INTRAVITREAL BEVACIZUMAB FOLLOWED BY LASER PHOTOCOAGULATION FOR RETINAL CAPILLARY HEMANGINOBLASTOMAS Eylem Yaman Pinarci, MD,* Humeyra Karacal, MD,† Berna Demirel, MD‡
Purpose: To report a patient with retinal capillary hemangioblastomas associated with Von Hippel–Lindau syndrome who achieved long-term visual improvement with single intravitreal bevacizumab injection followed by laser photocoagulation. Methods: Intravitreal bevacizumab injection was performed in a 17-year-old girl with bilateral multiple retinal capillary hemangioblastomas. Laser photocoagulation was then performed to augment the initial response to bevacizumab. The visual acuity, fundus photography, fundus fluorescein angiography, and ocular coherence tomography were obtained at each visit. The patient was followed-up for 3 years. Results: Two weeks after injection, the macular edema and exudation significantly decreased with an improvement in the visual acuity. Laser photocoagulation performed 2 weeks after the intravitreal bevacizumab injection provided further regression of exudation and scarring of the hemangioblastomas. No further intervention was required, and the visual acuity returned to baseline at the third year of follow-up. Conclusion: Combined intravitreal bevacizumab with laser photocoagulation is a viable option in retinal capillary hemangioblastomas associated with Von Hippel–Lindau syndrome. RETINAL CASES & BRIEF REPORTS 6:76–79, 2012
diagnosis. In the absence of family history, at least two visceral hemangioblastomas or one RCH and a visceral hemangioblastoma are necessary for diagnosis. Some advocate molecular genetic testing.2 Retinal capillary hemangioblastoma is the most common manifestation of VHL syndrome and is seen in more than half of patients with VHL disease. The most frequent and earliest manifestation of VHL syndrome is RCH. Retinal capillary hemangioblastoma may also occur sporadically. Age at presentation, degree of visual impairment, morphology, and anatomical location of sporadic tumors are similar to those seen in VHL syndrome.3 Retinal capillary hemangioblastomas can cause loss of vision because of macular edema, lipid deposition, exudative retinal detachment, and tractional retinal detachment. Treatment decisions are based on size, location, extent of the subretinal fluid and retinal traction. Many experts recommend early treatment because of the tendency of RCH to enlarge, the difficulty in treating larger lesions, and the better visual outcome with smaller
From the *Department of Ophthalmology, School of Medicine, Baskent University, Ankara, Turkey; †Department of Ophthalmology, Washington University, St Louis, Missouri; and ‡Department of Ophthalmology, Beyoglu Eye Education and Research Hospital, Istanbul, Turkey.
V
on Hippel–Lindau (VHL) syndrome is an autosomal dominant, multisystem cancer syndrome. It is associated with retinal and visceral hemangioblastomas and other tumors, such as cerebellar hemangioblastomas, renal cell carcinomas, pheochromocytomas, and pancreatic and epididymal tumors.1 The diagnosis of VHL syndrome is based on family history or clinical presentation of a visceral or retinal capillary hemangioblastoma (RCH) or both. If there is a family history, presence of either visceral or RCH is necessary for The authors report no conflicts of interest to disclose. _ Cad. Reprint requests: Eylem Yaman Pinarci, MD, Mahir Iz No 43 Altunizade, Istanbul 34662, Turkey; e-mail: dreyaman@ hotmail.com
76
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lesions. Careful observation is suggested for lesions ,500 mm in diameter that are not associated with exudation, without subretinal fluid and if they are not visually threatening.1,4 Possible treatment options are laser photocoagulation, cryotherapy, anti–vascular endothelial growth factor (VEGF) treatment or combination therapy.4–8 Recent studies5,6 showed that therapeutic response to the multiple intravitreal pegaptanib (Macugen, Pfizer, New York, NY) and ranibizumab (Lucentis, Novartis, Basel, Switzerland) are limited. Combination therapies of intravitreal bevacizumab with photodynamic therapy (PDT)7 or retrobulbar steroid injection with argon laser photocoagulation and PDT had a long-lasting effect.8 Case Report A 17-year-old girl presented with sudden, painless, unilateral, decreased vision. Her medical and ocular histories were unremarkable. Family history was significant for VHL syndrome in her maternal grandmother, mother, and maternal aunt. All her relatives had cerebellar hemangioblastomas and RCHs. On ocular examination, visual acuity was 20/30 in the right eye and 20/20 in the left eye. The results of external examination, motility, pupil reaction, intraocular pressures, and anterior segment examination were normal. Ophthalmoscopy revealed multiple peripheral RCHs in both the eyes with hard exudate and macular edema in the right eye. There was serous macular detachment on ocular coherence
77 tomography in the right eye (Figure 1A). The central macular thickness was 299 mm in the right and 194 mm in the left eye. Fundus fluorescein angiography showed hyperfluorescence of the tumor vessels with leakage. As the patient had a strong family history of VHL syndrome, we made the diagnosis of RCHs associated with VHL syndrome. The initial neuroimaging with magnetic resonance imaging, abdominal ultrasound, and urinary vanilmandelic acid was unrevealing. After discussion about the options of treatment (observation, argon laser photocoagulation, intravitreal anti-VEGF agent injection, or PDT), consent was obtained to perform intravitreal bevacizumab injection in the right eye. Bevacizumab (1.25 mg) was injected into the vitreous of the right eye. The left eye was observed. The patient was seen 2 weeks after the initial injection. Visual acuity returned to 20/20 in the right eye, and the patient noticed decreased scotoma. The serous detachment regressed with decreased macular edema on fundus photographs and on ocular coherence tomography (central macular thickness decreased from 299 mm to 229 mm in the right eye) (Figure 1B). Although the patient’s vision improved, hemangioblastomas were not totally destroyed, so she was offered laser photocoagulation to prevent recurrent leakage. She agreed for supplemental argon laser photocoagulation. All peripheral RCHs in both the eyes were directly photocoagulated using argon laser. She was followed-up every month during the first 6 months and then every 6 months. At 1 year of follow-up, hemangioblastomas regressed in both the eyes. The central macular thickness remained stable with normal visual acuity in both the eyes without recurrence (228 mm in the right eye, 208 mm in the left eye). At the third year of follow-up, visual acuity and ocular coherence tomography stayed stable (Figure 1C). The feeding vessel was less
Fig. 1. A. Colored fundus photograph of the right eye showing the RCH and exudative detachment (top) with ocular coherence tomography of the macula (both horizontal [middle] and vertical [bottom] cuts). B. Same area, 2 weeks after intravitreal bevacizumab injection showing decreased exudation and macular thickness. C. Fundus photograph 3 years after bevacizumab injection and laser photocoagulation showing resolved macular exudate and thickness.
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engorged and tortuous in the left eye after laser photocoagulation of the distal hemangioblastoma, and the ocular coherence tomography results were normal (Figure 2, A and B). After 3 years of initial presentation, syncope episodes developed in the patient. Subsequent cranial magnetic resonance imaging showed cerebellar hemangioblastoma. She underwent excision of the cerebellar hemangioblastoma. At that time, she had normal vision.
Discussion The course of RCHs is usually progressive, and visual prognosis is not favorable because of macular exudation and serous or tractional retinal detachment.1,4 The location and size of the RCH and the presence of exudation determine the therapy. Laser photocoagulation, cryotherapy, radiation therapy, and transpupillary thermotherapy are available; intravitreal injection of anti-VEGF agents is another option for treatment.5–7 The pathogenesis and growth of VHL-associated tumors are reported to be related with VEGF.9 As such, anti-VEGF agents administered intravitreally may be useful for RCH.5,6 Wong et al5 reported five patients with VHLassociated RCH, who received intravitreal ranibizumab. Two patients showed a significant resolution; one patient received additional argon laser photocoagulation, one patient stayed stable, and macular edema increased in two patients. These patients received an average of 10 6 3.1 intravitreal injections. Dahr et al6 reported a small case series of five people. They administered intravitreal pegaptanib, at least
6 times, 6 weeks apart. The patients were followed-up for 1 year. Their outcome was not very favorable because progressive macular edema developed in three patients and another patient had tractional retinal detachment. Only one patient had an improved vision by 3 Snellen lines. The authors did not observe tumor regression and attributed this to the less dependence of large retinal hemangioblastomas on VEGF, for growth. They proposed other proinflammatory cytokines and bioactive breakdown products as stimulating factors for tumor growth. The other reason might be that pegaptanib inhibits the isoform VEGF 165 only. Mennel et al7 reported intravitreal injection of bevacizumab in conjunction with PDT in a patient. This patient had sporadic juxtapapillary RCH and received five intravitreal bevacizumab injections with two sessions of PDT, over a 5-month period. The patient’s vision improved from 20/60 to 20/40. They reported combination of intravitreal anti-VEGF agents with PDT to be an effective strategy but warned against the possible exacerbation of exudation if treatment with anti-VEGF agents is administered after PDT. We used argon laser to destroy the hemangioblastomas after intravitreal bevacizumab injection. Our patient had multiple retinal hemangioblastomas in the periphery, so argon laser was less likely to cause further loss of vision. We herein reported a patient with VHL-associated RCH, where single intravitreal injection of bevacizumab followed by argon laser photocoagulation resolved exudative detachment and improved vision,
Fig. 2. A. Colored fundus photograph of the left eye showing peripheral retinal hemangioblastoma with tortuous feeding vessel (top) and normal macula (middle) and ocular coherence tomography image (bottom). B. Same area, 3 years after argon laser photocoagulation of the peripheral retinal hemangioblastoma showing decreased tortuosity of the vessel (top) and normal ocular coherence tomography (bottom).
RETINAL CAPILLARY HEMANGINOBLASTOMAS
without significant complications. We are aware that more randomized, prospective, controlled studies are needed to determine the best treatment strategies in patients with RCHs. Conclusion Intravitreal anti-VEGF injection followed by argon laser photocoagulation or PDT is an effective therapy for patients with RCHs. In combined treatments, antiVEGF agents should be introduced before PDT or argon laser application. These patients should be followed closely for the possibility of other organ involvement. Key words: anti-VEGF, Avastin, retinal capillary hemangioblastoma, bevacizumab, laser photocoagulation, Von Hippel–Lindau syndrome. References 1. Singh AD, Shields CL, Shields JA. Von Hippel-Lindau disease. Surv Ophthalmol 2001;46:117–142.
79 2. Kreusel KM, Bechrakis NE, Heinichen T, Neumann L, Neumann HP, Foerster MH. Retinal angiomatosis and von Hippel-Lindau disease. Graefes Arch Clin Exp Ophthalmol 2000;238:916–921. 3. Webster AR, Maher ER, Bird AC, Gregor ZJ, Moore AT. A clinical and molecular genetic analysis of solitary ocular angioma. Ophthalmology 1999;106:623–629. 4. Singh AD, Nouri M, Shields CL, Shields JA, Perez N. Treatment of retinal capillary 4-hemangioblastoma. Ophthalmology 2002; 109:1799–1806. 5. Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology 2008;115:1957–1964. 6. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina 2007;27:150–158. 7. Mennel S, Meyer CH, Callizo J. Combined intravitreal antivascular endothelial growth factor (Avastin) and photodynamic therapy to treat retinal juxtapapillary capillary haemangioma. Acta Ophthalmol 2010;88:610–613. 8. Fortunato M, Di Pietro R, Gravina L, Maggi R, Ubaldi A, Vadala` P. Photodynamic therapy in von Hippel-Lindau disease in children. J Pediatr Ophthalmol Strabismus 2009;46:376–379. 9. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2:673–682.
Purpose: To report a patient with retinal capillary hemangioblastomas associated with Von Hippel–Lindau syndrome who achieved long-term visual improvement with single intravitreal bevacizumab injection followed by laser photocoagulation. Methods: Intravitreal bevacizumab injection was performed in a 17-year-old girl with bilateral multiple retinal capillary hemangioblastomas. Laser photocoagulation was then performed to augment the initial response to bevacizumab. The visual acuity, fundus photography, fundus fluorescein angiography, and ocular coherence tomography were obtained at each visit. The patient was followed-up for 3 years. Results: Two weeks after injection, the macular edema and exudation significantly decreased with an improvement in the visual acuity. Laser photocoagulation performed 2 weeks after the intravitreal bevacizumab injection provided further regression of exudation and scarring of the hemangioblastomas. No further intervention was required, and the visual acuity returned to baseline at the third year of follow-up. Conclusion: Combined intravitreal bevacizumab with laser photocoagulation is a viable option in retinal capillary hemangioblastomas associated with Von Hippel–Lindau syndrome. RETINAL CASES & BRIEF REPORTS 6:76–79, 2012
diagnosis. In the absence of family history, at least two visceral hemangioblastomas or one RCH and a visceral hemangioblastoma are necessary for diagnosis. Some advocate molecular genetic testing.2 Retinal capillary hemangioblastoma is the most common manifestation of VHL syndrome and is seen in more than half of patients with VHL disease. The most frequent and earliest manifestation of VHL syndrome is RCH. Retinal capillary hemangioblastoma may also occur sporadically. Age at presentation, degree of visual impairment, morphology, and anatomical location of sporadic tumors are similar to those seen in VHL syndrome.3 Retinal capillary hemangioblastomas can cause loss of vision because of macular edema, lipid deposition, exudative retinal detachment, and tractional retinal detachment. Treatment decisions are based on size, location, extent of the subretinal fluid and retinal traction. Many experts recommend early treatment because of the tendency of RCH to enlarge, the difficulty in treating larger lesions, and the better visual outcome with smaller
From the *Department of Ophthalmology, School of Medicine, Baskent University, Ankara, Turkey; †Department of Ophthalmology, Washington University, St Louis, Missouri; and ‡Department of Ophthalmology, Beyoglu Eye Education and Research Hospital, Istanbul, Turkey.
V
on Hippel–Lindau (VHL) syndrome is an autosomal dominant, multisystem cancer syndrome. It is associated with retinal and visceral hemangioblastomas and other tumors, such as cerebellar hemangioblastomas, renal cell carcinomas, pheochromocytomas, and pancreatic and epididymal tumors.1 The diagnosis of VHL syndrome is based on family history or clinical presentation of a visceral or retinal capillary hemangioblastoma (RCH) or both. If there is a family history, presence of either visceral or RCH is necessary for The authors report no conflicts of interest to disclose. _ Cad. Reprint requests: Eylem Yaman Pinarci, MD, Mahir Iz No 43 Altunizade, Istanbul 34662, Turkey; e-mail: dreyaman@ hotmail.com
76
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lesions. Careful observation is suggested for lesions ,500 mm in diameter that are not associated with exudation, without subretinal fluid and if they are not visually threatening.1,4 Possible treatment options are laser photocoagulation, cryotherapy, anti–vascular endothelial growth factor (VEGF) treatment or combination therapy.4–8 Recent studies5,6 showed that therapeutic response to the multiple intravitreal pegaptanib (Macugen, Pfizer, New York, NY) and ranibizumab (Lucentis, Novartis, Basel, Switzerland) are limited. Combination therapies of intravitreal bevacizumab with photodynamic therapy (PDT)7 or retrobulbar steroid injection with argon laser photocoagulation and PDT had a long-lasting effect.8 Case Report A 17-year-old girl presented with sudden, painless, unilateral, decreased vision. Her medical and ocular histories were unremarkable. Family history was significant for VHL syndrome in her maternal grandmother, mother, and maternal aunt. All her relatives had cerebellar hemangioblastomas and RCHs. On ocular examination, visual acuity was 20/30 in the right eye and 20/20 in the left eye. The results of external examination, motility, pupil reaction, intraocular pressures, and anterior segment examination were normal. Ophthalmoscopy revealed multiple peripheral RCHs in both the eyes with hard exudate and macular edema in the right eye. There was serous macular detachment on ocular coherence
77 tomography in the right eye (Figure 1A). The central macular thickness was 299 mm in the right and 194 mm in the left eye. Fundus fluorescein angiography showed hyperfluorescence of the tumor vessels with leakage. As the patient had a strong family history of VHL syndrome, we made the diagnosis of RCHs associated with VHL syndrome. The initial neuroimaging with magnetic resonance imaging, abdominal ultrasound, and urinary vanilmandelic acid was unrevealing. After discussion about the options of treatment (observation, argon laser photocoagulation, intravitreal anti-VEGF agent injection, or PDT), consent was obtained to perform intravitreal bevacizumab injection in the right eye. Bevacizumab (1.25 mg) was injected into the vitreous of the right eye. The left eye was observed. The patient was seen 2 weeks after the initial injection. Visual acuity returned to 20/20 in the right eye, and the patient noticed decreased scotoma. The serous detachment regressed with decreased macular edema on fundus photographs and on ocular coherence tomography (central macular thickness decreased from 299 mm to 229 mm in the right eye) (Figure 1B). Although the patient’s vision improved, hemangioblastomas were not totally destroyed, so she was offered laser photocoagulation to prevent recurrent leakage. She agreed for supplemental argon laser photocoagulation. All peripheral RCHs in both the eyes were directly photocoagulated using argon laser. She was followed-up every month during the first 6 months and then every 6 months. At 1 year of follow-up, hemangioblastomas regressed in both the eyes. The central macular thickness remained stable with normal visual acuity in both the eyes without recurrence (228 mm in the right eye, 208 mm in the left eye). At the third year of follow-up, visual acuity and ocular coherence tomography stayed stable (Figure 1C). The feeding vessel was less
Fig. 1. A. Colored fundus photograph of the right eye showing the RCH and exudative detachment (top) with ocular coherence tomography of the macula (both horizontal [middle] and vertical [bottom] cuts). B. Same area, 2 weeks after intravitreal bevacizumab injection showing decreased exudation and macular thickness. C. Fundus photograph 3 years after bevacizumab injection and laser photocoagulation showing resolved macular exudate and thickness.
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engorged and tortuous in the left eye after laser photocoagulation of the distal hemangioblastoma, and the ocular coherence tomography results were normal (Figure 2, A and B). After 3 years of initial presentation, syncope episodes developed in the patient. Subsequent cranial magnetic resonance imaging showed cerebellar hemangioblastoma. She underwent excision of the cerebellar hemangioblastoma. At that time, she had normal vision.
Discussion The course of RCHs is usually progressive, and visual prognosis is not favorable because of macular exudation and serous or tractional retinal detachment.1,4 The location and size of the RCH and the presence of exudation determine the therapy. Laser photocoagulation, cryotherapy, radiation therapy, and transpupillary thermotherapy are available; intravitreal injection of anti-VEGF agents is another option for treatment.5–7 The pathogenesis and growth of VHL-associated tumors are reported to be related with VEGF.9 As such, anti-VEGF agents administered intravitreally may be useful for RCH.5,6 Wong et al5 reported five patients with VHLassociated RCH, who received intravitreal ranibizumab. Two patients showed a significant resolution; one patient received additional argon laser photocoagulation, one patient stayed stable, and macular edema increased in two patients. These patients received an average of 10 6 3.1 intravitreal injections. Dahr et al6 reported a small case series of five people. They administered intravitreal pegaptanib, at least
6 times, 6 weeks apart. The patients were followed-up for 1 year. Their outcome was not very favorable because progressive macular edema developed in three patients and another patient had tractional retinal detachment. Only one patient had an improved vision by 3 Snellen lines. The authors did not observe tumor regression and attributed this to the less dependence of large retinal hemangioblastomas on VEGF, for growth. They proposed other proinflammatory cytokines and bioactive breakdown products as stimulating factors for tumor growth. The other reason might be that pegaptanib inhibits the isoform VEGF 165 only. Mennel et al7 reported intravitreal injection of bevacizumab in conjunction with PDT in a patient. This patient had sporadic juxtapapillary RCH and received five intravitreal bevacizumab injections with two sessions of PDT, over a 5-month period. The patient’s vision improved from 20/60 to 20/40. They reported combination of intravitreal anti-VEGF agents with PDT to be an effective strategy but warned against the possible exacerbation of exudation if treatment with anti-VEGF agents is administered after PDT. We used argon laser to destroy the hemangioblastomas after intravitreal bevacizumab injection. Our patient had multiple retinal hemangioblastomas in the periphery, so argon laser was less likely to cause further loss of vision. We herein reported a patient with VHL-associated RCH, where single intravitreal injection of bevacizumab followed by argon laser photocoagulation resolved exudative detachment and improved vision,
Fig. 2. A. Colored fundus photograph of the left eye showing peripheral retinal hemangioblastoma with tortuous feeding vessel (top) and normal macula (middle) and ocular coherence tomography image (bottom). B. Same area, 3 years after argon laser photocoagulation of the peripheral retinal hemangioblastoma showing decreased tortuosity of the vessel (top) and normal ocular coherence tomography (bottom).
RETINAL CAPILLARY HEMANGINOBLASTOMAS
without significant complications. We are aware that more randomized, prospective, controlled studies are needed to determine the best treatment strategies in patients with RCHs. Conclusion Intravitreal anti-VEGF injection followed by argon laser photocoagulation or PDT is an effective therapy for patients with RCHs. In combined treatments, antiVEGF agents should be introduced before PDT or argon laser application. These patients should be followed closely for the possibility of other organ involvement. Key words: anti-VEGF, Avastin, retinal capillary hemangioblastoma, bevacizumab, laser photocoagulation, Von Hippel–Lindau syndrome. References 1. Singh AD, Shields CL, Shields JA. Von Hippel-Lindau disease. Surv Ophthalmol 2001;46:117–142.
79 2. Kreusel KM, Bechrakis NE, Heinichen T, Neumann L, Neumann HP, Foerster MH. Retinal angiomatosis and von Hippel-Lindau disease. Graefes Arch Clin Exp Ophthalmol 2000;238:916–921. 3. Webster AR, Maher ER, Bird AC, Gregor ZJ, Moore AT. A clinical and molecular genetic analysis of solitary ocular angioma. Ophthalmology 1999;106:623–629. 4. Singh AD, Nouri M, Shields CL, Shields JA, Perez N. Treatment of retinal capillary 4-hemangioblastoma. Ophthalmology 2002; 109:1799–1806. 5. Wong WT, Liang KJ, Hammel K, Coleman HR, Chew EY. Intravitreal ranibizumab therapy for retinal capillary hemangioblastoma related to von Hippel-Lindau disease. Ophthalmology 2008;115:1957–1964. 6. Dahr SS, Cusick M, Rodriguez-Coleman H, et al. Intravitreal anti-vascular endothelial growth factor therapy with pegaptanib for advanced von Hippel-Lindau disease of the retina. Retina 2007;27:150–158. 7. Mennel S, Meyer CH, Callizo J. Combined intravitreal antivascular endothelial growth factor (Avastin) and photodynamic therapy to treat retinal juxtapapillary capillary haemangioma. Acta Ophthalmol 2010;88:610–613. 8. Fortunato M, Di Pietro R, Gravina L, Maggi R, Ubaldi A, Vadala` P. Photodynamic therapy in von Hippel-Lindau disease in children. J Pediatr Ophthalmol Strabismus 2009;46:376–379. 9. Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2002;2:673–682.
