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However, due to the surge in communication, we are experiencing longer than average hold times for calls. Three of these patients were using hydroxychloroquine alone, 2 were using chloroquine, and the final patient was taking both. There was equivocal evidence of progression for a further patient who had taken hydroxychloroquine patient 2 Table.
There was neither subjective nor objective evidence of visual improvement in the remaining 3 individuals with follow-up. In keeping with previous reports, the retinopathy associated with chloroquine in our series was more severe than that observed with hydroxychloroquine; all 3 women experienced gradual deterioration.
Patient 1 had hand motion vision with no discernible field on initial testing. Three months after stopping chloroquine therapy, no recovery of central VF was present, but rims of peripheral VF were detectable on kinetic and static perimetry Figure 1. Progressive loss of peripheral field occurred for 5 years Figure 1. Continued progression associated with previous hydroxychloroquine use was recorded up to 7 years after stopping the medication Table.
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The age of the 3 women patients 4, 11, and 14 with progressive retinal toxicity secondary to hydroxychloroquine ranged from 59 to 70 years, their exposure ranged from 10 to 15 years, and their cumulative dose was between and g Table. In 1 of these 3 patients, the daily dosage based on actual weight was greater than 6. When the daily dosage based on actual weight was calculated for the remaining 9 of 10 patients taking hydroxychloroquine alone without evidence of progression no data available for patient 6 , it was greater than 6.
The dosage exceeded this recommended maximum in 7 of these patients based on lean body weight range, 4. In patients 3 and 11, a perifoveal ring of increased AF was observed. Areas of decreased AF, corresponding to areas of atrophy seen ophthalmoscopically, were recorded in the 2 other patients patients 4 and 7. Within the bounds of follow-up information, there were no known adverse effects, including significant systemic or symptomatic relapse, in any patient consequent upon stopping medication.
We report detailed findings of 16 patients with retinal toxicity secondary to hydroxychloroquine and chloroquine use, monitored for a relatively short period, at a single institution. Although retinal toxicity is uncommon in the large number of patients who use hydroxychloroquine worldwide and derive great benefit from the therapy, our series suggests that the prevalence of retinopathy and risk of progression despite cessation of the drug may be higher than currently thought.
There are many readily apparent sources of bias that may contribute to the relative rarity of toxicity documented in the literature, including failure to report cases, inherent bias to not publish findings that are not novel, and underdetection by either the physician or patient. Several factors have been associated with the risk of developing hydroxychloroquine or chloroquine retinopathy. One of the most important appears to be dosage, with daily intake believed to be more significant than cumulative dosage.
However, if the daily dosage is estimated in all our patients on the basis of lean body weight, then 9 individuals now appear to have been taking a dosage that exceeded 6. Notwithstanding the inherent limitations of a retrospective case series, this observation suggests that it may be better to use lean body weight when calculating daily dose for all patients and that our findings may contribute to future review of hydroxychloroquine dosage recommendations.
Additional risk factors for retinal toxicity are age and length of treatment. Patients older than 60 years and with a duration of treatment greater than 5 years appear to be at greater risk for retinal toxicity. In keeping with the maxim that retinal appearance does not always correlate with function, we identified patients in our series with either a normal macular appearance or very mild retinal pigment epithelial disturbance who had profound VF and mfERG abnormalities, suggesting that significant dysfunction precedes clinically evident structural changes.
The physician should remain mindful that ophthalmoscopic abnormalities are likely to represent a late stage in antimalarial drug toxicity, thereby highlighting the importance of patient education, careful assessment for visual symptoms, and detailed investigations including VF testing, mfERG, FA, and SDOCT. The findings from imaging studies performed in some of our patients were similar to those recently reported in cases of retinal toxicity using FA hydroxychloroquine and chloroquine , 13 , 14 high-speed ultra-high-resolution optical coherence tomography hydroxychloroquine retinopathy , 12 and SDOCT chloroquine retinopathy.
Patient 2 had significant VF changes with minimal macular disturbance on clinical examination and no discernible abnormalities with SDOCT, implying that the outer retinal changes seen with optical coherence tomography are unlikely to be the earliest sign of toxicity.
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It has been suggested, on the basis of SDOCT observations, including retinal nerve fiber layer analysis, that the earliest findings may be located in the inner retinal layers, in keeping with nonhuman primate studies of quinolone toxicity. Of the 10 patients with follow-up data available, repeat electrophysiologic and VF assessment provided objective evidence of disease progression despite cessation of medication in 6 of these patients.
Continued progression associated with previous hydroxychloroquine use was recorded up to 7 years after stopping the drug. This serves to remind the physician that progression is not an infrequent finding, with close follow-up being required to identify the stability of retinal function and structure, and that mfERG and detailed VF testing are very helpful in monitoring change.
In addition, 4 patients in our series were asymptomatic and 3 had a normal macular appearance 1 of these patients was asymptomatic , indicating the important role of imaging, psychophysical, and electrophysiologic testing in the assessment of potential toxicity. Bilateral macular cone dysfunction was identified with mfERG in all patients in whom testing was undertaken in keeping with the increasing amount of data supporting its use in the screening and monitoring of patients using antimalarial drugs for associated retinal toxicity.
In the remaining 3 patients it was peripheral, which is of interest, especially in light of the observation on SDOCT of peripheral macular abnormalities in patients with chloroquine-associated toxicity, including a reduction in the thickness of the outer nuclear layer.
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It is plausible, however, that these patterns of VF loss may be reflective of disease progression per se rather than variable characteristics of retinal toxicity. The 3 patients in our series with peripheral and central VF loss were found to have combined VF defects at presentation, making it difficult to ascertain the sequence of events. During follow-up there was progression of both central and peripheral VF defects in all 3 patients.
Patient 1 had a transient, short-term improvement in peripheral VF upon stopping chloroquine use but subsequently lost the entire recovered field within several years. We did not observe objective or subjective evidence of sustained visual improvement in any patient in this series, and our identification of 6 patients with evidence of progression, using multiple objective measures, serves to remind physicians of the potentially devastating visual consequences of antimalarial-related retinopathy.
The proposed risk factors associated with increased likelihood of hydroxychloroquine-related retinal toxicity, while highly useful, especially in determining how frequently to monitor patients and by which tests, are not absolute and cannot preclude the development of toxicity.
This is illustrated by the toxicity that occurred in our patients, despite taking a lower daily dosage of hydroxychloroquine than deemed to be high risk, in 8 patients, including 4 younger than 60 years, as well as an individual with a duration of hydroxychloroquine therapy of less than 5 years. These patients were identified at a single institute during a short period, highlighting the fact that the possibility of toxicity should not be discounted due to its uncommon nature.
Correspondence: Richard G. Submitted for Publication: February 27, ; final revision received April 8, ; accepted April 13, All Rights Reserved. Figure 1.
View Large Download. Lancet ; PubMed High-speed ultra-high-resolution optical coherence tomography findings in hydroxychloroquine retinopathy. ISCEV guidelines for clinical multifocal electroretinography edition.
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