- Email: [email protected]
Treatment of Stage 2 Macular Hole by Intravitreous Injection of Expansile Gas and Induction of Posterior Vitreous Detachment
Treatment of Stage 2 Macular Hole by Intravitreous Injection of Expansile Gas and Induction of Posterior Vitreous Detachment Keisuke Mori, MD, PhD,1 Sumiyo Saito, MD,1 Peter L. Gehlbach, MD, PhD,2 Shin Yoneya, MD, PhD1 Purpose: To demonstrate the morphological and functional outcomes of intravitreous injection of an expansile gas bubble for the treatment of stage 2 macular holes. Design: Prospective interventional case series. Participants: Twenty eyes of 20 consecutive patients with unilateral stage 2 macular holes. Methods: The patients underwent intravitreous sulfur hexafluoride injection, followed by postoperative facedown positioning for 3 to 5 days. The patients were observed per protocol schedule with complete ophthalmological examination, including determination of corrected visual acuity (VA), slit-lamp biomicroscopic examination, funduscopic examination, and optical coherence tomography (OCT). Follow-up was greater than 12 months for all patients (mean, 19.5). Main Outcome Measures: Posterior vitreous detachment, anatomical closure of the hole, VA, and hole diameter as measured by OCT. Results: Detachment of the posterior vitreous at the macula was achieved in 19 of 20 eyes (95%). Ten cases (50%) had anatomical closure of the hole with intravitreous gas injection alone. The remaining 10 cases (50%) achieved anatomical closure of the hole after subsequent vitreous surgery. There was a significant difference in hole diameter (P ⫽ 0.004) and in pretreatment vision (P ⫽ 4.5⫻10⫺5) in patients for whom gas alone resulted in hole closure and those proceeding to vitreous surgery. Hole closure by gas injection alone was achieved in 7 of 7 eyes (100%) with pretreatment vision better than 20/40 and in 6 of 7 eyes (86%) when the hole was smaller than 200 m. There were no major complications in this series of patients. Successfully treated macular holes remained closed at all follow-up points during the study period. Conclusion: An intravitreous injection of an expansile concentration of the inert sulfur hexafluoride gas alone frequently induces detachment of the posterior vitreous in the aged eye. Anatomical closure of the hole without major complications is more likely in smaller holes with better pretreatment vision. This technique may have clinical application for stage 2 holes in selected cases. A number of potential advantages including decreased morbidity and a potential cost savings may result from successful utilization of this procedure. Ophthalmology 2007;114:127–133 © 2007 by the American Academy of Ophthalmology.
Surgical vitrectomy for the treatment of macular hole is now an accepted and established procedure. The benefit of macular hole surgery (MHS) is supported by a number of uncontrolled1– 4 and controlled5–11 investigations. A comprehensive review and evaluation of the available literature on the surgical management of macular holes was prepared by the American Academy of Ophthalmology, Ophthalmic Originally received: February 10, 2006. Accepted: July 1, 2006. Manuscript no. 2006-178. 1 Department of Ophthalmology, Saitama Medical University Faculty of Medicine, Iruma, Japan. 2 Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Supported in part by a grant-in-aid for scientific research (no. 16591765) from the Ministry of Education, Culture, and Science, Tokyo, Japan (KM), and Research to Prevent Blindness, New York, New York (PLG). Reprint requests to Keisuke Mori, MD, PhD, Department of Ophthalmology, Saitama Medical University Faculty of Medicine, 38 Morohongo, Moroyama, Iruma, Saitama, 350-0495, Japan. E-mail: [email protected]. © 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
Technology Assessment Committee, Retina Panel and was published in 2001.12 The review evaluated all controlled, randomized, multicenter studies5–10 available at that time. Surgical indications and results were reviewed for each stage as defined by Gass’s classification.13,14 In brief, stage 1 includes localized shrinkage of prefoveal cortical vitreous causing tractional shallow detachment of the foveola, creating an intraretinal yellow spot (stage 1A) and small yellow ring (stage 1B). The earliest biomicroscopic evidence of a full-thickness retinal defect indicates a stage 2 hole, which is typically diagnosed by evidence of a central or eccentric retinal defect. Stage 2 holes generally progress to stage 3 holes with partial vitreomacular separation around the macula, and then to stage 4 with complete separation of the vitreous from the entire macular surface and optic disc. The panel concluded that the available level I evidence supports surgery for stage 2 holes, to prevent progression to later stages and further visual loss. It also concluded that surgery improves vision in the majority of patients with stages 3 and 4 holes.12 In contrast, there was insufficient evidence to ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.07.001
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Ophthalmology Volume 114, Number 1, January 2007 recommend surgery for patients with stage 1 holes or to include adjuvant therapies available at that time.6,12 One question raised by the committee for the purpose of future study was how MHS impacts the patient’s quality of life. Issues related to improving the safety of intraocular surgery are of continuing interest. Despite the significant benefit of vitrectomy for stages 2 to 4 macular holes, there are patients who suffer from adverse consequences of intraocular surgery in this setting. Reported complications include acceleration of nuclear sclerosis in up to 80% of patients,15 and one study has reported various posterior segment complications in up to 41% of patients.16 The complications include both generally mild changes, such as retinal pigment epithelium (RPE) alteration (33%), and potentially serious complications, including retinal detachment (RD) (11%), persistence and reopening of the hole, cystoid macular edema (CME), visual field (VF) defects, choroidal neovascularization, and endophthalmitis.16,17 The frequency and potential seriousness of these events support further effort to reduce complications associated with MHS. Approximately 10 years ago, Chan et al demonstrated that an expanding gas bubble would consistently induce posterior cortical vitreous detachment in eyes with idiopathic macular holes (stages 1–3).18 In this pilot report, 10 of 11 stage 1 holes, 3 of 6 stage 2 holes, and 0 of 2 stage 3 holes closed after gas injection. No major complications were reported. Although high closure rates were reported in stage 1 holes, there is currently no evidence supporting surgery for patients with stage 1 holes because spontaneous resolution of vitreomacular traction occurs in approximately 40% to 50% of these patients. Moreover, there is no significant benefit reported after surgical vitrectomy for stage 1
holes. The number of patients with stage 2 or 3 holes tested by Chan et al was small.18 To determine whether the morphological and functional outcomes of this treatment were of potential benefit in stages 2 and 3 holes, we examined 20 consecutive patients with stage 2 macular holes treated by intravitreous injection of an inert expansile gas alone.
Materials and Methods Patients and Study Design This is a prospective, consecutive, interventional case series. Twenty consecutive eyes of 20 patients with a clinical diagnosis of idiopathic stage 2 macular hole but without other ocular complications were enrolled in this study. Excluded were macular holes associated with other causes, including trauma, pathologic myopia, laser photocoagulation, macular pseudohole with epiretinal membrane, and vitreomacular traction syndrome. The composition of the patient population was 14 women and 6 men, ranging in age from 47 to 77 years (64.5⫾7.5 [mean ⫾ standard deviation]). The duration of symptoms ranged from 1 to 7 months (1.7⫾1.4), and the follow-up period was longer than 1 year (19.5⫾4.7 months) (Table 1). Diagnosis and classification of macular holes were based on slit-lamp biomicroscopic examination using the criteria described by Gass13,14 and supported by optical coherence tomography (OCT) findings. All patients gave full informed consent. The study was in compliance with the Declaration of Helsinki.
Pretreatment and Posttreatment Examinations All patients were examined by indirect ophthalmoscopy, contact lens slit-lamp biomicroscopic examination, fundus photog-
Table 1. Summary of the Study Subjects logMAR
Case
Age (yrs)
Gender
Hole Diameter (m)
Pretreatment
Final
Hole and Vitreous Status after Gas Injection
Hole Status after Vitrectomy
Follow-ups (mos)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
72 47 63 62 70 69 55 62 65 74 68 69 77 65 62 73 57 54 59 66
M F F F F M M M F F F F F M F M F F F F
364 546 159 182 159 197 280 207 72 62 634 523 205 700 26 686 386 613 676 925
0.5 0.3 0.15 0.2 0.3 0.05 0 0.05 0.2 0.2 0.5 0.7 0.5 0.7 0.4 0.7 0.4 0.7 0.3 0.7
⫺0.09 0.15 ⫺0.09 0.15 ⫺0.09 0.05 ⫺0.09 ⫺0.09 0.1 0.15 0.7 0.8 ⫺0.09 0.05 0 1 0.15 0.5 0.5 0
Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫺) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹)
NA NA NA NA NA NA NA NA NA NA Closed Closed Closed Closed Closed Closed Closed Closed Closed Closed
24 24 18 24 18 18 24 24 24 12 18 12 24 24 18 12 18 24 12 18
F ⫽ female; logMAR ⫽ logarithm of the minimum angle of resolution; M ⫽ male; NA ⫽ not available; PVD ⫽ detachment of the posterior cortical vitreous. ⫹, present; ⫺, absent.
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Mori et al 䡠 Pneumatic Macular Hole Treatment raphy, visual acuity (VA) testing, and Watzke–Allen testing. Baseline data included identification of the study eye, date of onset of symptoms, refraction, best-corrected VA, fellow eye diagnosis, classification of the macular hole, description of any vitreous (traction), and hole diameter measured by OCT. Hole closure was defined as perfect apposition of the edges, determined by biomicroscopy and OCT examinations. All patients were observed for ⬎12 months and examined according to a predetermined schedule of visits during the follow-up period. The OCT images were taken through a dilated pupil by a trained examiner with knowledge of clinical findings in the retina
using 2 different commercially available systems (OCT2000 and OCT3000, Carl Zeiss Meditec, Dublin, CA). Standardized horizontal and vertical vitreoretinal sections through the macular hole were routinely collected. To examine the morphologic features of individual macular holes, more than 5 cross-sectional images, from edge to opposite edge of the hole, were obtained in each direction. The maximum diameter of the hole was determined from these sets of images. A paired or unpaired t test or chi-square test was used to compare baseline characteristics and treatment outcomes, before and after treatment. The significance level was prospectively set at P⬍0.05.
Figure 1. Fundus photographs and optical coherence tomography images of a stage 2 macular hole before (A, a) and 7 days (B, b), 1 month (C, c), and 24 months (D, d) after intravitreous expanding gas injection. Note the cortical vitreous detachment (b) and anatomical recovery of the foveal retina during the time course (C, D, b– d). Corrected visual acuity improved from 20/32 (pretreatment) to 20/16 (24 months). Optical coherence tomography scan length, 2.83 mm (a– c) and 5.00 mm (d).
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Figure 2. Fundus photographs and optical coherence tomography (OCT) images of a stage 2 macular hole before (A, a) and 1 day (a=), 2 days (a==), and 7 days (B, b) after intravitreous injection of expansile gas. The detachment of the posterior cortical vitreous was induced, and the hole progressed to stage 4. One month after the intravitreous gas injection, the patient was treated by subsequent vitrectomy. An anatomical closure of the hole was demonstrated by fundus photographs and OCT images documented at 1 month (C, c) and 18 months (D, d). Corrected visual acuity improved from 20/100 (pretreatment) to 20/20 (18 months). Optical coherence tomography scan length, 5.00 mm (a– d).
Surgical Procedure A topical anesthetic was applied, after which a lid speculum was placed. The ocular surface was prepared with a drop of 5% povidone–iodine solution (Isodine, Meiji Seika Kaisha, Tokyo, Japan) in a standard fashion. A subconjunctival injection of 2% xylocaine immediately overlying the site of planned injection was administered before each procedure. A transcleral intravitreous
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injection of 0.5 ml of 100% sulfur hexafluoride gas drawn up through a Millipore (Billerica, MA) filter and injected through a 27-gauge needle was performed via the pars plana. Immediately after the injection, eyes were rotated to position the puncture wound posteriorly to avoid leakage of injected gas. Anterior chamber paracentesis or IV infusion with acetazolamide was performed if pulsation of the central retinal artery was induced by intraocular pressure (IOP) increase. The IOP was measured by applanation to
Mori et al 䡠 Pneumatic Macular Hole Treatment be below 30 mmHg, and pulsation of the central retinal artery was noted to be absent before discharge of the patient. The patients were asked to keep their head in a prone position for as much time as possible during the 3 to 5 days after the procedure. By day 7, the sulfur hexafluoride gas bubble was completely absorbed. If the hole remained open after this procedure, the patient was scheduled for vitreous surgery on the next available date. All patients who underwent subsequent vitreous surgery did so no later than 1 month after gas injection. The surgical procedure included phacoemulsification, intraocular lens implantation, 3-port pars plana vitrectomy (removal of the vitreous), and air/gas tamponade without internal limiting membrane peeling.
Results Morphological and Functional Outcomes Posterior cortical vitreous adherent to the foveal surface of the retina was delineated by OCT in all cases before treatment. Two weeks after injection of gas, an absence of vitreomacular attachment was evident in 19 of 20 eyes (95%) on clinical examination (biomicroscopy and ophthalmoscopy) and was confirmed by OCT in all 19 cases (95%). In 10 cases (50%), intravitreous injection of gas alone resulted in anatomical closure of the macular hole. In 1 of the remaining 10 eyes (10%), a stage 2 hole remained (Fig 1). In the 9 remaining eyes (45%), macular hole progressed to stage 4 (Fig 2). All 10 cases in which anatomical success was not achieved by intraocular gas injection alone then underwent vitreous surgery. All 10 of these macular holes were closed successfully with a single surgical procedure. Logarithm of the minimum angle of resolution (logMAR) vision improved from 0.195⫾0.148 to 0.015⫾0.115 in eyes treated by intravitreous gas injection alone (P ⫽ 0.012). Postoperative logMAR vision in eyes treated by both intravitreous gas injection and subsequent vitrectomy was 0.361⫾0.389. Although the trend was towards improved vision, the numbers did not reach statistical significance as compared with pretreatment vision (0.56⫾0.158, P ⫽ 0.133) (Tables 1, 2).
Table 3. Baseline Factors Related to Anatomical Hole Closure after Intravitreous Gas Injection Hole Status Baseline Factors
Closed
Open
P
Age 63.9⫾8.2 65.0⫾7.2 0.753 Gender (male/female) 4/6 2/8 0.314 Duration of symptoms (mos) 2.3⫾1.8 1.1⫾0.3 0.072 Hole diameter (m) 223⫾144 537⫾264 0.004* Pretreatment logMAR 0.195⫾0.148 0.560⫾0.158 4.5⫻10⫺5* logMAR ⫽ logarithm of the minimum angle of resolution. Data are n or mean ⫾ standard deviation. *Significant.
alone (P ⫽ 0.004; 233⫾144 m and 537⫾264 m, respectively). Of the 20 eyes treated, 7 had holes ⬍ 200 m, 3 had holes 200 to 300 m, 2 had holes 300 to 400 m, 2 had holes 400 to 600 m, and 6 had holes ⬎ 600 m. Hole closure was achieved in 6 of 7 eyes (86%) when the hole was smaller than 200 m, in 8 of 10 holes (80%) when the hole was smaller than 300 m, in 9 of 12 holes (75%) when the hole was smaller than 400 m, and in 10 of 14 holes (71%) when the hole was smaller than 600 m. There was also a significant difference in pretreatment logMAR vision between eyes closed and eyes not closed with gas injection alone (P ⫽ 4.5⫻10⫺5; 0.195⫾0.148 and 0.560⫾0.158, respectively). Hole closure by gas injection alone was achieved in 7 of 7 eyes (100%) with pretreatment vision better than 20/40, in 9 of 12 holes (75%) with vision better than 20/60, and in 10 of 15 holes (67%) with vision better than 20/80 (Table 3, Fig 3).
Baseline Factors Related to Anatomical Hole Closure after Intravitreous Gas Injection Alone Pretreatment factors including age, gender, duration of symptoms, hole diameter, and pretreatment vision were analyzed for association with anatomical hole closure after intravitreous gas injection alone. There was a significant difference in hole diameter between eyes that were successfully closed and eyes that did not close after gas injection Table 2. Anatomical and Functional Outcomes after Treatment Hole closure by intravitreous gas injection alone Posterior cortical vitreous detachment Final hole closure Visual outcome of eyes treated by gas injection alone Pretreatment logMAR Final logMAR Visual outcome of eyes treated by gas injection and subsequent vitrectomy Pretreatment logMAR Final logMAR
10/20 (50%) 19/20 (95%) 20/20 (100%) 0.195⫾0.148 0.015⫾0.115, P ⫽ 0.012* 0.560⫾0.158 0.361⫾0.389, P ⫽ 0.133
logMAR ⫽ logarithm of the minimum angle of resolution. Data are n (%) or mean ⫾ standard deviation. *Significant.
Figure 3. Correlation of hole diameter and pretreatment corrected vision to anatomical closure of the hole by intravitreous gas injection alone. White bars, patients successfully treated by gas injection; gray bars, patients with holes not closed by gas injection. Data are n (%).
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Ophthalmology Volume 114, Number 1, January 2007 Adverse Events In the 10 patients with macular hole closure after gas injection alone, there were no reported complications during the study period. There was specifically no progression of nuclear sclerosis requiring cataract surgery or manifestation of lens injury. There was no RPE alteration, retinal break, RD, intraocular hemorrhage, reopening of the hole, CME, epiretinal membrane, choroidal neovascularization, endophthalmitis, or symptomatic VF defects. Moreover, there were no reported complications during the interval between intravitreous gas injection and vitrectomy in the remaining 10 patients treated by both expansile gas injection and vitrectomy. The 10 patients requiring vitreous surgery underwent routine and uncomplicated procedures.
Discussion In this study, we provide evidence that an intravitreous injection of an expansile concentration (100%) of sulfur hexafluoride gas (0.5 ml) will induce detachment of the posterior vitreous in the majority of aged eyes. In the setting of a stage 2 macular hole, long-term anatomical closure results in roughly half of the injected cases. The use of intravitreous sulfur hexafluoride gas alone does not appear to affect the likelihood of subsequent success with conventional MHS significantly, and no complications resulted from the injection of intravitreous gas alone in this series of 20 consecutive patients. The success rates for posterior cortical vitreous detachment and hole closure were 95% and 50%, respectively, which are consistent with a previous report by Chan et al, who evaluated six stage 2 eyes in their series of primarily stage 1 macular holes.18 We find that successful closure of macular holes occurs with significantly higher frequency in smaller holes (P ⫽ 0.004) and holes associated with better pretreatment vision (P ⫽ 4.5⫻10⫺5). In this series, rates of hole closure were 100% in eyes with corrected vision better than 20/40 and 86% in eyes with holes smaller than 200 m. These data suggest that clinical application of this technique to stage 2 holes, with vision better than 20/40 or ⬍200-m greatest diameter, may provide efficacy comparable to that of standard surgical approaches. The morbidity of gas injection alone, as compared with surgery plus gas injection, would be expected to be lower over time, as would the overall impact of the procedure on the patient. The cost of gas injection alone is less than surgery, and no apparent significant detrimental effect on subsequent surgical procedures is evident from this small series. Because 0.5 ml of sulfur hexafluoride gas was used in this study, our patients were asked to keep their heads in a prone position for no fewer than 3 days and no more than 5 days. Chan et al have reported use of 0.3 to 0.5 ml of 100% perfluoropropane, with the majority of patients positioning for 4 to 6 weeks.18 There is no difference in success rates for either posterior cortical vitreous detachment (18/19 vs. 19/ 20) or stage 2 hole closure (3/6 vs. 10/20) between Chan et al’s study and this one. This finding indicates that posterior vitreous detachment occurs early (during the days immediately after gas injection) rather than late (in weeks 2– 4 of intraocular gas treatment). Although patient quality-oflife measures were not used in this study, it is expected that
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such studies will reveal a benefit for the patient with regard to convenience, comfort, and complications related to intraocular surgery. A 3-day facedown positioning period is also supported by the work of Krohn, who found that 3 days was sufficient to achieve closure of even longstanding macular holes, when compared with 7 days of facedown positioning.19 With full consideration for the limitations of the procedure, we believe that there may be a patient care advantage for selected individuals with stage 2 macular holes. Efforts to reduce complications related to a given surgical procedure are a constant motivating force for continued innovation. In the case of MHS, the reported incidence of complications justifies further effort in this area.15–17 To this end, Spaide has designed a new instrument to incise the vitreomacular interface during MHS, thus requiring only limited vitrectomy. Three cases are reported.20 In this study of pneumatic treatment for macular hole, there were no major complications, such as significant nuclear sclerosis progression requiring cataract surgery, lens injury, RPE alteration, retinal breaks and/or detachment, intraocular hemorrhage, reopening of the hole, CME, epiretinal membrane, choroidal neovascularization, endophthalmitis, or new VF defects. Based on current experience with large numbers of intraocular injections of triamcinolone acetonide, pegaptanib, bevacizumab, and ranibizumab for the treatment of ocular neovascularization and macular edema, we expect that the full spectrum of complications will occur with increasing use and that they will be at a comparatively low rate. New retinal breaks have been reported to occur in 13% of 1274 eyes evaluated in a review article summarizing 26 series reports on the use of pneumatic retinopexy.21 Although available numbers are small, our series (20 cases) and Chan et al’s (18 cases)18 resulted in no new retinal break formation. It is possible that the predisposition for retinal break formation may be higher in eyes with existing RD than in eyes with a macular hole. Certainly, further study would be required to validate this point. In conclusion, a pneumatic approach to the treatment of stage 2 macular hole may have merit in selected cases. The stage 2 holes achieving anatomical success in this study included holes that were smaller (⬍200 m) and holes with better vision (better than 20/40). Advantages of this procedure as compared with current surgical approaches may include ease of the procedure, limited invasiveness, increased convenience, short-term prone positioning, the potential for reduced morbidity, and the apparent lack of detrimental effect on subsequent procedures. A potential cost savings is present for those patients who respond favorably to this approach. Although further study is indicated, the data presented here support a limited role for pneumatic macular hole repair.
References 1. Kelly NE, Wendel RT. Vitreous surgery for idiopathic macular holes: results of pilot study. Arch Ophthalmol 1991;109: 654 –9. 2. Wendel RT, Patel AC, Kelly NE, et al. Vitreous surgery for macular holes. Ophthalmology 1993;100:1671– 6. 3. Glaser BM, Michels RG, Kupperman BD, et al. Transforming growth factor-beta 2 for the treatment of full-thickness mac-
Mori et al 䡠 Pneumatic Macular Hole Treatment
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ular holes: a prospective randomized study. Ophthalmology 1992;99:1162–72. Freeman WR. Vitrectomy surgery for full-thickness macular holes. Am J Ophthalmol 1993;116:233–5. Freeman WR, Azen SP, Kim JW, et al. Vitrectomy for the treatment of full-thickness stage 3 or 4 macular holes: results of a multicentered randomized clinical trial. Arch Ophthalmol 1997;115:11–21. de Bustros S, Vitrectomy for Prevention of Macular Hole Study Group. Vitrectomy for prevention of macular holes: results of a randomized multicenter clinical trial. Ophthalmology 1994;101:1055–9. Kim JW, Freeman WR, Azen SP, et al. Prospective randomized trial of vitrectomy or observation for stage 2 macular holes. Am J Ophthalmol 1996;121:605–14. Smiddy WE, Glaser BM, Thompson JT, et al. Transforming growth factor-beta 2 significantly enhances the ability to flatten the rim of subretinal fluid surrounding macular holes: preliminary anatomic results of a multicenter prospective randomized study. Retina 1993;13:296 –301. Thompson JT, Smiddy WE, Williams GA, et al. Comparison of recombinant transforming growth factor-beta-2 and placebo as an adjunctive agent for macular hole surgery. Ophthalmology 1998;105:700 – 6. Paques M, Chastang C, Mathis A, et al. Effect of autologous platelet concentrate in surgery for idiopathic macular hole: results of a multicenter, double-masked, randomized trial. Ophthalmology 1999;106:932– 8. Ezra E, Gregor ZJ, Moorfields Macular Hole Study Group. Surgery for idiopathic full-thickness macular hole: two-year results of a randomized clinical trial comparing natural history, vitrectomy, and vitrectomy plus autologous serum.
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Moorfields Macular Hole Study Group report no. 1. Arch Ophthalmol 2004;122:224 –36. Benson WE, Cruickshanks KC, Fong DS, et al. Surgical management of macular holes: a report by the American Academy of Ophthalmology. Ophthalmology 2001;108:1328 –35. Gass JD. Idiopathic senile macular hole: its early stages and pathogenesis. Arch Ophthalmol 1988;106:629 –39. Gass JD. Reappraisal of biomicroscopic classification of stages of development of a macular hole. Am J Ophthalmol 1995;119:752–9. Thompson JT, Glaser BM, Sjaarda RN, Murphy RP. Progression of nuclear sclerosis and long-term visual results of vitrectomy with transforming growth factor beta-2 for macular holes. Am J Ophthalmol 1995;119:48 –54. Banker AS, Freeman WR, Kim JW, et al. Vision-threatening complications of surgery for full-thickness macular holes. Ophthalmology 1997;104:1442–52. Park SS, Marcus DM, Duker JS, et al. Posterior segment complications after vitrectomy for macular hole. Ophthalmology 1995;102:775– 81. Chan CK, Wessels IF, Friedrichsen EJ. Treatment of idiopathic macular holes by induced posterior vitreous detachment. Ophthalmology 1995;102:757– 67. Krohn J. Duration of face-down positioning after macular hole surgery: a comparison between 1 week and 3 days. Acta Ophthalmol Scand 2005;83:289 –92. Spaide RF. Macular hole repair with minimal vitrectomy. Retina 2002;22:183– 6. Hilton GF, Tornambe PE, Retinal Detachment Study Group. Pneumatic retinopexy: an analysis of intraoperative and postoperative complications. Retina 1991;11:285–94.
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Surgical vitrectomy for the treatment of macular hole is now an accepted and established procedure. The benefit of macular hole surgery (MHS) is supported by a number of uncontrolled1– 4 and controlled5–11 investigations. A comprehensive review and evaluation of the available literature on the surgical management of macular holes was prepared by the American Academy of Ophthalmology, Ophthalmic Originally received: February 10, 2006. Accepted: July 1, 2006. Manuscript no. 2006-178. 1 Department of Ophthalmology, Saitama Medical University Faculty of Medicine, Iruma, Japan. 2 Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. Supported in part by a grant-in-aid for scientific research (no. 16591765) from the Ministry of Education, Culture, and Science, Tokyo, Japan (KM), and Research to Prevent Blindness, New York, New York (PLG). Reprint requests to Keisuke Mori, MD, PhD, Department of Ophthalmology, Saitama Medical University Faculty of Medicine, 38 Morohongo, Moroyama, Iruma, Saitama, 350-0495, Japan. E-mail: [email protected]. © 2007 by the American Academy of Ophthalmology Published by Elsevier Inc.
Technology Assessment Committee, Retina Panel and was published in 2001.12 The review evaluated all controlled, randomized, multicenter studies5–10 available at that time. Surgical indications and results were reviewed for each stage as defined by Gass’s classification.13,14 In brief, stage 1 includes localized shrinkage of prefoveal cortical vitreous causing tractional shallow detachment of the foveola, creating an intraretinal yellow spot (stage 1A) and small yellow ring (stage 1B). The earliest biomicroscopic evidence of a full-thickness retinal defect indicates a stage 2 hole, which is typically diagnosed by evidence of a central or eccentric retinal defect. Stage 2 holes generally progress to stage 3 holes with partial vitreomacular separation around the macula, and then to stage 4 with complete separation of the vitreous from the entire macular surface and optic disc. The panel concluded that the available level I evidence supports surgery for stage 2 holes, to prevent progression to later stages and further visual loss. It also concluded that surgery improves vision in the majority of patients with stages 3 and 4 holes.12 In contrast, there was insufficient evidence to ISSN 0161-6420/07/$–see front matter doi:10.1016/j.ophtha.2006.07.001
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Ophthalmology Volume 114, Number 1, January 2007 recommend surgery for patients with stage 1 holes or to include adjuvant therapies available at that time.6,12 One question raised by the committee for the purpose of future study was how MHS impacts the patient’s quality of life. Issues related to improving the safety of intraocular surgery are of continuing interest. Despite the significant benefit of vitrectomy for stages 2 to 4 macular holes, there are patients who suffer from adverse consequences of intraocular surgery in this setting. Reported complications include acceleration of nuclear sclerosis in up to 80% of patients,15 and one study has reported various posterior segment complications in up to 41% of patients.16 The complications include both generally mild changes, such as retinal pigment epithelium (RPE) alteration (33%), and potentially serious complications, including retinal detachment (RD) (11%), persistence and reopening of the hole, cystoid macular edema (CME), visual field (VF) defects, choroidal neovascularization, and endophthalmitis.16,17 The frequency and potential seriousness of these events support further effort to reduce complications associated with MHS. Approximately 10 years ago, Chan et al demonstrated that an expanding gas bubble would consistently induce posterior cortical vitreous detachment in eyes with idiopathic macular holes (stages 1–3).18 In this pilot report, 10 of 11 stage 1 holes, 3 of 6 stage 2 holes, and 0 of 2 stage 3 holes closed after gas injection. No major complications were reported. Although high closure rates were reported in stage 1 holes, there is currently no evidence supporting surgery for patients with stage 1 holes because spontaneous resolution of vitreomacular traction occurs in approximately 40% to 50% of these patients. Moreover, there is no significant benefit reported after surgical vitrectomy for stage 1
holes. The number of patients with stage 2 or 3 holes tested by Chan et al was small.18 To determine whether the morphological and functional outcomes of this treatment were of potential benefit in stages 2 and 3 holes, we examined 20 consecutive patients with stage 2 macular holes treated by intravitreous injection of an inert expansile gas alone.
Materials and Methods Patients and Study Design This is a prospective, consecutive, interventional case series. Twenty consecutive eyes of 20 patients with a clinical diagnosis of idiopathic stage 2 macular hole but without other ocular complications were enrolled in this study. Excluded were macular holes associated with other causes, including trauma, pathologic myopia, laser photocoagulation, macular pseudohole with epiretinal membrane, and vitreomacular traction syndrome. The composition of the patient population was 14 women and 6 men, ranging in age from 47 to 77 years (64.5⫾7.5 [mean ⫾ standard deviation]). The duration of symptoms ranged from 1 to 7 months (1.7⫾1.4), and the follow-up period was longer than 1 year (19.5⫾4.7 months) (Table 1). Diagnosis and classification of macular holes were based on slit-lamp biomicroscopic examination using the criteria described by Gass13,14 and supported by optical coherence tomography (OCT) findings. All patients gave full informed consent. The study was in compliance with the Declaration of Helsinki.
Pretreatment and Posttreatment Examinations All patients were examined by indirect ophthalmoscopy, contact lens slit-lamp biomicroscopic examination, fundus photog-
Table 1. Summary of the Study Subjects logMAR
Case
Age (yrs)
Gender
Hole Diameter (m)
Pretreatment
Final
Hole and Vitreous Status after Gas Injection
Hole Status after Vitrectomy
Follow-ups (mos)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
72 47 63 62 70 69 55 62 65 74 68 69 77 65 62 73 57 54 59 66
M F F F F M M M F F F F F M F M F F F F
364 546 159 182 159 197 280 207 72 62 634 523 205 700 26 686 386 613 676 925
0.5 0.3 0.15 0.2 0.3 0.05 0 0.05 0.2 0.2 0.5 0.7 0.5 0.7 0.4 0.7 0.4 0.7 0.3 0.7
⫺0.09 0.15 ⫺0.09 0.15 ⫺0.09 0.05 ⫺0.09 ⫺0.09 0.1 0.15 0.7 0.8 ⫺0.09 0.05 0 1 0.15 0.5 0.5 0
Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Closed, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫺) Open, PVD (⫹) Open, PVD (⫹) Open, PVD (⫹)
NA NA NA NA NA NA NA NA NA NA Closed Closed Closed Closed Closed Closed Closed Closed Closed Closed
24 24 18 24 18 18 24 24 24 12 18 12 24 24 18 12 18 24 12 18
F ⫽ female; logMAR ⫽ logarithm of the minimum angle of resolution; M ⫽ male; NA ⫽ not available; PVD ⫽ detachment of the posterior cortical vitreous. ⫹, present; ⫺, absent.
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Mori et al 䡠 Pneumatic Macular Hole Treatment raphy, visual acuity (VA) testing, and Watzke–Allen testing. Baseline data included identification of the study eye, date of onset of symptoms, refraction, best-corrected VA, fellow eye diagnosis, classification of the macular hole, description of any vitreous (traction), and hole diameter measured by OCT. Hole closure was defined as perfect apposition of the edges, determined by biomicroscopy and OCT examinations. All patients were observed for ⬎12 months and examined according to a predetermined schedule of visits during the follow-up period. The OCT images were taken through a dilated pupil by a trained examiner with knowledge of clinical findings in the retina
using 2 different commercially available systems (OCT2000 and OCT3000, Carl Zeiss Meditec, Dublin, CA). Standardized horizontal and vertical vitreoretinal sections through the macular hole were routinely collected. To examine the morphologic features of individual macular holes, more than 5 cross-sectional images, from edge to opposite edge of the hole, were obtained in each direction. The maximum diameter of the hole was determined from these sets of images. A paired or unpaired t test or chi-square test was used to compare baseline characteristics and treatment outcomes, before and after treatment. The significance level was prospectively set at P⬍0.05.
Figure 1. Fundus photographs and optical coherence tomography images of a stage 2 macular hole before (A, a) and 7 days (B, b), 1 month (C, c), and 24 months (D, d) after intravitreous expanding gas injection. Note the cortical vitreous detachment (b) and anatomical recovery of the foveal retina during the time course (C, D, b– d). Corrected visual acuity improved from 20/32 (pretreatment) to 20/16 (24 months). Optical coherence tomography scan length, 2.83 mm (a– c) and 5.00 mm (d).
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Figure 2. Fundus photographs and optical coherence tomography (OCT) images of a stage 2 macular hole before (A, a) and 1 day (a=), 2 days (a==), and 7 days (B, b) after intravitreous injection of expansile gas. The detachment of the posterior cortical vitreous was induced, and the hole progressed to stage 4. One month after the intravitreous gas injection, the patient was treated by subsequent vitrectomy. An anatomical closure of the hole was demonstrated by fundus photographs and OCT images documented at 1 month (C, c) and 18 months (D, d). Corrected visual acuity improved from 20/100 (pretreatment) to 20/20 (18 months). Optical coherence tomography scan length, 5.00 mm (a– d).
Surgical Procedure A topical anesthetic was applied, after which a lid speculum was placed. The ocular surface was prepared with a drop of 5% povidone–iodine solution (Isodine, Meiji Seika Kaisha, Tokyo, Japan) in a standard fashion. A subconjunctival injection of 2% xylocaine immediately overlying the site of planned injection was administered before each procedure. A transcleral intravitreous
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injection of 0.5 ml of 100% sulfur hexafluoride gas drawn up through a Millipore (Billerica, MA) filter and injected through a 27-gauge needle was performed via the pars plana. Immediately after the injection, eyes were rotated to position the puncture wound posteriorly to avoid leakage of injected gas. Anterior chamber paracentesis or IV infusion with acetazolamide was performed if pulsation of the central retinal artery was induced by intraocular pressure (IOP) increase. The IOP was measured by applanation to
Mori et al 䡠 Pneumatic Macular Hole Treatment be below 30 mmHg, and pulsation of the central retinal artery was noted to be absent before discharge of the patient. The patients were asked to keep their head in a prone position for as much time as possible during the 3 to 5 days after the procedure. By day 7, the sulfur hexafluoride gas bubble was completely absorbed. If the hole remained open after this procedure, the patient was scheduled for vitreous surgery on the next available date. All patients who underwent subsequent vitreous surgery did so no later than 1 month after gas injection. The surgical procedure included phacoemulsification, intraocular lens implantation, 3-port pars plana vitrectomy (removal of the vitreous), and air/gas tamponade without internal limiting membrane peeling.
Results Morphological and Functional Outcomes Posterior cortical vitreous adherent to the foveal surface of the retina was delineated by OCT in all cases before treatment. Two weeks after injection of gas, an absence of vitreomacular attachment was evident in 19 of 20 eyes (95%) on clinical examination (biomicroscopy and ophthalmoscopy) and was confirmed by OCT in all 19 cases (95%). In 10 cases (50%), intravitreous injection of gas alone resulted in anatomical closure of the macular hole. In 1 of the remaining 10 eyes (10%), a stage 2 hole remained (Fig 1). In the 9 remaining eyes (45%), macular hole progressed to stage 4 (Fig 2). All 10 cases in which anatomical success was not achieved by intraocular gas injection alone then underwent vitreous surgery. All 10 of these macular holes were closed successfully with a single surgical procedure. Logarithm of the minimum angle of resolution (logMAR) vision improved from 0.195⫾0.148 to 0.015⫾0.115 in eyes treated by intravitreous gas injection alone (P ⫽ 0.012). Postoperative logMAR vision in eyes treated by both intravitreous gas injection and subsequent vitrectomy was 0.361⫾0.389. Although the trend was towards improved vision, the numbers did not reach statistical significance as compared with pretreatment vision (0.56⫾0.158, P ⫽ 0.133) (Tables 1, 2).
Table 3. Baseline Factors Related to Anatomical Hole Closure after Intravitreous Gas Injection Hole Status Baseline Factors
Closed
Open
P
Age 63.9⫾8.2 65.0⫾7.2 0.753 Gender (male/female) 4/6 2/8 0.314 Duration of symptoms (mos) 2.3⫾1.8 1.1⫾0.3 0.072 Hole diameter (m) 223⫾144 537⫾264 0.004* Pretreatment logMAR 0.195⫾0.148 0.560⫾0.158 4.5⫻10⫺5* logMAR ⫽ logarithm of the minimum angle of resolution. Data are n or mean ⫾ standard deviation. *Significant.
alone (P ⫽ 0.004; 233⫾144 m and 537⫾264 m, respectively). Of the 20 eyes treated, 7 had holes ⬍ 200 m, 3 had holes 200 to 300 m, 2 had holes 300 to 400 m, 2 had holes 400 to 600 m, and 6 had holes ⬎ 600 m. Hole closure was achieved in 6 of 7 eyes (86%) when the hole was smaller than 200 m, in 8 of 10 holes (80%) when the hole was smaller than 300 m, in 9 of 12 holes (75%) when the hole was smaller than 400 m, and in 10 of 14 holes (71%) when the hole was smaller than 600 m. There was also a significant difference in pretreatment logMAR vision between eyes closed and eyes not closed with gas injection alone (P ⫽ 4.5⫻10⫺5; 0.195⫾0.148 and 0.560⫾0.158, respectively). Hole closure by gas injection alone was achieved in 7 of 7 eyes (100%) with pretreatment vision better than 20/40, in 9 of 12 holes (75%) with vision better than 20/60, and in 10 of 15 holes (67%) with vision better than 20/80 (Table 3, Fig 3).
Baseline Factors Related to Anatomical Hole Closure after Intravitreous Gas Injection Alone Pretreatment factors including age, gender, duration of symptoms, hole diameter, and pretreatment vision were analyzed for association with anatomical hole closure after intravitreous gas injection alone. There was a significant difference in hole diameter between eyes that were successfully closed and eyes that did not close after gas injection Table 2. Anatomical and Functional Outcomes after Treatment Hole closure by intravitreous gas injection alone Posterior cortical vitreous detachment Final hole closure Visual outcome of eyes treated by gas injection alone Pretreatment logMAR Final logMAR Visual outcome of eyes treated by gas injection and subsequent vitrectomy Pretreatment logMAR Final logMAR
10/20 (50%) 19/20 (95%) 20/20 (100%) 0.195⫾0.148 0.015⫾0.115, P ⫽ 0.012* 0.560⫾0.158 0.361⫾0.389, P ⫽ 0.133
logMAR ⫽ logarithm of the minimum angle of resolution. Data are n (%) or mean ⫾ standard deviation. *Significant.
Figure 3. Correlation of hole diameter and pretreatment corrected vision to anatomical closure of the hole by intravitreous gas injection alone. White bars, patients successfully treated by gas injection; gray bars, patients with holes not closed by gas injection. Data are n (%).
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Ophthalmology Volume 114, Number 1, January 2007 Adverse Events In the 10 patients with macular hole closure after gas injection alone, there were no reported complications during the study period. There was specifically no progression of nuclear sclerosis requiring cataract surgery or manifestation of lens injury. There was no RPE alteration, retinal break, RD, intraocular hemorrhage, reopening of the hole, CME, epiretinal membrane, choroidal neovascularization, endophthalmitis, or symptomatic VF defects. Moreover, there were no reported complications during the interval between intravitreous gas injection and vitrectomy in the remaining 10 patients treated by both expansile gas injection and vitrectomy. The 10 patients requiring vitreous surgery underwent routine and uncomplicated procedures.
Discussion In this study, we provide evidence that an intravitreous injection of an expansile concentration (100%) of sulfur hexafluoride gas (0.5 ml) will induce detachment of the posterior vitreous in the majority of aged eyes. In the setting of a stage 2 macular hole, long-term anatomical closure results in roughly half of the injected cases. The use of intravitreous sulfur hexafluoride gas alone does not appear to affect the likelihood of subsequent success with conventional MHS significantly, and no complications resulted from the injection of intravitreous gas alone in this series of 20 consecutive patients. The success rates for posterior cortical vitreous detachment and hole closure were 95% and 50%, respectively, which are consistent with a previous report by Chan et al, who evaluated six stage 2 eyes in their series of primarily stage 1 macular holes.18 We find that successful closure of macular holes occurs with significantly higher frequency in smaller holes (P ⫽ 0.004) and holes associated with better pretreatment vision (P ⫽ 4.5⫻10⫺5). In this series, rates of hole closure were 100% in eyes with corrected vision better than 20/40 and 86% in eyes with holes smaller than 200 m. These data suggest that clinical application of this technique to stage 2 holes, with vision better than 20/40 or ⬍200-m greatest diameter, may provide efficacy comparable to that of standard surgical approaches. The morbidity of gas injection alone, as compared with surgery plus gas injection, would be expected to be lower over time, as would the overall impact of the procedure on the patient. The cost of gas injection alone is less than surgery, and no apparent significant detrimental effect on subsequent surgical procedures is evident from this small series. Because 0.5 ml of sulfur hexafluoride gas was used in this study, our patients were asked to keep their heads in a prone position for no fewer than 3 days and no more than 5 days. Chan et al have reported use of 0.3 to 0.5 ml of 100% perfluoropropane, with the majority of patients positioning for 4 to 6 weeks.18 There is no difference in success rates for either posterior cortical vitreous detachment (18/19 vs. 19/ 20) or stage 2 hole closure (3/6 vs. 10/20) between Chan et al’s study and this one. This finding indicates that posterior vitreous detachment occurs early (during the days immediately after gas injection) rather than late (in weeks 2– 4 of intraocular gas treatment). Although patient quality-oflife measures were not used in this study, it is expected that
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such studies will reveal a benefit for the patient with regard to convenience, comfort, and complications related to intraocular surgery. A 3-day facedown positioning period is also supported by the work of Krohn, who found that 3 days was sufficient to achieve closure of even longstanding macular holes, when compared with 7 days of facedown positioning.19 With full consideration for the limitations of the procedure, we believe that there may be a patient care advantage for selected individuals with stage 2 macular holes. Efforts to reduce complications related to a given surgical procedure are a constant motivating force for continued innovation. In the case of MHS, the reported incidence of complications justifies further effort in this area.15–17 To this end, Spaide has designed a new instrument to incise the vitreomacular interface during MHS, thus requiring only limited vitrectomy. Three cases are reported.20 In this study of pneumatic treatment for macular hole, there were no major complications, such as significant nuclear sclerosis progression requiring cataract surgery, lens injury, RPE alteration, retinal breaks and/or detachment, intraocular hemorrhage, reopening of the hole, CME, epiretinal membrane, choroidal neovascularization, endophthalmitis, or new VF defects. Based on current experience with large numbers of intraocular injections of triamcinolone acetonide, pegaptanib, bevacizumab, and ranibizumab for the treatment of ocular neovascularization and macular edema, we expect that the full spectrum of complications will occur with increasing use and that they will be at a comparatively low rate. New retinal breaks have been reported to occur in 13% of 1274 eyes evaluated in a review article summarizing 26 series reports on the use of pneumatic retinopexy.21 Although available numbers are small, our series (20 cases) and Chan et al’s (18 cases)18 resulted in no new retinal break formation. It is possible that the predisposition for retinal break formation may be higher in eyes with existing RD than in eyes with a macular hole. Certainly, further study would be required to validate this point. In conclusion, a pneumatic approach to the treatment of stage 2 macular hole may have merit in selected cases. The stage 2 holes achieving anatomical success in this study included holes that were smaller (⬍200 m) and holes with better vision (better than 20/40). Advantages of this procedure as compared with current surgical approaches may include ease of the procedure, limited invasiveness, increased convenience, short-term prone positioning, the potential for reduced morbidity, and the apparent lack of detrimental effect on subsequent procedures. A potential cost savings is present for those patients who respond favorably to this approach. Although further study is indicated, the data presented here support a limited role for pneumatic macular hole repair.
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