Ocular Manifestations of Isotretinoin
Isotretinoin (13-cis-RA) is a derivative of retinoic acid that is taken orally for the treatment of nodulocystic acne. It is postulated that isotretinoin alleviates severe cases of acne primarily by decreasing the size of sebaceous glands and sebum production, but other mechanisms are likely important since many patients do not face recurrence of acne despite sebaceous gland activity returning after termination of treatment. Changes in lipid composition of the skin likely lead to long term reductions in the level of Propionibacterium acnes, which is correlated with sebum levels at various skin sites. Isotretinoin may also be used as treatment in the setting of various skin conditions such as rosacea, Gram-negative folliculitis, keratinisation, ichthyosis and pityriasis rubra pilaris, palmoplantar keratoderma, and squamous and basal cell carcinomas.  Isotretinoin is strictly contraindicated in pregnant women and those who have paraben allergies.
Patients typically take isotretinoin 0.5 to 1 mg/kg per day until a cumulative dose of 120–140 mg/kg is reached. However, relapse after treatment and/or only partial responses warrant higher doses or repeat of treatment. Isotretinoin 1-2mg/day for 3-4 months typically leads to 60-95% clearance of nodulocystic lesions in patients and continued healing and prolonged remissions after withdrawal from treatment. Even doses as low as 0.1mg/kg/day have been reported to be effective in the treatment of nodular acne, but the duration of remission after termination of treatment is typically shorter.
There are many reported negative side effects associated with isotretinoin. Isotretinoin usage has been associated with raised serum triglyceride levels as well as potential long term spinal or skeletal bone toxicity. Isoretinoin has also been associated with a variety of other conditions such as depression, hypervitaminosis A, muscular or joint pain, gastrointestinal complications, pseudotumor cerebri, and headaches, eczema, and tiredness. The most commonly reported adverse reactions to accutane are those that involve the skin and mucous membranes such as skin fragility, paronychia, epidermal blistering, and hair loss. 98% of patients at a dosage of 1 mg/kg per day complain of adverse events. And half of patients at doses below 0.25 mg/kg per day experience no adverse effects at all, with those who do experience negative effects that are significantly less severe.
Ocular complications during and after isotretinoin treatment have also been highly reported. In a study conducted by Brezezinski et al., up to 8.96% of adverse effects in the setting of isotretinoin treatment are eye lesions. In this review, we attempt to describe the ocular manifestations and complications that may result from short term or long term isotretinoin use.
Ocular manifestations can occur within days or up to several years after the start of isotretinoin therapy, and in some cases severity can be dose-dependent. Ocular manifestations are typically less severe when low doses are used, and some patients may face more than one adverse ocular event. Dry eye disease, blepharitis, meibomian gland dysfunction, and conjunctivitis are the most frequently reported ocular adverse effects, but below we attempt to comprehensively describe the ocular manifestations that are both caused by and associated with isotretinoin treatment.
Vision Changes and Discomforts
Some of the most common ocular complaints due to isotretinoin usage include vision changes such as reduced or blurred vision, decreased dark adaptation, and refractive changes. In rarer cases, isotretinoin treatment can directly cause visual field alterations and myopia. In fact, there have been cases of up to 4 diopters of reversible myopia with or without astigmatism. Isotretinoin has also been reported to cause photophobia in a few patients. Treatment with isotretinoin can cause inability to wear contact lenses due to discomfort as well as general ocular discomfort.
Isotretinoin treatment is also the probable cause in instances of permanent night blindness. The development of decreased color perception has also been associated with isotretinoin treatment, but in most cases color vision returns to normal after termination of treatment. This drug has also been associated with decreased accommodations in patients, but a causal effect is unlikely.
The most common corneal complications caused by isotretinoin include keratitis and corneal opacities. A study conducted by Ozyol et al. found that isotretinoin treatment can induce epithelial thickening and stromal thinning as well as statistical differences in pachymetry-related parameters. In fact, the epithelial thickness of patients increased in all sectors of the eye during isotretinoin treatment. However, these pachymetry changes seen in the cornea typically return to baseline 3 months after termination of treatment. Santodomingo-Rubido et al. also reported corneal steepening in a patient after systemic treatment with isotretinoin for seven and a half weeks, but natural resolution occurred seven and a half weeks after termination of medication.
There have also been potential associations made between corneal herpes simplex activation and isotretinoin use. However, the association is weak and the occurrence of corneal herpes simplex activation is quite rare in the setting of isotretinoin.
Conjunctival and Eyelid Abnormalities
Treatment with isotretinoin can cause blepharoconjunctivitis, the most common conjunctiva-related complication in the setting of isotretinoin. The severity of blepharoconjunctivitis is dose dependent and characterized by chronic inflammation of the eyelid margin, crusting of the eyelid and eyelashes, and papillary conjunctivitis.
Isotretinoin can also cause keratoconjunctivitis sicca, and in rare instances the sicca syndrome can be permanent. However, most keratoconjunctivitis sicca cases resolve within one month after termination of treatment. These patients with sicca have normal Schirmer tests but poor tear film break-up times. Conjunctival epithelial cells, tear basal secretion, and tear quality can be affected significantly by isotretinoin treatment at 0.8 mg/kg. A prospective study conducted by Egger et al. found that out of 55 enrolled patients who took isotretinoin, 34.5% of patients developed symptoms of conjunctivitis sicca.
Isotretinoin also causes blepharitis, but it typically resolves naturally one month after termination of treatment.. Egger et al. also found that out of 55 patients, 40% developed blepharitis. The study also found that isotretinoin can alter the flora of the conjunctiva.
Although uncommon, subconjunctival hemorrhages have also been associated with isotretinoin use. The development of chalazions and hordoleums have also been associated with systemic isotretinoin. The formation of conjunctival cobblestone-like papillae has also been associated with isotretinoin use.
The development of disc edema due to idiopathic intracranial pressure has been associated with isotretinoin use. A case report by Roytman et al. described a 16-year old girl treated with isotretinoin at 0.7 mg/kg/day who developed papilledema and was found to have narrowing of the lateral ventricles and pseudotumor cerebri, which resolved after isotretinoin treatment was discontinued and systemic corticosteroids were administered. Lee et al. described a case of a 14-year-old boy who had been treated with isotretinoin for three weeks and developed pseudotumor cerebri. The patient had headaches and experienced bilateral visual loss secondary to papilledema. However, this patient also had been treated with tetracycline, and so a causal relationship in this instance cannot be established.
Isotretinoin has also been associated with optic neuritis. Perez et al. described a case in which a 16-year-old girl developed retrobulbar optic neuritis in the right eye three months after systemic isotretinoin 30mg/day (0.47/mg/kg/day).
Isotretinoin use has been associated with a myriad of retinal pathologies. Retinal or choroidal pigment disturbances have been seen in some patients who have taken isotretinoin. Some patients who take isotretinoin can potentially develop premacular hemorrhages as well as dysfunctional RPE, which can cause accumulation of excessive subretinal fluid and serous retinal detachment at the macula. In addition, a case report conducted by Watson et al. found that a patient who had taken isotretinoin was found with rod and cone photoreceptor damage. Toxicity or dysfunction of the retina can be revealed by ERG measurements, specifically b wave latency alterations. It is postulated that isotretinoin competes for normal retinol binding sites on cell surfaces or transport molecules, leading to abnormal ERG readings.
Several studies have found that isotretinoin can lead to thinning of the retinal nerve fiber layers and the macula. Another study found that isotretinoin treatment led to statistically significant thinning of the lower temporal retinal nerve fiber layer. However, other studies have found that systemic isotretinoin use for 6 to 12 months did not lead to thinning of the retinal nerve fiber layer or the ganglion cell complex.
Labiris et al. has also described a case of a 17-year-old boy with minimal preexisting risk for thrombosis, or a heterozygous carrier of the G20210A mutation of the prothrombin gene, who suffered from a central retinal vein occlusion that was associated with isotretinoin. This case had shown that isotretinoin treatment may greatly increase the risk of vision-threatening thrombosis even in patients who have minimal risk for thrombosis.
Although rare, systemic isotretinoin has been associated with posterior subcapsular opacities, anterior cortical opacities, cortical lens vacuoles, increased size or visibility of lens sutures, and nuclear sclerosis.
Isotretinoin can cause signs and symptoms of dry eye by reducing the function of the meibomian glands. A study by Mathers et al. found that isotretinoin can decrease the size of meibomian glands, increase tear osmolarities, and increase tear evaporation. In fact, this study suggests that isotretinoin-induced blepharitis is related to these changes.
|Area/Functionality of the Eye||Common Manifestations||Rare Manifestations|
|Vision Changes/Discomforts||Blurred/reduced vision, decreased dark adaptation, refractive changes||Visual field alterations, myopia, photophobia, decreased tolerance for contact lenses, ocular discomfort, permanent night blindness*, decreased color perception*, decreased accommodation*|
|Cornea||Keratitis, corneal opacities||Corneal herpes simplex activation*|
|Subconjunctival hemorrhages*, chalazions and hordeolums*, conjunctival cobblestone-like papillae*|
|Neuro-Ophthalmological||N/A||Optic disc edema*, optic neuritis*|
|Retina||N/A||Retinal or choroidal pigment disturbances*, rod and cone photoreceptor damage*, thinning of the retinal nerve fiber layers and/or the macula*, premacular hemorrhages*, CRVO*|
|Lens||N/A||Posterior subcapsular opacities*, anterior cortical opacities*, cortical lens vacuoles*, increased size or visibility of lens sutures*, nuclear sclerosis*|
|Gland||Meibomian gland shrinking/dysfunction||Lacrimal gland atrophy, changes in sebaceous gland secretions|
Diagnosis and Workup
The ocular effects of isotretinoin can usually be detected first by dermatologists during routine visits. The dermatologist should refer the patient to an ophthalmologist if the patient is experiencing any new ocular pain, eyelid swelling, unresponsive dry eye, decreased vision, reduced night vision, visual field alterations, color perception alterations, persistent foreigh body sensation, eyelid abnormality, and/or conjunctival secretions. A dermatologist could also distribute an ocular surface disease index (OSDI) 12-item questionnaire that covers dry eye symptoms and visual-related functions as patients tend to receive lower OSDI scores with isotretinoin treatment.
In an ophthalmological setting, a detailed, thorough history of symptoms related to dry eye disease, previous surgeries, and comorbidities such as cataracts, retinal diseases, glaucoma, and eyelid disorder is required. Any changes in visual acuity should be measured via a Snellen chart exam for both eyes, and if needed, ishihara plates can be used to assess any changes in the patient’s color perception. Any changes in the patient’s peripheral vision field should be measured with a visual field confrontation test. Bare eye examinations can assist in the diagnoses of blepharoconjunctivitis and dry eye disease, and pupil function can be tested with penlight in a dark setting. Schirmer tests can be conducted to test whether the eye produces enough tears. Slit lamp examinations should also be performed.
Further imaging techniques and lab measurements can be used to diagnose the patient. ERG b wave latency alterations indicate potential retinal toxicity. OCT imaging can be used to detect thinning of the retinal nerve fiber layer or ganglion cell complexes. Fundus imaging can detect retinal abnormalities such as retinal pigment disturbances, premacular hemorrhages, and/or optic edema.
Ocular adverse effects of isotretinoin are generally not serious and are reversible after discontinuation. Patients can generally be placed on a lower dose of isotretinoin to help alleviate symptoms, or in severe cases may discontinue isotretinoin if ocular symptoms persist or progress. Low-dose treatment reduces the adverse ocular effects of isotretinoin. We recommend that patients be given the low dose treatment of 0.15-0.40 mg/kg per day, with a cumulative dose of less than 120mg/kg, rather than the classical dose of 0.5-1.0 mg/kg per day administered bid in order to alleviate any potential ocular symptoms.
Patients can also be given supportive treatments, which will be described below. Unfortunately, some effects of isotretinoin can be permanent due to particular mechanisms such as isotretinoin inducing apoptosis in various cell types such as meibomian gland epithelial cells.
Ruiz-Lozano et al. recommends topical lubricants for symptoms of dry eye such as 0.3% hydroxypropyl methylcellulose 4x daily, sodium hyaluronate 0.1%-0.4% 4x daily, carboxymethylcellulose 0.25%-1% 3-4x daily, carbomer gel 0.2%-0.4% 3-4X daily, Hydroxypropyl-guar 0.3% 4x daily, or hypromellose 0.3%-1% 2-4 daily. Ruiz-Lozano et al. also recommended maintaining lid hygiene with warm compresses and scrubbing with cotton swabs. Particular lifestyle changes such as improved sleep and avoiding dry conditions to help alleviate particular symptoms such as dry eye were also recommended.
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