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Show Journal of Cliniclll Neuro-uphtlullmology 7(2): 87-91, 1987. © 1987 Raven Press, New York Ischemic Optic Neuropathy Secondary to Intracarotid Infusion of BeND Lance Pickrell, M.D., and Valerie Purvin, M.D. A 39-year-old man with a left parietal malignant glioma was treated with intracarotid infusion of l,3-bis(2-chloroethyl)- l-nitrosourea (BeND). Five weeks after a second infusion, he developed inferior altitudinal visual field loss and pallid optic disc edema ipsilateral to the injection. Retinal vasculitis is a well-recognized complication of intra-arterial BeND infusion. It is believed that this patient suffered a similar vasculopathy in the posterior ciliary artery circulation. Key Words: l,3-Bis(2-chloroethyl)-1-nitrosourea-Optic disc-Visual field. From the Departments of Ophthalmology (L.P. and V.P.) and Neurology (V.P.), Indiana University School of Medicine, Indianapolis, Indiana. Address correspondence and reprint requests to Valerie Purvin, M.D., Midwest Eye Institute, 1800 North Capitol Avenue, Indianapolis, IN 46202, U.S.A. 87 l,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) is a nitrosourea compound used in the treatment of a variety of malignant tumors. Its potential for causing toxic ocular side effects was initially recognized in dogs (1) and subsequently described in cancer patients undergoing BCND treatment via intravenous (2) and intra-arterial BCND infusion (3). Intracarotid administration of BCND was developed in an attempt to deliver a higher concentration of drug to the tumor bed. With intracarotid infusion, the level of BCND reaching the tumor, and hence the eye and adnexa, is four times greater than via the intravenous route (4). While this technique has allowed the use of a lower total dosage, thus decreasing the systemic toxicity, it has led to a significant increase in the incidence of ocular side effects. Both acute and delayed forms of ocular toxicity have been described. The former usually consists of transient ipsilateral orbital pain, conjunctival injection, chemosis, and periorbital swelling during and immediately following infusion (3). Delayed toxicity typically takes the form of retinal vasculitis characterized by arteriolar narrowing, nerve fiber infarcts, and intraretinal hemorrhages (5-8). We had the opportunity to examine a patient in whom intra-arterial BCND led to delayed infarction of the optic nerve head in the absence of the typical findings of retinal vasculopathy. CASE REPORT A 39-year-old white man was evaluated for a 3month history of headache, mild visual blurring, and memory impairment. A computed tomographic (CT) scan revealed a large, low-density lesion in the left parietal region, which enhanced following contrast infusion (Fig. 1). Cerebral angiography confirmed the presence of an avascular 88 1. PICKRELL AND V. PURVIN mass. On September 25, 1984, he underwent craniotomy for biopsy and partial resection of the tumor. Pathologic examination showed the tumor to be a gemistocytic astrocytoma. He was admitted to the Brain Tumor Study Group protocol and received a total radiation dosage of 6,000 rads in October 1984. Concomitantly he received two courses of intra-arterial BCND therapy via the left internal carotid artery. On October 10, 1984, he received 415 mg BCND dissolved in 100 ml sterile water, followed by 404 mg BCND dissolved in sterile water on December 17, 1984. After the completion of therapy he manifested a mild language disturbance, but the results of neurologic examination were otherwise normal. Follow-up CT scan showed a decrease in the tumor mass. In mid-January 1985, he experienced an episode of transient dysphasia, followed a few days later by severe headache associated with numbness and incoordination of the right hand. On January 22 he was admitted for evaluation. Neurologic examination revealed mild dysphasia and general slowness of responses but otherwise showed normal results. CT scan showed an increase in mass effect of the tumor compared with previous scans. On January 24 he was seen in the neuro-ophthalmology clinic of Indiana University Medical Center. His vision was 20/20 in the right eye and 20/20 - 2 in the left. He identified 15 of 15 pseudoisochromatic plates with the right eye and 14 of 15 with the left. Pupils were 4 mm in each eye and reactive with no relative afferent defect. The visual field was normal in the right eye and slightly constricted in the left eye, with mild enlargement of the blind spot (Figs. 2 and 3). Funduscopic exami- F!G. 1. Computed tomographic scan showing a large low-d>;!n~,ity enhancing mass in the left parietal region (arrows). .. I Gin Neuro-cphthalmol, Vol. 7, No.2, 1987 FIG. 2. Normal visual field in right eye. nation was normal in the right eye; the left optic disc was mildly swollen and hyperemic, with opacification of the adjacent nerve fib~r layer. On January 29 his vision was 20/15 In each eye, but he now had developed a left relative afferent pupillary defect. Goldmann perimetry revealed a normal field in the right eye and an inferior altitudinal defect and slight overall constriction in the left eye (Fig. 4). There was increased left optic disc edema and mild pallor of the superior portion of the nerve head; the right fundus remained normal (Figs. 5 and 6). On January 31 his vision was still 20/15 bilaterally, and the visual fields were not significantly changed, but funduscopic examination showed _--+-__ 14 FIG. 3. Initial visual field in left eye showing mild generalized constriction and enlargement of the physiologic blindspot. BCNU AND ISCHEMIC OPTIC NEUROPATHY 89 FIG. 4. Visual field in left eye 5 days after presentation showing an inferior altitudinal defect that is more severe nasally. increased left disc edema with superior pallor and some irregularity of peripapillary retinal vessels. Careful indirect ophthalmoscopic examination again failed to show any nerve fiber infarcts or retinal hemorrhages. Rapid-sequence fluorescein angiography showed left optic disc hyperfluorescence and some areas of mild capillary nonperfusion in the posterior pole (Fig. 7). On February 26 his vision was 20/15 in the right eye and 20/40 in the left eye. The visual field in the left eye was more constricted superotemporally but was unchanged centrally and still exhibited inferior altitudinal loss. There was a left relative afferent pupillary defect, superior disc pallor with FIG. 5. Normal right optic disc on January 29,1985. resolution of edema, and no retinal abnormalities (Fig. 8). The visual examination has been stable since that time. DISCUSSION BCNU is a chemotherapeutic drug of the nitrosourea type, which interferes with RNA, DNA, and protein synthesis. It achieves high levels in the brain owing to its lipophilic nature and small molecular size, which allows it to pass the bloodbrain barrier freely (9). It is currently used in the treatment of a wide variety of neoplasms, especially cerebral metastases and malignant gliomas. Ophthalmologic complications of intravenous BCND administration were first reported by McLennan and Taylor (2). They described a case of bilateral optic neuroretinitis occurring 8 days after systemic chemotherapy for plasma cell leukemia with a combination of BCND, procarbazine, cyclophosphamide, and prednisolone. Failure of vision progressed rapidly to no light perception in both eyes. There was slow return of vision over 6 weeks until the patient expired. Greenburg et al. were the first to report significant ocular toxicity secondary to intra-arterial BCND (5,6). This consisted of unilateral retinal exudates and hemorrhages developing in four of six patients -3 weeks after the second or third course of chemotherapy. Three of the four patients progressed to blindness. Fluorescein angiograms in two patients showed an arterial phase leak consistent with toxic retinal vasculitis. The ophthalmic FIG. 6. Left optic disc on January 29, 1985 showing edema inferiorly (arrow) and pallor superiorly. J Clin Neuro-ophthalmol, Vol. 7, No.2, 1987 90 L. PICKRELL AND V. PURVIN FIG. 7. Fluorescein angiogram in the left eye 1 week after presentation showing intense leakage from the optic disc and patchy areas of capillary nonperfusion. artery was normal on repeat internal carotid angiography (10). Shingleton et al. described in detail the constellation of ocular side effects in seven of 10 patients treated with intra-arterial BCNU (3). They described ipsilateral visual loss accompanied by retinal infarcts, arterial narrowing, nerve fiber layer thickening, flame-shaped hemorrhages, and disc elevation. These manifestations occurred from 2 to 14 weeks following the second or third course of chemotherapy, with an average interval of 6 weeks. FIG. 8..Left optic disc 1 month after presentation. The edema IS gone, and marked superior pallor is evident (large, black arrow). Contrast with pinker lower disc I(Qp8n'Hrow). Note white beaded perivasculitic lei SiOnS.~Sni~i1 tli~cj(arrows). , Clin Neuro-ophthalmol, Vol. 7, No.2, 1987 More unusual complications of intra-arterial BCNU infusion have included corneal edema (11), anterior segment neovascularization and glaucoma (8,11), opacity of lens and vitreous (11), internal ophthalmoplegia (7), and fibrosis of extraocular muscles (12). There has been some controversy regarding the relative contribution to toxicity of the alochol diluent used to dissolve the BCNU. Greenberg et al. reported a decreased incidence of retinal toxicity from 38 to 7% when the alcohol diluent was decreased from 2 to 0.75 ml/100 mg BCNU (6). Unfortunately, studies have shown a 30% decrease in drug recovery from the manufacturer's bottle when the ethanol diluent is so decreased (13). Subsequently Miller et al. described significant visualloss in eight of 11 patients treated with intraarterial BCNU and/or cisplatinum (7). In all these cases the BCNU was dissolved in 5% dextrose solution. Thus, while the ethanol may playa role in the toxic side effects, BCNU alone appears to be sufficient to cause such complications. The risk of toxicity has been found to be greater with higher doses and with multiple courses of treatment (3,6,8). No relationship has been found between dosage and final visual outcome (7). The overall occurrence of ocular toxicity following BCNU infusion has been lowered by the more recently introduced technique of supra-ophthalrnic artery injection (14). BCNU ocular toxicity is thought to be due to segmental intraretinal vasculitis and/or obstruction (3). The site of injury is most likely the vascular endothelium, as suggested by Miller et al. (7). This would be consistent with the delayed onset of ischemic changes following infusion. Pathologic documentation of the nature of this insult is scanty. DeWhys and Fowler found necrotizing arteriolitis in the carotid circulation of dogs 8 to 15 days following intra-arterial BCNU (1). Three ?f four dogs treated in this manner developed retmal and corneal edema leading to blindness. One patient treated with intravenous BCNU and suff~ ring from bilateral nerve fiber layer infarcts and ~ISC edema was found at autopsy to have cilioretmal artery occlusion and fibrin thrombi in the choroidal circulation (2). Ou.r patient developed unilateral optic disc swellIng 5 weeks following a second intracarotid inf~sion o~ Bcr~U. Although it was initially unassocIated WIth vIsual loss, an altitudinal field defect and afferent pupillary defect developed within seve~al days. The observation of pallid disc swellmg and the nature of the visual field defect led to a diagnosis of disc infarction. The appear- BCNU AND ISCHEMIC OPTIC NEUROPATHY 91 ance of disc swelling in advance of visual loss has been well described previously in cases of idiopathic anterior ischemic optic neuropathy (13). Such a phase of asymptomatic disc edema may in fact be fairly common but unappreciated, since patients are not generally examined until visual loss has already occurred. Some of the previously reported cases of BCNU-related ocular toxicity have included the observation of optic disc swelling (3,6-8); however, in each case the findings of retinal pathology, mainly retinal artery attenuation, retinal hemorrhages, and cotton-wool spots, were predominant. In our patient, the clinical findings were those of an acute optic neuropathy rather than a retinopathy. Fluorescein angiography did show areas of capillary nonperfusion, similar to that seen in the more typical cases of retinal vasculopathy, but other characteristic features were lacking. We believe our patient suffered a toxic vasculitis affecting the posterior ciliary circulation and leading to infarction of the prelaminar portion of the optic nerve. To our knowledge, this particular sequela to BCNU has not been previously reported. REFERENCES 1. DeWys WD, Fowler EH. Report of vasculitis and blindness after intracarotid injection of 1,3-bis(2-ehlorethyl)-1-nitrosourea (BeNU; NSC-409962) in dogs. Cancer Chemother Rep 1973;57:33-40. 2. McLennan R, Taylor HR. Optic neuroretinitis in associa-tion with BCNU and procarbazine therapy. Med Pediatr 0nc011978;4:43-8. 3. Shingleton BJ, Bienfang DC, Albert OM, et al. Ocular toxicity associated with high-dose carmustine. Arch Opthalmol 1983;100:1766-72. 4. Crafts DC, Levin VA, Nielson S. Intracarotid BCNU (NSC-409962): a toxicity study in six rhesus monkeys. Cancer Treat Rep 1976;60:541-5. 5. Greenberg HS, Ensminger WD, Seeger JF, et al. Intra-arterial BCNU chemotherapy for the treatment of malignant gliomas of the central nervous system: a primary report. Cancer Treat Rep 1981;65:803-10. 6. Greenberg HS, Ensminger WD, Chandler WF, et al. Intraarterial BCNU chemotherapy for treatment of malignant gliomas of the central nervous system. J Neurosurg 1984;61:423-9. 7. Miller OF, Bay JW, Lederman RJ, et al. Ocular and orbital toxicity following intracarotid injection of BCNU (carmustine) and cisplatinum for malignant gliomas. Ophthalmology 1985;92:402-6. 8. Grimson BS, Mahaley MS Jr, Dubey HO, Dudka L. Ophthalmic and central nervous system complications following intracarotid BCNU (carmustine). JClin Neuro-OphthalmoI1981; 1:261-4. 9. Oliverio VT. Toxicology and pharmacology of the nitrosoureas. Cancer Chemother Rep 1973;4:13-20. 10. Gebarski 55, Greenberg HS, Gabrielsen TO, Vine AK. Orbital angiographic changes after intracarotid BCNU chemotherapy. AJNR 1984;5:55-8. 11. Kapp J, Vance R, Parker jL, Smith RR. Limitations of high. dose intra-arterial 1,3-bis(2-chloroethyl)-I-nitrosourea (BeND) chemotherapy for malignant gliomas. Neurosurgery 1982;10;715-9. 12. Kapp]P, Ross RL, Tucker EM. Supraophthalmic carotid infusion for brain-tumor chemotherapy: a technical note. J Neurosurg 1983;58:616-8. 13. Foulds WS. Ischemic optic neuropathy. In: Cant JS, ed. Proceedings of the William Mackenzie Center Symposium on the ocular circulation in health and disease. London: Kimpton, 1968:136-41. 14. Levin VA, Kabra PM, Freeman-Dove MA. Pharmacokinetics of intracarotid artery ItC-BCNU in the squirrel monkey. J Neurosurg 1978;48:587-93. JClin Neuro-ophtlullmol. Vol. 7, No.2, 1987 |
