Because numerous medications can cause adverse effects to the retina, it is particularly crucial to obtain a thorough list of a patient’s prescription and OTC medications.

Here, we discuss these systemic medications, the retinal conditions associated with them (in order of how commonly they are seen) and how, specifically, to identify them, so we can work to preserve these patients’ vision. (See “Medication-Induced Cystoid Macular Edema”.)

HYDROXYCHLOROQUINE

Hydroxychloroquine (HCQ), known as Plaquenil (Sanofi), is an anti-malarial drug commonly prescribed for autoimmune conditions, such as lupus.

• Retinal condition. Macular toxicity. Additional risk factors for toxicity are an HCQ daily dose > 5.0 mg/kg real weight; duration of use > 5 years; renal disease; liver disease; concomitant drug use (tamoxifen); and prior macular disease.¹
• Identification. Advanced stages of HCQ-induced macular toxicity cause a pigmentary maculopathy with a bull’s eye appearance. Automated VFs plus SD-OCT are the primary screening tests, although multifocal electroretinogram (mfERG) can provide objective affirmation for VFs, and fundus autofluorescence (FAF) can reveal damage topographically. In Asian patients, tests should go beyond the central macula.¹

Monitoring for irreversible maculopathy is critical. The American Academy of Ophthalmology recommends a baseline exam within one year of the patient initiating treatment, followed by annual monitoring after five years.¹ With typical dosing (400 mg daily), five years marks nearing the potential lifetime toxic cumulative dose of 1,000 grams, usually reached by seven years of use.²

Yearly screening visits should include a dilated fundus exam, SD-OCT and 10-2 automated VFs. Current guidelines recommend 24-2 VF in Asian populations.¹ Secondary tests, such as FAF and mfERG should be considered, if available (Figure 1).¹

When HCQ-using patients present with possible signs of maculopathy, the prescribing doctor should be immediately informed, and discontinuation of HCQ and alternative therapy should be seriously considered. It is important to note that maculopathy can progress even after discontinuation.³ Those detected at early stages had fairly good outcomes, but those who had visible bull’s eye lesions tended to have poorer visual outcomes.

TAMOXIFEN

Tamoxifen is an anti-estrogen drug used to treat breast cancer.

• Retinal condition. Crystalline maculopathy. (See image at bit.ly/3EziakA .) The risk for retinal toxicity includes total cumulative dose and duration of treatment. Additionally, high body mass index and high cholesterol may be risk factors. Tamoxifen maculopathy can result in progressive central vision loss and color vision loss.
• Identification. A careful fundus evaluation can reveal crystalline deposits in the macula. O.D.s should evaluate the fundus and consider using OCT imaging to aid in identifying reflectile deposits or cystic retinal spaces.

A recent study suggests OCT imaging may increase detection over fundus evaluation alone.⁴ Of note: Crystalline maculopathy may be difficult to distinguish from macular telangiectasia type 2 (MT2).⁵ MT2 is a bilateral, although often asymmetric, retinal degenerative condition with findings most concentrated in the temporal juxtafoveal region. Findings can include crystalline deposits and cystic spaces on OCT, hence why it can mimic tamoxifen maculopathy. However, patients may also have juxtafoveal temporal pigmentary plaques and irregular vasculature. In addition, fluorescein angiography shows classic telangiectatic vessels, primarily in the temporal juxtafoveal region that leak in later stages.

An oncologist should be notified to consider discontinuing tamoxifen in those who develop crystalline maculopathy, especially if VA is effected. The drug can result in reduction of central VA and loss of color vision. Crystalline deposits and cystic spaces are often reversible with medication cessation, but the effects may also progress, even after stoppage.

PENTOSAN POLYSULFATE

Pentoson polysulfate is used to treat interstitial cystitis (swollen or irritated walls of the bladder).

• Retinal condition. Macular pigmentary alterations that can mimic AMD or pattern dystrophies. Distinguishing macular toxicity from AMD or one of its many mimickers is difficult, especially due to the limited data available on Pentoson polysulfate maculopathy. (See image at bit.ly/3zqy11b .) Any alteration to the outer retina or RPE seen on OCT or visualized with FAF should be given serious consideration. If the diagnosis is unclear, a referral for a second opinion is warranted. Central vision loss can occur from outer retinal degeneration in these patients.
• Identification. It has been suggested to obtain a baseline fundus examination, OCT and FAF to aid in picking up on RPE alterations. The clinical exam should pay careful attention to any pigmentary changes in the macula. When evaluating the OCT, O.D.s should pay careful attention to the outer retina and RPE, looking for any disruption, such as outer retinal or RPE atrophy. On the FAF, optometrists should be on the lookout for reticular-type alterations to the auto fluorescent signal that may include both hyper or hypo-autofluorescence. This should then be followed by yearly testing and repeat imaging beginning at five years of treatment.⁶

The association of maculopathy with pentoson polysulfate is relatively new, so prescribing physicians may not be aware of it. Therefore, it seems reasonable for O.D.s to correspond with prescribing physicians, so that they are aware of the association, the benefit of keeping patients on the lowest dose possible for the shortest duration of time and to inform them the patient will be monitored for ocular findings, which will then be reported to the prescribing doctor.

SYSTEMIC CORTICOSTEROIDS

Systemic corticosteroids, as is the case with topical corticosteroids, are anti-inflammatory agents.

• Retinal condition. Central serous chorioretinopathy (CSCR), associated with oral, nasal, topical, intra-articular or joint injectables.⁷
• Identification. The classic presentation is a pigment epithelial detachment (PED) with overlying serous detachment (Figure 2). Clinical exam is important, but OCT is highly useful in confirming findings. Also, FAF may aid in identifying regions of RPE disruption from previous episodes, especially in chronic or recurrent cases.

Acute CSCR cases can typically be monitored and will self-resolve with good visual outcome. Chronic or recurrent cases can lead to permanent vision loss. Therefore, in chronic or recurrent cases, patients should be referred for consideration of treatment, which may include focal laser, photodynamic therapy, oral aldosterone inhibitors or anti-VEGF injections. The benefit of anti-VEGF injections for serous detachments in CSCR is controversial, but they would be considered standard treatment for secondary choroidal neovascularization.⁷

MAPK/ERK KINASE (MEK) INHIBITORS

MEK inhibitors are chemo-therapy drugs that inhibit mitogen-activated protein kinase enzymes MEK1 and/or MEK2. This class of drugs is approved to treat certain types of melanomas and lung cancer and are in clinical trials for thyroid cancer, breast cancer, multiple myeloma and colon cancer.

• Retinal condition. Typically self-limiting serous retinal detachments. These have been described as “multifocal CSCR,” but unique characteristics (described below) from CSCR have led to the proposed designation of MEK inhibitor-associated retinopathy (MEKAR) rather than “multifocal CSCR.”
• Identification. MEKAR appears as multiple, bilateral serous detachments located in the fovea and extrafoveally along the vascular arcades (See images at go.nature.com/3nNZFmO ). OCT imaging is recommended to help identify these serous detachments and monitor them. OCT findings common in CSCR are often lacking in MEKAR, such as the presence of pigment epithelial detachments. In addition, a thick choroid is not associated with MEKAR as it is with CSCR.⁸ Those without center-involving serous detachments may be asymptomatic, but center-involving serous detachments often lead to symptoms of reduced vision and metamorphopsia.

If retinopathy occurs, optometrists should notify the prescribing physician of this occurrence. It is recommended to interrupt therapy in cases of symptomatic retinopathy and to resume therapy at a lower dose when symptoms resolve. Retinopathy can resolve after medication cessation, but there are reports of ongoing serous macular detachments even after the medication is discontinued.⁹

ESTROGEN

Estrogen is used in birth control medications and to treat amenorrhea and menopause, among other conditions associated with estrogen deficiency.

• Retinal condition. Retinal thrombotic events: namely retinal vein occlusions (RVOs). RVOs can lead to vision loss in numerous ways, including macular edema, macular ischemia and complications of retinal and iris neovascularization, such as neovascular glaucoma, traction retinal detachments and vitreous hemorrhage.
• Identification. RVOs include central retinal vein occlusions (Figure 3), hemi-retinal vein occlusions and branch retinal vein occlusions. These may present with dilated and tortuous veins, as well as intraretinal and flame-shaped hemorrhages, cotton wool spots and exudation along the affected vein(s). OCT aids in identifying macular edema. FA as well as OCT-A may help in identifying areas of vascular non-perfusion and retinal neovascularization.

RVOs are associated with a variety of systemic disease and are most commonly seen in patients older than age 55 who have hypertension, diabetes, hyperlipidemia and in those who smoke. (When RVOs are seen in a younger, healthy patient, there should be increased concern for conditions that lead to a hypercoagulable or hyperviscosity state.)

RVO patients should be questioned regarding use of estrogen-containing drugs, particularly females of childbearing age. These patients should be co-managed with the prescribing physician to reduce the risk of future thrombotic events.¹⁰ Some RVOs self-resolve with good VA. The complications may require treatment, such as anti-VEGF, panretinal photocoagulation or vitrectomy, with variable outcomes.

LEUPROLIDE

Leuprolide is a chemotherapy drug used for breast, ovarian, endometrial and prostate cancers. Also, it can be used to treat non-cancerous conditions, such as endometriosis, uterine fibroids and infertility.

• Retinal condition. Thromboembolic events and RVO formation.¹¹
• Identification. RVO presentation, prognosis and treatment are described above.

Communication with the prescribing doctor is necessary to determine the risk, benefits and alternatives to discontinuing treatment. Treatment of RVO complications are described above.

SULFA DERIVATIVES

Sulfa derivatives are prescribed for various bacterial infections. Examples are acetazolamide, topiramate and sulfa antibiotics.

• Retinal condition. Swelling of the ciliary body and forward rotation of the iris-lens diaphragm. This can lead to transient myopia, uveal effusions, secondary angle closures and retinal striations (Figure 4).¹²

  

• Identification. Patients may present with transient myopic shifts, shallow anterior chamber, in-creased IOP, red, painful eye, choroidal detachments and retinal striations. Gonioscopy and AS-OCT may aid in evaluating the anterior chamber and angle anatomy. OCT and B-scan ultrasonography may help in evaluating the anatomy of the posterior segment to identify retinal striations or uveal effusions.

Medication discontinuation typically leads to resolution. Rises in IOP may need to be managed with topical drops, oral drugs or surgical intervention. Cycloplegia is helpful to relax the ciliary body and allow for posterior rotation.^12,13

PHENOTHIAZINES

Phenothiazines are antipsychotics used to treat conditions, such as schizophrenia. Thioridazine and chlorpromazine are examples.

• Retinal conditions. Retinopathy, which is higher with thioridazine use. Thioridazine is not commonly prescribed due to its potential for heart arrhythmias. Patients taking doses of thioridazine greater than 800 mg/day are at particular risk, but retinopathy has been reported even in doses as low as 100 mg/day.¹⁴ For those taking high doses, retinopathy can occur acutely within three to eight weeks of use.¹⁴
• Identification. Retinopathy presents as widespread diffuse pigmentary alterations that may begin as mild pigmentary mottling posterior to the equator and progresses to geographic regions of RPE and choriocapillaris atrophy. Widefield fundus photography and FAF are useful in early detection. Color vision may be abnormal, and VF testing may reveal paracentral or ring scotomas.¹⁴

O.D.s should monitor patients during treatment. The medication should be discontinued if retinopathy occurs.¹⁴ Toxicity can occur acutely with symptoms of nyctalopia, dyschromatopsia and blurred vision.¹⁴ Without intervention, patients can suffer severe, permanent vision loss from diffuse RPE and outer retinal atrophy.¹⁴

INTERFERONS

Interferons help regulate the immune system, causing cells to increase their defenses against viral infection. Interferon use is common in patients who have hepatitis C, but these drugs also are used to treat multiple sclerosis and various cancers.

• Retinal condition. “Interferon” retinopathy. Patients with comorbidities, such as diabetes and hypertension, may be at greater risk.¹⁵
• Identification. “Interferon” retinopathy presents as cotton wool spots, retinal hemorrhages, macular edema and, rarely, artery or vein occlusion (Figure 5). Patients should be evaluated with dilated fundus examination. Ancillary testing, such as OCT, and color photographs may aid in monitoring the retinopathy.

Retinopathy typically subsides with drug cessation. Coordination with the prescribing doctor is necessary in those who develop retinopathy, with consideration of therapy cessation in those who have sight-threatening lesions.^15-17

GLITAZONES

Glitazones, including pioglitazone, treat diabetes.

• Retinal condition. Increased fluid retention causing macular edema.
• Identification. Evaluation for macular edema should include clinical evaluation for macular thickening and OCT imaging of the macula.

Especially in those who have additional signs of peripheral edema, medication discontinuation should be considered. Drug cessation tends to lead to quick resolution of peripheral edema and macular edema.^18,19

PATIENT COMMUNICATION IS PARAMOUNT

Patients must always be educated regarding the importance of disclosing all medication — both prescription and OTC — to their eye care provider. Coordination with the prescribing doctor is crucial for good patient outcomes in those who present with retinal complications. OM

References

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DR. HAYNES practices full-time at Charles Retina Institute and part-time as consulting faculty at SCO in the Advanced Care Ocular Disease Clinic. She is a fellow in the Optometric Retina Society and lectures almost exclusively on posterior segment disease.

DR. RAFIEETARY is a consultative optometric physician at the Charles Retina Institute in Germantown, Tenn. He is on the advisory board of a number of professional organizations and lectures and writes on the topic of posterior segment disease.