Testing for Chloroquine and Hydroxychloroquine Retinopathy
Although the exact mechanism by which chloroquine (CQ) and hydroxychloroquine (HCQ - commonly known as Plaquenil) induce retinal toxicity is not well understood, but it is recognized as a serious ophthalmologic concern because it is not treatable.1 Guidelines from the American Academy of Ophthalmology (AAO) on screening for CQ and HCQ toxicity recommend that all patients starting therapy receive a baseline screening followed by annual follow-up visits beginning at 5 years after the start therapy—although some individuals with certain high risk factors might require closer monitoring.1 Above and beyond their role in screening, eye care professionals have a valuable role in educating patients and medical colleagues about safe dosing, risk factors, and the need for screening.
Risk Factors and Safe Dosing Recommendations
The 2016 guidelines from the AAO update previously published recommendations based on new clinical data. Prominently, the panel of experts reviewing the data acknowledged that the risk of retinal toxicity in patients using CQ or HCQ therapy is likely higher in patients on higher doses used for longer durations, although the data on what constitutes a “safe” dose is inconclusive. Evidence from a large-scale clinical trial found that the risk of developing retinopathy for individuals using a daily dose ≤5.0 mg/kg was less than 1% in the ﬁrst 5 years of therapy and less than 2% up to 10 years of use. 2 The panel recommended a daily dosage of <5.0 mg/kg real weight. It is important to note ideal weight formulas may introduce unwarranted risk, as they may result in overdosage in thin individuals and cannot accurately account for fluctuations in body type.
Several major risk factors (including dose and duration of use, renal disease, retinal and macular disease, and concomitant tamoxifen use) and lesser risk factors (age, liver disease, and potential genetic influences) for CQ/HCQ retinal toxicity have been identified. Recently available data suggest that ethnicity might be a factor in the clinical presentation of CQ/HCQ retinopathy, which may in turn impact how patients are screened.3,4 In particular, those of European descent tend to exhibit initial photoreceptor damage in the parafoveal region, while Asian individuals more often show initial damage in the peripheral extramacular region near the arcades. In clinical studies, individuals of African-American and Hispanic descent showed a similar pattern as those of European heritage, but greater tendency toward extramacular involvement.
Overall, the AAO maintained a strong emphasis on screening, with the caveat that therapy need not be discontinued immediately at the first clinical signs of retinopathy. Rather, central vision can likely be preserved if damage is detected before changes occur in the retinal pigment epithelium (RPE).5 Fortunately, the increased utilization of screening has reduced the number of cases detected at the later stages of disease characterized by bilateral bull’s-eye maculopathy, when irreversible cellular damage has occurred and RPE damage is observable on fundus examination or with imaging.
The Role of Visual Fields, OCT, and Multifocal ERG
The AAO guidelines recommend using automated visual fields and spectral-domain OCT as primary screening tests, “because these are widely available.”1 Visual fields are described as subjective, functional tests that, although sensitive, are also highly variable depending on the test-taker’s responses. Visual field results may also vary considerably between visits. In light of evidence suggesting different clinical patterns of retinopathy in individuals of various ethnicities, it is also necessary to tailor the field pattern to the patient (i.e., 24-2 or 30-2 for Asian patients).
OCT, on the other hand, is an objective, structural test, that is “highly speciﬁc, and generally sensitive for levels of damage that might be visually signiﬁcant.”1 Although OCT might depict initial distinct focal interruption of the photoreceptor outer segment structural lines, it is more useful for showing localized thinning of the RPE only after damage has occurred.
The AAO guidelines go on to recommend the use of the multifocal electroretinogram (multifocal ERG or mfERG) as a functional test that can provide objective corroboration for visual fields by documenting parafoveal or extramacular electroretinogram depression in early retinopathy.1 It is worth noting that the American Academy of Rheumatology (AAR) also recommends multifocal ERG be used as an objective test during the retinal exam.6 Multifocal ERG vision testing is a type of light induced visual response (LIVR) that records the electrical activity of bipolar cells, combined with smaller contributions from the photoreceptors, responding to localized flashes of light.
Given the different types of information visual fields and OCTs provide, as well as some inherent shortcomings, there may be a greater role for multifocal ERG, especially considering the availability of devices that make the technology more accessible to the ophthalmic practice. In the guidelines, the stated preference for OCT appears to be based on wide adoption of this platform and the structural information provided. The expert panel agreed that multifocal ERG is sufficiently sensitive to objectively document dysfunction in early retinopathy. There are now thousands of eye care professionals across the US, and more globally, that are using visual electrophysiology in their practice. This wide acceptance is in response to the need for objective, functional testing that complements other testing methods resulting in better patient outcomes.
In terms of confirmatory testing in light of an abnormal or suspicious visual field test, multifocal ERG provides important, actionable data to the clinical impression at a stage when toxic effects may be reversible.7 On the other hand, a subset of patients exhibit normal multifocal ERG patterns despite abnormal visual field findings, and therefore may be able to continue using CQ or HCQ.
There is an urgent need to detect early stage retinopathy considering that toxicity may continue to progress even after cessation of CQ or HCQ, with a potentially greater rate of decline if therapy is stopped at later stages of retinopathy. Thus, patients derive the greatest benefit in terms of long-term visual prognosis if they are diagnosed with retinal toxicity soon after changes begin to occur but before structural deficits can be observed on imaging. Because multifocal ERG testing is highly sensitive to early retinopathy and repeat multifocal electroretinograms can depict subtle changes, these objective tests contribute significantly to the overall clinical impression to initiate changes in care.7
The current AAO guidelines are not definitive as to if or when to suggest discontinuation of therapy, leaving it to the patient’s prescribing physician and ophthalmic specialist to collectively make a reasonable judgment based on available evidence. The ability to objectively detect subtle changes in retinal function using multifocal ERG at this early stage of disease places the patient and coordinating physicians in a better position to minimize vision loss from retinal toxicity.
1. Marmor MF, Kellner U, Lai TY, Melles RB, Mieler WF; American Academy of Ophthalmology. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 2016;123(6):1386-1394. 2. Melles RB, Marmor MF. The risk of toxic retinopathy in pa-tients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132:1453-1460. 3. Melles RB, Marmor MF. Pericentral retinopathy and racial differences in hydroxychloroquine toxicity. Ophthalmology 2015;122:110-116. 4. Lee DH, Melles RB, Joe SG, et al. Pericentral hydroxy-chloroquine retinopathy in Korean patients. Ophthalmology 2015;122:1252-1256. 5. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol 2014;132:1105-1112. 6. American College of Rheumatology Position Statement: Screening for Hydroxychloroquine Retinopathy. Updated: 10/4/2016. 7. Dettoraki M; Moschos MM. The Role of Multifocal Electroretinography in the Assessment of Drug-Induced Retinopathy: A Review of the Literature. Ophthalmic Res. 2016; 56(4):169-177.
The Diopsys® NOVA is an electrophysiology device that generates photic stimuli, and records, processes, and analyzes the resultant signals to provide information about the visual system. Diopsys Vision Testing Systems are FDA 510(k) cleared; carry the CE mark; and are IEC 60601 Certified.