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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 21  |  Issue : 3  |  Page : 187-193

Ganglion cell complex thickness in screening of hydroxychloroquine maculopathy


1 Department of Ophthalmology, Ophthalmology Hospital, Kafr El-Sheikh, Egypt
2 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission22-Mar-2020
Date of Decision30-Mar-2020
Date of Acceptance01-Jun-2020
Date of Web Publication23-Sep-2020

Correspondence Address:
MBBCh Yasmin M.M Amin
El Awqaf, El Kholafaa Elrashdeen Street, Kafr El-Sheikh 33512
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/DJO.DJO_23_20

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  Abstract 


Background Screening of early hydroxychloroquine (HCQ) maculopathy is important to prevent permanent structural and functional retinal damage. Spectral domain optical coherence tomography (SD-OCT) ultra-high-resolution imaging and speed allows better visualization of retinal architecture and measurement of the thickness of the retinal layers.
Objective The aim of this study was to evaluate the macular ganglion cell complex (GCC) thickness by using SD-OCT for screening of early HCQ maculopathy.
Patients and methods A total of 128 patients were included in the present study. They were divided into two groups: HCQ group, comprising 128 eyes of 64 patients treated with HCQ, and a control group, comprising 128 eyes of 64 healthy individuals. Average, minimum, and sectorial macular GCC thickness and photoreceptor layer (PL) integrity were compared between the two study groups. Correlations between GCC thickness and duration of HCQ use, PL integrity, uncorrected visual acuity, and best-corrected visual acuity in the HCQ group were analyzed.
Results There were no statistically significant differences between the two groups regarding the average, minimum, and sectorial macular GCC thickness. However, a statistically significant difference between the two groups was found regarding the PL integrity. In addition, the PL integrity was found to have the highest independent correlation with the average macular GCC thickness, followed by the duration of treatment with HCQ, and lastly, the uncorrected visual acuity.
Conclusion Unique SD-OCT findings in the retina can identify early HCQ retinopathy and may play a role as a complementary objective tool in HCQ maculopathy screening.

Keywords: ganglion cell complex, hydroxychloroquine, maculopathy, photoreceptor


How to cite this article:
Amin YM, Nassar MK, Ibrahim AM. Ganglion cell complex thickness in screening of hydroxychloroquine maculopathy. Delta J Ophthalmol 2020;21:187-93

How to cite this URL:
Amin YM, Nassar MK, Ibrahim AM. Ganglion cell complex thickness in screening of hydroxychloroquine maculopathy. Delta J Ophthalmol [serial online] 2020 [cited 2020 Oct 30];21:187-93. Available from: http://www.djo.eg.net/text.asp?2020/21/3/187/295879




  Introduction Top


Hydroxychloroquine (HCQ), originally an antimalarial drug, is used in the treatment of various rheumatological diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus, and some autoimmune dermatological conditions [1]. Despite lesser systemic toxicity compared with other drugs, it can cause severe retinal dysfunction and loss of vision in ∼3% of the patients on chronic use [2].

Although early HCQ retinopathy may be asymptomatic, in advanced stages of the disease, patients will experience vision loss and paracentral scotoma [3]. The typical clinical sign of HCQ retinal toxicity is characterized by bilateral pigmentary change of the macula sparing the foveal center known as bull’s eye maculopathy [4].

The initial pathological changes were observed in the retinal ganglion cells (RGCs) in the form of membranous cytoplasmic bodies that leads to cellular degeneration which affects also the photoreceptors and the retinal pigment epithelium, respectively at alater stage [5]. The cellular degeneration at this stage occurs secondary to alterations in protein synthesis and lipid peroxidation [6]. The structural and functional damage at this advanced stage becomes irreversible [7]. Discontinuing the drug in the early course of HCQ retinopathy can prevent the permanent retinal damage. So, screening for early HCQ retinal toxicity is critical [8],[9],[10]. The screening of HCQ retinopathy includes a complete ophthalmological examination with dilated fundus examination, Amsler grid testing, and/or visual field testing. Other methods include color vision, fundus photography, and fluorescein angiography. In recent years, multifocal electroretinogram, fundus autofluorescence, and high-resolution spectral domain optical coherence tomography (SD-OCT) have proved to be valuable in the early detection of HCQ retinal toxicity [11].

The modern advances in the OCT technology have made the Cirrus high-definition optical coherence tomography (HD-OCT) to characterize the early changes in the retinal architecture in patients on HCQ therapy [12],[13],[14].

The present study aimed to evaluate the role of ganglion cell complex (GCC) thickness measurement by using HD-OCT in screening of early HCQ maculopathy before it becomes clinically visible.


  Patients and methods Top


This comparative study included 128 patients recruited from the Ophthalmology and Rheumatology Outpatient Clinics of Menoufia Faculty of Medicine. The work was done in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Menoufia Faculty of Medicine. A written informed consent was obtained from all participants to participate in the study and for publication of data. Patients were divided into two groups: group A (HCQ group) included 128 eyes of 64 patients having RA treated with HCQ, and group B (control group) included 128 eyes of 64 age-matched healthy individuals. Inclusion criteria for both groups were patients aged more than 20 years old with normal fundus examination. The HCQ group included patients treated with HCQ for more than 3 months. Exclusion criteria for both groups were patients having retinopathy, such as diabetic retinopathy or age-related macular degeneration; patients having optic neuropathy such as glaucoma; and history of previous intraocular surgery.

Patients’ evaluation included history taking about daily dose and duration of intake of HCQ in group A and history of systemic diseases such as diabetes and hypertension in both groups. The uncorrected visual acuity (UCVA) and the best-corrected visual acuity (BCVA) were assessed with Landolt’s broken ring chart. The intraocular pressure (IOP) was measured by the Goldmann applanation tonometer (Haag-Streit, Gartenstadtstrasse, Koeniz, Switzerland). Anterior segment examination by slit lamp and dilated fundus examination were also done. OCT examination was performed by SD-OCT (Carl Zeiss Meditec, Dublin, California, USA) with the macular cube 512×128 scan protocol and ganglion cell analysis (GCA) software version 7.0 to measure the average, minimum, and sectorial macular GCC thickness in an annulus area (a vertical inner and outer radius of 0.5 and 2.0 mm, respectively, and a horizontal inner and outer radius of 0.6 and 2.4 mm, respectively) around the fovea. Photoreceptor layer (PL) integrity was evaluated from the horizontal OCT macular B scans which allowed its distinction into four lines: the external limiting membrane (ELM) formed by the back reflection of the zonulae adherents that join the inner segment to the Müller cells; the inner and outer segments of the photoreceptors (IS/OS) junction also named ellipsoid zone representing the boundary between the inner and outer segments of the photoreceptors and is localized between the ELM and the retinal pigment epithelium (RPE) histologically; the cone outer segment tips also named interdigitation zone or Verhoeff’s membrane zone representing the outer tips of the cones; and the outermost RPE line that separates the photoreceptors from Bruch’s membrane and choriocapillaris. Patients were described to have disrupted PL integrity when the ELM, IS/OS junction, interdigitation zone, and RPE integrity were lost ([Figure 1]). This was done for all patients by the same experienced ophthalmologist (A.M.I.). In addition, the correlation between the GCC thickness and duration of HCQ use, PL integrity, UCVA, and BCVA in the HCQ group was analyzed.
Figure 1 (a) Left eye horizontal spectral domain optical coherence tomography (SD-OCT) macular B scan with distinction of the photoreceptor layer into four lines: the innermost external limiting membrane (ELM), inner/outer segment junction (IS/OS), interdigitation zone (IZ), and the outermost retinal pigment epithelium (RPE) line. (b) Left eye horizontal SD-OCT macular B scan with normal photoreceptor layer integrity with normal ELM, IS/OS junction, IZ, and RPE line. (c) Left eye horizontal SD-OCT macular B scans with abnormally disrupted photoreceptor layer integrity with lost ELM, IS/OS, IZ, and RPE integrity.

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Statistical analysis

Statistical analysis of the data was done by using the statistical package for social science (SPSS software package, version 20.0; IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. The Kolmogorov–Smirnov test was used to verify the normality of distribution of data. Quantitative data were described using range (minimum and maximum), mean, SD, median, and interquartile range. Significance of the obtained results was judged at the 5% level. The used tests were χ2 test for categorical variables to compare between different groups, Student t test for normally distributed quantitative data to compare between two groups, and Mann–Whitney test for abnormally distributed quantitative variables, to compare between two groups.


  Results Top


The HCQ group (group A) included 128 eyes of 64 patients (60 females and 4 males) treated with HCQ, with age range from 22 to 63 years (mean=40.37±11.13 years), UCVA range from 0.0 to 1.0 LogMAR, BCVA between 0.0 and 1.0 LogMAR, and an average IOP of 16.64±0.74 mmHg. The control group (group B) included 128 eyes of 64 patients (42 females and 22 males), with age range from 23 to 60 years (mean=41.19±12.21 years), UCVA range from 0.0 to 0.60 LogMAR, BCVA range from 0.0 to 0.20 LogMAR, and an average IOP of 16.78±0.76 mmHg. Sex, UCVA, and BCVA were statistically significantly different between the two groups (P<0.001, P<0.001, and P=0.019, respectively, [Table 1]).
Table 1 Demographic and clinical data

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The duration of treatment with HCQ in the HCQ cases ranged between 1 and 20 years (mean=7.50±5.87 years), with a daily dose of HCQ of 400 mg/day in all patients. The anterior and posterior segment examination for all patients were apparently normal.

There was no statistically significant difference between the two groups regarding the average, minimum, and sectorial macular GCC thickness ([Table 2]). Disrupted PL integrity was detected in 40.6% of the HCQ cases and in none of the control group. There was a statistically significant difference between the two groups regarding the PL integrity (P<0.001, [Table 3]). We observed that 22 patients of the HCQ cases experienced both macular GCC thinning and disrupted PL integrity.
Table 2 Ganglion cell complex thickness

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Table 3 Photoreceptor layer integrity

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Univariate analysis showed a statistically significant association between the average GCC thickness, in the HCQ group, and the duration of treatment with HCQ, UCVA, BCVA, and PL integrity (P<0.001 for all variables). On the contrary, the multivariate analysis revealed that the duration of treatment with HCQ, UCVA, and the PL integrity were the only variables that were independently associated with the average GCC thickness. The PL integrity was the highest independent variable correlated with the average GCC thickness, followed by the duration of treatment with HCQ, and lastly, the UCVA (P<0.001, P=0.005, and P=0.043, respectively, [Table 4]). A representative case is illustrated in [Figure 2].
Table 4 Univariate and multivariate analyses for the parameters affecting average ganglion cell complex thickness in hydroxychloroquine cases

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Figure 2 Hydroxychloroquine (HCQ) retinopathy in the right (OD) and left (OS) eyes of a 62-year old female patient who was diagnosed with rheumatoid arthritis (RA) and had used HCQ for 20 years with a dose of 400 mg/day. Her uncorrected visual acuity (UCVA) was 0.6 LogMAR in both eyes and best-corrected visual acuity (BCVA) was 0.2 LogMAR in both eyes. Spectral domain optical coherence tomography (SD-OCT) ganglion cell analysis (a) reveals markedly reduced average, minimum, and sectorial ganglion cell complex (GCC) thickness in both eyes. Horizontal B scans (b) demonstrate disrupted parafoveal photoreceptor layer integrity in both eyes.

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  Discussion Top


Retinal toxicity is uncommon in patients with RA on chronic HCQ use. Patients with HCQ retinopathy are usually asymptomatic in the early stages. However, in the advanced stage of the disease, the bull’s eye maculopathy will be evident with paracentral scotoma, diminished color vision, and central vision loss. HCQ maculopathy becomes irreversible in the advanced stages of the disease and even can progress after HCQ therapy discontinuation [15]. Moreover, the increasing number of patients treated with HCQ owing to its better systemic safety profile compared with chloroquine arouses interest in early screening for HCQ maculopathy. The revised American Academy of Ophthalmology recommendations suggest that annual screening should be performed on all patients within the first year of use and annually after 5 years of HCQ use unless there is other risk factors such as renal impairment, preexisting maculopathy, tamoxifen use, or increased dose of HCQ more than 5 mg/kg actual body weight (ABW) or 6.5 mg/kg ideal body weight [11].

SD-OCT advanced technology has facilitated ultra-high-resolution and cross-sectional imaging of the retina and is recommended as one of the objective screening tools for HCQ retinal toxicity [16]. Several studies showed that the OCT findings that can be used in early screening of HCQ retinopathy included macular GCC thinning, retinal nerve fiber layer thinning, and disrupted PL integrity. The Cirrus HD-OCT ganglion cell analysis (GCA) algorithm had successfully provided the macular GCC thickness with excellent reproducibility [17].

In the present study, the changes in macular GCC thickness were investigated in patients who were on chronic HCQ therapy by using the Cirrus SD-OCT. In addition, its correlation with the duration of HCQ use, PL integrity, UCVA, and BCVA was analyzed in the early screening of HCQ maculopathy.

There was no statistically significant difference between the two groups regarding the average, minimum, and sectorial macular GCC thickness. Previous studies have reported localized thinning of the parafoveal inner retina on SD-OCT in patients with chronic exposure to HCQ. Pasadhika and Fishman [8] found that patients with abnormal fundus showed thinning of the inner, outer, and full-thickness retina, and patients with chronic exposure to HCQ without fundus changes showed significant thinning of the inner retina only. Another study by Pasadhika et al. [12] on patients who were visually normal and without fundus abnormality or any defect on Humphrey 10-2 visual field testing reported that selective thinning of the GCC was observed only in the parafoveal area. However, this study enrolled only eight patients and eight controls. On the contrary, the current study included a larger number of asymptomatic patients with normal fundus and varying duration of exposure to HCQ, and correlation between the duration of HCQ use and GCC thickness was investigated.

In agreement with the present study, de Sisternes et al. [18] reported that the inner retina was not affected by HCQ exposure to any clinically relevant degree. The small decrease in users for longer than 15 years with Cirrus data could result from greater variability or represent a small population difference or that inner retina might slide into parafoveal defects of the outer retina or even using GCA measurements designed for glaucoma. Cirrus data from other studies of the inner retina might have been influenced by errors in GCA measurements when the outer retina was abnormal [19],[20],[21]. Therefore, we excluded patients with retinal diseases that might affect outer retinal structures on SD-OCT.

The study by Lee and colleagues included 130 patients, who were divided into three groups: group 1A included 55 patients with HCQ use more than or equal to 5 years, group 1B included 46 patients with HCQ use less than 5 years, and group 2 included 29 normal controls. The average and minimum macular GCC thicknesses of group 1 patients were not significantly different from those of group 2. On the contrary, the average and minimum macular GCC thickness of group 1A patients were significantly lower than those of groups 1B and 2. However, the average and minimum macular GCC thicknesses of group 1B patients were not significantly different from those of group 2. When excluding patients with HCQ use more than 1000 g in group 1A, the average and minimum macular GCC thickness were also significantly lower than those of groups 1B and 2. It was suggested that the loss in the inner retinal layers by SD-OCT could be helpful for follow-up of patients on HCQ therapy to detect early macular changes compared with baseline measurements [13].

In the present study, we also observed statistically significant difference between the two studied groups regarding the PL integrity. Histological studies had shown that the perifoveal photoreceptor cells are the most severely affected retinal cells in HCQ maculopathy and that might be a secondary effect owing to disruption of RPE metabolism [22]. Previous studies on symptomatic patients receiving HCQ therapy reported retinal thinning and loss of outer retinal layers with early retinal toxicity [23],[24]. Stepien et al. [25] described a ‘moth-eaten’ photoreceptor inner segment/outer segment (IS/OS) junction owing to HCQ toxicity in the absence of clinical signs or field defects. The IS/OS junction loss was explained by preferential loss of cone photoreceptors and is considered a confirmed sign of damage in early retinopathy. Kellner et al. [26] found that loss of the PL integrity detected by OCT corresponds to PL dysfunction detected by the multifocal electroretinogram.

In the present study, the duration of treatment with HCQ, UCVA, BCVA, and PL integrity were associated with the average GCC thickness in the HCQ-treated patients on univariate analysis. On the contrary, the multivariate analysis revealed that only the PL integrity was the highest variable that was independently associated with the average GCC thickness, followed by the duration of treatment with HCQ, and lastly, the UCVA.

Previous studies had reported that the photoreceptor loss might impair the inner retinal cells, including the RGCs in the long term [27],[28],[29],[30],[31]. Therefore, thinning of macular GCC does not necessarily mean that RGC loss is caused by HCQ. Photoreceptor loss followed by consecutive transneuronal degeneration of RGCs also may lead to thinning of the GCC. The inner retinal structure is preserved for long time [27],[31]. This could explain the findings of the present study that the 22 patients with RA with thinning of GCC also showed disrupted PL and that some patients with lost PL integrity have no evidence of GCC thinning. It also reflects the statistically significant independent association between the average GCC thicknesses in the HCQ group with the PL integrity.

In the present study, a statistically significant correlation was found between the average macular GCC thickness and the duration of HCQ use on univariate and multivariate analyses. A previous study showed that the prevalence of HCQ retinopathy was 7.5%, but this increased to around 20% after 20 years of use for those taking 4.0–5.0 mg/kg ABW/day and can exceed 50% at 20 years for those taking greater than 5.0 mg/kg ABW/day [32]. Similarly, Bulet et al. [33] found a linear negative correlation between the average GCC thickness and the duration of HCQ use (P=0.006). A similar correlation was observed by Lee et al. [13].

In another study, Lee and colleagues found that the macular GCC thickness had a weak but significant negative correlation with cumulative dose of HCQ. However, when analyzing after exclusion of the patients with high cumulative doses (>1000 g), no significant correlations were observed. These findings suggest that although some patients, especially with HCQ retinopathy or high cumulative doses, showed thin GCC, thinning of the GCC was not a general phenomenon in patients with exposure to HCQ [21].

The present study revealed that the macular GCC thickness was significantly correlated with UCVA on both univariate and multivariate analyses. This is in agreement with what was reported by Walter et al. [34] who reported linear correlation between macular GCC thickness and visual disability.

The reasons of presence of a correlation between GCC thickness and BCVA in univariate analysis and its absence in multivariate analysis might be that some eyes with poor visual acuity had preserved thickness of the GCC and that the present OCT could not distinguish the transition between the ganglion cell layer and the inner plexiform layer. So, a larger study cohort and new OCT with a more precise segmentation of the retinal layers are needed in future studies [35].

This study demonstrated that unique SD-OCT findings in the retina can identify early HCQ retinopathy and could be a complementary objective tool in HCQ maculopathy screening.

The limitation of the present study could be the lack of combined application of more structural and functional retinal assessment techniques that should be done to determine the best screening regimen. In addition, assessment of doses according to ABW with follow-up of the patients during and after discontinuation of HCQ would have been more valuable. Further studies are needed to determine the mechanism of HCQ maculopathy, the additional risk factors, and the optimal screening protocol.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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