The Effect of High Dose Radioiodine Therapy on Formation of Radiation Retinopathy During Thyroid Cancer Treatment

Objective: Non-thyroidal complication of high-dose radioiodine therapy for thyroid carcinoma might cause salivary and lacrimal gland dysfunction, which may be transient or permanent in a dose-dependent manner. However, radiation retinopathy complicating 131I therapy, has not been previously well characterized. The aim of this study was to evaluate the extent of retinal damage among patients who had received high doses of radioiodine treatment. Methods: Forty eyes of 20 patients (3 male, 17 female) who received 250-1000 mCi during 131I therapy and on ophthalmological follow up for a year after the last treatment were included in the study. Mean age of the study group was 50 years (range 25-70 years). In ophthalmologic examination, visual acuity was measured in order to determine visual loss. Intraocular pressure was measured in all the patients. Then lens examination was carried out with slit lamp biomicroscopy in order to investigate cataract or partial lens opacities. Fundus observation was carried out through the dilated pupil with slit lamp biomicroscopy using 90 D noncontact lens. Result: The best corrected visual aquity with Snellen chart was found as 1.0 in 36 eyes (90%) and between 0.6 and 0.9 (10%) in 4 eyes (10%). At the biomicroscopic fundus examination, retinal hemorrhage consistent with radiation retinopathy, microaneurysm, microinfarction, edema or exudation, vitreus hemorrhage, partial or total optical disc pallor indicating papillopathy in the optic disc were not observed in any of the eyes. Conclusion: This result indicates that there is not any significant correlation between repeated high-dose radioiodine therapy and radiation retinopathy in differentiated thyroid carcinomas. Even though there is not a significant restriction in use of higher doses of radioiodine therapy in differentiated thyroid carcinoma, more extensive studies are needed in order to obtain more accurate data on possible occurrence of retinopathy.


Introduction
Radioiodine (Radioiodine (RI) (iodine-131, or 131I)) is used for the ablation of postoperative residual thyroid tissue in differential thyroid carcinomas (1). Although serious acute complications are extremely rare following radioiodine treatment, several side effects could occur (2,3,4). Gastrointestinal complaints, salivary gland and lacrimal gland swelling with pain are mainly reported side effects, although there are no large prospective series on the side effects of radioiodine therapy in the literature. The current literature on this subject is mainly consists of retrospective studies and case reports (5).
Radiation retinopathy is an occlusive vasculopathy which begins in the late period following radiotherapy. It is generally seen after ionized radiation and 125I brachytherapy applied to the intraocular tumors, showing a slow progression and causing occlusion in retinal capillary, nonperfusion and large retinal vessels with neovascularization (6).
The literature about radiation-related retinopathy consists of the studies about external radiotherapy and brachytherapy. Clinical trials evaluating the patients for retinopathy following the treatment with radionuclides are quite limited. The aim of this study was to investigate whether high doses of radioiodine causes retinal damage during thyroid cancer treatment. Investigation of the clinical and pathological conditions regarding the ocular damage after external beam radiotherapy and brachytherapy may guide on the alterations after the treatment with radionuclides.

Materials and Methods
Between January 2000 and January 2007, 40 eyes of 20 patients who received 9250-37000 MBq (250-1000 mCi) during the therapy and on ophthalmological follow up for a year after the last treatment were included in the study. Three of the patients were males and 17 of them females aged between 25 and 70 (mean age:50±11). All patients were examined for detailed medical history, total blood count, routine biochemical tests, hypertension, hypercholesterolemia and diabetes. Patients with additional pathologies that might cause retinopathy were excluded.
Out of 20 patients, 17 were followed-up for papillary thyroid carcinoma and 3 for follicular thyroid carcinoma. Four of the patients had a history of radiotherapy received in the thyroid region and 2 due to metastasis to the lumbar vertebrae and pelvic bones. Characteristics of the patients are summarized in Table 1.
Radioiodine ablation is performed four to six weeks after thyroid cancer surgery. After the operation patients are asked to avoid substances containing iodine. For postoperative ablation of thyroid bed remnants, activity in the range of 3700-7400 MBq (100-200 mCi) is typically administered. The patients, who developed recurrence during follow-up and received a total of 250-1000 mCi (mean dose 472 i±265) radioiodine with repeating doses, were included in the study. In addition, patients were questioned for the radiation damage to salivary and lacrimal glands and nasolacrimal duct that are the known side effects of radioiodine.
In the ophthalmologic examination, first distance visual acuity rate was defined in order to determine visual loss.
Patients were asked to read the Snellen chart with correction from a distance of 6 meters and the best corrected visual acuity (BCVA) was measured.
Intraocular pressure was measured in all patients with Goldman applanation tonometry. Proparacaine hydrochloride 0.5% was applied to all patients for the measurement. Then iris and iridocorneal angle were evaluated with slit lamp biomicroscope (Topcon SL-3C Tokyo, Japan) using Goldmann three-mirror contact lense. Iridocorneal angle was examined for neovascularization. Tropicamide drops of %1 was applied and the pupilla was dilated. Then lens examination was carried out with slit lamp biomicroscopy in order to investigate cataract or partial lens opacities.
Fundus observation was carried out on the dilated pupil with slit lamp biomicroscopy using 90 D noncontact lens. Especially symptoms including vitreus hemorrhage, partial or total optical disc pallor indicating papillopathy in the optic disc, retinal hemorrhage indicating retinopathy, microaneurysm, neovascularization, microinfarction, edema and exudation were examined. Colored images of fundus through dilated pupils were taken in all patients with digital retinal camera (Canon Inc Tokyo, Japan).
There was pseudophakic posterior capsule opacification in one eye (5%) of two patients which has developed secondary to previous cataract surgery, reducing the best corrected acuity under 1.0. These patients later underwent neodymium-doped yttrium aluminum garnet (Nd:YAG) posterior capsulotomy procedure. The best corrected visual aquity reached to the level of 1.0 after the procedure. Nuclear cataract was found in 2 eyes (5%) of one patient, reducing the best corrected visual aquity under 1.0. After the surgeries , best corrected visual acuity of the patients reached to the level of 1.0 at the followups.
At the biomicroscopic fundus examinations, retinal hemorrhage consistent with radiation retinopathy, microaneurysm, microinfarction, edema or exudation, vitreus hemorrhage, partial or total optical disc pallor indicating papillopathy in the optic disc were not observed in any eye. Two patients (10%) underwent dacryocystorhinostomy due to bilateral nasolacrimal duct obstruction developed following high dose RI therapy. Figure 1 shows images taken with a digital retinal camera in a patient.

Discussion
In the experimental trials, first alterations in the retina exposed to ionized radiation were detected to begin between the 12 th and 24 th months (7). Mainly capillary nonperfusion develops in the retinal capillary endothelial cells following focal loss. First damage occurs in the endothelial cells and pericytes. Early alterations seen in the retinal vessels include capillary dilatation, telangiectasia, microaneurysms and capillary occlusion. Then soft exudations are detected. Retinal edema and macular involvement may be seen. First symptoms are seen in deep small retinal vessels and later the large vessels are involved (8,9,10,11).
Following diffuse capillary occlusion and retinal ischemia, vitreous hemorrhage and retinal detachment as a result of retinal and/or disc neovascularization, atrophy of the retinal pigment epithelium, central retinal artery and central retinal vein obstructions have been reported (12,13).
Occlusive microangiopathy in radiation retinopathy is a progressive and slow process (8,14,15). Radiation retinopathy is observed after intraocular tumor irradiation (mainly uveal melanoma, less often retinoblastoma) or intracranial tumor radiotherapy. It is also seen following the irradiation for choroidal neovascularization due to age-related macular degeneration. Radiation doses and tumor location are mainly responsible for macular and/or optic nerve head vascular complications. Furthermore, choriocapillaris and main choroidal vessels may also be affected after the vascular and tissular retina complications (16). In a study with 218 patients who received radiotherapy with a diagnosis of paramacular choroidal malignant melanoma, retinopathy symptoms were observed in 89% of the patients in a duration between 5 months and 15 years (mean 40 months) (17). Amoaku et al., reported that radiation retinopathy could be observed in an average period of 4.7 years after radiation therapy (range 1 to 8.5 years) (8).
Whereas Brown et al. stated that radiation retinopathy may develop in 18.7 months (7-36 months) following teletherapy and 14.6 months (4-32 months) after brachytherapy (18). The cases included in that study were the patients in whom 1-10 years elapsed from the last radioiodine therapy. In this period, no pathological finding was found in these patients consistent with radiation retinopathy.
Incidence of radiation retinopathy depends on the total and fractionated dose applied (19). In the study by Brown et al., in the eyes undergone brachytherapy and developed radiation retinopathy, hard exudate was found in 85%,microaneurysms in 75%, intraretinal hemorrhages in 65%, retinal vascular telangiectasia in 35%, soft exudates in 30% and vascular encasement in 20%. Of the eyes undergone teletherapy and developed radiation retinopathy, hard exudate was found in 38%, microaneurysms in 81%, intrarenal hemorrhages in 88%, retinal vascular telangiectasia in 38%, soft exudates in 38% and vascular encasement in 25%. Of these eyes, macular edema was found in 87% at a 3-year follow-up and only 5% experienced spontaneous resolution (18).
The medium-long term side effects following radioiodine therapy were analyzed in an extensive study by Alexander et al. with 203 patients. The side effects occurred in the intermediate-term (up to 3 months) after therapy in 76.8% of the patients and in the long term (3 months and longer) in 61.1% of the patients. Cytoclastic side effects including sialoadenitis developed in 33% of the patients.
Following radioiodine therapy, damage to lacrimal gland was reported in 42.9% of the patients after a period longer than 1 year. Complete xerostomia developed in 4.4% of the patients. Hematological abnormalities were observed in 9 patients, alopecia in 28.1% and chronic or repeating conjunctivitis in 22.7% of the patients, while 4 patients required dacryocystorhinostomy (20). There was not any study or case report in the literature about development of radiation retinopathy following radioiodine therapy. In our study, patients undergone high-dose radioactive iodine with repeated doses due to the recurrence and metastasis with a mean dose reached to 500 mCi (250-1000 mci) were included. Complaints of dry mouth, dysphagia and taste disorders were found in 10 patients (50%), while xerophthalmia was found in 2 (10%) and nasolacrimal duct obstruction in 2 (10%) patients. No clinical symptoms suggesting radiation retinopathy were found in any patients. We believed this was caused by the rapid excretion of radioiodine from the body in all the patients, because they had undergone thyroidectomy and neck dissection.
The most sensitive structure to ionized radiation in the eye is the lens. Cataract occurs in the lens at the end of a latent stage following the radiation. On the other hand, conjunctiva and cornea are moderately sensitive structures, Figure 1A and B. A 62 year old female patient had undergone total thyroidectomy and neck dissection due to follicular thyroid carcinoma 6 years ago. Shepostoperatively received 150mCi radioiodine therapy for ablation. The patient received a total of 900 mCi in repeated doses due to the development of lung and bone metastases. The patient has a complaint of lacrimal and salivary reduction. She was operated for nasolacrimal duct obstruction one year ago. Images taken with a digital retinal camera are presented above. At the fundus examinations, retinal hemorrhage, microaneurysm, microinfarct, edema or exudation were not observed. while the retina and optic nerve are the most resistant structures in the eye (24). Epidemiological studies indicate an increase in incidence of the lens opacities at the doses under 1 Gy (25). Cataract stimulated by ionizing radiation (x-rays and gamma rays) is usually seen as posterior capsular or cortical cataract (26,27). Whereas, the cataract observed in one of our patients was of nuclear characteristics and evaluated as age-related senile cataract.
High-dose radioiodine therapy applied in thyroid carcinomas shows uptake in the head and neck region, suggesting partial exposure of the orbita and retina to the radiation. Based on this opinion, we evaluated the eyes of the patients exposed to high-dose radioiodine therapy. However, we did not find a significant correlation between repeated high-dose radioiodine therapy and radiation retinopathy in any of our patients. This might be a result of rapid excretion of radioiodine from the body in all the patients, because all cases had undergone thyroidectomy and neck dissection. The limitations of this study are the small group of patients and lack of control group. However, further extensive studies are needed on this subject.

Conclusion
This study indicates that there is not any significant correlation between repeated high-dose radioiodine therapy and radiation retinopathy in differential thyroid carcinomas. Even though there is not any significant restriction in use of higher doses of 131I radioiodine therapy in differentiatedthyroid carcinomas, more extensive studies are needed in order to obtain more accurate data on possible occurrence of retinopathy in these cases.

Conflicts of Interest
There are no conflicts of interest.