Selective thinning of the perifoveal inner retina as an early sign of hydroxychloroquine retinal toxicity

BackgroundCurrent melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort.MethodsRabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 μg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. Patients: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan.ResultsIntravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%–79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 μV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged.ConclusionsTaken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

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Pre‐implant global longitudinal strain as an early sign of pacing‐induced cardiomyopathy in patients with complete atrioventricular block

Echocardiography ◽

10.1111/echo.14942 ◽

2021 ◽

Author(s):

Jung Yeon Chin ◽

Ki‐Woon Kang ◽

Sang Hyun Park ◽

Yu Jeong Choi ◽

Kyung Tae Jung ◽

...

Keyword(s):

Atrioventricular Block ◽

Longitudinal Strain ◽

Global Longitudinal Strain ◽

Early Sign ◽

Complete Atrioventricular Block ◽

Complete Atrioventricular

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OP0133 THE PREVALENCE AND RISK FACTORS OF RETINAL TOXICITY ASSOCIATED WITH LONG-TERM HYDROXYCHLOROQUINE USE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.328 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 77-78

Author(s):

S. Do ◽

J. H. Du ◽

J. X. An ◽

J. Wang ◽

A. Lin

Keyword(s):

Risk Factors ◽

Cumulative Dose ◽

Daily Intake ◽

Retinal Toxicity ◽

Factors Associated ◽

Duration Of Therapy ◽

Increased Risk ◽

Hydroxychloroquine Retinopathy ◽

Risk Of Retinopathy

Background:Hydroxychloroquine (HCQ) is commonly used for the treatment of various autoimmune diseases. The medication is generally well-tolerated. However, long-term use after 5 years may increase the risk of retinopathy. One study in 2014 has demonstrated the risk can be as high as 7.5%. Optical Coherence Tomography (OCT) has become a major modality in screening retinopathy.Objectives:To evaluate the prevalence of retinal toxicity among patients using hydroxychloroquine and to determine various risk factors associated with hydroxychloroquine-associated retinal toxicity.Methods:We performed a retrospective chart review on a cohort of adult patients with long-term use (≥ 5 years cumulative) of HCQ between January 1st, 2011 to December 31st, 2018 from the Kaiser Permanente San Bernardino County and Riverside medical center areas in Southern California, USA. Patients were excluded if they had previously been diagnosed with retinopathy prior to hydroxychloroquine use, were deceased, or had incomplete OCT exam. Our primary endpoint was the prevalence of patients who developed retinal toxicity detected by OCT, and later confirmed by retinal specialist. Potential risk factors (age, duration of therapy, daily consumption per actual body weight, cumulative dose, confounding diseases and medication) for developing retinopathy were also evaluated. Univariable and multivariable logistic regression analyses were used to determine risk factors associated with retinal toxicity.Results:Among 676 patients exposed to more than 5 years of HCQ, the overall prevalence of retinal toxicity was 6.8%, and ranged from 2.5% to 22.2% depending on the age, weight-based dosing, duration of use and cumulative dose. Duration of therapy for 10 years or more increased risk of retinopathy by approximately 5 to 19 folds. Similarly, weight-based dose of 7 mg/kg/day or greater was assciated with increased risk of retinopathy by approximately 5 times. Patients with cumulative dose of 2000 grams or more had greater than 15 times higher risk of developing retinopathy. Duration of use for10 years or more (odd ratio 4.32, 95% CI 1.99 – 12.49), age (odd ratio 1.04; 95% CI 1.01 - 1.08), cumulative dose of more than 1500 g (odd ratio 7.4; 95% CI 1.40 – 39.04) and atherosclerosis of the aorta (odd ratio 2.59; 95% CI, 1.24 – 5.41) correlated with higher risk of retinal toxicity.Conclusion:The overall prevalence of retinopathy was 6.8%. Regular OCT screening, especially in patients with hydroxychloroquine use for more than 10 years, daily intake > 7 mg/kg, or cumulative dose > 1500 grams is important in detecting hydroxychloroquine-associated retinal toxicityReferences:[1]Hobbs HE. Sorsby A, & Freedman A. Retinopathy Following Chloroquine Therapy. The Lancet. 1959; 2(7101): 478-480.[2]Levy, G. D., Munz, S. J., Paschal, J., Cohen, H. B., Pince, K. J., & Peterson, T. Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis & Rheumatism: 1997; 40(8): 1482-1486.[3]Ding, H. J., Denniston, A. K., Rao, V. K., & Gordon, C. Hydroxychloroquine-related retinal toxicity. Rheumatology. 2016; 55(6): 957-967.[4]Stelton, C. R., Connors, D. B., Walia, S. S., & Walia, H. S. Hydrochloroquine retinopathy: characteristic presentation with review of screening. Clinical rheumatology. 2013; 32(6): 895-898.[5]Marmor, M. F., Kellner, U., Lai, T. Y., Melles, R. B., & Mieler, W. F. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy (2016 revision). Ophthalmology. 2016; 123(6): 1386-1394.[6]Melles, R. B., & Marmor, M. F. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA ophthalmology. 2014; 132(12): 1453-1460.Disclosure of Interests:None declared

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Subcellular Localization and Complements of GABAA and GABAC Receptors on Bullfrog Retinal Bipolar Cells

Journal of Neurophysiology ◽

10.1152/jn.2000.84.2.666 ◽

2000 ◽

Vol 84 (2) ◽

pp. 666-676 ◽

Cited By ~ 37

Author(s):

Jiu-Lin Du ◽

Xiong-Li Yang

Keyword(s):

Subcellular Localization ◽

Receptor Antagonist ◽

Gaba Receptor ◽

Drug Application ◽

Bipolar Cells ◽

Visual Signals ◽

Receptor Subtypes ◽

Inner Retina ◽

Axon Terminals ◽

Retinal Bipolar Cells

γ-Aminobutyric acid (GABA) receptors on retinal bipolar cells (BCs) are highly relevant to spatial and temporal integration of visual signals in the outer and inner retina. In the present work, subcellular localization and complements of GABAA and GABACreceptors on BCs were investigated by whole cell recordings and local drug application via multi-barreled puff pipettes in the bullfrog retinal slice preparation. Four types of the BCs (types 1–4) were identified morphologically by injection of Lucifer yellow. According to the ramification levels of the axon terminals and the responses of these cells to glutamate (or kainate) applied at their dendrites, types 1 and 2 of BCs were supposed to be off type, whereas types 3 and 4 of BCs might be on type. Bicuculline (BIC), a GABAA receptor antagonist, and imidazole-4-acetic acid (I4AA), a GABAC receptor antagonist, were used to distinguish GABA receptor-mediated responses. In all BCs tested, not only the axon terminals but also the dendrites showed high GABA sensitivity mediated by both GABAA and GABACreceptors. Subcellular localization and complements of GABAA and GABAC receptors at the dendrites and axon terminals were highly related to the dichotomy of offand on BCs. In the case of off BCs, GABAA receptors were rather evenly distributed at the dendrites and axon terminals, but GABAC receptors were predominantly expressed at the axon terminals. Moreover, the relative contribution of GABAC receptors to the axon terminals was prevalent over that of GABAA receptors, while the situation was reversed at the dendrites. In the case of on BCs, GABAA and GABAC receptors both preferred to be expressed at the axon terminals; relative contributions of these two GABA receptor subtypes to both the sites were comparable, while GABAC receptors were much less expressed than GABAA receptors. GABAA, but not GABAC receptors, were expressed clusteringly at axons of a population of BCs. In a minority of BCs, I4AA suppressed the GABAC responses at the dendrites, but not at the axon terminal, implying that the GABAC receptors at these two sites may be heterogeneous. Taken together, these results suggest that GABAA and GABAC receptors may play different roles in the outer and inner retina and the differential complements of the two receptors on off and on BCs may be closely related to physiological functions of these cells.

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