Systemic medications are often associated with various adverse side effects that affect multiple organs, including the eyes and the retina.
This article will review potential ocular findings of toxicity, what precautions and examinations should be taken to monitor for these effects, and how to manage the complications.
Retinal toxicity caused by systemic medications
Rheumatology drugs
Hydroxychloroquine (Plaquenil) and chloroquine
Hydroxychloroquine (Plaquenil) and chloroquine are medications commonly used to treat malaria and some rheumatologic diseases, such as systemic lupus erythematosus. Patients taking higher or lower doses over long periods of time are at risk of developing retinopathy.1,2 It classically affects the parafoveal and perifoveal regions of the retinal pigment epithelium (RPE), which manifests as bull’s-eye maculopathy.2
According to the American College of Rheumatology (ACR), American Academy of Dermatology (AAD), Rheumatologic Dermatology Society (RDS), and American Academy of Ophthalmology (AAO) 2020 Joint Statement on Hydroxychloroquine Use, daily dosages of ≤5mg/kg/day have a risk of retinal toxicity that is less than 2% for up to 10 years.3 Chloroquine, the more lipophilic drug in this class, has demonstrated lower toxicities at <3mg/kg over long periods with a cumulative dose of around 460mg.4
The risk of developing retinopathy is correlated with higher dosage per body weight and cumulative dosage.3 Both hydroxychloroquine and chloroquine are renal excretion drugs, so patients with impaired renal function are at increased risk of developing retinopathy.3
It is recommended that baseline retinal testing be done before or within a few months of starting medication. The first screening tests are ideally done 1 year after starting but can be postponed to as late as 5 years after starting and repeated annually after that.3
The gold standard for early detection is optical coherence tomography (OCT) imaging of the macula.3 Other exams, such as fundus photography (FP) and 10-2 visual field (VF) testing, can also be done to detect early retinal toxicity. When toxic retinopathy secondary to hydroxychloroquine occurs, it is irreversible, and the medication should be stopped immediately to halt further progression.
Retinal toxicity caused by urology drugs
Pentosan polysulfate sodium (PPS, Elmiron)
PPS is used for symptomatic management of interstitial cystitis. In recent years, there have been reports of progressive, dose-dependent pigmentary maculopathy in patients with chronic PPS use.5 Symptoms include prolonged dark adaptation, nyctalopia, blurred vision, metamorphopsia, and paracentral scotomas.1,5 The risk of developing this maculopathy increases with increased cumulative dosage.1,5
Early examinations may reveal yellowish subretinal deposits and hyperpigmented macular spots best seen on fundus autofluorescence (AF) imaging.5 OCT and near-infrared reflectance imaging (NIR) can also show hyperreflective nodules in the RPE that correlate to the pigmented spots in FAF. Late-stage complications include chronic macular edema, macular choroidal neovascularization, vitelliform maculopathy, RPE atrophy, and outer retinal atrophy.1,5
It is recommended that patients get a baseline fundoscopic examination with AF, OCT, and NIR before starting PPS and annual follow-up examinations, as toxicity is expected to develop within 2 years or at around 500g cumulative dose.1,5 Patients are encouraged to stop medication once signs of toxicity begin. However, progression of retinopathy is often seen after cessation.1
Oncology drugs and retinal toxicity
There are several drugs used in the treatment of cancer that are responsible for adverse ocular findings.
MEK inhibitors: Trametinib, cobimetinib, and binimetinib
Mitogen-activated protein kinase kinase (MEK) inhibitors are chemotherapeutic agents used to treat some cancers. Its toxicity most commonly causes the development of fluid foci within the retina that are bilateral multifocal, with at least one concentrate, including the fovea.6
Most patients experienced mild visual defects, with no statistical difference in corrected visual acuity, no loss of more than two Snellen lines from baseline, and no irreversible vision changes or eye damage.6,7 Some of these side effects are reported to be self-limiting with continuous use and self-resolving after discontinuing.7
OCT imaging is the optimal way of seeing the extent and characterization of the fluid foci and can help distinguish between central serous chorioretinopathy.1 The four morphologies characterized in MEK inhibitor-induced retinopathy are, from most to least common, dome, caterpillar, wave, and splitting.6
Interferon-α therapy
Interferon-α is used to treat a wide variety of cancers, such as lymphoma, melanoma, hairy cell leukemia, and Kaposi sarcoma as well as some viral infections, such as chronic hepatitis B and C. Retinopathy associated with interferon-α therapy occurs more frequently in patients with preexisting microvascular co-morbidities such as diabetes and hypertension.1,4
Patients often report no visual symptoms, but on fundoscopy, cotton-wool spots and intraretinal hemorrhages may be visualized as early as within the first 4 to 8 weeks of initiating medication.1,4 On higher dosages, other more severe findings associated with interferon use include branch arterial and venous occlusion, anterior ischemic optic neuropathy, optic disc edema, central retinal vein occlusion, epiretinal membrane, and chronic macular edema.1
It is recommended to have a baseline fundoscopic exam before starting interferon therapy and recheck 3 months after starting.6 The adverse effects can be self-resolving, but in the event of severe development of retinopathy or visual changes, the medication can be adjusted and discontinued, which typically results in the resolution of these changes.1,4
Tamoxifen
Tamoxifen is a selective estrogen receptor modulator often used in the treatment of breast cancer. On typical dosages (10 to 20mg/day), toxicity occurs in between 0.9% to 12%.1,4 On higher initial dosages (>60mg/day), white crystalline retinopathy of the inner retina of the macula and punctate gray lesions of the outer retina can develop with chronic macular edema.1,4
Toxicity occurs around 2 to 3 years after starting treatment but can occur earlier on higher dosages, in patients with higher body mass indexes (BMIs), or in patients with dyslipidemias.4 FA imaging can reveal hyperfluorescence of lesions and chronic macular edema with late staining, and OCT can also show hyperreflective punctate lesions of the inner retina with external limiting membrane and atrophy of the photoreceptor layer of the inner retina.1,4
Electroretinography (ERG) is reported to show decreased photopic and scotopic a-wave and b-wave amplitudes.1,4 It is recommended for patients on tamoxifen to be monitored closely for the development of ocular changes, and that careful discussion with the patient and their oncologist be done before deciding to stop medication.1,4
Retinal toxicity secondary to anti-microtubule therapies
Paclitaxel and docetaxel
Antimicrotubule agents, such as paclitaxel and docetaxel, are used in the treatment of lung, prostate, and breast cancer. Both medications can cause chronic macular edema that does not leak on FA.1
Toxicity has been treated with topical or systemic carbonic anhydrase inhibitors such as dorzolamide, intravitreal anti-vascular endothelial growth factor (VEGF) injections such as bevacizumab, and cessation of medication, which has been shown to resolve the macular edema with time on spectral domain OCT (SD-OCT).1
Infectious disease drugs and retinal toxicity
Clofazimine
Clofazimine is an antibiotic used in the United States to treat mycobacterium avium complex (MAC) infections in patients with acquired immune deficiency syndrome (AIDS).1,4 There are two case reports that describe AIDS patients who develop bull’s eye retinopathy with 200 to 300mg/d dosage,8,9 and one report of pre-maculopathy with 100mg/week dosage in an immunocompetent patient that showed a central scotoma, which was reversed upon cessation of medication.10
The reports generally recommended early and frequent fundus and color vision testing for retinal adverse effects and that medication be stopped to lower the risk of further development of retinopathies.9,10
Ritonavir
Ritonavir is a highly active antiretroviral therapy (HAART) used to treat human immunodeficiency virus (HIV) or AIDS. A few case studies report the development of a retinal pigment retinopathy with parafoveal telangiectasia and crystalline deposits after use ranging from 19 months to 5 years—of which most experienced symptoms after 5 or more years of treatment.1,4
The telangiectasias can be visualized on FA, and crystalline deposits can be appreciated on OCT along with retinal thickening.1,4 Drug cessation may result in improvement of retinopathy and symptoms, but some patients in advanced stages of toxicity experience continued progression of retinopathy after cessation.4
Didanosine/dideoxyinosine
Didanosine, also known as dideoxyinosine, is a nucleoside reverse-transcriptase inhibitor and a HAART, which is used to treat HIV or AIDS. It is reported to cause peripheral atrophy of the RPE in both children, particularly in higher dosages, and adults.11,12
Another case report describes nine cases of peripheral chorioretinal degeneration in adults, of which three progressed into the RPE and photoreceptor atrophy after stopping medication.13
Fundus examination may show irreversible mid-peripheral retinal atrophy with surrounding RPE hypertrophy and hyperpigmentation.1,4 OCT imaging of the macula can be used to confirm atrophy.4 These changes can also be seen with rod and cone dysfunction on ERG.1,4
Although there is one case of improvement after stopping the medication, most cases report irreversible changes, and some see progression of retinopathy years after cessation.13,14,15
Quinine
Quinine is an antimalarial drug used for nocturnal leg cramps, though this is no longer recommended due to severe side effects. Quinine is typically dosed at 2mg/day, but when taken in higher doses (>4g), patients can experience temporary total blindness with dilated, nonreactive pupils.1,4
In acute toxicity, fundus exams may be normal or show mild retinal edema, mildly dilated retinal arteries, veins, or mild retinal edema.1,4 ERG may show a slowing of a-wave with increased depth, decreased b-wave, and loss of oscillatory potential.1,4
A few weeks to months after acute overdose, fundus examination may show attenuation of retinal arterioles and optic nerve atrophy. At this time,1,4 OCT and full-field ERG also demonstrate inner retinal atrophy and dysfunction.4
Sulfa-containing drugs and retinal toxicity
Acetazolamide and hydrochlorothiazide
Sulfa-containing drugs, such as acetazolamide, hydrochlorothiazide, and sulfa antibiotics, are associated with multiple ocular side effects, such as ciliary body swelling, choroidal effusion, and lens swelling.
This can lead to subsequent displacement of the lens-iris diaphragm and the development of retinal folds.1,4 These folds can be visualized on fundoscopy and FA and usually resolve with discontinuation of the sulfa drug.1,4
Retinal toxicity caused by neurological drugs
Phenothiazines: Thioridazine and chlorpromazine
Phenothiazines are a class of first-generation anti-psychotic medications used to treat psychotic disorders such as schizophrenia and bipolar disorders. Thioridazine is reported to cause retinal toxicity as early as 2 weeks, especially at higher daily dosages.1,4 Toxicity is rare when the daily dosage is under <800mg but can still develop over a more extended period with accumulation.
Early fundoscopy may show subtle pigment stippling in a salt-and-pepper pattern of the retina.1,4 Intermediate-stage toxicity typically shows circumscribed nummular areas of the RPE on fundoscopy and choriocapillaris atrophy in the retina posterior pole and mid-periphery.1,4 Visual field testing can show mild constriction, paracentral scotomas, or ring scotomas in the early stages of toxicity.1,4
Late-stage toxicity typically shows alternating areas of hypopigmentation, hyperpigmentation, and vascular attenuation on fundoscopy.1,4 Discontinuing medication early can improve vision and ERG testing in the first year after, but stopping during later stages can lead to continued progression of retinopathy.1,4
In general, chlorpromazine has a lower risk of toxicity compared to thioridazine; however, in patients on higher daily dosages, retinal vessel attenuation and pigmentary changes can be observed on fundoscopy.1,4 An example of a higher daily dosage of chlorpromazine is 2400mg/day.1
Vigabatrin
Vigabatrin is an anti-epileptic often used to treat childhood seizures but can be used in cases of adult seizures. It is found to cause dose-dependent retinal pigmentation and optic and retinal atrophy, which is seen on fundus examination.1,4
Approximately 40 to 50% of patients develop bilateral visual field deficits.1 OCT imaging can also appreciate thinning on the retinal nerve fiber layer on the nasal side that spares the temporal side.4
The FDA recommends that patients receive a baseline exam within 4 weeks of starting medication and be re-examined every 3 months until discontinuation and 3 to 6 months after discontinuation.
Miscellaneous drugs and retinal toxicity
Deferoxamine
Deferoxamine is an iron chelator often used in patients with iron overload conditions such as hemochromatosis. High dosages can result in peripheral and central vision field loss, color vision loss, and nyctalopia.1,4
Early fundoscopy exams may be normal or show a faint gray hue in the macula. Deferoxamine toxicity most commonly causes pigmentary retinopathy, which on FA can be seen in the macula and periphery, and shows diffuse RPE hyperfluorescence in early stages.1,4 ERG can show a diminished response and decreased rod photoreceptor and post-receptor sensitivity.4,16
While there are no official guidelines for managing deferoxamine retinopathy, some suggestions in the literature include not exceeding 50mg/kg of body weight for adults and 25 to 35mg/kg for children, and using the lowest dosage appropriate for treatment.16
Patients on deferoxamine should have regular examinations early and followed every 6 months and be reexamined every 3 months after stopping medication.16 Adverse effects have been reported to be seen as early as after one dose.4
Tacrolimus
Tacrolimus is a calcineurin inhibitor commonly used for immunosuppression in solid organ transplant recipients. Potential retinal adverse effects include cotton-wool spots and hemorrhage to cortical blindness and optic neuropathy.
Of note, three case reports have noted maculopathies, including a Purtscher-like retinopathy, associated with tacrolimus.1,17,18,19 In one case, vision was restored after medication cessation, but macular damage was irreversible.17
Other treatment options suggested include intravenous (IV) corticosteroid therapy with or without plasmapheresis.1 Full and careful ophthalmic examinations are recommended for patients taking tacrolimus who begin to experience visual disturbances.17,18
Epinephrine
Topical epinephrine can be used to achieve local hemostasis or vasoconstriction on applied superficial areas. OCT imaging can show cystoid changes in symptomatic patients.4
In aphakic or pseudophakic eyes, it may cause macular edema, similar to post-operative aphakic chronic macular edema.1,4 The macular edema resolves by stopping epinephrine, and it is generally recommended not to use topical epinephrine in these patients.1,4
Niacin
Nicotinic acid, also known as niacin, can be used to manage cholesterol by increasing high-density lipoprotein (HDL) cholesterol. One common adverse effect of niacin use is chronic macular edema that does not leak on FA.
However, at high doses (>1.5g/day), some patients are reported to develop decreased central vision with paracentral scotoma or metamorphopsia.1,4 The macular edema typically resolves by stopping or reducing medication.1,4
Notably, if the chronic macular edema develops into pigment atrophy, vision can be permanently lost.1,4 Ophthalmic evaluations are recommended only if patients experience symptoms or take high doses.1
Canthaxanthin
Canthaxanthin is a carotenoid used to treat photosensitivity disorders as a natural food-coloring agent and sun-tanning dye. Toxicity is often in the setting of sun tanning with high cumulative doses (over 19g over 2 years) and typically presents with yellow-orange crystal deposits in a ring-like pattern in the macula around the fovea.1,4
Concurrent use of beta-carotene can increase crystal deposits seen on examination.1,4 Patients are typically asymptomatic, and reports note various normal and abnormal electrooculogram (EOG), ERG, dark adaptation, and static threshold perimetry.1,4 Stopping canthaxanthin may allow these deposits to clear gradually, taking as long as 20 years or more.1,4
Phosphodiesterase-5 inhibitors: Sildenafil, vardenafil, and tadalafil
Phosphodiesterase (PDE)-5 inhibitors are a class of medications used to treat erectile dysfunction and pulmonary hypertension. Within 1 to 2 hours of ingestion, some patients may report changes in color vision, such as blue dyschromatopsia as well as changes in perception of brightness or blurred vision.1,4
These changes are noted to be dose-dependent and self-resolve.1,4 On ERG, some may show transient depression.4
In summary
Various systemic medications and their reported retinal adverse effects, associated symptoms, risk factors associated with toxicity, physical exam findings, and recommendations for the management of toxicity are discussed in this article.
Ophthalmologists are highly encouraged to thoroughly review the medication history, dosages, and length of use of each patient's medication to supplement their physical examination and determine the likelihood of developing complications.
The exact extent and pathophysiologies of retinal toxicities from some systemic medications are currently not well established. Thus, it is essential that ophthalmologists are aware of new pathologies not previously reported with these systemic medications and use their clinical judgment to determine management.
