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09.11.2017 | Clinical Case Report | Ausgabe 1/2018 Open Access

Documenta Ophthalmologica 1/2018

Perifoveal interdigitation zone loss in hydroxychloroquine toxicity leads to subclinical bull’s eye lesion appearance on near-infrared reflectance imaging

Documenta Ophthalmologica > Ausgabe 1/2018
Avenell L. Chew, Danuta M. Sampson, Enid Chelva, Jane C. Khan, Fred K. Chen
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1007/​s10633-017-9615-9) contains supplementary material, which is available to authorized users.



To characterize the ultrastructural and functional correlates of hydroxychloroquine (HCQ)-induced subclinical bull’s eye lesion seen on near-infrared reflectance (NIR) imaging.


An asymptomatic 54-year-old male taking HCQ presented with paracentral ring-like scotoma, abnormal multifocal electroretinography (mfERG) and preserved ellipsoid zone on optical coherence tomography (OCT). Dense raster OCT was performed to create en face reflectivity maps of the interdigitation zone. Macular Integrity Assessment (MAIA) microperimetry and mfERG findings were compared with NIR imaging, en face OCT, retinal thickness profiles and wave-guiding cone density maps derived from flood-illumination adaptive optics (AO) retinal photography.


The bull’s eye lesion is an oval annular zone of increased reflectivity on NIR with an outer diameter of 1450 µm. This region corresponds exactly to an area of preserved interdigitation zone reflectivity in en face OCT images and of normal cone density on AO imaging. Immediately surrounding the bull’s eye lesion is an annular zone (3°–12° eccentricity) of depressed retinal sensitivity on MAIA and reduced amplitude density on mfERG. Wave-guiding cone density at 2° temporal was 25,400 per mm2. This declined rapidly to 12,900 and 1200 per mm2 at 3° and 4°.


Multimodal imaging illustrated pathology in the area surrounding the NIR bull’s eye, characterized by reduced reflectance, wave-guiding cone density and retinal function. Further studies are required to investigate whether the bull’s eye on NIR imaging and en face OCT is prominent or consistent enough for diagnostic use.

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Supp Fig. 1 10–2 Humphrey automated perimetry output in a field view perspective for the left (A) and right (B) eyes retinal threshold values and deviation from the mean of a healthy population. The symbols in the total and pattern deviation plots denote retinal threshold deviations that were in the bottom 5, 2 or 1 percentile of healthy population based on non-Gaussian statistics provided by the Humphrey field perimeter. (TIFF 341 kb)
Supp Fig. 2 10–2 Macular Integrity Assessment (MAIA) microperimetry presented in a normalized deviation plot in retinal view perspective showing locations where measurement values were -2.00 to -2.99 standard deviations (yellow) or -3.00 or more standard deviations (red) from the expected mean derived from 36 healthy controls. Results from the right (A) and left (B) eyes in 2014 and right (C) and left (D) eyes in 2015 showed worsening of pericentral incomplete ring scotoma with increased number of loci having sensitivity dropping below -2 or -3 standard deviations from normal. Note that the central 4 loci at 1° and 1° eccentricity are spared except in the left eye in 2014. (TIFF 899 kb)
Supp Fig. 3 Multifocal electroretinography presented in a normalized deviation plot in retinal view perspective showing a ring-like zone of amplitude density reduction (toward dark green color: negative standard deviation) in the right (A) and left (B) eyes and corresponding region of implicit time delay (toward orange-red color: positive standard deviation) in the right (C) and left (D) eyes. Ring ratio (Rx:R6) plot showing significant reduction in response density at 4° to 12° eccentricity (red colored region) in right (E) and left (F) eyes, but the implicit time delay did not exceed the expected normal range (shown in green). Y-axis is the ring ratio, and x-axis is the retinal eccentricity from fixation in degrees. Red line denotes normal mean. Black line denotes patient data. Green zone denotes normative range within 2 standard deviations from the mean. Red zone denotes deviation of patient line outside the normative range. The smoothed ring ratio plot is a cubic spline interpolation provided by the manufacturer to facilitate visualization. (TIFF 1798 kb)
Supp Fig. 4 Multifocal electroretinography presented in a normalized deviation plot in a retinal view perspective showing stimulus locations where measurement values were 2.00 to 2.99 standard deviation (yellow) or 3.00 or more standard deviations (red) from the expected mean derived from a control cohort. A complete ring of reduced amplitude density is seen in the right (A), but only a partial ring is present in the left (B) eye. Implicit time delay is only found in scattered locations forming an incomplete ring in both the right (C) and left (D) eyes. Note that rings 1 (central hexagon) and 2 (6 surrounding hexagon) have response densities and implicit times within 2 standard deviation of mean from the control sample. (TIFF 9938 kb)
Supp Fig. 5 Near-infrared reflectance (NIR) image (A) and optical coherence tomography (OCT) image (B) of the patient with hydroxychloroquine (HCQ) toxicity showing a bull’s eye lesion and its correlation with interdigitation zone attenuation between 2° and 3° of eccentricity. Yellow scale marks visual angle in degrees of eccentricity, and the inserts below the horizontal OCT scan show zoomed images of the four outer hyper-reflective bands corresponding to external limiting membrane, ellipsoid zone, interdigitation zone and retinal pigment epithelium, respectively, at 0°, 1, 2°, 3°, 4° and 5° of retinal eccentricities. In the healthy control eye, NIR (C) shows no bull’s eye lesion and OCT (D) shows no attenuation of the interdigitation zone up to 5° of eccentricity (insert denoting retinal location in visual angle). (TIFF 1939 kb)
Supp Fig. 6 Retinal thickness map in the Early Treatment of Diabetic Retinopathy Study grid presented in a normalized deviation plot in a retinal view perspective showing regions where thickness (A, B) and volume (C, D) were -2.00 to -2.99 standard deviation (yellow) from the expected mean derived from a control cohort. In all eyes, the central 1-mm zone thickness and volume were within normal range. The right (A) eye retinal thickness map shows retinal thinning of all quadrants in the inner ring (diameter 1 to 3 mm) and only the temporal zone of the outer ring (diameter 3 to 6 mm). The left eye (B) retinal thickness map shows thinning in the temporal and superior zones of the inner ring and temporal zone of the outer ring. There is also reduction in retinal volume in temporal, superior and inferior zones of the inner ring and temporal zones of the outer ring in right (C) and left (D) eyes. (TIFF 4076 kb)
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