Background: Radiation optic neuropathy may be one side effect of ionizing radiation exposure to the eye found in a minority of patients. It is generally devastating for visual function and has been the subject of a small but growing literature with respect to its pathophysiology, treatment, and expected outcomes. Summary: Clinical features include optic disc edema, peripapillary hemorrhages, cotton wool spots, and hard exudates. Visual acuity is generally significantly reduced. Treatment has been attempted with outcomes that have not been assessed by randomized trials. Observation may be indicated in addition to treatment. Key Messages: Radiation optic neuropathy is known to generally be devastating to vision though an uncommon side effect of radiation. Treatment has been attempted with mixed results.
Although poorly understood, ionizing radiation is believed to compromise the optic nerve through injury to both glia and vascular endothelial cells, causing what is known as radiation optic neuropathy (RON) . After exposure, neurons degenerate as glia cannot maintain their supportive function and blood supply is reduced; with attrition comes demyelination and loss of neuronal tissue. Vascular occlusion producing necrosis and inflammation leads to secretion of ischemia-specific cytokines. Pathology studies have shown tissue samples with decreased number of endothelial cells and endothelial cell-lined vessels as well as fibrosis of vessel walls, reactive gliosis, and perivascular inflammation . Here, we critically review the literature for management options for RON.
RON often presents with sudden, painless, monocular vision loss in its acute variant. Patients may also have dyschromatopsia or red-green color deficiency. The modality and delivery of radiation is likely a determinative factor in the time of onset and the duration of acute symptoms. Features of optic neuropathy in addition to disc edema include disc hyperemia, peripapillary subretinal fluid, hard exudates, and hemorrhages . Optic nerve head swelling eventually resolves, resulting in a pale and featureless nerve. Angiography reveals early and late exudation at the disc and often ischemia and non-perfusion within the surrounding retinal and nerve fiber layer tissues. With time, the leakage is replaced by total vascular occlusion; vessels are dark on angiography and appear white on exam. A very common result is limited central vision either due to ischemia at the nerve and/or in combination with the macula. Most develop central acuity worse than 20/100 with a reduction or elimination of some or all peripheral vision [3, 4].
Given close proximity to the globe and disc, juxtapapillary plaques produce ischemia to vessels anterior to the lamina cribrosa, leading to RON. The prevalence of neuropathy after brachytherapy ranges from 8 to 16% in 3–5 years and may be influenced by radiation dose, tumor size, and proximity to the disc . In one review, the cumulative incidence of RON in large COMS tumors was 39% at 3 years and 46% at 5 years . When tumors less than 4 mm from the disc were treated and followed, 50% developed neuropathy . A large retrospective review describing 558 patients over 5 years treated with small- to medium-sized tumors found that the probability of neuropathy increased when the nerve was exposed to between 41 and 65 Gy, below which nerve injury was less probable . (Fig. 1). A separate study conducted decades later redemonstrated the dose exposure-nerve injury relationship. Investigators performed a multivariate analysis for 201 patients finding that the total radiation dose to the optic nerve was the only independent significant predictor for RON .
Several treatments have been proposed and utilized for patients with RON. Usually therapy is targeted at regulation or inhibition of the inflammatory and vaso-occlusive aspects of the condition. What medical evidence is available to adjudicate superiority to observation or non-inferiority between potential options is limited to small case series, almost all of which are retrospective. Given that some spontaneously resolve with expectant management producing improved acuity and resolution of acute exam findings, particularly when radiation is delivered anterior to the equator, and the absence of prospective randomized (including observation) trials, treatment is not firmly established .
A considerable number of patients have a spontaneous return of function without intervention. One review found that after a mean of 34 months, 33% experienced a decline in acuity with subsequent improvement and/or stability. At the end of follow-up, 20% retained better than 20/200 Snellen acuity without any treatment (Fig. 2) . Others have described similar results for patients who underwent proton beam therapy for parapapillary tumors, finding that 23% retained 20/200 or better acuity in 5 years . There was an additional difference in outcomes for retained and/or improved vision dependent on the distance between the zone of radiation and the disc. Among those who were treated 0.1 to 1 disc diameter to the nerve (considered far from the nerve), half had improved or stable acuity in 4 years following onset of RON. If radiation was directed to a juxtapapillary tumor (considered close to the nerve), 10% still experienced improved acuity, gaining 2 or more lines over the same period (Fig. 3).
Systemic and intra-ocular corticosteroids have been attempted for RON. When a series of 12 patients who underwent radiation for central nervous system lesions received a combination of high-dose intravenous prednisone or methylprednisolone weeks after onset of visual symptoms, there was no difference noted in the trajectory of disease . Thinking that perhaps intraocular delivery may produce different results, others reported 9 patients who were prospectively treated and followed. All underwent a single 4 mg intravitreal injection of triamcinolone at the time of acute onset of symptoms and were followed for a mean of 11 months (Fig. 4A) . Eight had improved or stable acuity, and two had unchanged vision but also suffered from substantial confounders (one had a macular hole, and the other a retinal vein occlusion).
Vaso-occlusive processes occur in RON, and therefore, anti-vascular endothelial growth factor (anti-VEGF) agents have been used to counteract the cytokine’s harmful effects when secreted in excess. One retrospective study included 14 patients with RON who underwent two initial injections of bevacizumab (1.25 mg, Avastin, Genentech, San Francisco, CA, USA), separated by 6–8 weeks, and were followed for a mean of 25 months and continued to receive treatment if deemed necessary (Fig. 4B) . In all patients, the acute exam findings typical of RON resolved (including disc edema, hemorrhaging), and 7 patients had improved acuity. Including the 7 who experienced improved acuity, 11 patients in total were recommended to continue therapy, given that the vision was preserved in the setting of persistent angiographic evidence of infarction that they believed would have otherwise progressed to worsening acuity in the absence of therapy. The mean number of injections per patient was 11 (median 13; range 2–21). Similar to the use of triamcinolone, a theory of prophylaxis and comparison with historical controls was employed to judge the utility of anti-VEGF treatment, finding that these patients performed superior to what has been considered generally poor outcomes produced by RON.
Combination (Steroid + Anti-VEGF Agents)
Considering mixed pathophysiology involving both vascular occlusion and inflammation, combined agent therapy has been attempted. A retrospective comparative case series involving 93 patients who underwent proton beam, later developing RON, were evaluated for effects of various monotherapy strategies when compared to each other and a control observation group . There were some differences between intervention and control groups, specifically median radiation dose delivered to the macula was 55.8 Gy in control and 0 in the intervention group. Tumors tended to be larger in the intervention group with no T4s and fewer T3s in the observation group (11.1% T3s in intervention vs. 4.2% T3s in observation). There was a minimum of 24 months of follow-up (median 55 months). The observation group included 48 patients, whereas 45 were treated with either intravitreal triamcinolone (26 patients), bevacizumab (23 patients), or dexamethasone-eluting implant (6 patients). For some patients, combined therapy was attempted with more than one medication (9 patients). There was stable or improved visual acuity for 16 patients (33%) in the observation group and 21 patients (47%) in the treatment group at last follow-up (median 34 months; range 24–125 months). The 14% difference found between groups was not statistically significant (p = 0.21) (Fig. 4C). Additionally, there was no statistical difference between the groups in the incidence of optic atrophy in long-term follow-up. Each agent was evaluated individually after eliminating those who received combination therapy. Similarly, authors did not find statistically significant differences comparing change in visual acuity before and after proton beam therapy between various monotherapy groups, although the number of cases in each monotherapy groups was low, a major limitation of this study.
In a prospective noncomparative case series of 9 patients, intravitreal bevacizumab at the time of diagnosis and 2 mg of intravitreal injection of triamcinolone 1 week later was administered . Both agents were readministered 1 month later followed by monthly bevacizumab monotherapy until the papillopathy (RON) resolved. A mean of 6.75 months (+/− 2.60) of bevacizumab was delivered. The visual acuity improved in 44% and stabilized in 44%. Overall, an equal proportion (44%) of patients remained stable in all three groups, while greatest proportion improved (44%) and least worsened (11%) in those receiving combined therapy. These data should be interpreted with caution as there was no observation group for comparison and the number of cases in each group was small.
Some have theorized that medical therapy delivered only at the onset of acute disease may be too late after inflammation and vascular occlusion have caused injury. Therefore, treatments with preventative intention have been studied for RON. They have yielded mixed results.
One retrospective investigation evaluated 292 patients treated every 4 months with bevacizumab for 2 years after plaque . When compared with a control group of 162 patients, both having statistically comparable radiation exposure, there was no difference in the incidence of RON. A median of 4 injections were delivered over the study period which some may consider insufficient. Another study was more rigorous. It showed that less RON developed at 24 months with the empiric use of bimonthly ranibizumab (0.5 mg, Lucentis, Genentech, San Francisco, CA, USA) injections after proton beam therapy . However, patients treated with this more aggressive strategy did not have superior visual outcomes; therefore, it remains unclear if empiric therapy is indicated even if given aggressively .
Of all the complications associated with radiotherapy, optic neuropathy may be the most devastating to long-term visual function. It is our experience that most cases of severe visual loss following treatment are the results of this seemingly unavoidable and untreatable complication. Although commonly used treatments outlined above may have questionable utility, there is some evidence to suggest at the empiric or prophylactic use of anti-VEGF agents , and local corticosteroids may reduce the risk of residual loss of function or in some cases, improve acuity from acute RON.
Methods of Literature Search
A search of the MEDLINE database was conducted using the key words optic neuritis, radiation-induced optic neuropathy, radiation neuritis, radiation optic neuropathy. Additional references were culled from the bibliographies of these references. References spanned the period 1959–2020. These references were evaluated for their pertinence to the topic, with special consideration given to papers that detailed clinical outcomes of various treatments for RON. Articles that were repetitious or decidedly nonclinical were omitted from consideration.
Conflict of Interest Statement
Arun D. Singh reported having relevant financial activities outside the submitted work: Aura Biosciences (stock options), IsoAid LLC (consultancy), Immunocore (consultancy), and Eckert and Ziegler (consultancy). No other disclosures were reported. Zackery Oakey and Yagmur Yesiltas have no conflicts of interest to report.
This work was supported in part by an unrestricted grant from Research to Prevent Blindness to the Cole Eye Institute. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Zackery Oakey: conceptualization, methodology, writing – original draft preparation, developed conceptualization and medical literature search. Yağmur Yeşiltaş and Arun Singh: conceptualization, methodology, and writing – reviewing and editing.