Radiation optic neuropathy (RON) is an optic nerve disorder caused by delayed ischemic changes following radiation exposure to the optic apparatus. The optic apparatus is highly radiosensitive, and visual function is lost through mechanisms primarily involving vascular endothelial damage.
The most common site is the optic chiasm or its adjacent regions, classified into anterior RON and posterior RON. Anterior RON results from proton beam therapy or plaque brachytherapy for orbital, choroidal, or retinal tumors, while posterior RON arises from treatment of paranasal sinus or skull base tumors.
The risk of onset is closely related to the radiation dose. The following table shows the relationship between dose and risk.
| Irradiation Condition | Risk of Onset |
|---|---|
| Total dose less than 5,000 cGy | Rare |
| Total dose 5,000–6,000 cGy | Up to 5% within 10 years |
| Single dose ≤2 Gy, total dose ≤50 Gy | Relatively safe |
| Gamma Knife 800–1,000 cGy single fraction (1–3 sessions) | Relatively safe |
The onset time ranges from 3 months to several years after irradiation, with most cases occurring within 3 years. The peak onset is at 1.5 years after irradiation, and the most common onset is 8–16 months after treatment. With the widespread use of Gamma Knife, the incidence of RON has significantly decreased.
With fractionated irradiation at a total dose of less than 5,000 cGy (50 Gy), onset is rare. At 5,000–6,000 cGy, it is reported to occur with a probability of up to 5% within 10 years. A single dose of 2 Gy or less and a total dose of 50 Gy or less are considered relatively safe, and these values serve as standards when planning irradiation.
Anterior RON
Optic disc edema: In the anterior ischemic optic neuropathy type, optic disc edema, hemorrhage, and microvascular abnormalities are present.
Optic disc pallor: Edema transitions to optic disc pallor after 4 to 6 weeks.
Coexisting radiation retinopathy: May be observed concurrently.
Posterior RON
Normal or pale optic nerve: In posterior RON, fundus findings are scarce, and the optic nerve appears normal or pale.
Visual field defect patterns: Optic chiasm damage causes bitemporal hemianopia, and optic tract damage causes contralateral homonymous hemianopia with band atrophy.
A 42-year-old woman (50 Gy irradiation for brain metastasis of breast cancer) presented with superior altitudinal visual field defect, inferior segmental optic disc pallor, and positive RAPD in the right eye one year after irradiation. Eventually, the right eye had only light perception (amaurotic pupil) 1).
A 74-year-old woman (54 Gy irradiation after meningioma resection) had left eye visual acuity of 20/20 and was asymptomatic at 22 months after irradiation, but OCT detected thinning of pRNFL and GCIPL 2).
Radiation damages cells through two pathways: direct disruption of molecular bonds and indirect damage via free radical generation. As stated by the Bergonie-Tribondeau law, cells with high mitotic activity and low differentiation are more susceptible to radiation damage. Damage to vascular endothelial cells leads to increased vascular permeability and capillary occlusion, ultimately causing ischemic optic neuropathy.
Patients with diabetes have a higher risk of ischemic vascular disease, which is thought to increase the risk of developing RON. Hypertension and pre-existing vascular lesions are also risk factors. Concurrent chemotherapy may further increase the risk. In cases with multiple risk factors, particularly careful radiation planning and follow-up are required.
Radiation optic neuropathy is a diagnosis of exclusion, made after ruling out similar diseases.
The main differential diagnoses include the following:
Cerebrospinal fluid analysis via lumbar puncture (to rule out carcinomatous meningitis) and serological tests (to search for paraneoplastic syndromes) may also be necessary.
The following is an overview of the OCT-A grading scale.
| Grade | Findings |
|---|---|
| 0 | Regular radial distribution of RPCP |
| 1 | Loss of initial radial pattern of RPCP |
| 2 | Peripapillary hypoperfusion in less than 2 quadrants |
| 3 | Hypoperfusion in 2 or more quadrants |
| 4 | Diffuse hypoperfusion in all 4 quadrants |
Grades 1 to 3 have a ”+” subclass (involvement of the papillomacular bundle), which correlates with decreased visual acuity.
Detection of pRNFL and GCIPL thinning by OCT may capture changes before subjective symptoms appear 2). MRI shows contrast enhancement of the affected optic nerve. Regular ophthalmic monitoring after radiotherapy is thought to lead to early detection of RON, and some reports propose routine MRI monitoring 10 to 20 months after completion of external beam radiation 2).
There is essentially no curative treatment, and the prognosis is generally poor. For early-stage cases without optic atrophy, the following treatments may be somewhat useful.
There is no curative treatment, and the prognosis is generally poor. In 45% of affected eyes, final visual acuity is less than 20/200 to light perception, and about half result in no light perception. Systemic steroids, hyperbaric oxygen therapy, and anticoagulation therapy may be somewhat useful for recent-onset cases, but none guarantee recovery of visual function.
The pathogenesis of RON involves both vascular damage (radiation vasculitis) and direct radiation damage to the optic apparatus. Whether the initial damage appears in the vascular system or the neural parenchyma remains unclear.
Early stage (within a few weeks)
Reversible inflammation and exudative vascular damage: Increased vascular permeability is central. Changes at this stage are considered reversible.
Progressive stage (months to years)
Vascular occlusion and endothelial cell proliferation: Free radical damage is added.
Microvascular insufficiency: Microvascular insufficiency with hypoxia is induced. Direct damage to cellular DNA and the blood-brain barrier also occurs.
Irreversible stage
Demyelination and reactive astrocytosis: Damage spreads to surrounding nerves, leading to irreversible visual loss.
Radiation-induced cell damage occurs via two pathways. The first is direct damage through disruption of molecular bonds, and the second is indirect damage through free radical generation. According to the Bergonie-Tribondeau law, cells with higher mitotic frequency and less differentiation are more susceptible to damage. Damage to vascular endothelial cells leads to increased capillary permeability and occlusion, and through local VEGF elevation and inflammatory response, ischemic optic neuropathy is established.
Bevacizumab has attracted attention as a treatment targeting local VEGF elevation associated with endothelial cell damage. Systemic administration (once every 3 weeks, total of 4 doses) or intravitreal administration (at least 2 doses every 6-8 weeks) has been reported, with reports of stable improvement in visual acuity and color vision over 3 years.
Pentoxifylline (Trental), a methylxanthine derivative, has been shown to modify blood viscosity and may help improve circulation, with promising results reported. In actual case reports, pentoxifylline 1,200 mg/day has been prescribed2).
There is a report that administration of an ACE inhibitor (ramipril) starting 2 weeks after radiation exposure for about 6 months reduces the release of inflammatory cytokines. However, this has only been demonstrated in rat models so far, and its application to humans is not yet established.
Vitamin E has been shown to reduce reactive oxygen species production and inhibit fibrosis in in vitro studies, but clinical evidence is limited.
By detecting thinning of pRNFL and GCIPL on OCT, it may be possible to diagnose radiation optic neuropathy before it becomes symptomatic 2). A grading scale using OCT-A is also expected to be useful as a non-invasive monitoring tool in the future. The establishment of an international registry is expected to further elucidate the clinical profile.
