The eye is a complex organ composed of different types of tissues. Its different components range from extremely radiosensitive tissues, such as the lens, to radioresistant tissues, such as the retina and the optic nerve.¹⁰ The variations in radiation effect on the eye are dependent not only on tissue sensitivities but also on the methods of radiation delivery. Today, a majority of ophthalmic radiotherapy protocols involve the use of external beam radiation therapy (EBRT); indications for brachytherapy are fewer.^1,5 Newer techniques of radiation delivery decrease the rates of ocular toxicity. For example, a combination of proton- and photon-accelerated fractionated radiation allows the delivery of high doses to advanced tumors of the nasal cavity and paranasal sinus with tolerable eye complication rates.¹¹ Modern EBRT techniques such as stereotactic fractionated radiation therapy (SFRT) and photon EBRT appear to allow safe delivery of high target doses to patients with locally advanced orbital malignancies.^12,13

From the standpoint of radiation toxicity, the eye and periocular tissues can be divided into several zones: the external eye (the conjunctiva, cornea, sclera, and tear layer); anterior intraocular components (the iris, anterior chamber angle, and lens); posterior intraocular components (the retina, choroid, and optic disc); the eyelid; and orbital tissues.

External Eye

Most of the tissues of the external eye, including the epithelium of the conjunctiva, cornea, glandular excretory ductules, and lacrimal drainage apparatus, have the same sensitivity as that of skin because these structures are lined with epithelial cells, which are characterized as vegetative intermitotic cells (VICs). During the acute phase of radiation (within 6 months), fractional doses of 20 Gy cause erythema and edema of the eyelid skin and conjunctiva; if the dose is high enough, keratinization of the epithelium also takes place. The tear layer becomes thinner and irregular as a result of edema of the parenchyma of the lacrimal and meibomian glands and goblet cells. In addition, the damage to the epithelial cells of glandular ductules reduces the inflow of tears. Disruption of the tear layer is a serious matter, causing problems ranging from a scratchy sensation and mild visual distortion to severe external eye infections and cornea-sclera melt, which may even lead to perforation. Among its other functions, the tear layer possesses bactericidal properties because it contains immunoglobulins and lysosomes; it also flushes away foreign materials and bacterial debris from the external eye into the lacrimal drainage system. When the composition and the quantity of the tear layer are distorted by radiation-induced changes, both of these antibacterial properties are lost. As the radiation dose approaches 40 to 50 Gy, a confluent mucositis appears. At this stage, lacrimal gland secretions are reduced and thickened, and the external eye may become infected. During this period, photophobia may also be noted.

In the subacute period, ranging from 6 to 24 months, telangiectasias may develop in the skin and the conjunctiva, and the dryness worsens. The cornea demonstrates few structural changes until fractionated doses are in the range of 50 Gy; at this point, superficial punctate keratitis may develop. The cause of corneal damage is twofold: (1) the direct toxicity of ionizing radiation on its epithelial cells and stromal collagen and (2) developing dry eye syndrome. Total dose and dose per fraction are significant in terms of developing dry eye syndrome, leading to visual compromise in the radiotherapy of head and neck tumors.¹⁴

Punctate keratitis, which develops during the acute stages as a result of focal epithelial erosion and edema, becomes worse. Along with epithelial changes, the corneal sensation diminishes for weeks to months. During the subacute phase, scarring of the cornea may advance if deep keratitis was present during the acute period. Further scarring may lead to vascularization and thinning of the stroma, which in turn may lead to total opacification or perforation.¹⁵ Medical and surgical management of radiation keratopathy may be difficult because of poor wound healing. Moreover, patients treated with chemotherapy are also known to experience severe dry eye syndrome.

It would be an error to underestimate the consequences of the dry eye syndrome and to send the patient home with artificial tears and antibiotic or steroid eye drops or ointments. The management of dry eye should be undertaken jointly by the radiation oncologist and an ophthalmologist who are familiar with current treatment of dry eye syndrome, ranging from simple supplementation with eye drops to complex surgical interventions such as stem cell transplants and amniotic membrane grafts.16,17

The sclera, which maintains the structural integrity of both the anterior eye and posterior eye, consists of thick, irregular collagen bundles and is less affected by ionizing radiation than the cornea.¹⁸ No scleral radiation damage has been reported after EBRT at doses up to 60 Gy. However, extremely high scleral doses, which may be given during brachytherapy (e.g., in excess of 600 Gy), can cause melting of the sclera.¹⁹ In practice, strontium-90 (⁹⁰Sr) and ruthenium-106 (¹⁰⁶Ru) are more likely to deliver much higher scleral doses than is either iodine-125 (¹²⁵I) or palladium-103 (¹⁰³Pd) during plaque radiation therapy of intraocular tumors.²⁰

Anterior Intraocular Components

The iris and ciliary body are composed of fibroblasts, smooth muscle, vessels, and columnar pigmented and nonpigmented epithelial cells. Many of these cells are reverting postmitotic cells and therefore are quite resistant to radiation. Iritis has been reported with a single dose of 10 to 20 Gy, but severe anterior uveitis is not observed until higher doses of 30 to 40 Gy (in 10-Gy fractions) are given, and then it appears only after 6 to 8 weeks. Radiation iritis may be followed by secondary glaucoma. Dry eye–related corneal ulceration also may exacerbate iritis and secondary iris neovascularization.²¹ Localized iris atrophy has been noted after brachytherapy for iridociliary melanomas but not after EBRT for orbital tumors.²¹

Among the anteriorly located intraocular tissues, the crystalline lens is uniquely susceptible to radiation injury. The lens is an avascular protein structure covered by an elastic tissue capsule. The anterior surface of the lens has a layer of epithelial cells that do not show much mitotic activity; these cells behave as reverting postmitotic cells. Near the equator of the lens, however, the epithelial cells divide regularly and thus behave as VICs. Formation of cataracts is the most frequently encountered delayed radiation effect in the mammalian eye. It is known that DNA damage and abnormal protein cross-linking lead to development of opacities within the lens protein; however, the exact mechanism of the DNA damage by radiation is not known.²² The best clinical description of radiogenic cataracts has been reported by Cogan and associates²³ (Fig. 67-1).

Figure 67-1 A–C, Slit-lamp appearance of cataracts resulting from radiation.

The development of radiation opacity is dose, time, and age dependent (Fig. 67-2). Significant variation, however, is observed among persons who receive the same dose. The lenticular opacities do not always interfere with vision; clinically significant cataract development usually requires higher radiation doses and longer postradiation times. The latent period for production of cataracts from the time of exposure is on average 2 to 3 years but may range from 6 months to 3 decades.

Figure 67-2 Influence of radiation dose and exposure time on cataract formation in humans. (Data from Mettler FA, Moseley RD. Medical effects of ionizing radiation. Orlando, FL: Grune & Stratton; 1985.)

In the classic study by Merriam and Focht,²⁴ a large series of patients undergoing EBRT for ocular and orbital malignancies was studied from the standpoint of cataract formation.²⁴ The higher the absorbed dose, the shorter the latent period to cataract formation. Single doses of 2 Gy or fractionated doses of 4 Gy result in the formation of posterior lens opacities but rarely in significant visual impairment. The lowest cumulative ionizing radiation dose to the crystalline lens that can produce a cataract has been estimated also to be around 2 Gy. Recent literature indicates that this margin is substantially smaller than previously thought.²⁵

A dose of 7.5 Gy invariably causes clinically significant cataract formation. Merriam and Focht concluded that a given dose of radiation becomes less likely to produce a cataract when it is fractionated over a longer period. Fractionation of the radiation dose delays the onset and decreases the incidence of cataract development and slows its progression, as does the use of partial and total shielding of the equatorial areas of the lens.²⁶

After hematopoietic stem cell transplantation, Gurney and co-workers ²⁷ reported an incidence of cataracts of 36% at 15 years after the procedure; cataracts developed only in patients who received total-body irradiation as a conditioning regimen or head irradiation before transplantation. Of 4000 cancer survivors, 4% had cataracts.²⁸ Cataracts develop as a result of total-body irradiation or prolonged corticosteroid use. Cataracts that develop after moderate-dose fractionated radiation often do not impair vision significantly enough to be removed.²⁹

Another concern with radiation toxicity is the ocular exposure during modern imaging procedures. Although the great majority of computed tomography (CT) scanners deliver lower than the threshold dose for the development of cataracts, nevertheless, the potential exists for delivery of higher doses.³⁰

It has been reported that comprehensive imaging procedures may result in radiation exposure up to local doses of 490 mGy. Although critical doses for organ damage (e.g., cataract formation or hair loss) are not reached, physicians need to be aware of possible radiation-induced complications, particularly with repetitive studies.³¹ For decades it has been known that in utero exposure to radiation, particularly during the first trimester, can result in cataract formation, as well as pigmentary degeneration of the retina or microphthalmia.^32,33 In humans and experimental animals, even a low dose of radiation given with steroid treatment accelerates the development of lenticular opacities.³⁴

There is no doubt that many forms of radiation treatment in the eye may lead to cataract formation. However, in today’s medical practice, cataract management is a minor issue that can be resolved effectively and rapidly, and thus this complication should be viewed within the perspective of the many beneficial effects of radiation in the treatment of eye tumors.

Posterior Intraocular Components

The retina, choroid, and optic nerve are composed of relatively radioresistant tissues. At common therapeutic dose levels, acute effects of irradiation are rare; however, at doses higher than 50 Gy, acute retinal edema may occur, although this effect usually is transient (Fig. 67-3).

Figure 67-3 A, Acute radiation toxicity with focal intraretinal hemorrhages and cotton-wool spots. B and C, Chronic radiation toxicity of the fundus with hard exudates, edematous and necrotic retina, infarcted choroid, and vascular changes ranging from tortuosity and engorgement (B) to diffuse atrophy (“silver-wire vessels”) (C). D, Acute papillitis resulting from external beam irradiation for treatment of retinoblastoma. (A and B courtesy Dr. Edward Chaum, Memphis, TN.)

Chronic radiation damage to posterior ocular tissues is a form of microangiopathy. Because of the radiation damage to endothelial cells, vascular lumina are narrowed or obliterated and abnormal vascular permeability occurs. As a result of vascular disruption, the nerve fiber layer of the retina becomes ischemic, with the potential for the development of infarcts, exudates, and hemorrhages. The retinal vascular changes include totally occluded “ghost” vessels, vascular sheathing, microaneurysm formation, increased tortuosity, retinal telangiectasis, and eventually neovascularization (Fig. 67-3). The associated abnormal vascular permeability may impair vision as a result of macular exudates, often in a circinate pattern. Vascular occlusions of both the arterial and venous circulation may occur. Radiation retinopathy is a common vision-threatening complication following EBRT or brachytherapy. During the past two decades, most choroidal melanomas have been treated with plaque brachytherapy, which has increased the incidence of radiation retinopathy, with higher rates associated with larger tumors. When the damage involves the macula, serious visual loss occurs. Typically, onset of radiation retinochoroidal disease is between 6 months and 3 years after treatment; in some patients, however, the disease develops after much longer periods.^35,36 Laser photocoagulation, photodynamic therapy, oral pentoxyphylline, and intraocular injections of anti-VEGF have been attempted as treatment modalities with unsatisfactory results.³⁷

It has been reported that retinal damage may be produced by EBRT at doses as low as 15 Gy but is more common after EBRT at fractionated doses of 30 to 35 Gy. (At total fractionated doses of 70 to 80 Gy, retinopathy occurs in 85% of eyes.) Diabetes and chemotherapy, when combined with irradiation, seem to have an additive effect on progression of retinopathy. An associated papillitis often is seen with radiation retinopathy.

Both anterior ischemic optic neuropathy and posterior vascular occlusions can occur in the optic nerve, leading to visual loss (Fig. 67-3). Optic atrophy may be found as a result of ganglion cell degeneration or after a direct vascular insult. Radiation optic neuropathy can temporarily cause decreased vision, with later improvement over several months. This entity involves the anterior optic nerve and is characterized acutely by hyperemia and disc edema. Peripapillary hemorrhages and subretinal fluid also may be present. With EBRT, the mean total fractionated dose causing this effect is 55 Gy, with a range of 36 to 72 Gy. The mean latent period after radiotherapy is 19 months (5 to 36 months).³⁸ The risk of toxicity increases significantly at doses over 60 Gy at approximately 1.8 Gy/fraction and at over 12 Gy for single-fraction radiation. Generally, the radiation tolerance is increased with a reduction in the dose per fraction.³⁹ Current reports indicate that it is possible to detect the characteristics of radiation optic neuropathy quantitatively by optical coherence tomography (OCT).⁴⁰

Eyelid and Orbital Tissues

The main eyelid changes associated with EBRT include acute erythema, depigmentation, atrophy, telangiectasias of the eyelid skin, and loss of eyelashes; lid malpositions and fibrosis of the puncta are also seen.⁴¹ Eyelid skin behaves like skin of other sites, but it is thinner. The first reaction is erythema (typically seen at 2 to 4 weeks after initiation of treatment), followed by dry and moist desquamation. Erythema usually is transient and subsides rapidly. The higher the radiation dose, the more quickly the erythema develops. Erythema increases during the first week and usually fades during the second week; it then may return 2 to 3 weeks after the initial insult and last for 20 to 30 days. The early reddening presumably is due to release of vasoactive amines. The second phase of erythema is due to vessel damage; thermographic studies demonstrate increased blood flow during the first 2 to 3 months. Desquamation usually is healed by the time treatment has ended because compensatory regeneration occurs in the basal layer of the skin. Moist desquamation is more common after doses of 50 to 60 Gy (in 1.8- to 2.2-Gy daily fractions) given over 5 to 6 weeks and also is more common where superficial lesions break the skin. Healing typically is slow and may take up to 4 weeks. No radiation-related scar usually results unless an unusually high dosage is used or a complication such as secondary infection occurs.

Scarring can result in entropion or ectropion of the eyelids. Slowly progressive skin alterations may lead to depigmentation and telangiectasias. The accessory glands around the eye (including Moll, meibomian, and lacrimal glands) contain reverting or fixed postmitotic cells; the ductal epithelium for some of these glands contains VICs as well. Thus the excretory ducts, particularly in the meibomian glands, are relatively sensitive to direct effects of radiation, as are the equatorial regions of the lens and the basal cell layer of the cornea. Meibomian glands are of about the same radiosensitivity as that of hair follicles, but sweat glands are somewhat more resistant.

Doses in the range of 30 to 40 Gy can be delivered to the entire orbit without functional effect on the main lacrimal gland. On the other hand, evidence of histopathological atrophy of the lacrimal gland has been reported with single doses of 20 Gy and after 50 to 60 Gy given over a 6-week period.⁴¹ Although the mesenchymal tissues of the orbit including the extraocular muscles, fibroconnective tissue, and fat are rather resistant to radiation, orbital deformity leading to fascial asymmetry remains a major problem, particularly in children younger than 6 to 8 years who receive a tumor dose of approximately 50 Gy ⁴¹ (Fig. 67-4).

Figure 67-4 A patient who underwent orbital exenteration and external beam irradiation for unilateral retinoblastoma. Note the deformity of the left socket and ulceration of the skin posteriorly.

Another very serious adverse effect of orbital EBRT is that it increases the incidence of multiple primary malignancies in patients with retinoblastoma and other childhood malignancies.42–45 The relative risk of death was found to exceed the expected rates for malignant tumors of bone and soft tissues by 300-fold, for melanoma by 100-fold, and for brain tumors by about 25-fold.^46,47

At 40 years of follow-up, the cumulative mortality rate for all second primary malignancies was approximately 25% (expected 1.3%) for bilateral tumors and 1.5% (expected 1.1%) for unilateral disease. In the patients with bilateral retinoblastoma, radiotherapy further increases the risk of death. Early detection and management of these tumors are very difficult.

Hypothalamic and pituitary dysfunction with growth hormone deficiency with weight loss is also seen in children who undergo irradiation for optic nerve glioma.48,49

Intraocular Tumors

The most commonly encountered malignancies in the eyes of adults and children—uveal melanoma, metastatic tumors to the globe, leukemia, intraocular lymphoma, and retinoblastoma—are reviewed in this section.

Uveal Melanoma

Uveal melanoma is the most common primary malignancy of the adult eye, but it constitutes only about 5% of all melanomas in the body.⁵⁰ Up to 85% of ocular melanomas are uveal (primarily choroidal) in origin. The annual incidence of this tumor is approximately 4 per million population in the United States; this incidence is similar to that reported from European countries. The most recently reported male-to-female ratio is 4.9 to 3.7.⁵⁰

Pathogenesis

Approximately 98% of cases of uveal melanoma occur in the white population. This racial predisposition to uveal melanoma has been explained on the basis of the susceptibility of white persons to the oncogenic effects of sunlight. Although this hypothesis is convincing for skin melanoma, the evidence with regard to uveal melanoma is conflicting.⁵¹ It is well known that intraocular melanoma develops as a result of the proliferation of uveal melanocytes, but the knowledge regarding this tumor’s molecular pathogenesis is rather limited. It seems conceivable that these cells are intrinsically resistant to apoptosis because of constitutive Bcl2 expression. Hypothetically, the main event in the neoplastic conversion of the uveal melanocyte appears to be the inhibition of the Rb pathway. Genetic alterations that subvert the Rb and p53 pathways probably occur early, allowing the altered melanocytes to reenter the cell cycle and proliferate. The proliferation of the melanocytes may then become arrested by other tumor suppressor mechanisms, resulting in a dormant nevus; most of the nevi are permanently arrested at this stage. For further growth to occur, activation of a “malignant switch,” such as a reinhibition of the p53 pathway, may be necessary subsequent to another genetic shift.⁵²

During the past 15 years, considerable attention has been directed to the relevance of genetic testing of uveal melanoma, suggesting that the presence of chromosome 3 monosomy is a reliable predictor of worse prognosis.52,53

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