IMMEDIATE HYPHEMA AFTER INTRAVITREAL INJECTIONS OF RANIBIZUMAB Veronica A. Kon Graversen, MD, Travis Meredith, MD, Maurice B. Landers, III, MD, Seema Garg, MD, PhD
Purpose: To report two cases of immediate hyphema formation after the intravitreal injection of ranibizumab. Methods: Retrospective case reports. Results: A patient with choroidal neovascularization caused by exudative age-related macular degeneration and a patient with cystoid macular edema caused by branch retinal vein occlusion underwent an intravitreal injection of 0.5 mg/0.05 mL of ranibizumab. The development of hyphema was seen immediately after the intravitreal injection in both cases. One patient was pseudophakic, taking 325 mg of aspirin daily. The other patient was phakic without any anticoagulation history. Conclusion: To the best of our knowledge, this is the third report of the development of hyphema associated with intravitreal injections. RETINAL CASES & BRIEF REPORTS 7:242–244, 2013
From the Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Case Report Case 1 We report the case of a 77-year-old man with diagnosis of wet macular degeneration in the right eye who comes for his scheduled monthly visit without complaints. Medical history was unremarkable. Medications included pravachol, vitamins, and 325 mg of aspirin. Best-corrected visual acuity was 20/200 in the right eye and 20/30 in the left eye. Anterior segment examination revealed a trace nuclear sclerosis and cortical changes in both eyes. No iris neovascularization was seen. Intraocular pressure (IOP) was 14 mmHg in the right eye and 13 mmHg in the left eye. A dilated fundus evaluation demonstrated findings consistent with an active choroidal neovascularization in the right eye and multiple scattered drusen in the left eye. Vitreous cavity was clear showing a posterior vitreous detachment in both eyes. An optical coherence tomography was performed confirming the presence of subretinal fluid with an associated pigment epithelial detachment in the right eye. Treatment options were reviewed and ranibizumab (Lucentis) was chosen. The patient had a history of 26 monthly intravitreal injections in the right eye without complications. An informed consent was obtained. The right eye was prepped in the usual sterile fashion and 0.05 mL of Lucentis was injected intravitreally with a 32-gauge needle, 3.5 mm posterior to the limbus (measured with a caliper) in the superotemporal quadrant. At the moment of the insertion of the needle through the sclera, the surgeon felt an increased resistance to the needle. Indirect ophthalmoscopy was performed and the view of the fundus was blurred. Slit-lamp examination showed blood emanating from the
V
isual loss from exudative age-related macular degeneration is not a growing problem anymore. Recently, several molecules were developed to bind the vascular endothelial growth factor, blocking its angiogenic effects.1 Ranibizumab (Lucentis; Genentech, Inc., San Francisco, CA), the monoclonal antibody fragment anti–vascular endothelial growth factor, has shown a rapid and favorable prognosis in the clinical setting of exudative age-related macular degeneration.2 That is why, even after ocular adverse events have been described, including corneal abrasion, uveitis, vitreous hemorrhage, chemosis, retinal detachment, or retinal pigment epithelium tear, its use has been spread worldwide. We report two cases with clinically evident hyphema immediately after the intravitreal injection. The authors have no proprietary or commercial interest in any materials discussed in this article and there was no funding provided for this study. Reprint requests: Veronica A. Kon Graversen, MD, 9303 Fawn Lake Drive, Raleigh, NC, 27617; e-mail: veronicakonjara@gmail. com
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HYPHEMA AFTER INTRAVITREAL RANIBIZUMAB angle at the same meridian (10:30) as the injection site. There was 25% hyphema and the patient complained of blurry vision. Intraocular pressure was measured as 35 mmHg and dropped to 15 mmHg within 10 minutes. The patient was seen 2 days later, and his vision had returned to baseline levels in the right eye. Intraocular pressure was 18 mmHg. Anterior segment revealed 2+ red blood cells in the anterior chamber (AC). No vitreous cells were seen. The next follow-up visit in 4 weeks showed a visual acuity of 20/70 in the right eye. He has continued receiving intravitreal injections without problems.
Case 2 We report the case of a 66-year-old man with a history of bilateral orbital inflammatory syndrome and branch retinal vein occlusion in the right eye. The patient had previously received 2 intravitreal injections of ranibizumab (Lucentis) for the treatment of cystoid macular edema in the right eye. The procedures were uneventful. Current medications include doxycycline, hydrochlorothiazide, omeprazole, and prednisone. Visual acuity seems to remain stable. On examination, visual acuity was 20/50 in the right eye and 20/20 in the left eye. Anterior segment examination revealed trace nuclear sclerosis and cortical changes in both eyes. Intraocular pressure was 13 mmHg in the right eye and 14 mmHg in the left eye. Dilated fundus examination of the right eye showed residual hemorrhages in the superotemporal quadrant with evidence of subretinal fluid and intraretinal cysts. These findings were confirmed on the optical coherence tomography. Left eye findings were unremarkable. Ranibizumab was injected intravitreally in the superotemporal quadrant, 3.5 mm posterior to the limbus (measured with a caliper) in the right eye. Right after the injection, a small hyphema was detected in the AC coming from the same meridian as the site of the injection. Intraocular pressure was checked in 32 mmHg (Figure 1). Patient stated that there was no blurrier vision in his right eye but was experiencing ocular pain and was given 700 mg of Tylenol. The patient returned for a pressure check 2 days later, and the IOP was within normal limits. Then, the patient was seen the following week and his vision had improved to 20/30 in the right eye. Anterior segment evaluation revealed a quiet conjunctiva and
Fig. 1. Immediately after the intravitreal injection, a small hyphema (white arrows) was evident with blood coming from the same meridian of the injection site (white arrowhead).
AC. The patient subsequently received another intravitreal injection without complications.
Discussion Ranchod et al1 recently reported three cases of hyphema after an intravitreal injection of ranibizumab for the treatment of exudative macular degeneration. Mansour2 previously described a patient with Eales disease, cystoid macular edema, and rubeosis iridis who developed a subtotal hyphema after rubbing her eye after an intravitreal injection of bevacizumab. In the present series, ranibizumab was used in both cases; however, hyphema immediately after intravitreal injection is unlikely to be related to the medication delivered. As Ranchod et al1 described, it is unclear whether anticoagulation increased our patient’s risk of postinjection hyphema; however, Mason et al3 previously reported an extremely low rate of hemorrhagic complications in patients systemically anticoagulated. Hyphema can be associated with elevated eye pressure, and this effect is directly related with the amount of blood in the AC. In our series, there was a transient increase in eye pressure after the injection in both cases, which is a known side effect immediately after the injection, but the pressure returned to a normal range within 10 minutes to 15 minutes. No topical treatment was needed, and the patients were followed during the next 48 hours. The IOP remained within normal limits on the subsequent evaluations. The appearance of hyphema is a rare complication of intravitreal injections and can be influenced by at least two factors: The first is because of the needle track being located anterior to the edge of the vitreous base and anterior hyaloid face,1 which may deviate the flow of blood toward the AC rather than the vitreous cavity; this factor may be related to the injection technique (direction of the needle, distance from the limbus). In the present series, we used a caliper to accurately measure 3.5 mm from the limbus. The second factor is a change in the pressure gradient between the AC and the episcleral venous plexus.4 This latter mechanism is by virtue of the communications between the aqueous outflow channels and the intrascleral and episcleral venous plexuses, which can be occluded with the needle. The Schlemm canal is attached to these vascular plexus, and if any of these channels is occluded during the injection, a sudden increase in pressure may produce regurgitation of blood into the Schlemm canal with subsequent development of hyphema. This "occlusion effect" would seem to depend on the magnitude of pressure difference created by the procedure, which according to Sharei et al5 seems to be 25.5 ± 13.6 mmHg between
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preoperative IOP and immediately after the injection IOP. Could it be possible that the episcleral venous plexus bursts from a rapid change in pressure, particularly if this area has undergone several intravitreal injections? That remains uncertain, but continued injections in the same quadrant may have produced some histological changes in the tissue. If this is correct, it may represent the unusual resistance to the needle that the treating physician felt during the procedure in the first case. Key words: branch retinal vein occlusion, exudative age-related macular degeneration, cystoid macular edema, hyphema, ranibizumab.
References 1. Ranchod T, Walsh M, Capone A, et al. Hyphema after intravitreal injection of ranibizumab or bevacizumab. Retinal Cases Brief Rep 2011;5:87–90. 2. Mansour AM. Visual loss from hyphema following intravitreal bevacizumab [published online ahead of print 2010]. BMJ. doi: 10.1136/bcr.12.2009.2520. 3. Mason JO, Frederick PA, Neimkin MG, et al. Incidence of hemorrhagic complications after intravitreal bevacizumab (Avastin) or ranibizumab (Lucentis) injection on systemically anticoagulated patients. Retina 2010;30:1386–1389. 4. Begg IS. Significance of goniohaemorrhage in heretochromic cyclitis. Br J Ophthalmol 1969;53:1–8. 5. Sharei V, Hohn F, Kohler T, et al. Course of intraocular pressure after intravitreal injection of 0.05 ml of ranibizumab (Lucentis). Eur J Ophthalmol 2010;20:174–179.
Purpose: To report two cases of immediate hyphema formation after the intravitreal injection of ranibizumab. Methods: Retrospective case reports. Results: A patient with choroidal neovascularization caused by exudative age-related macular degeneration and a patient with cystoid macular edema caused by branch retinal vein occlusion underwent an intravitreal injection of 0.5 mg/0.05 mL of ranibizumab. The development of hyphema was seen immediately after the intravitreal injection in both cases. One patient was pseudophakic, taking 325 mg of aspirin daily. The other patient was phakic without any anticoagulation history. Conclusion: To the best of our knowledge, this is the third report of the development of hyphema associated with intravitreal injections. RETINAL CASES & BRIEF REPORTS 7:242–244, 2013
From the Department of Ophthalmology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Case Report Case 1 We report the case of a 77-year-old man with diagnosis of wet macular degeneration in the right eye who comes for his scheduled monthly visit without complaints. Medical history was unremarkable. Medications included pravachol, vitamins, and 325 mg of aspirin. Best-corrected visual acuity was 20/200 in the right eye and 20/30 in the left eye. Anterior segment examination revealed a trace nuclear sclerosis and cortical changes in both eyes. No iris neovascularization was seen. Intraocular pressure (IOP) was 14 mmHg in the right eye and 13 mmHg in the left eye. A dilated fundus evaluation demonstrated findings consistent with an active choroidal neovascularization in the right eye and multiple scattered drusen in the left eye. Vitreous cavity was clear showing a posterior vitreous detachment in both eyes. An optical coherence tomography was performed confirming the presence of subretinal fluid with an associated pigment epithelial detachment in the right eye. Treatment options were reviewed and ranibizumab (Lucentis) was chosen. The patient had a history of 26 monthly intravitreal injections in the right eye without complications. An informed consent was obtained. The right eye was prepped in the usual sterile fashion and 0.05 mL of Lucentis was injected intravitreally with a 32-gauge needle, 3.5 mm posterior to the limbus (measured with a caliper) in the superotemporal quadrant. At the moment of the insertion of the needle through the sclera, the surgeon felt an increased resistance to the needle. Indirect ophthalmoscopy was performed and the view of the fundus was blurred. Slit-lamp examination showed blood emanating from the
V
isual loss from exudative age-related macular degeneration is not a growing problem anymore. Recently, several molecules were developed to bind the vascular endothelial growth factor, blocking its angiogenic effects.1 Ranibizumab (Lucentis; Genentech, Inc., San Francisco, CA), the monoclonal antibody fragment anti–vascular endothelial growth factor, has shown a rapid and favorable prognosis in the clinical setting of exudative age-related macular degeneration.2 That is why, even after ocular adverse events have been described, including corneal abrasion, uveitis, vitreous hemorrhage, chemosis, retinal detachment, or retinal pigment epithelium tear, its use has been spread worldwide. We report two cases with clinically evident hyphema immediately after the intravitreal injection. The authors have no proprietary or commercial interest in any materials discussed in this article and there was no funding provided for this study. Reprint requests: Veronica A. Kon Graversen, MD, 9303 Fawn Lake Drive, Raleigh, NC, 27617; e-mail: veronicakonjara@gmail. com
242
243
HYPHEMA AFTER INTRAVITREAL RANIBIZUMAB angle at the same meridian (10:30) as the injection site. There was 25% hyphema and the patient complained of blurry vision. Intraocular pressure was measured as 35 mmHg and dropped to 15 mmHg within 10 minutes. The patient was seen 2 days later, and his vision had returned to baseline levels in the right eye. Intraocular pressure was 18 mmHg. Anterior segment revealed 2+ red blood cells in the anterior chamber (AC). No vitreous cells were seen. The next follow-up visit in 4 weeks showed a visual acuity of 20/70 in the right eye. He has continued receiving intravitreal injections without problems.
Case 2 We report the case of a 66-year-old man with a history of bilateral orbital inflammatory syndrome and branch retinal vein occlusion in the right eye. The patient had previously received 2 intravitreal injections of ranibizumab (Lucentis) for the treatment of cystoid macular edema in the right eye. The procedures were uneventful. Current medications include doxycycline, hydrochlorothiazide, omeprazole, and prednisone. Visual acuity seems to remain stable. On examination, visual acuity was 20/50 in the right eye and 20/20 in the left eye. Anterior segment examination revealed trace nuclear sclerosis and cortical changes in both eyes. Intraocular pressure was 13 mmHg in the right eye and 14 mmHg in the left eye. Dilated fundus examination of the right eye showed residual hemorrhages in the superotemporal quadrant with evidence of subretinal fluid and intraretinal cysts. These findings were confirmed on the optical coherence tomography. Left eye findings were unremarkable. Ranibizumab was injected intravitreally in the superotemporal quadrant, 3.5 mm posterior to the limbus (measured with a caliper) in the right eye. Right after the injection, a small hyphema was detected in the AC coming from the same meridian as the site of the injection. Intraocular pressure was checked in 32 mmHg (Figure 1). Patient stated that there was no blurrier vision in his right eye but was experiencing ocular pain and was given 700 mg of Tylenol. The patient returned for a pressure check 2 days later, and the IOP was within normal limits. Then, the patient was seen the following week and his vision had improved to 20/30 in the right eye. Anterior segment evaluation revealed a quiet conjunctiva and
Fig. 1. Immediately after the intravitreal injection, a small hyphema (white arrows) was evident with blood coming from the same meridian of the injection site (white arrowhead).
AC. The patient subsequently received another intravitreal injection without complications.
Discussion Ranchod et al1 recently reported three cases of hyphema after an intravitreal injection of ranibizumab for the treatment of exudative macular degeneration. Mansour2 previously described a patient with Eales disease, cystoid macular edema, and rubeosis iridis who developed a subtotal hyphema after rubbing her eye after an intravitreal injection of bevacizumab. In the present series, ranibizumab was used in both cases; however, hyphema immediately after intravitreal injection is unlikely to be related to the medication delivered. As Ranchod et al1 described, it is unclear whether anticoagulation increased our patient’s risk of postinjection hyphema; however, Mason et al3 previously reported an extremely low rate of hemorrhagic complications in patients systemically anticoagulated. Hyphema can be associated with elevated eye pressure, and this effect is directly related with the amount of blood in the AC. In our series, there was a transient increase in eye pressure after the injection in both cases, which is a known side effect immediately after the injection, but the pressure returned to a normal range within 10 minutes to 15 minutes. No topical treatment was needed, and the patients were followed during the next 48 hours. The IOP remained within normal limits on the subsequent evaluations. The appearance of hyphema is a rare complication of intravitreal injections and can be influenced by at least two factors: The first is because of the needle track being located anterior to the edge of the vitreous base and anterior hyaloid face,1 which may deviate the flow of blood toward the AC rather than the vitreous cavity; this factor may be related to the injection technique (direction of the needle, distance from the limbus). In the present series, we used a caliper to accurately measure 3.5 mm from the limbus. The second factor is a change in the pressure gradient between the AC and the episcleral venous plexus.4 This latter mechanism is by virtue of the communications between the aqueous outflow channels and the intrascleral and episcleral venous plexuses, which can be occluded with the needle. The Schlemm canal is attached to these vascular plexus, and if any of these channels is occluded during the injection, a sudden increase in pressure may produce regurgitation of blood into the Schlemm canal with subsequent development of hyphema. This "occlusion effect" would seem to depend on the magnitude of pressure difference created by the procedure, which according to Sharei et al5 seems to be 25.5 ± 13.6 mmHg between
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preoperative IOP and immediately after the injection IOP. Could it be possible that the episcleral venous plexus bursts from a rapid change in pressure, particularly if this area has undergone several intravitreal injections? That remains uncertain, but continued injections in the same quadrant may have produced some histological changes in the tissue. If this is correct, it may represent the unusual resistance to the needle that the treating physician felt during the procedure in the first case. Key words: branch retinal vein occlusion, exudative age-related macular degeneration, cystoid macular edema, hyphema, ranibizumab.
References 1. Ranchod T, Walsh M, Capone A, et al. Hyphema after intravitreal injection of ranibizumab or bevacizumab. Retinal Cases Brief Rep 2011;5:87–90. 2. Mansour AM. Visual loss from hyphema following intravitreal bevacizumab [published online ahead of print 2010]. BMJ. doi: 10.1136/bcr.12.2009.2520. 3. Mason JO, Frederick PA, Neimkin MG, et al. Incidence of hemorrhagic complications after intravitreal bevacizumab (Avastin) or ranibizumab (Lucentis) injection on systemically anticoagulated patients. Retina 2010;30:1386–1389. 4. Begg IS. Significance of goniohaemorrhage in heretochromic cyclitis. Br J Ophthalmol 1969;53:1–8. 5. Sharei V, Hohn F, Kohler T, et al. Course of intraocular pressure after intravitreal injection of 0.05 ml of ranibizumab (Lucentis). Eur J Ophthalmol 2010;20:174–179.
