CLINICAL

  POSTERIOR

TACKLE TOXICITY

HOW TO IDENTIFY AND SCREEN FOR MEDICATION-CAUSED RETINAL TOXICITY IN 2016

DIANNA SHECHTMAN, O.D., F.A.A.O., AND SHERROL A. REYNOLDS, O.D., F.A.A.O.

AN 87-YEAR-OLD Caucasian female presented complaining of blur while reading from her current prescription. Her medical history revealed AMD diagnosed 30 years ago (for which she was now using the AREDS2 formula), cataract surgery OU and medications for hypertension, hypercholesterolemia and rheumatoid arthritis (RA). The latter drug was hydroxychloroquine sulfate (Plaquenil, Sanofi-Aventis) 200mg b.i.d. for 10 years. The patient’s daughter, who accompanied her to this visit, mentioned her mother was taken off the hydroxychloroquine sulfate due to findings “in the back of the eyes” more than 40 years ago.

The patient’s BCVA was 20/30+ OD and 20/25- OS. All preliminary testing was unremarkable. Slit lamp evaluation revealed posterior chamber IOLs OU. Dilated fundus exam (DFE) showed a parafoveal ring-shaped “bull’s eye” in the macula OU. SD-OCT revealed saucerization of the subfoveal area with associated loss of the parafoveal photoreceptor integrity line OU. The vessels and peripheral exam were normal OU. The verdict: hydroxychloroquine sulfate toxicity.

Here, we discuss this toxicity, risk factors, symptoms, clinical signs and recently revised diagnosis/screening guidelines, courtesy of the American Academy of Ophthalmology (Academy).

TOXICITY

Hydroxychloroquine sulfate and the less used chloroquine-CQ (Arlen, Sanofi-Aventis) are anti-malarial medications widely prescribed for various dermatologic and rheumatological conditions, such as systemic lupus erythematosus and RA. Hydroxychloroquine sulfate is being considered for new use in diabetes mellitus, heart disease and adjunct cancer therapy, according to Ophthalmology.

Although hydroxychloroquine sulfate is relatively safe systemically, it can lead to macular toxicity, which may result in devastating vision loss, even after the medication is stopped. The mechanism of this toxicity is not clearly understood, though it is believed that the drug molecule binds to melanin in the retinal pigment epithelium (RPE). This, in turn, leads to disruption and damage to the photoreceptors and outer nuclear and plexiform layer, with sparing of the foveal center and the resulting “bull’s eye” appearance, according to the Archives of Ophthalmology. Binding of the drug to melanin in the RPE contributes to, or prolongs, its toxic effects. The drug molecules also deposit within the corneal epithelium, leading to vortex keratopathy. Thus, anterior segment changes should prompt a thorough retinal examination.

Toxicity does not discriminate by race or sex, but the classic “bull’s-eye” pattern is found infrequently in Asian patients, who show early damage in a more peripheral pattern, according to Ophthalmology.

RISK FACTORS

Numerous high and low risk factors promote the development of hydroxychloroquine sulfate macular toxicity, according to the 2016 Academy guidelines.

High risk factors:

• Duration of use > 5 years. The prevalence of hydroxychloroquine sulfate toxicity was 7.5% in those who used the drug longer than five years, according to JAMA Ophthalmology. Further, the risk of toxicity doubles by 10 years and reaches 20% after 20 years of use, according to JAMA.

• Dosage > 5.0 mg/kg (real weight). Hydroxychloroquine sulfate is available in 200 mg tablets and is commonly prescribed two 200 mg pills per day — anything above that increases macular toxicity risk. Also, data show “real weight” is better than “ideal weight” for calculating dosage. (The 2011 Academy recommendations to use ideal body weight for the calculation of dose was based on the idea that hydroxychloroquine sulfate was not retained in fat.) The drug is stored primarily in melanotic tissue, the liver and kidney, with low concentrations found in a variety of other organs and muscle fat, according to the American Journal of Medicine. Thus, thin patients are at increased risk when dose is calculated by ideal weight, as previously recommended.

• Renal disease. As the drug is cleared by the kidney, renal disease effectively increases the circulating level of the drug and the risk of toxicity, according to JAMA Ophthalmology.

• Retinal or macular disease. Retinal or macular disease increases the risk because damage makes these ocular areas more susceptible to toxicity.

• Tamoxifen use. Use of tamoxifen (Nolvadex, AstraZeneca) for the long-term treatment of breast cancer in conjunction with hydroxychloroquine sulfate has been shown to increase the risk of toxicity approximately five-fold, according to JAMA Ophthalmology. Although the reasons are unclear, tamoxifen may cause macular toxicity in its own right. Thus, patients taking tamoxifen need careful dosing and screening.

Lower risk factors:

• Age. Elderly patients appear at higher risk, though a recent demographic study found no significant association between age and risk of toxicity, according to JAMA Ophthalmology.

• Liver disease. The liver participates in the metabolism of hydroxychloroquine sulfate, however, no clear association between liver disease and toxicity has been demonstrated, according to the new Academy guidelines.

• Genetic factors. There have been suggestions that some patients have a genetic predisposition to hydroxychloroquine sulfate toxicity. That said, a new report suggests that certain genes may be protective, according to the Arthritis Rheumatology Journal.

SYMPTOMS

Although most patients are asymptomatic, the following symptoms are associated with hydroxychloroquine sulfate toxicity:

• Blurred vision

• Color vision deficits

• Decreased central vision

• Glare (or halos especially with vortex keratopathy)

• Metamorphopsia

• Paracentral scotoma

• Photopsia

DIAGNOSIS/MANAGEMENT

The following tests, particularly use of both automated visual fields and SD-OCT, are recommended to diagnose and screen for hydroxychloroquine sulfate toxicity, according to the 2016 Academy guidelines:

• Automated threshold visual fields. A central 10-2 white-stimulus visual field reveals defects in macular function. However, for Asian patients, a 24-2 or 30-2 visual fields is recommended because hydroxychloroquine sulfate toxicity often manifests changes beyond the macula in these patients.

• SD-OCT. This technology shows localized thinning of the photoreceptor layers in the parafoveal region. There is focal disruption of the inner segment (IS)/outer segment (OS) line, with an intact outer retina found directly under the fovea. This creates a “flying saucer,” saucerization sign or ovoid appearance of hydroxychloroquine sulfate-caused toxic maculopathy.

• Fundus autofluorescence (FAF). FAF imaging can reveal early parafoveal or extramacular photoreceptor damage as an area of increased autofluorescence that may precede retinal thinning on SD-OCT. Late RPE loss appears as a dark area of reduced autofluorescence. FAF is especially valuable in providing a topographic view of damage across the posterior fundus, and wide-angle images can show extramacular patterns of damage in Asian eyes.

• Microperimetry. This allows for specific testing of macular function. It can aid in the detection of early functional change and enable you to monitor progression of the disease.

• Adaptive optics retinal imaging. This provides automated functional assessment of dark adaptation time, enabling the evaluation of macular cone damage seen with early toxicity.

• Multifocal electroretinogram (mfERG). This documents parafoveal or extramacular depression in early maculopathy. For hydroxychloroquine sulfate toxicity, there is paracentral amplitude loss indicative of decreased retinal function in the susceptible perifoveal area, according to the American Journal of Ophthalmology.

In terms of managing patients who have hydroxychloroquine sulfate toxicity, the vision loss is irreversible, and there is no cure. Therefore, the best management is the early monitoring of patients who begin using the drug, so early clinical findings can be identified and vision loss prevented. Long-term monitoring is critical, as cessation of the drug does not prevent progression of toxic maculopathy.

Specifically, the 2016 Academy Guidelines state that all patients beginning hydroxychloroquine sulfate therapy have a baseline eye exam that includes retinal photos within the first year of starting the drug to rule out pre-existing macular or retinal disease that might make the use of these drugs unwise.

Note the parafoveal circular ring-shaped “bull’s eye” appearance in both maculas of this patient, who took hydroxychloroquine sulfate for rheumatoid arthritis more than 40 years ago.

Additionally, you should perform recommended testing, such as baseline visual fields and SD-OCT. Most importantly, communicate baseline findings to prescribing physicians. (Insurance pays for OCT and VF even if no abnormal findings are seen on DFE.)

If the user has high-risk factors, an annual examination is recommended. It is important to also check the dosage relative to weight at every visit and to ask about changes in systemic status, such as major weight loss, kidney disease or tamoxifen use.

For patients with low risk factors, an annual eye exam can be deferred until five years of use. If probable or definite toxicity is detected, hydroxychloroquine sulfate should be stopped immediately in consultation with the patient’s rheumatologist. These patients require six-month to annual monitoring as progression of toxicity can endure after discontinuing the medication.

THAT PATIENT

The patient mentioned above had significant hydroxychloroquine sulfate macular toxicity, even though she discontinued the drug a long time ago. Her vision remained relatively good, and she is being monitored closely.

Hydroxychloroquine sulfate is effective for several conditions, but it can lead to vision loss. Early detection is key to prevent decreased visual function. Thus, close monitoring is essential, even if the drug is discontinued. OM

	DR. SHECHTMAN is a professor of optometry at Nova Southeastern University College of Optometry, where she serves as a clinician in the Eye Institute. She is also the coordinator of the macula diabetes service, the director of interdisciplinary education and a member of the Optometric Retinal Society. Email her at dianashe@nova.edu.
	DR. REYNOLDS is an associate professor at the Nova Southeastern University College of Optometry and clinical preceptor/attending in the college’s diabetes and macular clinic. She is a fellow of the Optometric Retina Society and chairperson for the Florida Optometric Association Healthy Eyes Healthy People Committee. Comment at tinyurl.com/OMcomment.