|Year : 2018 | Volume
| Issue : 2 | Page : 122-127
Early detection of hydroxychloroquine-related changes with fundus autofluorescence: confocal scanning laser ophthalmoscope versus fundus camera
Saber H El-Sayed, Asmaa M Ibrahim, Mohamed S Abd Elaziz, Naglaa M Mohamed
Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
|Date of Submission||06-Jan-2018|
|Date of Acceptance||06-Mar-2018|
|Date of Web Publication||7-Jun-2018|
Naglaa M Mohamed
Zagazig 11311, Sharkia Governorate
Source of Support: None, Conflict of Interest: None
Objective The aim of this study was to detect early fundus changes accompanying hydroxychloroquine (HCQ) treatment by using fundus autofluorescence (FAF) with confocal scanning laser ophthalmoscope (CSLO) in comparison to fundus camera.
Patients and methods This is a cross-sectional study of 80 eyes of 40 rheumatoid arthritis patients on HCQ treatment. All patients were subjected to full and detailed history taking and ophthalmic examination followed by fundus imaging using fundus camera (colored and FAF images) and the CSLO image.
Results The mean age of the patients was 43.75±8.71 years. The HCQ treatment duration ranged from 2 to 60 months with a mean of 29.12±19.42 months. The FAF by fundus camera had a 57% sensitivity in detecting hyperfluorescent lesions and 96% specificity in detecting negative lesions in relation to fundus picture, whereas FAF by CSLO had a 43% sensitivity in detecting hyperfluorescent lesions, and 88% specificity in detecting negative lesions in relation to fundus picture. CSLO had a 29% sensitivity in detecting hyperfluorescent lesions and 86% specificity in detecting negative lesions in relation to FAF by a fundus camera. There were no significant associations between the duration of HCQ treatment and the findings detected by different methods.
Conclusion FAF showed damage at a relatively early stage of HCQ toxicity, although it was not predicable which technique of FAF detection will be most definitive for any given individual. FAF by fundus camera was superior to FAF by CSLO as it had high sensitivity and less specificity.
Keywords: confocal scanning laser ophthalmoscope, fundus autofluorescence, hydroxychloroquine, rheumatoid arthritis
|How to cite this article:|
El-Sayed SH, Ibrahim AM, Abd Elaziz MS, Mohamed NM. Early detection of hydroxychloroquine-related changes with fundus autofluorescence: confocal scanning laser ophthalmoscope versus fundus camera. Delta J Ophthalmol 2018;19:122-7
|How to cite this URL:|
El-Sayed SH, Ibrahim AM, Abd Elaziz MS, Mohamed NM. Early detection of hydroxychloroquine-related changes with fundus autofluorescence: confocal scanning laser ophthalmoscope versus fundus camera. Delta J Ophthalmol [serial online] 2018 [cited 2018 Jun 22];19:122-7. Available from: http://www.djo.eg.net/text.asp?2018/19/2/122/233927
| Introduction|| |
Hydroxychloroquine (HCQ), sold under the brand name Plaquenil (Sanofi-Aventis), is an antimalarial drug that has gained widespread use in treating various autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis (RA) . Accordingly, in recent years there has been an increased emphasis on more effective screening measures utilizing multimodal imaging techniques to elicit early signs of toxicity before the characteristic advanced changes manifest clinically . In the earliest stages of HCQ toxicity, patients are often asymptomatic with preservation of visual acuity. However, perceptive individuals may report difficulty with night vision, glare, or paracentral scotomas that interfere with reading . In contrast, visible bull’s-eye retinopathy, characterized by a ring of retinal pigment epithelium (RPE) degeneration often sparing the foveal center, is a late finding indicative of advanced damage. Thus, ophthalmoscopy alone is not sufficient to screen for HCQ toxicity .
Lipofuscins (LFs) are ubiquitous lipoprotein pigments accumulating in postmitotic cells in nervous, myocardial, and retinal cells during aging. N-retinylidene-N-retinylethanolamine (A2E) represents LF’s major fluorophore. It accumulates in the lysosomes because it is not recognized by lytic enzymes as a consequence of photo-oxidative alterations . Its chemical structure is responsible for the detergent-like action on the RPE cell membranes, and its conjugated double bonds promote light absorption and fluorescence emission .
Fundus autofluorescence (FAF) is the concept of using naturally occurring fluorescence from the retina to provide an indicator of RPE health. Illuminating the retina with blue light at 488 nm causes certain cellular components (LF and melanolipofuscin) to ‘glow’ without injecting any dye. This glow (fluorescence) returning from the retina can be used to create a black-and-white image which can be interpreted by recognizing the characteristic patterns, in much the same way .
In-vivo FAF was observed for the first time during vitreous fluorophotometry. Subsequently von Rückmann et al.  introduced the confocal scanning laser ophthalmoscope (CSLO) that elicits retinal autofluorescence (AF) by scanning the retina with a low-powered laser beam. By adopting confocal optics, this technology overcomes the interference of AF preretinal structures, such as the lens.
Differently from CSLO-AF, fundus cameras do not have a confocal optics system, so the AF gets elicited also from preretinal structures, such as the crystalline lens. Potential interferences may be overcome by using specific filters with longer wavelengths (an excitation filter of 535–580 nm and a barrier filter of 615–715 nm) that were developed by Schmitz-Valckenberg et al. . This type of FAF is also called green AF.
The aim of this study was to detect early fundus changes in RA patients receiving HCQ treatment by using FAF with CSLO in comparison to fundus camera.
| Patients and methods|| |
This is a cross-sectional study of 6 months duration (from January 2017 to June 2107) on 80 eyes of 40 RA patients on HCQ treatment. It was carried out at the Ophthalmology Outpatient Clinic of Menoufia University Hospitals which is a tertiary referral center in Menoufia Governorate, Egypt.
All patients included in the study suffered from RA and were receiving HCQ for variable periods. Patients with corneal opacities, cataract, age-related macular degeneration, hereditary fundus dystrophies, and retinopathies were excluded from the study.
The Ethics Committee of the College of Medicine, Menoufia University approved this study. The research followed the tenets of the Declaration of Helsinki. All patients signed a written informed consent before participating in the study.
Full detailed history was obtained from every patient including HCQ intake (dose and duration). Then best spectacle-corrected visual acuity (BCVA) was recorded (in logMAR).
Pupillary dilatation was achieved by mydriacyl 1% eye drops. Fundus examination was performed by using slit-lamp biomicroscopy with +90 D lens for examination of the posterior segment. Then all patients were assigned for further investigation with both Topcon fundus camera (Topcon Medical Systems Inc., Oakland, New Jersey, USA) as well as Heidelberg Spectralis (Heidelberg Retina Angiograph-Optical Coherence Tomography; Heidelberg Engineering, Heidelberg, Germany). Each eye got one colored fundus picture with fundus camera, as well as, two FAF imaging with both fundus camera and CSLO, respectively.
Results were collected, tabulated, and statistically analyzed by an IBM compatible personal computer with SPSS statistical package, version 20 (released 2011; IBM Corp., Armonk, New York, USA).
Two types of statistical analysis were done:
- Descriptive statistics, for example, expressed in number, percentage, mean, and SD.
- Analytic statistics:
- Mann–Whitney’s test was used for comparison of quantitative variables between two groups of not normally distributed data.
- Spearman’s correlation was used for not normally distributed ones.
- Sensitivity of the test was defined as the ability of the test to identify true-positive cases, whereas specificity was defined as the ability of the test to detect true-negative cases. Overall accuracy was defined as: (true positive+true negative)/(true positive+true negative+false positive+false negative).
A P value of less than 0.05 was considered statistically significant.
| Results|| |
The age of the study group ranged from 24 to 63 years. The average duration of HCQ intake ranged from 2 to 60 months. BCVA ranged from 0 to 1 with a mean of 0.3±0.24 ([Table 1]).
Fundus camera was taken as a reference; any suspicious lesion was weighed with FAF to detect specificity and sensitivity. The FAF by fundus camera had a 96% ability to detect hyperfluorescent lesions ([Figure 1]) and a 57.0% ability to detect negative cases in relation to the fundus picture, whereas FAF by CSLO had an 88.0% ability to detect hyperfluorescent lesions ([Figure 2]) and a 43.0% ability to detect negative cases in relation to fundus picture ([Table 2]).
|Figure 1 Fundus autofluorescence by fundus camera detecting hyperfluorescent lesions around the fovea.|
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|Figure 2 Fundus autofluorescence by confocal scanning laser ophthalmoscope detecting hyperfluorescent lesion around the fovea.|
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FAF by CSLO had an 86.0% ability to detect hyperfluorescent lesions and a 29.0% ability to detect negative cases in relation to FAF by fundus camera ([Table 3]).
|Table 3 Validity of fundus autofluorescence by fundus camera and by confocal scanning laser ophthalmoscope in relation to fundus picture|
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The FAF by fundus camera had a 93.0% ability to detect hyperfluorescent lesions and a 17.0% ability to detect negative cases in relation to FAF by CSLO ([Table 4]).
|Table 4 Validity of fundus autofluorescence by fundus camera in relation to fundus autofluorescence by confocal scanning laser ophthalmoscope|
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Fundus picture and FAF by fundus camera had a significant and moderate type of agreement, whereas CSLO had a fair agreement with fundus picture and FAF by fundus camera ([Figure 3]).
|Figure 3 Level of agreement between different methods. CSLO, confocal scanning laser ophthalmoscope; FAF, fundus autofluorescence.|
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There was no significant association between the duration of HCQ treatment and the findings of the different methods ([Table 5]). In addition, no significant correlation was found between BCVA and the duration of HCQ treatment ([Table 6]).
|Table 5 Association between duration of hydroxychloroquine and the findings of different methods|
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|Table 6 Spearman’s correlation between best corrected visual acuity and duration of hydroxychloroquine|
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| Discussion|| |
RA is a chronic systemic inflammatory autoimmune disease. Its main manifestation is persistent synovitis that affects peripheral joints symmetrically. Hydroxychloroquine sulfate toxicity remains a relatively rare disease, with the incidence of toxicity estimated to be ∼1% after 5 years of use and rising with continued drug use. The retinopathy, classically described as a bull’s-eye, is untreatable and tends to progress even after discontinuing the use of the drug. Thus, it is important for screening to catch signs of toxicity early before central vision is threatened .
The publication of revised screening recommendations for hydroxychloroquine toxicity has raised awareness of objective modalities, such as multifocal electroretinography, spectral domain optical coherence tomography, and FAF, as adjuncts or successors to the traditional visual field as screening tools . However, data are still limited on the relative sensitivity and specificity of these procedures. Therefore, the aim of the current study was to detect whether FAF by CSLO has a significant and sensitive role in early detection of HCQ-related changes in RA patients in comparison to FAF by fundus camera.
This study showed that the mean age of the patients was 43.75±8.71 years. Patients received HCQ 400 mg/day with a mean duration of 29.12±19.42 months (ranging from 2 to 60 months).
In this study, all patients were women. This could be explained by the fact that RA is much more prevalent in women than men. Women are two to three times more likely to develop RA than men .
There were no significant associations between the duration of HCQ treatment and the findings of the different methods and between normal or hyperfluorescent lesions by different methods regarding BCVA. There was no significant correlation between BCVA and duration of HCQ treatment.
Marmor et al.  have suggested that most toxic cases occur with dosages greater than 6.5 mg/kg or after long-term use of the drug. The incidence of toxicity increases to greater than 1% after 5–7 years or an ∼1000 g cumulative dose for patients using 400 mg/day (which is the most typical dose prescribed).
Marmor  compared different screening procedures for hydroxychloroquine sulfate (Plaquenil) toxicity at different stages of damage. Patients ranged in age from 27 to 77 years and there was no clear relation between age or sex and the presence or severity of toxicity. Visual acuity was mostly excellent but was modestly subnormal in some of the more affected patients. The daily HCQ sulfate dosage was 400 mg for all patients except patient S2 (who took 400 mg for 12 years and 200 mg for 10 years). Relative to the recommended dose of 6.5 mg/kg or less, patients with early and moderate toxicity received close to that level.
In this study, the FAF by fundus camera had 96% sensitivity in detecting hyperfluorescent lesions and a 57.0% in detecting negative lesions in relation to fundus picture, whereas FAF by CSLO had an 88.0% sensitivity in detecting hyperfluorescent lesions and a 43.0% in detecting negative lesions in relation to fundus picture. FAF by CSLO had an 86.0% sensitivity in detecting hyperfluorescent lesions and a 29.0% in detecting negative lesions in relation to FAF by fundus camera. The FAF by fundus camera had 93.0% sensitivity in detecting hyperfluorescent lesions and 17.0% in detecting negative lesions in relation to FAF by CSLO. Thus, fundus picture and FAF by fundus camera had a significant and moderate type of agreement, whereas CSLO had a fair agreement with fundus picture and FAF by fundus camera.
Marmor  examined the right macula of all patients. Patients with early and moderate toxicity had generally unremarkable fundus examination findings, whereas those with severe toxicity showed abnormal fundi. All patients with moderate toxicity showed hyperfluorescence around the fovea. Patients with severe toxicity showed more extensive hyperfluorescence.
In addition, Marmor  found that overdosage with HCQ seemed a significant risk factor for toxicity. Different individuals were more or less sensitive to different tests. Fields can be sensitive but only if read with a low threshold for change. HCQ causes early parafoveal loss of the outer segment lines on spectral domain optical coherence tomography, with the first changes are often evident in the inferotemporal quadrant. Parafoveal thinning of the outer nuclear layer follows, before RPE damage is visible. Careful screening with multiple tests can detect toxic damage before prominent loss of the outer nuclear layer.
| Conclusion|| |
FAF is a noninvasive method for the detection of retinal pigment epithelial damage, which is the target tissue affected by HCQ toxicity, but to our knowledge no specific technique of AF detection showed superiority in detecting HCQ damage. Fundus camera AF was superior to FAF by CSLO as it has high sensitivity and less specificity.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Tehrani R, Ostrowski RA, Hariman R, Jay WM. Ocular toxicity of hydroxychloroquine. Semin Ophthalmol 2008; 23:201–209.
Mititelu M, Wong BJ, Brenner M, Bryar PJ, Jampol LM, Fawzi AA. Progression of hydroxychloroquine toxic effects after drug therapy cessation: new evidence from multimodal imaging. JAMA Ophthalmol 2013; 131:1187–1197.
Marmor MF. Comparison of screening procedures in hydroxychloroquine toxicity. Arch Ophthalmol 2012; 130:461–469.
Boyer NP, Higbee D, Currin MB, Blakeley LR, Chen C, Ablonczy Z et al.
Lipofuscin and N
-retinylethanolamine (A2E) accumulate in retinal pigment epithelium in absence of light exposure: their origin is 11-cis-retinal. J Biol Chem 2012; 287:22276–22286.
Schütt F, Bergmann M, Kopitz J, Holz FG. Detergent-like effects of the lipofuscin retinoid component A2-E in retinal pigment epithelial cells. Ophthalmologe 2002; 99:861–865.
Sparrow JR, Zhou J, Ben-Shabat S, Vollmer H, Itagaki Y, Nakanishi K. Involvement of oxidative mechanisms in blue-light-induced damage to A2E-laden RPE. Invest Ophthalmol Vis Sci 2002; 43:1222–1227.
Von Rückmann A, Fitzke FW, Bird AC. In vivo fundus autofluorescence in macular dystrophies. Arch Ophthalmol 1997; 115:609–615.
Schmitz-Valckenberg S, Holz FG, Bird AC. Fundus autofluorescence imaging: Review and perspectives. Retina 2008; 28:385–409.
Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2010; 62:775–784.
Marmor MF, Kellner U, Lai TY, Lyons JS, Mieler WF, American Academy of Ophthalmology. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011; 118:415–422.
Aletaha D, Neogi T, Silman AJ. Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62:2569–2581.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]