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Purpose Multifocal electroretinogram (mfERG) shows great utility as a screening tool to detect early hydroxychloroquine (HCQ) retinopathy, but its widespread use is limited by the lack of accessibility and long test duration. In this study, we evaluated a novel concentric 5-ring mfERG stimulus to provide a simplified and rapid protocol for screening HCQ toxicity. Methods Patients referred for HCQ retinopathy screening were consented to this observational cross-sectional study. Patients with amblyopia, high refractive error (more than 8 diopters), other retinal diseases precluding appropriate evaluation or history of retinal surgery were excluded. The data were collected from patients undergoing HCQ screening at a single center from July 2019 to March 2020. Patients were tested with the new concentric 5-ring mfERG stimulus, standard 61-hexagon mfERG stimulus, spectral domain optical coherence tomography and automated 10-2 visual fields. For the main outcome, the 5-ring mfERG was compared to 61-hexagon stimulus to determine the time-to-test completion and assess the association between ring (R1–R5) amplitude and ring ratio compared against cumulative dose, dose by real body weight and duration of therapy using Pearson correlation. Results In total, 52 patients (104 eyes; 5 males and 47 females) were recruited with a mean age of 59 years (range 23–85 years). The 5-ring protocol was markedly quicker to perform (1.3 ± 0.2 min; mean (SD)) compared to the 61-hexagon protocol (5.2 ± 0.6 min), p n = 10 patients. The new R2/R5 ring ratio showed a moderate correlation with daily dose (r = − 0.640), cumulative dose (r = − 0.581) and duration of therapy (r = − 0.417). Similar correlations were observed with the new R2/R4 ring ratio which were not significantly different from the new R2/R5 correlation coefficients. The new R2/R5 ring ratio demonstrated a stronger correlation with daily (p = 0.002) and cumulative dose (p = 0.0001) compared to the 61-hexagon stimulus. Conclusions In this exploratory study, our novel 5-ring mfERG protocol significantly shortened data acquisition time while providing comparable results to the standard 61-hexagon stimulus for detecting HCQ-induced electrophysiological changes that are correlated with HCQ dosages and treatment duration. Our protocol has the potential to be more clinically practical by simplifying routine screening.

No contexto da pandemia do novo coronavírus, as drogas cloroquina e hidroxicloroquina foram divulgadas massivamente e utilizadas como tratamento contra a COVID-19. Sabe-se que esses medicamentos possuem efeitos colaterais, dentre eles complicações oculares. O presente estudo analisa se é possível a ocorrência desses efeitos colaterais oftalmológicos, considerando a prescrição destes fármacos recomendada para o tratamento precoce da COVID-19 pelo Ministério da Saúde do Brasil em 2020. Este trabalho tem por objetivo realizar uma revisão integrativa no intuito de identificar quais são os efeitos colaterais oftalmológicos pelo uso de cloroquina (CQ) e hidroxicloroquina (HCQ). Com busca na plataforma PUBMED. O processo utilizou como termos de busca “Hidroxicloroquina”, “Cloroquina”, “Oftalmopatia” e “Retinopatia”. Incluídos artigos científicos publicados entre 2015 e 2020, em inglês ou português e de acesso livre ao texto integral. Foram coletados dados referentes aos autores, principais resultados, fatores de risco e ano da publicação. Foram selecionados 14 estudos, em que toxicidade retinal ou retinopatia por HCQ/CQ são abordadas. Foi observado que os fatores de risco mais importantes o desenvolvimento das complicações oculares são uma dose acumulativa de, ao menos, 600g de HCQ ou de, pelo menos, 460g de CQ e uma terapia com duração de, no mínimo, 3 anos. Além disso, foram expostos outros fatores de risco como a dose diária ingerida, tipo físico, uso concomitante de tamoxifeno e as comorbidades dos pacientes. O desenvolvimento da retinopatia por hidroxicloroquina e cloroquina é dependente, principalmente, da dose acumulativa e da duração da terapia.

Background: Guidelines from the Royal College of Opthalmologists in February 2018 were developed for retinal screening for patients on hydroxychloroquine, as recent evidence suggests the risk of retinal toxicity is higher than previously reported. The prevalence of retinal toxicity in long term use appears to be 7.5% and depending on dose and duration of therapy can increase to 20-50% after 20 years of therapy. Risk is increased for patients taking more than 5mg per kg per day of hydroxychloroquine, patients on Tamoxifen and those with renal impairment. The guidelines recommend the use of a standardised referral proforma to help identify patients who are high risk. Objectives: 1. Audit of Hydroxychloroquine use and retinal screening in the Belfast Health and Social Care Trust (BHSCT) 2. Develop a regional referral proforma and screening service for retinal toxicity Methods: Patients who were treated with hydroxychloroquine, under the care of a consultant rheumatologist were identified on the database. A proforma was used to aid data collection and patients’ electronic records were reviewed. We audited the use of hydroxychloroquine and retinal screening against current Royal College of Ophthalmology (RCO) guidelines. We designed a standardised referral proforma and regional screening strategy in conjunction with ophthalmology colleagues. Results: There were 151 patients identified on hydroxychloroquine on the database. 40 of these patients had stopped hydroxychloroquine, 2 of which had retinal toxicity. Therefore the rate of retinal toxicity in this sample was 1.3% (2/151). There were 111 patients who remained on hydroxychloroquine treatment with a female: male ratio of 9:1. Age range was from 22 to 84, with a mean age of 55. There were 44% of patients on hydroxychloroquine for rheumatoid arthritis, 25% had systemic lupus erythematosus, 8% had Sjogrens syndrome, 6% had pallindromic rheumatoid arthritis and 13% had other connective tissue diseases. The majority (79%) of patients were on 200mg hydroxychloroquine daily and 19% were on 400mg daily. 6% of patients had an eGFR Conclusion: In this sample, only 1.3% of patients had evidence of retinal toxicity, although 64% of patients were overdue retinal screening. We developed a referral proforma and a regional screening strategy in line with RCO guidelines. In order to meet the RCO guidelines, we recognise the need for substantial investment in regional ophthalmology services. References: [1] Royal College of Ophthalmologists. (2018) Clinical Guidelines. Hydroxychloroquine and Chloroquine Retinopathy:Recommendations on Screening. Disclosure of Interests: None declared

Background: Hydroxychloroquine (HCQ) is prescribed for rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and inflammatory osteoarthritis (IOA). A potential side effect of HCQ is drug-induced retinopathy, with an increased risk reported for patients taking >5mg/kg/day and those who have renal impairment. In the United Kingdom, the Royal College of Ophthalmologists (RCO) has published new screening guidelines for HCQ, recommending 1) patients receive doses Objectives: This audit aimed to: 1) audit dose prescription by body weight, 2) estimate the screening burden on ophthalmology services, 3) estimate service needs for additional drug education appointments to counsel patients starting HCQ. Methods: A list of all patients who were started on HCQ from January 2017 to February 2018 was obtained from the outpatient pharmacy at Salford Royal Hospital. Demographic and clinical data were extracted from electronic patient records. High-risk patients were defined as those who were prescribed an initial dose of >5mg/kg/day or those with an eGFR ≤50 ml/min/1.73m2. Patients were followed until the most recent follow-up visit by July 2018 to determine drug persistence and reasons for HCQ cessation, if any. Results: 177 patients were started on HCQ, with most (62%) diagnosed with rheumatoid arthritis (Table). Most patients were female (76%) and a third (35%) were older than 60 years old. 9 patients (5.1%) had impaired renal function. 83 patients (47%) were prescribed an initial daily dose of HCQ >5mg/kg/day. By July 2018 (follow-up duration 6-19 months), 127 patients (71.8%) remained on HCQ and will need baseline eye screening. The remaining 50 patients (28.2%) stopped HCQ due to inefficacy (7.3%), GI disturbance (3.4%), rash (3.4%). Conclusion: Clinicians need to be cognisant of recent guidelines and adjust HCQ dosing to the recommended 5mg/kg/day. Additional specialist pharmacist input for DED (∼12-13 extra appointments per month) is required. Almost a third of the patients had stopped HCQ by July 2018, mostly due to side effects and reported inefficacy. However, a large proportion (71%) of HCQ starters remain on the drug by 6-12 months and will need baseline screening. Ophthalmology services can estimate services and capacity required for baseline HCQ screening per annum. Reference: [1] Royal College of Ophthalmology Guideline: Hydroxychloroquine and Chloroquine Retinopathy Screening 2018 Acknowledgement: We would like to thank Lloyds Pharmacy of Salford Royal NHS Foundation Trust for providing the data on HCQ prescribing from Jan 2017 to Feb 2018. Disclosure of Interests: None declared

Background:Hydroxychloroquine (HCQ) has attracted much attention especially during the COVID-19 pandemic. HCQ and closely related chloroquine (CQ) have known ocular and cardiac toxicity. However, although screening guidance now exists from the Royal College of Ophthalmologists for the former (RCOphth)1, little is known regarding predictors of both forms of toxicity.Objectives:To systematically explore the literature on predictors of toxicity limited to cardiac and ocular toxicity.Methods:A detailed search of the following databases was conducted: PubMed, Medline, Embase, Web of Science, The Cochrane library, EMCare and Academic Search Premier. Studies addressing predictors of HCQ toxicity with relevant search terms used were included. Exclusion criteria were: non-English articles, pre-clinical and paediatric studies. Three authors (SR, NC, PK) independently screened titles and abstracts for inclusion, ensuring each article was screened twice. Disagreement over inclusion was adjudicated by senior reviewers (EN, JG). Data extraction (SR, NC, PK) focused on predictors of toxicity.Results:The search strategy retrieved 3103 studies. 147 studies were included for data extraction, of which 92 were eventually excluded due to: not identifying predictors (n=17), reviews (n=19), not ocular or cardiovascular toxicity (n=18), case reports (n=3), paediatrics (n=1), screening articles that focused on detecting retinopathy (n=30), article unobtainable at time of abstract submission (n=4), leaving 55 studies for full review.Studies addressing cardiac toxicity (n=16) included: cohort, retrospective observational, a comparative pharmacovigilance, systematic monitoring protocol and a randomised control trial (RCT). The majority of these involved high-dose (>5mg/kg/day) use for acute COVID-19 infection. The main significant predictors identified were: Hydroxychloroquine (HCQ) use in combination with azithromycin (6/7 studies), cumulative dose (2 studies), pre-existing cardiovascular morbidity (2/3 studies) and prolonged baseline QTc (2 studies). Individual associations were also identified in the following: longer treatment duration, daily dosage, increased age, male gender, severe COVID-19 infection, abnormal liver function tests (LFTs) and concurrent use of loop-diuretics.Regarding predictors of ocular toxicity (n=39), only one study was a RCT. The remainder were observational studies: case-control, cohort, retrospective chart reviews and letters to the editor which included original patient data.Several predictors of retinopathy and maculopathy were examined in two or more studies and included: duration of use (16/18 studies), daily dosage (7/13 studies), cumulative dose (11/14 studies), increased age (10/11 studies), body weight or BMI (3/5 studies), renal impairment (5 studies), HCQ blood levels (2 studies), keratopathy (2 studies) and tamoxifen use (2 studies). Sex (2 studies) and history of cataract surgery (2 studies) were not found to be predictors of toxicity.Only few studies performed regression analysis presenting odds and/or hazard ratios with confidence intervals.Conclusion:The most recognised predictor of cardiac toxicity was co-administration with azithromycin. In ocular toxicity, commonly cited predictors included those already recognised by the RCOphth1, as well as cumulative dose, increased age, weight considerations, HCQ blood levels and keratopathy. Further research is warranted on better characterising predictors of cardiac and ocular toxicity in patients on HCQ and CQ therapy.References:[1]The Royal College of Ophthalmologists. Hydroxychloroquine and Chloroquine Retinopathy: Recommendations on Monitoring [Internet]. The Royal College of Ophthalmologists; 2020 [cited 2021 Jan 25].Disclosure of Interests:Natasha Citeroni: None declared, Sanketh Rampes: None declared, Pinky Kotecha: None declared, Jan Schoones: None declared, Elena Nikiphorou: None declared, James Galloway Speakers bureau: JG has received honoraria / speaker fees from Abbvie, BMS, Celgene, Chugai, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UCB.

Background:Hydroxychloroquine (HCQ) is a relatively safe and effective drug widely used as primary or adjunctive treatment for several rheumatological and dermatological disorders1. HCQ modulates immune response through several mechanisms and has a tropism for pigmented ocular tissues, particularly retinal pigment epithelium (RPE)2. Its accumulation within RPE cells can lead to sight threatening retinal toxicity, with bull’s eye maculopathy (BEM) representing its advanced phenotype. 3 Quantitative Auto-Fluorescence (qAF) is an imaging modality that allows the measurement of retinal auto-fluorescence following short-wavelength light (488nm) excitation of retinal fluorophores (lipofuscin). 4 Two recent studies have focused on qAF values in patients treated with HCQ 5,6. In both cases qAF was increased in eyes with BEM. Furthermore, Reichel et al.6 were able to detect increased values of qAF in patients without BEM as early as 6 months after the start of HCQ treatment using an experimental imaging analysis procedure.Objectives:To measure quantitative autofluorescence (qAF) in patients under treatment with hydroxychloroquine (HCQ) with no apparent signs of retinal toxicity and to compare it with that of untreated subjects.Methods:Consecutive patients at risk for the development of HCQ retinal toxicity (duration of treatment >5 years or daily HCQ dose >5 mg/kg of actual body weight (ABW) and/or renal insufficiency)7 but no alterations on Spectral Domain - Optical Coherence Tomography, Short-Wavelength Autofluorescence and 10-2 Visual Field examination were recruited. Healthy subject matched by age and sex were also enrolled in the study. All subjects underwent qAF measurements in one eye. Images were analyzed using the conventional qAF grid by Delori calculating the qAF of 8 sectors of the intermediate ring and the mean of those values (qAF8).Results:Thirty-nine patients treated with HCQ (38 females, mean age 52,1 ± 8,6 years) and 39 untreated subjects (38 females, mean age 51,2 ± 8,6 years). In both HCQ patients and untreated subjects, qAF8 was positively correlated with age (p=0.004) (Figure 1). Although HCQ patients showed a higher mean qAF8 compared to untreated subjects (294,7 ±65,3 vs 268,9 ± 57,5), the difference was not significant (p=0.068). HCQ patients showed significantly higher mean qAF values in the inferior-temporal, inferior and inferior-nasal sectors of the intermediate ring of qAF grid compared to untreated subjects (all pFigure 1.Visual representation of a model predicting the standardized qAF values as influenced by age and HCQ daily dose/ABW, calculated for a treatment duration of 15 years.Conclusion:These results suggest a possible preclinical increase of qAF values in inferior parafoveal sectors probably induced by HCQ exposure. Further studies are required to improve our understanding of preclinical stages of HCQ retinopathy and the possible role of qAF in the HCQ toxicity screening.References:[1]Haładyj, E., Sikora, M., Felis-Giemza, A. & Olesińska, M. Antimalarials - are they effective and safe in rheumatic diseases? Reumatologia56, 164–173 (2018).[2]Rosenthal, A. R., Kolb, H., Bergsma, D., Huxsoll, D. & Hopkins, J. L. Chloroquine retinopathy in the rhesus monkey. Invest. Ophthalmol. Vis. Sci.17, 1158–1175 (1978).[3]Modi, Y. S. & Singh, R. P. Bull’s-Eye Maculopathy Associated with Hydroxychloroquine. N. Engl. J. Med.380, 1656 (2019).[4]Sparrow, J. R., Duncker, T., Schuerch, K., Paavo, M. & de Carvalho, J. R. L. J. Lessons learned from quantitative fundus autofluorescence. Prog. Retin. Eye Res.74, 100774 (2020).[5]Greenstein, V. C. et al. Quantitative Fundus Autofluorescence in HCQ Retinopathy. Invest. Ophthalmol. Vis. Sci.61, 41 (2020).[6]Reichel, C. et al. Quantitative Fundus Autofluorescence in Systemic Chloroquine/Hydroxychloroquine Therapy. Transl. Vis. Sci. Technol.9, 42 (2020).[7]Yusuf, I. H., Sharma, S., Luqmani, R. & Downes, S. M. Hydroxychloroquine retinopathy. Eye (Lond).31, 828–845 (2017).Disclosure of Interests:Salvatore Parrulli: None declared, Mariano Cozzi Grant/research support from: Bayer, Nidek, Zeiss, Matteo Airaldi: None declared, Francesco Romano: None declared, Francesco Viola: None declared, Piercarlo Sarzi-Puttini: None declared, Giovanni Staurenghi Grant/research support from: Heidelberg Engineering (C), QuantelMedical (C), Centervue (C), Carl Zeiss Meditec (C), Alcon (C), Allergan (C), Bayer (C), Boheringer (C), Genentech (C), GSK (C),Novartis (C), and Roche (C), Optos (F), Optovue (F) and Centervue (F), Alessandro Invernizzi Grant/research support from: Novartis (C), Bayer (C)

Purpose: To describe the clinical features of a 57-year-old female with palindromic rheumatism and a 15-year history of chloroquine use and bilateral vision loss. Methods: Ophthalmological examination, including ultrawide field (UWF) fundus images (Optomap-200TX) and cross-sectional retinal scans obtained with Zeiss spectral domain optical coherence tomography angiography (SD-OCTA, HD-5000, Angioplex), was performed. Results: Best-corrected visual acuity was 20/60 in both eyes. Ultrawide field fundus images revealed a ring-shaped area of pericentral and paracentral mottling of the retinal pigment epithelium (RPE), vascular attenuation, and loss of foveal reflex bilaterally. The SD-OCT showed obvious thinning in the outer retina, loss of the photoreceptor inner/outer segment junction corresponding to the location of the hypofluorescent lesion in the macular inferior temporal area, as well as a granular appearance of the RPE. Optical coherence tomography angiography showed the integrity of the superficial capillary plexus in both eyes, but the deep capillary plexus and the choriocapillaris layer detailed the loss of vasculature and the hyperreflective lesions located pericentrally. Multifocal central electroretinogram diminished in both the eyes. Conclusions: Optical coherence tomography angiography is able to show alterations produced by chloroquine toxicity. New technologies, such as UWF imaging and OCTA, could be suitable alternatives for screening and follow-up of chloroquine retinopathy.

To describe the prevalence and risk factors associated with corneal vortex keratopathy in a childhood-onset systemic lupus erythematosus (c-SLE) cohort. Consecutive outpatients with c-SLE were evaluated by a pediatric ophthalmologist and pediatric rheumatologist in an outpatient clinic setting in an urban Children’s Hospital. Demographic, clinical, laboratory, and disease characteristics were documented for each patient. Cumulative drug dosage, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology damage index (SLICC/ACR-DI) scores were calculated. A total of 76 c-SLE patients (61 (80.26%) females; mean age = 17.9 (SD ± 3.07)) were included. Ophthalmologic abnormalities were observed in 36 (47.36%) patients of which 16 (21.10%) had corneal vortex keratopathy (p = 0.03). c-SLE patients with corneal vortex keratopathy were all female. We did not observe any additional clinical, laboratory, or treatment feature associated with corneal vortex keratopathy. We observed a high prevalence of corneal vortex keratopathy in female c-SLE. We hypothesize that this finding may be an initial, dose-related toxicity due to antimalarial use. Follow-up studies are necessary to determine if these changes are an early predictor of retinal toxicity due to antimalarial in c-SLE. • Corneal vortex keratopathy was frequently observed in female patients with c-SLE on a chloroquine medication. • Corneal vortex keratopathy may be an early marker of chloroquine retinopathy.

Purpose To evaluate multifocal electroretinography (mfERG) as a screening test for detecting hydroxychloroquine and chloroquine toxicity. Design Diagnostic accuracy study. Methods 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. Results 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. Conclusions 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.

Background The Royal College of Ophthalmologists (RCOPHTH) published in 2017 revised recommendations regarding screening for hydroxychloroquine (HCQ) toxicity. Recent data reported the prevalance of retinopathy to be around 7.5% and depending on dose and duration can rise to 20%–50% after 20 years of therapy. Much higher than the 0.5% reported previously in the 2009 guidelines. Risk is increased in patients taking more than 5 mg/kg/day, and those with renal dysfunction, pre-existing retinopathy or also taking tamoxifen. Retinopathy appears as damage to the photoreceptors, followed by degeneration of the retinal pigment epithelium (RPE). This can produce visual loss and a ”Bull’s eye maculopathy”. Current guidelines state patients looking to take HCQ long term should have a baseline screening (10–2 Humphrey visual test) in a hospital eye department, and then be referred for annual screening after 5 years of therapy. Dosage should ideally be kept ≤5 mg/kg/day. Previous guidelines recommend a maximum dose of ≤6.5 mg/kg/day, and baseline optometrist review. Referral to ophthalmologist only if a visual impairment or eye disease is detected at the baseline assessment or the patient notices reduced vision whilst on treatment. Long term HCQ patients, were advised to agree and individual screening arrangement with the local ophthalmologist. Objectives This single point of care audit was to assess real world practice at Central Middlesex Hospital against the new 2017 guidance as a gold standard. Methods HCQ questionnaires were collected from patients attending regular appointments over one month October-November and recorded: 1) date commenced HCQ, 2) est. total dose, 3) weight and 4)last retinal screen; Hospital EPR database was used to confirm or assist documentation of therapy data. Results In one calendar month 152 of 414 patients were prescribed HCQ. 94/152 of the patients had been on HCQ for >5 years. 63/152 patients were high risk with doses of >5 mg/kg/day. 55/152 patients had either failed to attend a baseline screening, or had no record of having had a baseline screen. Of the 21 patients that had started HCQ after the introduction of the new guidlines (2017); only 5 had failed to have a baseline hospital screen (3/5 instead had optometrist/high street screen instead). No cases of HCQ related retinopathy had been reported. Conclusions Real world OHC retinal screening was poor compared to new Guidance. These figures imply a huge medico-legal responsibility for the previously considered rare risk of retinal damage from OHQ. The logistics of the workload in Eye Clinics will necessitate local solutions including nurse screening clinics and closer monitoring and documentation of outcomes. This rare but serious complication of a very well tolerated and effective agent will not come at a cheap price today. A repeat audit following 12 months of an agreed screening policy is recommended. References [1] RCOPTH (2018). [online]https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2009-SCI-010-Ocular-Toxicity.pdf [Accessed 31 Jan. 2018]. [2] Opthalmologists, T. (2018). Hydroxychloroquine and Chloroquine Retinopathy: Recommendations on Screening – Membership Consultation. [online]https://www.rcophth.ac.uk/2017/07/hydroxychloroquine-and-chloroquine-retinopathy-recommendations-on-screening-membership-consultation/ [Accessed 31 Jan. 2018]. Disclosure of Interest None declared

Background Hydroxychloroquine (HCQ) is commonly used to treat a variety of rheumatological and inflammatory conditions such as RA, SLE and Sjogrens. Retinal toxicity is a well known complication of HCQ therapy. Initially, the incidence of retinal toxicity was believed to be quite minimal1. However, subsequent large epidemiological studies have highlighted its much greater prevalence-up to 7.5% in certain populations2,3. Furthermore, the visual toxicity is typically permanent with possible progression up to years after drug cessation and with no current treatment4. Detection at an early stage has been shown to be crucial in preserving central vision and foveal architecture5. As a result ophthalmological screening is an essential consideration for any patient on HCQ therapy. In view of the updated scientific data available on toxicity prevalence and the benefits of screening, the American Academy of Ophthalmology (AAO) have updated their screening recommendations for 20166. This includes baseline fundus examination to rule out pre-existing maculopathy and annual screening after 5 years of treatment. Objectives To investigate compliance with the AAO Recommendation on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016)6 in a regional rheumatology centre. Methods A retrospective analysis was undertaken of the electronic patient records of 161 patients with a diagnosis of connective tissue disease at a single regional centre assessing level of antimalarial usage, adherence to screening guidelines and level of documented toxicity. Results Of our cohort, 91 (56%) were on regular HCQ. Of these, 12 had received routine ophthalmology screening and 4 developed documented ocular toxicity. 15 suffered non-ophthalmic toxicity requiring therapy cessation. 46 had been on therapy greater than 5 years and of these 9 (21.5%) had been screened. Conclusions Our analysis revealed significant deficiencies in routine screening and demonstrated a high level of toxicity in patients who were routinely screened. This indicates that there may be a significant number of patients with toxicity that is not being picked up and reinforces the importance of screening. We would recommend a more streamlined referral pathway for rheumatology patients on HCQ and hypothesise that this would lead to greater and earlier pick-up of ocular toxicity in this population, ultimately reducing morbidity in this population. References Elman A, Gullberg R Nilsson E, et al. Chloroquine retinopathy in patients with rheumatoid arthritis. Scand J Rheumatol. 1976;5(3):161–66. Melles RB, Marmor MF. The risk of toxic retinopathy in patients on long-term hydroxychloroquine therapy. JAMA Ophthalmol 2014;132:1453–60. Levy GD, Munz SJ, Paschal J, et al. Incidence of hydroxychloroquine retinopathy in a large multicentered outpatient practice. Arthritis Rheum. 1997 Aug;40(8):1482–6. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmol 2014;132:1105–12. Marmor MF, Hu J. Effect of disease stage on progression of hydroxychloroquine retinopathy. JAMA Ophthalmic 2014;132:1105–12. Michael F, Marmor MD et al, Recommendations on Screening for Chloroquine and Hydroxychloroquine Retinopathy (2016 Revision) Ophthalmology Volume 123, Number 6, June 2016. Disclosure of Interest None declared

Aims To evaluate progression of morphological alterations in chloroquine (CQ) or hydroxychloroquine (HCQ) retinopathy after drug cessation. Methods Eleven female patients (age range at drug cessation 46–78 years; treatment duration 5–20 years) were examined between 2.1 and 7.1 years after drug cessation. In addition to clinical examination, they underwent high-resolution optical coherence tomography (OCT) (spectral domain OCT (SD-OCT); Spectralis OCT, Heidelberg Engineering, Germany), fundus autofluorescence (FAF), near-infrared autofluorescence (NIA; HRA2, Heidelberg Engineering, Germany) and ultra-wide-angle fundus autofluorescence (UW-FAF; Optos 200Tx; Optos PLC, UK). Results Two patients with very limited parafoveal retinopathy did not present with progression within 3 years. In the remaining nine patients, visual acuity deteriorated and progression of retinal degeneration could be documented. FAF, UW-FAF and NIA changes included an increase of affected area or a regional increase or decrease of FAF or NIA intensity. SD-OCT changes included reduction of retinal thickness, an increased area of photoreceptor or retinal pigment epithelial loss, development or increase of cystoid macular oedema (4/9) or development of epiretinal membranes (5/9). Therapy of cystoid macular oedema was of limited benefit. Conclusions CQ retinopathy can progress over a long period of time after drug cessation and may be complicated by cystoid macular oedema, epiretinal membrane formation and peripheral involvement.

Hydroxychloroquine (HCQ) is generally used to treat systemic lupus erythematosus (SLE) in Western countries. However, chloroquine retinopathy became a problem in Japan, and chloroquine has never been used since then. Even now HCQ remains non-approved. Therefore, the Japanese Hydroxychloroquine Study Group has been organized, and activities have started to have HCQ approved within Japan. In the present study, we investigated the effectiveness of HCQ against the skin manifestations of lupus erythematosus. There were seven patients, all female, and they consisted of four patients with SLE (skin lesion type: discoid lupus erythematosus [DLE] in three, subacute cutaneous lupus erythematosus in one and lupus erythematosus profundus in one), two patients with cutaneous lupus erythematosus (both DLE), and one patient with a combination of SLE and dermatomyositis. HCQ was effective in three patients and ineffective in the two patients. We could not judge the efficacy of HCQ in the other two patients. There were no adverse effects in any of the patients. Efficacy was exhibited against telangiectasia and erythema. HCQ is also an effective and safe treatment for Japanese patients, and it is hoped that it will be approved for use in Japan very soon.

Near infrared autofluorescence (excitation 787 nm, emission >800 nm) is a non-invasive imaging technology that provides information on the distribution of melanin within the retinal pigment epithelial cell/choroid complex. This review contains an introduction to near infrared autofluorescence imaging methods. Characteristics of near infrared imaging in a variety of retinal diseases, including age-related macular degeneration, choroidal nevus, retinal degenerations, retinal dystrophies, central serous chorioretinopathy, pseudoxanthoma elasticum and chloroquine retinopathy, are summarized.

Based on experience and analysis of a few articles, devoted to this topic, the authors diagnose and describe the clinical case of the rare symptoms' group, associated with taking of hydroxychloroquine by the patient with sarcoidosis and diabetes type 1. The diagnostics of this lesion is difficult problem in the regular ophthalmologic practice, because of the uncommon disease, the lack of information and continuity between specialists, especially rheumatologists and pulmonologists. The recommendations of American Academy of Ophthalmology for effective screening of patients undergoing hydroxychloroquine therapy are given in this report.

Background: Chloroquine and hydroxychloroquine are drugs that are primarily used for the treatment of malaria and are also recommended for treating connective tissue disorders, autoimmune diseases, and some dermatological and inflammatory diseases. Treatment with these drugs has potential risk for the development of retinopathy, clinically characterized by bilateral pigment changes in the macula, as one serious ocular complication. The aim of this research was to evaluate the parafoveal and perifoveal macular retinal thickness, as central foveal thickness in adult patients with rheumatoid arthritis (RA) on chloroquine therapy using optical coherence tomography (OCT). Materials and Methods: In this cross-sectional study, 56 RA patients (56 eyes) were included and examined. All patients were treated with chloroquine (tablets resochin or delagil) at a dose of 250 mg/day without treatment with steroids and other immunosuppressive drugs. Patients were divided into two groups, namely, Group I patients - no visible changes in the macula (26 patients) and Group II patients- with visible changes in the macula (30 patients). The central fovea thickness and parafoveal and perifoveal retinal thickness in all quadrants were measured by OCT and compared in both groups. Results: There are a significantly higher number of eyes without thinning of the macula in Group I patients than in Group II (P < 0.001) patients. There are a higher number of patients with recorded parafoveal thinning in Group II patients, especially in the inferior, nasal, and temporal sectors, respectively (P < 0.05). Conclusion: Maculopathy is the main side effect of chloroquine therapy in RA patients that can be detected by OCT in the early stages of the macular involvement.

Retinal toxicity of chloroquine has been extensively studied since its first description in 1957. This drug is used on a chronic basis to treat several rheumatologic and dermatologic diseases, a there is a trend to use hydroxychloroquine rather than chloroquine. The recommended dose for hydroxychloroquine is 4 mg/kg lean body weight per day. The clinical picture of chloroquine retinopathy is characterized by a paracentral visual field scotoma with associated parafoveal retinal pigment epithelium atrophy, known as 'bull's eye maculopathy. The visual field and Amsler grids are the exams that early detect toxicity retinopathy. The authors aim to review the pathogenesis, clinical features, differential diagnosis, complementary exams, and treatment. The sources of references were PubMed (MEDLINE), LILACS and Ophthalmology Library databases.

Purpose. To evaluate the role of spectral-domain optical coherence tomography (SD-OCT) in early detection of Chloroquine maculopathy in rheumatoid arthritis (RA) patients.Methods. 40 left eyes of 40 female rheumatoid arthritis patients who received treatment chloroquine for more than one year were recruited in the study. All patients had no symptoms or signs of Chloroquine retinopathy. They were evaluated using SD-OCT, where the Central Foveal Thickness (CFT), parafoveal thickness and perifoveal thickness, average Retinal Nerve Fiber Layer (RNFL) thickness, and Ganglion Cell Complex (GCC) measurements were measured and compared to 40 left eyes of 40 normal females.Results. The mean CFT was found to be thinner in the Chloroquine group (238.15 µm ± 22.49) than the normal controls (248.2 µm ± 19.04), which was statistically significant (pvalue = 0.034). The mean parafoveal thickness was lesser in the Chloroquine group than the control group in all quadrants (pvalue<0.05). The perifoveal thickness in both groups showed no statistically significant difference (pvalue>0.05) in all quadrants. No significant difference was detected between the two groups regarding RNFL, GCC, or IS/OS junction.Conclusions. Preclinical Chloroquine toxicity can lead to early thinning in the central fovea as well as the parafoveal regions that is detected by SD-OCT.

Purpose: To determine the sensitivity of spectral domain ocular coherence tomography (SD-OCT) and fundus auto fluorescence (FAF) images as a screening test to detect early changes in the retina prior to the onset of chloroquine retinopathy. Method: The study was conducted using patients taking chloroquine (CQ), referred by the Rheumatology Department to the Ophthalmology Department at Tygerberg Academic Hospital. Group A consisted of 59 patients on CQ for less than 5 years, and Group B consisted of 53 patients on CQ for more than 5 years. A 200 × 200 macula thickness map, 5-line raster SD-OCT on a Carl Zeiss Meditec Cirrus HD-OCT and FAF images on a Carl Zeiss Meditec Visucam 500 were recorded for 223 eyes. Images were reviewed independently, and then those of Groups A and B compared. Results: There were no statistically significant differences between Groups A and B. The criteria included the internal limiting membrane and the retinal pigment epithelium (ILM-RPE) thickness, interdigitation zone integrity ( p = 0.891, df = 1, χ ² = 0.1876), ellipsoid zone integrity ( p = 0.095, df = 2, χ ² = 4.699) and FAF image irregularities ( p = 0.479, df = 1, χ ²= 4995978). Conclusion: The inclusion of SD-OCT and FAF as objective tests into the prescribed screening guidelines does not appear to simplify the detection of subclinical injury in patients on chloroquine treatment.

BackgroundSelf-medication with chloroquine is common in Ibadan, Sub-Sahara Africa. Retinopathy from chloroquine is not uncommon. The aim was to determine the pattern of presentation.MethodologyCases of Chloroquine retinopathy seen at the Retina and Vitreous Unit of the University College Hospital, Ibadan between 2008 and 2014 were reviewed. Information on age, sex, duration of chloroquine use, and visual loss were retrieved. Visual acuity at presentation, anterior, and posterior segment findings were documented. The results were analyzed using proportions and percentages.ResultsFourteen cases were seen during the study period. Mean age was 50.7 years. Male to female ratio was 3.5 : 1. Average duration of visual loss before presentation was 2.7 years. Average duration of self-medication with chloroquine was 5.3 years. Presenting visual acuity showed 2(14%) cases of bilateral blindness(VA

PURPOSE: To report hydroxychloroquine and chloroquine retinopathy and consider screening for drug toxicity. DESIGN: Retrospective observational case series. METHODS: Review of clinical records, visual fields, fundus photographs, and fluorescein angiography of six patients from a retina referral practice. RESULTS: All cases arose because of failure by physicians to avoid dosing above published safe levels. Five cases developed despite accepted ophthalmologic patterns of screening for toxicity. All cases developed parafoveal retinal pigment epithelial atrophic changes and paracentral scotomas to threshold visual field testing. CONCLUSIONS: New cases of hydroxychloroquine and chloroquine toxicity continue to develop in a screening environment. Increased ophthalmologic attention to dosing, awareness of location and nature of early visual field defects, and traditional attention to presence or absence of maculopathy can reduce the incidence of this avoidable condition.

David J Browning, Chong Lee Charlotte Eye, Ear, Nose and Throat Associates, Charlotte, NC, USA Background: The purpose of this study was to determine the relative sensitivity and specificity of 10-2visual fields (10-2VFs), multifocal electroretinography (mfERG), and spectral domain optical coherence tomography (SD-OCT) in detecting hydroxychloroquine retinopathy.Methods: A total of 121patients taking hydroxychloroquine (n=119) or chloroquine (n=2) with 10-2VF, mfERG, and SD-OCT tests were retrospectively reviewed. Rates of test abnormality were determined.Results: Retinopathy was present in 14and absent in 107. Eleven of 14(78.6%) patients with retinopathy were overdosed. Twelve (85.7%) had cumulative dosing greater than 1,000g. The sensitivities of 10-2VF, mfERG, and SD-OCT in detecting retinopathy were 85.7%, 92.9%, and 78.6%, respectively. The specificities of 10-2VF, mfERG, and SD-OCT in detecting retinopathy were 92.5%, 86.9%, and 98.1%, respectively. Positive predictive values of 10-2VF, mfERG, and SD-OCT in detecting retinopathy were less than 30% for all estimates of hydroxychloroquine retinopathy prevalence. Negative predictive values were >99% for all tests.Conclusion: Based on published estimates of hydroxychloroquine retinopathy prevalence, all three tests are most reliable when negative, allowing confident exclusion of retinopathy in patients taking ≤6.5mg/kg/day. Each test is less useful in allowing a confident diagnosis of retinopathy when positive, especially in patients taking ≤6.5mg/kg/day. Keywords: hydroxychloroquine, chloroquine, retinopathy, multifocal electroretinography, spectral domain optical coherence tomography, ideal body weight, toxicity

· Background: A study was carried out to evaluate the regional variance of retinal dysfunction in chloroquine retinopathy. · Methods: In three patients with different stages of chloroquine retinopathy, ophthalmologic evaluations including recording of full-field electroretinogram (ISCEV standard) and multifocal electroretinogram were performed. · Results: In one patient with mild chloroquine retinopathy the visual acuity, visual fields and full-field electroretinogram were normal, but retinal dysfunction was indicated by color vision disturbances. The second patient had moderate chloroquine retinopathy with normal visual acuity, visual fields and dark-adapted full-field electroretinogram; light-adapted and flicker full-field electroretinogram responses were, however, borderline and color vision was abnormal. The third patient had severe chloroquine retinopathy with reduced visual acuity, visual field and color vision defects, and a reduced full-field electroretinogram. In the multifocal electroretinogram, recorded with 61 hexagons, amplitudes and implicit times were evaluated in rings surrounding the center. In all three patients severe dysfunction (either amplitudes or implicit times) was found in the parafoveal and perifoveal areas. In the fovea and towards the periphery the function was normal or only moderately reduced. · Conclusion: Chloroquine retinopathy of different severity presents with characteristic alterations in the multifocal electroretinogram. Regional distribution of cone dysfunction is in agreement with previously reported histologic findings. The multifocal electroretinogram can detect retinal dysfunction in chloroquine retinopathy even when the full-field electroretinogram is normal and retinal alterations are subtle.

Purpose To describe the efficacy of microperimetry (MP-1) in detecting early retinal toxicity as a result of chronic use of chloroquine and in monitoring the changes in macular sensitivity in an asymptomatic patient with best-corrected visual acuity of 20/20 bilaterally. Methods A 60-year-old woman presented for routine ocular examination with a medical history of severe rheumatoid arthritis, for which she had been receiving 3 mg chloroquine (CQ) per kilogram for the past 17 years. The patient was asymptomatic with best-corrected visual acuity of 20/20 bilaterally. Results Microperimeter showed loss of sensitivity in the macular region with a dense scotoma within the central 12 degrees (2.80 ± 4.7 dB right eye and 2.84 ± 4.7 dB left eye). CQ treatment was discontinued and substituted by Plaquenil. Conclusions Chloroquine retinal toxicity can be recognized in a subclincal form by the presence of early changes in macular sensitivity, detected by MP-1.

Objective The effect of chloroquine toxicity on color vision is unclear. The authors identified the color defects seen in chloroquine retinopathy and determined the sensitivity and specificity of clinical color vision tests for detecting the presence of previously diagnosed chloroquine retinopathy. Design Case-control study. Participants Chloroquine retinopathy was defined using previously published criteria. Data from 30 patients with retinopathy and 25 patients using chloroquine but with no evidence of retinal toxicity were collected. Methods All patients were tested with the following six clinical color vision tests: Ishihara, Farnsworth D-15, and Adams Desaturated-15 (Dsat-15), City University 2nd Edition (CU), Standard Pseudoisochromatic Plates Part 2 (SPP-2), and American Optical Hardy Rand Rittler (AO HRR). Main outcome measures The number of failures was determined for each test. The types of color vision defects were classified as blue-yellow (BY), red-green (RG), or mixed RG and BY (mixed). Results Of the 30 patients with retinopathy, 28 (93.3%) of 30 patients failed at least 1 color vision test, demonstrating predominantly mixed defects. Five (25%) of 25 of the control subjects failed at least 1 test, and these defects were predominantly BY. The sensitivity and specificity of the tests are as follows: SPP-2 (93.3%, 88%), AO HRR (76.7%, 88%), Ishihara (43.3%, 96%), Dsat-15 (33.3%, 84%), D-15 (16.7%, 96%), and CU (20%, 92%). Conclusions Color vision can be affected by chloroquine and should be tested routinely with a color vision test designed to detect both mild BY and protan RG defects to maximize sensitivity for toxicity. The SPP-2 and AO HRR are two tests that meet these criteria. The Ishihara has a low sensitivity, as do the D-15 tests and CU. All of the tests have similar specificity for chloroquine toxicity. If color vision defects are detected in patients at risk of developing chloroquine retinopathy, additional testing is indicated to rule out toxicity.

Purpose The effects of chronic chloroquine administration on serum proteins and free amino acids of rabbits and the accompanying ultrastructural changes in the retina were investigated. Methods Thirty pigmented rabbits were injected intramuscularly with chloroquine diphosphate (14 mg/Kg bw). Fifteen rabbits served as control. Blood samples drawn after 1, 2, 3, 4, 5, 6 and 12 months were assayed for serum proteins by Bio-analytic kits and horizontal electrophoretic technique. Free amino acids were determined by Beckman analyzer. Central retinal tissue was fixed in 4% glutaraldehyde, embedded in araldite CY212 and sectioned for ultrastructural examination. Results Histopathologic changes were apparent within three months, initially affecting the pigment epithelium and photoreceptors and later involving the remaining neuroretinal layers. Hypoproteinemia gradually developed mainly due to a sharp drop in albumin and alpha 1 and 2 globulin fractions, inspite of an increase in beta and gamma globulin fractions. The concentration of non-essential amino acids varied considerably from a depletion of taurine, aspartine, glutamine, tryptophan and arginine to an increase of serine, alanine, GABA and ornithine. The most outstanding effect was the disappearance of tyrosine and its return to normal value at the end of the experiment. Conclusion The disturbances in protein pattern and free amino acid levels are an indication of chloroquine toxicity and may be implicated in the retinopathy.

The prevalence of 4-aminoquinoline retinopathy has not been scientifically determined, but flawed data indicate that the prevalence of chloroquine retinopathy is higher than the prevalence of hydroxychloroquine retinopathy. In patients who are dosed properly according to ideal body weight, the prevalence of hydroxychloroquine retinopathy is much less than 1 %. The prevalence of chloroquine retinopathy in properly dosed patients is unclear.

In the United States, screening for 4-aminoquinoline retinopathy (4AQR) is the standard of care. In this environment, a few cases occur despite attention to dosing by ideal body weight, other predisposing risk factors, and proper use and interpretation of ancillary tests. However, most clinically serious cases are iatrogenic, and arise from overdosing, missed screening for retinopathy, or tardy recognition of evidence of toxicity on ancillary testing. Symptoms and visual acuity are unreliable indicators of retinopathy, which develops as a continuum with three broadly defined stages: premaculopathy, early retinopathy, and advanced retinopathy. The boundaries between stages have been inconsistently specified. The probability of reversing retinopathy with cessation of 4-aminoquinolines decreases and the probability of progression despite cessation increases as the stage of retinopathy increases. No treatment exists for 4AQR.

The most important purpose of 4-aminoquinoline retinopathy (4AQR) screening, detecting overdosing, requires no ancillary testing. However, a subsidiary purpose, detecting the rare occurrence of 4AQR among properly dosed patients, requires ancillary testing, because clinical examination is insensitive. In Bayesian reasoning, the sensitivity and specificity of an ancillary test interact with the estimated prior probability of disease to determine the estimated posterior probability of the disease. For a condition of low prior probability a single test is rarely dispositive for management. Instead, the common role for each test is to adjust the clinician’s estimate of the probability of 4AQR before applying another test, until a level of certainty is achieved indicating that the 4-aminoquinoline (4AQ) will be stopped or continued. Testing with 10-2 visual fields, multifocal electroretinography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence is useful for this purpose when applied selectively rather than universally. SD-OCT is especially helpful because it has the lowest test variability, the highest specificity, and similar sensitivity to the other tests.

Screening for 4-aminoquinoline retinopathy (4AQR) became common internationally in the 1960s when inappropriately high doses of chloroquine were often prescribed. As knowledge of toxic thresholds increased and hydroxychloroquine supplanted chloroquine, the prevalence of 4AQR declined. As a result, professional guidelines discouraging screening were published in the United Kingdom. In the United States, guidelines continue to recommend screening. In 2011, those guidelines added the use of multifocal electroretinography (mf ERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) to the list of recommended tests. Such additional testing comes at considerable added expense. Screening for overdosing, which is common, is rational in all settings. Screening for 4AQR in properly dosed patients is probably a waste of resources.

Lack of agreement in defining 4-aminoquinoline retinopathy has impeded progress in understanding and preventing the condition. There are stages of retinopathy, but unclear boundaries separate them. An international working group to standardize definitions would help lay the foundation for clearer communication and synthesis of knowledge.

Over 80 % of patients taking 4-aminoquinolines (4AQs) have risk factors for retinopathy. The most important risk factor is the adjusted daily dose. Taking hydroxychloroquine at a dose less than 6.5 mg/kg/d based on the lesser of actual and ideal body weight is typically safe. Failure by prescribing physicians to dose correctly and by screening eye care providers to detect and suggest correction of overdosing are the most common factors contributing to 4-aminoquinoline retinopathy. Currently, at least one eighth of patients taking 4AQs are overdosed.

OBJETIVOS: Comparar a tela de Amsler modificada com o campo visual Humphrey® 10-2 vermelho nos usuários de cloroquina, na detecção da maculopatia precoce, e correlacionar com as variáveis de risco. MÉTODOS: Foram analisados 116 olhos de 58 pacientes, acompanhados no Serviço de Oftalmologia do Hospital do Servidor Público Estadual de São Paulo, entre abril de 2006 e abril de 2008. Todos os usuários tinham fundo de olho normal e mais de dois anos de terapia com cloroquina. Os participantes tiveram seus dados clínicos avaliados e foram submetidos ao exame da acuidade visual corrigida, biomicroscopia de fundo, campimetria macular automatizada e tela de Amsler. RESULTADOS: A incidência da maculopatia precoce foi de 7 a 10%, dependendo do exame considerado. A concordância entre a tela de Amsler e o campo visual foi baixa. Para o grupo de olhos que apresentaram ambos os exames alterados, houve significância estatística com a alta dose diária, dose cumulativa elevada e baixa acuidade visual; a idade do paciente e a duração do tratamento não mostraram boa correlação nestes casos, mas suas médias (67,4 anos e 8,4 anos, respectivamente) situaram-se dentro da faixa dos fatores de alto risco. CONCLUSÕES: O estudo sugere que a tela de Amsler pode ser útil na complementação das informações do campo visual no rastreamento periódico da retinopatia por cloroquina, sobretudo naqueles com fatores de alto risco bem estabelecidos, selecionando melhor os candidatos à realização de testes objetivos, como o OCT de alta resolução e o ERG multifocal. PURPOSE: To compare the modified Amsler grid to the Humphrey® 10-2 red visual field in chloroquine users for the detection of early maculopathy, and to correlate with the risk variables. METHODS: The study included 116 eyes of 58 patients followed at the Department of Ophthalmology of Hospital do Servidor Público Estadual de São Paulo, from April, 2006 to April, 2008. All users had normal fundus and more than 2 years of chloroquine therapy. Their clinical data were evaluated and they underwent visual acuity examination, fundus biomicroscopy, visual field and Amsler grid. RESULTS: The incidence of early maculopathy was 7 to 10%, depending on the examination considered. The agreement between the Amsler grid and visual field was low. There was statistical significance with the use of high daily dose, elevated cumulative dose and low visual acuity in patients whose eyes had both abnormal tests; patient age and duration of treatment did not show good correlation in these cases, but their averages (67.4 years and 8.4 years, respectively) were within the range of high risk factors. CONCLUSIONS: The study suggests that Amsler can be useful in complementing the information on the visual field for chloroquine retinopathy periodic screening, especially for those patients who present high risk factors well established, selecting better candidates for objective tests, such as HD OCT and mfERG.

THE occurrence of ocular lesions of variable severity in patients with rheumatoid arthritis, discoid and systemic lupus erythematosus and other diseases who have received long-term chloroquine ther...

This report describes the typical manifestations of chloroquine retinopathy with some advanced new technology. A series of examinations were performed on the patients, including the fundus fluorescein angiography, optical coherence tomography, GDxVCC Nerve Fiber Analyzer, full-field electroretinography, multifocal electroretinography and visual field examinations, to provide a better understanding of chloroquine retinopathy.

Clinical electrophysiology allows a detailed analysis of retinal function in various disorders. When for decades the morphological examination of the retina was limited to ophthalmoscopy and fluorescein angiography, electrophysiological techniques allowed detection of retinal abnormalities in morphologically ‘‘normal’’ retina: e.g. cone dystrophies with the fullfield ERG, early stages of macular dystrophies with the pattern ERG (PERG) or multifocal ERG (mfERG), early stages of chloroquine retinopathy with the mfERG, non-manifesting carriers of Best disease with the EOG or retinal ganglion cell damage in autosomal dominant optic atrophy with the VEP. In recent years, new techniques for the evaluation of retinal morphology have been introduced in clinical practice. Optical coherence tomography (OCT) within the last 15 years has evolved from frequency domain techniques to the fourth generation with spectral domain techniques, and further development with even higher resolution and additional possibilities is only a question of time [1]. The OCT has changed our understanding of retinal morphology in several diseases and, in addition, has allowed the detection of subclinical alterations, which are difficult to visualize otherwise, e.g. residual subfoveal fluid after retinal detachment surgery or beginning retinal edema in diabetic maculopathy or retinitis pigmentosa [2]. New non-invasive imaging devices allow the detection of autofluorescent pigments in the retinal pigment epithelium (RPE) with different wavelengths of autofluorescence, predominantly lipofuscin (fundus autofluorescence, FAF) and melanin (near-infrared autofluorescence, NIA) [3, 4]. Increased production of lipofuscin is associated with multiple degenerative disorders in the photoreceptorRPE complex. FAF allows us to determine structural integrity of the RPE and to define areas of degenerative activity. FAF can be used for early detection of retinal dystrophies or chloroquine retinopathy, or for separation between nevi or small uveal melanomas. The utility of FAF has been demonstrated in small children in whom electrophysiology is difficult to perform [5]. More recently near-infrared autofluorescence has been introduced which promises additional information in retinal dystrophies or degenerations and ocular tumours [4, 6]. The development of new retinal imaging techniques results in certain disadvantages and advantages for the experts in clinical electrophysiology. Disadvantages are predominately present in clinical U. Kellner (&) Retina Science, Bonn, Germany e-mail: kellneru@retinascience.de

In a prospective study using sex-matched pigmented and non-pigmented rabbits, the role of pigmentation or melanin on chloroquine-induced retinal or ocular toxicity was determined. Results showed that chloroquine produced a series of ocular toxicity ranging from loss of pupillary and corneal reflex to severe retinopathy. The minimal dose at which these ocular toxicities develop on pigmented rabbits was found to be 5 mg/kg daily for 30 days or a cumulative dose of 225 mg of chloroquine. Furthermore, the cumulative effect of the drug depends on the body weight of the animal, total dose administered and duration of therapy. It is concluded that the effect of chloroquine on pigmentation depends on total amount of drug used, which would predispose to retinal pathology. Keywords : Chloroquine, pigmentation, melanin, retinopathy, retinotoxic West African Journal of Pharmacology and Drug Research Vol. 21 (1&2) 2005: pp. 55-59

Purpose To determine the validity of multifocal electroretinography (mfERG) as a screening tool for detecting chloroquine (Aralen, Sanofi Aventis, Bridgewater, NJ) (CQ) and hydroxychloroquine (Plaquenil, Covis Pharmaceuticals, Inc, Zug, Switzerland) (HCQ) retinal toxicity in patients using these medications. To evaluate the sensitivity and specificity of mfERG when compared with automated visual fields (AVFs), fundus autofluorescence (FAF), and optical coherence tomography (OCT). Clinical Relevance The 2011 American Academy of Ophthalmology recommendations on screening for CQ/HCQ retinopathy recommended a shift toward more objective testing modalities. Multifocal electroretinography may be effective in detecting functional change before irreversible structural damage from CQ/HCQ toxicity. Methods We performed a search for records reporting the use of mfERG for screening CQ/HCQ retinopathy in MEDLINE (PubMed and OVID), EMBASE, and Web of Science, and assessed these using the QUADAS-2 risk of bias tool. We conducted an analysis of 23 individual studies and their reported individual patient data (449 eyes of 243 patients) published from January 2000 to December 2014. Results Multifocal electroretinography had the greatest proportion of positive test results, followed by AVF. The pooled sensitivity and specificity of mfERG were 90% (95% confidence interval [CI], 0.62–0.98) and 52% (CI, 0.29–0.74), respectively, with AVF as reference standard (13 studies). Sensitivity was high, but specificity was variable when OCT, FAF, and the positivity of 2 of 3 tests was used as the reference standard. When verified against AVF as the reference test, patients with a false-positive mfERG result received higher HCQ cumulative doses (1068 g) than patients with true-negative (658 g, P P Conclusions Multifocal electroretinography was shown to have a high sensitivity but variable specificity when verified against AVF, OCT, FAF, and a combination of tests. The greater average cumulative dose in the false-positive group compared with the true-negative group when mfERG was verified against AVF suggests that mfERG may have the ability to detect cases of toxicity earlier than other modalities. There is an unclear risk of bias in the available evidence, and future studies should adhere to Standards for Reporting of Diagnostic Accuracy reporting guidelines.

Purpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication. Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed. Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10°) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48°) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes. Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity.

Objective: To review patients with clinical features of chloroquine retinopathy seen during the study period with the view of identifying the trend and creating public awareness for behavioural change. Methods: A retrospective review of case notes of patients seen between 1996 and 2002. Results: 19 patients with features of presumed chloro-quine retinopathy were reviewed: 5 women and 14 (73.7%) men. The age range is: 36-69 years, mean 50.7 years. Approximately 63% were civil servants, health care workers and teachers. Duration of chloroquine use ranged from six months to ten years, with a mean of 4.1 years. Total cumulative dose ranged from 10 gm to 312 gm, with a mean of 108 gm. Best corrected visual acuity of subjects ranged from 6/5-CF, mean 6/18. Conclusion: The majority of people using large amounts of chloroquine over long periods are educated, middle-aged males, whose loss of vision would have far reaching effects on their families. There is, therefore, a need to create public awareness of the danger of long-term chloroquine use. A follow up national survey would be desirable to determine the actual magnitude of the problem [Nig. J. Ophthalmology Vol.11(1) 2003: 24-28]

Chloroquine still remains the most widely used antimalarial of present time. Cumulative dose retinopathy has been reported with the use of chloroquine therapy, especially seen in patients on its chronic therapy in rheumatological disorders. A rare case report on chloroquine induced idiosyncratic retinopathy while being used in treatment of Falciparum malaria is being presented. (Med J Indones 2002; 11: 176-8) Keywords: cloroquine, adverse effects, idiosyncratic, malaria, retinopathy

Twenty-six patients with heart block were examined for evidence of chloroquine retinopathy. Detailed histories of chloroquine intake showed that 50% (13 of 26) of these patients were chloroquine abusers. Retinal changes typical of chloroquine retinopathy were seen in 53.8% (7 of 13) of the chronic chloroquine abusers. Patients with heart block of unknown cause should have their fundi examined so that signs of chloroquine retinopathy may be sought.