In the two patients described here, SD-OCT and AO imaging detected abnormalities from hydroxychloroquine retinopathy that correlate topographically with clinical funduscopic findings and visual field loss as demonstrated by HVF 10-2 perimetry. SD-OCT images showed complete loss of the photoreceptor IS/OS junction with relative preservation of the RPE and external limiting membrane as previously described by Rodriguez-Padilla and colleagues23
; however, our SD-OCT images were acquired on two different commercially available SD-OCT machines instead of a research prototype. Additionally, our SD-OCT images reveal a distinct downward displacement, or “sink-hole effect,” of inner retina layers in areas overlying outer retinal abnormalities. Areas of outer retinal loss were very precise and localized to areas of toxicity in perifoveal areas corresponding to HVF 10-2 defects and ophthalmoscopic clinical examination findings. Adaptive optics images from an area with hydroxychloroquine retinopathy as seen both clinically and with HVF 10-2 defects showed disruption of the normal cone mosaic and quantitative alterations in cone packing.
SD-OCT and AO imaging also exhibited abnormalities in areas that appeared unaffected on HVF 10-2 and clinical funduscopic examination. These changes may represent a potential “preclinical” state of hydroxychloroquine toxicity. The exact mechanism of hydroxychloroquine retinal toxicity is not fully understood. Animal studies have shown that the first evidence of toxicity with chloroquine is seen in the retinal ganglion cells.24
However, histology has shown that perifoveal photoreceptor cells are most severely affected25
and that this may be a secondary effect due to disruption of RPE metabolism. Chloroquine and hydroxychloroquine are known to disrupt lysosomal function of the RPE, leading to increased accumulation of lipofuscin.26,27
Daily phagocystosis of photoreceptor outer segments occurs in the lysosomal apparatus of the RPE, and alterations in RPE metabolism may play a role in retinal toxicity.26,27
Mahon and associates27
also found an apparent accumulation of autophagic granules in cone photoreceptor cells exposed to chloroquine in an animal model. Rod photoreceptors did not show these granules, and the investigators hypothesize that this defective degradative capacity that appears more predominant in cone photoreceptors could also play a role in toxicity. Given this information, it makes sense that early toxicity would present with subtle changes in the photoreceptor mosaic, and that this would precede the dramatic loss of outer retinal structures seen with more severe hydroxychloroquine retinopathy. Evidence of a defective degradative capacity in cones may also suggest that they are preferentially affected more than rod photoreceptors, and this may be apparent even in early stages of toxicity.
In areas that appeared unaffected by funduscopic examination and with no visual field defects as seen on automated perimetry, our SD-OCT imaging showed areas of a characteristic “moth-eaten” appearance in the photoreceptor IS/OS layer with preservation of inner retina architecture (eg, , location 3). AO imaging done at this same location ( and C) showed a decrease in photoreceptor spacing, indicating an increased density of photoreceptor cells of approximately 98,000 cells/mm2
. Normal cone density in this location is approximately 23,000 cones/mm2
, making it more likely that most photoreceptors imaged at this location are rod photoreceptors instead of the cone photoreceptors. Densities calculated from AO imaging are similar to histological samples of normative rod photoreceptor data at this retinal eccentricity.22
This suggests that cone photoreceptors are missing or significantly diminished in number at this location and also that cone photoreceptors may be more susceptible to plaquenil toxicity than rod photoreceptors. This decrease of cone photoreceptors may be responsible for the “moth-eaten” photoreceptor IS/OS appearance seen on SD-OCT. These areas likely represent a “preclinical” stage of hydroxychloroquine retinopathy that with time will develop a severe loss of outer retinal structures and become apparent on clinical examination and visual field testing.
Adaptive optics imaging may also be more sensitive than SD-OCT in identifying these “preclinical” areas of retinal toxicity. In AO images taken at location 2 in the left eye of patient 1, the cone mosaic had patches of contiguousness, but cone spacing was increased to 1.10 ± 0.15 arc min (mean ± 1 SD). Average cone spacing at this retina eccentricity is approximately 0.8 arc min.18
Increased cone spacing indicates a reduced density of photoreceptors at this location. The photoreceptor spacing at this location also falls more than 2 SDs from the mean of normative cone data obtained from histological samples.22
This suggests that the structures imaged are morphologically compromised swollen cones or that the overall number of cone photoreceptors in this location is decreased. This may represent the first signs of hydroxychloroquine toxicity with cone photoreceptor dropout. SD-OCT images were normal at this location.
Current screening methods for hydroxychloroquine retinopathy are limited in that they detect toxicity only after retinal damage has occurred as seen on funduscopic abnormalities and visual field defects. Furthermore, funduscopic changes can be subtle and tend to be a late finding, Amsler grid testing is highly subjective, and automated perimetry can show a steep learning curve. Recently mERG has been shown to be abnormal in hydroxychloroquine retinopathy, and it may be able to detect subtle changes in earlier stages of toxicity.28–30
However, mERG is limited by clinical availability, patient cooperation, specialized training for administration and interpretation, and cost.
This study has shown that both SD-OCT and AO imaging are able to demonstrate abnormalities in the outer retina in hydroxychloroquine retinopathy. Furthermore, both SD-OCT and AO may be able to detect abnormalities at an early, “preclinical” stage of hydroxychloroquine toxicity. Obvious limitations of the study include its small sample size and its retrospective nature that allows one to look for abnormalities that may or may not be attributed to hydroxychloroquine. That being said, the noninvasive, amazing resolution and quantitative aspects of SD-OCT and AO imaging make them attractive as possible screening options for hydroxychloroquine toxicity. SD-OCT machines are becoming more common in clinical settings, and AO imaging development will likely result in a clinical model soon. These modalities may prove to be useful and effective tools for hydroxychloroquine retinal toxicity screening. Further research is needed.