Multifocal Electroretinographic Changes in Patients Receiving Hydroxychloroquine Therapy

doi:10.1016/j.ajo.2005.05.046

American Journal of Ophthalmology

Volume 140, Issue 5, November 2005, Pages 794-807.e1

https://doi.org/10.1016/j.ajo.2005.05.046 Get rights and content

Purpose

To evaluate the longitudinal changes in multifocal electroretinography (mfERG) in patients receiving hydroxychloroquine and to assess the effects of cumulative hydroxychloroquine dose on mfERG.

Design

Prospective cohort study.

Methods

Twenty-four eyes in 12 patients receiving hydroxychloroquine underwent mfERG recordings at baseline and 1 to 2 years later. The first negative (N1) and first positive (P1) response amplitudes and peak latencies were compared with normal controls. Serial changes in the pattern of mfERG abnormalities and in response amplitudes and peak latencies were also compared between eyes in which hydroxychloroquine therapy was continued or stopped. Correlation analyses were performed to assess the effects of a cumulative dose of hydroxychloroquine on mfERG.

Results

At baseline, reductions in N1 and P1 response amplitudes were observed in patients receiving hydroxychloroquine compared with controls. At follow-up, in addition to the reductions in N1 and P1 response amplitudes, increases in P1 peak latencies compared with controls were observed. In patients who stopped hydroxychloroquine therapy, there were significant increases in N1 and P1 response amplitudes at follow-up mfERG.

Conclusions

Patients receiving hydroxychloroquine showed a longitudinal decline in retinal function; patients who stopped hydroxychloroquine therapy showed improvement. Although these data are insufficient to demonstrate the sensitivity of mfERG for evaluating early hydroxychloroquine toxicity, the results suggest that serial mfERG assessment may help detect early retinal changes associated with hydroxychloroquine therapy. Further studies with long-term results will be useful in clarifying the value of mfERG in evaluating early retinal toxicity due to hydroxychloroquine.

Section snippets

Methods

All patients receiving hydroxychloroquine referred for mfERG evaluation at Hong Kong Eye Hospital were prospectively recruited. Patients’ current and past medical illnesses—in particular the dose, duration, and indication of hydroxychloroquine use, and any associated visual symptoms—were recorded. Complete ocular examinations were performed at baseline and at follow-up assessments that included best-corrected visual acuity (BCVA) testing, color vision testing with Ishihara chart, red Amsler

Results

Twenty-four eyes of 12 patients were included in the study, whose demographic details are listed in TABLE 1, TABLE 2. All patients were women, and indications for hydroxychloroquine use included systemic lupus erythematosus (n = 8), rheumatoid arthritis (n = 3), and systemic vasculitis (n = 1). The mean ± SD age of the patients on baseline testing was 45.0 ± 9.5 years (range 26 to 62 years). The mean ± SD duration of hydroxychloroquine treatment before baseline assessment was 3.0 ± 1.1 years

Discussion

Hydroxychloroquine, initially developed as an antimalarial drug, is now most commonly used in the treatment of various rheumatologic conditions such as systemic lupus erythematosus and rheumatoid arthritis. Toxic retinopathy is a potentially severe side effect associated with its use, and risk factors for the development of hydroxychloroquine retinopathy include high daily drug dose, long duration of treatment, high level of body fat, concomitant renal or liver disease, and age older than 60

Timothy Lai, MD, is an ophthalmologist of the surgical and medical retina unit at the Hong Kong Eye Hospital and an honorary staff of the Department of Ophthalmology and Visual Sciences, Chinese University of Hong Kong. His main research interests include techniques in macular surgery and visual electrophysiology particularly in multifocal techniques.

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To evaluate multifocal electroretinography (mfERG) as a screening test for detecting hydroxychloroquine and chloroquine toxicity.
Diagnostic accuracy study.
Patients referred to the University of Ottawa for hydroxychloroquine or chloroquine retinopathy screening during 2011–2014 underwent 10-2 automated visual field, spectral domain optical coherence tomography, and mfERG testing. Patients with amblyopia, high myopia or hyperopia, coexisting retinal disease, or prior surgery were excluded. Abnormalities in parafoveal ring amplitudes or ring ratios were considered a positive mfERG result. We used the definition for hydroxychloroquine and chloroquine toxicity provided by the 2016 American Academy of Ophthalmology recommendations. Area under the curve (AUC) for each mfERG parameter and the sensitivity and specificity of mfERG were calculated. Logistic regression was used to model the effect of covariates in receiver operating characteristic (ROC) analyses.
In total, 63 patients (47 female, 16 male) were included. Of 120 eyes, 16 (13.3%) had toxicity according to the American Academy of Ophthalmology guidelines, and 39 (32.5%) had positive mfERG findings. mfERG was found to have a sensitivity of 1.00 (95% CI 0.79–1.00) and a specificity of 0.78 (95% CI 0.69–0.85). Ring 2 amplitude had the best performance among all parameters (AUC 0.97, 95% CI 0.94–1.00). Ring 2 amplitude decreased linearly with increasing cumulative dose and daily dose.
The high sensitivity of parafoveal depression on mfERG and its relationship to cumulative and daily dose illustrates an important role for objective functional testing. The high false-positive rate suggests a potential period where physiologic dysfunction is detected objectively on mfERG before structural change on spectral domain optical coherence tomography.
Desirable and Adverse Effects of Antiinflammatory Agents on the Heart
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Antiinflammatory drugs have greatly improved the quality of life and management of several rheumatic conditions. However, the benefits of antiinflammatory therapies should be weighed against the potential consequences, with careful evaluation of side effects. The aim of the present chapter is to summarize current evidence on potential cardiovascular effects of antiinflammatory therapies including either adverse or potentially desirable effects. Nonsteroidal antiinflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs) are reviewed, with a focus on hydroxychloroquine, methotrexate, sulfasalazine, minocycline, varespladib, leflunomide, and colchicine.
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Cohort study.
Twelve patients with chronic GVHD treated with 800 mg/day HCQ between June 2005 and December 2010.
Patients in this study underwent ophthalmologic examination yearly and ancillary studies including colour vision, Amsler grid, fundus photographs, Humphrey 10-2 automated perimetry, spectral-domain optical coherence tomography (SD-OCT), and multifocal electroretinography (mfERG). Evidence of HCQ toxicity was determined by the presence of scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, and confirmed by at least 1 objective test including SD-OCT or mfERG.
Of the 12 patients, 7 were male and 5 were female. Mean age was 49 years. Mean best corrected visual acuity at baseline was 20/25 and remained 20/25 at final follow-up. Median duration of HCQ treatment was 22.8 months. Median adjusted daily dosage was 11.5 mg/kg/day. Seven patients developed vortex keratopathy. No signs of pigmentary retinopathy or bull’s-eye maculopathy were found in any of the patients. Three patients developed retinal toxicity with scotomas in the Amsler grid and Humphrey 10-2 automated perimetry, as well as abnormal mfERG. Retinal structure measured by SD-OCT was abnormal in 2 of the 3 patients with retinal toxicity. Colour vision measured by Ishihara plates, as well as by 100 Hue colour test, was abnormal in 2 of the 3 patients with retinal toxicity.
High-dose HCQ in patients with GVHD was associated with higher incidence and earlier development of retinal toxicity.
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Toxicité de l’HCQ démontrée par la présence de scotomes (test d’Amsler et périmétrie automatisée) et confirmée par au moins un test objectif (TCO-DS ou électrorétinographie multifocale).
Des 12 patients, 7 étaient des hommes et 5 étaient des femmes. L’âge moyen était de 49 ans. La meilleure acuité visuelle corrigée moyenne de référence était de 20/25; elle était toujours de 20/25 au suivi final. La durée médiane du traitement à l’HCQ était de 22,8 mois. La dose ajustée médiane était de 11,5 mg/kg/jour. Sept patients ont développé une cornée verticillée. Aucun signe de rétinopathie pigmentaire ni de maculopathie en œil de bœuf n’a été relevé chez aucun des patients. Trois patients ont développé une toxicité rétinienne avec scotomes selon le test d’Amsler et la périmétrie automatisée, de même qu’une électrorétinographie multifocale anormale. La structure rétinienne mesurée par TCO-DS était anormale chez 2 des 3 patients présentant une toxicité rétinienne. La vision des couleurs mesurée par le test d’Ishihara et par le test de Farnsworth-Munsell 100 Hue était anormale chez 2 de ces 3 mêmes patients.
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: See accompanying Editorial on page 894.

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Original articleMultifocal Electroretinographic Changes in Patients Receiving Hydroxychloroquine Therapy

Purpose

Design

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Lancet

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Ophthalmology

Ophthalmology

Vision Res

Regul Toxicol Pharmacol

Ocular abnormalities in patients treated with synthetic antimalarial drugs

N Engl J Med

Comparison of hydroxychloroquine and chloroquine use and the development of retinal toxicity

J Rheumatol

Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice

Arthritis Rheum

Ocular safety of hydroxychloroquine

Ann Ophthalmolol

Original article
Multifocal Electroretinographic Changes in Patients Receiving Hydroxychloroquine Therapy