Radiation Optic Neuropathy After Whole-Brain Radiation Therapy

Radiation optic neuropathy (RON) is a rare complication of external beam radiation therapy (RT) in which exposure of the anterior visual pathway (AVP) to radiation results in acute, painless vision loss in one or both eyes, months to years after treatment (1). The diagnosis of RON is supported by constant enhancement on MRI in an involved area of previous radiation treatment without evidence of tumor involvement. No treatment has proven effective in reversing this vision loss; therefore management is individualized.

Clinical Correspondence Radiation Optic Neuropathy After Whole-Brain Radiation Therapy Ian Ferguson, BA, Jiayi Huang, MD, Leah Levi, MBBS, Gregory Van Stavern, MD R adiation optic neuropathy (RON) is a rare complication of external beam radiation therapy (RT) in which exposure of the anterior visual pathway (AVP) to radiation results in acute, painless vision loss in one or both eyes, months to years after treatment (1). The diagnosis of RON is supported by constant enhancement on MRI in an involved area of previous radiation treatment without evidence of tumor involvement. No treatment has proven effective in reversing this vision loss; therefore management is individualized. Maximum radiation dose to the optic apparatus is the most significant known risk factor for RON. Clinical and experimental data support a dose tolerance for the AVP of 50 Gy with the incidence of RON approaching 0% below this threshold (2). Dose prescriptions for central nervous system and head-and-neck tumors often are constrained by the sensitivity of the optic apparatus to radiation. Most RT protocols therefore limit maximum point doses to the optic pathway to 54-55 Gy in 1.8-2 Gy fractions (2). Whole brain radion therapy (WBRT) is a palliative intervention for patients with multiple brain metastases. The most common WBRT regimens deliver a total dose of 30 Gy in 3 Gy fractions or 35 Gy in 2.5 Gy fractions, which corresponds to a biologically equivalent dose at 2 Gy fractions (EQD2) of 37.5 or 39.4 Gy, respectively (using the linear quadratic model and assuming an a/b ratio [tissue repair capacity] of 2 for the optic apparatus) (3). Biologically equivalent doses allow for comparison of WBRT regimens with differing fractions. The biologically equivalent dose in these regimens is well below the dose-tolerance threshold of the AVP even accounting for larger fraction size. A lower, palliative dose for brain metastases is essentially a compromise between toxicity and tumor control, resulting in control of disease in approximately 50% of patients at 6 months (4). Washington University School of Medicine (IF, JH, GVS), St. Louis, Missouri; and Scripps Clinic (LL), La Jolla, California. Supported by DOVS Core Grant 5 P30 EY02687, Institute for Clinical and Translational Sciences Grant RR023496, Biostat Core Grant U54 RR023496, an unrestricted grant from Research to Prevent Blindness, NIH Core Vision Grant P30 EY02687. Multiple long-term neurological sequelae after WBRT have been described, including dementia, more subtle cognitive deficits in memory and attention, ataxia, incontinence, and death (5,6). Here, we report 3 cases of RON following WBRT. CASE REPORTS Case 1 A 59-year-old man with no significant medical history was diagnosed with metastatic lung adenocarcinoma. He was a nonsmoker. He underwent WBRT at an outside institution of 30 Gy in 3 Gy fractions more than 10 treatments (EQD2 of 37.5 Gy) with a calculated maximum dose to the optic nerves of 30.8 cGy (hot spot of approximately 103% and EQD2 of 39.1 Gy) and chiasm of 29.8 cGy (EQD2 of 37.1 Gy). He began adjuvant chemotherapy with carboplatin and pemetrexed 2 weeks after completing WBRT. After the first 2 cycles, bevacizumab was added and continued every 3 weeks. Eleven months after completing WBRT, he reported progressive vision loss in his left eye. On examination, visual acuity was 20/20 in the right eye and 20/80 in the left eye. He had a left relative affect pupillary defect (RAPD) and diminished color vision in his left eye. Visual field testing showed marked depression in his left eye, and his left optic disc showed mild temporal pallor. The remainder of his examination was unremarkable. Lumbar puncture with large volume cytology was negative. MRI demonstrated thickening and enhancement of the intracranial portion of the left optic nerve and the left side of the chiasm with no evidence of metastases (Fig. 1). The patient received 21 treatments of hyperbaric oxygen at 2.4 atm. Pentoxifylline 400 mg 3 times per day was added, and he was continued on bevacizumab (7). Despite this, his left eye vision deteriorated to counting fingers in the temporal visual field. His right eye vision and visual field remained normal. Follow-up MRI obtained 6 months later showed resolution of optic nerve enhancement. The authors report no conflicts of interest. Case 2 Address correspondence to Gregory Van Stavern, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, 660 South Euclid Avenue, Box 8096, St. Louis, MO 63110; E-mail: [e-mail] A 58-year-old man, who was a nonsmoker but did have a history of hypertension and hyperlipidemia, was diagnosed with metastatic lung adenocarcinoma. He initially Ferguson et al: J Neuro-Ophthalmol 2019; 39: 383-387 383 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Case 1. Postcontrast coronal T1 MRI shows enhancement of the intracranial left optic nerve (arrow). underwent 6 cycles of carboplatin and paclitaxel plus dasatinib. Because of progression of disease, dasatinib was switched to pemetrexed. He subsequently was found to have brain metastases and underwent WBRT at an outside institution of 35 Gy in 2.5 Gy fractions more than 14 treatments (EQD2 of 39.4 Gy) for a calculated maximum dose to the optic nerves of 34.3 Gy (EQD2 of 38.2 Gy) and chiasm of 35.2 Gy (EQD2 of 39.6 Gy). During his WBRT, he received concurrent carboplatin, paclitaxel, and pemetrexed. Six months after completing WBRT, he reported rapid progressive loss of vision in his left eye, and 2 months later, he noted blurring of vision in his right eye. On neuroophthalmologic examination, vision was 15/200 in his right eye and light perception in his left eye. Both pupils were poorly reactive to light. Confrontation visual fields showed preserved temporal islands bilaterally. His funduscopic examination showed mild temporal optic disc pallor in his right eye and diffuse pallor in his left eye. The remainder of his examination was unremarkable. The patient declined lumbar puncture. MRI showed moderate, focal enhancement of both intracranial optic nerves with no adjacent metastases (Fig. 2). Treatment for RON was deferred. Visual acuity worsened to hand motion in the right eye and light perception in the left eye before stabilizing. Follow-up MRI was not pursued. Case 3 A 61-year-old man with a 40-pack-year smoking history and an unremarkable medical history was diagnosed with 384 FIG. 2. Case 2. Postcontrast coronal T1 scan reveals enhancement of the prechiasmal portions of both optic nerves (arrows). rectal adenocarcinoma and small-cell lung cancer. He was subsequently diagnosed with brain metastases. He underwent WBRT at an outside institution of 30 Gy in 3 Gy fractions more than 10 treatments (EQD2 of 37.5 Gy) for a calculated maximum dose to the optic nerves of 30.3 Gy (EQD2 of 38.1 Gy) and chiasm of 30.4 Gy (EQD2 of 38.3 Gy). He received concurrent carboplatin and etoposide for 4 cycles followed by single-agent irinotecan. Nine months after completing WBRT, he reported abrupt onset of vision loss in his right eye. On examination, visual acuity was hand motions in the right eye and 20/30 in the left eye. He had a right RAPD, and confrontation fields showed a superotemporal defect in his left eye. There was mild temporal optic disc pallor in his right eye. The remainder of his examination was unremarkable. Lumbar puncture was not performed. MRI showed increased FLAIR signal and enhancement of both intracranial optic nerves with no adjacent metastases (Fig. 3). He was treated with pentoxifylline 400 mg 3 times per day and Vitamin E 1000U one time per day. His examination remained stable. Follow-up MRI was not pursued. DISCUSSION The report of RON after standard WBRT has significant implications. As overall survival of patients with brain metastases continues to improve with better systemic Ferguson et al: J Neuro-Ophthalmol 2019; 39: 383-387 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 3. Case 3. Postcontrast coronal T1 image demonstrates enhancement of the intracranial segments of both optic nerves (arrows). therapy (8), additional cases of this late-delayed complication of RT may become apparent. Standard WBRT delivers biologically equivalent doses in 2 Gy fractions that are considered well below the currently accepted dose-tolerance threshold of the optic apparatus. A number of possible determinants may contribute to the occurrence of RON after WBRT in rare cases. Increased fraction size seems to increase the risk of developing RON. Within the 60-70 Gy range, the 15-year actuarial rate is reported at 50% vs. 11% for $1.9 vs ,1.9 Gy dose per fraction, respectively (9). Given standard WBRT is typically delivered with . 2 Gy per fraction, this may be a contributing factor for the development of RON in our patients. The known dose tolerance of the optic apparatus was developed mostly from patients receiving partial rather than whole-brain irradiation. Evidence that the mean dose is greater for patients with adverse outcomes, despite comparable maximum doses, suggests that a volume effect does occur (10). Unlike potentially focal exposure to higher doses of partial-brain external brain RT, WBRT exposes the entire volume of the optic apparatus to a lower dose of ionizing radiation. Emami et al (11) previously estimated that 50 Gy to the entire optic apparatus would cause 5% risk of toxicity at 5 years (TD5/5). Current data on dose-volume relationships for the optic apparatus are scarce. Precise contouring of the optic apparatus to record accurate dose-volume histograms may more fully elucidate this relationship. Ferguson et al: J Neuro-Ophthalmol 2019; 39: 383-387 Dose inhomogeneity in WBRT exposes the optic apparatus to doses in excess of the treatment prescription -so called "hot spots." In WBRT, hot spots preferentially localize over the superior and median frontal region of the brain. James et al (12) found that, for a nominal treatment plan of 30 Gy, the mean percentage of brain receiving .105% of dose was 29.3%, the mean percentage of brain receiving .110% of dose was 2.4%, and the mean maximum point dose was 3,378 cGy (113%) (13). In Case 1, where the delivered dose to the optic apparatus was available, the maximum dose was 103% of the prescription dose (EQD2 of 39.1 Gy). However, such hot spots would still be well below the tolerance of the AVP. The use of chemotherapy with WBRT in our 3 patients may have contributed to the occurrence of RON. Each of the chemotherapeutic agents taken at the time of WBRT by patients in this series has been reported to possess radiosensitizing properties. Carboplatin, for instance, was administered to all 3 patients in association with WBRT and is a known radiosensitizing agent that crosses the blood-brain barrier. Carboplatin and paclitaxel, coadministered in Case 2, have a synergistic interaction that enhances their radiosensitizing effect (13). Pemetrexed is associated with radionecrosis after stereotactic radiation (14). Previous randomized studies combining WBRT with chemotherapy did not show improved survival but, instead, showed increased toxicity. Thus, concurrent chemotherapy with WBRT is not typically recommended in routine clinical practice. To our knowledge, RON has not been reported in these randomized studies (8). The timing of vision loss after radiation treatment, ophthalmologic examination, and neuroimaging findings reported in this case series is most consistent with RON; however, the possibility that these cases represent a multifactorial disease process involving chemotherapy-associated radiosensitization is not without merit. Unlike reported cases of ocular toxicity from chemotherapies such as cisplatin, the patients presented here showed no disc edema or neovascularization concerning for retinopathy (15,16). They presented months after the cessation of adjuvant chemotherapies, which is consistent with the late-delayed radiation injury of RON (1). Moreover, they progressively worsened before stabilizing, rather than improving after cessation of the offending chemotherapeutic agents (17). Rare cases of vision loss after WBRT not attributed to RON were associated with adjuvant targeted therapies (e.g., crizotinib) (18). Although the clinical course presented here argues strongly in favor of a diagnosis of RON, evidence suggests that various chemotherapies (cytotoxic, targeted, and perhaps even immunologic) may sensitize the optic apparatus to radiation injury. Such a scenario-radiosensitizing chemotherapies lowering the dose tolerance of the optic apparatus-may not change the primary diagnosis from RON, but may change the expected course or treatment, and warrants additional consideration. 385 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence Various other potential risk factors for RON have been postulated. These include diabetes mellitus (19), compression of the optic nerve (20), vascular pathology (hypertension, hyperlipidemia, smoking) (21), and age (9,22), although a recent case-control study found no significant associations (23). In this series, one patient had an extensive smoking history, and another had a history of hypertension and hyperlipidemia, which provided anecdotal evidence for the role of vascular risk factors. This is consistent with the proposed pathogenesis of RON as an endotheliopathy (24). It is plausible that concurrent administration of radiosensitizing chemotherapies lowered the dose-tolerance threshold of the optic apparatus thus predisposing these patients to RON. Perhaps the true predisposition lies in a "perfect storm" of pre-existing optic nerve injury, individual vasculopathic risk factors, interactions between specific chemotherapeutic agents and radiation, and as yet unidentified biologic factors (25). Caution should be exercised when prescribing chemotherapies with radiosensitizing property to patients who have undergone WBRT. In settings where concurrent chemotherapy is indicated, it may be necessary to take additional measures to minimize radiation exposure to the optic apparatus. A possible solution would be to replace WBRT with intensitymodulated radiation therapy (IMRT), designed to conformally avoid the AVP thus sparing these structures from the full dose delivered to the whole brain. IMRT has been demonstrated to decrease dose heterogeneity over conventional WBRT: decreasing the mean percentage of brain receiving .105% of dose reduced to 0.03%, decreasing the mean maximum dose reduced to 3,162 cGy (105%), and decreasing the mean maximum point dose reduced to 3,163 Gy (105%) (13). IMRT has been shown to enable dose reduction of the hippocampus to reduce neurocognitive effect of WBRT; similarly, it may be used to avoid doses to the optic apparatus (26). We recognize limitations to this report. Although the clinical course and neuroimaging findings were consistent with RON, there is no definitive test to confirm the diagnosis. Not having well-documented ocular histories for our patients limits our conclusions; none of the patients had pretreatment neuro-ophthalmologic examinations, which would have better defined the severity and character of visual decline. Although neuroimaging did not show meningeal enhancement, without spinal MRI or cytological evidence in the cerebrospinal fluid, the possibility of microscopic leptomeningeal disease cannot be excluded. With no brain lesions abutting the optic apparatus on brain MRI, the reported cases are unlikely to be due to brain metastases. Unfortunately, follow-up MRI studies were not performed in our patients. The authors leveraged the expertise of a radiation oncologist specializing in neurooncology to review RT plans and expected dose to the optic apparatus from WBRT. The actual dose delivered for Case 2 was estimated from a mock plan using the patient's MRI and treatment prescription. 386 This report of RON after WBRT suggests that the purported dose tolerance of the AVP may be lower than previously reported for select patients, particularly those receiving chemotherapy in association with WBRT. 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