March 2016 · Vol. 47, No. 3 207

Practical RetinaIncorporating current trials and technology into clinical practice

Hydroxychloroquine: A Brief Review on Screening, Toxicity, and Progressionby Yasha S. Modi, MD; Rishi P. Singh, MDIn 2011, the American Academy

of Ophthalmology published up-dated guidelines on screening for retinal toxicity from chloroquine and hydroxychloroquine. Al-though hydroxychloroquine has been in clinical use for decades, initially as an anti-malarial drug and then as an immunosuppres-sant for a number of autoimmune conditions, protocols to screen for retinal toxicity continue to evolve as our imaging technology advances.

Part of the challenge lies in the fact that there exists no single gold-standard objective test for toxicity; rather, clinicians must interpret clues from a number of imaging modalities. Early signs of toxicity can be subtle, but it is imperative to detect disease promptly, as the classic “bull’s-eye maculopathy” is a late finding. Late toxicity is devastating and typically associ-ated with severe, bilateral, and ir-reversible vision loss.

In this installment of Practi-cal Retina, Yasha S. Modi, MD, and Rishi P. Singh, MD, provide a welcome and well-illustrated guide to current screening guide-lines, pearls for interpreting each screening modality, and insights into future research for earlier reli-able detection

Howard F. Fine

Practical Retina

Co-Editor

The anti-malarial drugs chloroquine (CQ) and hy-droxychloroquine (HCQ) are used to treat a variety of au-toimmune diseases such as rheumatoid arthritis and sys-temic lupus erythematous.1,2 HCQ, the hydroxylated form of chloroquine, has demon-strated a more favorable side

effect profile with decreased ocular toxicity, although the risk for retinopathy is still present with rates varying between 1% to as high as 7.5% in patients with long-term exposure.3-9

Historically, HCQ retinal toxicity was identified by symptoms such as central visual loss, including difficulty reading, reduced color vision, and central scotoma. Funduscopic exam demon-strated signs ranging from fine pigmentary stippling of the macula and loss of the foveal light reflex, referred to as premaculopathy, to the characteristic bilateral bull’s-eye maculopathy.10,11 Given these irreversible late clinical findings, screening guidelines with the intended goal of detecting functional and anatomic ab-normalities prior to symptom onset, have been implemented.

SCREENING GUIDELINES

In 2011, the American Academy of Ophthalmology (AAO) re-vised its 2002 guidelines for HCQ retinal toxicity screening.12 In contradistinction to the 2002 guidelines, the 2011 guidelines recommended subjective testing with a 10-2 Humphrey visual field that could no longer be substituted by the previously ac-cepted Amsler grid test.12-14 An alternatively accepted objective test in the 2011 guidelines includes a multifocal electroretino-gram (mfERG). Additional recommended objective tests to detect

Rishi P. SinghYasha S. Modi

doi: 10.3928/23258160-20160229-02

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anatomic change include spectral-domain optical co-herence tomography (SD-OCT) and fundus autofluo-rescence (FAF). Acceptable pairs of screening tests include a HVF 10-2 (subjective test) with either a SD-OCT or FAF (objective tests). An alternatively accept-ed screening modality is an mfERG as a stand-alone test, given the test is both objective and conveys in-formation on subtle retinal functional abnormalities.

The guidelines further reiterated specific risk factors associated with toxicity and made screen-ing guidelines accordingly. The designation of high-risk included patients with: cumulative HCQ consumption greater than 1 kg, daily dosing greater than 6.5 mg/kg/day of ideal body weight, or con-comitant renal or liver disease. Additional, albeit less definitive, risk factors included advanced age or comorbid retinal or macular disease. For those without high-risk characteristics, a baseline screen-ing upon initiation of HCQ was recommended fol-lowed by a 5-year examination-free window. For patients with high-risk factors, annual screening was recommended.12

DETECTING HCQ TOXICITY

There remains no established criterion for di-agnosing HCQ toxicity and, as such, the physi-cian must rely on a combination of characteristic functional and anatomic abnormalities to diagnose a patient with HCQ toxicity. An understanding of each screening modality and a keen eye to detect subtle abnormalities is critical to diagnosing early disease.

SD-OCT has emerged as a sensitive and repro-ducible screening modality to detect early HCQ screening. The earliest observable qualitative alter-ations include outer retinal changes, such as loss of the cone outer segment tip line and parafoveal loss of the ellipsoid zone, which advances to parafoveal thinning of the outer nuclear layer and subsequent damage of the retinal pigment epithelium.15 This later, classic stage is described as the “flying sau-cer” sign (Figures 1A-1C).16 If the screening oph-thalmologist detects any level of outer retinal at-tenuation or thinning in the parafoveal region, a high degree of suspicion for HCQ toxicity must be maintained and corroborated with other screening modalities.

FAF is a test that indirectly evaluates the func-tionality of the retinal pigment epithelium (RPE). Lipofuscin, which is stored in the RPE and has in-herent autofluorescent properties, is detected by this screening modality. It is believed that hyper-autofluorescence corresponds to a dysfunctional or “sick” RPE manifesting as an accumulation of lipo-fuscin, whereas hypoautofluorescence corresponds to the absence of the RPE.16 In the setting of HCQ toxicity, parafoveal changes of hyperautofluores-cence precede the development of hypoautofluo-rescence. Figure 2A demonstrates a classic example of hyper- and hypoautofluorescence corresponding to RPE dysfunction and loss in a bull’s-eye pattern, whereas Figure 2B demonstrates a more subtle ab-

A

B

C

Figure 1. (A) Nasal and temporal parafoveal outer-retinal thinning and ellipsoid zone (EZ) attenuation that progresses to frank loss of the EZ and external limiting membrane, resulting in the classic UFO sign (B). In severe toxicity, there is near total loss of the outer retina, pigment migration into the outer retina, and cystoid retinal changes (C).

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normality manifesting solely abnormal hyperauto-fluorescence. Of note, pathologic involvement of the RPE in HCQ toxicity has been demonstrated to be a later-stage finding than parafoveal outer reti-nal changes seen on OCT,15 and thus the authors believe FAF may be better used as a confirmatory screening test or test to follow patients with known toxicity.

Humphrey visual field 10-2 remains a gold stan-dard in HCQ screening. Although earlier publica-tions have espoused the use of a red stimulus,7 the 2011 AAO recommendations advocate the use of the white stimulus.17 When evaluating a reliable visual field result, any central or paracentral abnor-malities, particularly if there are contiguous points of depression, should be taken as a potential sign of HCQ toxicity. Any abnormalities should be corre-lated with objective tests, including OCT and FAF, and the visual field should be repeated in a short time frame to corroborate the abnormal result. Fig-ure 3 demonstrates a case of reproducible paracen-tral scotomas in a patient with HCQ toxicity but an otherwise seemingly normal SD-OCT and FAF. This example underlies the importance of this imaging modality, as it suggests that the earliest pathologic sign may manifest through a reliable HVF.

mfERG is a recent addition to the armamentarium of HCQ screening tools in HCQ. This test generates localized and topographic ERG responses across the posterior pole and can objectively and reproducibly

detect paracentral ERG depression in HCQ toxicity.17 The characteristic waveform abnormalities seen in-clude paracentral amplitude loss.18 A protracted im-plicit time, in conjunction with a paracentral decrease in retinal function, has demonstrated increased spec-ificity in evaluating patients with HCQ toxicity.18 Al-though the test is highly sensitive in detecting macu-lar dysfunction,19-21 the limited availability, longer testing time, and need for specialized expertise in in-terpretation limits its use. A recent study by Cukras et al. utilizing mfERG as a “gold standard” for identify-ing HCQ toxicity reported that SD-OCT retinal thick-ness and Humphrey visual field 10-2 mean deviation detected toxicity in all cases and the combination of these tests might serve as suitable and less-expensive surrogate markers of toxicity.22

PROGRESSION OF HCQ TOXICITY

Once HCQ toxicity is diagnosed, it is critical to stop or change the medication while maintain-ing control of the patient’s underlying systemic disease. This oftentimes requires frequent com-munication between the ophthalmologist, rheuma-tologist, and patient to optimize both ocular and systemic health.

With the exception of stopping HCQ, there are no other treatment options for preventing further HCQ toxicity. Additionally, there are no estab-lished guidelines for following patients with toxic-ity. Retrospective reports have demonstrated that

Figure 2. (A) A broad area of hyperautofluorescence throughout the macula and hypoautofluorescence corresponding to loss in a bull’s-eye pattern. (B) Perifoveal hyperautofluorescence, suggestive of retinal pigment epithelium dysfunction.

A B

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Figure 3. (A, B) A case of reproducible paracentral scoto-mas in a patient with hydroxychloroquine toxicity. The spectral-domain optical co-herence tomography demonstrates a shag-gy outer plexiform layer appearance but otherwise minimal outer-retinal parafo-veal attenuation (C). The macular fundus autofluorescence pat-tern is otherwise unre-markable (D).

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patients with HCQ may remain stable or continue to progress despite stopping the medication.23,24 Marmor et al., evaluating a small series of patients with toxicity, demonstrated that severe disease in-volving paracentral RPE loss is more likely to prog-ress despite cessation of the medication, whereas early and moderate disease demonstrates greater anatomic and functional stability over time with progression confined mostly to the first year.9,23 More recently, Mittelu et al. demonstrated subclin-ical regeneration of the ellipsoid zone for patients with an intact ELM at the time of diagnosis,24 sug-gesting there may be a threshold level that under-lies the transition from stable or reversible toxicity to progressive toxicity.

CURRENT RESEARCH AND POTENTIAL APPLICATION TO CLINICAL CARE

Research in HCQ has consistently focused on elucidating pathophysiologic mechanisms of tox-icity as well as detecting disease at incrementally earlier levels of toxicity. Although the pathophysi-ology of HCQ toxicity remains unknown, animal models of chloroquine toxicity have demonstrated inner-retinal changes (lysosomal damage in the ganglion and bipolar cells) as the first abnormality that ultimately progresses to lysosomal disruption in the photoreceptors or RPE.25,26 These inner-ret-inal abnormalities have been correlated in human studies in which OCT demonstrated relative thin-ning of the inner retina in HCQ toxicity relative

to control.27-29 These findings, however, have not been uniformly substantiated, and controversy ex-ists regarding the layers affected in HCQ toxicity, as well as which layers are first involved.9 Despite this controversy, this body of research has applied novel segmentation algorithms (Figure 4), which consistently demonstrate paracentral outer-retinal thinning in the setting of toxicity. This affords the clinical opportunity to follow patients longitudi-nally and rely on a quantitative rather than qualita-tive assessment to identify parafoveal outer retinal attenuation at an earlier stage.

CONCLUSION

Macular toxicity is a rare, but potentially devastat-ing finding in patients exposed to long-term or high-dose HCQ use. The disease follows a predictable pat-tern that makes it amenable to screening. Although HVF 10-2 has remained a gold standard in HCQ screening, the addition of SD-OCT, FAF, and mfERG to the screening armamentarium allow for increasing-ly earlier detection of subtle toxicity. A keen recogni-tion of subtle imaging abnormalities remains critical to making the diagnosis in the subclinical window.

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Figure 4. Individual layer segmentation lines in a patient with mild hydroxychloroquine toxicity. The Iowa reference algorithm was utilized in this example. The segmentation yields thickness and volume measurements for each layer that can be longitudinally followed across clinic visits. This algorithm currently remains as a research tool only but may have significant clinical applications in the near future.

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Yasha S. Modi, MD, can be reached at the Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; 914-474-3020; email: yasha.modi@gmail.com.

Howard F. Fine, MD, MHSc, can be reached at NJ Retina, 10 Plum Street, Suite 600, New Brunswick, NJ 08901; 732-220-1600; fax: 732-220-1603; email: hffine@gmail.com.Rishi P. Singh, MD, can be reached at the Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk i32, Cleveland, OH 44195; email: drrishisingh@gmail.com.Disclosures: Dr. Modi has no relevant financial disclosures. Dr. Singh is a consultant for Alcon, Regeneron, Shire, and Genentech and has sponsored research from Alcon, Regeneron, Genentech, Neurotech, and Apellis. Dr. Fine is a consultant for Allergan, Genentech, and Regeneron and has pat-ent and equity interest in Auris Surgical Robotics.