There is a significant association between the skin and the eyes. There are some diseases which manifest jointly with the involvement of the skin and the eyes, called oculocutaneous diseases. There is another group where some drugs used commonly in managing skin diseases have a high incidence of eye side effects leading rarely to even blindness. The eye is the second most common site to manifest drug toxicity, after the liver [1] [Level II-1]. It is essential for a dermatologist to be aware of the potential complications before starting a systemic drug to limit eye damage [2] [Level II-2].

Level of Evidence

• Level I: Evidence obtained from at least one properly designed randomized controlled trial.
• Level II 1: Evidence obtained from well-designed controlled trials without randomization.
• Level II 2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
• Level II 3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.
• Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of the expert committee.

Etiopathogenesis

The drug reaches the eye via systemic circulation and through choroidal and retinal circulation.[3] At times, the drug sensitizes the immune system to develop antibodies against ocular tissue or forms immune complex deposit and targets the eye. The drugs find difficulty in entering the eye because of its avascular structures such as cornea and vitreous. There are three major hindrances which impede drugs from causing toxicity in the eye: blood–brain barrier, blood-aqueous barrier, and blood-retinal barrier. In states of inflammation, the blood-aqueous and blood-retinal barriers leak and the drug finds its way into the eye.[4]

Some of the predisposing factors for eye damage are listed in Table 1. [5]

The following hypothetical factors have been postulated to cause adverse effects in the eye:

• Specific biochemical reaction
• Altered metabolism of the drug
• A drug enters the systemic circulation and then the eye through retinal or uveal circulation. The normal anatomy further facilitates the drug to enter into structures such as lens, cornea
• The drug or its metabolite can accumulate in certain sites such as lens and cornea causing toxicity v. Drugs such as chloroquine and chlorpromazine have a high affinity to melanin and damage ocular tissues [4] [Level II-3]
• Underlying liver or renal damage. Altered pharmacology such as decreased excretion, prolonged half-life, or metabolite formation leads to more drug concentration in the eye causing damage to ocular tissue [6] [Level II-1]
• Lens filters ultraviolet (UV) rays in a normal eye. However, photosensitizers such as allopurinol, phenothiazine, and chloroquine. can cause changes in the lens, enhance the penetration of UV rays leading to eye changes such as cataract formation.[7]

The drugs used commonly in dermatology causing definite ocular side effects are listed in Table 2 and are discussed briefly here

Antibiotics

Aminoglycosides

Massive doses can cause retinal hemorrhages, retinal edema, cotton-wool spots, arteriolar narrowing, venous beading, rubeosis iridis, neovascular granuloma, pigmentary retinopathy and optic atrophy. Preservatives (methylparaben, propylparaben, and edetate disodium) may play an additive role in the toxicity[8] [Level II-2].

Fluoroquinolones

A study found a 4.5-fold increase in the risk of retinal detachment in patients using oral fluoroquinolones, observed within 5 days of starting the medication. The authors hypothesized that fluoroquinolones might alter the vitreous of the eye leading to the detachment, possibly in a similar way that fluoroquinolone use has been associated with an increased risk of Achilles tendon rupture[9] [Level II‑1].

Others

Linezolid, an oxazolidinone antibiotic, can contribute to optic nerve damage when treated beyond 28 days[10] [Level III]. Nalidixic acid causes increased fluid pressure, leading to headache, vision disturbance, color vision defect and swollen optic nerve, leading to papilledema, and reversible sixth nerve palsy.[11] Synthetic penicillins (amoxicillin and ampicillin) can cause mild redness of the eyes, itching, and dry eyes. They are commonly associated with causing Steven– Johnson syndrome (SJS) and toxic epidermal necrolysis.[12]

Table 1: Predisposing factors for eye damage Atopic individuals Preexisting medical illness - diabetes, liver, or renal disorders Preexisting eye disease - glaucoma, etc. Preexisting skin disease - photosensitivity

Known drug allergy history - penicillin, SJS, etc.  Overdose Pregnancy SJS: Steven-Johnson syndrome

Table 2: Systemic drugs commonly used in dermatology that can lead to eye damage Alpha - 1 blockers: Finasteride, saw palmetto, dutasteride Aminoglycides Anti-convulsants: Phenytoin, carbamazepine

Antifungal drugs: Griseofulvin Antihistamines: Loratadine, fexofenadine, hydroxyzine, and cetirizine

Anti-inflammatory agents: Acetaminophen, ibuprofen, and indomethacin Antileprosy drugs: Clofazimine Antimalarials: Hydroxychloroquine and chloroquine Antipsychotics: Chlorpromazine, clozapine Anti-tubercular drugs: INH, ethambutol, RMP Bisphosphonates: Alendronate sodium, risedronate sodium, zoledronic acid Antiviral: Cidofovir Corticosteroids Cyclic antidepressants: Amitriptyline, doxepin, nortriptyline Hormones: OCPs Interferon Nalidixic acid Penicillins Retinoids: Acitretin, isotretinoin Sulfonamides

Tetracyclines: Doxycycline, minocycline, and tetracycline

INH: Isoniazid, RMP: Rifampicin, OCPs: Oral contraceptives Sulfonamides both topically and systemically administered cause the conjunctival and corneal scarring in SJS[13] [Level I]. Tetracycline[14] has similar side effects as synthetic penicillins. In addition, it causes light sensitivity, blurred vision, diplopia, and rarely papilledema. Long-term use has been associated with idiopathic intracranial hypertension sometimes leading to permanent vision loss. Pigmentation of various body sites including the skin, nails, bone, mouth, and eyes secondary to minocycline therapy is well-known. Although skin and mucosal pigmentation is reversible, eye pigmentation is usually irreversible. Scleral pigmentation consists of a blue-gray 3–5 mm band starting at the limbus.[15] If pregnant women take tetracycline antibiotics, it may cause cataract in the developing fetus[16] [Level III].

Anticonvulsants

Phenytoin causes nystagmus, diplopia, frequent weakness of accommodation, and convergence. [17,18]

Antimalarials

Chloroquine and hydroxychloroquine (HCQ) are used in treating various autoimmune diseases. Reported incidence of toxicity ranges from 1% to 25%. Studies have shown that the incidence of retinopathy is 10% and 4% in unmonitored patients taking 250 mg/d of chloroquine and 400 mg/d of HCQ[19] [Level II-3]. The pattern of retinopathy caused by both HCQ and chloroquine is similar, but it is much less common with HCQ. They bind to melanin and gets concentrated in the iris, ciliary body, and retinal pigment epithelium (RPE), altering normal physiologic function. This leads to degenerative changes of the RPE. Early changes are characterized by the asymptomatic blunting of the foveal reflex and RPE granular pigmentary changes. Later with the progression of the disease, it manifests as blurred vision, scotomas, and photopsias. Bull’s-eye maculopathy (BEM) and arterial attenuation occur in the later stages of the disease[20,21] [Level II-2]. Corneal deposits are frequently bilateral. Macular degeneration is reversible initially, but when the total dose is >100 g irreversible changes occur[22] [Level II-2]. Chloroquine retinopathy progresses from near normal prematurity through the various stages of maculopathy and finally to end-stage maculopathy characterized by paracentral and eventually central scotoma with a characteristic BEM, a clear zone of depigmentation around the fovea.[23] Reported risk factors for ocular toxicity of the drug include age >60-year-old, high-fat level, daily dose >400 mg, or >6.5 mg/kg body weight for short individuals, cumulative dose >1000 g, duration of use >5 years, renal or hepatic dysfunction, obesity, and preexisting retinal disease or maculopathy[24] [Level II-3]. Damage to the eyes can happen even after stopping the drug because of its long half-life (50 days).[25] In fact, the drug may be detected in the blood and urine of the patients 5 years after stopping therapy. Damage has been reported to continue for up to 7 years after cessation of therapy[26] [Level III]. There is no general consensus on the definition of true hydroxychloroquine retinopathy. Bernstein [27] required the development of persistent paracentral or central visual field scotomas, >9 months treatment, a bull’s eye lesion. Easterbrook [28] suggested bilateral, reproducible, and positive field defects shown by two different visual field tests, namely, Amsler grid test and an automated 10° visual field test as definitive evidence of retinal toxicity. The Royal College of Ophthalmologists[29] and the American Academy of Ophthalmology (AAO)[30] have published guidelines for baseline, and periodic tests to be done while on therapy with chloroquine and HCQ. They recommend baseline fundus examination and no examinations for 5 years. After 5 years, high-risk patients should be followed yearly and nonhigh risk patients should be followed at every 3 years [Level II-3]. Diagnosis of early antimalarial toxicity: Methods recommended include ophthalmological examination, visual field testing, color vision testing, fluorescein angiography, and electrophysiological tests. Central field testing comprising the Amsler grid and Humphrey field test are the two most commonly used visual field testing methods.[31,32] Male patients should have a baseline color vision test performed to exclude any underlying congenital color deficiency that may otherwise be confused with toxicity.[33] [Level II-3]. Using tools such as spectral-domain ocular coherence tomography multifocal electroretinogram (mf-ERG), or fundus autofluorescence will help detect retinopathy at an early stage [Level II-3]. There is currently no gold standard for identifying ocular toxicity before its development, which has led to controversy regarding recommendations for screening patients taking HCQ. Some authors [34,35] suggest that routine screening for ocular toxicity be abandoned when recommended dosages are prescribed. Canadian Rheumatology Association,[36] Spalton [22] and Block [37] suggest screening once in 12–18 months, 3 years, and 5 years, respectively. After examining the available evidence, the AAO recently recommended different screening approaches, according to the risk status [33] [Level II-2]. In spite of differing recommendations, studies have confirmed the doctor’s willingness to continue screening for eye toxicity due to factors such as legal liability and patient safety.[38,39]

Antitubercular Drugs

Rifabutin has been associated with a characteristic hypopyon, anterior uveitis, intermediate uveitis, panuveitis, and retinal vasculitis.[40] Dosage, duration, and co-administration of drugs such as clarithromycin and ritonavir are significant risk factors through the inhibition of hepatic cytochrome P450 enzymes [Level-III]. Rifampin is intensely red and causes tears to become orange-red. Tears may permanently stain soft-contact lenses. Ethambutol: Optic neuritis is the most important potential side effect of ethambutol hydrochloride. Retrobulbar neuritis is most common, with the involvement of either axial fibers or less commonly, periaxial fibers. [41] It is an optic nerve toxin causing dose-dependent damage slowly and bilaterally, and irreversible changes. The incidence of nerve damage after 2 months of therapy is 18%, 6%, and 1% in participants receiving 35, 25, and 15 mg/kg/day of ethambutol, respectively[42] [Level II-2]. There are two types of visual defects in ethambutol-induced damage. In the central type, there is central or centrocecal scotomas and impairment of blue-yellow color vision. Peripheral type causes red-green dyschromatopsia. The mean interval between the onset of therapy and toxic effects ranges from 3 to 5 months.[43] Regular eye examination aids in the early diagnosis. Visual field typically shows a cecocentral or bitemporal defect. Dyschromatopsia may be the earliest sign of toxicity, and blue-yellow color changes are the most common color defect.[44] Isoniazid rarely causes toxic optic neuropathy and optic atrophy, particularly when given in combination with ethambutol.[45] Some authors recommend stopping both isoniazid and ethambutol in severe ocular toxicity. In less severe cases, isoniazid should also be stopped if no vision improvement occurs 6 weeks after stopping ethambutol.[46,47]

Nonsteroidal Anti inflammatory

Drugs Ibuprofen causes disturbance of color vision, xerosis, diplopia, blurring of vision and optic neuritis, and permanent visual deformities in prolonged usage.[48] Indomethacin causes whorl-like stromal opacities in 11%– 16% of patients. Corneal deposit, diplopia, mydriasis, and possible retinal damage are also reported.[4] These usually improve with discontinuation of the drug. Phenylbutazone, sulfa derivatives of nonsteroidal anti-inflammatory drugs, and acetaminophen are associated with Stevens Johnson syndrome [49] [Level-III].

Botulinum toxin

 Because botulinum toxin diffuses into levator muscles, it may cause eyelid ptosis and double vision.[50]

Bisphosphonates

It is used in postmenopausal women or as an adjunct to systemic steroids therapy to prevent the bone calcium loss. It can cause reversible orbital inflammation, uveitis, and scleritis. [51,52]

Cyclosporine and tacrolimus

They cause reversible posterior encephalopathy syndrome. These patients will present with bilateral vision loss. Magnetic resonance imaging usually confirms the diagnosis and the source of the lesion.(53)

Griseofulvin

Griseofulvin causes macular degeneration, macular edema, papilledema, pseudotumor cerebri, and photosensitivity.

Cidofovir

Intravenous Cidofovir causes anterior uveitis in 26%– 44% of patients.  

Patients are usually asymptomatic. All patients receiving cidofovir should be followed by careful eye examination. If anterior uveitis develops, withdrawal of cidofovir and treatment with topical steroids help to resolve the symptoms. Oral probenecid along with IV cidofovir delays the onset of uveitis[54] [Level II-3]. Clofazimine is a red phenazine dye used mainly in leprosy and some other dermatological disorders.[55] Clofazimine crystal deposition occurs in cornea leading to irreversible BEM and retinopathy, especially with dosages of 300 mg/day.[56] Corticosteroids Steroids are commonly used for a wide range of dermatological conditions - allergies, inflammatory conditions, postherpetic neuralgia, autoimmune conditions, vesiculobullous disorders, etc. Any route of administration - topical, oral, intramuscular, intravenous, etc., can damage the eye. The two major complications of steroid use in the eye are cataract and glaucoma.[7] Cataract is often the posterior subcapsular type. Later, the anterior subcapsular can be affected. It develops rapidly and becomes symptomatic in weeks to months. In general, patients on 10 mg prednisolone/day, treated for years do not develop cataract. Children are more susceptible and a genetic relation is also postulated to susceptibility. Once the cataract is formed, the course of the disease is not predictable. Some might resolve, whereas others may continue to progress.[16] Screening for cataracts may be performed by the slit-lamp examinations conducted three or four times a year for patients on long-term therapy and twice a year for patients taking intermittent topical ocular or systemic steroids[57] [Level II-2]. Glaucoma usually manifests when steroids are used for at least 2 weeks. They are usually asymptomatic and reversible on discontinuation. Interestingly, glaucoma is more common in patients who are steroid responders. Glaucoma is more often associated with topical ocular or periocular steroids than with systemic steroids.[58] A person with glaucoma planned for steroids therapy should consult an ophthalmologist for monitoring of eye pressure. Recommended screening includes a baseline intraocular pressure measurement, then routine pressure measurements obtained for every few weeks initially, and then every few months.[59]

Interferons

Interferon-α is a recombinant DNA-based protein. Toxicity is due to the deposition of immune complexes in the vessels and activated complement C5a with infiltration of leukocytes.[60] Interferon causes the retinal damage anywhere from 2 weeks to 3 months after starting. Changes include cotton-wool spots, intra-retinal, preretinal hemorrhage, and macular edema finally leading to retinopathy. Other manifestations include central retinal artery and vein occlusion, cystoid macular edema, and optic disc edema leading to irreversible vision loss. They are more common in patients with diabetes and hypertension. The damage is asymptomatic, dose-independent and self-limiting with cessation of the drug.[61,62]

Isotretinoin

It is known to cause dryness of mucous membranes including the eye. Other ocular side effects include meibomian gland dysfunction, blepharoconjunctivitis, corneal opacities, decreased dark adaptation, keratitis, photophobia, teratogenic ocular abnormalities, and disturbances in the night vision. The dryness and irritation can cause difficulty in wearing the contact lenses.[63] Visual disturbances may also occur as a part of pseudotumor cerebri.[4] Dermatologists should always ask patients about any vision symptoms before and during isotretinoin therapy and refer to ophthalmologist, if any complain. Another warning to be given is that it precludes them from having refractive surgery such as laser-assisted in situ keratomileusis. A meta-analytic study of reported adverse events due to isotretinoin grouped the adverse ocular events to isotretinoin into three as follows:

1. “Certain” includes abnormal meibomian gland secretion, blepharoconjunctivitis, corneal opacities, decreased dark adaptation, decreased tolerance to contact lens, decreased vision, increased tear osmolarity, keratitis, meibomian gland atrophy, myopia, ocular discomfort, ocular sicca, photophobia, and teratogenic ocular abnormalities
2. “Probable/Likely” are decreased color vision and permanent loss of dark adaptation and
3. “Possible” association includes permanent keratoconjunctivitis sicca. Guidelines for ocular examination for patients on isotretinoin are available[63] [Level-I].

Tricyclic antidepressants

They decrease tears, leading to dry eye problem, pupillary dilatation, a decrease in focusing ability (accommodation), and worsen acute closed‑angle glaucoma. Gonioscopy examination helps in the early diagnosis.[64-66]

Antihistamines

Antihitamines in people with narrow-angle glaucoma result in blurred vision, redness, halos around light objects, and pain. Other ocular side effects include mydriasis (pupil dilation), dry eye, keratitis sicca, contact lens intolerance, decreased accommodation (focusing ability), etc. Antihistamines have weak atropine-like action, can cause mydriasis, anisocoria, decreased accommodation, and blurred vision.[4]

Birth control pill

Birth control pills can lead to dry eye syndrome, photosensitivity, and rarely cataracts, macular

degeneration, and retinal vascular problems.[67]

Phosphodiesterase type 5 inhibitors

Phosphodiesterase type 5 inhibitors include sildenafil, vardenafil, and tadalafil. They inhibit cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE 5), increasing the effect of nitric oxide which is responsible for the degradation of cGMP in the corpus cavernosum. Increased levels of cGMP result in smooth muscle relaxation and inflow of blood. These drugs have an affinity for PDE 6 enzyme found in the retina. Ocular side effects occur in 3%, 10%, and 50% of individuals taking 50 mg, 100 mg, and 200 mg doses, respectively [Level II-2]. The side effect starts 15–30 min after ingestion of the drug and peaks in 60 min. They include pupillary dilation, redness, dryness, blurred vision, and a temporary bluish discoloration to the vision. Caution is required in individuals with retinitis pigmentosa, macular degeneration, and diabetic retinopathy[68] [Level‑III]. Some patients, who have genetic disorders of retinal PDE, have been associated with nonarteritic ischemic optic neuropathy, leading to permanent vision loss. All patients had a low cuptodisk ratio. “Disks at risk”

are full disks with little to no cupping.[69] The Federal Aviation Administration has recommended that pilots not to fly within 6 h of taking the drug.[70]

Psoralen

Psoralens and psoralen‑ultraviolet A (PUVA) are used in a wide range of dermatologic disorders commonly vitiligo and psoriasis. Adequate eye protection from sun is always advised to prevent the eye damage.[71] Dermatologists who employ PUVA treatment should be concerned about photo keratoconjunctivitis and the dry eye syndrome.[72] Guidelines should be strictly adhered to[73] [Level-III].

Biologics

Biologics are a new class of drugs with target specific action used as an alternative to conventional immunosuppressives and immunomodulators. They are used commonly in conditions such as psoriasis,

Table 3: Warning symptoms patient should be asked

to report with Redness, itching, swelling, pain in the eye Watery, purulent discharge in the eyes

Dry eyes

Foreign body sensation

Visual glare, blurring, or double vision Trouble with night vision/reading Sensitivity to the light exposure

Table 4: Determinants of drug reactions Cumulative dose of the drug Route of administration Preexisting genetic/medical illnesses Pharmacologic properties of the drug Age and gender Drug-drug interactions

History of allergies to drugs Idiosyncras

pemphigus and related disorders, collagen vascular disorders, and extensive alopecia areata. Common drugs are alefacept, adalimumab, etanercept, infliximab, etc. Limited use of these drugs still has limited the expression of many side effects. Optic neuritis, which is an inflammatory demyelination of the optic nerve, has been observed in patients on etanercept, infliximab, and adalimumab. Dermatologists should monitor for the early symptoms which include periocular pain and unilateral loss of visual acuity.[74] Etanercept is reported to cause orbital myositis, rituximab causing optic neuritis and uveitis, and secukinumab causing conjunctivitis are reported.[75]

Role of dermatologist to limit eye side effects

Dermatologists need to be aware of ocular side effects potentially posed by certain common medications. Before starting on high‑risk medications, they should ask about a history of glaucoma, cataract, or any other issues. While starting medications patients should be encouraged to report, if they notice any of the complaints as given in Table 3. Also they need to be cautious about the various factors that determine the damage to the eye [Table 4]. Correct diagnosis, using principles of rational prescription for a dermatologist goes a long way in minimizing the damage to the eye and thus saving the patient of a potential critical toxicity – blindness.[76] Furthermore, prompt reporting of new adverse drug reactions will enhance our knowledge and effectively treat the patient.[77]

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