BASICS

DESCRIPTION

• Chloroquine and hydroxychloroquine (HCQ) (Plaquenil), drugs used to treat malaria and various dermatologic and inflammatory conditions – such as lupus and rheumatoid arthritis, can cause a maculopathy.

• Because of a lesser degree of retinotoxicity, HCQ has largely replaced chloroquine in the United States.

EPIDEMIOLOGY

Incidence

• Reported anywhere from 0 to 4%, with most reports citing an incidence of less than 1%

• Less than 50 cases reported from 1960 to 2005 (1)

RISK FACTORS

• Daily dose

– This is the most important risk factor. Nearly all reports of toxicity have occurred in those taking greater than 6.5 mg/kg/day of HCQ and greater than 3 mg/kg/day of chloroquine (2).

• Duration of treatment

– Reports of retinal toxicity at doses lower than 6.5 mg/kg/day have occurred almost universally in patients with more than 5 years of continuous usage (2).

• Age

– Malfunction of retinal pigment in the elderly may result in reduced drug clearance with increased accumulation (1).

– One case series of 47 patients showed that none of 9 patients younger than 60 years manifested retinopathy, whereas 13 patients older than 60 years did (3).

• Obesity

– Antimalarials do not accumulate in fat, which is why ideal body weight should be used in calculating dosages.

• Hepatic/renal failure

– Both chloroquine and HCQ are cleared via hepatic and renal pathways, with failure of either system potentially resulting in toxicity.

• Cumulative dose

– Initially believed to be the most important risk factor but there are reports of patients with no retinopathy despite very high cumulative doses of drug (3).

GENERAL PREVENTION

Absolute prevention requires avoidance of the drug; however, risk is extremely low when taking appropriate doses.

PATHOPHYSIOLOGY

• The mechanism of maculopathy is not well understood; however, it is known that both agents bind to melanin in the retinal pigment epithelium (RPE) (2), where they affect RPE metabolism, including its function of scavenging shed outer photoreceptor segments. This may in turn lead to photoreceptor degeneration.

– HCQ demonstrates less ocular toxicity due to the presence of the hydroxyl group, which renders it less able to traverse the blood–retinal barrier (1).

ETIOLOGY

Use of chloroquine or HCQ

COMMONLY ASSOCIATED CONDITIONS

In addition to retinopathy, these drugs are associated with intraepithelial corneal deposits, ciliary body involvement with impaired accommodation, and cataracts. These are less common with HCQ compared with chloroquine.

DIAGNOSIS

HISTORY

Symptoms can range anywhere from severe to asymptomatic. Most patients describe: decreased vision, blurry vision, difficulty reading, missing central vision, glare, light flashes, or metamorphopsia (1).

PHYSICAL EXAM

• Visual field testing

– Central visual field testing is the most important test for early diagnosis as functional loss in the area around the macula may appear prior to funduscopic changes.

– Defect begins as paracentral scotoma that may progress to confluence as a pericentral ring scotoma “bull’s eye” and finally a central scotoma.

– Peripheral loss occurs in advanced stages.

• Visual acuity testing

– Acuity defect does not typically manifest until a central scotoma occurs.

• Funduscopic examination

– In early, “premaculopathy” stages, the earliest visible signs of toxicity may include macular stippling and loss of foveal reflex.

– True maculopathy shows hyperpigmentation of the macula surrounded by a clear zone of depigmentation, which is surrounded by another ring of hyperpigmentation, giving the classic “bull’s eye” appearance.

– More extensive damage may show diffuse RPE atrophy over the entire fundus as well as vascular attenuation and disk pallor (1).

– Findings are almost always bilateral and symmetric.

• Funduscopic photography is used to document fundus appearance for later comparison.

• Color vision is not usually affected until later in disease course. Baseline screening of males is helpful to discern preexisting color deficits.

DIAGNOSTIC TESTS & INTERPRETATION

Imaging

Fluorescein angiography may not be helpful early as in early toxicity the subtle macular changes precede angiographic alterations (1).

Diagnostic Procedures/Other

• Electrophysiologic testing

– Electroretinogram (ERG) and electrooculogram (EOG) will show abnormalities in late toxicity and are helpful to assess extent of damage but have little role in screening for early toxicity.

– Multifocal ERG (mfERG) is newer technology that may be better able to detect a bull’s eye maculopathy; however, its role as a screening test remains unclear (2).

– Optical Coherence Tomography (OCT) can demonstrate “flying saucer” sign.

Pathological Findings

• Widespread destruction of rods/cones and the outer nuclear layer, with relative foveal sparing

• Migration of pigment from the RPE in the form of large pigment-laden cells has been reported in both the inner (4) and the outer (5) nuclear layer.

– Arteriolar narrowing in more advanced stages

DIFFERENTIAL DIAGNOSIS

• HCQ toxicity must be distinguished from cone dystrophy, cone-rod dystrophies, Stargardt’s disease, chronic macular hole, neuronal ceroid lipofuscinosis, and fenestrated sheen macular dystrophy.

• Premaculopathy must be distinguished from age-related macular degeneration (ARMD).

TREATMENT

ADDITIONAL TREATMENT

General Measures

• Cessation of the offending agent is critical. However, cessation of HCQ should be performed in conjunction with the internist or rheumatologist.

• Use ideal instead of actual body weight in calculating daily dose requirement.

• Ideal body weight for males = 50 kg + 2.3 kg/inch over 5 ft. For females = 45.5 kg + 2.3 kg/inch over 5 ft (1).

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

• The American Academy of Ophthalmology (AAO) prepared a consensus recommendation as follows (2):

– Within the first year of beginning therapy, all patients should have a baseline examination that includes visual acuity testing, dilated examination of cornea/retina, as well as central visual field testing using either red Amsler grid or Humphrey Visual Field 10-2 perimetry. Color vision testing, fundus photography, fluorescein angiography, and multifocal ERG are considered optional. Autofluorescence testing was not widely available but may also be considered.

– Each patient should be risk stratified as either high risk or low risk. A patient is high risk if they have: (1) a daily dose exceeding above recommendations, (2) duration of use more than 5 years, (3) obesity, (4) renal or liver disease, (5) concomitant retinal disease, or (6) age above 60 years.

– Low-risk patients (no risk factors) should be screened at least once from age 20–29 years, at least twice from age 30–39 years, every 2–4 years for age 40–64 years, and every 1–2 years for 65 years and older. Exams should include dilated corneal/retina exams and Amsler grid or Humphrey 10-2 fields. Other tests are optional at the discretion of the physician.

– High-risk patients should be screened annually. Exams should include the same components as in low-risk patients.

– Patients can be given Amsler grids to use at home and all patients should be instructed to return if they note any change in vision.

– Any patient with early toxicity should discuss drug cessation. Any patient with findings that may indicate early toxicity should be seen again in 3 months for reevaluation.

PATIENT EDUCATION

• Patient counseling is imperative.

– Antimalarials are typically prescribed by nonophthalmologists, so patients may not be fully informed of the ocular risk at the onset of treatment. It is important to emphasize that, although rare, retinopathy is a real and potentially devastating entity.

– Once retinopathy is suspected, a frank discussion regarding risks/benefits of continuing versus stopping the drug is important.

– Even with drug cessation, the majority of cases show persistence or even worsening of visual symptoms.

PROGNOSIS

• Depends on the severity of the retinopathy at the time of medication cessation. If stopped in premaculopathy stages, reversal is possible and visual prognosis is good.

• If true retinopathy exists, it will likely remain stable or can continue to progress.

COMPLICATIONS

Impaired vision

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