Retinal Toxicity of Systemic Medications

Leanne T. Labriola, DO David Jeng, MD Amani A. Fawzi, MD

Introduction

Similar to the brain with its blood-brain barrier, the retina is somewhat protected from systemic chemicals by virtue of the inner and outer blood-retina barrier formed by the tight junctions between retina endothelial cells and retina pigment epithelium cells, respectively. This chapter will provide a comprehensive review of systemic medications that affect the retina.

Retinal Pigment Epithelial (RPE) Toxicities

Quinones: Hydroxychloroquine and Chloroquine

Hydroxychloroquine Hydroxychloroquine is a chloroquine derivative used in the past for malaria prophylaxis, but currently is more commonly used to treat autoimmune diseases, particularly systemic lupus erythematosis and rheumatoid arthritis because of its ability to suppress cytokine cell signaling and lymphocyte proliferation.1 At the recommended dose of 6.5 mg/kg/d for an average of 8.7 years, retina toxicity develops in 0.05% of patients.1 The risk increases to 1% in some reports with >5 years use or a cumulative dose >1000 g.1,2 In order to decrease the incidence of toxicity, the American Academy of Ophthalmology developed new dosing guidelines and high-risk characteristics including short stature, morbid obesity, elderly patients, and patients with renal, hepatic, or other retinal disease. Short stature patients can still be dosed as 6.5 mg/kg based on ideal body weight. In contrast, obese patients should be dosed based on height to more accurately estimate
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ideal body weight and avoid overdosing from using actual weight.2 Lower doses should be used in elderly patients or those with renal and liver disease because of the limited drug clearance. Lastly, preexisting evidence of maculopathy is a contraindication to treatment with hydroxychloroquine because underlying abnormalities will mask early toxicity; therefore, these patients should try alternative therapy.2 Every patient prescribed hydroxychloroquine should have an eye exam before initiation of therapy and annual exams after 5 years of treatment.2 The earliest visual change is a paracentral scotoma, and may be associated with subtle RPE stippling with loss of the foveal light reex on fundus exam.3 Later changes result in decreased visual acuity or altered color perception when RPE changes involve the fovea in a bulls-eye pattern of RPE disturbance characterized by rings of hyperpigmentation interspersed with hypopigmentation. In more advanced toxicity, the peripheral retina may be affected with RPE proliferation, vascular attenuation, and optic disc atrophy simulating rod-cone dystrophy.3 The new guidelines suggest the use of ancillary screening tests, including fundus photos and Humphrey visual eld (HVF) 10-2 with white target at baseline with repeat HVF tests at follow-up visits. The HVF 10-2 should be scrutinized for even subtle changes and any change should be conrmed on repeated testing. In mild cases of toxicity with normal fundoscopy, spectral-domain optical coherence tomography (OCT) can reveal evidence of early disruption of the parafoveal inner segment-outer segment (IS-OS) junction with thinning of the outer nuclear layer. In late stages, there is complete loss of the IS-OS junction throughout the fovea (Fig. 1).4 Fundus autouorescence can highlight mild increased autouorescence in a pericentral ring around the fovea, followed by a complete loss of autouorescence in severe cases indicating RPE cell death (Figs. 23).4 Color or Amsler grid assessments have low specicities for distinguishing retinal toxicity due to hydroxychloroquine from other causes of maculopathy and should not be used for screening.2 In addition, uorescein angiography can miss early disease. Multifocal electroretinography focuses on macular dysfunction and can

Figure 1. A spectral-domain optical coherence tomography image (OCT) of a patient with retinal toxicity from hydroxychloroquine use, which shows disruption of the inner segments/outer segment junction of the photoreceptor layer as well as atrophy of the retinal pigment epithelium identied by the presence of increased transmission of the OCT signal in the parafoveal area, consistent with late toxicity.
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Figure 2. An autouorescence (AF) image of the (A) right eye and (B) left eye of a patient with hydroxychloroquine toxicity, which shows early changes of pathological hyperautouorescence in the fovea on blue-light AF and stippling of the retinal pigment epithelium in the parafoveal area.

be an extremely useful objective measurement of this toxicity with abnormalities detected in 50% of patients with cumulative doses of >1250 mg.5 The most common defects are pericentral loss of amplitude and delayed implicit time.6 In contrast to multifocal electroretinography, full-eld electroretinography (ERG) evaluates the function of the entire retina and will only show abnormal results in advanced toxicity, when changes extend beyond the macula. Patients suspected of early toxicity should be followed every 3 months with additional testing in order to conrm toxicity. There are no treatments for this irreversible macular toxicity so early detection of

Figure 3. A blue-light autouorescence image of a patient with hydroxychloroquine toxicity, which shows later changes of toxicity with the classic bulls-eye macular appearance from concentric rings of retinal pigment epithelial cell loss. (A) right eye, (B) left eye.
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retinopathy is essential, and immediate cessation of therapy is suggested as long as it is medically safe from the internists standpoint. Unfortunately, because of the extended half-life of this medication, retinopathy may continue to progress, with reports of damage occurring 5 years after stopping the medication and evidence of the medication in RPE cells up to 7 years after cessation.7 Chloroquine Chloroquine is similar to hydroxychloroquine. It is a lipophilic medication with a high volume of distribution, which may contribute to the side effects that have been reported. Most cases of RPE toxicity developed at high doses exceeding 3 mg/kg of ideal body weight over a long period of time with a total cumulative dose of around 460 mg.2 Most cases occur when patients use >250 mg/d for a period of at least 1 year.8 Management and screening is similar to patients on hydroxychloroquine (see the above section for details).
Phenothiazines: Thioridazine, Chlorpromazine

Thioridazine Thioridazine is an antipsychotic medication used to treat anxiety disorders from alcohol withdrawal or epileptic patients with dysphoria as well as multidrug resistant Mycobacterium tuberculosis. This medication has life-threatening side effects such neuroleptic malignant syndrome, which mandates careful monitoring by an internist. In addition to the systemic side effects, this medication can cause retinal and optic nerve atrophy with permanent vision loss; which may develop within 2 weeks of therapy, if high daily doses are used.9 Fortunately, retinopathy is rare with doses <800 mg/d, although cumulative longterm use of low doses may lead to retinal changes as well.10 Toxicity may present with a sudden decrease in visual acuity, dyschromatopsia (difculty distinguishing red and brown colors), and nyctalopia.11 Early on, fundus exam may be normal or may show subtle pigment stippling in a salt-and-pepper pattern and there may be retinal edema and disc hyperemia.12 More advanced changes include wellcircumscribed nummular areas of RPE and choriocapillaris atrophy in the posterior pole and the midperiphery.13 Further progression may lead to complete atrophy with alternating areas of hypopigmentation and hyperpigmentation and vascular attenuation with optic atrophy.14 Ancillary testing can help to monitor patients as evidenced by mild constriction or paracentral scotomas on HVF or decreased oscillatory potentials with later rod and cone dysfunction on ERG.11 Early discontinuation of the medication can improve visual function and improve ERG recordings.15 However, advanced toxicity can cause a progressive retinopathy even after cessation of the medication. This medication needs to be discontinued slowly with internist consultation, as an abrupt stop in use can lead to withdraw symptoms.
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Chlorpromazine Chlorpromazine is another phenothiazine used as an antipsychotic that lacks the protective piperidyl side chain and can lead to retinal toxicity.12 Doses can range from 40 to 800 mg/d. Although toxicity is rare, patients will be symptomatic and should be monitored with fundus examinations for RPE changes, retinal vessel attenuation, and optic nerve pallor, especially in patients on extremely high doses of the medication.12
Iron Chelators: Deferoxamine, Deferasirox

Deferoxamine Deferoxamine is administered through intravenous or subcutaneous route to chelate iron overload, in patients who require frequent blood transfusions, such as in sickle cell anemia or other blood dyscrasias. High-dose treatment with deferoxamine can cause peripheral or central visual eld loss, nyctalopia, and abnormal color vision. Early fundoscopic changes may reveal a dull gray hue of the macula. Vitelliform lesions may develop within several weeks in the posterior pole, as well as pigmentary changes in the macula and periphery. Fluorescein angiography can reveal early toxicity as diffuse RPE hyperuorescence.16 ERG demonstrates a diminished darkadapted ERG and decrease in rod photoreceptor and postreceptor sensitivity on full-eld ERG.17,18 Visual function generally improves with discontinuation of the medication. However, toxicity may be permanent and can occur after a single dose.18 Deferasirox A related medication, deferasirox (or ExJade), is a rationally designed iron chelator in oral formulation that has also been reported to lead a subtle maculopathy. In a case report, fundus exam ndings, uorescein angiography, and full-eld ERG were unremarkable; however, visual eld showed central scotomata and spectraldomain OCT demonstrated outer retinal thinning in the perifoveal area with disruption of the IS-OS junction bilaterally (Fig. 4). Cessation of the medication allowed some improvement in visual elds, but the OCT ndings were not reversible.19
HAART Medications: Didanosine, Ritonavir, Rifabutin, and Cidofovir

Didanosine Didanosine, or 20 ,30 -dideoxyinosine, a reverse transcriptase inhibitor used to treat HIV, can produce a pigmentary retinopathy and optic neuritis.20 Whitcup et al21 studied the retinal toxicity of this drug in 43 children affected with HIV in a Phase I-II prospective study with a mean follow-up of 71 weeks. In this study, 3 subjects developed a peripheral RPE atrophy. Two of these subjects were taking the highest dose of didanosine (540 mg/m2/d). A later report
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Figure 4. Spectral-domain optical coherence tomography with 3 images taken through the fovea (A-C) of a patient with deferasirox toxicity demonstrating outer retinal thinning in the nasal perifoveal area with disruption of the inner segment-outer segment junction. These changes were bilateral and corresponded with visual eld scotoma.

demonstrated peripheral retinopathy in adult patients on this medication.22 Fundus ndings include midperipheral retinal atrophy with surrounding RPE hypertrophy and hyperpigmentation.20 The retinopathy can be associated with rod and cone dysfunction on ERG as well as electrooculogram abnormalities. Once retinopathy is diagnosed, the medication should be stopped as soon as safely possible. Cessation of the medication can lead to a substantial improvement in objective testing, suggesting that macular function can be salvaged; however, the peripheral atrophy is irreversible.20 Ritonavir Recently, ritonavir, an antiretroviral also used in the treatment of HIV, was linked to 3 cases of retinal pigment epitheliopathy with parafoveal telangectasis and intraretinal crystal deposits without ocular evidence of cytomegalovirus infection or immune recovery uveitis. Two of the patients had evidence of parafoveal telangectasias on uorescein angiography. OCT ndings indicated retinal thickening with inner retinal cysts in all 3 patients. One patient had fundus
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autouorescence evidence of well-dened perifoveal areas of RPE loss. These ndings were attributed to ritonavir use. The duration of treatment ranged from 19 months to 5 years.23 Rifabutin Rifabutin is an antibiotic used in the treatment of mycobacterial infections and has been associated with uveitis. Patients who developed uveitis were on 300 to 450 mg/d.24 Low doses of rifabutin were not associated with uveitis; however, there may be signicant drug interactions between this drug and other systemic medications that increase its toxicity.25 Most commonly patients present with anterior uveitis, but vitritis and retinal vasculitis have been reported as well.25 Interestingly, initial reports of this medication, showed no ocular side effects in 292 patients on 300 mg of rifabutin. Cidofovir Cidofovir can cause severe vision loss, photophobia, and redness from an iridocyclitis associated with ocular hypotony26; other ocular ndings can include panuveitis and retinal detachment. Management of ocular inammation from these medications can include topical, periocular, or oral steroids. Continuation of the medication may be medically necessary if the inammation and intraocular pressure can be controlled, but in severe cases cessation of the offending medication may be necessary to control the inammation.26 Patients who developed iritis were more likely to have previous infection with cytomegalovirus or to be on protease inhibitors.26
Clofazimine

Clofazimine is used for treatment of mycobacterium avium complex infections in AIDS patients. Few reports have documented a bulls-eye maculopathy in AIDS patients using doses between 200 and 300 mg/d.27 Visual acuity was only mildly affected and ERG abnormalities included diminished scotopic, photopic, and icker amplitudes. The retinopathy was permanent even after discontinuation of the medication.27

Retinal Crystalline Deposits

Tamoxifen

Tamoxifen is an antiestrogen medication with mixed agonist/ antagonist affects on the estrogen receptor. It is commonly used in the treatment of estrogen receptor-positive breast cancer in premenopausal women. Crystalline retinopathy is more frequently seen in patients who start on higher initial doses (>60 mg/d). However, current therapy is generally low dose (10 to 20 mg/d) and toxicity is rare. Reports have documented incidence of tamoxifen retinopathy at 0.9%28 and
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prevalence as low at 3.1%.29 The cause of toxicity is unknown, but theories have suggested an impairment in glutamate transporters, leading to accumulation of glutamate and cell toxicity and axonal degeneration.30 Most patients are asymptomatic, but a few case reports have documented a decrease in vision.31 The fundus shows bilateral white refractile crystals located in the inner retina of the macula and punctate gray lesions located in the outer retina and RPE.30 Fluorescein angiography reveals hyperuorescence of the lesions with late staining. Fluorescein images can be helpful in differentiating from other disease similar to tamoxifen retinopathy, such as idiopathic parafoval telangiectasia, the latter revealing telangiectatic vessels on imaging. Previously, it was thought that tamoxifen maculopathy caused cystoid macular edema (CME), but careful analysis of OCT in these patients has revealed outer cavitary lesions or atrophy of the photoreceptor layer rather than typical CME of the inner retina.30 ERG changes include decreased photopic and scotopic a-wave and b-wave, whereas other reports have described normal ERGs in the presence of retinal crystals from tamoxifen use. Recommending cessation of the medication for evidence of ocular toxicity should be done only if visual function is affected and only after careful discussion with the patient and oncologist. The presence of crystals alone, without vision loss may not be an indication for discontinuing the medication.
Canthaxanthine

Large doses of canthaxanthine, an over-the-counter oral tanning agent used medically for treatment of vitiligo as well as protoporphyria, psoriasis, and photosensitive eczema, can cause a dose-related crystalline retinopathy affecting 100% of patients on 60 g of canthaxanthin and only 50% of subjects on 37 g of the medication.29 Reports suggest that a cumulative dose over 19 g is required for the deposition of crystals and concurrent use of b-carotene can exacerbate the retinopathy.29 Patients with the crystalline deposits have very few visual symptoms. Fundus changes include highly refractile, yellow-orange deposits, 30 mm in size that form a ring-like pattern in the macula. The crystals are typically found perifoveally or in a ring-like conguration around the fovea. Although crystals are rarely located anterior to the equator, they may extend as far out as the ora serrata.32 Mass spectrometry of the crystals conrmed that they are canthaxanthine molecules that are birefringent, lipid-soluble, and most likely bound to a lipoprotein molecule.32 Toxicity can result in higher threshold levels on HVF and decreased retinal sensitivity as well as increase in rod threshold at very early stage or later stages on the ERG.29,31 Discontinuation of the medication may
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allow the threshold HVF testing to return to normal as these deposits clear slowly over years.31
Methoxyurane

Methoxyurane, a uorinated hydrocarbon used as an inhalational anesthetic, can cause calcium oxalate crystals to accumulate within various tissues in the body including the retina, kidney, thyroid and epicaridium and bronchi.33 Methoxyurane is not used in clinical practice in the United States because of its nephrotoxicity; however, it is still used in Australia for emergency medical therapeutic procedures.34 Patients can be asymptomatic. Careful ocular examination reveals retinal deposits similar to a eck retinopathy, with numerous yellowwhite punctate deposits. The retina crystals are located in the RPE. Calcium oxalate crystals generally aggregate in the posterior pole, often surrounding the arteries.
Talc

Talc is composed of hydrous magnesium silicate and is frequently used as an inert lling compound in several oral medications, including methylphenidate (Ritalin) and methadone. If oral pills with talcum powder are crushed and injected intravenously, the talc can cause vascular emboli and irreversible ischemic retinopathy. Patient may present with visual symptoms of decrease vision or scotoma. Ocular ndings from the talc emboli include crystalline retinopathy, ischemic retinopathy, microaneurysms, cotton-wool spots, arteriovenous anastomosis, neovascularization of the disc or in the periphery, and vitreous hemorrhage.35 The crystalline retinopathy is associated with tiny glistening talc compounds that occlude the small arterioles. Fluorescein angiography can show nonperfusion of small arterioles and macular capillaries.36 Full-eld ERG and color vision testing can be normal; however, focal ERG can be abnormal.36 Treatment of subsequent neovascularization can include laser, and vitreous hemorrhage may warrant vitrectomy. Education of the patient is essential for the management of this disease. They should be counseled on risk of embolic side effects associated with further use. If active intravenous injection of talc powder is occurring, the patient needs to be monitored for new emboli and their ischemic sequelae.
Nitrofurantoin

Nitrofurantoin is an antibiotic commonly used to treat urinary tract infections. It can affect the microvasculature and can cause lung and kidney as well as ocular toxicity. Two patients with ocular disease
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associated with nitrofurantoin have been reported. The rst case was a 10-year-old patient who developed ptosis and diplopia and was diagnosed with ocular myasthenia gravis induced by nitrofurantoin. Symptoms resolved when the medication was stopped.37 The second case was a 69-year-old male on nitrofurantoin chronically for 19 years who developed gradual vision loss of 5 months. The retina ndings were described as inner crystalline deposits throughout the posterior pole. There were no abnormalities on objective testing including HVF and ERG. The patients vision improved after cessation of the medication.37,38

Vasculopathy: Aminoglycosides, Interferon, Estrogen, and Progesterone and Chemotherapeutics

Aminoglycosides: Gentamicin, Netilmicin, Tobramycin, Amikacin, and Kanamycin

Intravitreal administration of aminoglycosides has been shown to be toxic to the retina. The most toxic aminoglycoside is gentamicin, followed by netilmicin and tobramycin, with the least toxic being amikacin and kanamycin.39 High intravitreal doses of any of these medications can lead to irreversible retinal damage. Lower doses of the least toxic aminoglycosides, such as amikacin, can be used effectively in treatment of bacterial endophthalmitis, but even low doses of amikacin (0.2 to 0.4 mg) have been reported to cause retinal damage, so their use should be moderated.39 The more toxic medications, such as gentamicin, should never be used intravitreally. Toxicity can also be seen after subconjunctival injection.36 The use of aminoglycosides as prophylactic periocular injections or intravitreal endophthalmitis treatment has largely been abandoned with the availability of new generation antibiotics providing improved coverage against Gram-negative bacteria. Patients with retinal damage can present with severe vision loss. Clinical exam ndings include intraretinal hemorrhages, retinal edema, cotton-wool spots, attenuation of arterioles, venous beading, and macular infarction.40 Fluorescein angiography in acute toxicity shows peripheral retinal nonperfusion, which can lead to neovascularization of the iris, neovascular glaucoma, and optic atrophy. Retinal toxicity can cause decreased b-wave ERG amplitudes.39 In severe cases of gentamicin toxicity the b-wave ERG signal can be completely abolished, which correlates to the histopathologic evidence of total destruction of the inner retina and disruption of the nerve ber layer and inner plexiform layer.39 Unfortunately, there is no proven treatment for this severe toxicity, so gentamicin should not be given intravitreally, and only low doses of amikacin should be used if necessary.
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Gancyclovir

Gancyclovir is another medication used intravitreally in treatment of viral retinitis, which can cause a dose-dependent toxicity. Repeat dosing or dosing errors of this medication have caused severe damage to the outer retina. Animal models have shown decrease in ERG function with toxicity. Once damage has occurred, no treatment is available.39
Interferon

Interferon-a 2a and 2b are cytokines used as therapies for certain viral infections, such as hepatitis B and C, as well as medical diseases such as multiple sclerosis and cancers. Patients should have baseline ophthalmic evaluation including fundoscopic exam prior to the initiation of interferon therapy. Patients should then be seen 3 months after starting interferon therapy to check for initial retinopathy. Fundus changes usually occur within the rst 4 to 8 weeks of treatment and are more frequently seen in patients with preexisting microvascular disease, such as in diabetes and hypertension. Patients are often asymptomatic, despite prominent retinal ndings including intraretinal hemorrhages and cotton-wool spots, which can range from mild to severe. These ndings can spontaneously resolve even without adjusting the medication level. However, the cotton-wool spots can leave behind focal defects in the retinal nerve ber layer detected on OCT.41 Although most objective tests of visual function are normal, there is 1 report of temporary electrooculogram changes in a patient with decreased vision while on interferon and ribavirin for hepatitis C, which may implicate a temporary pathology of the RPE cells.41 Screening includes a pretreatment fundoscopic exam with repeat exam 3 months after initiation of interferon. Patients with retinal changes should be carefully monitored for signicant visual changes or worsening of retinopathy. Therapy can be adjusted or suspended if severe vision change or retinopathy develops; however, as permanent vision decit is rare on interferon, most patients can be monitored.
Estrogen and Progesterone

Oral contraceptives have been implicated in retinopathy due to vascular occlusion from an induced hypercoagulable state. However, retinal vein occlusions associated with these medications are more common with older formulations that are no longer in use.42
Chemotherapeutics

Cisplatin and carmustine (BCNU) are 2 alkylating agents used to treat cancer. When these drugs are given by intracarotid infusion, retinal
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toxicity can develop, which may lead to permanent vision loss secondary to retinal arterial occlusive vasculitis. There have also been case reports of pigmentary retinopathy and optic atrophy.43

Macular/Retinal Edema
Epinephrine

Topical epinephrine and its prodrug dipivefrin, previously used in treatment of glaucoma, can cause a temporary CME in aphakic or pseudophakic eyes that can resolve with cessation of the medication.44 If cystic changes are large, patients can be symptomatic. Use of SD-OCT can delineate the cystoid changes. If disc hyperuorescence is present on FA the inammatory cause for the CME should be considered. With improved glaucoma therapies, the use of epinephrine and dipivefrin has decreased.
Niacin

Niacin therapy has been used to decrease serum cholesterol levels. It has been reported that at high doses (>1.5 g/d) some patients develop decreased central vision with a paracentral scotoma or metamorphopsia.45 As opposed to classic CME, uorescein angiography does not demonstrate leakage. It has been suggested that Muller cells may be affected, leading to intracellular uid retention, rather than extracellular edema. Symptoms improve with resolution of the cystoid changes after medication is discontinued.46 However, if left untreated, chronic CME can lead to permanent vision loss and retinal atrophy.
Latanprost

The recent emergence of prostaglandin analogs in the treatment of glaucoma can be complicated by CME as a side effect. The risk of CME appears to increase with the presence of other factors that may cause macular edema, such as diabetes or vitreous loss during cataract surgery.47 The cystoid changes resolve with discontinuation of the medication.
Methanol

Methanol, a toxic alcohol, may lead to decreased central and/or peripheral vision with the ingestion of as little as 10 mL. Within 18 hours of ingestion, there may be retinal and optic disc edema. With time, the optic nerve appears atrophic. Damage to the optic nerve is mediated by formic acid, a direct byproduct of methanol. Hemodialysis may be effective in removing methanol from the body. If vision does not improve after 6 days, it is unlikely to recover.48
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Thiazolidinediones: Rosiglitazone, Pioglitazone

Thiazolidinediones are a class of oral antihyperglycemic medications, including rosiglitazone and pioglitazone, that have been associated with congestive heart failure, pulmonary edema, and peripheral edema as well as macular edema. The systemic complications are dose dependent and occur more often in patients with renal insufciency. A large, prospective cohort study has shown that use of this medication class can be associated with macular edema with an odds ratio of 1.6.49 It is advised to consider discontinuation or substitution of this medication in diabetic patients who develop macular edema.

Visual Disturbances
Retinoids: Vitamin A, Isotretinoin, Etretinate, and Retinoin

Isotretinoin is a topical medication used for severe nodular acne and psoriasis as well as to induce remission of leukemia.50 The most common visual side effect is transient and permanent loss of dark adaptation, or night vision, which resolves in the majority of patients following discontinuation of the medication.50 The mechanism of action involves slowing rhodopsin regeneration and chromophore recycling by inhibition of 11-cis retinol dehydrogenase.51
Cardiac Glycosides: Digitalis

Digitalis is used in the treatment of congestive heart failure. It can cause ocular and renal toxicity. The most common ocular complaint is xanthopsia, or yellow vision, but blurred vision and photopsias have also been reported. Fundus exam is usually normal. Full-eld ERG can show depressed cone function.52 If visual symptoms occur, doses should be reduced. After discontinuation of these medications, vision and ERG normalize.
Erectile Dysfunction Medications: Sildenal, Vardenal, Tadalal

Sildenal and related medications inhibit phosphodiesterase type 5, which increases cyclic guanosine monophosphate in smooth muscle.50 Patients on these medication may report a change in color vision, perception of light or brightness, blurred vision, or photopsias, most commonly 60 minutes after ingestion. Vision changes are correlated to serum concentrations of the medication with symptoms in 40% to 50% of patients taking 200 mg of Sildenal, but only 3% of patients taking <50 mg.53 Symptoms can occur without evidence of ocular disease on exam and are usually transient; however, there are unconrmed reports
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of nonischemic anterior optic neuropathy associated with this medication. The general recommendation is that patients with prior history of nonischemic anterior optic neuropathy should not take this class of medications.50
Vigabatrin

Vigabatrin is an antiepileptic agent that inhibits GABA catabolism by blocking GABA transaminase. Its main ocular side effect is bilateral visual eld defects estimated in 40% to 50% of patients.50 Generally, visual acuity is spared, unless the visual eld defect encroaches centrally. Nasal thinning of the retinal nerve ber layer with temporal preservation is diagnostic of Vigabatrin toxicity and can help in monitoring progression. The visual eld loss is often not associated with any optic nerve or retinal abnormalities on fundoscopy, although there have been reports of peripheral RPE changes, narrowing of vessels, and optic nerve pallor.50 Animal testing showed that rabbits with serum levels detectable for vigabatrin had normal rod ERGs in all rabbits and depressed cone ERGs in 2 of the 5 rabbits. There were also histopathological changes noted in treated animals.54
Quinine

Quinine was used for over 300 years as the rst effective treatment for malaria, but has now been largely replaced by newer agents. Although it also has been used to treat autoimmune diseases, today this medication has limited use in that area. Quinine can also be found in tonic water and can lead to toxicity in patients who consume large quantities of tonic water. Although quinine does not produce pigmentary retinopathy, it causes an interesting retinal toxicity. Acute overdose of quinine with ingestion of over 4 g (normal dose 2 g) may lead to a syndrome called cinchonism, with systemic symptoms including headache, nausea, vomiting, tremor, hypotension, loss of consciousness, and even death. Often, patients diagnosed with cinchonism may report total blindness with dilated, nonreactive pupils. Vision loss may partially recover, but most cases are left with only a small central island of remaining vision on automated visual eld testing.15,55 Fundus ndings during the acute phase may include mild retinal edema, mild venous dilation, and normal-appearing arteries. The arterioles become attenuated and optic atrophy sets in a few weeks after the acute overdose. The nal fundus appearance is similar to a central retinal artery occlusion.55,56 ERG performed in the acute phase demonstrates slowing of the a-wave with increased depth, loss of oscillatory potentials, and decreased b-wave, leading to a negative waveform. The ERG will eventually normalize, but then revert to a slow reduction in the b-wave.
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Retinal Folds
Sulfa Medications: Diamox, Hydrochlorothiazide

Sulfa medications, including Diamox, sulfa antibiotics, and hydrochlorothiazide have been described to cause anterior displacement of the lens-iris diaphragm either through ciliary body edema or choroidal effusions. This shift induces axial myopia, anterior chamber shallowing with narrow angles, and retinal folds. Fluorescein angiography does not demonstrate leakage. Cessation of the medication relieves the anterior lens-iris diaphragm shift, and the retinal folds resolve without visual sequelae.

Photoreceptor Damage
Alkyl Nitrite

Volatile nitric oxide donors formed from alkyl nitrate can be used for recreational drug use and are known as poppers and can cause retinal toxicity. Patients can report decrease in vision. Fundus examinations of patients admitting to popper abuse have shown small bilateral, yellow, circular, foveal lesions. High-resolution OCT showed subfoveal disruption in the photoreceptor layer.57 Full-eld ERG was normal. The mechanism of retinal toxicity is unknown. Unfortunately, vision loss from photoreceptor damage was permanent in the few reported cases.57

Summary

Physicians should be aware of the potential adverse effects of drugs upon the retina. The retinal exam along with appropriate ancillary testing can be instrumental in identifying early evidence of toxicity. Early recognition and proper management are critical for prevention of vision loss.

The authors declare that they have no conicts of interest to disclose.

References

1. Mavrikakis I, Skakis PP, Mavrikakis E, et al. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal. Ophthalmology. 2003;110:13211326. 2. Marmor MF, Kellner U, Lai TY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 2011;118:415422.
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