SURGICAL OUTCOMES OF FLORID DIABETIC RETINOPATHY TREATED WITH ANTIVASCULAR ENDOTHELIAL GROWTH FACTOR AUDE COUTURIER, MD,* BÉNÉDICTE DUPAS, MD,* JEAN-LAURENT GUYOMARD, MD,† PASCALE MASSIN, MD, PHD* Purpose: To evaluate the effectiveness of vitreoretinal surgery combined with antivascular endothelial growth factor therapy to treat florid diabetic retinopathy, a rare and severe form of diabetic retinopathy in young patients. Methods: Retrospective observational case series including 61 eyes of 45 patients operated on for florid diabetic retinopathy over the past 5 years, with preoperative or intraoperative intravitreal injection of bevacizumab. Cases were classified into three stages of disease severity, according to the extension of the fibrovascular membranes. Main outcome measures were mean change in visual acuity, anatomical outcome, and surgical complications. Results: After a mean follow-up of 20.3 months, the mean visual acuity significantly increased from +1.7 logMAR before surgery to +0.8 logMAR after surgery (P , 0.01). The visual gain was significant in Stages I and II (P , 0.05) but not significant in Stage III. A flat retina without silicone oil was achieved in 84% of eyes. Eight eyes (13%) progressed to neovascular glaucoma and/or phthisis despite repeated surgeries. Conclusion: Vitrectomy combined with antivascular endothelial growth factor therapy allows both favorable visual and anatomical outcomes in this rapidly evolving disease. Prognosis remains poor in severe stages, suggesting that the earlier the surgery performed, the better is the visual prognosis. RETINA 34:1952–1959, 2014
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reduces the postoperative bleeding.3–7 Florid diabetic retinopathy (FDR) is a serious but rare form of DR occurring in young diabetic patients with poor metabolic control.8–10 Its main clinical characteristics have been defined by Kohner et al8 in 1976: it occurs in patients with Type I diabetes, aged ,40 years, presenting with a documented history of rapid DR progression, from no retinal lesions or nonproliferative DR to either high-risk or complicated proliferative DR in ,6 months.11,12 The prognosis remains poor with high risk of tractional retinal detachment (RD), neovascular glaucoma (NVG), or anterior hyaloidal fibrovascular proliferation (AFVP), leading to blindness.13 Despite early and intensive pan-retinal laser photocoagulation (PRP), pars plana vitrectomy may also be required, but the surgical management remains difficult and may lead to visual loss.9 Intravitreal bevacizumab (IVB) injection seems of interest for these severe proliferative retinopathies because it facilitates the dissection of proliferative tissues, reduces the
he surgical management of late complications of proliferative diabetic retinopathy (DR) remains complex and challenging. However, both anatomical and visual outcomes are constantly improving since the Diabetic Retinopathy Vitrectomy Study (DRVS) has been published,1 given the progress in surgical instruments used for vitreoretinal surgery and the use of intravitreal antivascular endothelial growth factor (VEGF) agents such as bevacizumab (Avastin).2 When administered preoperatively, the latter facilitates the surgical dissection of proliferative membranes and From the *Department of Ophthalmology, APHP, University of Denis Diderot, Paris, France; and †Department of Ophthalmology, University Hospital of Rennes, Rennes, France. Paper presented at Société Française d’Ophtalmologie, May 2012, Paris, France. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Pascale Massin, MD, PhD, Service d’Ophtalmologie, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, France; e-mail: [email protected]
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intraoperative bleeding, and also could reduce the postoperative risk of AFVP. The purpose of this study was to evaluate the effectiveness of vitrectomy combined with intravitreal injection of bevacizumab in a large consecutive series of patients with this rare and severe form of DR. Methods Participants The records of patients with FDR, who had undergone surgery in our institution performed by the same surgeon between 2006 and 2011, were retrospectively reviewed. This study has been approved by the Ethics Committee of the French Society of Ophthalmology (IRB 00008855 Societe Française d’Ophtalmologie IRB#1). The inclusion criteria for patients were those defined by Kohner et al8 (i.e., Type I diabetes, aged ,40 years, documented history of rapid progression of DR in ,6 months), and patients should have undergone surgery for one of the following complications: tractional RD involving or threatening the macula, combined tractional and rhegmatogenous RD, rapid onset of fibrovascular proliferations (FVP) despite PRP with or without extramacular tractional RD, vitreous hemorrhage without spontaneous clearing, or recurrent vitreous hemorrhage. All patients received IVB injection (1.25 mg/0.05 mL) preoperatively or intraoperatively. The exclusion criteria were patients with Type II diabetes and history of vitrectomy. Data Data collected included baseline demographics (gender, mean duration of diabetes, hemoglobin A1c, blood
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pressure, nephropathy) and ocular findings (initial and final best-corrected visual acuity [BCVA], postoperative status of the retina, the use of tamponade, preoperative and postoperative complications: retinal tears, recurrence of RD, progression to NVG). Additional information included indication for the procedure, the presence of previous PRP, surgical techniques used, the time of IVB injection, and duration of the follow-up. Cases were classified into three stages of disease severity, according to the location and extension of the FVP. This classification was based on the clinical examination and fundus photography, and when not assessable preoperatively, on surgical findings. In Stage I, FVP was located at the posterior pole, along the vascular arcades and posterior to the equator (Figure 1). In Stage II, FVP extended beyond the equator (Figure 2). Stage III was defined by the presence of AFVP and/or rubeosis iridis (Figure 3). Anterior hyaloidal fibrovascular proliferation was characterized by FVP originating from the anterior retina and extending along the anterior hyaloid. Surgery Pars plana vitrectomy was performed using a standard 20-gauge 3-port system or a sutureless 23-gauge system with a chandelier lighting as follows: central vitrectomy and opening of the posterior hyaloid, then dissection of the vitreoretinal FVP with the vitreous probe, or with a bimanual technique of delamination, using forceps and scissors. Peripheral shaving of the vitreous base was then performed with indentation. Visualization during surgery was obtained using the Quadrasphéric or Volk MiniQuad lens wide-angle contact system (Volk Optical, Mentor, OH) and flat and prismatic Landers lenses (Ocular Instruments, Bellevue,WA).
Fig. 1. A. The left eye of a 35-year-old man, presenting with Stage I FDR. Preoperative color montage showing FVP at the posterior pole and vitreous hemorrhage. B. The right eye of a 36-year-old woman presenting with Stage I FDR. Preoperative color montage showing vitreous hemorrhage and a large FVP located behind the equator.
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Fig. 2. A and B. The right eye of a 25-year-old man presenting with Stage II FDR. A. Preoperative color montage showing that the FVP extended beyond the equator and caused tractional RD threatening the macula. The visual acuity was 20/320 Snellen equivalent. B. Postoperative color montage 2 months after 2 procedures. The first procedure consisted of vitrectomy with FVP dissection, endolaser, and silicone oil tamponade and was combined with IVB 7 days ago. The second procedure was limited to silicone oil removal combined with IVB. The visual acuity improved to 20/20 and remained stable during a 31month follow-up. C and D. The left eye of a 29-year-old woman who had undergone surgery for Stage II FDR. C. Preoperative color montage showing an extensive FVP covering the posterior pole. The visual acuity was limited to counting fingers. D. Postoperative color photography of the posterior pole showing complete flattening of the retina under silicone oil 4 months after 2 procedures. The visual acuity improved to 20/250. Ten months later, the fundus and visual acuity remained stable after silicone oil ablation.
An extensive pan-retinal endophotocoagulation extending up to the ora serrata was performed, as well as photocoagulation around the retinal breaks; preoperative phakoemulsification was performed when needed (in case of major lens opacities or AFVP requiring
dissection). Retinectomy was performed in case of extensive AFVP. Expandable gases were used as tamponade when retinal breaks were observed. Silicone oil tamponade was indicated in Stages II and III eyes associated with multiple or inferior tears, when retinectomy
Fig. 3. A. The right eye of a 30-year-old man presenting with Stage III FDR. Preoperative color montage showing that the AFVP led to a tabletop RD. He had undergone vitrectomy with FVP dissection, endolaser, and silicone oil tamponade, combined with IVB 7 days before surgery. Visual acuity was limited to hand motion. No functional improvement was observed after surgery, and he progressed to NVG. B and C. The left eye of a 28-year-old woman who had undergone surgery for Stage III FDR. B. Preoperative color montage showing retrohyaloidal hemorrhage and extensive FVP extended toward the inferotemporal periphery. This FVP was associated with rubeosis iridis. The visual acuity was reduced to counting fingers. C. Postoperative color montage 3 months after a second surgery for silicone oil removal. The visual acuity improved to 20/125 and remained stable during a 26-month follow-up.
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was carried out, or for visual purpose in monocular patients. Silicone oil removal was usually combined with IVB injection. Intravitreal bevacizumab was injected during the surgery, at the end of the procedure, in the less severe cases, mainly Stage I. In these cases, the operator did not expect to experience major difficulties when dissecting the proliferative tissues so that the injection was only carried out at the end of the procedure, to reduce postoperative complications such as postvitrectomy hemorrhage and AFVP. In the cases with severe and extensive FVP, mainly Stages II and III, the injection was carried out preoperatively to facilitate the surgical procedure (the reduction of bleeding and easier dissection of fibrovascular tissues), whereas maintaining the benefits of reduced postoperative complications as previously described. A very close postoperative follow-up was performed (weekly for the first month, then monthly for 3 months) to carefully detect any potential complication including NVG, rubeosis iridis, and/or AVFP. Outcome Measures The primary endpoint was to measure the mean change in BCVA at the end of follow-up. Secondary endpoints were to measure the following: 1) the anatomical outcome (the anatomical success was defined by a flat retina without tamponade at the end of followup); 2) the mean number of surgeries underwent per eyes; and 3) the number of surgical complications. Statistics For statistical analysis, continuous variables are presented as mean ± standard deviation. Series comparisons were made using a Student’s t-test or Wilcoxon rank test as appropriate for continuous variables, and chi-square statistics or Fisher’s exact test as appropriate for categorical variables. A P , 0.05 was considered significant. A linear regression model was used to analyze the relationship between the severity of the initial retinopathy and the number of surgeries underwent. Results A total of 61 eyes of 45 patients were studied. Patient preoperative characteristics are summarized in Table 1. Initial ocular characteristics are presented in Table 2. Before surgery, 23 eyes (38%) had RD. The macula was detached in 16 eyes (69.5% of the eyes with RD). Among these 16 detachments, 5 had a “tabletop” configuration (1 Stage II and 4 Stage III eyes) (Figure 3A). Five patients did not have pre-
vious PRP (1 Stage I, 3 Stage II, and 1 Stage III eyes). Anti-VEGF injection was performed preoperatively in 42 eyes (69%) and intraoperatively in 19 (31%). Visual and Anatomical Outcomes Visual outcomes after surgery are reported in Table 3. The mean BCVA gain was of −0.85 logMAR. The visual gain was significant in Stage I and II eyes (P , 0.05), but not in Stage III eyes. Forty-six of 61 eyes (75.4%) had a BCVA gain of at least 2 Snellen lines (80 and 83% in Stage I and II eyes, respectively, and 29% in Stage III eyes). At baseline, 24 patients (53%) were considered legally blind, that is, logMAR BCVA .+1 (Snellen Equivalent ,20/200) in the better eye. At the end of the follow-up, only 8 patients (18%) were still legally blind. At baseline, 13 patients (29%) had no ambulatory vision, defined by BCVA of at least +1.6 logMAR (,20/800, Snellen equivalent) in the better eye. Six of these patients recovered an ambulatory visual acuity at the end of the follow-up. At the end of follow-up, 24 eyes (39.3%) had BCVA $20/40, 22 eyes (36%) had BCVA between 20/40 and 20/200, and 15 (24.6%) had a final BCVA #20/200. Among the 15 eyes with the final BCVA #20/200, 5 eyes had macular ischemia, 2 had recurrent tractional RD under silicone oil, and 8 eyes progressed to NVG or phthisis. No statistical difference was found between the preoperatively and intraoperatively injected groups regarding the functional outcomes (the final visual acuity +0.92 logMAR and +0.67 logMAR, respectively, P = 0.35). Table 4 shows the anatomical outcome of surgery at the end of the follow-up. Overall, 51 eyes (84%) had an anatomical success defined as a flat retina without Table 1. Description of the Study Sample No. patients/eyes Male/female, n Age, years Mean ± SD Range Duration of diabetes, years Mean ± SD Range HBP, n (%) Nephropathy, n (%) Neuropathy, n (%) HbA1c, % Mean ± SD Range Follow-up, months Mean ± SD Range
45/61 19/26 30.8 ± 4.7 18–40 19.8 ± 5.2 11–31 18 (40) 18 (40) 8 (18) 9.40 ± 2.1 5.0–14.8 20.3 ± 15.6 6–63
HbA1c, hemoglobin A1c; HBP, high blood pressure; SD, standard deviation.
1956 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES Table 2. Ocular Status at Baseline Initial retinopathy stage, n (%) Stage I Stage II Stage III Phakic eyes, n (%) Surgical indication, n (%) Macular tractional RD Combined RD VH Rapid FVP Previous complete PRP, n (%) Previous partial PRP, n (%) No previous PRP, n (%) Preoperative IVB, all stages, n (%) Stage I Stage II Stage III Intraoperative IVB, all stages Stage I Stage II Stage III Mean duration before IVB, days Mean ± SD Range
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underwent a 23-gauge vitrectomy. Tamponade was unnecessary in 27 eyes (44%). Gas tamponade was required in 15 eyes (24.6%) and silicone oil tamponade in 19 eyes (31%). Localized retinectomy was performed in 3 eyes (5%) for AFVP. The mean number of surgeries per eye was 1.82 (1–9) for all stages. The more severe the stage, the higher the number of surgeries, mean number of surgeries was 1.56 (1–6) in Stage I eyes, 2.04 (1–4) in Stage II eyes, and 2.28 (1–6) in Stage III eyes. Eleven of 19 patients (58%) with silicone tamponade underwent definitive silicone ablation during the follow-up, combined with IVB injection at the end of the surgery in five patients. After silicone oil removal, all patients achieved an anatomical success, except one who progressed to phthisis. During the follow-up, the postoperative complications after the first surgery included: 1) Recurrence of RD in 6 eyes (10%) (2 Stage I, 3 Stage II, and 1 Stage III); 2) occurrence of AFVP in 2 Stage II eyes (3%); and 3) Recurrence of vitreous cavity hemorrhage in 22 eyes (36%). Among these 22 eyes, 7 (32%) required a deferred cavity lavage.
30 (49) 24 (39) 7 (12) 59 (97) 10 (16) 6 (10) 31 (51) 14 (23) 31 (51) 25 (40) 5 (9) 42 (69) 16 (53) 20 (83) 6 (86) 19 (31) 14 (47) 4 (17) 1 (14) 7.17 ± 0.99 4–11
SD, standard deviation.
silicone oil (93 and 88% in Stages I and II eyes, respectively, and 29% in Stage III eyes), and 8 (13%) progressed to NVG or phthisis (7 and 8% in Stage I and II eyes, respectively, and 57% in Stage III eyes). Among the five patients without previous PRP, an anatomical success was achieved in four patients whereas one progressed to phthisis. No statistical difference was found between the preoperatively and intraoperatively injected groups regarding the anatomical outcomes (anatomical success observed in 80.9% [34 of 42 eyes] and in 89.5% [17 of 19 eyes], respectively, P = 0.48).
Discussion Although many studies have already demonstrated the efficacy of this combined approach in PDR,3,4,7,14–17 especially meta-analyses of the clinical outcomes of vitrectomy with or without IVB pretreatment in patients with severe DR (in which some patients with FDR were included),18,19 our study is unique and novel because it is a dedicated analysis of a small subgroup of patients with FDR, on a large number of cases. Our results showed that a significant visual acuity improvement by 2 Snellen lines was obtained in 75% of the eyes, and that an anatomical success was achieved in 84% of the eyes, with a mean of 1.82 surgeries per eye. The favorable outcomes in this FDR series suggest that the combined approach is also effective for the treatment of this more aggressive form of the disease.
Surgery Features and Complications The mean time of IVB injection was of 7.16 days before surgery (range, 4–11 days). Pars plana vitrectomy was performed using a standard 20-gauge 3-port system in 55 eyes (90%). The 6 other eyes (10%)
Table 3. Visual Acuity Evolution Preop VA ± SD, logMAR All stages Stage I Stage II Stage III
1.7 1.5 1.7 2.16
± ± ± ±
Final VA ± SD, logMAR 0.8 0.5 ± 0.6 0.8 ± 0.9 2.2 ± 1.0
0.7 0.7 0.6 0.5
SD, standard deviation; VA, visual acuity.
P
Mean Change in VA
Gain $2 Lines, n (%)
Loss $2 Lines, n (%)
0.03 0.02 0.03 0.10
−0.856 −1.04 −0.88 −0.04
46 24 20 2
8 1 4 3
(75.4) (80) (83.3) (28.6)
(13.1) (3.3) (16.6) (42.8)
Stabilization, n (%) 7 (11.5) 5 (16.6) 0 (0) 2 (28.6)
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SURGERY FOR FLORID DIABETIC RETINOPATHY COUTURIER ET AL Table 4. Anatomical Outcomes Flat Retina Without Silicone Oil, n (%) All stages (n = 61) Stage I (n = 30) Stage II (n = 24) Stage III (n = 7)
51 28 21 2
(84) (93) (88) (29)
There are few data available in the literature on the outcomes of vitrectomy for FDR, but our results appear to be better than those in the other FDR series, which were not treated with anti-VEGF. In a Lattanzio et al11 study, 19 eyes with FDR underwent vitrectomy without anti-VEGF, and the initial and final visual acuities were both of 20/200 Snellen equivalent with a high rate of blindness (31%). In 1996, Favard et al9 published a series of 40 eyes of 20 patients with FDR of which 37 eyes (92.5%) underwent PRP and 15 (37.5%) underwent vitrectomy. In their series, the prognosis of the 15 eyes that underwent vitrectomy was poor: the final visual acuity was ,20/200 in 4 eyes (27%) (vs. 18% in our series) and $20/40 in 5 eyes (33%) (vs. 39% in our series). Among these 15 eyes treated with vitrectomy, 2 still had RD under silicone oil (13%) (vs. 3% in our series).9 The better outcomes obtained in our series could be due to a better knowledge and screening of florid diabetic retinopathy, instrumentation and surgical technique improvements, and also anti-VEGF injection effectiveness. Several reports have suggested that the IVB injected preoperatively could facilitate the surgical dissection of fibrovascular membranes in eyes with severe active proliferative retinopathy and reduce intraoperative and postoperative complications, allowing better visual acuity outcomes.3,4,7,14–17 However, since to our knowledge no study has specifically reported the surgical outcomes of patients with FDR treated with IVB injection, we also compared our results to the previous studies performed in diabetic patients with severe DR who underwent surgery in association with perioperative anti-VEGF. The rate of active progressive proliferative DR was usually lower in most studies than in ours. In a larger series of 68 eyes, Amadieh et al15 reported 10% of rapidly progressive FVP versus 23% in our series.15 Moreover, the number of Type 1 diabetic patients, who potentially had FDR, was usually low (0–20%),4,7,20 except for the DRIVE UK Study which included 58 Type I diabetic patients of 158 patients (37%).21 The anatomical success rate was similar to that observed in our series (84%) but the use of preoperative silicone tamponade was lower than that in our FDR series (4.8 vs. 31% in our study).21 The rate of visual acuity #20/200 at the end of follow-up was also lower (6.4 vs. 24.6% in our
RD Under Silicone Oil, n (%) 2 (3) 0 (0) 1 (4) 1 (14)
NVG or Phthisis, n (%) 8 2 2 4
(13) (7) (8) (57)
series).21 The severity of FDR compared with the other forms of proliferative DR could explain these results. Indeed, FDR has a poor prognosis because of the rapid FVP extension and the risk of AFVP after vitrectomy,22 as described in the different reports of the DRVS.1,23 Report 1 described the natural history and poor prognosis of the rapidly progressive proliferative DR.24 Report 2 highlighted the effectiveness of early vitrectomy for intravitreous hemorrhages in young Type 1 diabetic patients,25 and Reports 3 and 4 highlighted the effectiveness of early vitrectomy for rapid FVP.1,23 In our series, the visual prognosis of early Stages (I and II) was improved by an aggressive and appropriate surgical management, and it seems that the earlier the surgery performed, the better was the visual prognosis, confirming the results published in the DRVS Report 5.26 An anatomical success was achieved in 93% of Stage I eyes and 88% of Stage II eyes, with a better postoperative visual acuity outcome in Stage I eyes. After surgery, 67% of the patients were withdrawn from legal blindness. However, it is noteworthy that FDR requires a very close followup because of its severity and unusual rapidity of progression even postoperatively. In our series, two Stage I eyes progressed to phthisis, and these two patients did not comply with the postoperative monitoring and were lost to follow-up. Conversely, the prognosis of stage III eyes usually remains poor after surgery. In our series, an anatomical success was achieved in only 2 Stage III patients (29%), and no functional improvement was observed after surgery (the initial and final visual acuities were +2.1 and +2.2 logMAR, respectively). Preoperative rubeosis is a known poor prognosis factor27; consequently, for severe FDR (including Stage III eyes), the benefits of the surgery should be discussed because most often no visual improvement and an accelerated progression to NVG and phthisis are observed (4 of 7 Stage III eyes [57%] at the end of follow-up in this study). It was interesting to compare our series with the former FDR series, which had undergone surgery without combined anti-VEGF therapy in our institution between 1991 and 2002 and consisted of 53 eyes of 37 patients (Guyomard JL, Massin P, Tadayoni R, et al.
1958 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Florid diabetic retinopathy: results of the surgery. Paper presented at: SFO Annual Meeting; May 14, 2003; Paris, France). The comparison of baseline characteristics showed that both series were well balanced at baseline for demographic and ocular characteristics, as well as for the mean follow-up duration (P , 0.005). The postoperative visual acuity gain was higher in the bevacizumab series: +1.1 logMAR (Snellen, 20/250) versus +0.8 logMAR (Snellen, 20/125) (P = 0.03), with a lower mean number of surgeries (1.8 ± 1.3 vs. 2.4 ± 1.6, respectively). Furthermore, the surgical procedure seemed to be facilitated when anti-VEGF was injected preoperatively. The number of iatrogenic and peripheral tears was lower (18 vs. 35, P , 0.01 and 8 vs. 24, P , 0.01, respectively) in the series treated with bevacizumab. Finally, the anatomical success rate was higher in the bevacizumab series (84 vs. 66%, P = 0.054) with a lower recurrence rate of RD (10 vs. 39%). Thus, the comparison of our results with those obtained in the previous FDR series, which had undergone surgery without combined anti-VEGF, highlighted the benefits of anti-VEGF as an adjunctive treatment on the FDR surgery outcomes. However, this comparison has a major limitation—the instrumentation and surgical techniques have progressed between the two study periods. Our study has some limitations such as its retrospective nonrandomized design. Indeed, the very low incidence rate of FDR and its high severity did not allow conducting a prospective assessment of the benefits of anti-VEGF on the surgical outcomes. The smaller number of patients in the Stage 3 group compared with Groups 1 and 2 could also affect the conclusions drawn about the eyes with the most severe FDR. In conclusion, vitrectomy performed early and combined with anti-VEGF therapy seems to be a good option for managing FDR, improving both the visual and anatomical outcomes in this severe form of DR, with potential poor prognosis. Key words: anti-VEGF therapy, diabetic retinopathy, fibrovascular proliferation, intravitreal injection, surgery, tractional retinal detachment, type I diabetes, vitreous hemorrhage, vitrectomy, young patients. References 1. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Clinical application of results of a randomized trial–Diabetic Retinopathy Vitrectomy Study Report 4. Ophthalmology 1988;95:1321–1334. 2. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695, e1–e1715.
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3. Rizzo S, Genovesi-Ebert F, Di Bartolo E, et al. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol 2008;246:837–842. 4. Da R Lucena D, Ribeiro JA, Costa RA, et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study). Br J Ophthalmol 2009;93:688–691. 5. Ishikawa K, Honda S, Tsukahara Y, Negi A. Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye (Lond) 2009; 23:108–111. 6. Oshima Y, Shima C, Wakabayashi T, et al. Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat diabetic traction retinal detachment. Ophthalmology 2009;116:927–938. 7. Yeh PT, Yang CM, Lin YC, et al. Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina 2009;29:768–774. 8. Kohner EM, Hamilton AM, Joplin GF, Fraser TR. Florid diabetic retinopathy and its response to treatment by photocoagulation or pituitary ablation. Diabetes 1976;25:104–110. 9. Favard C, Guyot-Argenton C, Assouline M, et al. Full panretinal photocoagulation and early vitrectomy improve prognosis of florid diabetic retinopathy. Ophthalmology 1996; 103:561–574. 10. Polkinghorne PJ, Uliss AI, Hamilton AM. Macular oedema and retinal neovascularisation in juvenile diabetics. Int Ophthalmol 1992;16:133–137. 11. Lattanzio R, Brancato R, Bandello FM, et al. Florid diabetic retinopathy (FDR): a long-term follow-up study. Graefes Arch Clin Exp Ophthalmol 2001;239:182–187. 12. Beaumont P, Hollows FC. Classification of diabetic retinopathy, with therapeutic implications. Lancet 1972;1:419–425. 13. Ben Mehidi A, Massin P, Guyot-Argenton C, et al. Diabetic retinopathy in children and adolescents [in French]. Diabetes Metab 2003;29:300–306. 14. Modarres M, Nazari H, Falavarjani KG, et al. Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol 2009;19:848–852. 15. Ahmadieh H, Shoeibi N, Entezari M, Monshizadeh R. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients: a randomized clinical trial. Ophthalmology 2009;116:1943–1948. 16. Di Lauro R, De Ruggiero P, di Lauro MT, Romano MR. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010;248:785–791. 17. Mason JO III, Nixon PA, White MF. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142:685–688. 18. Zhao LQ, Zhu H, Zhao PQ, Hu YQ. A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy. Br J Ophthalmol 2011;95:1216–1222. 19. Zhang ZH, Liu HY, Hernandez-Da Mota SE, et al. Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: a meta-analysis of randomized controlled trials. Am J Ophthalmol 2013;156:106–115.e2. 20. Yang CM, Yeh PT, Yang CH, Chen MS. Bevacizumab pretreatment and long-acting gas infusion on vitreous clear-up after diabetic vitrectomy. Am J Ophthalmol 2008;146:211– 217.
SURGERY FOR FLORID DIABETIC RETINOPATHY COUTURIER ET AL 21. Gupta B, Sivaprasad S, Wong R, et al. Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: the DRIVE UK study. Eye (Lond) 2012;26:510–516. 22. Lewis H, Abrams GW, Williams GA. Anterior hyaloidal fibrovascular proliferation after diabetic vitrectomy. Am J Ophthalmol 1987;104:607–613. 23. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial–Diabetic Retinopathy Vitrectomy Study Report 3. Ophthalmology 1988; 95:1307–1320. 24. The Diabetic Retinopathy Vitrectomy Study Research Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic
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Retinopathy Vitrectomy Study (DRVS) report 1. Ophthalmology 1985;92:492–502. 25. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. Arch Ophthalmol 1985;103:1644–1652. 26. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol 1990;108:958–964. 27. Blankenship GW. Preoperative prognostic factors in diabetic pars plana vitrectomy. Ophthalmology 1982;89:1246–1249.
T
reduces the postoperative bleeding.3–7 Florid diabetic retinopathy (FDR) is a serious but rare form of DR occurring in young diabetic patients with poor metabolic control.8–10 Its main clinical characteristics have been defined by Kohner et al8 in 1976: it occurs in patients with Type I diabetes, aged ,40 years, presenting with a documented history of rapid DR progression, from no retinal lesions or nonproliferative DR to either high-risk or complicated proliferative DR in ,6 months.11,12 The prognosis remains poor with high risk of tractional retinal detachment (RD), neovascular glaucoma (NVG), or anterior hyaloidal fibrovascular proliferation (AFVP), leading to blindness.13 Despite early and intensive pan-retinal laser photocoagulation (PRP), pars plana vitrectomy may also be required, but the surgical management remains difficult and may lead to visual loss.9 Intravitreal bevacizumab (IVB) injection seems of interest for these severe proliferative retinopathies because it facilitates the dissection of proliferative tissues, reduces the
he surgical management of late complications of proliferative diabetic retinopathy (DR) remains complex and challenging. However, both anatomical and visual outcomes are constantly improving since the Diabetic Retinopathy Vitrectomy Study (DRVS) has been published,1 given the progress in surgical instruments used for vitreoretinal surgery and the use of intravitreal antivascular endothelial growth factor (VEGF) agents such as bevacizumab (Avastin).2 When administered preoperatively, the latter facilitates the surgical dissection of proliferative membranes and From the *Department of Ophthalmology, APHP, University of Denis Diderot, Paris, France; and †Department of Ophthalmology, University Hospital of Rennes, Rennes, France. Paper presented at Société Française d’Ophtalmologie, May 2012, Paris, France. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Pascale Massin, MD, PhD, Service d’Ophtalmologie, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris Cedex 10, France; e-mail: [email protected]
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intraoperative bleeding, and also could reduce the postoperative risk of AFVP. The purpose of this study was to evaluate the effectiveness of vitrectomy combined with intravitreal injection of bevacizumab in a large consecutive series of patients with this rare and severe form of DR. Methods Participants The records of patients with FDR, who had undergone surgery in our institution performed by the same surgeon between 2006 and 2011, were retrospectively reviewed. This study has been approved by the Ethics Committee of the French Society of Ophthalmology (IRB 00008855 Societe Française d’Ophtalmologie IRB#1). The inclusion criteria for patients were those defined by Kohner et al8 (i.e., Type I diabetes, aged ,40 years, documented history of rapid progression of DR in ,6 months), and patients should have undergone surgery for one of the following complications: tractional RD involving or threatening the macula, combined tractional and rhegmatogenous RD, rapid onset of fibrovascular proliferations (FVP) despite PRP with or without extramacular tractional RD, vitreous hemorrhage without spontaneous clearing, or recurrent vitreous hemorrhage. All patients received IVB injection (1.25 mg/0.05 mL) preoperatively or intraoperatively. The exclusion criteria were patients with Type II diabetes and history of vitrectomy. Data Data collected included baseline demographics (gender, mean duration of diabetes, hemoglobin A1c, blood
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pressure, nephropathy) and ocular findings (initial and final best-corrected visual acuity [BCVA], postoperative status of the retina, the use of tamponade, preoperative and postoperative complications: retinal tears, recurrence of RD, progression to NVG). Additional information included indication for the procedure, the presence of previous PRP, surgical techniques used, the time of IVB injection, and duration of the follow-up. Cases were classified into three stages of disease severity, according to the location and extension of the FVP. This classification was based on the clinical examination and fundus photography, and when not assessable preoperatively, on surgical findings. In Stage I, FVP was located at the posterior pole, along the vascular arcades and posterior to the equator (Figure 1). In Stage II, FVP extended beyond the equator (Figure 2). Stage III was defined by the presence of AFVP and/or rubeosis iridis (Figure 3). Anterior hyaloidal fibrovascular proliferation was characterized by FVP originating from the anterior retina and extending along the anterior hyaloid. Surgery Pars plana vitrectomy was performed using a standard 20-gauge 3-port system or a sutureless 23-gauge system with a chandelier lighting as follows: central vitrectomy and opening of the posterior hyaloid, then dissection of the vitreoretinal FVP with the vitreous probe, or with a bimanual technique of delamination, using forceps and scissors. Peripheral shaving of the vitreous base was then performed with indentation. Visualization during surgery was obtained using the Quadrasphéric or Volk MiniQuad lens wide-angle contact system (Volk Optical, Mentor, OH) and flat and prismatic Landers lenses (Ocular Instruments, Bellevue,WA).
Fig. 1. A. The left eye of a 35-year-old man, presenting with Stage I FDR. Preoperative color montage showing FVP at the posterior pole and vitreous hemorrhage. B. The right eye of a 36-year-old woman presenting with Stage I FDR. Preoperative color montage showing vitreous hemorrhage and a large FVP located behind the equator.
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Fig. 2. A and B. The right eye of a 25-year-old man presenting with Stage II FDR. A. Preoperative color montage showing that the FVP extended beyond the equator and caused tractional RD threatening the macula. The visual acuity was 20/320 Snellen equivalent. B. Postoperative color montage 2 months after 2 procedures. The first procedure consisted of vitrectomy with FVP dissection, endolaser, and silicone oil tamponade and was combined with IVB 7 days ago. The second procedure was limited to silicone oil removal combined with IVB. The visual acuity improved to 20/20 and remained stable during a 31month follow-up. C and D. The left eye of a 29-year-old woman who had undergone surgery for Stage II FDR. C. Preoperative color montage showing an extensive FVP covering the posterior pole. The visual acuity was limited to counting fingers. D. Postoperative color photography of the posterior pole showing complete flattening of the retina under silicone oil 4 months after 2 procedures. The visual acuity improved to 20/250. Ten months later, the fundus and visual acuity remained stable after silicone oil ablation.
An extensive pan-retinal endophotocoagulation extending up to the ora serrata was performed, as well as photocoagulation around the retinal breaks; preoperative phakoemulsification was performed when needed (in case of major lens opacities or AFVP requiring
dissection). Retinectomy was performed in case of extensive AFVP. Expandable gases were used as tamponade when retinal breaks were observed. Silicone oil tamponade was indicated in Stages II and III eyes associated with multiple or inferior tears, when retinectomy
Fig. 3. A. The right eye of a 30-year-old man presenting with Stage III FDR. Preoperative color montage showing that the AFVP led to a tabletop RD. He had undergone vitrectomy with FVP dissection, endolaser, and silicone oil tamponade, combined with IVB 7 days before surgery. Visual acuity was limited to hand motion. No functional improvement was observed after surgery, and he progressed to NVG. B and C. The left eye of a 28-year-old woman who had undergone surgery for Stage III FDR. B. Preoperative color montage showing retrohyaloidal hemorrhage and extensive FVP extended toward the inferotemporal periphery. This FVP was associated with rubeosis iridis. The visual acuity was reduced to counting fingers. C. Postoperative color montage 3 months after a second surgery for silicone oil removal. The visual acuity improved to 20/125 and remained stable during a 26-month follow-up.
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was carried out, or for visual purpose in monocular patients. Silicone oil removal was usually combined with IVB injection. Intravitreal bevacizumab was injected during the surgery, at the end of the procedure, in the less severe cases, mainly Stage I. In these cases, the operator did not expect to experience major difficulties when dissecting the proliferative tissues so that the injection was only carried out at the end of the procedure, to reduce postoperative complications such as postvitrectomy hemorrhage and AFVP. In the cases with severe and extensive FVP, mainly Stages II and III, the injection was carried out preoperatively to facilitate the surgical procedure (the reduction of bleeding and easier dissection of fibrovascular tissues), whereas maintaining the benefits of reduced postoperative complications as previously described. A very close postoperative follow-up was performed (weekly for the first month, then monthly for 3 months) to carefully detect any potential complication including NVG, rubeosis iridis, and/or AVFP. Outcome Measures The primary endpoint was to measure the mean change in BCVA at the end of follow-up. Secondary endpoints were to measure the following: 1) the anatomical outcome (the anatomical success was defined by a flat retina without tamponade at the end of followup); 2) the mean number of surgeries underwent per eyes; and 3) the number of surgical complications. Statistics For statistical analysis, continuous variables are presented as mean ± standard deviation. Series comparisons were made using a Student’s t-test or Wilcoxon rank test as appropriate for continuous variables, and chi-square statistics or Fisher’s exact test as appropriate for categorical variables. A P , 0.05 was considered significant. A linear regression model was used to analyze the relationship between the severity of the initial retinopathy and the number of surgeries underwent. Results A total of 61 eyes of 45 patients were studied. Patient preoperative characteristics are summarized in Table 1. Initial ocular characteristics are presented in Table 2. Before surgery, 23 eyes (38%) had RD. The macula was detached in 16 eyes (69.5% of the eyes with RD). Among these 16 detachments, 5 had a “tabletop” configuration (1 Stage II and 4 Stage III eyes) (Figure 3A). Five patients did not have pre-
vious PRP (1 Stage I, 3 Stage II, and 1 Stage III eyes). Anti-VEGF injection was performed preoperatively in 42 eyes (69%) and intraoperatively in 19 (31%). Visual and Anatomical Outcomes Visual outcomes after surgery are reported in Table 3. The mean BCVA gain was of −0.85 logMAR. The visual gain was significant in Stage I and II eyes (P , 0.05), but not in Stage III eyes. Forty-six of 61 eyes (75.4%) had a BCVA gain of at least 2 Snellen lines (80 and 83% in Stage I and II eyes, respectively, and 29% in Stage III eyes). At baseline, 24 patients (53%) were considered legally blind, that is, logMAR BCVA .+1 (Snellen Equivalent ,20/200) in the better eye. At the end of the follow-up, only 8 patients (18%) were still legally blind. At baseline, 13 patients (29%) had no ambulatory vision, defined by BCVA of at least +1.6 logMAR (,20/800, Snellen equivalent) in the better eye. Six of these patients recovered an ambulatory visual acuity at the end of the follow-up. At the end of follow-up, 24 eyes (39.3%) had BCVA $20/40, 22 eyes (36%) had BCVA between 20/40 and 20/200, and 15 (24.6%) had a final BCVA #20/200. Among the 15 eyes with the final BCVA #20/200, 5 eyes had macular ischemia, 2 had recurrent tractional RD under silicone oil, and 8 eyes progressed to NVG or phthisis. No statistical difference was found between the preoperatively and intraoperatively injected groups regarding the functional outcomes (the final visual acuity +0.92 logMAR and +0.67 logMAR, respectively, P = 0.35). Table 4 shows the anatomical outcome of surgery at the end of the follow-up. Overall, 51 eyes (84%) had an anatomical success defined as a flat retina without Table 1. Description of the Study Sample No. patients/eyes Male/female, n Age, years Mean ± SD Range Duration of diabetes, years Mean ± SD Range HBP, n (%) Nephropathy, n (%) Neuropathy, n (%) HbA1c, % Mean ± SD Range Follow-up, months Mean ± SD Range
45/61 19/26 30.8 ± 4.7 18–40 19.8 ± 5.2 11–31 18 (40) 18 (40) 8 (18) 9.40 ± 2.1 5.0–14.8 20.3 ± 15.6 6–63
HbA1c, hemoglobin A1c; HBP, high blood pressure; SD, standard deviation.
1956 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES Table 2. Ocular Status at Baseline Initial retinopathy stage, n (%) Stage I Stage II Stage III Phakic eyes, n (%) Surgical indication, n (%) Macular tractional RD Combined RD VH Rapid FVP Previous complete PRP, n (%) Previous partial PRP, n (%) No previous PRP, n (%) Preoperative IVB, all stages, n (%) Stage I Stage II Stage III Intraoperative IVB, all stages Stage I Stage II Stage III Mean duration before IVB, days Mean ± SD Range
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underwent a 23-gauge vitrectomy. Tamponade was unnecessary in 27 eyes (44%). Gas tamponade was required in 15 eyes (24.6%) and silicone oil tamponade in 19 eyes (31%). Localized retinectomy was performed in 3 eyes (5%) for AFVP. The mean number of surgeries per eye was 1.82 (1–9) for all stages. The more severe the stage, the higher the number of surgeries, mean number of surgeries was 1.56 (1–6) in Stage I eyes, 2.04 (1–4) in Stage II eyes, and 2.28 (1–6) in Stage III eyes. Eleven of 19 patients (58%) with silicone tamponade underwent definitive silicone ablation during the follow-up, combined with IVB injection at the end of the surgery in five patients. After silicone oil removal, all patients achieved an anatomical success, except one who progressed to phthisis. During the follow-up, the postoperative complications after the first surgery included: 1) Recurrence of RD in 6 eyes (10%) (2 Stage I, 3 Stage II, and 1 Stage III); 2) occurrence of AFVP in 2 Stage II eyes (3%); and 3) Recurrence of vitreous cavity hemorrhage in 22 eyes (36%). Among these 22 eyes, 7 (32%) required a deferred cavity lavage.
30 (49) 24 (39) 7 (12) 59 (97) 10 (16) 6 (10) 31 (51) 14 (23) 31 (51) 25 (40) 5 (9) 42 (69) 16 (53) 20 (83) 6 (86) 19 (31) 14 (47) 4 (17) 1 (14) 7.17 ± 0.99 4–11
SD, standard deviation.
silicone oil (93 and 88% in Stages I and II eyes, respectively, and 29% in Stage III eyes), and 8 (13%) progressed to NVG or phthisis (7 and 8% in Stage I and II eyes, respectively, and 57% in Stage III eyes). Among the five patients without previous PRP, an anatomical success was achieved in four patients whereas one progressed to phthisis. No statistical difference was found between the preoperatively and intraoperatively injected groups regarding the anatomical outcomes (anatomical success observed in 80.9% [34 of 42 eyes] and in 89.5% [17 of 19 eyes], respectively, P = 0.48).
Discussion Although many studies have already demonstrated the efficacy of this combined approach in PDR,3,4,7,14–17 especially meta-analyses of the clinical outcomes of vitrectomy with or without IVB pretreatment in patients with severe DR (in which some patients with FDR were included),18,19 our study is unique and novel because it is a dedicated analysis of a small subgroup of patients with FDR, on a large number of cases. Our results showed that a significant visual acuity improvement by 2 Snellen lines was obtained in 75% of the eyes, and that an anatomical success was achieved in 84% of the eyes, with a mean of 1.82 surgeries per eye. The favorable outcomes in this FDR series suggest that the combined approach is also effective for the treatment of this more aggressive form of the disease.
Surgery Features and Complications The mean time of IVB injection was of 7.16 days before surgery (range, 4–11 days). Pars plana vitrectomy was performed using a standard 20-gauge 3-port system in 55 eyes (90%). The 6 other eyes (10%)
Table 3. Visual Acuity Evolution Preop VA ± SD, logMAR All stages Stage I Stage II Stage III
1.7 1.5 1.7 2.16
± ± ± ±
Final VA ± SD, logMAR 0.8 0.5 ± 0.6 0.8 ± 0.9 2.2 ± 1.0
0.7 0.7 0.6 0.5
SD, standard deviation; VA, visual acuity.
P
Mean Change in VA
Gain $2 Lines, n (%)
Loss $2 Lines, n (%)
0.03 0.02 0.03 0.10
−0.856 −1.04 −0.88 −0.04
46 24 20 2
8 1 4 3
(75.4) (80) (83.3) (28.6)
(13.1) (3.3) (16.6) (42.8)
Stabilization, n (%) 7 (11.5) 5 (16.6) 0 (0) 2 (28.6)
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SURGERY FOR FLORID DIABETIC RETINOPATHY COUTURIER ET AL Table 4. Anatomical Outcomes Flat Retina Without Silicone Oil, n (%) All stages (n = 61) Stage I (n = 30) Stage II (n = 24) Stage III (n = 7)
51 28 21 2
(84) (93) (88) (29)
There are few data available in the literature on the outcomes of vitrectomy for FDR, but our results appear to be better than those in the other FDR series, which were not treated with anti-VEGF. In a Lattanzio et al11 study, 19 eyes with FDR underwent vitrectomy without anti-VEGF, and the initial and final visual acuities were both of 20/200 Snellen equivalent with a high rate of blindness (31%). In 1996, Favard et al9 published a series of 40 eyes of 20 patients with FDR of which 37 eyes (92.5%) underwent PRP and 15 (37.5%) underwent vitrectomy. In their series, the prognosis of the 15 eyes that underwent vitrectomy was poor: the final visual acuity was ,20/200 in 4 eyes (27%) (vs. 18% in our series) and $20/40 in 5 eyes (33%) (vs. 39% in our series). Among these 15 eyes treated with vitrectomy, 2 still had RD under silicone oil (13%) (vs. 3% in our series).9 The better outcomes obtained in our series could be due to a better knowledge and screening of florid diabetic retinopathy, instrumentation and surgical technique improvements, and also anti-VEGF injection effectiveness. Several reports have suggested that the IVB injected preoperatively could facilitate the surgical dissection of fibrovascular membranes in eyes with severe active proliferative retinopathy and reduce intraoperative and postoperative complications, allowing better visual acuity outcomes.3,4,7,14–17 However, since to our knowledge no study has specifically reported the surgical outcomes of patients with FDR treated with IVB injection, we also compared our results to the previous studies performed in diabetic patients with severe DR who underwent surgery in association with perioperative anti-VEGF. The rate of active progressive proliferative DR was usually lower in most studies than in ours. In a larger series of 68 eyes, Amadieh et al15 reported 10% of rapidly progressive FVP versus 23% in our series.15 Moreover, the number of Type 1 diabetic patients, who potentially had FDR, was usually low (0–20%),4,7,20 except for the DRIVE UK Study which included 58 Type I diabetic patients of 158 patients (37%).21 The anatomical success rate was similar to that observed in our series (84%) but the use of preoperative silicone tamponade was lower than that in our FDR series (4.8 vs. 31% in our study).21 The rate of visual acuity #20/200 at the end of follow-up was also lower (6.4 vs. 24.6% in our
RD Under Silicone Oil, n (%) 2 (3) 0 (0) 1 (4) 1 (14)
NVG or Phthisis, n (%) 8 2 2 4
(13) (7) (8) (57)
series).21 The severity of FDR compared with the other forms of proliferative DR could explain these results. Indeed, FDR has a poor prognosis because of the rapid FVP extension and the risk of AFVP after vitrectomy,22 as described in the different reports of the DRVS.1,23 Report 1 described the natural history and poor prognosis of the rapidly progressive proliferative DR.24 Report 2 highlighted the effectiveness of early vitrectomy for intravitreous hemorrhages in young Type 1 diabetic patients,25 and Reports 3 and 4 highlighted the effectiveness of early vitrectomy for rapid FVP.1,23 In our series, the visual prognosis of early Stages (I and II) was improved by an aggressive and appropriate surgical management, and it seems that the earlier the surgery performed, the better was the visual prognosis, confirming the results published in the DRVS Report 5.26 An anatomical success was achieved in 93% of Stage I eyes and 88% of Stage II eyes, with a better postoperative visual acuity outcome in Stage I eyes. After surgery, 67% of the patients were withdrawn from legal blindness. However, it is noteworthy that FDR requires a very close followup because of its severity and unusual rapidity of progression even postoperatively. In our series, two Stage I eyes progressed to phthisis, and these two patients did not comply with the postoperative monitoring and were lost to follow-up. Conversely, the prognosis of stage III eyes usually remains poor after surgery. In our series, an anatomical success was achieved in only 2 Stage III patients (29%), and no functional improvement was observed after surgery (the initial and final visual acuities were +2.1 and +2.2 logMAR, respectively). Preoperative rubeosis is a known poor prognosis factor27; consequently, for severe FDR (including Stage III eyes), the benefits of the surgery should be discussed because most often no visual improvement and an accelerated progression to NVG and phthisis are observed (4 of 7 Stage III eyes [57%] at the end of follow-up in this study). It was interesting to compare our series with the former FDR series, which had undergone surgery without combined anti-VEGF therapy in our institution between 1991 and 2002 and consisted of 53 eyes of 37 patients (Guyomard JL, Massin P, Tadayoni R, et al.
1958 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Florid diabetic retinopathy: results of the surgery. Paper presented at: SFO Annual Meeting; May 14, 2003; Paris, France). The comparison of baseline characteristics showed that both series were well balanced at baseline for demographic and ocular characteristics, as well as for the mean follow-up duration (P , 0.005). The postoperative visual acuity gain was higher in the bevacizumab series: +1.1 logMAR (Snellen, 20/250) versus +0.8 logMAR (Snellen, 20/125) (P = 0.03), with a lower mean number of surgeries (1.8 ± 1.3 vs. 2.4 ± 1.6, respectively). Furthermore, the surgical procedure seemed to be facilitated when anti-VEGF was injected preoperatively. The number of iatrogenic and peripheral tears was lower (18 vs. 35, P , 0.01 and 8 vs. 24, P , 0.01, respectively) in the series treated with bevacizumab. Finally, the anatomical success rate was higher in the bevacizumab series (84 vs. 66%, P = 0.054) with a lower recurrence rate of RD (10 vs. 39%). Thus, the comparison of our results with those obtained in the previous FDR series, which had undergone surgery without combined anti-VEGF, highlighted the benefits of anti-VEGF as an adjunctive treatment on the FDR surgery outcomes. However, this comparison has a major limitation—the instrumentation and surgical techniques have progressed between the two study periods. Our study has some limitations such as its retrospective nonrandomized design. Indeed, the very low incidence rate of FDR and its high severity did not allow conducting a prospective assessment of the benefits of anti-VEGF on the surgical outcomes. The smaller number of patients in the Stage 3 group compared with Groups 1 and 2 could also affect the conclusions drawn about the eyes with the most severe FDR. In conclusion, vitrectomy performed early and combined with anti-VEGF therapy seems to be a good option for managing FDR, improving both the visual and anatomical outcomes in this severe form of DR, with potential poor prognosis. Key words: anti-VEGF therapy, diabetic retinopathy, fibrovascular proliferation, intravitreal injection, surgery, tractional retinal detachment, type I diabetes, vitreous hemorrhage, vitrectomy, young patients. References 1. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Clinical application of results of a randomized trial–Diabetic Retinopathy Vitrectomy Study Report 4. Ophthalmology 1988;95:1321–1334. 2. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695, e1–e1715.
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3. Rizzo S, Genovesi-Ebert F, Di Bartolo E, et al. Injection of intravitreal bevacizumab (Avastin) as a preoperative adjunct before vitrectomy surgery in the treatment of severe proliferative diabetic retinopathy (PDR). Graefes Arch Clin Exp Ophthalmol 2008;246:837–842. 4. Da R Lucena D, Ribeiro JA, Costa RA, et al. Intraoperative bleeding during vitrectomy for diabetic tractional retinal detachment with versus without preoperative intravitreal bevacizumab (IBeTra study). Br J Ophthalmol 2009;93:688–691. 5. Ishikawa K, Honda S, Tsukahara Y, Negi A. Preferable use of intravitreal bevacizumab as a pretreatment of vitrectomy for severe proliferative diabetic retinopathy. Eye (Lond) 2009; 23:108–111. 6. Oshima Y, Shima C, Wakabayashi T, et al. Microincision vitrectomy surgery and intravitreal bevacizumab as a surgical adjunct to treat diabetic traction retinal detachment. Ophthalmology 2009;116:927–938. 7. Yeh PT, Yang CM, Lin YC, et al. Bevacizumab pretreatment in vitrectomy with silicone oil for severe diabetic retinopathy. Retina 2009;29:768–774. 8. Kohner EM, Hamilton AM, Joplin GF, Fraser TR. Florid diabetic retinopathy and its response to treatment by photocoagulation or pituitary ablation. Diabetes 1976;25:104–110. 9. Favard C, Guyot-Argenton C, Assouline M, et al. Full panretinal photocoagulation and early vitrectomy improve prognosis of florid diabetic retinopathy. Ophthalmology 1996; 103:561–574. 10. Polkinghorne PJ, Uliss AI, Hamilton AM. Macular oedema and retinal neovascularisation in juvenile diabetics. Int Ophthalmol 1992;16:133–137. 11. Lattanzio R, Brancato R, Bandello FM, et al. Florid diabetic retinopathy (FDR): a long-term follow-up study. Graefes Arch Clin Exp Ophthalmol 2001;239:182–187. 12. Beaumont P, Hollows FC. Classification of diabetic retinopathy, with therapeutic implications. Lancet 1972;1:419–425. 13. Ben Mehidi A, Massin P, Guyot-Argenton C, et al. Diabetic retinopathy in children and adolescents [in French]. Diabetes Metab 2003;29:300–306. 14. Modarres M, Nazari H, Falavarjani KG, et al. Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. Eur J Ophthalmol 2009;19:848–852. 15. Ahmadieh H, Shoeibi N, Entezari M, Monshizadeh R. Intravitreal bevacizumab for prevention of early postvitrectomy hemorrhage in diabetic patients: a randomized clinical trial. Ophthalmology 2009;116:1943–1948. 16. Di Lauro R, De Ruggiero P, di Lauro MT, Romano MR. Intravitreal bevacizumab for surgical treatment of severe proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010;248:785–791. 17. Mason JO III, Nixon PA, White MF. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142:685–688. 18. Zhao LQ, Zhu H, Zhao PQ, Hu YQ. A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy. Br J Ophthalmol 2011;95:1216–1222. 19. Zhang ZH, Liu HY, Hernandez-Da Mota SE, et al. Vitrectomy with or without preoperative intravitreal bevacizumab for proliferative diabetic retinopathy: a meta-analysis of randomized controlled trials. Am J Ophthalmol 2013;156:106–115.e2. 20. Yang CM, Yeh PT, Yang CH, Chen MS. Bevacizumab pretreatment and long-acting gas infusion on vitreous clear-up after diabetic vitrectomy. Am J Ophthalmol 2008;146:211– 217.
SURGERY FOR FLORID DIABETIC RETINOPATHY COUTURIER ET AL 21. Gupta B, Sivaprasad S, Wong R, et al. Visual and anatomical outcomes following vitrectomy for complications of diabetic retinopathy: the DRIVE UK study. Eye (Lond) 2012;26:510–516. 22. Lewis H, Abrams GW, Williams GA. Anterior hyaloidal fibrovascular proliferation after diabetic vitrectomy. Am J Ophthalmol 1987;104:607–613. 23. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial–Diabetic Retinopathy Vitrectomy Study Report 3. Ophthalmology 1988; 95:1307–1320. 24. The Diabetic Retinopathy Vitrectomy Study Research Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic
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Retinopathy Vitrectomy Study (DRVS) report 1. Ophthalmology 1985;92:492–502. 25. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic Retinopathy Vitrectomy Study report 2. Arch Ophthalmol 1985;103:1644–1652. 26. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Four-year results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Arch Ophthalmol 1990;108:958–964. 27. Blankenship GW. Preoperative prognostic factors in diabetic pars plana vitrectomy. Ophthalmology 1982;89:1246–1249.
