Sayjal J. Patel,
Andrew P. Schachat
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Key Features |
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INTRODUCTION
Radiation has been used therapeutically for the treatment of neoplastic lesions for over 100 years. According to del Regato, in 1896, 3 weeks after reading about Roentgen's discovery of 'X-rays', Grubbe was the first to use radiation to treat breast cancer.[1] In the 1930s, Moore and Stallard began using radiation for the treatment of ocular tumors.[2,3] Ocular complications following radiation were described by Stallard in 1933 subsequent to treatment for retinoblastoma and retinal capillary hemangioma.[3] He described retinal hemorrhages, exudative changes in a circinate pattern, optic disk edema and optic atrophy occurring over a period of ~20 months postradiation. Since these early reports, many reports of retinopathy following radiation to various tumors of the head and neck have been described.[4-16]
The onset of radiation retinopathy is usually delayed and generally does not appear for months or years after initial exposure to radiation. Characteristics of radiation retinopathy include retinal microaneurysms and intraretinal hemorrhages, telangiectasia, perivascular sheathing, cotton wool spots, exudate, macular edema, retinal pigment epithelial atrophy, optic disk edema and atrophy. The appearance can mimic diabetic retinopathy and there is a similar underlying cause - microvascular leakage and occlusion. Areas of ischemia can lead to retinal, optic disk or iris neovascularization which can further develop into vitreous hemorrhage, retinal detachment or glaucoma. The primary cause of vision loss is usually due to exudative or ischemic maculopathy or optic neuropathy. The severity, although multifactorial, is largely dependent on dose, frequency, location as well as total area treated. Patients with diabetes or patients undergoing chemotherapy are at increased risk for developing radiation retinopathy.[11,12]
PATHOPHYSIOLOGY
Ionizing radiation can be used therapeutically in two general forms: external beam radiation (teletherapy, or radiation from a distance) and plaque radiation (brachytherapy, or radiation from a nearby source). Many variables may have an effect on the ocular manifestations of radiation therapy. Total dose, fraction number and size, as well as location most likely have a large influence. Normal eyes indirectly or directly exposed to radiation for nonocular tumors may manifest different effects of radiation compared to eyes with tumors being treated directly. Local damage due to the effects of the tumor may be difficult to differentiate from radiation damage alone. Chemotherapy used concurrently with radiation or systemic diseases such as diabetes can further confound the interpretation of retinopathy seen after radiation.
Studies using angiography and histopathology have been pivotal in an attempt to understand the effects of radiation on the retina. Most of these studies have concentrated on findings after external beam radiation, presumably since external beam radiation is most common. The doses used in these studies vary and therefore the dose-effect relationship findings are difficult to compare and interpret.
In 1958, histologic studies of primate eyes previously exposed to external beam radiation by Cibis et al showed the acute sequelae of radiation therapy primarily involved the outer retinal layer and the photoreceptors, specifically the rods, and the delayed sequelae involved the inner retina and retinal vasculature.[4] The acute changes were noted as early as 19 min following radiation exposure. The dose used in this study is much higher than the typical doses used today.
In 1970, Hayreh was the first to describe the fluorescein characteristics of radiation retinopathy followed over time in three patients with choroidal melanoma.[15] All three patients had been treated with plaque radiation at a dose of 80 Gy to the tumor apex. Over a 22 month to 4 year follow-up, he noted a variety of changes in the inner and outer retina including obliteration of retinal capillary vessels and the choriocapillaris as well as areas of retinal ischemia.
In 1980, Egbert et al described the histological changes seen in 17 human eyes with retinoblastoma after receiving 35-60 Gy of external beam radiation.[17] They described the arteriolar and capillary walls as thickened due to a fie fibrillary material with fibrin deposition within the walls and outside the vessel walls. They postulated that the occlusion of the vessels could be due to narrowing of the vessel lumen. Brown et al, in 1982, found areas of retinal capillary obliteration in all eyes studied with fluorescein angiography after cobalt-60 plaque radiation and external beam radiation.[12] They suggested the diagnosis of radiation retinopathy should be questioned if retinal capillary nonperfusion is not demonstrated.
In 1987, Irvine et al reported the clinical and histological changes seen in 11 primates after radiation levels of up to 35 Gy.[18] Early findings were focal loss of capillary endothelial cells and pericytes. As more capillaries became incompetent, areas of retinal capillary nonperfusion followed. Nonperfusion led to intraretinal neovascularization and eventual neovascular glaucoma. Elevated levels of a vasoproliferative factor were found in an eye with rubeosis while lower levels were found in an eye without rubeosis. Interestingly, intravitreal proliferative retinopathy was not noted.
In 1991, Archer et al described their observations after enucleating seven human eyes that had received external beam radiation for various head and neck tumors with radiation levels up to 55 Gy.[13] With the help of trypsin digest and electron microscopy, a preferential loss of vascular endothelial cells and preservation of pericytes was demonstrated. Early structural changes in capillaries such as outpouchings, fusiform dilations, and microaneurysms were described. With further damage, fenestrated endothelial cells were seen in both the small caliber and larger caliber vessels. There was atrophic retinal parenchyma surrounding these vessels with hypertrophy of glial cells and degeneration of neurons. They postulated that endothelial cell damage from radiation and free radical exposure was the inciting factor leading to a chain of events. These events included the activation of the clotting cascade, capillary occlusion and formation of incompetent capillary collaterals.
In 1992, Krebs et al described their histological findings after examining an eye that had been enucleated 13 years following 60 Gy of external beam radiation and subsequent chemotherapy for embryonal rhabdomyosarcoma.[19] ERG studies done prior to enucleation showed severely reduced cone responses and no rod responses. They concluded that radiation damage enhanced by chemotherapy may have damaged the retinal vasculature and pigment epithelium with a secondary loss of photoreceptors. They noted that rods seemed to be more affected than cones.
Histologic studies of three primate eyes previously treated with iodine-125 brachytherapy were done in 1999 by Robertson et al.[20] A theoretical choroidal tumor with apical height of 5 mm was assumed so that 80 Gy was to be delivered to the apex. Revised dose calculations revealed 5 mm apical doses ranged from 64 to 82 Gy and the inner scleral doses ranged from 280 to 420 Gy. Their findings showed an atrophic retina, retinal pigment epithelium, and choroid with macrophage invasion of the tissues in the area overlying the site of the radioactive plaque. Trypsin digest studies further confirmed capillary remodeling with loss of endothelial cells and pericytes.
In 2003, Sefau et al described the histopathologic changes in the choroidal circulation seen in three enucleated human eyes from three patients after external beam radiation.[21] The dose for the first patient treated for congenital hemangioma was unknown. In the second patient, the total dose used was 57.6 Gy followed with chemotherapy to treat malignant mesenchymoma. The third patient had retinoblastoma initially treated with 36 Gy and a year later with 30 more Gy due to persistence of the tumor. Findings similar to those seen in paving stone degeneration such as extensive loss of the retinal pigment epithelium and choriocapillaris with adhesion of the degenerated retina to Bruch's membrane were noted.
CLINICAL FEATURES
NONPROLIFERATIVE RADIATION RETINOPATHY
Most cases of radiation retinopathy are diagnosed between 1 and 3 years after treatment with rare cases reported as early as 1 month and as late as 15 years. The most common time of onset is of course dose related but changes are infrequent before a year and often become apparent at 18-24 months.[9,11,12,22] In general, the nonproliferative manifestations of radiation retinopathy consist of focal capillary closure, irregular dilation of surrounding vessels, microaneurysms, intraretinal hemorrhages, cotton wool spots, retinal exudates, retinal edema, nerve fiber layer infarctions, and focal retinal pigment epithelial changes.[9-12,14] If any of these findings are within 3 mm of the foveola, the term radiation maculopathy is used.[9] In patients with choroidal melanoma, local tumor effects may resemble changes similiar to radiation related retinopathy such as macular edema and intraretinal hemorrhages. The similarity in findings may make it difficult to distinguish between these two possible causes.
Just as the manifestations of radiation vary with dose, fraction number, size, location, and external beam versus plaque therapy, so does the incidence. In one study of 96 patients with large uveal melanoma who underwent plaque radiation, the 5-year incidence of maculopathy was 52%.[5] Gunduz et al studied 1300 patients treated with plaque radiation for posterior uveal melanoma.[9] Their overall incidence of radiation maculopathy was 43%. A 5% incidence of nonproliferative retinopathy was seen after 1 year and 42% after 5 years. The most important predictor of nonproliferative retinopathy in their study was the posterior location of the tumor. Guyer et al reported a radiation maculopathy incidence of 89% in their study of 218 patients who had received external beam radiation for paramacular choroidal melanomas.[10] The earliest and most common sign was macular edema, found in 61% of the patients at 1 year and 87% at 3 years. In their study of 32 patients with radiation retinopathy, Brown et al found hard exudates in 85% of those treated with plaque radiation compared to 38% in those treated with external beam radiation.[12] The possibility of leakage of serum products from necrotic tumor tissue as a cause of the disparity in incidence could not be excluded. In the group treated with plaque radiation, microaneurysms were seen in 75%, intraretinal hemorrhages were seen in 65%, telangiectasia were seen in 35%, cotton wool spots were seen in 30% and 20% had vascular sheathing. In the group treated with external beam radiation, microaneurysms and intraretinal hemorrhages were seen in 81% and 88% respectively, 38% had telangiectasia and cotton wool spots, and vascular sheathing was seen in 25%.
In addition to the previously mentioned manifestations of radiation retinopathy, other rare presentations of radiation retinopathy including central retinal artery occlusion or central retinal vein occlusion have also been reported.[12,15] Maberley et al have also postulated that radiation may be a contributing factor to idiopathic perifoveal telangiectasia.[23]
PROLIFERATIVE RADIATION RETINOPATHY
The proliferative manifestations of radiation retinopathy include any neovascularization of the retina or optic disk. Brown et al reported a higher rate of neovascularization after treatment with external beam radiation (43%) compared to plaque radiation (5%).[12] Subsequent reports have not shown this disparity. Guyer et al reported an incidence of 6% after external beam radiation and Gunduz et al observed a proliferative retinopathy incidence of 1% at 1 year and 8% at 5 years after plaque radiation.[9,10] In a study of 558 patients treated with external beam radiation for choroidal melanoma, Gragoudas et al reported a proliferative retinopathy incidence of 3%.[8] In addition to the possible manifestations described above, an atypical case of subretinal neovascularization originating from telangiectatic vessels has been reported.[24] Spaide et al have also identified unusual vascular, bleb-like choroidal complexes located at the outer border of choroidal neovascularization.[25] They have proposed the term 'radiation-associated choroidal neovasculopathy' (RACN) to identify their observations.
DOSIMETRY
Dosimetry varies widely based on the method of radiation delivery (plaque versus external beam), the type of lesion, and location of therapy. Standard fractionation for external beam radiation is typically 1.8-2.0 Gy of radiation in single daily doses until the total dose desired is achieved. The benefits of fractionated radiation therapy had been established a few years prior to Moore and Stallard's use of radiation to treat ophthalmic tumors.[1] Hyperfractionation refers to even smaller fractions applied more than once daily over the same treatment time. The theoretical benefits of hyperfractionation for the retina are to allow normal retinal tissue to repair single-strand DNA breaks and limit late damage to double-strand breaks.[22] There is also a potential to deliver a higher total radiation dose which may limit late sequelae. Randomized trials have not been undertaken to prove any clinical benefit of this approach.
Reports of the incidence of retinopathy vary from 35% to 56% with doses above 45 Gy.[8,12,16,22] Brown et al have reported an incidence of 85% with doses between 70 and 80 Gy.[12] A specific threshold dose that will result in retinopathy has not been determined. Factors such as varying radiation fractionation and hyperfractionation techniques, retinal dose measurement techniques and co-morbid disease make establishing this threshold difficult.
In a review of patients who had undergone external beam radiation with varying fractionation schedules for various head and neck tumors, Amoaku et al reported the threshold dose for radiation retinopathy was between 25 and 30 Gy.[11] The mean follow-up was 8 years. Parsons et al investigated radiation-induced retinopathy according to total radiation dose and fraction size both retrospectively from data in the literature and also prospectively in 64 patients receiving external beam radiation for various extracranial head and neck tumors.[16] A sigmoid dose-response curve was created indicating that with fraction sizes less than or equal to 2 Gy, total dose of 30 Gy seemed to be the threshold prior to the development of retinopathy. In a prospective study of 42 patients with Graves ophthalmopathy, Robertson et al observed the development of retinopathy in three patients within 3 years.[7] The dose received by all patients was 20 Gy delivered in 10 doses of 2 Gy. Their results were confounded by the fact that retinal microvascular abnormalities were observed prior to radiation in one patient and the other two had factors known to be associated with retinopathy such as uveitis, systemic hypertension and abnormal glucose levels. More recently, Monroe et al identified 186 patients undergoing external beam radiation for various head and neck tumors and followed them prospectively for a median of 6.7 years.[22] Their studies indicated the threshold for retinopathy was 40 Gy with standard fractionation. The threshold for retinopathy was 50 Gy with a hyperfractionation schedule. Hyperfractionation reduced the incidence of retinopathy by more than half compared to standard fractionation (13% vs 37%) in those patients who received more than 50 Gy.
In the Brown et al study of radiation retinopathy, 20 eyes had been treated with plaque radiation and 16 eyes with external beam radiation.[12] They reported a higher mean dose of radiation with plaque radiation was needed compared to external beam radiation therapy to produce foveopathy. The mean dose with plaque radiation was 150 Gy, whereas a mean of 49 Gy was needed with external beam radiation. In their study of plaque radiation therapy for posterior melanoma, Gunduz et al found a significantly higher risk for nonproliferative retinopathy with doses above 57 Gy to the fovea.[9] The median dose to the fovea in those developing retinopathy was 70 Gy.[9]
OTHER ASSOCIATIONS
Independent factors thought to exacerbate radiation retinopathy are chemotherapy and systemic conditions such as diabetes, hypertension and collagen diseases.[11] These conditions may decrease the threshold dose required to develop radiation retinopathy. For example, Brown et al found radiation retinopathy in four of seven eyes that had received chemotherapy in addition to external beam radiation.[12]All four eyes progressed to total blindness. Parsons et al observed four of 10 patients treated with external beam radiation that developed radiation retinopathy compared to two of two that were treated with external beam radiation in addition to chemotherapy.[16]
With regard to diabetes and radiation retinopathy, Brown et al observed the only patient to develop proliferative retinopathy in the plaque radiation group was known to have diabetes. The minimal dose shown to induce foveal damage was 45 Gy, whereas excluding this patient would have raised the minimal dose to 100 Gy.[12] Parsons et al described a diabetic patient with no evidence of retinopathy and normal visual acuity prior to treatment for advanced skin cancer of the central face with external beam radiation.[16] He subsequently developed radiation retinopathy in both eyes resulting in hand-motion vision by 47 months after treatment. Other large studies following plaque therapy for melanoma have supported the theory that diabetes increases the risk of retinopathy following radiation.[9]
DIFFERENTIAL DIAGNOSIS
Because the clinical features of radiation retinopathy are similar to those seen in other retinal vasculopathies, it is important to elicit a thorough history and review any prior medical records available. If a history of radiation exposure is obtained, important details such as the date, dose, frequency and area of radiation should be reviewed. Information about the fields will allow an estimate of whether the eye was or was not likely included in the field or radiation.
The clinical manifestations of diabetic retinopathy and hypertensive retinopathy can be difficult to distinguish from radiation retinopathy. Other retinal vascular abnormalities such as arterial or venous occlusive disease and telangiectasia must be differentiated. Ocular ischemic syndrome can also mimic radiation retinopathy although the intraretinal hemorrhages are generally found in the midperipheral retina whereas in radiation retinopathy, intraretinal hemorrhages are generally found diffusely throughout the retina or in the localized area of treatment.
TREATMENT
The natural history of radiation maculopathy is characterized by progressive retinal damage with eventual resolution of edema as ischemia develops. Proliferative retinopathy can result in vitreous hemorrhage, retinal detachment or neovascular glaucoma and loss of vision is often due to ischemia or optic neuropathy. The optimal treatment of radiation retinopathy is not well established. Because of the similarities to diabetic retinopathy and branch vein occlusion, data from the Branch Retinal Vein Occlusion Study (BRVO) and Early Treatment Diabetic Retinopathy Study (ETDRS) has been extrapolated to study the use of laser photocoagulation for the treatment of macular edema and proliferative retinopathy after radiation.[26-28]
Hykin et al retrospectively studied the effect of focal laser- on radiation-induced macular edema with a treatment group of 19 patients and a matched observation group of 23 patients.[27] Their results showed an initial 6-month modest improvement in visual acuity and resolution of macular edema in the treatment group; however, at 2-year follow-up, no significant difference in visual acuity was found compared to the observation group. Other techniques to treat radiation maculopathy have been proposed such as the use of oral pentoxifylline to treat capillary nonperfusion, intravitreal triamcinolone acetonide or verteporfi photodynamic therapy, and hyperbaric oxygen.[29-32] These treatments have either been described in small cases series or have not proven to have lasting effects.
In a retrospective study of 14 eyes of 10 patients with proliferative radiation retinopathy, Kinyon et al reported a 91% rate of resolution after panretinal photocoagulation for proliferative radiation retinopathy.[28] The visual acuity, however, went from an initial median of 20/90 to 20/400 after an average follow-up of 75 months. Significant contributing factors to visual loss included optic neuropathy, macular ischemia, and vitreous hemorrhage.
Recently, Finger et al have proposed a four-stage classification for radiation retinopathy (Table 175.1).[26] Based on this classification, they studied the effects of sector scatter laser photocoagulation through an interventional case series in two groups of patients that had been previously treated with plaque radiation for posterior choroidal melanoma. The first group of 45 patients had signs of radiation retinopathy and the second group of 16 patients did not have any clinical evidence of radiation retinopathy but were considered 'high risk' based on the posterior location of the tumor.[26] Radiation retinopathy in the first group was defied as any iris or retinal neovascularization or any stage-1 fiding, with the exception of isolated ghost vessels, uveal effusion, or chorioretinal atrophy. They reported a regression rate (defied as disappearance or regression of initial treatment indications) of 64% and a loss of three lines or more in visual acuity in 47% after a mean follow-up of 48 months. In a third of the patients who lost three lines of vision, the cause was due to maculopathy. In the second group, three patients developed radiation retinopathy which regressed with further treatment. No patients lost more than three lines of vision due to radiation maculopathy. The authors suggested that sector scatter laser photocoagulation may regress radiation retinopathy under their proposed classification and preserve vision. The findings, however, were not statistically significant and further prospective studies were recommended.
TABLE 175.1 -- Finger Classification of Radiation Retinopathy
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Stage 1 (Findings Are Limited to Outside the Macula) |
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Cotton wool spots |
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Retinal hemorrhages |
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Retinal microaneursyms |
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Ghost vessels |
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Exudate |
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Uveal effusion |
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Choroidal atrophy |
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Choroidopathy |
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Retinal ischemia <5 DA |
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Stage 2 (Findings from Stage 1 but Found Within the Macula) |
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Stage 3 (Any Stage 1-2 in Addition to the Following) |
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Retinal vascularization |
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Macular edema |
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Stage 4 (Any Stage 1-3 in Addition to the Following) |
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Vitreous hemorrhage |
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Retinal ischemia >5 DA |
With new treatments targeting vascular endothelial growth factors now available, perhaps future studies will involve the use of these growth factor inhibitors to treat permeability-related pathology in radiation retinopathy, or to achieve regression of new vessels. However, it is not likely to alter the tendency to develop progressive ischemia or optic neuropathy, so the vision outcomes may not be good. Prospective studies will be necessary.
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