Atypical Presentations of Hydroxychloroquine Retinopathy

 

Jung Min Lee1*, Hyeon Yoon Kwon1*, Seong Joon Ahn1

 

1Department of Ophthalmology, Hanyang University Hospital, Hanyang University College of Medicine, Seoul, Korea

*Jung Min Lee and Hyeon Yoon Kwon contributed equally to this work.

 

Running head: Atypical Hydroxychloroquine Retinopathy

 

* Correspondence:

Seong Joon Ahn, MD, PhD
Department of Ophthalmology,

Hanyang University Seoul Hospital

222-1 Wangsipli-ro, Seongdong-gu, Seoul 04763, Republic of Korea

Tel.: 82-2-2290-8574

Fax: 82-2-2291-8517

E-mail: ahnsj81@gmail.com


 

ABSTRACT

Hydroxychloroquine retinopathy, traditionally characterized by parafoveal or pericentral outer retinal damage, is explored for atypical presentations. This challenges conventional beliefs regarding onset, regional dominance, and associated visual field defects. Ninety-five patients diagnosed with hydroxychloroquine retinopathy at Hanyang University Hospital underwent screening from January 2010 to December 2023 were included for this study. Swept-source optical coherence tomography (SS-OCT), ultrawide-field fundus autofluorescence (UWF-FAF), and automated visual fields (VF) were employed for detailed structural and functional evaluations. Among 95 patients, 14 (14.7%) exhibited atypical presentations, including very early onset (n = 1), (far) peripheral-dominant damages (n = 4), perivascular involvement (n = 1), bitemporal hemianopsia due to nasal extensive lesions (n = 1), unilateral involvement (n = 2), asymmetric involvement in retinopathy pattern or severity between the eyes (n = 7). Findings suggest a need for expanded screening, including ultrawide-field FAF imaging, to atypical presentations on the dominant area of retinal damages. Clinicians must recognize these atypical presentations for timely diagnosis and appropriate management. Further research with larger sample sizes is warranted to validate our findings and explore additional atypical presentations.

INTRODUCTION

Hydroxychloroquine retinopathy, a recognized toxic retinopathy, manifests as paracentral or pericentral outer retinal damage, posing a significant concern for individuals undergoing prolonged hydroxychloroquine treatment.1,2 Typically emerging after 5 years of hydroxychloroquine use, this condition is more prevalent in individuals with major risk factors, such as a high daily dose (daily dose/body weight > 5 mg/kg), extended duration of use (beyond 5 years), kidney disease, combined macular disease, and concurrent tamoxifen usage.1 The American Academy of Ophthalmology (AAO) advocates for regular screening, including optical coherence tomography (OCT), fundus autofluorescence (FAF), automated visual fields (VF), and/or multifocal electroretinogram (mfERG) after 5 years of hydroxychloroquine use. In cases with major risk factors, screening may be initiated earlier to ensure timely detection.1,3

             Typically, hydroxychloroquine retinal toxicity presents as photoreceptor defects in the parafoveal or pericentral areas, with or without accompanying retinal pigment epithelium (RPE) defects on OCT. These alterations correspond to hyper- or hypo-autofluorescence in the parafoveal or pericentral areas on FAF.1,4,5 Automated visual fields may reveal patchy scotoma, paracentral ring scotoma, or central island, contributing to functional evidences on the retinal damages caused by hydroxychloroquine.1,4,5 Furthermore, multifocal electroretinogram (mfERG) provides a spatially specific evaluation of retinal function and aiding in the comprehensive characterization of hydroxychloroquine-induced retinopathy, decreased amplitude in the parafoveal or pericentral regions.

             In this case series, we report atypical presentations of hydroxychloroquine retinopathy in a cohort of 95 Asian (Korean) patients with hydroxychloroquine retinopathy. Our exploration not only highlights the uniqueness of these cases but also addresses the imperative to distinguish them from typical presentations of hydroxychloroquine retinopathy. We present a thorough analysis of multimodal imaging, with the overarching goal of contributing to the early detection of atypical presentations of hydroxychloroquine retinopathy, as well as typical manifestations. This comprehensive approach aims to mitigate the risk of delayed diagnoses and enhance the overall management of patients undergoing hydroxychloroquine treatment.

 

METHODS

Subjects

This study examined 95 patients diagnosed with hydroxychloroquine retinopathy at Hanyang University Hospital between January 2010 and December 2023. Screening for toxicity included OCT, FAF, and VF assessments for all participants, with mfERG utilized in selected cases requiring additional evidence of retinal toxicity. Diagnosis of hydroxychloroquine retinopathy was made based on a combination of abnormalities from at least two of the following tests: OCT, VF, FAF, and mfERG.6,7 The research adhered to the principles outlined in the Declaration of Helsinki and obtained approval from the Institutional Review Board (IRB) at Hanyang University Hospital. Due to the retrospective nature of the study and deidentified data, the IRB of Hanyang University Hospital waived the requirement for informed consent.

 

Evaluation

Specifically, to detect structural damage caused by hydroxychloroquine toxicity, we conducted swept-source OCT (SS-OCT) and FAF. SS-OCT, utilizing the DRI-Triton device from Topcon Inc., Tokyo, Japan, involved a 3D macular volume scan covering a 9 × 12-mm² grid centered on the fovea. The scan speed was set at 100,000 A-scans per second, and the axial resolution was 8 µm. Additionally, a 12-mm radial scan was performed, producing 12 radially oriented line scans passing through the fovea, with a scan length of 12 mm, at both baseline and follow-up visits.8,9 FAF images were acquired using either an ultrawide-field (UWF) scanning laser ophthalmoscope (Optos 200Tx; Optos PLC, Dunferm-line, United Kingdom) or a conventional (40°) scanning laser ophthalmoscope (F-10; Nidek, Tokyo, Japan).2 To assess functional defects, standard automated perimetry, employing the 30–2, 10–2, or both strategies, was conducted using the Humphrey Field Analyzer II or III (Carl Zeiss Meditec, Dublin, CA).(6) Additionally, mfERG was performed in selected cases requiring additional objective evidence of retinal toxicity based on the 61-hexagon stimulus pattern of the VERIS Clinic system (Electro-Diagnostic Imaging, Inc., Redwood, CA, USA) according to the guidelines of the International Society for Clinical Electrophysiology of Vision (ISCEV).

Based on the primary site of retinal damage, eyes affected by hydroxychloroquine retinopathy were categorized into distinct groups: parafoveal (involving photoreceptor/RPE disruption within 2–8° of the fovea), pericentral (exhibiting outer retinal damage beyond 8° from the fovea), or mixed (displaying similar or extensive involvement in both areas).2,9 The severity of retinopathy in these eyes was classified as early (localized hyper-autofluorescence on FAF and/or localized photoreceptor defects without RPE involvement on OCT), moderate (involving photoreceptor damage [hyperautofluorescence] with a partial [> 180°] or complete ring on FAF), or severe (manifesting as combined RPE damage represented by hypoautofluorescence on FAF).2,5,9 The determination of severity was primarily based on FAF, with the addition of OCT in cases where FAF abnormalities were inconclusive or unidentified.10

 

Definitions and Statistical Analysis

The structural and functional findings, along with clinical characteristics, in typical cases are summarized in Table 1. Typical cases, as defined in the literature, exhibit parafoveal or pericentral (or both) photoreceptor defects with or without accompanying retinal pigment epithelium (RPE) defects on OCT in both eyes. These manifestations typically occur after 5 years of hydroxychloroquine use.1,2,4,5 Additionally, these cases exhibited parafoveal- or pericentral-dominant hyper- or hypo-autofluorescence on FAF, along with corresponding visual field defects, as illustrated in Figure 1. The patterns (parafoveal or pericentral) or severities (early, moderate, or severe) retinal damages are typically symmetric in both eyes.

In instances where patients exhibited atypical presentations of hydroxychloroquine retinopathy, involving significant variations in disease onset and structural/functional abnormalities, findings from multimodal imaging and functional modalities, including OCT, FAF, VF, and mfERG were thoroughly evaluated and documented. A comprehensive comparison of each atypical case with typical presentations of hydroxychloroquine retinopathy was tabulated. Descriptive statistics were used to summarize the demographic and clinical characteristics of the patients with atypical presentations. The prevalence of each atypical presentation was evaluated.

 

RESULTS

Among the 95 patients diagnosed with hydroxychloroquine retinopathy, atypical presentations were observed in 16 (16.8%) cases. Table 2 provides a summary of these presentations, including instances of very early onset of the disease (Case 1), (far) peripheral-dominant retinal damages (Cases 2 and 3), perivascular involvement (Case 4), bitemporal hemianopsia due to nasal half-ring lesion (Case 5), and asymmetric involvement in terms of pattern (Case 6) and severity (Case 7).

 

Atypical presentation #1: Very early (within 1 year) onset of disease

A 44-year-old Korean woman, weighing 56 kg, underwent baseline hydroxychloroquine retinopathy screening. She had received 300 mg hydroxychloroquine daily for 6 months for rheumatoid arthritis (RA) and reported progressive loss of peripheral visual field and light flashes for 1 month. She had no other medical conditions except for rheumatic disease, and her family history did not indicate retinal diseases. The initial systemic workup by the rheumatologist was unremarkable. Her BCVA was 20/20 in both eyes and slit-lamp examination revealed no abnormalities. Dilated fundus examination and FAF (Figure 2A, B) showed a normal retina. However, OCT revealed photoreceptor loss in the paracentral areas of both eyes (Figure 2C). The 30-2 strategy of automated perimetry identified paracentral scotomas in both eyes (Figure 2D). Multifocal ERG demonstrated a generalized depression of amplitude and delayed latency in the paracentral area (Figure 2E). Discontinuation of the drug did not cause further progression of symptoms or damage to the photoreceptor over 1 year (Figure 2C, bottom). The early onset of disease within 1 year of hydroxychloroquine use was noted in only 1 (1.1%) out of 95 patients.

 

Atypical presentation #2: retinal damages in nasal retinal periphery

A 72-year-old woman undergoing hydroxychloroquine treatment with a daily dose of 200 mg for 25 years for RA (Case 2) underwent hydroxychloroquine retinopathy screening. UWF-FAF (Figure 3A) revealed subtle hyperautofluorescence around the right eye's inferior vascular arcade, equivocal peripapillary hypoautofluorescence in the left (arrowheads), and bilateral circumferential hypoautofluorescence in the nasal periphery (arrows). However, OCT confirmed characteristic photoreceptor loss in the inferior pericentral areas (arrowheads). Figure 3B depicted more severe and extensive damages than Figure 3A but with a similar distribution of far peripheral and posterior pole lesions in another 75-year-old woman with hydroxychloroquine retinopathy, taking a daily dose of 200 mg for 20 years (Case 3). UWF-FAF (B) showed hypoautofluorescence over the nasal far periphery and posterior pole (arrowheads) bilaterally, corresponding to photoreceptor and retinal pigment epithelium (RPE) defects on OCT (arrows). Similar to the case in Figure 3A, both eyes exhibited a relatively intact retina with normal autofluorescence between the far peripheral and posterior pole lesions. Peripheral dominance was noted in 4 of 95 (4.2%) patients in our cohort of hydroxychloroquine retinopathy.

 

Atypical presentation #3: perivascular involvement

A 60-year-old woman with hydroxychloroquine treatment, with a daily dose of 300 mg for systemic lupus erythematosus for 20 years (Case 4; Figure 4), exhibited perivascular hypoautofluorescence (white arrows) in the peripheral retina, along with characteristic parafoveal and pericentral hypoautofluorescence on FAF and outer retinal defects on OCT (arrowheads). This case highlighted atypical hydroxychloroquine retinopathy affecting perivascular areas in the peripheral retina. The unusual presentation of perivascular involvement was noted in only 1 patient (1.1%).

 

Atypical presentation #4: bitemporal hemianopsia due to nasal extensive lesion

The 54-year-old female in Figure 5, who had been using hydroxychloroquine for almost 6 years for Sjögren’s syndrome, underwent standard 40° FAF (Figure 5, top left) and Humphrey visual field tests (Figure 5, top right). These tests revealed peripapillary and pericentral hypoautofluorescence (yellow arrowheads) and bitemporal hemianopsia sparing the central field on grayscale (left) and pattern deviation (right) plots of Humphrey 30-2 test in both eyes, respectively. Brain imaging was performed to identify potential neurological causes for bitemporal hemianopsia, which yielded no abnormal findings. However, UWF-FAF imaging indicated nasal peripheral hypoautofluorescence of a half-ring shape in both eyes, corresponding well with temporal hemianopsia in both eyes. Although bitemporal hemianopsia was noted in only 1 (1.1%) patient, a similar lesion, pericentral and nasally extensive, was observed in 6 of 95 patients (6.3%).

 

Atypical presentation #5: unilateral involvement

The 75-year-old female patient (Case 6), with a history of RA spanning 23 years and ongoing hydroxychloroquine use, is depicted in Figure 6. Utilizing FAF and OCT, the left eye exhibited parafoveal ring-shaped hypoautofluorescence on FAF (Figure 6A) and parafoveal outer retinal defect on OCT, graded as severe hydroxychloroquine retinopathy, while the right eye displayed only photoreceptor attenuation without definite defect or loss in the photoreceptor layers on OCT and no definite abnormality on FAF. Another case in Figure 6B showed asymmetric pattern of retinopathy as pericentral photoreceptor loss on the inferotemporal area, corresponding to focal hyperautofluorescence (arrowheads), in the right eye and no identifiable abnormality in the left. This atypical presentation, unilateral hydroxychloroquine retinopathy, was identified in 2 of 95 patients (2.1%).

 

Atypical presentation #6: asymmetric involvement in retinopathy severity/pattern

Figures 7 and 8 demonstrate the photographic examples showing asymmetric involvement in severity or pattern of hydroxychloroquine retinopathy. Figure 7 showed the case with parafoveal retinopathy in the right eye and pericentral retinopathy in the left eye in a patient with 42-year-old female (Case 7) taking hydroxychloroquine 200 mg for 12 years. Figure 8 shows baseline and 18-month follow-up images of fundus autofluorescence and OCT, showing early stage in the right and severe one in the left. The left eye showed hypoautofluorescence (arrowhead) around the inferior vascular arcade at baseline, leading to more extensive and definite hypoautofluorescence 18 months later. In contrast, the right eye with early retinopathy showed no progression of photoreceptor defect or hyperautofluorescence. The difference in retinopathy progression between the two eyes seemed originated from the difference in retinopathy severity.

             Among the 95 patients with hydroxychloroquine retinopathy, asymmetric involvement either in retinopathy pattern (parafoveal or pericentral) or severity (early, moderate, or severe) was noted in 7 (7.4%) patients. Specifically, asymmetry in retinopathy pattern was noted in 6 (6.3%) patients whereas that in retinopathy severity was observed in 2 (2.1%). Table 3 summarizes the atypical presentations of the aforementioned cases and their relative prevalences, along with appropriate screening methods for detection.

 

DISCUSSION

Hydroxychloroquine retinopathy is a well-established concern, with its typical manifestations widely recognized. However, our case series reports atypical presentations of hydroxychloroquine retinopathy in Asian (all Korean) patients. The outlined atypical presentations in this study include very early onset of disease, (far) peripheral-dominant retinal damages, perivascular involvement, bitemporal hemianopsia due to nasal extensive lesions, unilateral involvement, and asymmetricity between the eyes in retinopathy severity and pattern. These presentations deviate from the disease onset and conventional areas seen in typical cases of hydroxychloroquine retinopathy.

In our case series, a strikingly early onset of hydroxychloroquine retinopathy was observed in a 44-year-old patient within just 6 months of drug use. This early-onset toxicity, which has been recently reported,11,12 challenges the conventional belief that toxic retinal effects typically manifest after at least 5 years of hydroxychloroquine use.1,7 The rapid onset raises concerns about the current screening recommendations, which suggest performing baseline screening within 1 year using fundus examination for pre-existing macular conditions and beginning annual screening from 5 years of use,1,7 because following this recommendation might have led to a very advanced stage at diagnosis in Case 1.

Another atypical presentation is the dominance of retinal damages in the (far) peripheral regions rather than the parafoveal or pericentral areas. This peripheral dominance challenges the established understanding of hydroxychloroquine retinopathy as a predominantly central pathology.13,14 The observed peripheral involvement underscores the importance of comprehensive retinal imaging over the whole retina, such as ultrawide-field imaging, to capture these unusual manifestations.2 Our series also includes a case demonstrating perivascular involvement in the peripheral retina, a presentation not previously reported for hydroxychloroquine retinopathy. This finding suggests that the toxic effects of hydroxychloroquine might extend beyond the photoreceptor and retinal pigment epithelium, affecting the peripheral retina adjacent to vascular structures or highlight the vulnerability of perivascular areas to hydroxychloroquine-induced retinal toxicity. Recognition of such atypical presentations is crucial for a thorough understanding of the disease spectrum and for close monitoring and identification of retinal damages.

Bitemporal hemianopsia due to nasal extensive lesions, as illustrated in one of our cases, emphasizes the potential impact of hydroxychloroquine retinopathy on visual fields and necessitates a careful differential diagnosis with neurological visual field defects. This manifestation might lead to misdiagnosis, as the symptoms could be erroneously attributed to neurological causes. Awareness of this atypical presentation is essential for clinicians, highlighting the need for a comprehensive retinal evaluation, including the nasal periphery, when hydroxychloroquine users present with visual field defects.

Another noteworthy atypical presentation observed was unilateral involvement, as illustrated by Case 6. Despite both eyes being exposed to hydroxychloroquine, significant retinal changes were only observed in the left eye. The underlying condition predisposing the left eye to retinopathy remains unclear. It is possible that the other eye may have subclinical involvement, necessitating long-term follow-up to identify characteristic changes. Such unilateral presentations present diagnostic challenges, as outer retinal changes typically associated with unilateral conditions such as central serous chorioretinopathy and other macular degenerative diseases.

Furthermore, our report identified cases with asymmetric involvement in retinopathy severity or pattern, exemplified in Figures 7 and 8. Notably, these patients displayed parafoveal retinopathy in the right eye and pericentral retinopathy in the left eye, demonstrating a discrepancy in the distribution or different progression of retinal changes between the two eyes. These findings underscore the heterogeneity of hydroxychloroquine retinopathy and suggest potential variations in disease mechanisms or susceptibility between the eyes. The observation of asymmetry in retinopathy severity and pattern highlights the importance of individualized assessment and monitoring strategies for each eye (e.g. 10-2 for the eye with parafoveal retinopathy and wider test for the other with pericentral retinopathy) in patients receiving hydroxychloroquine therapy, considering the possibility of differential involvement and progression between the eyes.

The identification of these atypical presentations raises important considerations for screening and diagnosis. The current guidelines, which primarily emphasize the detection of parafoveal or pericentral pathology that typically occurs after 5 years of use, may not be sufficient to detect these atypical presentations of hydroxychloroquine retinopathy.1,7 Our findings underscore the need for a more comprehensive approach to whole retinal screening, incorporating ultrawide-field FAF imaging, given its ability to capture peripheral changes, suggesting its usefulness in identifying uncommon presentations in hydroxychloroquine retinopathy.2

This study has certain limitations, including its retrospective nature and the small number of atypical cases identified in our evaluation of atypical presentations from a relatively large cohort of hydroxychloroquine retinopathy (n = 95). Further research with a larger sample size is warranted to validate our findings and explore additional atypical presentations. Additionally, the ethnic background (Asians) contributing to the variations in presentation patterns of hydroxychloroquine retinopathy is crucial for understanding our cases, as pericentral cases are more prevalent in Asian patients than in other ethnic groups.1,5

In conclusion, our case series reports the atypical presentations of hydroxychloroquine retinopathy in Asian patients, suggesting variable presentations of hydroxychloroquine retinopathy that clinicians should be aware of. Furthermore, screening physicians need to be vigilant in retinopathy screening for possibility of early onset disease, peripheral dominance, perivascular involvement, and unusual visual field defects.

 

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

 

 

REFERENCES

1          Marmor, M. F. et al. Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision). Ophthalmology. 123, 1386-1394 (2016).

2          Ahn, S. J., Joung, J. & Lee, B. R. Evaluation of Hydroxychloroquine Retinopathy Using Ultra-Widefield Fundus Autofluorescence: Peripheral Findings in the Retinopathy. American journal of ophthalmology. 209, 35-44 (2020).

3          Marmor, M. F., Kellner, U., Lai, T. Y., Lyons, J. S. & Mieler, W. F. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology. 118, 415-422 (2011).

4          Ahn, S. J., Ryu, S. J., Lim, H. W. & Lee, B. R. TOXIC EFFECTS OF HYDROXYCHLOROQUINE ON THE CHOROID: Evidence From Multimodal Imaging. Retina (Philadelphia, Pa.). 39, 1016-1026 (2019).

5          Ahn, S. J. et al. Long-Term Progression of Pericentral Hydroxychloroquine Retinopathy. Ophthalmology. 128, 889-898 (2021).

6          Yusuf, I. H., Charbel Issa, P. & Ahn, S. J. Novel imaging techniques for hydroxychloroquine retinopathy. Front Med (Lausanne). 9, 1026934 (2022).

7          Yusuf, I. H., Charbel Issa, P. & Ahn, S. J. Hydroxychloroquine-induced Retinal Toxicity. Front Pharmacol. 14, 1196783 (2023).

8          Ahn, S. J., Joung, J., Lim, H. W. & Lee, B. R. Optical Coherence Tomography Protocols for Screening of Hydroxychloroquine Retinopathy in Asian Patients. American journal of ophthalmology. 184, 11-18 (2017).

9          Kim, K. E., Kim, J. H., Kim, Y. H. & Ahn, S. J. Clock-hour topography and extent of outer retinal damage in hydroxychloroquine retinopathy. Sci Rep. 12, 11809 (2022).

10        Kim, K. E., Kim, Y. H., Kim, J. & Ahn, S. J. Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer Thicknesses in Hydroxychloroquine Retinopathy. Am J Ophthalmol. 245, 70-80 (2023).

11        Ozawa, H. et al. Ocular findings in Japanese patients with hydroxychloroquine retinopathy developing within 3 years of treatment. Jpn J Ophthalmol. 65, 472-481 (2021).

12        Jeltsch, B. M. et al. Rapid onset hydroxychloroquine toxicity. Retin Cases Brief Rep. (2023).

13        Yusuf, I. H., Sharma, S., Luqmani, R. & Downes, S. M. Hydroxychloroquine retinopathy. Eye (Lond). 31, 828-845 (2017).

14        Marmor, M. F., Durbin, M., de Sisternes, L. & Pham, B. H. Sequential Retinal Thickness Analysis Shows Hydroxychloroquine Damage before Other Screening Techniques. Retin Cases Brief Rep. 15, 185-196 (2021).


 

Acknowledgements

This work was supported by National Research Foundation of Korea grants (NRF-2021R1G1A1013360) funded by the Korean Government MSIT. Neither the sponsor nor the funding organization had any role in the design or conduct of this research.

Author contributions

All authors planned and designed the study. All authors wrote the main manuscript text, and prepared the figures. J.M.L. and H.Y.K. provided the data mining and statistical assistance. All authors acquired, analyzed and interpreted the data. S.J.A. did critical revision of the manuscript for important intellectual content. S.J.A. obtained funding. S.J.A. supervised the study. All authors reviewed the manuscript.

Competing interests

The authors declare no competing interests.

 

Figure Legends

Figure 1. Illustration of typical cases demonstrating pericentral, parafoveal, and mixed patterns of hydroxychloroquine retinopathy in 63-, 69-, and 65-year-old Korean women who have been taking hydroxychloroquine for 7, 24, and 20 years, respectively. Top: fundus autofluorescence images; middle: optical coherence tomography scans; bottom: grayscale (left) and pattern deviation (right) plots of Humphrey visual fields.

 

Figure 2. Fundus photograph (A), fundus autofluorescence (B), optical coherence tomog-raphy (OCT; C), Humphrey 30-2 visual field (HVF) results (D), and multifocal electro-retinogram (ERG; E) of Case 1 with 6-month-onset hydroxychloroquine retinopathy. Alt-hough the fundus photograph and autofluorescence images show normal findings, OCT and HVF show characteristic paracentral photoreceptor loss (C) and scotoma (D) in both eyes. Multifocal ERG also shows a decrease in amplitude in the paracentral areas (E).

 

Figure 3. Fundus autofluorescence (top) and optical coherence tomography images (bot-tom) of Cases 2 (A) and 3 (B). Yellow arrowheads indicate characteristic (parafoveal or pe-ricentral) damages, whereas white arrows indicate an atypical presentation of hy-droxychloroquine retinopathy, nasal (far) peripheral hypoautofluorescence.

 

Figure 4. Fundus autofluorescence (top) and optical coherence tomography images (bot-tom) of Case 4 with perivascular involvement, which is more prominent in the left eye. Yellow arrowheads indicate characteristic (parafoveal or pericentral) damages, whereas white arrows indicate perivascular hypoautofluorescence.

 

Figure 5. Conventional 40˚ (top left) and ultrawide-field fundus autofluorescence (UWF-FAF), Humphrey 30-2 visual field test (HVF; top right), and optical coherence to-mography images (bottom) of Case 5 with pericentral retinopathy (yellow arrowheads) showing bitemporal hemianopsia sparing the central field on HVF and nasal peripheral extension (white) on UWF-FAF.

 

Figure 6. Fundus autofluorescence (top) and optical coherence tomography images (bot-tom) of Case 6 with unilateral involvement of retinopathy. Yellow arrowheads indicate characteristic (parafoveal or pericentral) damages.

 

Figure 7. Fundus autofluorescence (top) and optical coherence tomography images (bottom) of Case 6 with asymmetric involvement of retinopathy pattern. The right eye shows loss of the parafoveal ellipsoid zone line (parafoveal retinopathy), whereas the left demonstrates inferior pericentral photoreceptor loss (pericentral retinopathy).

 

Figure 8. Fundus autofluorescence (top) and optical coherence tomography images (bottom) of Case 7 with asymmetric involvement of retinopathy severity at baseline and 18-month fol-low-up visits. The right eye shows localized hyperautofluorescence, early retinopathy, whereas the left demonstrate mild hypoautofluorescence (yellow arrowheads), more distinguishable in the magnified image (inbox in the right upper corner). At month 18, the right eye shows no pro-gression, whereas the left reveals retinopathy progression as more extensive and definite hypo-autofluorescence (yellow arrowheads). White arrowheads indicate artifact due to cataract pro-gression.