might have had other confounding factors in the development of the glaucoma. Such factors included the use of silicone oil, severe proliferative diabetic retinopathy, and periocular or intravitreal triamcinolone injection. It is not clear whether the mechanisms of oxidative stress that are proposed here might also be a contributing factor in the development of these other forms of glaucoma. Only prospective studies might provide further insight into this problem.
      Finally, there has been a progressive expansion in the role of vitrectomy in retinal disorders. For instance, a recent survey of retinal surgeons found that 39% of pseudophakic retinal detachments were managed with vitrectomy with or without scleral buckling.

      American Society of Retinal Specialists. Preferences and trends survey 2004. Last accessed: July 1, 2005. Available at: http://www.retinaspecialists.org.

      In previous years, this number was approximately 10%. In addition, the trends have also promoted the use of vitrectomy and gas injection even for the management of retinal detachment with inferior retinal breaks.
      • Sharma A.
      • Grigoropoulos V.
      • Williamson T.H.
      Management of primary rhegmatogenous retinal detachment with inferior breaks.
      • Martinez-Castillo V.
      • Boixadera A.
      • Verdugo A.
      • Garcia-Arumi J.
      Pars plana vitrectomy alone for the management of inferior breaks in pseudophakic retinal detachment without facedown position.
      • Wickham L.
      • Connor M.
      • Aylward G.W.
      Vitrectomy and gas for inferior break retinal detachments Are the results comparable to vitrectomy, gas, and scleral buckle?.
      Increasingly, we are beginning to see the use of vitrectomy for debris such as floaters. Because these patients tend to be younger in age, the lifetime risk of the development of glaucoma may be higher, and an alternative vitreous-sparing procedure for the repair of retinal detachment might be preferred.
      In summary, the risk of OAG is increased after vitrectomy, and this reports the outcomes of a series of patients in whom glaucoma developed after the operation. The glaucoma is more likely to appear years after cataract surgery. In patients with pre-existing glaucoma, the eyes required more medication after vitrectomy. The hypothesis of the pathogenetic mechanisms presented seems plausible. In most cases, the conditions were well-controlled and rarely required surgery. Further work is necessary to determine the incidence of and to investigate and prove the causes of this finding.

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      Biography

      Stanley Chang, MD, is currently a Edward Harkness Professor and Ku Teh Ying and K. K. Tse Professor and Chairman, Department of Ophthalmology, Columbia University, New York, New York. Dr Chang graduated from the College of Physicians and Surgeons of Columbia University and completed his Ophthalmology residency training at Massachusetts Eye and Ear Infirmary and a vitreoretinal fellowship at Bascom Palmer Eye Institute. Dr Chang pioneered the development of perfluorocarbon liquids and panoramic viewing, and surgical techniques for the management of complex retinal detachments.