Isotretinoin (13-cis-retinoic acid) is a retinoid (vitamin A derivative) used to treat nodulocystic acne. It works by reducing sebaceous gland size and suppressing sebum production, typically administered at 0.5–1 mg/kg/day until a cumulative dose of 120–140 mg/kg is reached. It leads to disappearance of 60–95% of nodulocystic lesions and provides long-term remission.
However, isotretinoin has a wide range of side effects. 98% of patients experience some side effect, and ocular lesions account for up to 8.96% of them. Besides acne, it is sometimes used to treat rosacea, ichthyosis, pityriasis rubra pilaris, and squamous cell carcinoma.
The most frequent ocular side effects are dry eye, blepharitis, meibomian gland dysfunction, and conjunctivitis, but various ocular complications such as corneal abnormalities, visual changes, retinal disorders, and lens opacities have been reported. It has been shown that 13-cis-retinoic acid, a metabolite of isotretinoin, is harmful to meibomian gland health1)2)3).
QDo eye side effects always occur when taking isotretinoin?
A
The frequency of ophthalmic side effects from isotretinoin is reported to be about 9%, and they do not occur in all patients. There is also a dose-dependent tendency; at low doses of less than 0.25 mg/kg per day, the frequency and severity of side effects are significantly reduced. Dryness and discomfort of the eyes are the most common symptoms, but most improve after treatment ends. If you have any concerning symptoms, you should see an ophthalmologist early.
Meibomian gland dysfunction: Reduction in size and function of the meibomian glands. Leads to increased tear osmolarity and enhanced evaporation.
Blepharitis: Chronic inflammation of the eyelid margin. Occurs in 34.5–40% of patients. Usually resolves within 1 month after drug discontinuation.
Dry keratoconjunctivitis: Characterized by shortened tear film breakup time (TBUT). Schirmer test is often normal.
Blepharoconjunctivitis: Dose-dependent. Characterized by eyelid margin inflammation, crusting, and papillary conjunctivitis.
Corneal, Retinal, and Lens Abnormalities
Keratitis and corneal opacity: Corneal epithelial thickening and stromal thinning occur, but return to baseline 3 months after drug discontinuation.
Retinal abnormalities: Pigmentary changes, premacular hemorrhage, thinning of the retinal nerve fiber layer, and central retinal vein occlusion have been rarely reported.
In a prospective study by Egger et al., 34.5% of 55 patients taking isotretinoin developed dry conjunctivitis and 40% developed blepharitis. It was also suggested that the conjunctival bacterial flora may change.
Reversible myopia of up to 4 diopters has been reported as a refractive change. Decreased color vision has also been associated with isotretinoin, but most cases recover after discontinuation.
QDo the ocular side effects of isotretinoin resolve after stopping treatment?
A
Many ocular side effects are reversible and improve within 1 to 3 months after discontinuation. However, changes mediated by apoptosis of meibomian gland epithelial cells may be permanent, and chronic dry eye may persist. Rare cases of permanent night blindness have also been reported. If ocular symptoms appear during treatment, an early ophthalmology consultation is recommended, and dose adjustment or discontinuation should be considered as needed.
The central mechanism of ocular complications of isotretinoin is direct toxicity to meibomian gland epithelial cells. 13-cis-retinoic acid has the following effects 1)3).
Inhibits proliferation of meibomian gland epithelial cells
Promotes cell death (apoptosis)
Alter gene expression
Modify signal transduction pathways
Promote expression of inflammatory mediators and proteases
These actions cause atrophy and keratinization of the meibomian glands, impairing lipid secretion. Reduction of the lipid layer of the tear film leads to increased tear evaporation, resulting in evaporative dry eye1)2).
Isotretinoin is listed as a risk factor for ocular surface disease in the international TFOS (Tear Film & Ocular Surface Society) classification 4). Acne and rosacea medications can cause dry eye, meibomian gland dysfunction, conjunctival inflammation, and corneal nerve damage 4).
Concomitant use with tetracycline antibiotics increases the risk of idiopathic intracranial hypertension. In patients with thrombotic predisposition, attention should be paid to an increased risk of central retinal vein occlusion.
Ocular effects of isotretinoin are often first detected during regular dermatology visits. Patients with the following symptoms should be referred to an ophthalmologist:
Electroretinography: Changes in b-wave implicit time (screening for retinal toxicity)
Visual field testing: Evaluation of peripheral visual fields using confrontation or automated perimetry
A characteristic feature of dry eye caused by isotretinoin is that the Schirmer test is normal but TBUT is shortened. This reflects an evaporative mechanism due to meibomian gland dysfunction2).
If ocular side effects occur, first consider switching to a lower dose. Reducing to 0.15–0.40 mg/kg per day alleviates many symptoms. In severe cases or if symptoms persist or worsen, consider discontinuing isotretinoin.
0.3% hydroxypropyl methylcellulose (4 times daily)
Warm compresses and eyelid hygiene: For meibomian gland dysfunction, daily warm compresses to melt meibomian gland lipids and cleaning of the eyelid margins with a cotton swab.
Ophthalmic ointment at bedtime: Effective for preventing corneal dryness at night.
Environmental adjustments: Avoid dry environments, use a humidifier
Contact lenses: Switch to glasses if discomfort occurs
Idiopathic intracranial hypertension: Discontinue isotretinoin and administer systemic steroids
Retinal vascular disorders: Screen for thrombophilia and manage appropriately
QAre there ways to prevent dry eye during isotretinoin treatment?
A
Prophylactic use of preservative-free artificial tears from the start of treatment is recommended. Daily warm compresses and eyelid hygiene are also important to maintain meibomian gland function. Some studies suggest that omega-3 fatty acid intake may improve the quality of meibum (meibomian gland secretion). Low-dose administration (0.15–0.40 mg/kg per day) is effective in reducing ocular complications. Avoid dry environments and use moisture goggles as needed.
The central pathology of ocular side effects of isotretinoin is meibomian gland dysfunction. 13-cis-retinoic acid directly acts on meibomian gland epithelial cells, causing growth inhibition, promotion of apoptosis, and changes in gene expression 1)3).
The International Workshop on Meibomian Gland Dysfunction reported that 13-cis-retinoic acid and retinoids in general can cause significant damage to the meibomian glands, including keratinization, gland atrophy, and secretion abnormalities 2).
Atrophy of the meibomian glands reduces the lipid layer of the tear film, leading to increased tear evaporation. This is the pathophysiology of evaporative dry eye. Studies by Mathers et al. showed that isotretinoin causes a reduction in meibomian gland size, increased tear osmolarity, and increased tear evaporation.
Retinoic acid reduces androgen receptor expression in lacrimal gland cells and suppresses their proliferation 2). This may lead to lacrimal gland atrophy and decreased tear secretion. However, since many patients have normal Schirmer test results, the main cause of dry eye due to isotretinoin is thought to be evaporative dry eye from meibomian gland dysfunction.
Isotretinoin induces corneal epithelial thickening and stromal thinning. Corneal steepening has also been reported, which may cause refractive changes (myopic shift). These changes recover within 3 months after discontinuation.
Isotretinoin may compete with normal retinol binding sites on cell surfaces and transport molecules, potentially damaging rod and cone photoreceptors. Changes in the b-wave implicit time on electroretinography reflect this retinal toxicity. In patients with thrombophilia, isotretinoin may increase the risk of central retinal vein occlusion.
In a study of patients who used systemic isotretinoin therapy for 4 months or more, the group receiving omega-3 fatty acids in addition to lower punctal plugs showed no significant differences in OSDI, TBUT, tear osmolarity, or Schirmer scores, but meibum quality significantly improved 2). This suggests that omega-3 fatty acids may contribute to the prevention of meibomian gland dysfunction.
In the 2025 TFOS DEWS III report, it was reaffirmed that isotretinoin (13-cis-retinoic acid) is harmful to meibomian gland health 3). Inhibition of proliferation and promotion of cell death in meibomian gland epithelial cells are clearly indicated as the mechanism inducing meibomian gland dysfunction.
Establishment of an optimal dosing protocol to minimize ophthalmic side effects of isotretinoin, development of early detection markers for meibomian gland damage, and large-scale RCTs on the efficacy of preventive interventions (omega-3 fatty acids, punctal plugs, etc.) are needed.
Tavares RSN, Maria-Engler SS, Colepicolo P, et al. Skin Irritation Testing beyond Tissue Viability: Fucose-Rich Polysaccharide Restores Epidermal Homeostasis. In: TFOS Lifestyle: Impact of cosmetics on the ocular surface. Ocul Surf. 2024. [nihms-2004149]
Markoulli M, Ahmad S, Engel L, et al. TFOS Lifestyle: Impact of nutrition on the ocular surface. Ocul Surf. 2023;29:226-271.
TFOS DEWS III Management and Therapy Report. Am J Ophthalmol. 2025.
Craig JP, Nichols KK, Akpek EK, et al. TFOS Lifestyle: Impact of elective medications and procedures on the ocular surface. Ocul Surf. 2023;30:240-253.
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