The problem of the impact of ionizing radiation on eye structures is one of the most important and topical in radiobiology. Knowledge of tissue radiosensitivity and induced tissue changes in the eye is essential for understanding the nature of radiation damage and the behavior of medical professionals. In this publication, the early and late determined radiation-induced impairments of the eye are presented as a result of radiotherapy or radiation incidents. The risk factors determining post-irradiation eye reactions, pathophysiological mechanisms, clinical picture, diagnosis, prevention, and new approaches in therapy are presented. We found that the typically found radiation-induced eye impairments are those of the eyelids – dermatosis and madarosis, conjunctiva – acute conjunctivitis, varied damage to the lacrimal apparatus, cornea – edema and ulceration, iris – rarely inflammation or neovascularization, sclera – rarely atrophy or necrosis, eye lens – cataract, retina – characteristic retinopathy, and optical nerve – rarely neuropathy. We provide the current consensus on prevention and treatment protocols in radiation-induced eye impairments, though most suggested treatment so far should qualify as experimental.

The aim of our study was to summarize and describe the current scientific consensus on the possible radiation-induced eye impairments, circumstances under which they arise, and identify the available prevention and treatment options. To this end, we performed a systematic literature review in 2023. Keywords entered in relevant databases such as PubMed, were ionizing radiation, radiation-induced eye impairment, radiotherapy, radiation incidents, post-irradiation eye reactions. Languages used during the literature search were English, German, French and Russian, though we settled finally on citing English and German sources.

The effects of ionizing radiation on the eye were first described by Chalupecky as early as 1897 [1]. In-depth systematic studies on the action of ionizing radiation on the structures of the eye began to be conducted by Rohrschneider, who in 1929 proposed a scale reflecting the different radiosensitivity of the eye structures - starting with the lens, as the most radiosensitive tissue, followed by the conjunctiva, the cornea, the uvea, the retina and ends with the most radiation- resistant – the sclera [2]. Poppe continued these studies and in 1942 published their results [3]. The first scientific reports describing the effects of ionizing radiation on the eyes of those working in such an environment - with a cyclic accelerator (cyclotron) were made by Abelson and Kruger, and in individuals who survived the atomic bombings, by Cogan et al. in 1949. Early damage mainly affects the rapidly proliferating epithelial cells and occurs during the course of irradiation or several weeks after. Blepharitis, conjunctivitis and keratitis usually develop. Late radiation-induced damages develop after a latent period of several months to tens of years, depending on the individual biological characteristics and the absorbed dose. These changes are mainly due to endothelial damage and microcirculatory dysfunction or to genomic damage to epithelial cells that do not die immediately after irradiation but have the potential to divide and differentiate, as in radiation cataract. Typical late radiation-induced injuries are cataracts, radiation retinopathy, and radiation-induced optic neuropathy [4, 5].

Eyelids

Early radiation-induced damage to the eyelids includes dermatitis and madarosis at cumulative doses > 20 Gy with conventional fractionation, and extremely rarely at doses of 10 Gy delivered over three days. Loss of eyelashes can cause irritation conjunctiva and cornea. The skin of the eyelids reacts to ionizing radiation like the skin of other anatomical sites. The first reaction is erythema (usually after 2 weeks), which is followed shortly by dry desquamation. The skin at this time is warm and sometimes edematous. Microscopically, the overlying dermal vessels are dilated and an inflammatory infiltration with granulocytes, macrophages, eosinophils, plasma cells, and lymphocytes is observed. Erythema is usually transient and resolves quickly [6]. Hamilton et al. found that predisposing factors for increased skin radiosensitivity were advanced age, previous prolonged sun exposure and male gender. At cumulative doses exceeding 50 Gy, moist desquamation, sometimes secondary infection, and cicatrixes, resulting from unhealed ulcers, more often develop.

Late radiation-induced damage to the eyelids is relatively rare. These include telangiectasia and skin atrophy, permanent loss of eyelashes and depigmentation, usually at cumulative doses > 50 Gy. Fibrosis, scarring, and clinically significant eyelid deformity may develop. Regrowth of eyelashes sometimes leads to trichiasis or distichiasis, intense pain caused by growing eyelashes, irritation and even ulceration of the cornea. Keratinization of the palpebral conjunctiva, especially of the upper eyelid, may also cause corneal damage. Cicatrization can lead to entropion or ectropion [6].

Conjunctiva

Acute radiation-induced conjunctivitis occurs relatively frequently at doses ≥ 30 Gy. Studies by Stafford et al. found manifestations of radiation conjunctivitis in 46% of patients treated for orbital lymphoma with a mean cumulative dose of 27 Gy [7]. Clinical symptoms are characterized by conjunctival injection, often accompanied by significant chemosis, watery discharge and discomfort. Secondary bacterial or less commonly viral infections, usually from adenoviruses, may develop. Patients have the feeling of sand in the eye and piercing pain. There may be rhinorrhea or other respiratory symptoms. Viral conjunctivitis is often accompanied by enlarged periauricular lymph nodes, which helps in the correct diagnosis. Late radiation-induced damage to the conjunctiva usually occurs at doses ≥ 35 Gy. Conjunctival telangiectasias are relatively common. Stafford et al. described such vascular changes in the conjunctiva, in patients treated for orbital lymphoma, even at doses of 30 Gy [7]. Subconjunctival hemorrhages develop rarely and do not threaten vision. Chronic conjunctivitis, squamous epithelial metaplasia, and conjunctival keratinization have been observed at doses exceeding 50 Gy. In parallel, corneal abrasion may also occur. At doses > 60 Gy, permanent damage to the conjunctiva can cause symblepharon, leading to desiccation or restriction of eye movements [7].

Lacrimal apparatus

Early radiation-induced xerophthalmia results from either damage to the acinar cells of the lacrimal gland or damage to the meibomian glands, which are the major source of tear lipids and maintain normal tear film stability. Dysfunction of the Meibomian glands in itself is a state of inflammation and contributes to disruption of homeostatic regulation of the tear film and development of dry eye syndrome (DES, keratoconjunctivitis sicca). The pathology of the "dry eye" syndrome is more accurately represented by the term "ocular surface disease". It is categorized into three degrees – mild, moderate and severe, with the severity of the clinical symptoms being directly dependent on the dose and varying from itching, burning, feeling of a foreign body and fatigue in the eyes to severe redness, inflammation and pain. Various methods are used to diagnose and assess the severity of the disease – biomicroscopy; examination of the basal tear production by means of the Schirmer test; diagnostic staining of the anterior eye segment with fluorescein, rose bengal, lissamine green; measuring the osmolality of the tear film; determining the size of the tear meniscus; study the stability of the tear film, by tracking the time to tear; meibography, etc., through the use of corneal topographers. The standardized questionnaire OSDI (Ocular surface disease index) can be used to objectify the severity of the subjective symptoms and the effectiveness of the therapy. Early effects include conjunctival inflammation, chemosis, and tear film instability with subsequent dry eye sensation. These symptoms usually subside, but sometimes they can be quite persistent [8]. Kennerdell et al. reported that at doses of about 25 Gy for the treatment of orbital lymphoma, half of the patients had an early mild form of xerophthalmia. With moderate dose irradiation, between 30 and 45 Gy, late manifestations of dry eye syndrome manifest after 4 to 11 years. High doses of ionizing radiation aggravate the clinical picture and lead to a permanent decrease in the number of Goblet cells and loss of serous acinar cells. According to Merriam et al. the risk of atrophy and fibrosis of the lacrimal gland increases significantly with cumulative doses ≥ 50 Gy conventional fractionation, as well as after a single dose of 20 Gy. At doses above 57 Gy, severe dry eye syndrome develops [9]. Clinical symptoms appear within 1 month after irradiation, with dry eye usually resulting in vascularization and corneal opacification, which appear after 9 to 10 months. Doses > 60 Gy result in permanent loss of lacrimal secretion and profound keratoconjunctivitis sicca. Patients with severe lacrimal gland dysfunction complain of burning, redness, thick secretion, "foreign body sensation", blurred vision and photophobia. Dry eye syndrome can progress to vision loss, corneal opacification, ulceration, and vascularization. In rare cases, complications of secondary infection or perforation may occur. Bulbar phthisis and symblepharon can sometimes be seen. The tolerated doses to the lacrimal gland with conventional fractionation are similar to the tolerated doses to the salivary glands and are estimated to be about 30 to 40 Gy [9]. According to Emami et al., TD 5/5 (5% risk of dry eye syndrome over 5 years) was estimated at 35 Gy and TD 50/5 (50% risk of dry eye syndrome over 5 years) at 50 Gy [10] Studies by Parsons et al. showed a negligible risk at doses < 30> 40 Gy, and 100

The effects of ionizing radiation on the eye were first described by the end of the 19th century. The first scientific reports describing the effects of ionizing radiation on the eye came around the time of the Second World War. Early damage mainly affects the rapidly proliferating epithelial cells and occurs during the course of irradiation or several weeks after. Blepharitis, conjunctivitis and keratitis usually develop. Late radiation-induced damages develop after a latent period of several months to tens of years, depending on the individual biological characteristics and the absorbed dose. These changes are mainly due to endothelial damage and microcirculatory dysfunction or to genomic damage to epithelial cells that do not die immediately after irradiation but have the potential to divide and differentiate, as in radiation cataract. Typical late radiation-induced injuries are cataracts, radiation retinopathy, and radiation-induced optic neuropathy. Radiation-induced eye injuries turn out to be common and sometimes unavoidable complications of radiotherapy but should also be anticipated as a result of radiation accidents and possible radiological terrorism. Some problems are apparent here: the knowledge of most medical personnel on radiation-induced injuries, including eye injuries, is limited; prevention and treatment options are also limited and with somewhat unconfirmed effect. We came to some conclusions which follow. 

Radiation-induced damage to the eye is a common and sometimes unavoidable complication of both radiotherapy and radiation accidents. Reducing their frequency is possible by enriching our knowledge about radiation tolerance of eye structures, risk factors, pathogenetic mechanisms, clinical picture, prevention and treatment measures. A more active and detailed study of pathogenesis, immunological and pathophysiological changes is needed in order to introduce new approaches in therapy. More prevention and treatment options are necessary and research into them should be accelerated.