Radiation Retinopathy: Detection and Management Strategies

Despite advances in precise localization and dosage calculation, patients encounter several forms of ocular complications as collateral damage. Radiation retinopathy (RR) is a chronic progressive vasculopathy developing secondary to ionizing radiation to the retina. This article comprises review of clinical features and investigations of radiation retinopathy and the current strategies being studied for its treatment.

Epidemiology and Risk Factors

While radiotherapy offers an eye-sparing alternative for patients and allows them to maintain some level of visual acuity, an increase in the incidence of radiation-related complications has been seen.

Several factors determine the incidence of radiation retinopathy. The risk factors can be divided into intrinsic or extrinsic. One of the most important intrinsic/patient factors is the presence of concurrent diabetes. There appears to be a synergistic action of radiation and diabetes on the capillaries that predisposes these eyes to retinopathy and can increase the risk of visual loss by 300%.

Tumor characteristics and patient demographics play a crucial role in the development of RR. Eyes with larger tumors may require high doses of radiation, increasing the chance of developing RR. Also, eyes with tumor proximity to the critical structures of the eye such as the optic disc or macula are at high risk for developing vision loss in the form of radiation optic neuropathy or radiation maculopathy (RM).

Concomitant chemotherapy makes the retinal vasculature more vulnerable to radiation damage by increasing oxygen-derived free radicals. It also increases the risk of progression to the proliferative stage, higher visual morbidity, development of retinopathy at lower radiation dose and decrease in the latent period between exposure and retinopathy. Pregnancy has been thought to accelerate radiation retinopathy.

Extrinsic factors responsible for the development of RR are related to the radiation itself. These include the type of radiation, radiation dose, fractionation schedule, elapsed time in the course of treatment, and errors in treatment.

Ruthenium-106 has been shown to have limited depth of penetration, resulting in less radiation exposure to surrounding retinal structures. However, when compared to Iodine-125, rates RR have been seen to be similar between the two, although a few studies have reported slightly higher rates for Iodine-125. Considering the slight advantage of Iodine-125 in certain cases in terms of tumor control, the choice of plaque can be individualised on a case-to case basis.

Hyper-fractionation with a dose of less than 1.9G/fraction has been demonstrated to decrease the risk of RR development. Although the worst visual outcome has been seen after gamma knife treatment, it needs to be emphasized here that gamma knife treatment still remains a valid treatment option in selected cases, with excellent results. The area of retina irradiated also plays a significant role in RR manifestations.

RR usually develops after around 6 months to 3 years (range 1 month to 15 years) following radiation therapy. The type of radiation therefore plays an important role in this latency period, with higher dose and single fraction regimen resulting in lower latency period. Thus, authors recommend close monitoring, with 6 monthly follow-ups if there are no signs of retinopathy, and subsequent follow-ups can be tailored on a case-to case basis. Detection and follow-up of RR can be especially challenging when the patients are being treated with external beam radiotherapy (EBRT) and are less likely to be seen by an ophthalmologist.

Pathogenesis

Following radiotherapy, the primary retinal vascular event is an endothelial cell loss followed by vascular occlusion and capillary dropout, which results in vascular incompetence and retinal ischemia. Radiation significantly alters the structure and function of the retinal microvasculature due to the compromised blood-retinal barrier.

Ionizing radiation can cause direct damage to molecular bonds, resulting in damage to DNA base-pairs, cell membranes rupture and lysosome disruption. This affects the cell's ability to divide, and they undergo senescence and eventually die. Radiation can also cause indirect damage to cells by exposing the endothelial cells to high concentrations of free radicals that result in cell membrane damage. This leads to occlusion of capillary beds and subsequent microaneurysm formation. The areas of retinal non-perfusion cause retinal ischemia, which eventually leads to macular edema, neovascularization, vitreous hemorrhage, and tractional retinal detachment. This could be one of the reasons why signs of retinopathy predominate in the macular region, where oxygen concentration is highest. Nonreplicating cells like photoreceptors are relatively resistant to radiation damage. Patchy degeneration of the RPE in the form of loss of melanin, accumulation of lipofuscin, and hyperplasia, and beading, telangiectasia, microaneurysm, sclerosis and closure of choroidal vessels, have also been described.

Clinical Features

RR can closely resemble diabetic retinopathy, as the manifestations and patterns of progression of these two entities are very similar. Both diseases progress from a nonproliferative to a proliferative stage and can result in rapid deterioration of vision.

Clinical manifestations of RR include microaneurysms, macular edema, cottonwool spots, hard exudates, retinal edema, telangiectasia, and perivascular sheathing, which may follow in variable sequence and latency. Microaneurysms are the first ophthalmoscopically detectable structural changes to appear in RR and are almost universally present. The clinical manifestations of RR are more often severe in the posterior than in the anterior retina, which is due to higher blood flow of the macula. Ischemic retinal changes include macular capillary nonperfusion, nerve fiber layer infarcts, retinal neovascularisation, choriocapillaris non-perfusion, choroidal ischemia, vitreous hemorrhage, tractional retinal detachment, exudative retinal detachment, and neovascular glaucoma. Ghost vessels can appear in the later part of the disease.

The retina is the most common site of neovascularization. Rarely, choroidal neovascularization, retinal angiomatous proliferation, intravitreal polypoidal choroidal vasculopathy can occur after radiotherapy.

It is particularly important to distinguish RR from another post-radiotherapy complication, known as "toxic tumor syndrome", which is characterized by exudative retinal detachment and iris rubeosis. While RR develops as a result of direct damage of the healthy retina by the ionizing radiation, toxic tumor syndrome has been hypothesized to result from radiation-induced vasculopathy within the tumor, which causes exudation from the damaged and incompetent tumor vasculature.

Eyes with proliferative retinopathy invariably progress to legal blindness without treatment and even those in the non-proliferative stage tend to gradually lose vision over time

Differential Diagnosis

Clinical features of RR can be difficult to distinguish from other vascular diseases of the retina like diabetic retinopathy, hypertensive retinopathy, and other vascular occlusive disorders. Thus, a dilated ophthalmic examination, a careful documentation of history, along with a thorough review of the treatment records, is usually necessary to reach a diagnosis. RR should be considered as a differential diagnosis after cephalic radiation for head and neck malignancies. Diabetic retinopathy and RR are closely associated and sometimes both may coexist. RPE atrophy and, possibly, unilaterality of the disease are the two features of RR that can distinguish it from diabetic retinopathy. There are also fewer microaneurysms in cases of RR as compared to diabetic retinopathy. Other conditions that can closely mimic radiation retinopathy are retinal vein occlusions, ocular ischemic syndrome, hypertensive retinopathy, Coats' disease, and parafoveal telangiectasia

Apart from meticulous clinical examination and adequate history taking, newer multimodal imaging such asoptical coherence tomography (OCT), OCT angiography (OCTA), fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) are useful in making diagnosis and treatment of RR.

Investigation

Clinical features of radiation retinopathy can often be unremarkable in the early stages of the disease, and it might be necessary to take the help of adjunctive investigations.

• Optical Coherence Tomography (OCT)

• Fundus Fluorescein Angiography

• OCT Angiography

Treatment

Although spontaneous improvement can occur, it is very uncommon. There are no specific guidelines for treatment and the primary goal in most cases remains visual stabilization or prevention of vision loss. Due to similarities in pathogenesis and natural history, treatment of radiation retinopathy follows closely to that of diabetic retinopathy. The type of retinopathy determines the management protocol.

• Laser Photocoagulation

• Anti-VEGF Agents

• Steroids in RM

Radiation retinopathy is a potentially blinding condition. Unlike patients undergoing treatment with plaque brachytherapy, who routinely undergo evaluation by retina specialists, those who are treated with EBRT are less likely to be checked by an ophthalmologist. Thus, considering the progressive nature of the disease, it is imperative to follow a regular post-treatment check-up in order to avoid undue delays in diagnosis and treatment.

Source: Sahoo et al;Clinical Ophthalmology 2021:15 3797–3809

https://doi.org/10.2147/OPTH.S219268