Periorbital complications caused by radiation therapy is the general term for acute and chronic complications that occur in periorbital structures such as the eyelids, lacrimal drainage system, orbit, and cornea and conjunctiva after radiation to the area around the eyes.
Radiation therapy (radiotherapy) mainly includes two types.
External beam radiation therapy: A method that delivers ionizing radiation to a specific area from a source outside the body.
Internal radiation therapy (brachytherapy): A method in which sealed sources (plaques, seeds, wires) are placed inside or next to the tumor site, or unsealed radioisotopes are injected.
Indications include eyelid cancer, intraocular cancer, and orbital tumors, and it is used for curative, postoperative adjuvant, preoperative adjuvant, and palliative purposes. In children, it is used to treat retinoblastoma and rhabdomyosarcoma, and in both adults and children it is also used for orbital inflammatory diseases such as orbital pseudotumor and thyroid eye disease.
Radiation directly damages DNA and induces apoptosis in cells. Complications appear over the following time course.
Acute complications (within weeks after treatment): edema, vascular congestion
Chronic complications (months to years later): fibrosis, scarring, vascular injury, atrophy, nerve damage, secondary malignancy
QHow long does it take for complications of radiation therapy to appear?
A
Acute complications (edema, congestion, erythema) appear within weeks after treatment. Chronic complications (fibrosis, scarring, bone atrophy, secondary malignancy) occur months to years later. See also the section “Causes and risk factors”.
The findings vary depending on the structures exposed to radiation.
Eyelid findings
Acute skin changes: Erythema appears within 24 hours after irradiation and progresses to blanching or hyperpigmentation and crusting. Crusting peaks at 10 to 20 days, disappears in 2 to 4 weeks, and heals completely by 8 weeks.
Chronic skin changes: Skin atrophy, fibrosis, and telangiectasia. Shortening of the anterior lamella can cause cicatricial ectropion.
Eyelid margin changes: Madarosis, trichiasis, and acquired distichiasis.
Findings in the lacrimal drainage system and glandular tissue
Lacrimal gland atrophy: Damage and necrosis of the serous acini. The earliest changes appear within 48 hours after the first dose of radiotherapy, and atrophy begins within 2 days after radiotherapy.
Dry eye: This develops from a combined reduction in the aqueous layer of the tear film (damage to the lacrimal gland, glands of Krause, and glands of Wolfring) and the lipid layer (meibomian gland dysfunction).
Lacrimal drainage obstruction: Reactive adhesion, narrowing, and scarring impair tear outflow. Proximal injury leads to canalicular stenosis. Distal injury leads to acquired nasolacrimal duct obstruction. Symptoms of acquired nasolacrimal duct obstruction include tearing, foreign body sensation, blurred vision, mucopurulent discharge, pain, and dacryocystitis.
Orbital findings
Children: Impaired bone growth causes underdevelopment of the orbit, eyelids, and face. Raney et al. reported orbital hypoplasia in 59% after radiotherapy for rhabdomyosarcoma.
Adults: Atrophy and fibrosis of the orbital soft tissues, together with bone atrophy and deformity, cause facial asymmetry and enophthalmos. High-dose irradiation can cause osteonecrosis.
Patients without an eye: Post-enucleation socket syndrome (PESS) and orbital contraction syndrome may make it impossible to retain an ocular prosthesis.
QWhy does dry eye occur after radiation therapy?
A
Damage and atrophy of the serous acini of the lacrimal gland reduce the aqueous layer of the tear film. At the same time, meibomian gland dysfunction causes loss of the lipid layer, so evaporative dry eye and aqueous-deficient dry eye occur together.
The main cause is radiation to the orbital area (external beam radiotherapy and brachytherapy). Radiation damages DNA and induces apoptosis, and inadvertent exposure of adjacent normal tissue causes complications. All damage is dose dependent, and injury to the lacrimal drainage system and gland tissue progresses cumulatively and in a dose-dependent manner.
The risk factors for skin complications are shown below.
Risk factor
Content
Sex
Male
Age
Older age
Environmental exposure
History of past sun exposure
Systemic diseases
Diabetes and connective tissue diseases
In children, a particular risk is that radiation exposure during the period of bone growth can markedly impair bone development. The younger the child, the more severe the deformity and growth suppression.
As a long-term complication after radiation therapy, secondary malignant tumors may occur. Levergood et al. (2024) reported a patient with a history of facial radiation who developed progressive unilateral multiple cranial neuropathy and was diagnosed with malignant peripheral nerve sheath tumor on lymph node biopsy2).
QWho is at higher risk of radiation-related skin complications?
A
Men, older adults, people with a history of sun exposure, and people with systemic diseases such as diabetes and connective tissue disease are at higher risk. The more of these factors you have, the more caution is needed.
Slit-lamp microscopy: evaluation of the anterior segment. Check eyelid position abnormalities, the direction of the eyelashes, and the tear film. Confirm narrowing of the punctal openings.
Tear tests: Schirmer test (tear production) and tear film break-up time for dry eye assessment.
Exophthalmometry (eye protrusion measurement): evaluation of enophthalmos. A right-left difference of 2 mm or more is clinically significant.
Imaging tests: CT and MRI to evaluate orbital bone structure and to assess soft-tissue atrophy, fibrosis, and osteonecrosis.
Lacrimal drainage tests: lacrimal irrigation and dacryocystography to identify the site of blockage.
Histopathology (lacrimal gland biopsy): confirmation of damage to serous acini, reduced size and number, and necrosis.
Manual lash epilation (epilation): a simple procedure that can be repeated.
Topical lubricants: protect the ocular surface with eye drops and eye ointment.
Therapeutic contact lens (bandage contact lens): protects the ocular surface and reduces pain.
Surgical management: for trichiasis and distichiasis, perform electrolysis (suitable for localized lesions), cryotherapy of the lash roots, lamellar splitting of the eyelid margin plus grafting, or oral mucous membrane grafting (limited to refractory cases).
Management of cicatricial entropion by severity is shown below.
Residual meibomian gland dysfunction: low-dose oral doxycycline suppresses bacterial lipase, reduces inflammatory mediators, and stabilizes the tear film.
Complete loss of meibomian gland function: replenish the lipid component with perfluorohexyl octane eye drops (brand name Meibo). It mimics natural meibum and relieves evaporative dry eye.
Surgical management:
Partial proximal canalicular obstruction: restore the lumen with trephination, then stent placement or balloon canaliculoplasty.
Prophylactic stent placement: preventive placement before RT may lower the risk of complications, but clear indications have not been established.
Children: the key to management is promoting normal orbital, eyelid, and facial development. After enucleation, place the largest possible implant and use conformers with gradual size increase and expanders (hydrogel, silicone, hydrophilic).
Enophthalmos: a side-to-side difference of 2 mm or more is clinically significant. Perform orbital reconstruction (sheet implants to the medial wall and orbital floor).
Post-enucleation socket syndrome / orbital contraction syndrome: reconstruct the fornix, lengthen the posterior lamella (mucosal grafts, auricular cartilage grafts, hard palate grafts), perform dermis-fat grafting, and for severe contraction use a microvascular free flap (co-managed with plastic surgery).
Osteonecrosis: Bone grafting (depends on the blood supply of the recipient bed) or an osseocutaneous flap (depends on microvascular anastomosis). Poor vascularity raises the risk of infection and graft failure.
QWhat surgeries are available for lacrimal drainage obstruction after radiation therapy?
A
The surgical approach depends on the site of obstruction. Partial obstruction in the proximal canaliculus is treated with stent placement or balloon canaliculoplasty. Obstruction of the common canaliculus or distal structures responds well to dacryocystorhinostomy, which can relieve acquired nasolacrimal duct obstruction in most cases after head and neck radiotherapy. Dacryocystorhinostomy may fail when scarring is severe.
6. Pathophysiology and detailed mechanism of onset
Radiation-induced cell injury results from direct DNA damage caused by ionizing radiation and induction of apoptosis.
Acute response: Inflammatory reaction after irradiation -> edema, vascular congestion. Skin erythema and crusting peak at 10 to 20 days. Even a small dose below 1.5 Gy per fraction can cause acute erythema.
Mechanism of chronic response:
Fibrosis: Early terminal differentiation of fibroblasts -> marked collagen deposition (over months) -> tissue hardening and contraction. Shortening of the anterior lamella -> cicatricial ectropion -> lagophthalmos -> may progress to keratopathy, corneal keratinization, corneal neovascularization, corneal ulcer, and corneal perforation.
Vascular injury: damage to vascular endothelium → tissue hypoxia → atrophy and fibrosis of soft tissues.
Effects on bone: damage to osteocytes, osteoblasts, and osteoclasts → impaired bone remodeling. In children, it inhibits bone growth; in adults, it can cause bone atrophy and deformity; at high doses, bone necrosis.
Pathology of the lacrimal gland: damage, atrophy, and necrosis of the serous acini. The earliest changes appear within 48 hours after the first dose of radiotherapy, and lacrimal gland atrophy begins within 2 days after radiotherapy.
Pathology of the tear drainage system: reactive adhesions, fibrotic narrowing, and scarring → outflow obstruction → canalicular stenosis or acquired nasolacrimal duct obstruction.
Radiation vasculopathy can threaten vision, but it can be controlled with regular intravitreal anti-VEGF therapy (bevacizumab, ranibizumab, aflibercept), making long-term vision preservation possible1). Radiation retinopathy, optic neuropathy, and cataract are also important intraocular complications1).
As a long-term complication after radiation exposure, secondary malignant tumors may occur. Cases of malignant peripheral nerve sheath tumor developing after facial irradiation have been reported2).
7. Latest research and future prospects (reports at the research stage)
Preventive canalicular stent placement: Prophylactic stent placement before radiotherapy may reduce the risk of tear drainage obstruction, but clear indications have not yet been established.
Perfluorohexyloctane ophthalmic solution (Meibo): In cases where meibomian gland dysfunction has completely disappeared, it is attracting attention as a new option for externally supplementing the lipid layer. It is a formulation that mimics natural meibum, and its effect on evaporative dry eye is expected.
Management of radiation vasculopathy with anti-VEGF therapy: Intravitreal anti-VEGF therapy is attracting attention as a treatment for radiation maculopathy. Early treatment is said to lead to better visual outcomes, and reports suggest that starting within 6 months after plaque irradiation may be effective in preventing severe vision loss in high-risk patients1).
Advances in radiation therapy techniques: Techniques for localizing and confining treatment to the target tissue have made major progress, but the risk of exposure to nearby normal tissue still remains.
Abhilasha Maheshwari, Paul T. Finger. Laser treatment for choroidal melanoma: Current concepts. Survey of Ophthalmology. 2023;68(2):211-224. doi:10.1016/j.survophthal.2022.05.002.
Levergood NR, Hepp C, Mackay DD. Unraveling a Rare Cause of Progressive Unilateral Cranial Polyneuropathy. Ophthalmology. 2025;132(4):e67. doi:10.1016/j.ophtha.2024.05.013. PMID:38864788.
