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Retinal Complications of Systemic Drug Therapy

The retina appears to be especially vulnerable to toxicity from certain systemic medications. Part 2 of a 2-part series.

By: M. STEPHANIE R. JARDELEZA, MD, FACS, FASRS
New Retinal Physician November 1, 2023 Vol Retinal Physician 20, Issue November/December 2023 Page(s): 11-13, 17, 24

Systemic medications can have significant and potentially visually debilitating effects on the retina. The first part of this series, which appeared in the July/August issue of New Retinal Physician, discussed how medications like hydroxychloroquine (HCQ) and pentosan polysulfate (PPS) can cause irreversible vision loss if not monitored carefully and stopped at the earliest signs of ocular toxicity.1,2 Part 2 reviews many other medicines that can cause retinal toxicity, including chemotherapeutic agents and other cancer-fighting medicines, antiseizure and antipsychotic medications, heart medications, and antivirals used to treat human immunodeficiency virus (HIV).

CANCER TREATMENTS

Cancer-fighting chemotherapeutic agents circulate in the bloodstream to attack cancerous cells throughout the body but can have a toxic effect on the retina. For example, MEK inhibitors block the mitogen-activated protein kinase kinase enzymes MEK 1 or MEK 2. However, these anticancer agents disrupt the blood-ocular barrier and can cause exudative retinal detachment or subretinal fluid accumulation (Figure 1). These findings mimic central serous chorioretinopathy, but without the retinal pigment epithelial (RPE) detachment.3 In clinical trials of MEK inhibitors, reports of ocular toxicity occurred in 5% to 38% of patients; the wide range may be due to variance in the description, diagnosis, and reporting of the same condition; differences in inhibitors’ potency; or other factors.4,5

FIGURE 1. Optical coherence tomography (OCT) scan of a 71-year-old patient with melanoma, who had been treated for 4 months with trametinib, a MEK inhibitor. The imaging revealed intraretinal and subretinal fluid on macula with cystoid changes in the perifoveal area in both eyes, with significant thickening of the ellipsoid zone and subretinal granular deposits overlying an apparently intact retinal pigment epithelium (RPE). After cessation of trametinib, the cystoid macular edema resolved over a 6-month period. IMAGE ORIGINALLY PUBLISHED IN: TYAGI P, SANTIAGO C. NEW FEATURES IN MEK RETINOPATHY. BMC OPHTHALMOL. 2018;18(SUPPL 1):221. DOI:10.1186/S12886-018-0861-8. REPRINTED WITH PERMISSION UNDER HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/
FIGURE 1. Optical coherence tomography (OCT) scan of a 71-year-old patient with melanoma, who had been treated for 4 months with trametinib, a MEK inhibitor. The imaging revealed intraretinal and subretinal fluid on macula with cystoid changes in the perifoveal area in both eyes, with significant thickening of the ellipsoid zone and subretinal granular deposits overlying an apparently intact retinal pigment epithelium (RPE). After cessation of trametinib, the cystoid macular edema resolved over a 6-month period. IMAGE ORIGINALLY PUBLISHED IN: TYAGI P, SANTIAGO C. NEW FEATURES IN MEK RETINOPATHY. BMC OPHTHALMOL. 2018;18(SUPPL 1):221. DOI:10.1186/S12886-018-0861-8. REPRINTED WITH PERMISSION UNDER HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/

Fibroblast growth factor receptor (FGFR) antagonists are used to treat malignancies that originate in the skin or in tissues that line or cover internal organs (carcinomas). They can cause central serous chorioretinopathy or a pseudovitelliform maculopathy.6,7

Immune checkpoint inhibitors are agents that enhance the immune system’s reactivity. They can cause varying degrees of ocular inflammation, such as macular edema or uveitis.8 Subretinal fluid, macular detachment, and bullous areas of peripheral serous detachment can also occur in more severe cases.9

Taxanes such as paclitaxel (Taxol; Bristol-Myers Squibb) are mitotic inhibitors that interfere with mitosis. They are used to treat breast and ovarian cancers, as well as some other cancers. In rare cases, taxane injections can cause cystoid macular edema.10 Photopsias can also occur during and up to 3 hours after drug infusion.11

Aromatase inhibitors such as anastrozole (Arimidex; AstraZeneca) are estrogen receptor inhibitors used in breast cancer treatment. Vitreoretinal traction occurs due to estrogen depletion and can cause photopsias, floaters, and retinal hemorrhages.12,13

Tamoxifen is not a chemotherapy drug; it is an estrogen-antagonist that is used to treat metastatic breast cancer, sold under the trade names Nolvadex (AstraZeneca) and Soltamox (Mayne Pharma). It can cause crystalline macular deposits and macular pigmentary changes. Symptoms include blurred vision and floaters. SD-OCT demonstrates perifoveal cystoid changes in early maculopathy, which eventually progresses to outer retinal cavitation and foveal thinning with advanced maculopathy.14-16 Patients on high doses can also develop peripheral retinal crystalline deposits.17 Caution should be exercised when starting tamoxifen in patients with age-related macular degeneration and/or underlying macular pathology. Patients with a high body mass index (BMI) and dyslipidemia are at a higher risk for developing tamoxifen retinopathy.18

Interferons are currently used to treat viral infections, such hepatitis B or C, and as adjuvant therapy for various cancers. Cotton wool spots are the most common retinal findings with interferon use. Vascular occlusions and retinal hemorrhages can also occur.19

ANTISEIZURE AND ANTIPSYCHOTIC TREATMENTS

The US Food and Drug Administration (FDA) has approved the antiseizure medication vigabatrin (Sabril; Lundbeck) for use in the United States when the potential benefit against seizures outweighs the risk of visual loss. The FDA label warns that Sabril “can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability.”20 This tunnel vision is irreversible, and in some cases Sabril may also decrease visual acuity. Children are susceptible to retinal atrophy with nasal optic disc atrophy.

Monitoring of vision is required for people taking vigabatrin, because up to 30% of patients who take the drug experience some visual loss (Figure 2).21 Patients require baseline dilated fundus exams and visual fields. These exams should be repeated every 3 months and continue for 3 to 6 months after drug discontinuation.22,23

FIGURE 2. Retinal nerve fiber layer (RNFL) thickness map of a 46-year-old female being treated for seizures with 2,000 mg of vigabatrin per day. Over 33 months, imaging showed a bilateral decrease in RNFL thickness, with left RNFL loss greater than right. (Green corresponds to normal RNFL thickness, yellow borderline, and red below normal thickness.) Although the patient ended vigabatrin therapy at the end of this period, her vision did not improve. IMAGE ORIGINALLY PUBLISHED IN: BARRETT D, ET AL. VIGABATRIN RETINAL TOXICITY FIRST DETECTED WITH ELECTRORETINOGRAPHIC CHANGES: A CASE REPORT. J CLIN EXP OPHTHALMOL. 2014;5(5):1000363. DOI:10.4172/2155-9570.1000363. REPRINTED WITH PERMISSION UNDER HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/
FIGURE 2. Retinal nerve fiber layer (RNFL) thickness map of a 46-year-old female being treated for seizures with 2,000 mg of vigabatrin per day. Over 33 months, imaging showed a bilateral decrease in RNFL thickness, with left RNFL loss greater than right. (Green corresponds to normal RNFL thickness, yellow borderline, and red below normal thickness.) Although the patient ended vigabatrin therapy at the end of this period, her vision did not improve. IMAGE ORIGINALLY PUBLISHED IN: BARRETT D, ET AL. VIGABATRIN RETINAL TOXICITY FIRST DETECTED WITH ELECTRORETINOGRAPHIC CHANGES: A CASE REPORT. J CLIN EXP OPHTHALMOL. 2014;5(5):1000363. DOI:10.4172/2155-9570.1000363. REPRINTED WITH PERMISSION UNDER HTTPS://CREATIVECOMMONS.ORG/LICENSES/BY/4.0/

Phenothiazines are antipsychotic medications used to treat schizophrenia, bipolar disorders, and other psychotic disorders. Thioridazine is a phenothiazine that, due to its side effects, is only prescribed to patients who do not respond to other antipsychotics. Thioridazine binds to melanin in the RPE, and long-term use leads to irreversible pigmentary retinopathy and vision loss.24 RPE deterioration can progress after drug discontinuation. Macular toxicity is rare at daily dose of <800 mg. Early symptoms include blurred vision and nyctalopia. Advanced toxicity can mimic retinitis pigmentosa. Visual function may improve after discontinuing the drug.22,24

HEART MEDICATIONS

Digoxin is used to treat congestive heart failure and arrhythmias. Its use is associated with scotomas and photopsias; “yellow vision” or yellow/blue color vision deficits can also occur. Symptoms are reversible at lower doses.22

Amiodarone (Pacerone; Upsher-Smith) is a cardiac dysrhythmia medication, used to treat tachyarrhythmias. It is known to cause corneal verticillate; the most common symptom is blue-green colored halos or rings around lights.25 This does not prevent continuation of amiodarone treatment, and the verticillate typically resolves with cessation. However, in rare cases, optic neuropathy has been reported in amiodarone patients; in these cases, the medication should be discontinued if possible.25

Niacin (nicotinic acid) is a lipid-lowering agent prescribed to treat elevated cholesterol and triglycerides. It can cause a reversible toxic cystoid maculopathy. These macular cysts characteristically do not leak on fluorescein angiography.26

TABLE 1. Summary of systemic medications discussed in this review that have demonstrated toxic effects on the retina, and pertinent signs and/or features.
SYSTEMIC MEDICATION PRESCRIBED USE EFFECTS ON THE RETINA
Hydroxychloroquine Antimalarial; also used to treat lupus and rheumatoid arthritis Changes in the photoreceptor layer and the RPE, usually in the parafoveal and perifoveal regions, in long-term users.
Pentosan polysulfate sodium Treatment of interstitial cystitis Paracentral hyperpigmentation in the RPE layer with surrounding vitelliform deposits in long-term users.
MEK inhibitors(ie, binimetinib cobimetinib, selumetinib, and trametinib) Chemotherapy Exudative retinal detachment or subretinal fluid accumulation; self-limiting serous retinopathy.
FGFR inhibitors(ie, erdafitinib, pemigatinib) Chemotherapy Central serous retinal detachment, usually asymptomatic or very mild symptoms.
Taxanes (ie, paclitaxel) Chemotherapy Cystoid macular edema in rare cases.
Aromatase inhibitors(ie, anastrozole) Chemotherapy Increased risk of retinal hemorrhage and vitreoretinal traction.
Tamoxifen Estrogen antagonist for breast cancer treatment. Crystalline macular deposits and macular pigmentary changes.
High-dose interferon therapy Adjuvant treatment for high-risk melanomas Cotton wool spots, vascular occlusions, and retinal hemorrhages.
Vigabatrin Antiseizure Permanent bilateral concentric constriction of visual field (“tunnel vision”).
Thioridazine Antipsychotic Irreversible pigmentary retinopathy at dose >800 mg/day.
Digoxin Heart disease Scotomas and photopsias.
Amiodarone Cardiac dysrhythmia Corneal verticillate; optic neuropathy in rare cases.
Niacin Cholesterol-lowering Cystoid maculopathy.
Didanosine HIV treatment Peripheral chorioretinal atrophy.
Ritonavir HIV treatment Retinopathy, including intraretinal crystals, foveal cysts, and macular telangiectasias.
Phosphodiesterase-5 inhibitors(ie, sildenafil or tadalafil) Erectile dysfunction Visual effects; in rarer cases, central retinal artery occlusion and/or central serous chorioretinopathy.
Oral contraceptives(ie, containing drospirenone, ethinylestradiol, levomefolate, et al) Oral contraceptives Central retinal artery or vein occlusions, retinal hemorrhages, and macular edema.

Anticoagulants like aspirin, warfarin, and heparin predispose patients to vitreous, subretinal, and intraretinal hemorrhages. Judicious cessation of these medications should be considered during vitreoretinal surgeries.27,28

HIV ANTI-RETROVIRAL THERAPIES

Didanosine is a nucleoside reverse transcriptase inhibitor approved by the FDA in 1991 for the treatment of HIV infection. Patients can experience gradual bilateral vision loss, along with photopsias and nyctalopias. Didanosine retinopathy presents as extensive well demarcated peripheral chorioretinal atrophy that eventually coalesces to mimic gyrate atrophy. The macula and optic nerve are typically spared. No proven treatment exists. Toxicity can progress despite discontinuation of the medication and patients on this medication should be monitored with fundus photographs and fundus autofluorescence.29,30

Ritonavir (Norvir; AbbVie) is an HIV protease inhibitor used in combination with other protease inhibitors. HIV protease inhibitors increase retinal dehydrogenase activity and increase the production of reactive oxygen species. The higher biochemical activity of the macula could predispose it to oxidative stress. Patients with ritonavir maculopathy present with a slow profressive deterioration in central visual acuity and color vision. Macular RPE changes can include macular retinal pigment epitheliopathy, intraretinal crystals, foveal cysts, and macular telangiectasias. Maculopathy progresses with continued use and can continue to progress if detected at its later stages. Toxicity can occur from 1.5 to 16 years after starting the medication, so regular screening with dilated examinations, SD-OCT, and fundus autofluorescence is necessary.30,31

OTHER MEDICATIONS

Phosphodiesterase-5 inhibitors, which include agents used to treat erectile dysfunction—such as sildenafil (Viagra; Viatris) or tadalafil (Cialis; Lilly)—divert blood flow from the brain. Photoreceptor changes cause “blue vision” or “shimmering” around objects, but these effects are reversible with drug cessation.32,33 Patients can also develop central retinal artery occlusion and/or central serous chorioretinopathy.34

Oral contraceptives can cause a hypercoagulable state and predispose to central retinal artery or vein occlusions. Isolated retinal hemorrhages and macular edema can also occur. Vascular complications are associated with thrombosis of the cerebral vessels or can be limited to the retinal vessels. Less commonly, color vision disturbances can also occur.35,36 Acute macular neuroretinopathy has also been reported in oral contraceptive users.37

Canthaxanthin is a naturally occurring carotenoid most often used for treatment of photosensitivity disorders or vitiligo. It is also found in some tanning pills. At high doses (cumulative dose >19 g over 2 years), bilateral red to yellow crystalline macular deposits may appear in a ring-shaped configuration. Most patients are asymptomatic. Deposits slowly disappear once the drug is discontinued, but this process may take years, with variable regression and/or reversibility.38,39

Excessive caffeine intake, especially in patients who consume many energy drinks, can predispose to rare vascular occlusion/micro-infarcts in the inner retina and/or acute macular neuroretinopathy. Central or paracentral scotomas/visual blurriness are the primary symptoms. These typically resolve when caffeine intake is moderated.40

Various amyl nitrate compounds (“poppers”) are used recreationally (and illegally) due to their psychoactive components. After the drug’s main component was changed from isobutyl nitrite to isopropyl nitrite in 2006, “poppers maculopathy” became more widely reported.41 Subtle yellow foveal spots are seen on fundus evaluation42 and SD-OCT demonstrates disruption on the inner and outer foveal photoreception segments. The mechanism of central foveal photoreception damage is unknown. The prognosis for visual recovery is improved with cessation of use.43

Scan here to read Dr. Jardeleza’s initial article in this series in the July/August 2023 issue of New Retinal Physician.
Scan here to read Dr. Jardeleza’s initial article in this series in the July/August 2023 issue of New Retinal Physician.

CONCLUSION

Detecting retinal complications of systemic medications requires a high index of suspicion, especially as novel therapies continue to emerge. Review the patient’s medication usage history carefully. Care must be taken when diagnosing toxicity, especially prior to recommending drug cessation, as many patients greatly benefit from their medications. Systemic medications should always remain within a retinal specialist’s differential diagnosis for atypical or unusual presentations of known retinal conditions. NRP

M. STEPHANIE R. JARDELEZA, MD, FACS, FASRS, is a vitreoretinal disease specialist at Southeast Eye Specialists in Chattanooga, Tennessee. She reports no disclosures. Reach Dr. Jardeleza at stefjmd@gmail.com.

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