Response of the Normal Eye to High Dose Radiotherapy
Response of the Normal Eye to High Dose Radiotherapy
Parsons and colleagues present an excellent summary of their clinical experience with ocular complications of radiotherapy for primary periocular malignancies, together with a retrospective review of the literature on this subject. The authors emphasize the roles of both total dose and dose-per-fraction in radiation-associated eye complications.
Severe Dry-Eye Syndrome
According to the authors, total radiation dose to the lacrimal gland and dose-per-fraction are both important risk factors for dry-eye syndrome, and the probability of this complication increases steeply at doses above 40 Gy. Our experience is in general agreement with these findings, although several caveats should be pointed out. First, it is difficult to use meta-analysis for ocular radiation complications due to differences in radiation sources, fractionation schedules, and the use of CT for treatment planning. In addition, there have been inconsistencies in several studies with regard to reporting of total number of patients treated, use of adjunctive chemotherapy, and other significant variables . The authors acknowledge the limitations of a combined data pool, but it should be reemphasized that their dose-response curves are, at best, "first approximations."
Second, radiation injury to several disparate ocular structures, including the lacrimal gland, conjunctival goblet cells, accessory lacrimal glands, and meibomian glands, may cause severe dry-eye syndrome. (Often, there is radiation damage to more than one of these structures.) Clearly, it is not sufficient simply to exclude the lacrimal gland from the radiation field to avoid dry-eye syndrome.
The authors note that about 40% of eyes that received radiation to the retina developed visual acuity £ 20/200 due to retinopathy, and 52% of these eyes developed neovascularization of the iris. Total dose and dose-per-fraction were both associated with retinopathy, and the probability of retinopathy increased steeply above a total dose of 50 Gy. Since radiation-induced cataract and optic neuropathy may coexist with retinopathy, however, assigning the visual loss to one or the other cause may be overly simplistic and somewhat misleading. We are now addressing this problem by using a standardized, objective scale to quantitate data on radiation injury .
Neovascularization of both the retina and iris occurs with radiation retinopathy, diabetic retinopathy, and other retinal vascular diseases and is presumed to be due to diffusible vasoproliferative factors elaborated by ischemic retina. Vascular endothelial growth factor (VEGF) has been strongly implicated in diabetic retinopathy  and may also be involved in radiation retinopathy. It is uncertain whether radiation-induced iris neovascularization is due to retinal vasoproliferative factors or to direct radiation injury to the iris.
Panretinal laser photocoagulation is used to treat severely ischemic, irradiated eyes in an attempt to control neovascular glaucoma , although the precise indications and efficacy of this treatment are uncertain. The identification of putative vasoproliferative factors may eventually lead to pharmacologic interventions to prevent or reverse this devastating complication. Focal or grid laser treatment for radiation-induced macular edema is seldom beneficial, except in rare patients with retinal leakage from a few extrafoveal microaneurysms.
Radiation Optic Neuropathy
About 2% of patients treated by Parsons et al developed anterior optic neuropathy, and 6% developed retrobulbar optic neuropathy, with visual acuity 20/100 or less. The dose-per-fraction was a more important risk factor for this complication than was the total dose, and the probability of optic neuropathy increased steeply above a total dose of 60 Gy. An awareness of this sensitivity of the optic nerve to daily fraction size has been observed by other workers and is an important consideration in treatment planning. The sensitivity of normal (uninvolved) optic nerves to daily dose size is uncertain, since most reported patients had pituitary tumors or craniopharyngiomas and possibly had nerve injury on that basis.
Radiation Injury to Other Ocular Structures
Radiation injury to several other ocular structures can be clinically significant and should be considered in treatment planning. Radiation-induced cataracts may occur at doses to the lens as low as 12 Gy, particularly when delivered in large fractions . The risk of cataracts also is proportional to the amount of lens included in the radiation beam . Radiation-induced cataracts in adults can usually be extracted using ordinary surgical techniques. However, such cataracts in children can be more problematic. First, cataracts in very young children may cause significant amblyopia ("lazy eye") before surgery can be performed. Second, cataract surgery is more difficult in children and may require either a contact lens or a second operation for intraocular lens implantation. Third, in patients with intraocular tumors (eg, retinoblastoma), early cataract surgery is contraindicated until the reproductive integrity of the tumor has been destroyed.
Radiation effects on orbital structures can also have important clinical consequences. First, orbital soft-tissue atrophy and fibrosis can lead to enophthalmos (sunken globe), mucous membrane contracture, and symblepharon (fusion of opposing conjunctival surfaces). These complications usually are seen only at higher radiation doses in the range of 60 Gy . Second, young children who receive ocular irradiation are at high risk for arrest of orbital bone growth, leading to midfacial hypoplasia . The severity is inversely related to the patient's age, is usually minimal beyond 3 years, and appears to be less common with megavoltage, as opposed to orthovoltage, radiation. Third, children with hereditary retinoblastoma are at significant risk for second primary malignancies in the radiation field.
In summary, Parsons et al provide an excellent summary of ocular complications of radiation. They synthesize the experience of several centers in order to establish thresholds for radiation injury to various ocular structures. Although the results of their "meta-analysis" are only rough approximations, they are useful. Hopefully, future investigators will use standardized classification schemes for ocular radiation complications,1 in order for more direct, useful comparisons to be made between studies.
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