From the Ulucanlar Eye Research Hospital, Ankara, Turkey.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Ufuk Elgin, MD, 24 Sokak, 13/4 06490, Bahcelievler, Ankara, Turkey.
Neurofibromatosis type 1 (NF-1) is a hereditary syndrome that shows associated ocular manifestations such as plexiform neurofibromas of the eyelid, Lisch nodules in the iris, congenital glaucoma, optic glioma, retinal astrocytic hamartomas, retinal capillary hemangiomas, combined hamartomas of the retina and retinal pigment epithelium, branch retinal vein occlusion, macular lesions, microvascular retinal abnormalities, and abnormal development of the orbital bones.1–8 This report describes the association of NF-1 and peripheral retinal ischemia–induced neovascular glaucoma, which to the best of our knowledge has not been reported previously.
Our presentation was approved by the Ethics Committee of our institution and informed consent was obtained from the patient’s parents.
A 12-year-old girl with NF-1 was referred to the emergency clinic of Ankara Ulucanlar Eye Research Hospital for ophthalmic evaluation for pain, redness, and blurred vision in her right eye for the past 2 weeks. Her medical history was significant for the presence of NF-1, which had been diagnosed 7 years ago. She had multiple cutaneous café-au-lait spots, freckles, and neurofibroma on her neck, trunk, axillary area, and extremities, which had been confirmed by a skin biopsy performed by a dermatologist. She had no other systemic problems, such as diabetes mellitus, hypertension, or nephropathy. Her mother and two sisters also had multiple cutaneous café-au-lait spots and mass lesions, but did not have ocular complaints.
Ophthalmic examination of the left eye revealed normal findings except for Lisch nodules on the iris, an open angle, and best-corrected visual acuity of 20/20. The visual acuity of the right eye was 20/200 and slit-lamp examination revealed conjunctival hyperemia, central corneal microcystic edema, and rubeosis. The intraocular pressure (IOP) was 48 mm Hg in the right eye and 17 mm Hg in the left eye by Goldmann applanation tonometer. Gonioscopy disclosed neovascularization, peripheral anterior synechiae, and abundant basal iris processes throughout nearly the entire angle in her right eye.
Fundus examination revealed glaucomatous optic atrophy and dense vitreous haze, retinal exudates, neovascularization, and multiple dilated and tortuous collateral channels. An arteriovenous communication bridged the perfused and nonperfused retina in the far peripheral region of the inferior retina (Fig. 1). Fundus fluorescein angiography revealed retinal ischemia and hyperfluorescence caused by leakage from these pathological vessels in the same retinal region in the middle and late angiographic phases (Fig. 2). A clinical diagnosis of peripheral retinal ischemia associated with possible microvascular retinal abnormalities was considered in view of the fundus findings and she was hospitalized.
Figure 1. Color Fundus Photograph Shows Dilated and Tortuous Collateral Channels and Vitreous Haze Located in the Inferior Far Peripheral Part of the Retina.
Figure 2. Fundus Fluorescein Angiography Shows Ischemia and Hyperfluorescence Caused by Leakage from the Pathological Vessels in the Same Retinal Region in the Middle and Late Angiographic Phases.
Blood biochemistry tests, complete blood count, erythrocyte sedimentation rate, TORCH test, anti-converting enzyme level, HLA analysis, ELISA tests for acquired immunodeficiency syndrome and hepatitis, chest and skull x-rays, and urine analysis were performed. Polymerase chain reaction analysis with vitreous sample was performed. The pediatric hematology and neurology departments were also consulted.
The IOP of the right eye was 30 mm Hg on the second day of the maximal medical treatment (topical timolol maleate–dorzolamide fixed combination, brimonidine and oral dorzolamide 3 × 125 mg), which had been begun immediately after the diagnosis. Because of the failure of medical treatment, she under-went trabeculectomy with mitomycin C 3 days after intravitreal bevacizumab injection to control the IOP, which was 6 mm Hg on the first postoperative day.
One week after the surgery, retinal photocoagulation by argon laser was performed (Fig. 3). The visual acuity was 20/80, the IOP was 8 mm Hg without medications, and there was no leakage on fundus fluorescein angiography at the third week after laser treatment. She had no pain, redness, or irritation. The IOP was under control during the 4-month follow-up period without any anti-glaucoma medications.
Figure 3. Color Fundus Photograph of Inferior Peripheral Retina 3 Weeks After Retinal Photocoagulation.
At the final visit (at the fifth postoperative month), the visual acuity was 20/80 and slit-lamp examination revealed peripheral iridectomy and diffuse bleb at the 12-o’clock position. The IOP was 22 mm Hg and there was no leakage or any other retinal pathology according to ocular examination and fundus fluorescein angiography. Gonioscopy revealed peripheral iridectomy, peripheral anterior synechiae, and abundant basal iris processes throughout nearly 270° of the angle in her right eye. Complete regression of rubeosis was detected on slit-lamp and gonioscopic examinations. Timolol maleate–dorzolamide fixed combination was begun to control IOP, which was 15 mm Hg after 1 week.
Optic glioma, retinal astrocytic hamartomas, retinal capillary hemangiomas, combined hamartomas of the retina and retinal pigment epithelium, and micro-vascular retinal abnormalities are the retinal manifestations of NF-1 reported previously.1–8 Mori et al. reported a 64-year-old case of NF-1 with branch retinal vein occlusion.5 Thölen et al.,6 Moadel et al.,7 and Kadoi et al.8 have reported young cases of NF-1 similar to ours. Their cases had similar unilateral retinal vascular occlusive diseases. In all three reports, a long-standing decrease of arterial inflow and retinal vascular occlusive disorder were thought to be the causes of progressive retinal ischemia. However, none of their cases had rubeosis or neovascular glaucoma like ours.
Although the exact mechanism of vascular pathology is unclear, hyperproliferation of vascular mural cells (pericytes) and endothelial cells is thought to be a cause of vascular occlusion and neovascularization in NF-1.9 Ozerdem investigated an ischemia-induced corneal and retinal angiogenesis model in 24 eyes in mice in which malignant peripheral nerve sheath tumor xenografts were established by using human tumor cell lines derived from patients with NF1.9 According to his study, NF-1 gene mutations have been reported to cause an increased proliferation of pericytes and endothelial cells that might increase the angiogenic response of the retina to ischemia. Also, loss of neurofibromin expression in endothelial cells might alter the interactions between endothelial cells and pericytes, which could be the reason both cell types proliferate and cause vascular occlusion.9 We also thought the retinal ischemia in our case was associated with this hypothesis. All of these cases reported before had unilateral retinal vascular occlusion like ours. The exact mechanism of this unilaterality is not clear and we think it is by chance.
Glaucoma is also one of the ocular manifestations of the disease.10,11 Cases of NF-1 with congenital glaucoma have been reported before, but, to the best of our knowledge, no case of NF-1 with neovascular glaucoma has been reported. In our case, arteriolar occlusion associated with microvascular abnormalities and peripheral retinal ischemia was thought to be the cause for neovascular glaucoma. It is possible that a vitreal hemorrhage from these new vessels may have played a role in the formation of vitreal opacities in the inferior region. In addition, vasculitis associated with sarcoidosis, pars planitis, or any other cause, sickle cell retinopathy, retinal telangiectasia, and acute retinal necrosis were thought to be other probable mechanisms for neovascular glaucoma, but we excluded these pathologies based on results of the systemic tests or examinations performed before treatment and ocular examinations including fundus fluorescein angiography.
Bevacizumab, a humanized monoclonal antibody that binds to all isoforms of vascular endothelial growth factor, has shown promising results in regression of neovascularization and is well tolerated.12,13 Ehlers et al. reported that the combination of intravitreal bevacizumab injection and retinal photocoagulation was more effective than retinal photocoagulation alone for the treatment of neovascular glaucoma.12 We used the combination of intravitreal bevacizumab injection, retinal photocoagulation, and filtering surgery in the treatment of our case. We performed filtering surgery with mitomycin C 3 days after intravitreal bevacizumab injection. After the resolution of vitreous haze at the postoperative first week, we also performed retinal photocoagulation.
Our patient had an unusual association of NF-1 and peripheral retinal ischemia–induced neovascular glaucoma and, to the best of our knowledge, there have been no previous reports like our case. NF-1 should be considered a risk factor for retinal vascular occlusive disease associated with microvascular abnormalities and peripheral retinal ischemia. Our report also emphasizes the importance of the examination of the peripheral fundus in cases with NF-1.
- Destro M, D’Amico DJ, Gragoudas ES, et al. Retinal manifestations of neurofibromatosis: diagnosis and management. Arch Ophthalmol. 1991;109:662–666.
- Karadimas P, Hatzispasou E, Bouzas EA. Retinal vascular abnormalities in neurofibromatosis type 1. J Neuroophthalmol. 2003;23:274–275.
- Ruggieri M, Pavone P, Polizzi A, et al. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol. 2004;88:1429–1433. doi:10.1136/bjo.2004.043802 [CrossRef]
- McLoone EM, Buchanan TA. Unusual macular lesions in a patient with neurofibromatosis type-1. Int Ophthalmol. 2005;26:115–117. doi:10.1007/s10792-006-9002-0 [CrossRef]
- Mori F, Kawai M, Sato E, Igarishi S, Hikichi T, Yoshida A. Branch retinal vein occlusion in a Japanese patient with neurofibromatosis 1. Jpn J Ophthalmol. 2001;45:634–635. doi:10.1016/S0021-5155(01)00421-X [CrossRef]
- Thölen AM, Messmer EP, Landau K. Peripheral retinal vascular occlusive disorder in a young patient with neurofibromatosis 1. Retina. 1998;18:184–186.
- Moadel K, Yannuzzi LA, Ho AC, Ursekar A. Retinal vascular occlusive disease in a child with neurofibromatosis. Arch Ophthalmol. 1994;112:1021–1023.
- Kadoi C, Nagaki Y, Hayasaka S. Unilateral peripheral retinal vascular occlusion in a young Japanese woman with neurofibromatosis-1. Retina. 2003;23:541–543. doi:10.1097/00006982-200308000-00017 [CrossRef]
- Ozerdem U. Targeting neovascular pericytes in neurofibromatosis type 1. Angiogenesis. 2004;7:307–311. doi:10.1007/s10456-004-6643-3 [CrossRef]
- Payne MS, Nadell JM, Lacassie Y, Tilton AH. Congenital glaucoma and neurofibromatosis in a monozygotic twin: case report and review of the literature. J Child Neurol. 2003;18:504–508. doi:10.1177/08830738030180071101 [CrossRef]
- Castillo M, Quencer RM, Glaser J, Altman N. Congenital glaucoma and buphthalmos in a child with neurofibromatosis. J Clin Neuroophthalmol. 1988;8:69–71.
- Ehlers JP, Spirn MJ, Lam A, Sivalingam A, Samuel MA, Tasman W. Combination intravitreal bevacizumab/panretinal photocoagulation versus panretinal photocoagulation alone in the treatment of neovascular glaucoma. Retina. 2008;28:696–702. doi:10.1097/IAE.0b013e3181679c0b [CrossRef]
- Gheith ME, Siam GA, de Barros DS, Garg SJ, Moster MR. Role of intravitreal bevacizumab in neovascular glaucoma. J Ocul Pharmacol Ther. 2007;23:487–491. doi:10.1089/jop.2007.0036 [CrossRef]