Radiotherapy is a well-established line of treatment in several neoplastic and non-neoplastic conditions of the orbit, head, neck, and nasopharynx. Its ophthalmic complications include dry eye disease, blepharitis, keratoconjunctivitis, scleral necrosis, glaucoma, cataract, optic neuropathy, and radiation retinopathy. Radiation retinopathy is a late-onset, slowly progressive, occlusive microangiopathy involving retinal vasculature. Factors critical for its development are dosage, location, total amount of radiation delivered, concurrent chemotherapy, and comorbid conditions such as hypertension, diabetes, and collagen vascular diseases. The overall incidence has been reported to be 17%, the highest being associated with radiation in the orbit (85.7%), followed by paranasal sinuses (45.4%), nasopharynx (36.4%), and the brain (3.1%). The clinical course follows a log dose-response curve and occurs with dosages between 15 Gy and 60 Gy. The threshold of radiation has been reported to be 35Gy with a daily fraction of 1.8–2G y in most literature.
We report a case of extremely delayed onset radiation retinopathy with recurrent macular edema (ME), presenting 17 years after exposure.
A 40-year-old man presented with reduced vision in the right eye for one week. A detailed medical history revealed that he had nasopharyngeal carcinoma 17 years back and had received two cycles of chemotherapy followed by 34 Gy of external beam radiotherapy over four months. He did not have any history of diabetes mellitus, hypertension, or immunological disorder. The best-corrected visual acuity (BCVA) at presentation was 20/40 and 20/20 in the right and left eye, respectively. Anterior segment examination was unremarkable except for bilateral focal posterior subcapsular cataract. Dilated fundus evaluation revealed localized microvascular telangiectasia distributed along the terminal blood vessels around the fovea and elsewhere in the macula with microaneurysms and multiple dot hemorrhages at the posterior pole in both the eyes [Fig. 1a and c]. The right eye also had ME and a small tortuous blood vessel with collaterals temporal to the fovea, which was better appreciated using red-free filter [Fig. 1b, 1d]. Fundus fluorescein angiography (FFA) revealed bilateral perifoveal capillary telangiectasia, pinpoint hyperfluorescence in early phase (microaneurysms) with late leakage, without neovascularization [Fig. 2a, 2b]. Swept-source optical coherence tomography (SS-OCT) of the right eye revealed a subfoveal neurosensory detachment (NSD) with pockets of intraretinal fluid temporal to the fovea, whereas SS-OCT was unremarkable for the left eye [Fig. 3a, 3b]. OCT angiography (OCTA) of both the eyes revealed abnormal telangiectatic vessels in superficial and deep retinal vasculature with capillary dropouts and irregular foveal avascular zone (FAZ) temporally [Fig. 4a–d]. Routine blood investigations showed a fasting blood glucose of 89 mg/dL, two-hour postprandial blood glucose of 97 mg/dL, glycosylated hemoglobin (HbA1c) of 5.9%, and non-reactive titers of HBsAg, anti-HCV antibody, and HIV-I and II. Blood pressure was 128/78 mmHg, which was normal as per the patient’s age. Based on history, clinical, imaging, angiographic, and blood investigation findings, a diagnosis of bilateral extremely delayed onset radiation retinopathy with right eye ME was made.
The presence of microaneurysms, dot hemorrhages, and ME along with microvascular telangiectasia temporal to the fovea led to few differential diagnoses. Macular branch retinal venous occlusion (BRVO) was considered because of the collaterals, microaneurysms, and ME. However, absence of sclerosed vessel and delayed dye transition on FFA ruled this out. Telangiectatic vessels temporal to the fovea and microaneurysms in the posterior pole favored macular telangiectasia type 2. However, dot hemorrhages and telangiectasias outside the macula and lack of OCT features ruled it out. Moreover, FFA in this condition characteristically shows telangiectatic capillaries predominantly temporal to the foveola in early phase and diffuse hyperfluorescence in late phase. Fundus findings were also similar to non-proliferative diabetic retinopathy, but the patient being non-diabetic ruled out this differential. HIV retinopathy also mimics radiation retinopathy and was ruled out by detailed history and negative serum titers for HIV-I and II.
The patient was administered one dose of intravitreal bevacizumab (IVB) injection (1.25 mg/0.05 mL) in the right eye. At one-month follow-up, vision improved to 20/20p in the right eye with OCT showing resolution of NSD, though there was persistence of intraretinal fluid [Fig. 3c, 3d]. Thereafter, two more doses of IVB were administered at one-month intervals, and significant resolution of ME was noted after the third dose [Fig. 3e]. He was lost to follow-up due to the then ongoing COVID-19 pandemic and presented nine months later with worsening vision in the right eye. OCT showed intraretinal cystic spaces and focal exudates in the affected eye [Fig. 3f]. As of this writing, repeat injection of IVB with focal laser photocoagulation of leaky microaneurysms has been planned. The left eye macula was without any changes till the last follow-up.
Radiation retinopathy usually begins within 6–12 months after completion of radiotherapy, and once it commences, it becomes almost irreversible. The posterior pole being the most radiosensitive region of the retina is affected early, as in this case. The pathogenesis appears to be related to vascular injury, which is evident clinically as microvascular damage, including vascular occlusion, telangiectasia, formation of collaterals, and microaneurysms. All of these findings were present in our case. FFA typically shows areas of capillary non-perfusion, which is considered the gold standard for diagnosis. Our patient had enlargement of FAZ temporally and perifoveal capillary telangiectasia in both eyes on FFA. One of the earliest manifestations of this disease is ME which can be picked up on OCT. Also, OCTA can detect early vascular changes like irregular widening of FAZ in superficial and deep layers, mild-to-moderate capillary dropouts, and microaneurysms before anatomical changes appear on OCT. Keeping the radiation dose below the threshold limits is the only preventive measure. However, this is not always possible in real life, especially after the sudden hit of SARS-CoV-2. Stone et al. showed a delay in review of ≥8 weeks in 39.6% of patients with neovascular age-related macular degeneration—retinal vein occlusion (RVO) or diabetic macular edema (DME)—out of which 30.4% returned for follow-up. Even though our patient responded to three initial doses of IVB, there was recurrence of edema due to non-compliance owing to the pandemic.
Radiation retinopathy can have late presentation, even decades after exposure. Long-term follow-up is crucial in patients receiving radiotherapy for head and neck carcinoma. Multimodal imaging with FFA, OCT, and OCTA can detect challenging cases with diagnostic dilemmas. Treatment should be re-initiated at the earliest in cases that have been lost to follow-up.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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