Chapter 121 – Radiation Retinopathy and Papillopathy
DESMOND B. ARCHER
• A chronic, progressive retinal and papillary vasculopathy induced by suprathreshold doses of ionizing radiation.
• Retinal microaneurysms.
• Retinal hemorrhages.
• Retinal telangiectatic vessels.
• Retinal hard exudates.
• Macular edema.
• Cotton-wool spots.
• Optic disc swelling.
• Intraretinal microvascular abnormalities.
• Retinal neovascularization.
• Vitreous hemorrhage.
• Traction retinal detachment.
• Rubeosis iridis.
• Optic atrophy.
• Occlusive choroidal vasculopathy.
Although Röntgen discovered X-rays more than a century ago, it was not until the mid-1930s that consistent reports of a retinal vasculopathy following radiotherapy began to emerge. It was soon appreciated that the clinical retinopathy and the less frequent papillopathy were dose related and had a characteristic, although variable, latent period.
In more recent years, a better understanding of the biological effects of ionizing radiation and more accurate targeting of radiation energy to the index tissue have reduced the incidence of collateral damage to the retina and optic nerve. Nevertheless, the posterior eye may be unavoidably exposed to excessive radiation in the treatment of cephalic malignancies by external beam irradiation (teletherapy) or in the treatment of retinal and choroidal tumors by teletherapy or plaque therapy (brachytherapy), and a sight-threatening vasculopathy can develop.   Careful monitoring of the developing vasculopathy and institution of therapy when required often serve to preserve vision in patients who have established and severe retinopathy.
EPIDEMIOLOGY AND PATHOGENESIS
The key determinants in the development of radiation retinopathy are the total dose of radiation administered to the retina and the fraction size in the case of teletherapy. In brachytherapy for choroidal melanoma or retinoblastoma, local retinal and choroidal changes are universal and the severity of retinopathy is directly proportional to the dose of radiation. Brachytherapy for posterior melanomas, especially within 5?mm of the macula, carries a significant risk of maculopathy and loss of vision.  The minimum dose of brachytherapy to induce maculopathy is unknown, although one study of brachytherapy for posteriorly located retinoblastomas recorded maculopathy in 7 of 18 eyes that received an estimated macular dose of 6000?rad (60?Gy) and in 9 of 10 eyes that received a macular dose of 7500?rad (75?Gy) or more. The threshold dose of teletherapy for clinical retinopathy is also unknown; estimates fall in the range 1500–6000?rad (15–60?Gy). The incidence of radiation retinopathy steadily increases with doses greater than 4500?rad (45?Gy).  Dose fractions, the field design, and the type and rate of administration of radiation also have to be taken into account. A general rule is that patients whose eyes receive radiation doses of less than 2500?rad (25?Gy) in fractions of 200?rad (2?Gy) or less are unlikely to develop significant retinopathy.
The precise incidence of radiation retinopathy is not known but is probably underestimated because many patients with early or mild retinopathy have few or no symptoms and some patients with established disease are so gravely ill that the ocular pathology goes unreported. One study of patients who received cephalic radiation for orbital, paranasal, and nasopharyngeal malignancies showed that, despite modern radiotherapeutic screening techniques, 55% developed clinical retinopathy and of these almost 50% progressed to sight-threatening vascular complications. Roughly one third of patients who received treatment for midline tumors (e.g., nasopharyngeal carcinomas) developed bilateral retinopathy.
Several different chemotherapeutic drugs used in tumor therapy may potentiate the injurious effects of ionizing radiation on the retinal and papillary microvasculatures by their effects on DNA synthesis and vascular endothelial cell repair and division.  Also experimental and clinical evidence suggests that coexisting diabetes mellitus is a risk factor for the development of radiation retinopathy and that patients who have diabetes are more likely to develop extensive retinal ischemia and neovascularization.  Patients who have systemic vascular disease (e.g., hypertension, collagen disease, and acute leukemias) also seem more vulnerable to radiation in terms of retinopathy. Concurrent chemotherapy is a risk factor for the development of optic neuropathy.
The length of time from radiotherapy to development of retinopathy is highly variable and unpredictable. Many patients who receive substantial radiotherapy develop only minor microvascular changes that do not materially affect vision—this
probably accounts for the great variation in reported latencies, 1 month to 15 years. The most commonly reported latent intervals are from 6 months to 3 years; the latent period is shorter for eyes with severe ischemia and proliferative retinopathy. The characteristic latent period to retinopathy is probably related to the turnover cycle of retinal vascular endothelial cells, which on average is about once every 2–3 years.
All retinal cells are relatively radioresistant, and the nonreplicating neural cells are highly radioresistant. The relative radiosensitivity of the retinal vascular cells seems to be related to the conformation of their nuclear chromatin. The heterochromatic nuclear DNA of retinal vascular endothelial cells and pericytes is less accessible to repair enzymes than the loosely arranged euchromatic DNA characteristic of neurons. Hence, the vascular cells are more vulnerable to ionizing radiation “hits,” which cause single- or double-stranded DNA breaks. Dividing retinal vascular cells are exquisitely sensitive to radiation as the chromatin of the mitotic cell is in the ultimate state of condensation. The differential sensitivity of retinal vascular endothelial cells with respect to pericyte and smooth muscle cells is probably a function of their particular exposure to high ambient oxygen and blood transition metals, such as iron, which induces free radical formation and cell membrane damage. 
Good histopathological and ultrastructural evidence indicates that the retinal vascular endothelial cell is the first and prime casualty of retinal irradiation and that its malfunction or demise is the starting point for the development of radiation retinopathy and its complications. With each radiation insult, it is likely that a small and scattered population of vascular endothelial cells that are undergoing mitosis suffer mitotic death. A few cells that absorb sufficient radiation may also suffer immediate interphase death. The first wave of cell death initiates division and migration of adjacent cells to establish endothelial continuity; however, some of these cells will have suffered sufficient radiation damage to cause mitotic death when compelled to replicate. This initiates a further round of division, and so on, until the vascular endothelium is unable to maintain its integrity and the clotting cascade is initiated.
Capillary occlusion leads to the formation of small dilated collateral channels that bypass the area of ischemia and assume a telangiectatic-like form. Microvascular abnormalities, such as microaneurysms, intraretinal microvascular abnormalities, and incompetent capillaries, develop in response to hemodynamic events and alteration in the local metabolism. Where areas of capillary closure are extensive, preretinal and papillary new vessels may form. The events that lead to radiation papillopathy are less certain, although the superficial retinal capillaries probably suffer the same fate as the peripapillary retinal vasculature. High doses of radiation cause an occlusive vasculopathy of the choroidal circulation. It is likely, but unproved, that the posterior ciliary-derived microcirculation of the optic nerve head is similarly compromised. The retinal ganglion cells are highly radioresistant and, although axoplasmic stasis is a feature of acute radiation papillopathy, it is probably secondary to ischemic changes at the optic nerve head.
The earliest clinical features of radiation retinopathy are discrete foci of occluded capillaries and irregular dilatation of the neighboring microvasculature at the posterior fundus. Fluorescein angiography confirms the extent of capillary dropout and the general capillary competence at this stage. As the retinopathy develops, microaneurysms and telangiectatic channels appear,
Figure 121-1 Exudative radiation retinopathy of right posterior fundus. A 45-year-old patient who received 6400?rad (64?Gy) of radiation and chemotherapy for a nasopharyngeal tumor.
Figure 121-2 Fluorescein angiogram of fundus shown Figure 121-1 . Note the microaneurysms, capillary fallout, and hypofluorescent area of retinal hemorrhage and exudation.
particularly in areas of depleted capillaries, and with time become incompetent. Retinal exudation and small intraretinal or nerve fiber hemorrhages may be superimposed on the gradually evolving ischemic retinopathy; however, with modest radiation damage the retinopathy and vision may change little over a period of years.
More substantial radiation injury is associated with diffuse capillary closure and microvascular incompetence that leads to macular exudation, edema, and decline in vision ( Figs. 121-1 and 121-2 ). An acute form of ischemic retinopathy may follow intense retinal irradiation, as in the course of eradicating a nasopharyngeal or orbital tumor, during which eye protection is limited. The clinical picture is one of ischemic retinal necrosis with widespread arteriolar occlusion, cotton-wool spots, and superficial and deep retinal hemorrhages, which affect both central and peripheral neural retina ( Figs. 121-3 and 121-4 ). Some resolution of hemorrhage and absorption of axoplasmic debris and edema typically occur, and a very limited reperfusion of ischemic areas may be evident. Intraretinal microvascular abnormalities are commonly observed in ischemic retinopathy, and, where vascular occlusion is extensive, preretinal and papillary neovascular membranes form. Most patients who have proliferative retinopathy develop the new vessels within 2 years of diagnosis of retinopathy. Vitreous hemorrhage, traction detachment, rubeosis iridis, and phthisis bulbi are end-stage complications of severe radiation damage to the eye.
Figure 121-3 Ischemic radiation retinopathy of left posterior fundus. Note the retinal hemorrhages, cotton-wool spots, and optic atrophy, which followed 5500?rad (55?Gy) of radiation for an anterior meningeal tumor.
Figure 121-4 Fluorescein angiogram of fundus shown in Figure 121-3 . Widespread capillary, arteriolar, and venular occlusion is seen, as well as staining of the vessels and nasal disc with dye.
The retinal pigment epithelium and choroid also display clinical and angiographic signs of radiation damage adjacent to radioactive plaques ( Fig. 121-5 ); this is also seen in patients who receive high-dosage teletherapy. These signs include scattered areas of hypo- and hyperpigmentation, evidence of choroidal vascular stasis and occlusion, serous detachment of the macula, and, very occasionally, choroidal neovascularization.
Radiation optic neuropathy may complicate either brachytherapy or teletherapy—most patients who suffer neuropathy have accompanying retinopathy. In the acute phase disc hyperemia and swelling occur, usually in association with peripapillary edema, hard exudates, hemorrhage, and cotton-wool spots ( Fig. 121-6 ). Fluorescein angiography demonstrates microvascular incompetence, together with areas of capillary nonperfusion of the disc and nearby neural retina. Optic nerve-head swelling may persist for weeks or months but eventually leads to a severe and striking optic atrophy. Vision loss is characteristically severe. The dose of radiation and latent period for clinical optic neuropathy are similar to those for retinopathy; diabetes and concurrent chemotherapy are also risk factors. 
A history of cephalic radiotherapy and the presence of an ischemic retinopathy usually suffice to secure a diagnosis of radiation retinopathy. Macular telangiectatic vessels are a feature,
Figure 121-5 Proliferative and exudative radiation retinopathy following brachytherapy for retinoblastoma. Note the chorioretinal atrophy at a prior tumor site inferior to left optic disc. There is hemorrhage and exudation from new and incompetent vessels that border the scar.
Figure 121-6 Radiation papillopathy. Swollen ischemic right optic nerve head with peripapillary hemorrhage exudation and cotton-wool spots: 27 months following 64?Gy for nasopharyngeal tumor.
if not a hallmark, of radiation damage and all the microvascular alterations can be displayed vividly by fluorescein angiography. Indocyanine green angiography may identify areas of choroidal hypoperfusion, precapillary arteriolar occlusion, and abnormal staining of the affected choroid. Electroretinographic (ERG) responses are depressed following acute retinal radiation—pattern ERG and visual evoked response abnormalities confirm inner retinal damage or the presence of a maculopathy. Visual fields show a spectrum of changes, which depend on the extent of ischemic retinopathy and neuropathy and usually correlate with the area of retina exposed to radiotherapy.
The differential diagnosis is given in Box 121-1 . The diagnosis of radiation retinopathy is usually self-evident, given the history of radiotherapy. However, for diabetic patients who receive radiotherapy for midline cephalic tumors it may be difficult to decide the exact nature of the retinopathy.
The presence of dilated telangiectatic channels at the macula and relative paucity of microaneurysms, venous beading, and vasoproliferative changes (despite sufficient inner neural retinal ischemia) suggest that radiation damage is predominant and may reflect relative sparing of pericytes and smooth muscle cells at the histological level.
Differential Diagnosis of Radiation Retinopathy
Branch retinal vein obstruction
Central retinal vein obstruction
Accelerated hypertensive retinopathy
Ischemic optic neuropathy
Radiation optic neuropathy in the absence of retinopathy may mimic the clinical picture of anterior ischemic optic neuropathy but tends to occur in younger, normotensive patients and little or no involvement of the short posterior ciliary vessels is seen on angiography. Elderly patients who have ischemic optic neuropathy merit an erythrocyte sedimentation rate or C-reactive protein assessment, despite a history of radiotherapy, to rule out temporal arteritis.
The interpretation of continuing visual loss after neurosurgery and radiotherapy for tumors of the sellar region is often difficult. A diagnosis of radiation-induced optic neuropathy may be facilitated by magnetic resonance imaging with gadolinium–pentetic acid and the presence of altitudinal field defects. 
Most histopathological studies show preferential preservation of the outer retina compared with the inner retina and alterations to the nerve fiber layer attributable to inner retinal ischemia. Trypsin digest preparations from irradiated eyes with vasculopathy show an early and unequivocal loss of retinal vascular endothelial cells with relative sparing of the pericyte population ( Fig. 121-7 ). Associated changes include microaneurysms and fusiform dilatation of capillaries, which predominate on the arterial side of the circulation. Acellular, nonperfused, and collapsed capillaries are a feature of ischemic retina and are associated with varying degrees of neuronal degeneration and gliosis. Large thin-walled channels with dense collagenous adventitia are the histopathological correlates of the telangiectatic-like vessels observed clinically. With intense radiation, such as 6000?rad (60?Gy) for an orbital rhabdomyosarcoma, widespread loss of photoreceptors, retina pigment epithelial cells, and choriocapillaries and atrophy of the associated inner retina and optic nerve may occur.
Only a few patients develop advanced radiation retinopathy, and to date no randomized controlled study exists to assess properly the value of photocoagulation in either limiting macular edema or containing the vasoproliferative response. Anecdotal and small group studies suggest that focal or grid laser photocoagulation, given as for diabetic retinopathy, has a favorable effect on radiation macular edema, particularly in the absence of severe macular ischemia or cystoid degeneration and where vision remains 20/80 (6/24) or better. Cataract, vitreous hemorrhage, prior panretinal photocoagulation or detachment, and optic neuropathy are all factors that may limit visual recovery. Focal photocoagulation may also prove beneficial for retinal and choroidal neovascularization that occurs at tumor sites following either plaque or external beam therapy. Panretinal photocoagulation, given as for proliferative diabetic retinopathy, has been used to contain preretinal and papillary neovascularization
Figure 121-7 Vascular endothelial cell loss in irradiated retina—5000?rad (50?Gy). Note the severe depletion of capillary endothelial cells but preservation of pericytes, that is, most of the residual capillary nuclei.
and reduce the incidence of vitreous hemorrhage and neural retinal detachment. In general, less intense photocoagulation is required to contain radiation retinopathy compared with that required for diabetic retinopathy. Retinal cryoablation has also been used to contain neovascularization in the presence of dense vitreous hemorrhage. 
Vitrectomy—Retinal Detachment Surgery
Persistent vitreous hemorrhage and retinal traction that affect the macula respond to pars plana vitrectomy and rhegmatogenous retinal detachments yield to conventional detachment surgery.
COURSE AND OUTCOME
Clinically significant radiation retinopathy or papillopathy usually follows teletherapy for nasopharyngeal, paranasal sinus, or orbital tumors, during which only limited protection can be afforded during the eradication of the tumor. Plaque therapy for retinal and choroidal neoplasms causes severe damage to the immediate retina and choroid and secondary alterations to the surrounding tissues for a distance of several millimeters. With teletherapy it is often difficult to compute precisely how much radiation the retina and optic disc will receive or the exact dose of radiation that will precipitate clinical retinopathy. Doses in excess of 3400?rad (34?Gy) are likely to induce retinopathy, especially if fraction doses exceed 200?rad (2?Gy) and other risk factors are present. Minor degrees of retinopathy, characterized by subtle capillary fallout and occasional dilated channels and microaneurysms, may not affect vision and may remain stable for years. No treatment is required, but such patients merit annual follow-up as the disease is slowly progressive. Macular exudation that causes significant retinal thickening and visual symptoms requires prompt laser photocoagulation. Treatment reduces edema and, in the absence of severe macular ischemia, improves or stabilizes visual acuity. Recurrent treatment may be required if fresh leaking foci develop. Patients who have nonproliferative retinopathy, on average, can expect to retain a visual acuity of 20/50 (6/15) for at least 4 years.
Severe ischemic retinopathy typically follows direct orbital irradiation for lymphoma, rhabdomyosarcoma, or lacrimal gland carcinomas; visual loss is attributable to macular or optic nerve ischemia. New vessels that may bleed profusely develop in some of these patients, who should be observed at regular intervals. Panretinal photocoagulation is effective in the long term in containing the vasoproliferative process. Patients who have proliferative radiation retinopathy have a poor prognosis for retaining good central vision, with a high proportion (86%) achieving only 20/200 (6/60) vision or worse after 6 years.
It is important that the ophthalmologist and radiotherapist liaise closely when patients receive cephalic radiation that involves the eye in the treatment field. Careful monitoring of the patient and judicious photocoagulation can help preserve vision
in patients who may otherwise be severely disabled for a variety of reasons.
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