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Show Hyperbaric Oxygen Therapy in the Treatment of Radiation Optic Neuropathy Amina Malik, MD, Karl Golnik, MD, MEd Abstract: Radiation optic neuropathy (RON) is characterized by the rapid onset of painless irreversible vision loss in one or both eyes. We report 4 consecutive patients who presented with unilateral or asymmetric bilateral RON. All had bilateral optic nerve enhancement on MRI and were treated with hyperbaric oxygen (HBO) and oral corticoste-roids. In the less affected eye, 2 of the 4 patients had preservation of vision, while in the other 2 patients, vision declined. No patient showed improvement in the more symptomatic eye, and in 2 patients, there was a significant decline in visual acuity. Our findings suggest that prompt treatment with HBO and oral corticosteroids may result in visual preservation in the less affected eye despite the presence of optic nerve enhancement on MRI. Journal of Neuro-Ophthalmology 2012;32:128-131 doi: 10.1097/WNO.0b013e3182464c88 © 2012 by North American Neuro-Ophthalmology Society Radiation optic neuropathy (RON) is an uncommon but devastating condition characterized by the rapid onset of painless irreversible visual loss, in one or both eyes. Most affected eyes have a final visual acuity of less than 20/200 and many progress to complete blindness (1,2). The onset varies from 3 months to more than 8 years after radiation therapy, with most cases developing between 8 and 12 months (3-5). Using external beam radiotherapy, this condition usually develops in cumulative doses greater than 50 Gy or fraction-ated doses greater than 2 Gy (6). Risk factors include older age, diabetes mellitus, and concurrent chemotherapy (7). Diagnosis is based on the appropriate clinical setting of an irreversible optic neuropathy in the absence of other causes. MRI typically shows the enhancement of the optic nerve(s) or chiasm (8,9). In patients in whom both optic nerves or the chiasm are exposed to radiation, it has been estimated that 75% will have bilateral involvement, with the second eye becoming affected within weeks of the first (1). Spontaneous visual recovery almost never occurs with typical RON (1,4), and treatment with either corticosteroids or heparin has been unsuccessful (9,10). Angiotensin-converting enzyme inhibitors have been shown in rat models to prevent the development of RON, but their clinical usefulness is yet to be determined (11). While hyperbaric oxygen (HBO) therapy was first described as successful treatment for RON in 1986 (12), its efficiency remains controversial (13). We report a retrospective case series of 4 consecutive patients who presented with unilateral or asymmetric RON and underwent treatment with HBO and oral corticosteroids. CASE REPORTS Case 1 A 61-year-old woman reported a 5-day history of dimin-ished vision in her right eye. She had been treated 12 months previously for brain metastasis from lung cancer, receiving a total of 30 Gy, with fractionated doses of 3.0 Gy. Visual acuity was light perception, right eye, and 20/25, left eye with mild right optic disc pallor. The right automated visual field was generally constricted, and the left was normal. MRI showed bilateral optic nerve enhancement (Fig. 1). The patient was prescribed 60 mg of oral prednisone daily with a 1-month taper and received HBO of 2.5 atm, 60 minutes/ day for 1 month. Following completion of this treatment regimen, there was resolution of enhancement on MRI, and 1 year after the initial presentation, visual acuity was no light perception, right eye, and 20/25, left eye. Case 2 A 47-year-old woman with a 3-month history of mildly blurred vision in the left eye reported acute onset of near complete left vision loss. She had a papillary adenocarcinoma of the pleural space with brain metastasis that required radiation therapy 7 months prior to her presentation. She had received a total radiation dose of 36.4 Gy, with a Department of Ophthalmology, Cincinnati Eye Institute, University of Cincinnati, Cincinnati, Ohio. The authors report no conflicts of interest. Address correspondence to Amina Malik, 260 Stetson, Suite 5300, Cincinnati, OH 45267; E-mail: aminamalikr@gmail.com 128 Malik and Golnik: J Neuro-Ophthalmol 2012; 32: 128-131 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. fractionated dose of 2.6 Gy. Initial neuro-ophthalmic examination showed visual acuity of 20/20, right eye, and counting fingers, left eye, with a left relative afferent pupillary defect. The rest of her ocular examination was unremarkable, with the exception of mild temporal left optic nerve pallor. Automated visual fields showed superior and inferior nerve fiber bundle defects in the right eye and gen-eralized constriction in the left eye. MRI disclosed bilateral intracranial optic nerve enhancement. Two days after the presentation, she was started on a 6-week taper of 60 mg of prednisone/day and HBO treatment of 2.5 atm, 90 minutes/ day for 3 months. MRI was repeated at 3 months and showed resolution of optic nerve enhancement. At that time, acuity was 20/25, right eye, and counting fingers, left eye. Automated visual fields remained unchanged, and visual function was stable 15 months later. Case 3 A 57-year-old woman awoke with a sudden loss of vision in her right eye. Several months prior to presentation, the patient was treated with radiation for a retroclival chordoma with left sphenoid wing involvement. She received 70.2 Gy of total radiation, with fractionated dose of 1.8 Gy. Her visual acuity was 20/50, right eye, and 20/25, left eye, with a right relative afferent pupillary defect. The remainder of her examination was notable for mild bilateral optic nerve pallor. Automated visual fields showed superior altitudinal loss in the right eye, and the left visual field was normal. One week later, visual acuity declined to hand motions in the right eye. MRI showed enlargement and enhancement of the optic chiasm. At that time, the patient was started on 60 mg of oral prednisone per day with a 6-week taper and HBO treatment of 2.5 atm, 90 minutes/day for 3 months. At the 3-month follow-up, her vision had worsened to light perception, right eye, and 20/200, left eye, with diffuse pallor of both optic nerves. Repeat MRI showed resolution of chiasmal enhancement; 2.5 years after the initial pre-sentation, vision was no light perception, right eye, and light perception, left eye. Case 4 A 70-year-old man complained of superior visual field loss in his left eye for 1 week. He had been treated with a total dose of 60 Gy of radiotherapy 6 months prior to presen-tation for non-Hodgkin lymphoma involving the paranasal sinuses and nasopharynx. Fractionated radiation dose was unavailable. Visual acuity was 20/25, right eye, and 20/80, left eye, with left relative afferent pupillary defect. The right optic disc appeared normal, while the left optic disc was mildly pale. Automated visual field testing on the right was normal with a superior arcuate scotoma on the left. MRI showed left greater than right optic nerve enhancement of the intracranial portion of the optic nerves. Nine days after presentation, the patient was started on a 2-week course of oral prednisone, and HBO treatment of 2.5 atm, 60 minutes/day for 1 month. Three months later, visual acuity was 20/30, right eye, and counting fingers, left eye. Automated visual field showed mild diffuse depression in the right eye and progression of superior altitudinal loss in the left eye. Nine months after presentation, the patient returned with acute onset of decreased right visual acuity of 20/50. While the right optic disc appeared normal, superior and inferior arcuate scotomas were now detected in the right visual field. MRI showed mild right optic nerve enhancement. The next day, the patient began treatment with 60 mg of oral prednisone with a 2-month taper and HBO therapy of 2.5 atm, 60 minutes/day for 6 weeks. After 1 month of treatment, the patient's vision was 20/100, right eye, and hand motions, left eye, with bilateral optic disc pallor. Six weeks later, MRI demonstrated resolution of right optic nerve enhancement. Three years after vision loss in the right eye and 4 years after vision loss in the left eye, the patient's acuity was 20/100, right eye, and hand motions, left eye. DISCUSSION RON is a known complication of external beam radiation (EBR) therapy. The degree of visual loss is usually severe and may progress to total blindness. We report 4 patients who presented with unilateral or asymmetric RON with bilateral optic nerve or chiasm enhancement on MRI. All of our patients were given radiation doses above the accepted safe limit to avoid RON. Two of the 4 patients (Cases 1 and 2) demonstrated preservation of vision in the less affected eye after treatment within 2 weeks of presen-tation with oral corticosteroids and HBO therapy. One FIG. 1. Patient 1. Contrast-enhanced T1 axial MRI with fat suppression shows enhancement of the intracranial seg-ments (arrows) of both optic nerves. Malik and Golnik: J Neuro-Ophthalmol 2012; 32: 128-131 129 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. patient (Case 4) experienced a decline in vision from 20/25 to 20/100 in the less affected eye and was treated 9 days after the initial visual loss. Another patient (Case 3) progressed from 20/25 to light perception vision in the less affected eye, despite treatment within 7 days of noting vision loss. Yet, this patient received a large total radiation dose (70.2 Gy) and had bilateral optic nerve pallor at the initial presentation. Total and fractionated dosages of radiation have been shown to correlate with the risk for the development of RON. In a series of patients who received radiation for nasal and paranasal sinus tumors, there was an increased incidence of visual pathway damage with higher radiation doses (14), and only patients who received greater than 50 Gy developed RON. In a case series of patients who received radiation for head and neck tumors, RON was noted only with total dosages greater than 59 Gy and those individuals who received fractionated doses greater than 1.9 Gy were more likely to develop RON (15). However, Roden et al (4) described the onset of RON among 13 patients who received EBR for tumors near the optic chiasm, with doses as low as 45 Gy (4). In our series, all patients received either total dose greater than 50 Gy or fractionated dose greater than 2.0 Gy. Diabetes mellitus, increasing age, and concurrent chemo-therapy have been shown to increase the susceptibility to RON (16). One of our patients (Case 1) was diabetic, and none were undergoing concurrent chemotherapy. Ages ranged from 47-70 years. The pathogenesis of RON is thought to occur by delayed radionecrosis. In the rat model, a time-dependent and dose-sensitive pathologic reaction in endothelial cells has been demonstrated with subsequent blood-brain barrier disrup-tion (17). Human optic nerves have shown depletion of vascular endothelial cells after radiation (18). Radiation is also thought to induce somatic mutations in glial cells, which gradually increase over time, causing demyelination and neu-ronal degeneration (19). The observations are consistent with a latent period of delayed RON, as both glial and endothelial cells have slow cellular turnover rate. Pathologic specimens of optic nerves with RON showed ischemic demyelination, reactive astrocytosis, endothelial hyperplasia, obliterative endarteritis, and fibrinoid necrosis (2,3). HBO therapy consists of delivery of near 100% oxygen, usually between 2 and 3 atmospheres of pressure. Treatment is given in a pressurized chamber with a series of "dives" of variable duration, generally from 30 to 60 minutes. In the setting of radionecrosis, oxygen levels are thought to be too low to support angiogenesis (20). Inducing an artificially high oxygen concentration is thought to disrupt the ongoing ischemic necrosis, and enhance fibroblastic activity, collagen synthesis, and angiogenesis in irradiated tissues (21,22). In 1996, Borruat et al (1) reported 2 of 4 patients with RON who received HBO and experienced improvement in visual function. They recommended commencing treatment within 3 days of vision loss at greater than or equal to 2.4 atm for 30 dives of 90 minutes each. The 2 patients in our study who experienced visual decline in the less affected eye began treatment 7 and 9 days after initial vision loss, while the 2 patients who had preserved vision were treated at 2 and 5 days after the onset of visual decline. All received more than 30 days of 100% oxygen at 2.5 atm for at least 60 minutes/day. In 2006, Levy and Miller (23) performed a Medline review of HBO treatment of RON. Finding highly variable results, they recommended HBO in only select cases of recent visual loss without optic nerve pallor. In our 2 patients (Cases 1 and 2) who maintained good visual acuity in the less affected eye, the optic disc appeared nor-mal. In the 2 cases in which vision declined in the less affected eye, initially one (Case 3) had optic disc pallor while the other (Case 4) had a normal optic disc. Known ophthalmic side effects of HBO therapy include dry eye, reversible myopic shift, and cataract (only shown in patients undergoing 150 total hours of treatment) (24,25). Other less common but more severe adverse effects include otic barotrauma, reversible bronchopulmonary toxicity, and seizures. All our patients tolerated HBO therapy well. One patient experienced a reversible myopic shift (−4.50 diopters). In treating RON, systemic corticosteroids have been used for their antioxidative effects, but results have been disap-pointing (1,2,23). All patients in our series received oral corticosteroids with adjuvant HBO, so the effect of cortico-steroids independently on visual outcome is uncertain. The data on effective treatment of RON remain limited and controversial. Our results suggest that if patients are identified early in their course and prior to the development of optic nerve pallor, timely treatment with oral cortico-steroids and HBO may result in the preservation of vision in the less affected eye despite the presence of optic nerve enhancement on MRI. REFERENCES 1. Borruat F-X, Shatz NJ, Glaser JS, Matos L, Feuer W. Radiation optic neuropathy: report of cases, role of hyperbaric oxygen therapy, and literature review. J Neuroopthalmol. 1996;16:255-266. 2. Miller NR. Radiation-induced optic neuropathy: still no treatment. Clin Experiment Ophthalmol. 2004;24:243-250. 3. Kline LB, Kim JY, Ceballos R. Radiation optic neuropathy. Ophthalmology. 1985;92:1118-1126. 4. 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