TRACTIONAL RETINAL DETACHMENT AFTER INTRAVITREAL INJECTION OF BEVACIZUMAB IN PROLIFERATIVE DIABETIC RETINOPATHY Mitzy E. Torres-Soriano, MD, Elizabeth Reyna-Castela´n, MD, Myrian Herna´ndez-Rojas, MD, Gerardo Garcı´a-Aguirre, MD, Vero´nica Kon-Jara, MD, Jose´ L. Diaz-Rubio, MD, Jose´ L. Guerrero-Naranjo, MD, Juan M. Jime´nez-Sierra, MD, Hugo Quiroz-Mercado, MD
Purpose: To assess the short-term complications of a single dose of intravitreal bevacizumab in patients with proliferative diabetic retinopathy (PDR). Methods: Retrospective review of 343 patients with PDR who were treated with intravitreal injection of bevacizumab (2.5 mg/0.1 mL). Results: Five patients (1.45%) presented tractional retinal detachment 1 to 6 weeks (mean 3 weeks) after intravitreal injection. All cases underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade. Conclusion: Tractional retinal detachment may occur in a short time post intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy with extensive areas of ischemia and fibrovascular proliferations, and may require prompt vitreoretinal surgery. RETINAL CASES & BRIEF REPORTS 3:70 –73, 2009
From the Retina Service, Asociacion Para Evitar la Ceguera, Hospital Dr. Luis Sa´nchez Bulnes, Coyoacan, Me´xico City, Me´xico.
ocular neovascularization. Therefore direct blocking of VEGF might be a possible therapeutic strategy to treat neovascularization.2 Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) is a full-length humanized anti VEGF monoclonal antibody and has been approved by the US Food and Drug Administration as first-line treatment for metastatic colorectal cancer. Recently, its use has been reported to be of benefit for the rapid resolution of iris and retinal neovascularization in patients with diabetes.3 In this article we report five patients with PDR who developed tractional retinal detachment (TRD) a short time after a single dose of intravitreal injection of bevacizumab.
R
etinal neovascularization in proliferative diabetic retinopathy (PDR) represents an important risk factor for severe vision loss in patients with diabetes mellitus. Panretinal photocoagulation (PRP) is the gold standard treatment to induce regression of neovascularization in PDR. However, this anatomically destructive treatment may be associated with side effects during such treatment and after treatment, as well as central vision loss and an associated increased risk of macular edema.1 Neovascularization is correlated highly with retinal ischemia which stimulates the production of vascular endothelial growth factor (VEGF), a key molecule in
Case Reports Case 1
Reprint requests: Hugo Quiroz-Mercado, MD, Retina Service, Asociacion Para Evitar la Ceguera, Hospital Dr. Luis Sa´nchez Bulnes, Vicente Garcı´a Torres 46, San Lucas Coyoacan 04030, Coyoacan, Me´xico City, Me´xico; e-mail: [email protected]
A 24-year-old woman presented with uncontrolled Type 1 diabetes mellitus. Visual acuity was 20/60 and 20/30 in the right and
70
TRACTIONAL RD AFTER INTRAVITREAL BEVACIZUMAB IN PDR
71
Visual acuity measured 20/80 in the right eye and hand motion in the left eye. Fundus examination revealed retinal neovascularization along the four arcades without retinal detachment in the right eye, and PRP was performed. In the left eye we observed significant fibrovascular proliferations involving the optic disk, and the area between the temporal arcades presented hyaloidal thickening with preretinal hemorrhage and retinal neovascularization in all arcades. We decided to offer the patient intravitreal bevacizumab as an off-label preoperative adjunctive therapy, and after discussion of the potential risks and benefits he signed a comprehensive consent form and underwent pars plana injection of 2.5 mg/0.1 mL of intravitreal bevacizumab. Ten days after treatment the patient presented a TRD involving the macula in the left eye. The patient then underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade (Figure 2).
Case 4 In a 57-year-old man with Type 2 diabetes mellitus, visual acuity measured count fingers in both eyes. Fundus examination revealed PDR in both eyes with mild vitreous hemorrhage and fluorescein angiography showing marked hyperfluorescence secondary to neo-
Fig. 1. A, Posterior pole of right eye: proliferative diabetic retinopathy with neovascularization of the disc, neovascularization elsewhere, and attached retina. B, Tractional retinal detachment involving the macula 5 days after intravitreal injection of bevacizumab.
left eye, respectively. Fundus examination and fluorescein angiography revealed PDR in both eyes. We decided to treat this patient with intravitreal bevacizumab (2.5 mg/0.1 mL) instead of PRP, which was performed without complications. Five days after injection, a TRD was observed and the visual acuity was hand motion perception (Figure 1). Vitrectomy was performed and visual acuity improved to 20/200. The other eye was treated with PRP.
Case 2 In a 57-year-old woman with Type 2 diabetes mellitus, visual acuity at the initial visit was count fingers in both eyes. Fundus examination revealed PDR with mild vitreous hemorrhage and fluorescein angiography showing marked hyperfluorescence secondary to neovascularization. We injected intravitreal bevacizumab (2.5 mg/0.1 mL) in the right eye and PRP was performed in the left eye. Two weeks after intravitreal injection a TRD was detected in the right eye, and was confirmed by ultrasonography. Vitrectomy was performed, with good anatomic result, but visual acuity remained count fingers 3 months after surgery.
Case 3 A 45-year-old man with Type 2 diabetes mellitus presented complaining of decreased visual acuity in the left eye for 2 months.
Fig. 2. A, Left eye with diabetic retinopathy without treatment, showing preretinal hemorrhage and important retinal neovascularization. B, Left eye 10 days after intravitreal injection of bevacizumab, showing a tractional retinal detachment.
RETINAL CASES & BRIEF REPORTSℜ
72
vascularization and severe capillary blockage in the right eye. Intravitreal bevacizumab (2.5 mg/0.1 mL) was injected in the right eye and PRP was performed in the left eye. Four weeks after intravitreal injection a TRD was detected in the right eye and the visual acuity was hand motion. The patient underwent vitrectomy and silicone oil tamponade.
Discussion VEGF has been shown to play an important role in retinal neovascularization. Injection of VEGF in primates can produce a retinopathy similar to diabetic retinopathy and even produce iris neovascularization.4 Early trials have demonstrated the benefit of Pegaptanib (Macugen, Eyetech, New York, NY) in reducing diabetic macular edema, and it has been noted to induce regression of small areas of retinal neovascularization.5 In one report of intravitreal bevacizumab injected in 45 eyes with PDR, a dramatic and rapid response to the injection was observed, with complete resolution of the vascular leakage in most cases and no report of TRD in any case.6 In a retrospective case review of three patients who underwent intravitreal injection of bevacizumab as part of their treatment for PDR, total regression of neovascularization occurred between 1 and 3 weeks after intravitreal injection of bevacizumab. No patient developed new vitreous hemorrhage or TRD.7 Given the overwhelming evidence for the role of VEGF in PDR, anti-VEGF treatments such as bevacizumab was offered to these patients with PDR. In our experience, 5 cases (1.45%) of 343 eyes injected with PDR developed TRD in a short time (1 to 6 weeks, mean 3 weeks) after intravitreal injection. The first case occurred in injection number 112 and after this observation, we were more careful to inject intravitreal bevacizumab in cases with extent areas of ischemia and severe fibrovascular proliferations; therefore we have few cases to report in this article. All cases underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade. The occurrence and severity of retinal detachment are influenced by the timing and degree of shrinkage of the vitreous and fibrovascular proliferations and by the type, extent, and location of the new vessels responsible for vitreoretinal adhesions. Extensive nets of large caliber new vessels accompanied by heavy fibrous tissue produce broad, tight vitreoretinal adhesions. Contraction of such proliferations is often followed by extensive retinal detachment. The composition of the vitreous is unique in that it is a highly hydrated, avascular, gelatinous body containing 98% water. Vitreous structural elements
●
2009
●
VOLUME 3
●
NUMBER 1
composed of type II collagen and hyaluronic acid occupy ⬍1% of the total volume. The human eye contains 3 mL to 4 mL of vitreous humor.8 The pharmacokinetic properties of compounds in the vitreous have been observed to change in the setting of intravitreal injections. Tears of the RPE have been reported in association with VEGF-modulating intravitreal therapies for the treatment of neovascular age-related macular degeneration. Anti-VEGF therapy may accelerate the natural history in those pigment epithelium detachments that were likely to tear spontaneously if not treated. Several potential mechanisms have been proposed, including fibrovascular contraction of the choroidal neovascularization (CNV) and mechanical forces from vitreomacular traction or extreme fluctuations in intraocular pressure.9 The bevacizumab may have caused severe contraction of the CNV, placing shearing forces on the RPE, and causing the weakened RPE to contract and tear.10 Similarly, the use of VEGF inhibitor in PDR may accelerate the physiopathologic process of occlusion of new vessels which are replaced with fibrous tissue, which in turn contracts, inducing TRD and vitreous hemorrhage. While the TRD in our patients occurred soon after the intravitreal injection, presumably as a consequence of the therapy, we appreciate the fact that this low occurrence rate of 1.45% may have been due to the natural history of this condition rather than due to the injection. However, we now believe that extreme care must be taken in using intravitreal bevacizumab in patients with PDR and extensive fibrovascular proliferation and that careful follow-up evaluation of these patients following injection is mandatory. Finally, physicians must be prepared to perform vitrectomy immediately on those patients in whom detachments occur.
References 1.
2.
3.
4.
Adamis AP, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23–28. Aiello LP, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1519–1520. Chen E, Park CH. Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 2006;26: 699–700. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103:1820–1828.
TRACTIONAL RD AFTER INTRAVITREAL BEVACIZUMAB IN PDR 5.
6.
7.
Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization following pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23–28. Avery RL, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695–1705. Mason JO 3rd, et al. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142:685–688.
8.
9.
10.
73
Drolet DW, et al. Pharmacokinetics and safety of an antivascular endothelial growth factor aptamer (NX 1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res 2000;17:1503–1510. Chang LK, Sarraf D. Tears of the retinal pigment epithelium: an old problem in a new era. Retina 2007;27:523– 534. Bakri SJ, Patel SP. Retinal pigment epithelial tear following intravitreal bevacizumab. Eye 2007;21:424–425.
Purpose: To assess the short-term complications of a single dose of intravitreal bevacizumab in patients with proliferative diabetic retinopathy (PDR). Methods: Retrospective review of 343 patients with PDR who were treated with intravitreal injection of bevacizumab (2.5 mg/0.1 mL). Results: Five patients (1.45%) presented tractional retinal detachment 1 to 6 weeks (mean 3 weeks) after intravitreal injection. All cases underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade. Conclusion: Tractional retinal detachment may occur in a short time post intravitreal injection of bevacizumab in patients with proliferative diabetic retinopathy with extensive areas of ischemia and fibrovascular proliferations, and may require prompt vitreoretinal surgery. RETINAL CASES & BRIEF REPORTS 3:70 –73, 2009
From the Retina Service, Asociacion Para Evitar la Ceguera, Hospital Dr. Luis Sa´nchez Bulnes, Coyoacan, Me´xico City, Me´xico.
ocular neovascularization. Therefore direct blocking of VEGF might be a possible therapeutic strategy to treat neovascularization.2 Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) is a full-length humanized anti VEGF monoclonal antibody and has been approved by the US Food and Drug Administration as first-line treatment for metastatic colorectal cancer. Recently, its use has been reported to be of benefit for the rapid resolution of iris and retinal neovascularization in patients with diabetes.3 In this article we report five patients with PDR who developed tractional retinal detachment (TRD) a short time after a single dose of intravitreal injection of bevacizumab.
R
etinal neovascularization in proliferative diabetic retinopathy (PDR) represents an important risk factor for severe vision loss in patients with diabetes mellitus. Panretinal photocoagulation (PRP) is the gold standard treatment to induce regression of neovascularization in PDR. However, this anatomically destructive treatment may be associated with side effects during such treatment and after treatment, as well as central vision loss and an associated increased risk of macular edema.1 Neovascularization is correlated highly with retinal ischemia which stimulates the production of vascular endothelial growth factor (VEGF), a key molecule in
Case Reports Case 1
Reprint requests: Hugo Quiroz-Mercado, MD, Retina Service, Asociacion Para Evitar la Ceguera, Hospital Dr. Luis Sa´nchez Bulnes, Vicente Garcı´a Torres 46, San Lucas Coyoacan 04030, Coyoacan, Me´xico City, Me´xico; e-mail: [email protected]
A 24-year-old woman presented with uncontrolled Type 1 diabetes mellitus. Visual acuity was 20/60 and 20/30 in the right and
70
TRACTIONAL RD AFTER INTRAVITREAL BEVACIZUMAB IN PDR
71
Visual acuity measured 20/80 in the right eye and hand motion in the left eye. Fundus examination revealed retinal neovascularization along the four arcades without retinal detachment in the right eye, and PRP was performed. In the left eye we observed significant fibrovascular proliferations involving the optic disk, and the area between the temporal arcades presented hyaloidal thickening with preretinal hemorrhage and retinal neovascularization in all arcades. We decided to offer the patient intravitreal bevacizumab as an off-label preoperative adjunctive therapy, and after discussion of the potential risks and benefits he signed a comprehensive consent form and underwent pars plana injection of 2.5 mg/0.1 mL of intravitreal bevacizumab. Ten days after treatment the patient presented a TRD involving the macula in the left eye. The patient then underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade (Figure 2).
Case 4 In a 57-year-old man with Type 2 diabetes mellitus, visual acuity measured count fingers in both eyes. Fundus examination revealed PDR in both eyes with mild vitreous hemorrhage and fluorescein angiography showing marked hyperfluorescence secondary to neo-
Fig. 1. A, Posterior pole of right eye: proliferative diabetic retinopathy with neovascularization of the disc, neovascularization elsewhere, and attached retina. B, Tractional retinal detachment involving the macula 5 days after intravitreal injection of bevacizumab.
left eye, respectively. Fundus examination and fluorescein angiography revealed PDR in both eyes. We decided to treat this patient with intravitreal bevacizumab (2.5 mg/0.1 mL) instead of PRP, which was performed without complications. Five days after injection, a TRD was observed and the visual acuity was hand motion perception (Figure 1). Vitrectomy was performed and visual acuity improved to 20/200. The other eye was treated with PRP.
Case 2 In a 57-year-old woman with Type 2 diabetes mellitus, visual acuity at the initial visit was count fingers in both eyes. Fundus examination revealed PDR with mild vitreous hemorrhage and fluorescein angiography showing marked hyperfluorescence secondary to neovascularization. We injected intravitreal bevacizumab (2.5 mg/0.1 mL) in the right eye and PRP was performed in the left eye. Two weeks after intravitreal injection a TRD was detected in the right eye, and was confirmed by ultrasonography. Vitrectomy was performed, with good anatomic result, but visual acuity remained count fingers 3 months after surgery.
Case 3 A 45-year-old man with Type 2 diabetes mellitus presented complaining of decreased visual acuity in the left eye for 2 months.
Fig. 2. A, Left eye with diabetic retinopathy without treatment, showing preretinal hemorrhage and important retinal neovascularization. B, Left eye 10 days after intravitreal injection of bevacizumab, showing a tractional retinal detachment.
RETINAL CASES & BRIEF REPORTSℜ
72
vascularization and severe capillary blockage in the right eye. Intravitreal bevacizumab (2.5 mg/0.1 mL) was injected in the right eye and PRP was performed in the left eye. Four weeks after intravitreal injection a TRD was detected in the right eye and the visual acuity was hand motion. The patient underwent vitrectomy and silicone oil tamponade.
Discussion VEGF has been shown to play an important role in retinal neovascularization. Injection of VEGF in primates can produce a retinopathy similar to diabetic retinopathy and even produce iris neovascularization.4 Early trials have demonstrated the benefit of Pegaptanib (Macugen, Eyetech, New York, NY) in reducing diabetic macular edema, and it has been noted to induce regression of small areas of retinal neovascularization.5 In one report of intravitreal bevacizumab injected in 45 eyes with PDR, a dramatic and rapid response to the injection was observed, with complete resolution of the vascular leakage in most cases and no report of TRD in any case.6 In a retrospective case review of three patients who underwent intravitreal injection of bevacizumab as part of their treatment for PDR, total regression of neovascularization occurred between 1 and 3 weeks after intravitreal injection of bevacizumab. No patient developed new vitreous hemorrhage or TRD.7 Given the overwhelming evidence for the role of VEGF in PDR, anti-VEGF treatments such as bevacizumab was offered to these patients with PDR. In our experience, 5 cases (1.45%) of 343 eyes injected with PDR developed TRD in a short time (1 to 6 weeks, mean 3 weeks) after intravitreal injection. The first case occurred in injection number 112 and after this observation, we were more careful to inject intravitreal bevacizumab in cases with extent areas of ischemia and severe fibrovascular proliferations; therefore we have few cases to report in this article. All cases underwent pars plana vitrectomy, removal of all epiretinal fibrovascular membranes, further endolaser panretinal photocoagulation, and silicone tamponade. The occurrence and severity of retinal detachment are influenced by the timing and degree of shrinkage of the vitreous and fibrovascular proliferations and by the type, extent, and location of the new vessels responsible for vitreoretinal adhesions. Extensive nets of large caliber new vessels accompanied by heavy fibrous tissue produce broad, tight vitreoretinal adhesions. Contraction of such proliferations is often followed by extensive retinal detachment. The composition of the vitreous is unique in that it is a highly hydrated, avascular, gelatinous body containing 98% water. Vitreous structural elements
●
2009
●
VOLUME 3
●
NUMBER 1
composed of type II collagen and hyaluronic acid occupy ⬍1% of the total volume. The human eye contains 3 mL to 4 mL of vitreous humor.8 The pharmacokinetic properties of compounds in the vitreous have been observed to change in the setting of intravitreal injections. Tears of the RPE have been reported in association with VEGF-modulating intravitreal therapies for the treatment of neovascular age-related macular degeneration. Anti-VEGF therapy may accelerate the natural history in those pigment epithelium detachments that were likely to tear spontaneously if not treated. Several potential mechanisms have been proposed, including fibrovascular contraction of the choroidal neovascularization (CNV) and mechanical forces from vitreomacular traction or extreme fluctuations in intraocular pressure.9 The bevacizumab may have caused severe contraction of the CNV, placing shearing forces on the RPE, and causing the weakened RPE to contract and tear.10 Similarly, the use of VEGF inhibitor in PDR may accelerate the physiopathologic process of occlusion of new vessels which are replaced with fibrous tissue, which in turn contracts, inducing TRD and vitreous hemorrhage. While the TRD in our patients occurred soon after the intravitreal injection, presumably as a consequence of the therapy, we appreciate the fact that this low occurrence rate of 1.45% may have been due to the natural history of this condition rather than due to the injection. However, we now believe that extreme care must be taken in using intravitreal bevacizumab in patients with PDR and extensive fibrovascular proliferation and that careful follow-up evaluation of these patients following injection is mandatory. Finally, physicians must be prepared to perform vitrectomy immediately on those patients in whom detachments occur.
References 1.
2.
3.
4.
Adamis AP, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23–28. Aiello LP, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1519–1520. Chen E, Park CH. Use of intravitreal bevacizumab as a preoperative adjunct for tractional retinal detachment repair in severe proliferative diabetic retinopathy. Retina 2006;26: 699–700. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology 1996;103:1820–1828.
TRACTIONAL RD AFTER INTRAVITREAL BEVACIZUMAB IN PDR 5.
6.
7.
Macugen Diabetic Retinopathy Study Group. Changes in retinal neovascularization following pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113:23–28. Avery RL, et al. Intravitreal bevacizumab (Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology 2006;113:1695–1705. Mason JO 3rd, et al. Intravitreal injection of bevacizumab (Avastin) as adjunctive treatment of proliferative diabetic retinopathy. Am J Ophthalmol 2006;142:685–688.
8.
9.
10.
73
Drolet DW, et al. Pharmacokinetics and safety of an antivascular endothelial growth factor aptamer (NX 1838) following injection into the vitreous humor of rhesus monkeys. Pharm Res 2000;17:1503–1510. Chang LK, Sarraf D. Tears of the retinal pigment epithelium: an old problem in a new era. Retina 2007;27:523– 534. Bakri SJ, Patel SP. Retinal pigment epithelial tear following intravitreal bevacizumab. Eye 2007;21:424–425.
