Subjective and objective screening tests for hydroxychloroquine toxicity

Abstract

Objective: To compare subjective and objective clinical tests used in the screening for hydroxychloroquine retinal toxicity to multifocal electroretinography (mfERG) reference testing.

Design: Prospective, single-center, case control study.

Participants: Fifty-seven patients with a previous or current history of hydroxychloroquine treatment of more than 5 years' duration.

Methods: Participants were evaluated with a detailed medical history, dilated ophthalmologic examination, color fundus photography, fundus autofluorescence (FAF) imaging, spectral-domain (SD) optical coherence tomography (OCT), automated visual field testing (10-2 visual field mean deviation [VFMD]), and mfERG testing. We used mfERG test parameters as a gold standard to divide participants into 2 groups: those affected by hydroxychloroquine-induced retinal toxicity and those unaffected.

Main outcome measures: We assessed the association of various imaging and psychophysical variables in the affected versus the unaffected group.

Results: Fifty-seven study participants (91.2% female; mean age, 55.7±10.4 years; mean duration of hydroxychloroquine treatment, 15.0±7.5 years) were divided into affected (n = 19) and unaffected (n = 38) groups based on mfERG criteria. Mean age and duration of hydroxychloroquine treatment did not differ statistically between groups. Mean OCT retinal thickness measurements in all 9 macular subfields were significantly lower (<40 μm) in the affected group (P < 0.01 for all comparisons) compared with those in the unaffected group. Mean VFMD was 11 dB lower in the affected group (P < 0.0001). Clinical features indicative of retinal toxicity were scored for the 2 groups and were detected in 68.4% versus 0.0% using color fundus photographs, 73.3% versus 9.1% using FAF images, and 84.2% versus 0.0% on the scoring for the perifoveal loss of the photoreceptor ellipsoid zone on SD-OCT for affected and unaffected participants, respectively. Using a polynomial modeling approach, OCT inner ring retinal thickness measurements and Humphrey 10-2 VFMD were identified as the variables associated most strongly with the presence of hydroxychloroquine as defined by mfERG testing.

Conclusions: Optical coherence tomography retinal thickness and 10-2 VFMD are objective measures demonstrating clinically useful sensitivity and specificity for the detection of hydroxychloroquine toxicity as identified by mfERG, and thus may be suitable surrogate tests.

Figure 1.

A, Multifocal electroretinography image demonstrating anatomic location for generation of ring ratios. Ring 1 corresponds to the central 3°, ring 2 represents the area from 3° to 10°, and ring 3 covers the area from 10° to 20°. B, Diagram showing the anatomic location of the optical coherence tomography subfields. The central subfield represents the central 3°, the inner subfield represents the area from 5° to 10°, and the outer subfield corresponds to the area from 10° to 20°.

Figure 2.

Graph showing multifocal electroretinography (mfERG) data from the worse eye of all participants. R1 central amplitudes are reported from the output of the mfERG directly and R1/R2 plots ring ratios. All eyes categorized as unaffected are shown in solid red circles. Participants with both eyes meeting criteria for the affected category are shown in solid black squares. Open red circles indicate individuals with one eye meeting mfERG criteria for toxicity with the other eye not meeting criteria. One eye meeting criteria is sufficient in this analysis to categorize the person as affected.

Figure 3.

Left column, Grading of Spectralis optical coherence tomography images of affected and unaffected participants with evaluation for disruption of the ellipsoid zone (EZ) in the paracentral retina. Right column, Examples of range of disruption in affected participants and images from affected participants without evidence of EZ disruption. Arrows indicate areas of disruption of the EZ.

Figure 6.

Rox-and-whisker plot for affected and unaffected patients showing (A) optical coherence tomography (OCT) inner inferior subfield retinal thickness and (B) the retinal thickness of inner inferior subfield from the OCT. Shaded boxes represent values from the 25th to 75th percentile with whiskers extending to the 1st percentile and 99th percentile. Receiver operating characteristic (ROC) curves for (C) OCT inner inferior subfield retinal thickness and (D) visual field mean deviation. AUC = area under the ROC curve.