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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 32  |  Issue : 1  |  Page : 60-65

Early detection of retinal changes in patients using hydroxychloroquine – An optical coherence tomography-based study


1 Department of Ophthalmology, Jubilee Mission Medical College And Research Institute, Thrissur, Kerala, India
2 Department of Dermatology, Jubilee Mission Medical College And Research Institute, Thrissur, Kerala, India
3 Department of Medicine, Jubilee Mission Medical College And Research Institute, Thrissur, Kerala, India

Date of Submission18-Dec-2019
Date of Acceptance25-Dec-2020
Date of Web Publication17-Apr-2020

Correspondence Address:
Dr. Aiswarya Sasidharan
Department of Ophthalmology, Jubilee Mission Medical College and Research Institute, Thrissur - 680 005, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_91_19

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  Abstract 

Background: Hydroxychloroquine (HCQ) is an antimalarial drug, which is now the mainstay treatment for autoimmune diseases. HCQ retinopathy is rare, but it is generally irreversible and can progress even after cessation of drug therapy. The screening tests recommended are dilated fundus examination, color vision, and Humphrey 10-2 visual fields. Now, it is recommended that at least one of the newer modalities such as multifocal electroretiogram and spectral-domain optical coherence tomography (SD-OCT) be used according to availability. The present study is to evaluate the early retinal toxic effects of HCQ using SD-OCT before the symptomatic visual loss or fundus changes have occurred and to assess the correlation between HCQ cumulative dose and effects on the retina. Materials and Methods: A comparative cross-sectional study was performed in 132 patients (66 cases and 66 controls). Macular thickness in nine segments, ganglion cell-inner plexiform layer (GC-IPL) thickness in six segments was assessed using Cirrus HD-OCT and compared with the control group. HCQ cumulative dose was calculated and compared with the retinal thickness. Results: Macular thickness showed statistically significant thinning in six out of nine segments. GC-IPL thickness showed thinning in all six segments. A significant negative correlation was obtained on comparison of HCQ cumulative dose and GC-IPL and macular thickness average. Conclusions: SD-OCT can be used for detecting retinal thinning and GC-IPL thinning in patients on HCQ to detect early structural and functional changes in retina due to HCQ toxicity before any visual symptoms or fundus changes occur.

Keywords: Cumulative dose, ganglion cell-inner plexiform layer, hydroxychloroquine, macular thickness, optical coherence tomography, screening


How to cite this article:
Sasidharan A, Kakkanatt AC, Paul M, Louis F, John A. Early detection of retinal changes in patients using hydroxychloroquine – An optical coherence tomography-based study. Kerala J Ophthalmol 2020;32:60-5

How to cite this URL:
Sasidharan A, Kakkanatt AC, Paul M, Louis F, John A. Early detection of retinal changes in patients using hydroxychloroquine – An optical coherence tomography-based study. Kerala J Ophthalmol [serial online] 2020 [cited 2020 Aug 12];32:60-5. Available from: http://www.kjophthal.com/text.asp?2020/32/1/60/282673




  Introduction Top


Hydroxychloroquine (HCQ) is an antimalarial drug which has been the mainstay treatment for autoimmune diseases since 1950s.[1] HCQ retinopathy is generally irreversible and can progress even after cessation of drug therapy.[2] The incidence of HCQ retinopathy is estimated to be 0.5% after 5 years of continuous therapy.[3],[4] However, newer studies indicate that the risk is substantially higher after prolonged use.[5]

The American Academy of Ophthalmology published guidelines for chloroquine and HCQ retinopathy screening, and it was revised in 2016.[6],[7] The present recommendations for screening suggest a baseline examination to serve as a reference point and to rule out any existing retinal diseases.[8],[9],[10],[11],[12] The screening tests recommended are dilated fundus examination, color vision, and Humphrey 10-2 visual fields. Newer investigation tools such as multifocal electroretinogram, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence are more sensitive than visual fields. Amsler grid testing which was initially a screening test, is no longer recommend.[7] Early detection of toxicity is crucial to allow for the cessation of drug and prevention of vision loss.[13]

SD-OCT is now a recommended screening test for detecting HCQ retinopathy, though unclear which screening tool detects HCQ retinopathy earliest.[14] The present study emphasizes on determining SD-OCT changes in patients on HCQ therapy before any fundus changes or visual symptoms sets in.


  Materials and Methods Top


This comparative cross-sectional study was conducted in the department of Ophthalmology, Dermatology and Medicine in a tertiary center from January 2018 to October 2019 and included 132 patients. Patients on HCQ therapy for duration between 6 months and 5 years with best-corrected visual acuity (BCVA) ≥6/9 were included in the study except for those patients with ophthalmic conditions where OCT could not be done, patients on drugs that can affect retinal thickness, patients with preexisting retinal pathologies, intraocular pressure >20 mmHg, and patients who had underwent previous intraocular and refractive surgeries.

Patients those who expressed their willingness to enroll in the study were included after taking their informed consent. Cases were considered as Group 1 and controls as Group 2. A detailed history about any previous or existing ophthalmic diseases, surgeries, or coexisting medical or surgical conditions was taken. Detailed ophthalmological evaluation including BCVA, color vision, slit-lamp examination, intraocular pressure measurement, fundus evaluation (90D lens), and field evaluation (10-2) was done and recorded in the pro forma. OCT using CIRRUS HD-OCT without pupillary dilatation and under the same intensity of dim room lighting was done, and the following parameters were being evaluated:

  1. Ganglion cell-layer with inner plexiform layer (GC-IPL) thickness measured in all six quadrants – superonasal, inferonasal, superotemporal, inferotemporal, superior quadrants, and inferior quadrants
  2. Macular thickness measured in the fovea, superior inner, inferior inner, nasal inner, temporal inner, superior outer, inferior outer, nasal outer, and temporal outer fields.


Based on the mean and standard deviation observed in earlier publications titled “SD-OCT for the early detection of retinal alterations in patients using HCQ [15]” and “effect of HCQ on the retinal layers: A quantitative evaluation with SD-OCT [16]” with 95% confidence level and 80% power minimum, sample size came to 66 in each group.

Qualitative (categorical) variables were represented by frequency and percentage analysis. Chi-square test was performed to compare qualitative variables between cases and controls. Quantitative variables were represented using the mean and standard deviation. Independent sample t-test was performed to compare quantitative variables between cases and controls. Pearson's correlation analysis was performed to find the correlation between duration/dose and the study variables. Data obtained from 132 patients were coded and entered into Microsoft Excel sheet and analyzed using SPSS VERSION 25 details: IBM (company name) Armonk, New York, US. P < 0.05 was considered as statistically significant.


  Results Top


Data were collected from 132 participants meeting the inclusion criteria which included 66 cases (on HCQ) and 66 controls (age and sex matched).

Age distribution

[Figure 1] shows age distribution in the study groups. The minimum and maximum ages were 20 and 60 years, respectively. The mean of cases in Group 1 was calculated to be 39.70 ± 12.52, and the mean age of the control group was 40.06 ± 12.22.
Figure 1: Bar diagram showing age distribution in study group

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Retinal thickness analysis in cases and controls

Both macular thickness and GC-IPL thickness were analyzed in 132 eyes of case and control group each.

Macular thickness analysis

Statistically significant thinning was observed in six segments of the macula [Figure 2]. Central macular thickness, superior outer macula, and temporal outer macula did not show significant thinning [Figure 3]a and [Figure 3]b.
Figure 2: Bar diagram showing macular thickness comparison in cases and controls

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Figure 3: (a) Optical coherence tomography macula of a case showing macular thinning. (b) Optical coherence tomography macula of a patient from control group showing normal macular thickness

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Ganglion cell-inner plexiform layer thickness analysis

All the six quadrants of GC-IPL showed significant thinning [Figure 4] with the maximum thickness being recorded in superotemporal GC-IPL and least at the superonasal GC-IPL [Figure 5]a and [Figure 5]b.
Figure 4: Bar diagram showing ganglion cell-inner plexiform layer thickness comparison in cases and controls

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Figure 5: (a) Optical coherence tomography macula of a case showing ganglion cell-inner plexiform layer thinning. (b) Optical coherence tomography macula showing normal ganglion cell-inner plexiform layer thickness

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Relation between hydroxychloroquine cumulative dose and macular thickness and ganglion cell-inner plexiform layer thickness

Increased dose of HCQ is associated with a decreased average thickness of macula [Figure 6], average GC-IPL thickness [Figure 7], and minimum GC-IPL thickness, Pearson's coefficient showing a negative correlation in both eyes.
Figure 6: Correlation between hydroxychloroquine cumulative dose and average macular thickness

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Figure 7: Correlation between hydroxychloroquine cumulative dose and average ganglion cell-inner plexiform layer thickness

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Visual field (HFA 10-2) was normal in all the patients.


  Discussion Top


This study was to assess the retinal changes in patients using HCQ before any visual symptoms or fundus changes occurred. Macular thickness and GC-IPL thickness of cases were compared with the control group. Macular thickness and GC-IPL thickness showed significant thinning in cases in comparison with the control group. HFA 10-2 was normal in all cases.

Comparison of macular thickness

Macular is divided into nine regions with three concentric rings measuring 1 mm (innermost ring), 3 mm (inner ring), and 6 mm in diameter (outer ring) centered on the fovea according to ETDRS map. The innermost 1-mm ring is the fovea, while the 3-mm inner ring and 6-mm outer ring are further divided into four equal regions. The full thickness of retina is determined by measuring the distance between the inner limiting membrane and the inner boundary of retinal pigment epithelium in each of the nine regions. Macular thickness measurements generated by the OCT system in all the nine regions of the ETDRS map were documented. Foveal thickness was defined as macular thickness within the innermost 1-mm ring. Mean macular thickness was defined as the average macular thickness from all nine regions of the ETDRS map.

Among 132 participants meeting the inclusion criteria which included 66 cases (on HCQ) and 66 controls (age and sex matched), statistically significant thinning was observed in the superior inner macula, temporal inner macula, inferior inner macula, nasal inner macula, inferior outer macula, and nasal outer macula. The results obtained were not significant in the central macula, superior outer macula, and temporal outer macula.

In a study conducted by Ulviye et al.,[15] statistically significant thinning of inner retina was observed in parafoveal and perifoveal area on comparing patients taking HCQ (n = 15) with the control group. On assessing full-thickness retina, significant thinning was demonstrated in full retinal thickness of the perifoveal area (P < 0.05). The observation in this study is comparable to the present study.

In a study by Pasadhika and Fishman,[17] patients on HCQ with fundus changes showed statistically significant thinning in inner, outer, and full-thickness retina. Patients on HCQ without fundus changes showed significant thinning only in the inner retina (P < 0.001). In the present study, full-thickness retina showed significant thinning in most of the segments except in central macula, superior outer macula, and temporal outer macula.

Comparison of ganglion cell-inner plexiform layer thickness

The sectoral (superotemporal, superior, superonasal, inferonasal, inferior, and inferotemporal) macular GC-IPL thicknesses are measured in an elliptical annulus with a vertical outer radius of 2.0 mm and a horizontal radius of 2.4 mm.[18]

The comparison of GC-IPL thickness in cases with age- and sex-matched control revealed significant thinning in all segments. Statistically significant thinning was observed in all six quadrants (P < 0.001). This correlated with the study performed by Bulut et al.[19] The values obtained in the present study were lower than the values obtained in the study by Bulut et al. In their study, GC-IPL was found to be statistically thinner both on an average and in all segments (superior, superonasal, inferonasal, inferotemporal, and superotemporal) except inferior segment when segmented (P < 0.05). In the present study, the thinnest segment is inferonasal which is comparable with the study by Bulut et al. [Table 1].
Table 1: Comparison of GC-IPL thickness with other studies

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The results of a study conducted by Kan et al.[20] showed that the average, minimum, and sectorial macular GC-IPL thicknesses were significantly lower in patients on HCQ when compared to normal controls in the absence of clinically evident maculopathy. These results were comparable to our study.

In a study conducted by Lee et al.,[21] on comparison of average and minimum GC-IPL thickness in patients on HCQ with the control group, significant thinning was observed only in patients with clinically evident maculopathy. In patients on HCQ for a duration of <5 years, no significant thinning was observed contradicting the results of our study. In a study conducted by Uslu et al.,[16] a statistically significant difference was obtained between minimum and temporal-inferior macular GC-IPL thicknesses in patients on HCQ on comparing with the controls. This result was in concordance with the result of the present study.

Similar to the present findings, a study conducted by Pasadhika et al.[22] in 2010 concluded that long-term HCQ exposure is associated with significant thinning of the perifoveal inner retinal layers (GC-IPLs) even in the absence of functional or structural clinical changes involving the photoreceptor or retinal pigment epithelial cell layers (P = 0.021).

Comparison of hydroxychloroquine dose, duration, and optical coherence tomography changes

In the present study, a statistically significant negative correlation was obtained on comparison of HCQ cumulative dose with average, minimum GC-IPL thickness, and macular thickness average. The study by Agarwal et al.[23] reported a statistically significant negative correlation of cumulative dose of HCQ with retinal thickness in parafoveal and perifoveal areas and not the central area. This is comparable with the results obtained in the present study.

The study by Lee et al.[21] compared the cumulative dose of HCQ with OCT changes. Statistically significant correlation was not obtained between the cumulative dose of HCQ and OCT findings. In a study conducted by Ulviye et al.,[15] full retinal thickness and inner retinal thickness were compared with the duration of HCQ intake. No significant correlation was obtained between the duration of HCQ treatment and retinal thickness. The results of the present study are in contradiction to the findings of the above mentioned studies.

Visual field changes

In the present study, HFA 10-2 perimetry was carried out in all patients and was found to be normal in all the cases. Hence it is suggestive that SD-OCT changes in early HCQ retinopathy precede visual field defects. A study conducted by Garrity et al.[14] reported characteristic outer retinal SD-OCT changes in patients on chronic HCQ therapy. Fields of all patients included in this study were normal, thus comparable to the present study. Marmor and Melles [24] studied the disparity between OCT and visual field in patients on HCQ. They reported that about 10% of patients enrolled in the study with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality contradicting the result of the present study.


  Conclusions Top


The study was conducted among 264 eyes of 132 patients and results were compared and reviewed with reported statistics and literature. The average age distribution of the patients was 39 years in cases and 40 years in controls. OCT macula showed thinning in all nine sectors with statistically significant thinning in the superior inner macula, temporal inner macula, inferior inner macula, nasal inner macula, inferior outer macula, and nasal outer macula on comparison with the control group. GC-IPL thickness showed statistically significant thinning in all six sectors on comparison with the control group. Significant negative correlation was observed on comparing cumulative dose and the duration of HCQ therapy with the SD-OCT findings. IOP measurements and HFA 10-2 was normal in all patients.

Hence, it can be concluded that SD-OCT can be used as a screening tool to detect early retinopathy due to HCQ. Hence, we suggest inclusion of SD-OCT to detect retinal thinning and GC-IPL thinning in patients on HCQ for the early diagnosis and progression of retinal changes. For this reason, prospective evaluation of retinal thickness and GC-IPL thickness during HCQ treatment may be helpful to detect early structural and functional changes before any symptoms occur. This can prevent the development of irreversible retinal damage.

Acknowledgments

The authors would like to acknowledge the support from Jubilee Mission Medical College, Thrissur, Kerala, India.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Pasaoglu I, Onmez FE. Macular toxicity after short-term hydroxychloroquine therapy. Indian J Ophthalmol 2019;67:289-92.  Back to cited text no. 1
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Marmor MF, Carr RE, Easterbrook M, Farjo AA, Mieler WF, American Academy of Ophthalmology. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: A report by the American Academy of Ophthalmology. Ophthalmology 2002;109:1377-82.  Back to cited text no. 6
    
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Lai TY, Chan WM, Li H, Lai RY, Lam DS. Multifocal electroretinographic changes in patients receiving hydroxychloroquine therapy. Am J Ophthalmol 2005;140:794-807.  Back to cited text no. 9
    
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Marmor MF. The dilemma of hydroxychloroquine screening: New information from the multifocal ERG. Am J Ophthalmol 2005;140:894-5.  Back to cited text no. 11
    
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Bernstein HN. Ocular safety of hydroxychloroquine. Ann Ophthalmol 1991;23:292-6.  Back to cited text no. 12
    
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Garrity ST, Jung JY, Zambrowski O, Pichi F, Su D, Arya M, et al. Early hydroxychloroquine retinopathy: Optical coherence tomography abnormalities preceding Humphrey visual field defects. Br J Ophthalmol 2019;103:1600-4.  Back to cited text no. 14
    
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Ulviye Y, Betul T, Nur TH, Selda C. Spectral domain optical coherence tomography for early detection of retinal alterations in patients using hydroxychloroquine. Indian J Ophthalmol 2013;61:168-71.  Back to cited text no. 15
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Uslu H, Gurler B, Yildirim A, Tatar MG, Aylin Kantarcı F, Goker H, et al. Effect of hydroxychloroquine on the retinal layers: A quantitative evaluation with spectral-domain optical coherence tomography. J Ophthalmol 2016;2016:8643174.  Back to cited text no. 16
    
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Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures. Eye (Lond) 2010;24:340-6.  Back to cited text no. 17
    
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Bulut M, Erol MK, Toslak D, Akidan M, Kaya Başar E, Çay HF. A new objective parameter in hydroxychloroquine-induced retinal toxicity screening test: Macular retinal ganglion cell-inner plexiform layer thickness. Arch Rheumatol 2018;33:52-8.  Back to cited text no. 19
    
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Kan E, Yakar K, Demirag MD, Gok M. Macular ganglion cell-inner plexiform layer thickness for detection of early retinal toxicity of hydroxychloroquine. Int Ophthalmol 2018;38:1635-40.  Back to cited text no. 20
    
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Lee MG, Kim SJ, Ham DI, Kang SW, Kee C, Lee J, et al. Macular retinal ganglion cell-inner plexiform layer thickness in patients on hydroxychloroquine therapy. Invest Ophthalmol Vis Sci 2014;56:396-402.  Back to cited text no. 21
    
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Pasadhika S, Fishman GA, Choi D, Shahidi M. Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity. Eye (Lond) 2010;24:756-62.  Back to cited text no. 22
    
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Agarwal P, Wong YH, Dasgupta E, Agarwal R, Livingstone BI, Ramamurthy S, et al. Early effect of hydroxychloroquine therapy: Relationship between cumulative dose and retinal thickness. Cutan Ocul Toxicol 2015;34:179-84.  Back to cited text no. 23
    
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Marmor MF, Melles RB. Disparity between visual fields and optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology 2014;121:1257-62.  Back to cited text no. 24
    


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