Purpose
To evaluate vitrectomy with subretinal tissue plasminogen activator (t-PA) injection, and air tamponade, followed by intravitreal anti–vascular endothelial growth factor (VEGF) therapy for submacular hemorrhage in polypoidal choroidal vasculopathy (PCV).
Design
Prospective, interventional case series.
Methods
setting : Two clinics. patients : Fifteen eyes of 15 consecutive patients (mean age 72 ± 7 years) with submacular hemorrhage attributable to PCV. inclusion criteria : PCV diagnosis with unorganized submacular hemorrhage greater than 500 μm thick. exclusion criteria : Submacular hemorrhage attributable to macular diseases (eg, high myopia, typical age-related macular degeneration, retinal angiomatous proliferation, and angioid streaks). intervention : Vitrectomy with 4000 IU t-PA injected subretinally and fluid/air exchange. Patients remained facedown for 3 days after surgery. Anti-VEGF drugs were administered as exudative changes required. main outcome measures : Submacular hemorrhage displacement from the macula and changes in best-corrected visual acuities (BCVAs).
Results
Mean time from onset to surgery was 9.5 ± 4.5 (range, 5–21) days. Mean follow-up period was 9.4 ± 3.1 (range, 6–17) months. Surgery successfully displaced submacular hemorrhages from the macula in all eyes. Mean BCVA at baseline (0.98 ± 0.44) had improved significantly both 1 month after surgery (0.41 ± 0.25, P < .01) and at final visits (0.23 ± 0.25, P < .001). In all eyes, exudative retinal changes relapsed after surgery but were completely resolved by anti-VEGF injections. No complications occurred in any patients.
Conclusion
Treating submacular hemorrhage with vitrectomy and subretinal t-PA injection, followed by intravitreal anti-VEGF therapy, is a promising strategy for improving visual acuity in PCV patients warranting further investigation.
Submacular hemorrhage can arise in a variety of diseases, including exudative age-related macular degeneration (AMD), retinal arterial macroaneurysm, pathologic myopia, choroidal neovascularization of various etiology, and trauma. Submacular hemorrhage causes sudden visual loss and results in a poor visual prognosis, especially when it is not appropriately treated. At present, the treatment options available for submacular hemorrhage are “nonvitrectomizing techniques,” with intravitreal injections of gas or tissue plasminogen activator (t-PA) or anti–vascular endothelial growth factor (VEGF) drugs or a combination of these, or “vitrectomizing techniques,” with injections of t-PA or anti-VEGF drugs or gas or a combination of these administered either as intravitreal or subretinal injections or by a combination of subretinal and intravitreal injections. Recently, Haupert and associates reported that the displacement of submacular hemorrhages by vitrectomy and subretinal injections of t-PA is effective in AMD patients. Furthermore, both intravitreal and subretinal injection of anti-VEGF drugs during vitrectomy and/or intravitreal injection of anti-VEGF drugs following vitrectomy have been reported to be effective in maintaining improved visual acuity.
Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy affecting vision, with a prevalence of 10%–54% in Asian patients and 8%–12% in white patients with presumed exudative AMD. Clinically, PCV is characterized by a complex choroidal vascular network with multiple, terminal, reddish-orange polypoidal lesions. Although, in general, the natural course of PCV is more stable than AMD, PCV has been shown to cause occasional, massive submacular hemorrhages, which eventually results in chorioretinal atrophy and permanent vision loss.
Previously, in PCV patients, we have reported the therapeutic effect of surgically removing submacular hemorrhages by retinotomy and the use of t-PA. Since the liquefaction of submacular hemorrhages by the subretinal injection of t-PA and the displacement of submacular hemorrhages by vitrectomy with air tamponade is a simpler and safer surgical procedure than retinotomy with mechanical submacular hemorrhage removal, we have investigated the therapeutic effect and safety of this procedure for submacular hemorrhage displacement in PCV patients. In addition, we have investigated the therapeutic effect of anti-VEGF therapy following surgery.
Methods
Study Design and Patients
This study was a prospective, interventional case series and all investigations adhered to the tenets of the Declaration of Helsinki. Each patient was informed about the risks and benefits of the surgery and participation in this research study. Their written informed consent for both the surgery and participation in this research study was obtained. The study was approved by the Institutional Review Boards of Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences and Inoue Eye Clinic.
Fifteen eyes of 15 consecutive patients who were diagnosed with submacular hemorrhage attributable to PCV between January 8, 2012 and February 15, 2014 were recruited to the study. Diagnosis of PCV was based on both the presence of elevated orange-red lesions observed at fundus examination and the presence of characteristic polypoidal vascular lesions by indocyanine green angiography (ICGA). The size of the submacular hemorrhage was recorded as the greatest linear dimension. The inclusion criteria used were: (1) submacular hemorrhage attributable to PCV, (2) the presence of submacular hemorrhage with a thickness greater than 500 μm, as measured by optical coherence tomography (OCT), and (3) unorganized submacular hemorrhage, as determined by fundus examination, in contrast to organized submacular hemorrhages, which we considered as white and/or fibrous in appearance. Patients with submacular hemorrhage attributable to other macular diseases, such as high myopia, typical AMD, retinal angiomatous proliferation, and angioid streaks, were excluded.
The patients’ demographic data are shown in the Table . The 1 female and 14 male patients had a mean age (±SD) of 72 ± 7 years, with a range of 61–84 years. The time from onset to surgery was 9.5 ± 4.5 days (range, 2–21 days), the mean diameter of submacular hemorrhages was 5.6 ± 4.7 disc diameters (range, 1.5–20 disc diameters), and the mean thickness of submacular hemorrhages was 793 ± 312 μm (range, 504–1422 μm). Six eyes were pseudophakic preoperatively and all 15 eyes were pseudophakic postoperatively. The mean follow-up period was 9.4 ± 3.1 months (range, 6–17 months). The mean number of anti-VEGF injections was 3.5 ± 1.9 (range, 1–7). No complications occurred during or after surgery in any patients.
| Case No. | Sex | Age (y) | Disease Duration (d) | Lesion Size (Disc Diameter) | Lens Status | BCVA (logMAR) | Ellipsoid Line at the Final Visit | Follow-up (mo) | Postoperative Anti-VEGF Therapy | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Pre | 1 Month | Final | Reagents (No. of Treatments) | ||||||||
| 1 | Male | 75 | 6 | 10 | Phakic | 1.22 | 0.70 | 0.10 | + | 17 | Ranibizumab (5) |
| 2 | Male | 62 | 2 | 6 | Pseudophakic | 0.52 | 0.15 | 0.10 | − | 13 | Aflibercept (6) |
| 3 | Male | 78 | 7 | 8 | Pseudophakic | 1.30 | 0.40 | 0.22 | + | 12 | Aflibercept (1) |
| 4 | Male | 67 | 9 | 2 | Pseudophakic | 1.22 | 1.05 | 1.05 | − | 12 | Aflibercept (5) |
| 5 | Male | 80 | 12 | 6 | Pseudophakic | 1.52 | 0.52 | 0.22 | + | 12 | Aflibercept (7) |
| 6 | Female | 84 | 10 | 1.5 | Phakic | 1.00 | 0.15 | 0.22 | + | 10 | Aflibercept (2) |
| 7 | Male | 70 | 8 | 20 | Phakic | 0.70 | 0.22 | 0.05 | + | 9 | Aflibercept (6) |
| 8 | Male | 73 | 7 | 2.5 | Phakic | 1.10 | 0.30 | 0.05 | + | 9 | Ranibizumab (3) |
| 9 | Male | 77 | 21 | 5 | Phakic | 2.00 | 0.30 | 0.15 | + | 8 | Aflibercept (1) |
| 10 | Male | 62 | 15 | 3 | Pseudophakic | 1.00 | 0.52 | 0.15 | + | 8 | Aflibercept (3) |
| 11 | Male | 66 | 10 | 3 | Phakic | 0.52 | 0.30 | −0.08 | + | 7 | Ranibizumab (1) |
| 12 | Male | 73 | 14 | 1.5 | Phakic | 1.00 | 0.52 | 0.40 | − | 6 | Aflibercept (3) |
| 13 | Male | 61 | 5 | 3 | Phakic | 0.30 | 0.22 | 0.10 | + | 6 | Aflibercept (2) |
| 14 | Male | 79 | 7 | 3.5 | Phakic | 0.82 | 0.70 | 0.40 | − | 6 | Aflibercept (3) |
| 15 | Male | 71 | 10 | 10 | Pseudophakic | 0.40 | 0.15 | −0.08 | + | 6 | Aflibercept (4) |
All patients underwent comprehensive ophthalmologic examinations before and after surgery, including measurement of best-corrected visual acuity (BCVA) with refraction, using the 5-m Landolt C acuity chart, and indirect and contact lens slit-lamp biomicroscopy. All eyes were examined by spectral-domain optical coherence tomography (SD OCT) before and after surgery and at follow-up, using commercially available instruments (Cirrus; Carl Zeiss Meditec, Inc, Dublin, California, USA; Spectralis; Heidelberg Engineering GmbH, Heidelberg, Germany; and DRI OCT-1 Atlantis; Topcon Medical Systems, Tokyo, Japan).
The main outcome measures were displacement of the submacular hemorrhage from the macula in OCT images and differences between preoperative and postoperative BCVAs.
Surgical Technique
The submacular hemorrhage displacement was carried out using a surgical procedure inspired by the report by Haupert and associates. Briefly, after a 25 gauge microincision vitrectomy was performed, 4000 IU t-PA (Cliactor, Eizai, Japan) in 0.1 mL was injected subretinally using a 38 gauge subretinal infusion needle (MedOne, Sarasota, Florida, USA) to liquefy the submacular hemorrhage, which was 14%–28% of the doses previously used. Before finishing the operation, fluid-air exchange was performed to displace the submacular hemorrhage. The patients remained facedown for 3 days after surgery. In 9 phakic eyes, phacoemulsifications with implantation of an intraocular lens were carried out simultaneously. All surgeries were performed by the same surgeon (F.S.).
Postoperative Anti–Vascular Endothelial Growth Factor Therapy
Intravitreal injections of anti-VEGF reagents were performed pro re nata (PRN) when exudative and/or hemorrhagic changes, such as the accumulation of subretinal fluid and recurrence of submacular hemorrhage, occurred after surgery. We used either 0.5 mg ranibizumab (Lucentis; Genentech, Inc, South San Francisco, California, USA) or 0.5 mg aflibercept (Eylea; Bayer, Basel, Switzerland).
Data Analysis
BCVAs were recorded as decimal values and converted to the logarithm of the minimal angle of resolution (logMAR) units for statistical analysis. The preoperative, 1 month, and final postoperative BCVAs were compared using the Mann-Whitney U test. P values less than .05 were considered significant. All statistical analyses were performed using SPSS for Windows version 17.0 (SPSS, Inc, Chicago, Illinois, USA). Data are presented as means ± standard deviation (SD).
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