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Show THE THIRD HOYT LECTURE William F. Hoyt, MD William Fletcher Hoyt, MD, professor emeritus of Ophthalmology, Neurology, and Neurosurgery, University of California, San Francisco, was born and raised in Berkeley, California. He took his undergraduate education at the University of California, Berkeley, and his medical education at the University of California, San Francisco ( UCSF). After a year's study at the Wilmer Institute, Johns Hopkins University, under the mentorship of Frank B. Walsh, MD, he returned to UCSF in 1958 to found the neuro-ophthalmology service. During a 36- year academic career- all of it at UCSF- he authored 266 journal articles, co- authored ( with Frank B. Walsh, MD) the biblical third edition of Clinical Neuro-ophthalmology, and trained 71 neuro- ophthalmology fellows. In 1983, he received the title of Honorary Doctor of Medicine from the Karolinska Institute. He is widely acknowledged as one of the titans of twentieth century neuro- ophthalmology. In recognition of his contributions, the North American Neuro- Ophthalmology Society ( NANOS), in conjunction with the American Academy of Ophthalmology, in 2001 initiated the Hoyt Lecture to be delivered each year at the Annual Meeting of the American Academy of Ophthalmology. Friendly Fire: Neurogenic Visual Loss From Radiation Therapy Simmons Lessell, MD Abstract: The author's experience and review of the medical literature suggest that radiation- induced neurogenic visual loss presents on average 18 months after treatment and usually after cumulative doses of radiation that exceed 50 Gy or single doses to the visual apparatus of greater than 10 Gy. Visual loss may result from lesions of the disc, retrobulbar segment of the optic nerve, optic chiasm, or retrogeniculate pathways. Magnetic resonance imaging, the best means of demonstrating radiation injury to the visual pathway, may show abnormalities before the loss of vision. The second eye may show clinical manifestations of optic neuropathy many months after the diagnosis in the first involved eye. Spontaneous improvement in visual function may rarely occur. Treatment has been disappointing, but if visual dysfunction is detected early, hyperbaric oxygen might be beneficial. The risk of neurogenic visual loss must be factored into the decision to irradiate the brain. ( JNeuro- Ophthalmol 2004; 24: 243- 250) The speed at which medical innovations are currently disseminated may seem unparalleled, but in the mid 1890s physicians were adopting new technologies with surprising alacrity. The application of ionizing radiation is a case in point. Withinmonths of Roentgen's 1895 discovery of x- rays, they were being used for diagnosis, and within 12 years for the treatment of brain tumors ( 1). In the modern Department of Ophthalmology, Harvard Medical School, and the Massachusetts Eye and Ear Infirmary, Boston, MA. Presented at the Annual Meeting of the American Academy of Ophthalmology, Anaheim, California, November 15- 18, 2003. Address correspondence to Simmons Lessell, MD, 243 Charles Street, Boston, MA 02114; E- mail: simmons_ lessell@ meei. Harvard. edu era, ophthalmologists and other physicians responsible for the management of patients with brain and orbital tumors often use ionizing radiation as primary or adjunctive therapy. Unfortunately, the proximity of these tumors to the visual apparatus makes it inevitable, at least in a very small percentage of recipients, that undesirable ocular and neurologic side effects of therapeutic radiation will occur. This presentation reviews a subset of these complications, namely those that involve the visual system. The term " friendly fire," applied to the inadvertent transmission of Creutzfeldt- Jakob disease in tissue grafts, seems appropriate in this context ( 2). PATHOPHYSIOLOGY OF RADIATION NEUROTOXICITY The twenty- first century radiation oncologist can select from several sources of radiation and multiple methods of delivery, all of which can be rather precisely focused ( 3). Regardless of the technique, the goal of radiation treatment remains the same- to maximize the dose delivered to the lesion while minimizing the dose to neighboring tissues. However, even with perfect planning and execution, the protection of normal tissue adjacent to the target cannot be assured. One explanation for this has recently been adduced ( 4). When cultured human skin fibroblasts are bombarded with alpha particles in quantities so low that only 1% of the cells are traversed by a particle, damage signals are transmitted to the adjacent bystander cells via gap junctions. The bystander effect has been documented by others, and nitric oxide may play a role in the process ( 5- 7). Nearly all the important neuro- ophthalmic complications of radiation therapy occur in a form called " late delayed radiation neurotoxicity," a predominantly white mat- J Neuro- Ophthalmol, Vol. 24, No. 3, 2004 243 JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Lessell " Simmons Lessell, Boston." His greeting tells you much about the man: clever, no middle name (" my family couldn't afford one"), precise, economical with words, and self- effacing ( no mention of Harvard). He was born and raised in Brooklyn, New York. A graduate of Stuyvesant High School, Amherst College, and Cornell University Medical College, he completed his medical internship at Bellevue Hospital, a year of neurology residency at the University of Vermont, and a two- year term at the Epidemiology and Genetics Branch of the National Institute of Neurological Diseases and Blindness ( including a year's stay on the lovely island of Guam). He then spent a year studying ocular histochemistry under the tutelage of Toichi Kuwabara, PhD, in the Howe Laboratory of the Massachusetts Eye and Ear Infirmary ( MEEI), Harvard Medical School, which was under the direction of David G. Cogan, MD. He went on to complete a residency in ophthalmology at MEEI, afterwards joining the faculty of Boston University and becoming director of its ophthalmology division at Boston City Hospital from 1966 to 1984. It was there that his interest in neuro- ophthalmology was stimulated by exposure to the two brilliant Harvard neurologists, Derek Denny- Brown, MD and Norman Geschwind, MD. In 1984, he returned to Harvard as Professor of Ophthalmology and Director of Neuro- Ophthalmology at the Massachusetts Eye and Ear Infirmary. Dr. Lessell's academic productivity has been enormous, with more than 200 superbly crafted, lean, precise, seminal articles. His publication list is an index of neuro- ophthalmology. It includes the first report of the Parkinson- dementia complex on Guam, ophthalmoplegia in myotonic dystrophy, the histochemical characteristics of animal optic nerves, laboratory models of cyanide intoxication, malignant optic nerve glioma, toxic and nutritional optic neuropathies, disorders of higher visual function, supranuclear paralysis of monocular elevation, the histopathology of experimental ethambutol intoxication, the syndrome of juvenile diabetes and optic atrophy, the neuro- ophthalmologic manifestations of systemic lupus erythematosus, ischemic optic neuropathy in patients with drusen, optic nerve hypoplasia and maternal diabetes mellitus, childhood pseudotumor cerebri, ocular neuromyotonia, perioperative posterior ischemic optic neuropathy, melanoma- associated retinopathy, indirect optic nerve trauma, ocular stroke in carotid dissection, giant cell arteritis, optic nerve sheath meningioma, Leber hereditary optic neuropathy, HIV optic neuropathy, radiation optic neuropathy, chiasmal syndromes, relapsing/ remitting neuro- ophthalmic signs from intracranial mass lesions, the differentiation of optic neuritis and ischemic optic neuropathy, and the Boston Prospective Study on Optic Neuritis. Dr. Lessell has been a consummate clinician and mentor to more than 30 fellows and hundreds of ophthalmology and neurology residents. Finding the best in all his tutees, he has taught them to practice high- quality medicine, to teach, and to write- all in an atmosphere of humor, warmth, and respect. With Irma, his partner of more than 50 years, he has made them a part of his extended family. He has been bestowed with countless distinguished teaching awards. Who among his tutees will soon forget the 16- foot lane, the " GFC", and the " thumb- screw" history? His legacy is a large, flowering branch on the family tree of neuro- ophthalmology. Simmons Lessell, MD ter disorder that develops months to years after treatment ( 8). Injury is initiated by the generation of free radicals when radiation damages the DNA of normal tissues. The primary site of cellular damage is the subject of some controversy, the leading suspects being the vascular endothelium and the neuroglial cell progenitors ( 9- 11). In theory, one would expect the latter to be the principal site, inasmuch as radiation predominantly damages white matter, where glial cell bodies predominate and where the capillary network is less dense than in the gray matter. Nevertheless, the evidence from animal experiments implicates the endothelial cells. In experimentally radiated rat brain, there is a time- dependent and dose- dependent pathologic response in vascular endothelium. Disruption of the blood- brain barrier is one of the characteristic results ( 12). The depletion of vascular endothelial cells after radiation has also been documented in the human optic nerve ( 13). A dose- related loss of endothelial cells was recognized in the optic nerves of patients who had received proton radiation for choroidal melanomas as compared with patients with choroidal melanomas who had not been radiated ( 13). Proton magnetic resonance spectroscopic analysis in living patients with radionecrosis of the brain supports the conclusion that the primary effect is not on glial cells. The early changes are incompatible with demyelination or glial cell injury ( 14). Severe lesions are associated with elevated levels of lactate, supporting a primary role for ischemia. Whatever may be the exact cellular pathogenesis, the result is " 3- H tissue": hypovascular, hypocellular, and hypoxic ( 15). The hypoxia differs from that in most other injuries in that the oxygen gradient between the normal and the radiated tissue is gradual, a situation that inhibits spontaneous repair. The end- stage pathology of radiation optic neuropathy is characterized by narrowed and occluded blood vessels, loss of axis cylinders and myelin, and the presence of fibrin exudates ( 16,17). 244 © 2004 Lippincott Williams & Wilkins Third Hoyt Lecture JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 SAFE AND UNSAFE RADIATION DOSES Radiation damage to the anterior visual pathway is not ordinarily encountered unless the total cumulative dosage of fractionated radiation exceeds 50 Gy. When radiation neuropathy has occurred after treatment with low cumulative dosages, the toxic effects of the radiation in some cases were probably potentiated by the concurrent administration of chemotherapeutic drugs ( 18). With stereotactic radiosurgery, patients may be treated with high doses of radiation at a single session ( 19,20). Generally, single doses to the anterior visual pathway of 8 Gy are safe. ( 19) In one large series, patients receiving as much as 12 Gy to a short segment of the optic nerve were protected unless they had received previous or concurrent external beam radiation ( 21). Patients receiving cancer chemotherapy, and those with Cushing syndrome, pituitary tumors ( especially growth hormone- producing tumors), or diabetes can have radiation neuropathy after receiving doses lower than those usually considered dangerous. Previous radiation may also potentiate the toxic effects of chemotherapy when the drugs are administered intra- arterially ( 22). The size of the radiation fractions is also an important variable: 1.9 Gy or less is considered safe ( 23,24). Other important variables include the interval between fractions, total treatment time, and the volume of irradiated tissue. CLINICAL FEATURES OF VISUAL PATHWAY RADIATION TOXICITY Visual symptoms usually do not develop until approximately 18 months after the completion of radiation therapy, but the latency range is wide ( 25- 27). There is some relation between the dose of radiation and the latency to the onset of symptoms, with the latency being shorter with higher doses. Pain is exceptional ( 28). The onset of visual symptoms may be acute and is apt to be marked by progressive loss of vision in one or both eyes. In my experience with bilateral visual loss associated with radiation, vision is lost first in one eye. The second eye typically becomes symptomatic as vision is fading in the first eye. Loss of vision can be severe, to the point of total or functional blindness. Radiation- induced lesions in the anterior visual pathway typically cannot be demonstrated on computerized tomographic ( CT) scans ( 29). Magnetic resonance imaging ( MRI) with gadolinium enhancement is the preferred diagnostic method. Damaged neural tissue shows enhancement and sometimes swelling ( 29,30). The enhancement fades within three months of symptom onset as atrophy supervenes. When the radiation has been directed to the eye or orbit, the optic disc may be the focus of damage ( radiation papillopathy), in which case ophthalmoscopic abnormalities will be obvious from the outset ( 31). The optic disc is edematous and often accompanied by subretinal fluid, peripapillary hard exudates, and cotton- wool spots. Fluorescein angiography shows nonperfusion of the superficial disc vasculature. The disc remains swollen for weeks to months and then atrophies. Brown et al ( 31) reported radiation injury in eight cases of choroidal melanoma, two paranasal sinus carcinomas, one retinoblastoma, one choroidal metastatic tumor, one lacrimal sac tumor, and one frontal astrocytoma. The mean interval from the completion of radiation to the onset of visual impairment was 12.6 months ( range, 3- 22 months) after 60Co plaque and 19.3 months ( range, 5- 36 months) after external beam radiation. The latency to visual loss ranged from two to four years in another study ( 32). In the study ofBrownetal ( 31), patients radiated from a 60Co plaque had typically received high doses of radiation ( a mean of 12.5 Gy), except for one diabetic patient. Among their patients who had received external beam total doses of 55 Gy, papillopathy occurred after as little as 36 Gy. Gragoudas et al ( 32) reported their experience with a cohort of patients who received proton radiation for uveal melanomas. Patients who received 30 cobalt Gray equivalent ( CGE) or less to the optic disc did not have radiation papillopathy. The risk of papillopathy increased with higher doses; at 70 CGE, nearly all patients had papillopathy. With the techniques currently used ( and that are being continuously improved), the complication rate is very low and the cost- to- benefit ratio is favorable. From an as- yet-unpublished study in which I participated at our institution, I have gained insight into the prevalence of optic neuropathy after radiation treatment by the sophisticated techniques now in use. Thirty- six consecutive patients with locally advanced paranasal and nasal cavity malignancies were treated with hyperfractionated- accelerated radiation therapy ( four MV photons and 160 MeV protons), with the optic nerves and chiasm receiving a daily dose of 20 CGE and a total cumulative dosage of 56 CGE. Neuro- ophthal-mic follow- up averaged 33.3 months ( range, 12.4- 108.5 months). Although one patient had ophthalmoscopic evidence of bilateral mild optic disc pallor during follow- up, no defect in acuity, color vision, or visual field could be identified in that patient or in any other patients. In the next section, I describe case histories of patients who represent examples of radiation toxicity to the visual pathway. MRI Abnormalities Before Clinical Manifestations A 71- year- old woman ( Case 1) had binocular diplopia consequent to a left sixth cranial nerve palsy. A tumor involving the left cavernous sinus, clivus, and sphenoid sinus was demonstrated on MRI scan. Biopsy showed that the lesion was an " atypical" meningioma and she received external beam radiation to a total dose of 55 Gy. One year after the completion of radiation, routine MRI scan 245 JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Lessell showed enhancement of the optic chiasm ( Fig. 1). However, she had normal visual acuity, color vision, static and kinetic visual fields, pupils, and fundi. No abnormalities were found when the visual tests were repeated two months later. Three weeks after that last examination, she noticed decreased vision OD. Best- corrected visual acuities had declined to 20/ 40 OD and 20/ 30 OS. The OD had dyschro-matopsia and there were bilateral nerve fiber bundle visual field defects. Both optic discs were slightly pale. Treatment with high intravenous doses of methylprednisolone and hyperbaric oxygen ( HBO) was instituted within 11 days of the onset of symptoms but vision relentlessly declined, eventuating in bilateral blindness. A 74- year- old woman ( Case 2) with polymyalgia rheumatica and hypertension had a head CT scan because of an episode of syncope. A mass demonstrated in the sphenoid sinus proved to be an inverted papilloma. The lesion was treated with radiation to a total dose of 54 Gy in 30 1.8 Gy fractions over 44 days. The average and maximum doses were 31.7 Gy and 57.6 Gy to the right optic nerve, 32.1 Gy and 57. lGy to the left optic nerve, and 42.3 Gyand 49.9 Gy to the optic chiasm. One year later, she noticed blurred vision OD, especially in the superior and temporal portions of the visual field. There were no other symptoms. The optic discs appeared normal at that time but right optic atrophy later developed. Examination two months after the onset of visual symptoms showed that visual acuity was 20/ 25 OU with normal Ishihara plate color vision. Bilateral nuclear cataracts appeared sufficiently dense to account for the reduced acuities. An incomplete, relative, upper altitu-dinal visual field defect was seen OD; the visual field OS was full. A relative afferent pupil defect was not demonstrable. The right optic disc was pale but the left was normal. There were no clinical symptoms or laboratory signs of temporal arteritis. An MRI performed one week later showed enhancement of the intracranial segments of both optic nerves without evidence of tumor ( Fig. 2). Two weeks after the MRI study, she noticed " waves of liquid" OS. Visual acuities were unchanged, but she now had marked dys-chromatopsia OD. The OS retained normal color vision. There was a complete, absolute, superior visual field defect OD and a superior Bjerrum scotoma OS to the I4e white stimulus on the Goldmann perimeter. Fundus appearance was unchanged, as was the MRI scan. Kihlstrom and Karlsson ( 34) indicate that clinically undetected radionecrosis may sometimes be revealed by MRI studies, but these authors were almost certainly referring to lesions outside of the visual pathways. In light of evidence that there is early disruption of the blood- brain barrier in radiation injury, it is not surprising that MRI signs may be present before the development of clinical symptoms and signs. The existence of such cases might have therapeutic implications ( see below). Normal MRI Soon Before Onset of Clinical Manifestations A 37- year- old man ( Case 3) had diplopia and pain OS. There was a left Horner syndrome and a partial left third cranial nerve palsy. Neuroimaging studies showed a mass involving the sella, the prepontine cistern, and both sides of the cavernous sinus that proved to be a nonchon-droid chordoma. After subtotal resection, he was treated with external beam radiation. The estimated dose to the chiasm was 60 CGE. Six months later, he was free of diplopia and there were no signs of radiation injury on enhanced MRI. However, within a month the visual acuity OS began to fail. Examination one month later showed that while the OD was normal in all respects, the OS acuity was 20/ 50, and there was dyschromatopsia, a dense superior altitudinal visual field defect, and a pale optic nerve. There was enhancement of the intracranial segment of the left optic nerve on MRI. Despite high doses of oral dexamethasone, he became blind OS. By that time, there was a temporal visual field defect OD and bilateral optic disc pallor. Despite HBO therapy, visual acuity declined to 20/ 40 OD and dyschromatopsia developed. The patient was anticoagulated but there was no further change in visual function. Cases of visual loss developing within weeks of a normal MRI lesions force us to acknowledge that a normal MRI scan does not exclude impending radiation optic neuropathy. MRI may actually underestimate the extent of radiation- induced brain lesions. At autopsy in one case ( 35), FIG 1. Case 1 ( 33). MRI signal abnormalities precede clinical manifestations of radiation chi-asmopathy. Routine sagittal (/ eft) and coronal { right) enhanced T1- weighted MRI scans performed one year after 55- Gy external beam radiation therapy was delivered to a 71 - year- old woman for a leftsphenoclivocavernous meningioma. The scan shows high signal in the optic chiasm. At the time of this scan, the patient had no neuro- ophthalmic manifestations. Three months later, manifestations of chiasmal dysfunction acutely developed. 246 © 2004 Lippincott Williams & Wilkins Third Hoyt Lecture JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 FIG. 2. Case 2. MRI signal abnormalities precede clinical manifestations of left radiation optic neuropathy. Unenhanced (/ eft) and enhanced { right) coronal T1- weighted MRI scans performed on a 71 - year- old woman who had received 54- Gy external beam radiation for a sphenoid sinus inverted papilloma one year earlier. They show enhancement of both optic nerves ( arrows). At the time of this scan, the patient had clinical manifestations of a right optic neuropathy. Two months later, manifestations of a left optic neuropathy developed. A repeat MRI scan at that time was unchanged. histopathologic evidence of radiation injury exceeded the boundaries of the lesion on MRI by as much as 46%. Long Interval Between Consecutive Involvement of the Two Optic Nerves A 70- year- old man ( Case 4) had pain in and below the left orbit and in the left pre- auricular region. CT scanning showed a tumor in the left maxillary, ethmoid, and sphenoid sinuses that proved to be an invasive squamous cell carcinoma. He was treated with external beam radiation to a total dose of 66.7 Gy. Eighteen months later, he noticed that he could not see well in the upper field OD and hallucinated " bursting bubbles" in that area. Two weeks later, the visual acuity OD was 20/ 200, and there was dyschromatopsia, a dense superior altitudinal visual field defect, a relative afferent pupil defect, and a pale right optic nerve. The visual field OS was completely normal ( Fig. 3). He refused an MRI scan. CT scanning showed no evidence of tumor and the right eye became blind. Seven months later, he presented with a superior altitudinal visual field defect OS ( Fig. 3), dyschromatopsia, and a pale left optic nerve. An MRI scan showed enhancement in both optic nerves. Within two weeks, visual acuity had declined to 6/ 200 OS. Despite HBO treatment and the administration of high doses of oral prednisone, he became blind OU. In my experience, it is distinctly unusual for a patient to have such a long hiatus ( seven months) before the second eye becomes symptomatic. o. s- e| « « l* » FIG. 3. Case 4. A long latency between development of clinical manifestations of radiation optic neuropathy in the two eyes. Serial Goldmann perimetry OS shows new nerve fiber bundle visual field loss seven months after radiation optic neuropathy had developed OD. Spontaneous Visual Improvement A malignant melanoma was resected from the temple of a 71- year- old man ( Case 5). When left parotid and cervical node metastases were detected one year later, he was treated with parotidectomy, radical neck dissection, and interferon. He received 50 Gy to the left parotid gland, followed by an electron boost totaling an additional 10 Gy. Nine months later, painless loss of vision developed OD, accompanied by visual hallucinations. The right optic disc was edematous and MRI showed enhancement of the right intraorbital optic nerve. Despite treatment with high doses of oral prednisone, the right eye developed NLP vision within two weeks. Two months later, vision had declined from 20/ 20 to 20/ 70 OS, despite daily 100- mg doses of oral prednisone. MRI disclosed enhancement of the optic chiasm and both optic nerves but no evidence of metastases; cerebrospinal fluid examination was normal. Several weeks later, the right eye remained NLP and acuity OS was 20/ 70. There was a new visual field defect OS ( Fig. 4) and dyschromatopsia. The right optic disc was atrophic and the retinal vessels were narrowed. The left fundus was unremarkable. He had to resort to large- print books. Subsequent to discontinuation of the prednisone, he began to appreciate some return of vision OS. Re- examination six months later showed a visual acuity of 20/ 40 OS, an expanded visual OS six months later FIG. 4. Case 5. Spontaneous improvement in visual field after radiation optic neuropathy. Serial Goldmann perimetry OS in a patient who had undergone radiation to the left parotid gland for metastatic melanoma. The initial visual field ( left) was performed 11 months after radiation; the follow- up field, which shows expansion, was performed six months later. 247 JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 Lessell field ( Fig. 4), and normal color vision OS. He could now read conventional- sized print. Despite literature suggesting that spontaneous improvement in vision in patients with late delayed radiation injury of the visual pathways is unknown ( 27), cases have been reported. Brown et al ( 31) mention three patients with radiation papillopathy who enjoyed improvement. In one case, visual acuity improved spontaneously from finger counting to 20/ 50 within eight months. In the two other cases, the improvement in acuity is not quantitated. The rate of spontaneous improvement in cases of radiation papillopathy may actually be higher than the literature would suggest when the irradiated lesion is intraocular, given that non- neurogenic visual loss from growth of the primary lesion, retinal detachment, or radiation- induced cataract could obscure spontaneous improvement. Retrogeniculate Blindness Four years after a 55- year- old man ( Case 6) had undergone resection of a renal cell carcinoma, visual hallucinations developed and he realized that his peripheral vision was restricted ( 36). Visual acuities were 20/ 20 OU, but there was a partial right homonymous quadrantanopia. MRI scans showed a hemorrhagic lesion in the left occipital lobe. The resected brain lesion was a metastasis. He was treated with external beam whole- brain radiation of 30 Gy with a 15- Gy boost to the region of resection. He also received two cycles of interleukin- 2. He was free of eye or neurologic symptoms until 18 months after the completion of radiation when he realized that his vision was decreasing OU. Examination showed that he could only see hand movements OU. His pupils reacted normally to light and fundus examination was unremarkable. T2- weighted MRI showed hyperinten-sity in both cerebral hemispheres ( Fig. 5). He was treated with high doses of oral dexamethasone but his vision never returned. This previously reported case ( 36) serves as a reminder that vision may be impaired when the retrogeniculate visual pathways are irradiated. This case appears to be the only published example of radiation- induced retrogeniculate blindness, but radiation necrosis can cause homonymous hemianopias ( 37). Radiation predisposes patients to cerebral hemorrhages from telangiectases ( 38) and to cerebral infarctions secondary to premature or accelerated atherosclerosis ( 39). TREATMENT Attempts to treat delayed radiation injury of the visual pathways have generally failed to reverse or even halt the loss of vision. A tabulation of virtually all reported cases of delayed radionecrosis of the optic nerves and chiasm shows this rather dramatically ( 40). With a few exceptions ( 41), patients have been unsuccessfully treated with large FIG. 5. Case 6. Retrogeniculate visual pathway radiation damage. Axial T2- weighted MRI scan performed 18 months after a 55- year- old man had received 45 Gy to the occipital region for metastatic renal cell carcinoma. The scan shows extensive bilateral white matter high signal. The patient's visual acuity was hand movements OU. Vision did not recover. ( Reproduced from reference 36, with permission.) intravenous doses of corticosteroids. Because radiation injury is not an inflammatory disorder, it is difficult to invoke the anti- inflammatory effects of corticosteroids. The role of corticosteroids in reducing vasogenic edema has been cited as a rationale for its use. Swelling of the chiasm and optic nerves are MRI features of radiation injury, but it is not clear that vasogenic edema contributes to tissue injury in this disorder. Because radiation injury may be initiated by free radicals, treatment with very high doses of prednisone, known to have antioxidant properties, could theoretically be justified. Heparin and warfarin have their advocates ( 42,43) who postulate that anticoagulation might promote blood flow to irradiated tissues. There are additional theoretical benefits of heparin, given that it suppresses certain injurious tissue mediators. There have been reports of treatment success, but not in cases of radiation injury to the visual pathway. Of note, one study ( 44) described a patient in whom bilateral radiation optic neuropathy developed while being treated with an anticoagulant. HBO therapy seems to offer more promise than any of these other forms of treatment ( 45,46). It can increase the 248 © 2004 Lippincott Williams & Wilkins Third Hoyt Lecture JNeuro- Ophthalmol, Vol. 24, No. 3, 2004 partial pressure of oxygen in tissue up to a limit of 3.0 atm in single- place chambers ( 47). Up to 6.0 atm can be achieved in multiple- place chambers. HBO changes the oxygen gradient and stimulates revascularization of the capillary bed ( 48). Common, relatively minor side effects include barotrauma ( 45) and lenticular myopia ( 49). The latter may persist for months. Rare side effects include seizures and pulmonary toxicity ( 50). Borruatt et al ( 27) reported their experience with HBO therapy in four patients with delayed radiation injury of the anterior visual pathways. Their patients were treated with three days of intravenous methylprednisolone and 30- to 90- minute " dives" in which they breathed 100% oxygen at 2.4 atm. One patient, treated 16 days after diagnosis, improved from no light perception to light perception in one eye. A temporal hemianopia in the other eye cleared within seven months. A second patient treated three weeks after onset of visual loss had improvement in visual field, color sense, and visual acuity. Visual acuity improved from 9/ 200 to 20/ 40 OD and from 3/ 200 to 20/ 40 OS. The third patient, treated with HBO two months after diagnosis, and the fourth patient, treated six weeks after diagnosis, sustained no benefit. In their review of published cases, Borruatt et al ( 27) compared visual outcomes among three groups of patients: those receiving no treatment, those receiving HBO therapy at 2.0 atm, and those receiving HBO therapy with 2.4 or greater atmospheres. The visual outcomes shown in Table 1 suggest that HBO is effective at higher atmospheres. Roden et al ( 51) used corticosteroids and HBO to treat 13 patients with delayed anterior visual pathway radiation injury. No patient responded to this treatment. Borraut et al ( 27) suggest that the failure in these cases might have resulted from a delay in instituting HBO therapy. If, as these authors suggest, HBO is effective only if given soon after the patient has symptoms, efforts should be made to detect anterior visual pathway radiation injury as early as possible. Guy and Schatz ( 52) advise that HBO treatment be initiated within three days of the onset of visual symptoms. As noted, some patients may have MRI signs of radiation injury that antedate the loss of vision. If a patient has had radiation to lesions near the optic nerves or chiasm, one could consider TABLE 1. Visual outcome ( by eyes) in radiation optic neuropathy ( 27) Worse No treatment 70 Hyperbaric oxygen 2.0 ATM 31 Hyperbaric oxygen > 2.4 ATM 18 Same 30 69 46 Better 0 0 36 ATM, atmospheres. obtaining frequent enhanced MRIs during the period of highest risk- 10 to 20 months after the radiation therapy has been completed. Because the two eyes are often involved serially, similar testing should be started after one eye has developed radiation neuropathy to detect the earliest evidence of radiation neuropathy on the other side. If the MRI scans show the signs of radiation optic neuropathy, HBO treatment could be given prophylactically. Electrophysiological testing might also help in the early detection of radiation damage to the visual pathway. Radiated animals show reduced signal amplitude and a delay in neural conduction ( 53). In patients with anterior visual pathway radionecrosis, the visual evoked potential ( VEP) may be abnormal months before the loss of vision ( 54). Kellner et al ( 55) evaluated the VEP in patients with normal vision who were radiated for uveal melanomas. Five patients had radiation papillopathy, all of whom also had abnormal VEP latency. There were also several cases in which the VEP was abnormal when visual function and the fundus examination were still normal. These findings suggest that serial testing of VEPs during the high- risk period in appropriate patients might provide early evidence of an optic neuropathy and allow optimal application of HBO therapy. CONCLUSION A small proportion of patients irradiated for tumors in proximity to the optic nerves, chiasm, and retrogeniculate visual pathways will have potentially devastating visual complications. Until ionizing radiation can be delivered without damaging the adjacent normal tissue, physicians must scrupulously factor this risk into all decisions involving the use of therapeutic radiation. They must also be vigilant to the signs of radiation injury and be receptive to such diagnostic and therapeutic measures as become available to detect, prevent, or reverse radiation neurotoxicity. REFERENCES 1. Beclere A. Le traitement medical des tumeurs hypophysaires du gigantisme et de l'acromegalie par la radiotherapie ( in French). Arch d'electric Med 1909; 17: 163- 180. Arch Roentgenol Ray 1909; 14: 142- 50. 2. Brown P, Preece MA, Will RG. Friendly fire in medicine: hormones, homografts and Creutzfeldt- Jakob disease. Lancet 1992; 340: 24- 7. 3. Lichter AS, Lawrence TS. 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