Volume 3, Chapter 36A. Radiation Retinopathy

Chapter 36A
Radiation Retinopathy
NEAL H. ATEBARA, JOHN H. DROUILHET and GARY C. BROWN
Main Menu Table Of Contents

PATHOPHYSIOLOGY
SYMPTOMS
OCULAR FEATURES
FLUORESCEIN AND INDOCYANINE GREEN ANGIOGRAPHY
DIFFERENTIAL DIAGNOSIS
RADIATION DOSAGE AND RADIATION RETINOPATHY
TREATMENT
CONCLUSIONS
REFERENCES

First described by Stallard¹ in 1933 in the fundi of patients with retinal capillary hemangiomas and retinoblastomas after radon seed implantation, radiation retinopathy has become increasingly more frequent as additional radiotherapeutic techniques have come into use. Ionizing radiation appears to have a pathologic effect on the small blood vessels of the retina and optic nerve. Characteristically, months to years after exposure to radiation, there is a slowly progressive dysfunction of the vasculature of the retina and optic nerve, leading to alterations in structure and permeability, occlusion, and neovascularization. The clinical picture of capillary telangiectasia, microaneurysms, intraretinal hemorrhages, hard exudation, macular edema, capillary nonperfusion, and neovascularization can be identical to that of diabetic retinopathy, suggestive of a common pathophysiologic mechanism of damage to capillary endothelial cells. Visual loss usually is caused by macular edema, macular hard exudates, macular ischemia, or optic nerve damage.

PATHOPHYSIOLOGY

Although it is not entirely clear how ionizing radiation causes radiation retinopathy, the primary site of damage appears to be the endothelial cells of the retinal and optic nerve vasculature.^2–6 Although the neural retina, like the central nervous system, is resistant to radiation damage,⁵^,⁷ the blood vessels within them are not.8 Ionizing radiation interrupts cell processes during interphase, and as the cells attempt division in the ordinary course of repair and replacement, radiation also interrupts mitosis (Fig. 1A). The primary event probably is endothelial cell damage with secondary loss of pericytes. This histologic picture is similar to that seen in diabetic retinopathy.

Fig. 1. Sequence of damage from irradiation. a. Ionizing radiation interrupts cell processes during interphase, causing cell death. b. Focal loss of endothelial cells and pericytes cause weakening of the cell wall. Microaneurysms form at the site of vascular weakening (c), and rupture of these outpouchings results in intraretinal hemorrhages (d).

Irvine and Wood⁹ irradiated monkey eyes with up to 30 Gy and examined them histologically. The first changes, seen 12 to 24 months after irradiation, were focal loss of capillary endothelial cells and pericytes (see Fig. 1b). Archer and colleagues¹⁰ examined human eyes enucleated after radiation treatment and found endothelial cell loss. Fusiform capillary dilations and microaneurysms develop in areas of poorly supported capillaries (see Fig. 1c). Telangiectatic channels also develop, presumably caused by alterations in hemodynamics.

Lower degrees of radiation damage cause the vascular endothelial cells to remain viable but lose the integrity of their intercellular tight junctions. The blood vessels become abnormally permeable to larger molecules, leading to leakage of fluid and proteins (see Fig. 1c). Archer and colleagues¹⁰ performed electron microscopic studies that revealed new intraretinal vessels containing fenestrated endothelium, suggesting an alternative mechanism of vascular leakage. Light microscopic examination of the retina reveals intraretinal blood from burst microaneurysms (see Fig. 1d) and eosinophilic exudates in the outer plexiform and inner nuclear layers (Fig. 2A).

Fig. 2. Light microscopic cross-section of the retina after enucleation after the development of neovascular glaucoma. A. Blood is present in the inner retinal layers and overlying vitreous cavity. Prominent eosinophilic deposits can be seen in the outer plexiform and inner nuclear layers, and the ganglion cell layer is atrophic. B. Cross-section of a retinal blood vessel shows hyalinization and thickening of the wall. C. New blood vessels extend from the optic nerve head onto the posterior hyaloid surface. Traction on these vessels produced the associated vitreous hemorrhage. Absence of the ganglion cell layer is readily apparent.

In more severe cases of radiation damage, the endothelial cells die, and the vascular channels become occluded, leading to capillary dropout and ischemia. As areas of capillary loss become confluent, cotton-wool spots are seen clinically. These subsequently fade as large areas of retinal capillary nonperfusion develop.⁹ Later in the course, larger vessels become affected, possibly related to thickening of the vessel walls from a deposition of fibrillary or hyaline material¹⁰ (see Fig. 2B). Retinal ischemia, presumably mediated by vasoproliferative factors, leads to neovascularization of the retina and optic disc (see Fig. 2C), vitreous hemorrhage, and neovascular glaucoma.

SYMPTOMS

Radiation retinopathy often is asymptomatic in its early stages. The disease process usually does not become manifest symptomatically or ophthalmoscopically for months to years after the irradiation. The first symptoms a patient typically notices is blurred or dimmed central vision. This usually results from macular edema or macular ischemia. Less commonly, abrupt and severe loss of vision can occur from central retinal artery occlusion,¹¹ central retinal vein occlusion,¹² ischemic optic neuropathy,¹³ or vitreous hemorrhage. In advanced cases of radiation damage, the eye can become blind and painful as a result of radiation-induced ocular ischemia or neovascular glaucoma.

OCULAR FEATURES

The first signs of radiation retinopathy typically occur months to years after the exposure to ionizing radiation. Brown and associates² found that an average of 14.6 months passed from the time of radioactive plaque therapy until the onset of radiation retinopathy, with a range of four to 32 months. The findings for external beam radiation were similar, with a mean period of 18.7 months and a range from 7 to 36 months. Guyer and colleagues¹³ report an even more delayed onset of signs after proton beam radiation, ranging from 5 months to 15 years, with a median of 40 months. Although Flick in 1948¹⁴ described acute retinal changes in survivors of the atomic blasts at Hiroshima and Nagasaki, these acute lesions correlated with low white blood cell counts and were thought to result from the radiation-induced pancytopenia, not direct injury to the retina.

The first ophthalmoscopic features of radiation retinopathy reflect vascular endothelial damage. Guyer and coworkers¹³ found that the earliest and most common finding was macular edema, present in 87% of patients within 3 years of radiation. Leakage of fluid and proteins into the neurosensory retinal tissue causes retinal edema and hard exudates. Structural decompensation of the vessel wall leads to intraretinal microaneurysms and intraretinal microvascular abnormalities. Hemorrhage of these microaneurysms result in dot and blot intraretinal hemorrhages.^2–4^,^15–17 This funduscopic appearance is similar to that of diabetic retinopathy except that fewer microaneurysms usually are seen. Recognizing the similarity in disease progression patterns with background diabetic retinopathy, this early stage of the disease has been called “background radiation retinopathy.”¹⁸ The fundus photographs and fluorescein angiograms shown in Figures 3 and 4 demonstrate the findings seen in background radiation retinopathy. Figure 5 also reviews these findings.

Fig. 3. Background radiation retinopathy in a 45-year-old man who had undergone bone marrow transplantation, chemotherapy, and radiation therapy for acute myelogenous leukemia 5 years previously. Visual acuity is 20/40 in the left eye. A. Fundus examination reveals two cotton-wool spots superior to the macula. There is a decreased foveolar reflex, microaneurysms of the perifoveolar capillaries, and edema of the inferior macula. B. Fluorescein angiography in the early phase reveals an enlarged and irregular foveal avascular zone with perifoveolar microaneurysms. C. In the late phase, there is diffuse perifoveolar leakage and a “petalloid” cystic pattern in the inferotemporal macula.

Fig. 4. Background radiation retinopathy caused by brachytherapy in a 65-year-old man with a choroidal melanoma. A. Fundus photograph of the left eye before brachytherapy reveals a large choroidal melanoma 7 by 9 mm, with a height of 5.6 mm. The macular in not affected, and the visual acuity is 20/20. B. Fluorescein angiography reveals staining of the deep tumor vessels, with an intact foveal avascular zone. C. Two years after iodine-125 radioactive plaque brachytherapy, there are sclerotic arterioles, macular edema, and circinate hard exudation. D. Fluorescein angiography reveals extensive capillary dropout in the retina overlying the treated tumor, and the macula shows enlargement and irregularity of the foveal avascular zone.

Fig. 5. Illustration of nonproliferative radiation retinopathy. Hard exudates in the outer plexiform layer (a), intraretinal dot hemorrhages (b), and flame hemorrhages in the nerve fiber layer (c) are shown.

The later ophthalmoscopic features of radiation retinopathy are reflective of vascular occlusion at various layers of the retina and choroid. These changes may be considered “preproliferative radiation retinopathy.” Capillary endothelial damage from ionizing radiation results on patches of capillary nonperfusion. Ischemia in the nerve fiber layer, perfused by the peripapillary capillary retinal network, results in retinal cotton-wool spots. Alterations in retinal vascular blood flow result in retinal venous beading. Less commonly, occlusion of the larger retinal vessels occur. Retinal arterial and vein occlusions can be seen, possibly related to the vessel wall sclerosis seen histologically. Uncommonly, occlusion of the choroidal circulation can be seen, detected on fluorescein angiography or seen later as retinal pigment epithelial alterations. The fundus photographs and fluorescein angiograms shown in Figure 6 demonstrate the findings seen in preproliferative radiation retinopathy. Recently, it has been suggested that the term nonproliferative radiation retinopathy be used rather than distinguishing “background” from “preproliferative” radiation retinopathies.

Fig. 6. Preproliferative radiation retinopathy in a 23-year-old man who underwent radiation teletherapy with 30 Gy 18 months previously for a brain tumor. The patient underwent focal macular laser photocoagulation for macular edema 5 months earlier, but the final visual acuity was limited to 20/60 because of macular ischemia. A. Fundus photograph of the left eye reveals cotton-wool spots, intraretinal hemorrhages, and macular scars from prior laser treatment. B. Fluorescein angiography reveals broad areas of capillary nonperfusion in the nasal fundus. C. In the later phase of the angiogram, staining of the major vessels is apparent.

Proliferative radiation retinopathy occurs when retinal ischemia leads to neovascularization of the retina or optic disc, often adjacent to areas of capillary nonperfusion. The neovascularization can hemorrhage into the vitreous cavity or into the subhyaloid space, causing significant loss of vision. Guyer and associates¹³ found that the incidence of retinal neovascularization was relatively rare after proton beam radiation, occurring in only 6% of patients. Neovascularization of the iris also can occur, leading to hyphema or neovascular glaucoma. The ophthalmologic features of proliferative radiation retinopathy are illustrated in Figures 7 and 8. The incidence of fundus features of radiation retinopathy is listed in Table 1.

Fig. 7. Proliferative radiation retinopathy in a 31-year-old man who underwent 50 Gy of radiation teletherapy for a cerebral astrocytoma of the left temporal lobe. A. In the left eye, there is neovascularization of the retina superior to the superotemporal arcade with adjacent preretinal hemorrhage. There is diffuse vitreous hemorrhage in the inferior fundus. There are dot and blot intraretinal hemorrhages temporal to the macula. The optic disc is pale. B. View of the superior fundus shows a frond of retinal neovascularization with early fibrovascular changes and hemorrhage. C. The fluorescein angiogram reveals patches of choroidal hypoperfusion caused by radiation damage to the choriocapillaris and larger choroidal vessels. D. Fluorescein angiogram of the superior fundus shows leakage from the retinal neovascularization.

Fig. 8. Illustration of proliferative radiation retinopathy. Patches of capillary nonperfusion (a), retinal neovascularization (b), preretinal hemorrhages (c), arteriolar sclerosis (d), choroidal occlusion (e), and cotton-wool spots (f) are shown.

TABLE 1. Incidence of Fundus Features of Radiation Retinopathy in 36 Eyes With Cobalt Radioactive Plaque Therapy (Brachytherapy) and 16 Patients Who Received External Beam Radiation (Teletherapy)

	Brachytherapy (%)	Teletherapy (%)
Hard exudates	85	38
Microaneurysms	75	81
Intraretinal hemorrhages	65	88
Retinal telangiectasia	35	38
Cotton-wool spots	30	38
Vascular sheathing	20	25

(Brown GC, Shields JA, Sanborn G et al: Radiation retinopathy. Ophthalmology 89:1494, 1982)

Radiation-induced optic papillopathy is another complication, presumably caused by ischemic damage to the small-caliber blood vessels that supply the optic nerve head.¹⁹ These blood vessels derive from the central retinal artery, the choroidal circulation, and penetrating branches from the posterior ciliary and ophthalmic arteries. The optic nerve head may be a watershed region particularly susceptible to ischemia. Radiation optic neuropathy is characterized acutely by the ophthalmoscopic appearance of a swollen optic disc, most often in conjunction with peripapillary hemorrhages, hard exudate, and subretinal fluid. Acute loss of vision often occurs. The disc swelling usually lasts for weeks to months, after which optic pallor may ensue.¹⁹ Optic disc pallor that is not preceded by disc swelling may be seen when radiation is directed at the optic chiasm.²⁰ The ophthalmologic features of radiation optic neuropathy are illustrated in Figure 9.

Fig. 9. Radiation optic neuropathy in a 59-year-old man who underwent irradiation to the right face with adjuvant chemotherapy for head and neck carcinoma 2 years previously. Four months previously, there had been sudden loss of vision in the right eye. A. Fundus examination reveals optic disc swelling and pronounced peripapillary intraretinal hemorrhages with extensive lipid exudation and retinal edema extending into the macula. B. Fluorescein angiography reveals capillary dropout in the inferonasal macula and in areas superior and inferior to the optic disc in areas that correspond to cotton-wool patches. C. In the late phase of the angiogram, there is disc staining and diffuse macular leakage with cystic changes of the inferior macula.

(Radiation optic neuropathy develops with doses similar to those encountered with radiation retinopathy without a neuropathic component. The latency period from the exposure to radiation usually parallels that of the retinopathy. Since the two are intimately related anatomically, most patients with radiation optic neuropathy also demonstrate at least minimal signs of radiation retinopathy. However, less than half of those afflicted with radiation retinopathy manifest optic neuropathy.¹⁹ The degree of visual loss from radiation optic neuropathy varies from mild to severe. Unlike decreased vision from retinopathy, the loss from optic neuropathy may partially reverse over weeks to months.¹⁹ The characteristic visual field defect appears to be a centrocecal scotoma.¹⁹

Ionizing radiation also can cause opacification of the crystalline lens.² Classically, this begins as a posterior subcapsular plaque, which later becomes more diffuse and dense.

FLUORESCEIN AND INDOCYANINE GREEN ANGIOGRAPHY

Fluorescein angiography is helpful in demonstrating the effects of ionizing radiation on the blood vessels of the retina, choroid, and optic disc. Chee¹⁵ and Gass²¹ report the microvascular changes of capillary closure, microaneurysm formation, telangiectasia, and associated intraretinal edema and exudation. In the review by Brown and coworkers of 36 eyes with radiation retinopathy, angiographic changes were seen in 4 to 32 months after brachytherapy and 7 to 36 months after teletherapy.²

Amoaku and Archer²² prospectively reviewed 15 patients after teletherapy for head tumors. Fluorescein angiographic changes were located mainly in the posterior pole and peripapillary areas, except in cases where the field of radiation was eccentric. The earliest microvascular changes noted were focal areas of capillary closure, dilation (telangiectasia) of adjacent vessels, and microaneurysm formation bordering nonperfused vessels. Later, capillaries became increasingly dilated and tortuous, with vascular hyperpermeability. Further progression, usually in the macula, resulted in capillary closure, intraretinal microvascular abnormalities, an increased number of microaneurysms, and increasing macular edema.²¹ Generalized macular edema, as well as cystoid macular edema, occurred in the more compromised eyes.²^,²¹

When neovascularization of the retina and optic disc occur, the typical fluorescein angiographic characteristics of early hyperfluorescence of the abnormal vessels with extensive leakage in the mid- and late-phase is seen. Such neovascularization usually is associated with large areas of retinal ischemia and capillary closure, sometimes associated with large retinal vessel occlusion.²³^,²⁴

Radiation can result in damage to the retinal pigment epithelium, which, on fluorescein angiography, shows up as mottled diffuse hyperfluorescent transmission defects. This finding is more likely to result from choriocapillary occlusion with secondary atrophy of the retinal pigment epithelium rather than a direct effect of radiation on retinal pigment epithelium cells. Midena and associates²⁵ report radiation damage causing choriocapillaris perfusion defects on fluorescein angiography and indocyanine green (ICG) angiography. Such occlusions of the choriocapillaris (that did not correlate with areas of retinal ischemia) have been demonstrated histologically by Irvine and colleagues.⁹^,²⁶

In radiation optic neuropathy, the fluorescein angiographic pattern demonstrates peripapillary retinal capillary nonperfusion, optic disc capillary nonperfusion, and late disc staining.¹⁹

Indocyanine green angiographic findings of radiation retinopathy were reported by Midena and coworkers²⁵ in patients after teletherapy. Patients with whole-eye teletherapy showed focal areas of choriocapillaris perfusion defects in the midperiphery with areas of late ICG choroidal staining. Eyes with posterior bilateral radiation were similar but had no areas of late ICG staining. Takahashima and others²⁷ found that ICG angiography revealed occlusion of the choriocapillaris and larger choroidal vessels in an area larger than that demonstrated by fluorescein angiography. The remaining patent choroidal vessels formed venovenous anastomoses.

DIFFERENTIAL DIAGNOSIS

Radiation retinopathy can be confused with a variety of entities, including diabetic retinopathy, hypertensive retinopathy, retinal vein occlusions, retinal arterial occlusions, systemic vasculitides, acquired telangiectasia, and human immunodeficiency virus retinopathy.⁴^,¹⁰ A careful history of any form of radiation therapy to the eye, ocular adnexa, orbit, or head usually helps with the diagnosis. Common modalities of radiation treatment associated with radiation retinopathy include treatment for thyroid orbitopathy,²⁸ pituitary and parasellar tumors,²⁹ nasopharyngeal carcinoma,³⁰ and intraocular tumors. Patients may not give a history of radiation for nonocular tumors unless specifically asked.²

RADIATION DOSAGE AND RADIATION RETINOPATHY

The severity of radiation retinopathy is dependent on total (cumulative) radiation dose, fraction size, concomitant chemotherapy, and the presence of diabetes mellitus. Although variability exists in the dosage of radiation that results in radiation retinopathy, brachytherapy tends to require higher dosages to the fovea (150 Gy) compared with teletherapy (49 Gy).2 Data from Parsons and colleagues³¹ suggest that radiation retinopathy increases with increased fraction size, and they recommend that individual dose fractions do not exceed 1.8 to 1.9 Gy.

Concomitant chemotherapy may produce retinopathy at lower levels of radiation therapy,³² possibly predisposing to a higher incidence of blindness.² In bone marrow transplant recipients, radiation retinopathy has been documented with total dosages as low as 12 Gy when accompanied by high-dose chemotherapy.³³

The incidence of radiation retinopathy also is thought to be higher in patients with diabetes mellitus.²^,³¹ Viebahn and associates³⁴ describe a diabetic patient with breast metastases to one eye, where the treated eye developed extensive retinopathy within 9 months after local radiation therapy. In this patient, the nonirradiated eye showed no progression of diabetic retinopathy, even after 9 years. This finding is not surprising, and it probably reflects a cumulative pathologic effect of ionizing radiation on vascular endothelial cells already damaged by diabetes mellitus.

TREATMENT

Although there have been no large trials to evaluate treatment efficacy for radiation retinopathy, the treatment strategies for diabetic retinopathy have been adopted because of the similarities between the disease processes. Background radiation retinopathy without any signs of macular edema or exudates may be followed without specific ocular treatment. In cases of retinal edema, the treatment guidelines of the Early Treatment for Diabetic Retinopathy Study (ETDRS) and the Diabetic Retinopathy Study²³ have been applied to radiation retinopathy with favorable results. Kinyoun and colleagues²⁴^,³⁵ report the findings of a study of 12 eyes with radiation retinopathy and clinically significant macular edema as defined by the ETDRS³⁶: (1) retinal thickening at or within 500 μm of the center of the macula; (2) hard exudates within 500 μm of the center of the macula if associated with adjacent retinal thickening; or (3) a zone or zones of retinal thickening one disc area of larger, any part of which is within one disc diameter of the center of the macula.

The focal and grid photocoagulation techniques were the same as those recommended by the ETDRS.³⁷ Focal macular laser treatment consisted of 50- and 100-μm spots using green and blue argon laser photocoagulation applied to microaneurysms to turn them dark red or white. Grid macular laser treatment consisted of 50- and 100-μm burns of moderate intensity and spaced one burn diameter apart to treat areas of capillary nonperfusion and diffuse leakage. Median visual acuity improved from 20/100 preoperatively to 20/75 at the final postoperative visit, with a mean follow-up of 39 months. Visual acuity improved by two or more Snellen lines in 58% of cases, changed by less than two lines in 25% of cases, and declined by two or more lines in only 17% of cases. Although these results suggest that macular laser photocoagulation is effective in decreasing macular edema and improving vision in these eyes, in some cases final vision ultimately may be limited by macular ischemia, optic neuropathy, cataract, and radiation choroidopathy.³⁵

When preproliferative and proliferative radiation retinopathy changes become apparent, scatter or panretinal photocoagulation should be applied.²³^,²⁴^,³⁸ Kinyoun and colleagues treated six eyes for proliferative radiation retinopathy using panretinal photocoagulation. Laser treatment was applied between the major vascular arcades and the vortex ampullae using a spot size of 500 μm and a duration of 0.1 seconds, with spots placed two burn diameters apart. Power settings were adjusted to achieve moderately white lesions, using 631 to 1361 laser applications. Because of preexisting optic disc pallor, Kinyoun and colleagues used fewer burns and spaced them further apart than the usual guidelines of the Diabetic Retinopathy Study³⁸^,³⁹ to minimize the risk of subsequent optic atrophy. Neovascularization regressed and vitreous hemorrhage cleared in three of the six eyes, with no recurrence of hemorrhage over follow-up periods of 19 to 66 months. In the remaining three eyes, pars plana vitrectomy was required to remove nonclearing vitreous hemorrhage before panretinal laser treatment could be completed. Vitreous traction to sites of fibrovascular proliferation with localized traction retinal detachment was present in each eye. Postoperative vision improved in each eye but was limited by radiation macular edema, macular ischemia, and optic neuropathy. Chaudhuri and coworkers²³ also report a case of proliferative radiation retinopathy treated with panretinal photocoagulation. There was complete regression within 2 weeks and no recurrence with 4 months of follow-up.

Although some cases of radiation optic neuropathy may show modest improvement without treatment over several months, this condition typically carries a poor visual prognosis. One report found stabilization of vision in two of four eyes treated with hyperbaric oxygen within 3 days of diagnosis of radiation optic neuropathy,⁴⁰ but a larger study with 13 patients failed to show any beneficial effect.⁴¹ In this study, none of the 13 patients treated with hyperbaric oxygen and cortical steroids showed any improvement in vision, and 25% of eye declined by two or more Snellen lines. Currently, there does not appear to be any effective treatment for this condition.

CONCLUSIONS

Radiation retinopathy is a distinct clinical entity caused by ionizing radiation damage to the vasculature of the neurosensory retina, choroid, and optic nerve. The vascular endothelial cells appear to be most susceptible to radiation damage, and the funduscopic appearance is similar to that of diabetic retinopathy. This has led some to classify this disease into nonproliferative (macular edema, hard exudates, intraretinal microaneurysms, dot and blot hemorrhages, venous dilation, and capillary nonperfusion) and proliferative (neovascularization of the retina or optic disc and vitreous hemorrhage) stages, similar to the classification of diabetic retinopathy.

The severity of radiation retinopathy is dependent on total radiation dose, individual fraction size, and modality of radiation delivery. Although there is significant variablity in the amount of radiation that produces retinopathy, brachytherapy produces retinopathy with a mean total dose of 150 Gy, whereas teletherapy produces retinopathy with a mean total dose of only 50 Gy.² For teletherapy, fraction doses of greater than 2 Gy probably predispose to greater damage.⁴²^,⁴³ Presence of diabetes mellitus and concomitant chemotherapy seem to have an additive effect to radiation damage to the posterior segment.

Although there have been no large trials to evaluate treatment efficacy for radiation retinopathy, the treatment strategies for diabetic retinopathy have been adopted because of the similarities to this disease. Focal- or grid-pattern macular laser photocoagulation may be attempted in cases of macular edema threatening vision, although final visual function may be limited by macular ischemia, radiation optic neuropathy, and radiation choroidopathy. Pan-retinal laser photocoagulation should be applied in cases of proliferative radiation retinopathy to decrease the risk or progression of neovascular glaucoma.

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