Abstract
Purpose.:
To analyze differences in ultra-widefield fluorescein angiography (UWFFA) findings between patients with recurrent postvitrectomy diabetic vitreous hemorrhage (PVDVH) and patients with non-PVDVH (NPVDVH).
Methods.:
Patients were categorized as PVDVH when vitreous hemorrhage recurred after diabetic vitrectomy. Age-matched control diabetic patients in whom vitreous hemorrhage did not recur after vitrectomy were assigned to the NPVDVH group. Baseline characteristics were compared between groups. Also peripheral angiographic findings such as peripheral neovascularization, nonperfusion, and late peripheral vascular leakage were analyzed by UWFFA.
Results.:
A total of 46 eyes were included this retrospective study: 22 with PVDVH and 24 with NPVDVH. Preoperative, 3-month postoperative, and final-visit best corrected visual acuity (BCVA) were not different between the two groups. The rate of peripheral neovascularization was significantly different (PVDVH 40.9%, NPVDVH 8.3%, P = 0.010). The rate of peripheral nonperfusion was significantly greater in PVDVH eyes than in NPVDVH eyes (81.8% vs. 37.5%, P = 0.002). The rate of late peripheral vascular leakage was also significantly greater in PVDVH eyes (90.9% vs. 29.2%, P < 0.001). These differences in peripheral angiographic findings were not seen within the conventional Early Treatment Diabetic Retinopathy Study (ETDRS) 7 standard fields. Ischemic index was also significantly higher in the PVDVH group than in the NVDVH group.
Conclusions.:
Compared with diabetic vitrectomized eyes that did not have recurring vitreous hemorrhage, PVDVH eyes had a higher rate of peripheral neovascularization, nonperfusion, and late peripheral vascular leakage. These differences were not found within the conventional ETDRS 7 standard fields. Therefore, it is important to assess peripheral retinal vessels by UWFFA after diabetic vitrectomy. Furthermore, in cases of peripheral neovascularization, peripheral nonperfusion, and late peripheral vascular leakage, additional treatment may be necessary to prevent PVDVH.
A retrospective review was conducted of all patients who underwent vitrectomy for diabetic vitreous hemorrhage at Asan Medical Center in Seoul, Korea, from January 2007 through October 2013. Inclusion criteria were as follows: (1) three-port pars plana vitrectomy for diabetic vitreous hemorrhage or tractional retinal detachment, with or without cataract surgery; (2) clinically significant PVDVH after a postoperative period in which the vitreous was clear; (3) panretinal photocoagulation performed before diabetic vitrectomy or during diabetic vitrectomy; (4) ultra-widefield fluorescein angiography (UWFFA) performed after PVDVH was cleared; and (5) an interval of more than 1 month between UWFFA and last intravitreal bevacizumab injection. As a control group, patients without recurrent vitreous hemorrhage after three-port pars plana vitrectomy for diabetic vitreous hemorrhage or tractional retinal detachment were also included in this study. Exclusion criteria included other ocular disease that might affect vision, active intraocular inflammation and/or infection, or recurrent vitreous hemorrhage caused by trauma. The study was approved by the Institutional Review Board of Asan Medical Center and followed the tenets of the Declaration of Helsinki.
Postvitrectomy diabetic vitreous hemorrhage was defined as occurring in eyes with recurrent vitreous hemorrhage after diabetic vitrectomy. Non-PVDVH was defined as occurring in eyes with no episode of recurrent vitreous hemorrhage after diabetic vitrectomy.
The Kolmogorov-Smirnov test was used to determine whether the data were normally distributed. Clinical characteristics were compared between PVDVH and NPVDVH groups using the Mann-Whitney U test. Fisher's exact test or Pearson χ2 test was used to analyze the difference in peripheral retinal neovascularization, peripheral retinal nonperfusion, and late peripheral vascular leakage between the two groups. The Mann-Whitney U test was used to compare BCVA between the two groups. SPSS version 21.0 (SPSS, Inc., Chicago, IL, USA) was used for all analyses, and a P value < 0.05 was considered statistically significant.
The etiology of PVDVH following successful complete vitrectomy is diverse. While advances in surgical treatment have decreased the incidence of PVDVH, it remains a serious complication for surgeons and patients. Determining the exact cause of PVDVH is important for the treatment and prevention of recurrent PVDVH. Many studies have reported that fibrovascular proliferation at the sclerotomy site is the main cause of PVDVH. Hershberger et al.
8 reported that 85% of PVDVH eyes had fibrovascular ingrowth at the sclerotomy site. Using UWFFA, peripheral retinal fluorescein angiographic images can be obtained. Several studies have reported the peripheral fluorescein angiographic findings for various diseases.
10–15 However, little is known about ultra-widefield fluorescein angiographic findings of PVDVH eyes. In this study, we analyzed the difference in peripheral fluorescein angiographic findings between PVDVH and NPVDVH patients.
Our current results show that the rates of peripheral retinal neovascularization, peripheral nonperfusion, and late peripheral vascular leakage were significantly greater in PVDVH eyes than in NPVDVH eyes. However, those differences were not found within the conventional ETDRS 7 fields.
Figure 3 shows the UWFFA of PVDVH eyes overlaid by the conventional EDTRS 7 field template; multiple instances of nonperfusion and late peripheral vascular leakage were found anterior to the conventional ETDRS 7 fields. We thought that the underlying cause of PVDVH might be peripheral retinal neovascularization if it was found on UWFFA. However, if peripheral retinal neovascularization was not found on UWFFA, the underlying cause of PVDVH might be related to fibrovascular ingrowth at the sclerotomy site or peripheral retinal neovascularization beyond UWFFA.
Oliver and Schwartz
17 reported that untreated peripheral nonperfusion and late peripheral vascular leakage detected using UWFFA are associated with retinal neovascularization in diabetic retinopathy. They suggested that upregulation of vascular endothelial growth factor (VEGF), which promotes capillary hyperpermeability, may result in late peripheral vascular leakage. Therefore, they hypothesized that late peripheral vascular leakage could be a marker for active diabetic retinopathy and may be a sensitive marker of ischemia in diabetic retinopathy.
17 Furthermore, Funatsu et al.
21 reported that high vitreous levels of VEGF are a significant risk factor for poor outcome of vitreous surgery in patients with PDR.
After diabetic vitrectomy, the higher VEGF concentration in the vitreous cavity may induce peripheral retinal neovascularization or fibrovascular proliferation at the sclerotomy site, and the induced peripheral retinal neovascularization or fibrovascular proliferation at the sclerotomy site may contribute to the development of PVDVH. In our present report, a higher rate of peripheral nonperfusion and late peripheral vascular leakage was observed in eyes with PVDVH. As previously mentioned, these peripheral angiographic findings may reflect a higher level of VEGF in the vitreous cavity and retinal ischemia. Therefore, a higher rate of peripheral nonperfusion and late peripheral vascular leakage in UWFFA may be associated with PVDVH.
Aiello et al.
22 reported that the VEGF concentration in vitreous fluid declines after successful laser photocoagulation. If upregulated VEGF levels are a causative factor for PVDVH, we hypothesized that additional peripheral laser photocoagulation or intravitreal bevacizumab maintenance treatment to diabetic vitrectomized eyes with peripheral fluorescein angiographic findings may result in mitigating VEGF upregulation. This would eventually prevent the development of PVDVH. In fact, in our present analyses, of 18 eyes that received intravitreal bevacizumab maintenance treatment for PVDVH, only three eyes (16.7%) developed recurrence of vitreous hemorrhage. And among 10 eyes that received additional panretinal photocoagulation after UWFFA, only one eye (10.0%) developed recurrence of vitreous hemorrhage. However, future prospective studies are needed to determine the exact preventive effect of laser and bevacizumab maintenance treatment on recurrent vitreous hemorrhage in eyes with peripheral nonperfusion and late peripheral vascular leakage.
All eyes were treated by intravitreal bevacizumab injection for PVDVH. Mean time to UWFFA after the last bevacizumab injection was 2.77 ± 2.31 months (range, 1–8 months). We analyzed whether the interval between UWFFA and the last intravitreal bevacizumab injection had an effect on ultra-widefield fluorescein angiographic findings of PVDVH eyes. As the retinal new vessel was regressed 2.9 months after intravitreal bevacizumab injection (Schmidinger et al.
23), we divided patients into two groups according to the interval between the last intravitreal bevacizumab injection and UWFFA: a <3-month group and a ≥3-month group. Similarly to previous findings (Schmidinger et al.
23), peripheral retinal neovascularization slightly regressed within 3 months after intravitreal bevacizumab injection (peripheral retinal neovascularization; less than 3 months = 35.7%, more than 3 months = 50.0%). However, we did not see statistically significant differences in the peripheral angiographic findings between the two groups. Therefore, we assumed that intravitreal bevacizumab injection does not change the peripheral fluorescein angiographic findings for PVDVH eyes at 1 month after injection. However, future studies with larger numbers of patients are needed to confirm the influence of bevacizumab on peripheral angiographic findings of PVDVH eyes.
Finally, we investigated whether PVDVH has an effect on patients' final vision. Mason et al.
24 reported that vitreous hemorrhage after diabetic vitrectomy appears to be a risk factor for light perception only and no light perception vision following diabetic vitrectomy. However, Tolentino et al.
25 have reported that postdiabetic vitrectomy hemorrhage did not significantly influence final visual outcome in their patients, and Shi and Huang
26 reported that with surgical and nonsurgical treatments, visual acuity increased in 86% of the PVDVH eyes. We compared the BCVA between PVDVH and NPVDVH eyes preoperatively, 3 months after vitrectomy, and at the last visit. In contrast to the findings by Mason et al.,
24 the BCVA preoperatively, 3 months postoperatively, and at the final visit did not differ between our two study groups. Therefore, we thought that prompt treatment of PVDVH with intravitreal bevacizumab injection or maintenance therapy of intravitreal bevacizumab or additional panretinal photocoagulation may improve visual prognosis of PVDVH patients.
The strength of our current study is that ultra-widefield fluorescein angiographic images were carefully analyzed by retinal subspecialists (DYK, YJK, and JGK) who were masked to the clinical information of the patients. In addition, this is the first report to analyze ultra-widefield fluorescein angiographic findings of PVDVH eyes. However, our study has limitations that are inherent to its retrospective design. The sample size of this study was also relatively small, which may have limited the statistical strength of the analysis. Therefore, future studies examining a larger number of patients are needed to confirm our ultra-widefield fluorescein angiographic findings of PVDVH.
In conclusion, compared with diabetic vitrectomized eyes in which vitreous hemorrhage not recur after diabetic vitrectomy, PVDVH eyes had a higher rate of peripheral neovascularization, peripheral nonperfusion, and late peripheral vascular leakage. However, these differences was not found within the conventional ETDRS 7 fields. Therefore, it is important to evaluate peripheral retinal vessels using UWFFA after diabetic vitrectomy, especially in PVDVH eyes. Furthermore, in cases of peripheral neovascularization, peripheral nonperfusion, and late peripheral vascular leakage, additional treatment such as peripheral laser photocoagulation and intravitreal bevacizumab injection may be necessary to prevent PVDVH.