- Email: [email protected]
The Delayed Cost of Treatment
SURVEY OF OPHTHALMOLOGY
VOLUME 58 NUMBER 4 JULY–AUGUST 2013
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
The Delayed Cost of Treatment Katherine M. Whipple, MD,1 Leah Levi, MBBS,1,2 and Michael S. Lee, MD3 1
University of California at San Diego Health System, Department of Ophthalmology—Shiley Eye Center, La Jolla, California; 2University of California at San Diego Health System, Department of Neurosciences, La Jolla, California; and 3 Departments of Ophthalmology, Neurology, and Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report
She completed this treatment 8 months prior to presentation. She was on latanoprost, timolol, rosuvastatin, valsartan, aspirin, and esomeprazole. She denied smoking and alcohol use and ate a regular diet. Her father and brother had open-angle glaucoma. Visual acuity was 1/200 OD and 6/200 OS. Six months earlier, her vision had been 20/40 OU. She missed all of the Ishihara pseudoisochromatic plates OD and recognized only one OS. Both pupils were 6 mm and sluggish, with a relative afferent pupillary defect OD. Extraocular movements were full. Applanation tonometry was 15mm Hg OU. Slit-lamp examination was significant for 2þ nuclear sclerosis OU. Funduscopy showed inferior and temporal rim loss in both eyes consistent with glaucomatous damage (Fig. 1). No optic nerve edema was present. The macula, vessels, and retinal periphery were normal OU. Automated perimetry is seen in Fig. 2A. Her visual field from 6 months previously showed an inferior arcuate defect in the right eye and superior arcuate defect with an inferior nasal step in the left eye (Fig. 2B).
A 78-year-old black woman with cataracts and glaucoma presented with a 2-month history of gradually decreasing vision in both eyes, worse in the right. She denied floaters, photopsias, metamorphopsia, fever, chills, weight loss, or previous trauma. Past medical history included non-insulindependent diabetes, hypertension, hypercholesterolemia, and coronary artery disease with cardiac stent placement in 2009. In 2008 the patient underwent lumpectomy for bilateral breast cancer. During her work-up for metastatic disease, a sellar mass was noted on magnetic resonance imaging (MRI). This was thought to be suspicious for metastatic disease given the surrounding dural enhancement seen on MRI. A neurosurgical consultant recommended biopsy; she refused, however, preferring to be monitored by serial neuroimaging. When the lesion did enlarge, she elected stereotactic radiation therapy rather than resection. Her radiation treatment consisted of 25 treatments of five dynamic conformation 6-MV photon arcing beams. Each treatment dose was 180 centigray (cGy). In total, 45 Gy of radiation was given. 370 Ó 2013 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter http://dx.doi.org/10.1016/j.survophthal.2012.01.013
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What are the possible diagnoses? What initial testing would you perform?
Comments COMMENTS BY MICHAEL S. LEE, MD
This patient has breast cancer status post stereotactic, fractionated radiation therapy to a presumptive sellar metastasis eight months ago. Her visual loss has been slowly progressive over 2 months, and she has a relatively unremarkable fundus examination. The first thing to do is to try to localize her visual loss. The visual fields show profound, global depression and do not help to pinpoint lesion location. The abnormality likely lies behind the globe. Because both eyes are simultaneously affected in both hemifields, this suggests involvement of the optic nerves and chiasm. Conceivably, lesions to both occipital lobes could cause this, but this is less likely. The greatest concerns here are radiation optic neuropathy (RON), expansion of her sellar mass, or new breast metastasis causing chiasmal or bilateral optic nerve compression. RON develops several months to years after completion of radiation and most often follows radiation for paranasal or parasellar lesions. The risk of RON increases with doses above 50 Gy, but this threshold is reportedly lower with lesions compressing the chiasm.1 This patient received only 45 Gy, and we are not told whether the initial mass exerted compression on the chiasm. The risk of RON also increases among diabetics or patients receiving chemotherapy.18 She has diabetes, and her current medication list did not include concomitant chemotherapy. The vision loss from RON progresses over weeks to months, consistent with this patient’s description. Other less likely considerations on the differential include posterior ischemic optic neuropathy (PION) secondary to giant cell arteritis (GCA), cancer associated retinopathy (CAR), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), and the ‘‘usual suspects’’ (systemic lupus erythematosus [SLE], sarcoidosis, syphilis, and Lyme disease). Although her age could suggest possible GCA causing PION, the slowly progressive visual loss over 2 months is not consistent with that diagnosis. Typically, CAR causes subacute progressive visual loss with nearly constant photopsias, which the patient denied. Patients with LHON can have simultaneous visual loss with slow progression over months. The most common demographic is a man in the second or third decade of life, but it can affect patients as old as 80 years. Vision loss generally occurs more rapidly over the course of days in NMO, SLE, sarcoidosis, and Lyme optic neuropathy, making these less likely.
Fig. 1. Optic nerve photos of the right (A) and left (B) eye. Both nerves demonstrate inferotemporal rim loss.
I would begin with an MRI of the brain and orbits. Depending on the outcome, I may consider serologic evaluation for some of the other entities listed here.
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Fig. 2. A: Automated perimetry showing almost complete visual field loss OD and diffuse depression OS, especially temporally. B: Automated perimetry from 6 months prior to presentation for decreased acuity.
Case Report (Continued)
Comments (Continued)
MRI of the brain and orbits revealed a large mass in the sellar region not compressing the optic chiasm (Fig. 3A). The intracranial segments of both optic nerves were enlarged and showed intense enhancement with contrast (Figs. 3B, 4B). The optic nerves demonstrated hyperintensity and without contrast as well (Fig. 4A). What would you do next?
The MRI shows enhancement of the prechiasmatic portion of both optic nerves. This scan combined with the clinical history is most consistent with RON. Controversy surrounds the management of patients with RON.18 The bottom line is that no good evidence exists that any therapy for RON improves visual outcome. Options have been explored
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Fig. 3. A: Coronal T1 post-contrast MRI image demonstrating the sellar mass lesion (arrowhead) and optic chiasm (arrow). The mass is not causing physical compression of the chiasm. B: Coronal T1 post-contrast images of the intracranial optic nerves showing bilateral enhancement (arrows).
including corticosteroids, anticoagulation, and hyperbaric oxygen therapy (HBOT). Unfortunately, because of the rarity of RON, nearly all of these reports represent case reports or small case series.18 HBOT has received the most attention for the potential treatment of RON. One report described
two of four patients with RON whose visual function improved following HBOT;8 meta-analyses and systematic reviews have not found any beneficial effect of HBOT in late radiation injury to any neurologic tissue, however.3--5 Therefore, in the absence of proof, I do not advocate HBOT in RON.
Fig. 4. A: Coronal T1 pre-contrast images of the intracranial optic nerves showing enhancement around both optic nerves (thin arrows). B: Axial T1 post contrast showing bilateral optic nerve enhancement involving the chiasm (thick arrows). Note there is no distortion of the nerves or chiasm from the pituitary mass.
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The treatment recommendations include 30 daily dives of 90 minutes each for an off-label use of HBOT, which may or may not be approved by insurance.8 Many desperate patients do not accept this decision, however, and choose to do something instead of nothing in the face of profound bilateral vision loss. I believe that intravenous solumedrol 1 g a day for 3--5 days is reasonable here. Although it would violate the law of medical parsimony, this MRI could represent an inflammatory optic neuritis that might respond to therapy.
Case Report (Concluded) The patient was diagnosed with radiation optic neuropathy (RON), and she was treated with hyperbaric oxygen therapy and intravenous methylprednisolone 1,000 mg per day. The patient received 3 days total of methylprednisolone before it was discontinued due to intolerable side effects. She received a total of 70 treatments of hyperbaric oxygen at 2.4 atmosphere absolutes with 90 minutes of 100% oxygen for each treatment. At her last follow-up visit 8 weeks after onset of the RON, her vision was count fingers at 1 foot OD and at 8 inches OS, but she reported subjective visual improvement. She stated that after one treatment, her sight improved so much that she was able to ambulate around her home without assistance. This lasted for 2 weeks before the vision decreased again.
Discussion The primary goal of radiation therapy is to focus maximal energy on abnormal tissue, with a sharp drop in energy to cause minimal damage to surrounding normal tissues. The use of radiation to treat intracranial tumors was described as early as 1909;2,14 it was not until 1956 that the first reports of visual system damage due to radiation were described, however.9,13 The incidence of RON peaks approximately 18 to 24 months following treatment, but has been reported as early as 3 months and as late as several years. Patients usually report an acute, painless decrease in their acuity, followed by progressive worsening of vision. In 75% the process is bilateral, with the second eye becoming involved most commonly within weeks of the first eye. Reports show that 85% have vision worse than 20/200, and 45% progress to no light perception. Most patients have retrobulbar damage; therefore, the initial optic nerve appearance is normal. Optic disc swelling may be seen in patients treated with radiation for anterior orbital, sinus, or intraocular tumors.17
WHIPPLE ET AL
Findings on MRI typically show enlargement and marked enhancement of the affected optic nerve. The pathophysiology of RON, although debated, is likely vascular. Laboratory and clinical evidence suggest that the inciting event is damage to endothelial cells, leading to breakdown of the tight junctions, depletion of the endothelial cells, and an obliterative vasculitis with secondary damage to the glial progenitor cells, causing demyelination and neuronal loss.10,19 Risk factors for RON include age, concurrent chemotherapy, and previous radiation. Pituitary adenoma also appears to be a risk factor, but this may be a function of previous optic nerve compression leading to decreased optic nerve tolerance. In addition, in cases of acromegaly, the enlarged frontal sinuses may lead to an increased effective dose if this is not accounted for in the treatment planning. Treatment variables also contributing to the risk of RON include the total radiation dose received, the maximum dose, the dose per fraction, the modality of treatment (external beam radiation treatment, stereotactic radiosurgery, particle), and the volume of the optic nerve exposed to maximum dose.7 Wigg et al demonstrated that both the maximum and the total dose are important in determining the risk of RON.28 The extent to which each of these factors individually or in combination changes anterior visual pathway tolerance to radiation remains uncertain. There have been multiple attempts to determine how much radiation can safely be given before RON becomes a significant risk.6,11,22,23,25,26 Mayo et al have compiled available studies and attempted to provide meaningful guidelines to practitioners. For external beam radiation therapy a total dose of !50 Gy has almost zero chance of developing RON; at !55 Gy RON is uncommon. Total dose of 55--60 Gy will have a 3--7% chance, and O60 Gy will have a 7--20% chance. For stereotactic radiosurgery at a total dose !8 Gy, RON is rare, !10 Gy is low risk, O12 Gy has a O10% chance of causing RON. Finally, for proton beam radiation, !54 Gray equivalents (GyE) has a low risk of developing RON, with 55--60 GyE reaching the threshold of a significant chance for RON.23 Many studies, however, are limited by small sample sizes, retrospective analysis, and variation in treatment modalities. Additionally, technological advances have allowed for steeper dose gradients and greater accuracy and precision in treatment planning and delivery. Therefore, previous guidelines may quickly be superseded. Applying these guidelines, our patient had almost no chance of developing RON, underscoring that it is not simply the total radiation dose that determines the risk of RON. In her case diabetes may have decreased her threshold for RON.
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The prognosis for RON remains dismal, with 75% of patients having bilateral eye involvement and 85% having acuity less than 20/200. Anterior RON (seen mainly after treatment for ocular melanoma and characterized by optic disc swelling) seems to have a better natural history, with 31% of patients showing some improvement.9 Both corticosteroid therapy and anticoagulation have been ineffective in halting progression of RON. Recently, pentoxifylline has been suggested a possible treatment, given its ability to improve perfusion and its anti-inflammatory effects. Thus far, studies have been inconclusive in radiation retinopathy and cerebral edema, and none have been done in RON.15,27 Hyperbaric oxygen has been shown to be effective in radiation necrosis of non-neuronal tissue, but its use in RON has been disappointing, with reports of vision declining even while on treatment. The timing of HBOT might be a factor in its effectiveness. Ramipril, an angiotensin-converting enzyme inhibitor, decreases the amount of axonal damage in rats with RON in a dose-dependent fashion, an effect thought to be the result of its ability to decrease proinflammatory cytokines. No further studies looking at the effect of ramipril on RON have yet been done.16,24 Bevacizumab, which shows promise in the treatment of cerebral radiation necrosis,21 has recently been used intravitreally for treatment of anterior RON, with 64% of patients showing improvement in vision.12 There was also a single case report of posterior RON treated with intravenous bevacizumab and corticosteroids with marked improvement in vision over a 3-month period.20 RON is an uncommon, unfortunate, and devastating consequence of radiation therapy. The risk of RON remains unpredictable, and its treatment, disappointing. It is difficult for ophthalmologists or radiation oncologists to give individual patients advice as to their risk of RON, given the limitations of the current understanding, the continued technological evolution that may make previous guidelines obsolete, and the lack of a risk calculator that takes numerous patient and treatment variables into account. It is important to have RON on the differential for all patients presenting with visual loss and a history of intracranial radiation.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this article was supported by an unrestricted grant from Research to Prevent Blindness, New York, NY.
References 1. Aristizabal S, Caldwell WL, Avila J. The relationship of time dose fractionation factors to complications in the treatment of pituitary tumours by irradiation. Int J Radiat Oncol Biol Phys. 1977;2:667--73 2. Be´cle`re A. Le traitement me´dical des tumeurs hypophysaires du gigantisme et de l’acrome´galie par la radiothe´rapie. Arch d’electric Med. 1909;17:163--80 3. Bennett MH, Feldmeier J, Hampson N, et al. Hyperbaric oxygen therapy for late radiation tissue injury. Cochrane Database Syst Rev. 2005;(3):CD005005 4. Bennett MH, Trytko B, Jonker B. Hyperbaric oxygen therapy for the adjunctive treatment of traumatic brain injury. Cochrane Database Syst Rev. 2004;(4):CD004609 5. Bennett MH, Waisiak J, Schnabel A, et al. Hyperbaric oxygen therapy for acute ischaemic stroke. Cochrane Database Syst Rev. 2005;(3):CD004954 6. Bergstrom CA, Stafford SL, Lazorova L, et al. Absorption classification of oral drugs base on molecular surface properties. Int J Radiat Oncol Biol Phys. 2003;55:1177--81 7. Bhandare N, Monroe AT, Morris CG, et al. Does altered fractionation influence the risk of radiation-induced optic neuropathy? Int J Radiat Oncol Biol Phys. 2005; 62:1070--7 8. Borruat FX, Schatz NJ, Glaser JS, et al. Radiation optic neuropathy: report of cases, role of hyperbaric oxygen therapy, and literature review. Neuroophthalmology. 1996; 16:255--66 9. Buys NS, Kerns TC Jr. Irradiation damage to the chiasm. Am J Ophthalmol. 1957;44:483--6 10. Chan YL, Yeung DK, Leung SF, et al. Proton magnetic resonance spectroscopy of late delayed radiation-induced injury of the brain. J Magn Reson Imaging. 1999;10:130--7 11. Demizu Y, Murakami M, Miyawaki D, et al. Analysis of the vision loss caused by radiation-induced optic neuropathy after particle therapy for head-and-neck and skull-base tumors adjacent to optic nerves. Int J Radiat Oncol Biol Phys. 2009;75:1487--92 12. Finger PT, Chin KJ. Antivascular endothelial growth factor bevacizumab for radiation optic neuropathy: secondary to plaque radiotherapy. Int J Radiat Oncol Biol Phys. 2012; 82(2):789--98 13. Forrest AP, Brown DA, Morris SR. Pituitary radon implant for advanced cancer. Lancet. 1956;270:399--401 14. Gramegna A. Un cas d’acrome´galie traite´ par la radiothe´rapie. Rev Neurol. 1909;17:15--7 15. Gupta P, Meisenberg B, Amin P, et al. Radiation retinopathy: the role of pentoxifylline. Retina. 2001;21:545--7 16. Kim JH, Brown SL, Kolozsvary A, et al. Modification of radiation injury by ramipril, inhibitor of angiotensinconverting enzyme, on optic neuropathy in the rat. Radiat Res. 2004;161:137--42 17. Kim IK, Lane AM, Egan KM, et al. Natural history of radiation papillopathy after proton beam irradiation of parapapillary melanoma. Ophthalmology. 2010;117:1617--22 18. Lee MS, Borruat FX. Should patients with radiation-induced optic neuropathy receive any treatment? J Neuroophthalmol. 2011;31:83--8 19. Levin LA, Gragoudas ES, Lessel S. Endothelial cell loss in irradiated optic nerves. Ophthalmology. 2000;107: 370--4 20. Lincoff NS, Osman F, Mechtler LL. Novel treatment for radiation optic neuropathy with IV bevacizumab. North American Neuro-Ophthalmology Society Annual Meeting. Vancouver, Canada; February 5--10, 2011 21. Matuschek C, Boike E, Nawatny J, et al. Bevacizumab as a treatment option for radiation-induced cerebral necrosis. Strahlenther Onkol. 2011;187:135--9 22. Mayo C, Martel MK, Marks LB, et al. Radiation dose--volume effects of optic nerves and chiasm. Int J Radiation Oncology Biol Phys. 2010;76:S28--35 23. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation optic neuropathy after megavoltage external-beam irradiation:
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analysis of time--dose factors. Int J Radiat Oncol Biol Phys. 1994;30:755--63 24. Ryu S, Kolozavary A, Jenrow KA, et al. Mitigation of radiation-induced optic neuropathy in rats by ACE inhibitor ramipril: importance of ramipril dose and treatment time. J Neurooncol. 2007;82:119--24 25. Tishler RB, Loeffler JS, Lunsford LD, et al. Tolerance of cranial nerves of the cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys. 1993;27:215--21 26. Urie MM, Fullerton B, Tatsuzaki H, et al. A dose response analysis of injury to cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat Oncol Biol Phys. 1992;23:27--39
WHIPPLE ET AL 27. Vakili A, Mojarrad S, Akhavan MM, et al. Pentoxifylline attenuates TNF-a protein levels and brain edema following temporary focal cerebral ischemia in rats. Brain Res. 2011; 1377:119--25 28. Wigg DR, Koschel K, Hodgson GS. Tolerance of the mature human central nervous system to photon irradiation. Br J Radiol. 1981;54:787--98
Reprint address: Katherine M. Whipple, MD, UCSD Shiley Eye Center, 9415 Campus Point Drive, La Jolla, CA 92093. e-mail: [email protected].
Abstract. A 78-year-old woman presented with acute decreased vision in both eyes. She had been treated for a pituitary mass with a total of 4,500 centigray of external beam radiation 8 months prior to presentation. She was diagnosed with radiation optic neuropathy. Treatment with hyperbaric oxygen and intravenous steroids were initiated but vision remained poor. (Surv Ophthalmol 58:370--376, 2013. Ó 2013 Elsevier Inc. All rights reserved.) Key words. optic neuropathy pituitary tumor neuropathy radiation treatment visual loss
radiation
treatment
radiation
optic
VOLUME 58 NUMBER 4 JULY–AUGUST 2013
CLINICAL CHALLENGES PETER SAVINO AND HELEN DANESH-MEYER, EDITORS
The Delayed Cost of Treatment Katherine M. Whipple, MD,1 Leah Levi, MBBS,1,2 and Michael S. Lee, MD3 1
University of California at San Diego Health System, Department of Ophthalmology—Shiley Eye Center, La Jolla, California; 2University of California at San Diego Health System, Department of Neurosciences, La Jolla, California; and 3 Departments of Ophthalmology, Neurology, and Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA
(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)
Case Report
She completed this treatment 8 months prior to presentation. She was on latanoprost, timolol, rosuvastatin, valsartan, aspirin, and esomeprazole. She denied smoking and alcohol use and ate a regular diet. Her father and brother had open-angle glaucoma. Visual acuity was 1/200 OD and 6/200 OS. Six months earlier, her vision had been 20/40 OU. She missed all of the Ishihara pseudoisochromatic plates OD and recognized only one OS. Both pupils were 6 mm and sluggish, with a relative afferent pupillary defect OD. Extraocular movements were full. Applanation tonometry was 15mm Hg OU. Slit-lamp examination was significant for 2þ nuclear sclerosis OU. Funduscopy showed inferior and temporal rim loss in both eyes consistent with glaucomatous damage (Fig. 1). No optic nerve edema was present. The macula, vessels, and retinal periphery were normal OU. Automated perimetry is seen in Fig. 2A. Her visual field from 6 months previously showed an inferior arcuate defect in the right eye and superior arcuate defect with an inferior nasal step in the left eye (Fig. 2B).
A 78-year-old black woman with cataracts and glaucoma presented with a 2-month history of gradually decreasing vision in both eyes, worse in the right. She denied floaters, photopsias, metamorphopsia, fever, chills, weight loss, or previous trauma. Past medical history included non-insulindependent diabetes, hypertension, hypercholesterolemia, and coronary artery disease with cardiac stent placement in 2009. In 2008 the patient underwent lumpectomy for bilateral breast cancer. During her work-up for metastatic disease, a sellar mass was noted on magnetic resonance imaging (MRI). This was thought to be suspicious for metastatic disease given the surrounding dural enhancement seen on MRI. A neurosurgical consultant recommended biopsy; she refused, however, preferring to be monitored by serial neuroimaging. When the lesion did enlarge, she elected stereotactic radiation therapy rather than resection. Her radiation treatment consisted of 25 treatments of five dynamic conformation 6-MV photon arcing beams. Each treatment dose was 180 centigray (cGy). In total, 45 Gy of radiation was given. 370 Ó 2013 by Elsevier Inc. All rights reserved.
0039-6257/$ - see front matter http://dx.doi.org/10.1016/j.survophthal.2012.01.013
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What are the possible diagnoses? What initial testing would you perform?
Comments COMMENTS BY MICHAEL S. LEE, MD
This patient has breast cancer status post stereotactic, fractionated radiation therapy to a presumptive sellar metastasis eight months ago. Her visual loss has been slowly progressive over 2 months, and she has a relatively unremarkable fundus examination. The first thing to do is to try to localize her visual loss. The visual fields show profound, global depression and do not help to pinpoint lesion location. The abnormality likely lies behind the globe. Because both eyes are simultaneously affected in both hemifields, this suggests involvement of the optic nerves and chiasm. Conceivably, lesions to both occipital lobes could cause this, but this is less likely. The greatest concerns here are radiation optic neuropathy (RON), expansion of her sellar mass, or new breast metastasis causing chiasmal or bilateral optic nerve compression. RON develops several months to years after completion of radiation and most often follows radiation for paranasal or parasellar lesions. The risk of RON increases with doses above 50 Gy, but this threshold is reportedly lower with lesions compressing the chiasm.1 This patient received only 45 Gy, and we are not told whether the initial mass exerted compression on the chiasm. The risk of RON also increases among diabetics or patients receiving chemotherapy.18 She has diabetes, and her current medication list did not include concomitant chemotherapy. The vision loss from RON progresses over weeks to months, consistent with this patient’s description. Other less likely considerations on the differential include posterior ischemic optic neuropathy (PION) secondary to giant cell arteritis (GCA), cancer associated retinopathy (CAR), Leber hereditary optic neuropathy (LHON), neuromyelitis optica (NMO), and the ‘‘usual suspects’’ (systemic lupus erythematosus [SLE], sarcoidosis, syphilis, and Lyme disease). Although her age could suggest possible GCA causing PION, the slowly progressive visual loss over 2 months is not consistent with that diagnosis. Typically, CAR causes subacute progressive visual loss with nearly constant photopsias, which the patient denied. Patients with LHON can have simultaneous visual loss with slow progression over months. The most common demographic is a man in the second or third decade of life, but it can affect patients as old as 80 years. Vision loss generally occurs more rapidly over the course of days in NMO, SLE, sarcoidosis, and Lyme optic neuropathy, making these less likely.
Fig. 1. Optic nerve photos of the right (A) and left (B) eye. Both nerves demonstrate inferotemporal rim loss.
I would begin with an MRI of the brain and orbits. Depending on the outcome, I may consider serologic evaluation for some of the other entities listed here.
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Fig. 2. A: Automated perimetry showing almost complete visual field loss OD and diffuse depression OS, especially temporally. B: Automated perimetry from 6 months prior to presentation for decreased acuity.
Case Report (Continued)
Comments (Continued)
MRI of the brain and orbits revealed a large mass in the sellar region not compressing the optic chiasm (Fig. 3A). The intracranial segments of both optic nerves were enlarged and showed intense enhancement with contrast (Figs. 3B, 4B). The optic nerves demonstrated hyperintensity and without contrast as well (Fig. 4A). What would you do next?
The MRI shows enhancement of the prechiasmatic portion of both optic nerves. This scan combined with the clinical history is most consistent with RON. Controversy surrounds the management of patients with RON.18 The bottom line is that no good evidence exists that any therapy for RON improves visual outcome. Options have been explored
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Fig. 3. A: Coronal T1 post-contrast MRI image demonstrating the sellar mass lesion (arrowhead) and optic chiasm (arrow). The mass is not causing physical compression of the chiasm. B: Coronal T1 post-contrast images of the intracranial optic nerves showing bilateral enhancement (arrows).
including corticosteroids, anticoagulation, and hyperbaric oxygen therapy (HBOT). Unfortunately, because of the rarity of RON, nearly all of these reports represent case reports or small case series.18 HBOT has received the most attention for the potential treatment of RON. One report described
two of four patients with RON whose visual function improved following HBOT;8 meta-analyses and systematic reviews have not found any beneficial effect of HBOT in late radiation injury to any neurologic tissue, however.3--5 Therefore, in the absence of proof, I do not advocate HBOT in RON.
Fig. 4. A: Coronal T1 pre-contrast images of the intracranial optic nerves showing enhancement around both optic nerves (thin arrows). B: Axial T1 post contrast showing bilateral optic nerve enhancement involving the chiasm (thick arrows). Note there is no distortion of the nerves or chiasm from the pituitary mass.
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The treatment recommendations include 30 daily dives of 90 minutes each for an off-label use of HBOT, which may or may not be approved by insurance.8 Many desperate patients do not accept this decision, however, and choose to do something instead of nothing in the face of profound bilateral vision loss. I believe that intravenous solumedrol 1 g a day for 3--5 days is reasonable here. Although it would violate the law of medical parsimony, this MRI could represent an inflammatory optic neuritis that might respond to therapy.
Case Report (Concluded) The patient was diagnosed with radiation optic neuropathy (RON), and she was treated with hyperbaric oxygen therapy and intravenous methylprednisolone 1,000 mg per day. The patient received 3 days total of methylprednisolone before it was discontinued due to intolerable side effects. She received a total of 70 treatments of hyperbaric oxygen at 2.4 atmosphere absolutes with 90 minutes of 100% oxygen for each treatment. At her last follow-up visit 8 weeks after onset of the RON, her vision was count fingers at 1 foot OD and at 8 inches OS, but she reported subjective visual improvement. She stated that after one treatment, her sight improved so much that she was able to ambulate around her home without assistance. This lasted for 2 weeks before the vision decreased again.
Discussion The primary goal of radiation therapy is to focus maximal energy on abnormal tissue, with a sharp drop in energy to cause minimal damage to surrounding normal tissues. The use of radiation to treat intracranial tumors was described as early as 1909;2,14 it was not until 1956 that the first reports of visual system damage due to radiation were described, however.9,13 The incidence of RON peaks approximately 18 to 24 months following treatment, but has been reported as early as 3 months and as late as several years. Patients usually report an acute, painless decrease in their acuity, followed by progressive worsening of vision. In 75% the process is bilateral, with the second eye becoming involved most commonly within weeks of the first eye. Reports show that 85% have vision worse than 20/200, and 45% progress to no light perception. Most patients have retrobulbar damage; therefore, the initial optic nerve appearance is normal. Optic disc swelling may be seen in patients treated with radiation for anterior orbital, sinus, or intraocular tumors.17
WHIPPLE ET AL
Findings on MRI typically show enlargement and marked enhancement of the affected optic nerve. The pathophysiology of RON, although debated, is likely vascular. Laboratory and clinical evidence suggest that the inciting event is damage to endothelial cells, leading to breakdown of the tight junctions, depletion of the endothelial cells, and an obliterative vasculitis with secondary damage to the glial progenitor cells, causing demyelination and neuronal loss.10,19 Risk factors for RON include age, concurrent chemotherapy, and previous radiation. Pituitary adenoma also appears to be a risk factor, but this may be a function of previous optic nerve compression leading to decreased optic nerve tolerance. In addition, in cases of acromegaly, the enlarged frontal sinuses may lead to an increased effective dose if this is not accounted for in the treatment planning. Treatment variables also contributing to the risk of RON include the total radiation dose received, the maximum dose, the dose per fraction, the modality of treatment (external beam radiation treatment, stereotactic radiosurgery, particle), and the volume of the optic nerve exposed to maximum dose.7 Wigg et al demonstrated that both the maximum and the total dose are important in determining the risk of RON.28 The extent to which each of these factors individually or in combination changes anterior visual pathway tolerance to radiation remains uncertain. There have been multiple attempts to determine how much radiation can safely be given before RON becomes a significant risk.6,11,22,23,25,26 Mayo et al have compiled available studies and attempted to provide meaningful guidelines to practitioners. For external beam radiation therapy a total dose of !50 Gy has almost zero chance of developing RON; at !55 Gy RON is uncommon. Total dose of 55--60 Gy will have a 3--7% chance, and O60 Gy will have a 7--20% chance. For stereotactic radiosurgery at a total dose !8 Gy, RON is rare, !10 Gy is low risk, O12 Gy has a O10% chance of causing RON. Finally, for proton beam radiation, !54 Gray equivalents (GyE) has a low risk of developing RON, with 55--60 GyE reaching the threshold of a significant chance for RON.23 Many studies, however, are limited by small sample sizes, retrospective analysis, and variation in treatment modalities. Additionally, technological advances have allowed for steeper dose gradients and greater accuracy and precision in treatment planning and delivery. Therefore, previous guidelines may quickly be superseded. Applying these guidelines, our patient had almost no chance of developing RON, underscoring that it is not simply the total radiation dose that determines the risk of RON. In her case diabetes may have decreased her threshold for RON.
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The prognosis for RON remains dismal, with 75% of patients having bilateral eye involvement and 85% having acuity less than 20/200. Anterior RON (seen mainly after treatment for ocular melanoma and characterized by optic disc swelling) seems to have a better natural history, with 31% of patients showing some improvement.9 Both corticosteroid therapy and anticoagulation have been ineffective in halting progression of RON. Recently, pentoxifylline has been suggested a possible treatment, given its ability to improve perfusion and its anti-inflammatory effects. Thus far, studies have been inconclusive in radiation retinopathy and cerebral edema, and none have been done in RON.15,27 Hyperbaric oxygen has been shown to be effective in radiation necrosis of non-neuronal tissue, but its use in RON has been disappointing, with reports of vision declining even while on treatment. The timing of HBOT might be a factor in its effectiveness. Ramipril, an angiotensin-converting enzyme inhibitor, decreases the amount of axonal damage in rats with RON in a dose-dependent fashion, an effect thought to be the result of its ability to decrease proinflammatory cytokines. No further studies looking at the effect of ramipril on RON have yet been done.16,24 Bevacizumab, which shows promise in the treatment of cerebral radiation necrosis,21 has recently been used intravitreally for treatment of anterior RON, with 64% of patients showing improvement in vision.12 There was also a single case report of posterior RON treated with intravenous bevacizumab and corticosteroids with marked improvement in vision over a 3-month period.20 RON is an uncommon, unfortunate, and devastating consequence of radiation therapy. The risk of RON remains unpredictable, and its treatment, disappointing. It is difficult for ophthalmologists or radiation oncologists to give individual patients advice as to their risk of RON, given the limitations of the current understanding, the continued technological evolution that may make previous guidelines obsolete, and the lack of a risk calculator that takes numerous patient and treatment variables into account. It is important to have RON on the differential for all patients presenting with visual loss and a history of intracranial radiation.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article. Publication of this article was supported by an unrestricted grant from Research to Prevent Blindness, New York, NY.
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Reprint address: Katherine M. Whipple, MD, UCSD Shiley Eye Center, 9415 Campus Point Drive, La Jolla, CA 92093. e-mail: [email protected].
Abstract. A 78-year-old woman presented with acute decreased vision in both eyes. She had been treated for a pituitary mass with a total of 4,500 centigray of external beam radiation 8 months prior to presentation. She was diagnosed with radiation optic neuropathy. Treatment with hyperbaric oxygen and intravenous steroids were initiated but vision remained poor. (Surv Ophthalmol 58:370--376, 2013. Ó 2013 Elsevier Inc. All rights reserved.) Key words. optic neuropathy pituitary tumor neuropathy radiation treatment visual loss
radiation
treatment
radiation
optic