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Show ORIGINAL CONTRIBUTION Ophthalmic Artery Occlusion Secondary to Radiation- Induced Vasculopathy Rita Singh, MD, Jonathan D. Trobe, MD, James A. Hayman, MD, and John P. Deveikis, MD Abstract: A 3 5- year- old man with neurofibromatosis type 1 ( NF1) had a left ophthalmic artery occlusion that caused no light perception OS 28 years after having been treated with external beam radiation therapy for a presumed glioma of the right optic nerve and chiasm. Clinical and imaging findings were consistent with radiation- induced cerebral vasculopathy. This ophthalmic complication has never been reported, despite the common occurrence of severe carotid- ophthalmic artery junction stenosis after radiation in NF1 patients. Even though modern radiation techniques limit collateral damage, this modality should be used with discretion in NF1 patients, given the vulnerability of their immature cerebral vasculature to radiation. ( JNeuro- Ophthalmol 2004; 24: 206- 210) Anterior visual pathway gliomas ( AVPG) are low- grade astrocytomas of the optic nerves and/ or chiasm that can also involve the hypothalamus. Without treatment some tumors remain indolent, but others will grow and compromise vision. The two nonsurgical treatment modalities are systemic chemotherapy and external beam radiation therapy ( 1,2). Although large reviews ( 3,4) attest to their ability to improve vision and survival and to stabilize or shrink the size of these tumors, no prospective, controlled study has ever been performed to verify their efficacy ( 1). The dangers of treatment with radiation in young children are well- documented. They consist primarily of cognitive deficits, hypopituitarism, bone growth abnormalities, second malignant neoplasms, and radiation-induced cerebral vasculopathy leading to stroke. In a retrospective study of 53 patients irradiated for AVPG, 17% had radiation- induced vasculopathy ( 5). A distinguishing risk factor was the presence of neurofibromatosis type 1 ( NF1), From the Departments of Ophthalmology ( Kellogg Eye Center) ( RS, JDT), Neurology ( JDT), Radiation Oncology ( JAH), and Neurosurgery and Radiology ( Neuroradiology) ( JPD), University of Michigan Medical Center, Ann Arbor, Michigan. Address correspondence to Jonathan D. Trobe, MD, Kellogg Eye Center, 1000 Wall Street, Ann Arbor, MI 48105; E- mail: jdtrobe@ umich. edu which increased the likelihood of this complication by fivefold. Other anecdotal reports have amplified the characteristics of radiation- induced cerebral vasculopathy ( 5- 14), disclosing that it may develop as early as five months after treatment, or as late as 15 years later. The angiographic changes include stenosis or occlusion of the large basal intracranial vessels, principally affecting the internal carotid artery, sometimes accompanied by dilation of net- like lep-tomeningeal and thalamic collaterals, creating the so- called moya moya pattern, named after the Japanese word for " puff of smoke." Most patients present with transient ischemic attacks or persistent cerebral hemispheric deficits ( contralateral hemiparesis, hemisensory paresthesias or numbness, dysarthria, dysphasia). Although occlusive disease of the internal carotid- ophthalmic artery junction has often been described, no visual deficits have been reported. We report the case of a 35- year- old man who suddenly became blind OS because of ophthalmic artery occlusion occurring 28 years after external beam radiation therapy for a presumed right optic nerve and chiasmal glioma. CASE REPORT A 35- year- old man had sudden painless visual loss OS. At age seven, NF1 and glioma of the right optic nerve and chiasm were diagnosed. He was treated with cobalt- 60 external beam radiation to a minimal dose of 50 Gy in 2 Gy fractions over 33 days using right and left 5x5 cm retro-orbital opposed lateral fields encompassing both optic nerves and the chiasm. His medical history included essential hypertension, well- controlled on an angiotensin-converting enzyme inhibitor. He had no other risk factors for arteriosclerosis. Three days before his sudden visual loss OS, he had undergone a routine ophthalmic examination that had disclosed best- corrected visual acuities of 20/ 200 OD, 20/ 20 OS with an afferent pupil defect OD, and pale optic discs OU. Three days after his acute visual loss OS, our examination disclosed a visual acuity of 20/ 200 OD and no light perception OS. An afferent pupil defect was present OS. Fundus examination of the OD showed a pale optic disc. 206 J Neuro- Ophthalmol, Vol. 24, No. 3, 2004 Ophthalmic Artery Occlusion JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Fundus examination of the OS disclosed a diffusely cloudy white retina with a cherry red spot and " box- car" blood flow within the arterioles and veins ( Fig. 1). His head had the " hour glass" deformity associated with hypoplasia of temporal bones because of treatment with radiation at a young age ( Fig. 2). Neurological examination was normal. Blood tests were negative for a hypercoagulability state. Magnetic resonance imaging ( MRI) revealed enlargement of the right optic nerve ( Fig. 3 A) and chiasm ( Fig. 3B), as well as focal increase in fluid attenuated inversion recovery ( FLAIR) signal in the white matter of left temporal ( Fig. 3C) and right basal frontal ( Fig. 3D) lobes. Magnetic resonance angiography ( MRA) suggested irregularities of the paraclinoid carotid arteries and severe stenosis or occlusion of the left posterior cerebral artery, ambient segment. Catheter cerebral angiography ( Fig. 4) confirmed that the right paraclinoid internal carotid artery was 25% narrowed and that the left paraclinoid internal carotid artery was 50% narrowed at the take- off of the ophthalmic artery. Both ophthalmic arteries were patent. There was abrupt occlusion of the left posterior cerebral artery. The right pericallosal artery was occluded and filled retrograde from leptomeninge-al collaterals. These angiographic abnormalities are compatible with radiation- induced vasculopathy. The patient was placed briefly on intravenous heparin and chronically on oral warfarin. Re- examination three months later revealed no change in visual function. DISCUSSION Twenty- eight years after conventional cobalt- 60 external beam radiation for an anterior visual pathway glioma, FIG. 1. Optic fundus, OS. The cloudy swelling of the posterior retina and cherry red spot are consistent with recent central retinal artery occlusion. The optic disc is pale from longstanding anterior visual pathway glioma. FIG. 2. An hourglass- shaped head caused by temporal muscle and bone atrophy from therapeutic radiation administered during the first decade of the patient's life for an anterior visual pathway glioma. our patient had complete loss of vision from ophthalmic artery occlusion in his only sighted eye. Given the angiographic findings, we presume that the primary cause is radiation- induced vasculopathy, with secondary contributions from his underlying NF1 and essential hypertension. This case is distinctive not only because of the extremely long interval between radiation and stroke but also because no such ophthalmic complication has been previously reported. Radiation- induced cerebral vasculopathy has been documented in more than 50 reported cases ( 14- 16). The majority of cases follow irradiation of tumors at the base of the middle cranial fossa in children aged younger than seven years. Angiographically, radiation- induced vasculopathy appears as steno- occlusive abnormalities of large intracranial vessels within the radiation field. In some cases, a rete of leptomeningeal collaterals bypasses the occluded trunk vessels to deliver blood to convexity cerebral arteries (" moya moya" pattern). Pathologically, radiation-induced vasculopathy appears as fibrous thickening of the intima with endothelial proliferation ( 17). Although many patients have acute, focal neurologic deficits, others may not have stroke, their vascular abnormalities discovered on routine follow- up of their tumors or in the investigation of chronic cognitive deficits. Patients who have the " moya moya" pattern may be better- protected against stroke because they have collateral channels. Vasculopathy, transient ischemic attack, and stroke occur as early as five months and as late as 15 years after radiation, with 36 207 JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Singh et al FIG. 3. The T1 - weighted enhanced axial MRI shows thickened right optic nerve ( A) and chiasm ( B), consistent with anterior visual pathway glioma. There is a focal increase in fluid attenuated inversion recovery ( FLAIR) signal in the white matter of the left temporal ( C) and right basal frontal ( D) lobes, consistent with radiation injury ( arrows). months being an average latency. Our case is a stand- out in that it occurred 28 years later. His systemic hypertension may have added to his vulnerability, but previous reports have not documented systemic hypertension as a risk factor for vascular complications of cranial radiation inNFl. Nearly 50% of cases of radiation- induced vasculo-pathy occur in children irradiated for AVPGs. Perhaps this is because so many patients with AVPG also have NF1, which is associated with a greatly increased likelihood of this complication. Nonirradiated NF1 patients may have identical angiographic and pathologic vascular abnormalities ( 18), but they are far less common or severe than those in NF1 patients who have been irradiated. The presence of NF1 not only increases the likelihood of vasculop-athy, it reduces the radiation dose needed to produce it ( 19,20). Is this complication less likely to occur with modern imaging and radiation treatment planning and delivery methods, which can more accurately define the target lesion and limit the dose of radiation to surrounding critical structures? Older treatment machines and techniques, which account for most of the reported vascular complications, delivered a high dose of radiation to the carotid siphon. Because the energy of the radiation emitted by cobalt- 60 is lower than the beams generated by modern linear accelerators, we would expect a lower dose to be delivered to the surrounding vasculature with modern methods. Proton beam therapy is ideally suited for this disease, given the relatively the discrete nature of the lesion and the ability to deposit a dose over a very short range because of the Bragg peak effect. The availability of MRI and software to accurately fuse computed tomograpgy and MRI data sets now allows radiation oncologists to target the glioma itself, TG^ r • V - 2k HJ • 1 FIG. 4. Cerebral angiogram. Lateral projections of right ( A) and left ( B) internal carotid injections show focal stenosis of paraclinoid segments of the internal carotid arteries ( large arrows), which is worse on the left. The ophthalmic arteries ( small arrows) are patent. There is occlusion of the ambient segment of the left posterior cerebral artery (*). Leptomeningeal collaterals from the right posterior cerebral artery reconstitute an occluded left pericallosal artery ( C). 208 © 2004 Lippincott Williams & Wilkins Ophthalmic Artery Occlusion JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 FIG. 5. A comparison of radiation treatment techniques used in treating chiasmal glioma. A: Isodose curves for 50 Gy delivered using cobalt- 60 and opposed lateral fields, as used in our patient 28 years ago. B: Isodose curves for 50 Gy delivered using megavoltage photons and an eight- field, noncoplanar, three- dimensional conformal treatment plan, as might be used today. The volumes being treated at each dose level are considerably smaller with the three- dimensional conformal technique than with the technique akin to that used in treating our patient. rather than a region encompassing the entire anterior visual pathway as was performed in this case. Improvements in hardware and software have also led to the use of three-dimensional conformal treatment techniques and optimized treatment plans that use intensity- modulated radiation therapy, both of which can achieve lower doses of radiation to surrounding normal structures ( Fig. 5). Given these advances in technique, the risk of a vascular complication would be significantly lower if such a patient were to undergo radiation treatment today. However, because of the proximity of these tumors to the vasculature and the possibility that even very low doses of radiation may cause vasculopathy ( 14,20), it is likely that the risk of such a complication in patients with NF1 will always exist. Chemotherapy should thus be used in place of radiation when young patients demonstrate growth of an AVPG or visual decline attributable to it ( 1). Radiation should be delayed as long as possible. REFERENCES 1. Listernick R, Louis DN, Packer RJ, et al. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the 10. 11. NF1 Optic Pathway Glioma Task Force. Ann Neurol 1997; 41: 143- 9. Halperin EC, Constine LS, Tarbell NJ, et al. Pediatric Radiation Oncology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins: 1999: 49- 50. Tao ML, Barnes PD, Billett AL, et al. Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. 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