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Show Journal of Neuro- Oplithalinology 17( 3): 195- 198, 1997. © 1997 Lippincott- Ravcn Publishers, Philadelphia Ocular and Orbital Complications of Intraarterial Cisplatin A Case Report Helen M. Wu, M. D., Andrew G. Lee, M. D., Daniel E. Lehane, M. D. T. Linda Chi, M. D., and Richard Alan Lewis, M. D. Despite advances in neurosurgery, radiation oncology, and chemotherapy, the prognosis for glioblastoma multiforme remains poor, with a median survival time of 11 - 12 months. Cisplatin ( tls- diamminedichlorideplatinum II) is one treatment for glioblastoma multiforme. Higher response rates have been achieved by intraarterial ( IA) infusion than by systemic infusion of this agent. Cisplatin therapy may cause neurologic complications, and IA delivery has been reported to cause ocular toxicity. We report a patient who experienced intraorbital and intraocular toxicity following supraophthalmic IA injection of cisplatin. Key Words: Cisplatin- Intra- arterial. Manuscript received September 10, 1996; accepted November 8, 1996. From the Departments of Ophthalmology ( H. M. W., A. G. L., R. A. L.), Neurology ( A. G. L.), Neurosurgery ( A. G. L.), Oncology ( D. E. L.), and Neuroradiology ( T. L. C.), Baylor College of Medicine, Houston, Texas, U. S. A. Address correspondence and reprint requests to Dr. Andrew G. Lee, Cullen Eye Institute, Baylor College of Medicine, One Baylor Plaza, NC- 200, Houston, TX 77030, U. S. A. Direct intraarterial ( IA) infusion of chemothera-peutic agents has been utilized for recurrent intracranial malignant glioma. The response rate of this treatment modality is variable and has reported at 30- 70% ( 1). We describe ocular and orbital complications following a course of supraophthalmic IA cisplatin ( ds- diamminedichlorideplatinum II; DDP) therapy for malignant cerebral glioma. CASE REPORT A 26- year- old white woman presented with headache, nausea, and vomiting in March 1995. Neuro-imaging revealed a large tumor of the right frontal lobe ( 6 x 5 x 5 cm), for which she underwent partial surgical resection. Evaluation of the pathology demonstrated glioblastoma multiforme with extensive areas of necrosis and prominent vascular proliferation. Because the patient was 20 weeks pregnant at the time of diagnosis, she chose to defer both postoperative radiation and chemotherapy. After delivery, an initial course of right supraophthalmic IA DDP and oral cyclohexylchloroethyl nitrosourea ( CCNU) was administered in August 1995. The patient developed seizures, left- sided hemiparesis, and cerebral edema, which was thought to be related to this chemotherapy. The patient was readmitted in September 1995 for her second course of IA DDP. CT scan of the head at that time showed marked reduction in size of the frontal lobe tumor and substantial improvement in cerebral edema. The right internal carotid artery was catheterized via a transfemoral approach, and a no. 18 tracker catheter was inserted coaxially and positioned in the supraclinoid internal carotid artery above the origin of the ophthalmic artery. The supraophthalmic position of the catheter tip was confirmed during fluoroscopy. There was no evidence of retrograde flow during the preinjection or injection phases. Cisplatin 200 mg was infused over 1 h, and the patient tolerated the procedure without difficulty. Approximately 36 h later, however, she developed extreme right facial and periorbital edema, proptosis, and che-mosis. 195 196 H. M. WU ET AL. Neuro- ophthalmologic examination revealed a complete right upper lid ptosis, and right facial and periorbital erythema and edema. Seven millimeters of relative proptosis of the right eye was measured by Hertel exophthalmometry. Visual acuity in the right eye was bare light perception and in the left eye was 20/ 20. She identified no Ishihara color plates with the right eye, but had normal responses with the left eye. The right pupil measured 8 mm and was not reactive to light. The left pupil measured 5 mm and reacted normally to light. Evaluation of ocular motility revealed 15 prism diopters of right hypo-tropia by Krimsky and a complete right ophthalmoplegia ( Fig. 1). The left eye moved normally. Slit-lamp examination of the right eye revealed 360° of conjunctival chemosis and injection, a clear cornea, and mild inflammation in the anterior chamber. Intraocular pressure measured by applanation was 12 mm Hg in each eye. Ophthalmoscopy revealed pallid optic disc edema of the right eye, multiple serous pigment epithelial detachments of various sizes, choroidal folds in the posterior retina, and an inferonasal serous retinal detachment. The left fundus was normal. The patient was treated empirically with high-dose intravenous corticosteroid. CT scan of the head and orbits showed soft- tissue hyperdensity in the subcutaneous fat of the right face, temporal fossa, orbital fat, and preseptal space. The superior ophthalmic veins on the two sides were symmetric, and there was no evidence for an orbital or facial hematoma. Multiple curvilinear densities in the intra- and extra-conal fat of the right orbit were present, consistent with engorged vascular structures. However, there was no evidence for a dural- arterial shunt vessel. Fluorescein angiography of the right eye revealed extensive retinal nonperfusion in the posterior pole ( Fig. 2). Three months later, visual acuity of the right eye was light perception with persistence of a fixed and dilated pupil. A right afferent pupillary defect and complete ophthalmoplegia remained. Advanced optic atrophy and diffuse coarse granularity of the retinal pigment epithelium ( RPE) was noted in the right eye ( Fig. 3). The examination of the left eye remained normal. The patient died in February 1996- 11 months after presentation. DISCUSSION Patients with glioblastoma multiforme have a poor prognosis despite recent advances in surgery, radiation therapy, and chemotherapy ( 1). Intracarotid administration of chemotherapeutic agents results in a higher local concentration of drug and a higher tissue level. Targeted intracerebral infusion of antineoplastic agents via the internal carotid artery has shown promise as a potential treatment and may lessen systemic side effects. The known toxic effects of DDP include nausea and vomiting, nephrotoxicity, ototoxicity, electrolyte abnormalities, myelosuppresion, peripheral neuropathy, encephalopathy, seizure, and vascular ischemic events leading to stroke and myocardial infarcts ( 2). DDP administered intravenously has been reported to cause such ocular complications as optic disc swelling, retrobulbar neuritis ( 3), transient cortical visual impairment, and seizures ( 4). Ostrow et al. ( 3) theorized that DDP, in the same family of heavy FIG. 1. Orbital appearance and motility at presentation. Note orbital congestion and edema, chemosis, ptosis, and complete ophthalmoplegia of the right eye. J Neuro- Ophthalmol, Vol. 17, No. 3, 1997 OCULAR AND ORBITAL COMPLICATIONS OF CISPLATIN 197 FIG. 2. By the arteriovenous phase of the angiogram, large areas of hypofluorescence of the macula and peripapillary choroid are present. Note the soft fluorescence of poorly marginated pigment epithelial detachments. metal elements as gold, mercury, and lead, may have a direct toxic effect on the optic nerves or indirectly may result in increased intracranial pressure. Walsh et al. ( 5) described a patient with bilateral optic disc swelling and loss of deep tendon reflexes after i. v. DDP. Subsequent pathologic study in that patient revealed thickening of the nerve fiber layer, degeneration and gliosis of the dorsal columns, and substantial axonal loss in the dorsal roots. These findings support a neurotoxic effect of DDP on optic nerves and CNS axons. FIG. 3. Three months after presentation, the photograph of the right fundus documents vascular attenuation, optic atrophy, and widespread granularity and atrophy of the macular pigment epithelium. Ocular and orbital complications reported after intracarotid DDP administration have included ipsi-lateral orbital pain ( 1), periorbital erythema and edema, cavernous sinus syndrome ( 6), transient and permanent retinal damage confirmed by electroreti-nogram ( ERG), and permanent blindness ( 1). Miller et al. ( 6) described an " unusual pigmentary retinopathy" with RPE mottling and retinal vessel attenuation in a patient treated with intracarotid DDP alone. Kupersmith et al. ( 7) described macular and paramacular RPE mottling after infraophthal-mic intracarotid DDP infusion in three of eight patients. Interestingly, the diffuse- flash ERG and electrooculogram responses were normal in both their affected and unaffected patients; in other series, ERG responses have shown an increase in rod threshold and depression of the scotopic b- wave ( 7). The etiology and source of variability of these effects are unknown, but may arise from either direct heavy metal toxicity, a localized retinal pigmentary disturbance with indirect effects on photoreceptors ( 7), a toxic vasculopathy, or a primary retinal neuropa-thy ( 6). Measures to reduce the toxicity of intracarotid DDP administration include concomitant IA steroids, heparin, filtration of medication, and variations in drug dosage, infusion time, and delivery ( 1). To avoid the ocular complications of IA chemotherapy, specialized catheters have been developed to deliver drugs in the supraclinoid internal carotid artery above the origin of the ophthalmic artery ( 8). Kupersmith et al. ( 9) studied patients with malignant gliomas treated with IA DDP or BCNU either proximal or distal to the origin of the ophthalmic artery. Of the eight patients receiving supraophthalmic DDP, none developed visual system defects. Three of the five patients given infraopthalmic DDP experienced visual loss, with either diffuse retinal ischemia and necrosis or retrobulbar optic neuritis. In contrast, Shimamura et al. ( 10) described a case of temporal hemianopsia and left eye blindness with histopathologic confirmation of optic nerve and tract degeneration despite supraophthalmic administration of chemotherapy. In our patient, orbital and ocular toxicity developed despite a definite angiographically monitored supraophthalmic delivery of DDP. Although pigmentary retinopathy has been reported after IA DDP, it probably represents the late sequela of DDP toxicity. To our knowledge, ours is the first case to demonstrate the early and acute orbital, ocular, and retinal toxicity of DDP after IA administration. Despite the fact that retrograde flow was not demonstrated by the cerebral angiography and the catheter was felt to be supraophthalmic during the procedure., retrograde flow may have accounted for the ocular and orbital complications in this patient. Although supraophthalmic delivery of DDP may reduce the risk of orbital and ocular toxicity compared with other locations of J Neuro- Ophthalmol, Vol. 17, No. 3, 1997 198 H. M. WU ET AL. administration, our experience illustrates the potential, substantive complications of IA DDP. Acknowledgment: This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc. REFERENCES 1. Stewart DJ, Wallace S, Feun L, et al. A phase I study of intracarotid artery infusion of cis- diamminedichloroplatinum ( II) in patients with recurrent malignant intracerebral tumors. 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