Hydroxchloroquine and Chloroquine Toxicity
THE KIDNEY AND LIVER CONNECTIONWritten by Larry J Alexander OD FAAO Friday, 30 November 2012
This update is in response to the fact that new information is continually being uncovered regarding Plaquenil toxicity and testing for Plaquenil toxicity. The primary objective of this paper is to highlight the fact that the levels needed to achieve toxicity are related to the status of functioning of the liver and kidneys which work to clear the drug.
Hydroxychloroquine and chloroquine are substances used worldwide for the treatment of malaria. Hydroxychloroquine, which is an analog of chloroquine, was created to ostensibly be less toxic than chloroquine. Within the United States this drug class is used primarily for inflammatory disorders such as systemic lupus erythematosus, rheumatoid arthritis, Sjogren’s Syndrome, and post-Lyme disease arthritis.
The possibility of retinotoxicity has always been an issue with the chloroquine drug class. Adherence to dosing guidelines essential, as cumulative dosage is critical in the genesis of retinotoxic complications . Total accumulated dosage should be monitored. The recommended dosage is no more than 6.5 mg/kg/day using the standard known as ideal weight. The formula for ideal weight for women is 100 lbs for 5 feet tall with 5 lbs per extra inch of height and for men 110 lbs for 5 feet tall with 5 lbs per extra inch of height. For a 5 foot 8 inches man this would equate to 150 lbs or 68 kg, with a recommended dosage at 440 mg/day. Obese individuals have the potential to be seriously overdosed if the ideal weight guidelines are not followed. Additionally, the drug has a long half-life, 1 to 2 months, implying that once discontinued effects can still be noted. Since chloroquine and hydroxychloroquine are cleared by both the liver and kidney, any compromise of these organs may also effect potential toxicity.
Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye, the cornea, and the macula. The cornea may become affected (relatively commonly) by an innocuous vortex keratopathy characterized by whorl-like corneal epithelial deposits. These changes are relatively benign and bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine. They may, however, be considered the harbinger of retinal toxicity.
The macular changes associated with toxicity are potentially serious and are related to dosage and duration. 1-3 Established maculopathy is classically characterized as moderate reduction of visual acuity and an obvious "bulls eye" macular lesion. End stage maculopathy is characterized by severe reduction in visual acuity and severe atrophy of the retinal pigment epithelium.
While relatively low in incidence, hydroxychloroquine and chloroquine retinal toxicity, represents a condition that is modifiable but not reversible or stoppable if detected early in development. Recent reports suggest that the risk of toxicity increases sharply to 1 % after 5 to 7 years of use with a cumulative dose of 1000 grams as the tipping point. 2, 3-6 It should be noted, however, that these estimates are based on testing technology that did not necessarily provide appropriate data for early detection and did not really consider the coexistence of liver or kidney disease. Put in perspective 1000 grams is equal to 1,000,000 mg. Using ideal weight criteria, a120 lb woman would have to be given a dose of 355 mg/day for 7.7 years to achieve critical level dosage. Further use increases the risk accordingly and discontinuation does not ensure halting progression because of the extremely long half-life of the drug and the fact that it firmly binds to melanin. The drug should be used with extreme caution in patients with pre-existing retinal disturbances such as retinal pigment epithelial disease.
Hydroxychloroquine and chloroquine has long been known to have potential to create retinal toxicity with potential threat to vision. The toxicity is dose related and associated with the cumulative effect of the drug. Recent revisions in the monitoring of this potential are the subject of this paper.
Co-existing liver and kidney disease may also impact on the genesis of plaquenil retinal toxicity. One additional issue is the fact that chloroquine and hydroxychloroquine are cleared by both the liver and kidney. Any compromise of these organs may also impact on potential toxicity. Said another way, with improper clearing a smaller dosage is needed with pre-existing liver and kidney disease. Clinical findings also suggest that the critical accumulated dosage is substantially compromised by altered liver function. While reports vary, it is generally accepted that often patients affected by systemic lupus erythematosus (SLE) have altered liver function. 7 The conclusions suggest that patients with SLE should have liver function tests performed and that drugs that further aggravate liver function should be avoided.8 It is also reported that over 50% of SLE patients have renal function abnormalities resulting in glomerular damage. 9 It has been suggested that dosage of plaquenil should be lowered in patients with pre-existing liver or kidney disease, with the corollary that standard dosages may create toxicity sooner.10-17 Said another way, since the drug is not effectively cleared more accumulation occurs at a lower dosage.
Drug Action and Mechanism of Toxicity
Hydroxychloroquine (belonging to the quinolone family) is in a class of drugs described as disease-modifying anti-rheumatic drugs –DMARD. Other drugs in the category include methotrexate, arava, sulphasalzine, gold, cyclines, D-penicillamine, azathioprine, cyclophosphamide, cyclosporine, and the new classes of biologics. Hydroxychloroquine also belongs to the family of medicines called antiprotozoals. While reasonably effective, hydroxychloroquine takes 3 to 6 months to demonstrate full efficacy. There is both a long ramp-up time as well as a long ramp-down time.
Hydroxychloroquine has been known for some time to increase lysosomal pH in antigen presenting cells, but its mechanism of action in inflammatory conditions is a bit elusive. It has been suggested that anti-malarials diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells and result in down-regulation of the immune response against auto-antigenic peptides. 18 More information has recently been presented that addresses blocking the activation of toll-like receptors on plasmacytoid dendritic cells (PDCs). Hydroxychloroquine, by decreasing TLR signaling, reduces the activation of dendritic cells thus mitigating the inflammatory process. 19-21
The mechanism of retinotoxicity is arguable but it is known that the drug has acute effects on retinal cells. It is known that the drug binds to melanin in the RPE, which then may concentrate the agent.22 Chloroquine is also known to affect perifoveal cells first 23 and disrupt lysosomal RPE function precipitating deposition of lipofuscin. 24-25 It has also been shown that the degradative capacity is more predominant in cone photoreceptors. 25 The ophthalmoscopic clinical view of retinotoxicity implies retinal pigment epithelial (RPE) changes and photoreceptor damage as a presenting sign. Animal studies suggest that photoreceptors are affected with reversible inner retinal lipidosis and irreversible photoreceptor degeneration. 26-27 It has also been reported in an animal study that inner and outer retinal changes were observed, first in the ganglion cell layer with accumulation of cytoplasmic bodies. In this report there was subsequent photoreceptor and RPE degeneration.28 This degeneration was attributable to an alteration of protein synthesis and lipid peroxidation.29-31 As far back as 1990 Hallberg suggested that the ganglion cells were affected early by alteration of the phospholipid metabolism with retinal nerve fiber layer death following. 32 The ganglion cell affectation, with subsequent RNFL thinning and ultimately photoreceptor damage has been corroborated in other reports. 33-35 A recent report suggests that significant retinal thinning occurs 1.0mm from the foveal center in patients with early and late toxicity and that measuring thickness at 1.0 mm from the fovea may help screen for early toxicity.36 Another report highlights the compromise of the photoreceptor inner segment/outer segment junction as an early diagnostic sign with SDOCT. The presentation has been characterized as the “flying saucer sign” as shown in the accompanying figure. 37
Figure 1 The flying saucer sign representing compromise of the perifoveal retinal tissue with maintenance of the foveal retinal tissue. From Chen E, Brown DM, Benz MS, et al. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clin Ophthalmol. 2010; 4: 1151–1158. Published online 2010 October 21. doi: 10.2147/OPTH.S14257
Retina Manifestations of Chloroquine and Hydroxychloroquine Toxicity
The classical definition of chloroquine toxicity is characterized by bilateral pigmentary change of the macula usually sparing the fovea. This has come to be known as bull’s-eye maculopathy. The retinal periphery may also be involved but infrequently. Visual complaints are primarily associated with central vision loss, and visual field or color vision anomalies. 38-40 There is one report of progressive hydroxychloroquine toxicity mimicking low-tension glaucoma after discontinuation in a patient with a cumulative dose of 2,200,000 mg. 41 It is also reported that there is a diminished ERG associated with hydroxychloroquine toxicity. 42
A 2007 report assessed the structural changes seen in the retina with ultra-high-resolution OCT and compared it to both multifocal electroretinogram (mfERG) and automated visual fields in patients receiving hydroxychloroquine. Both discontinuity of the perifoveal photoreceptor inner segment/outer segment junction and thinning of the outer nuclear layer was reported. The mfERG findings correlated well. 43
In a 2009 report SDOCT of two patients, imaging in hydroxychloroquine retinal toxicity demonstrated “loss of photoreceptor inner segment/outer segment (IS/OS) junction and a downward “sink-hole” displacement of inner retinal structures in areas of hydroxychloroquine toxicity” that preceded loss on 10-2 visual field testing. 44
Kellner et al in 2009 reported multifocal electroretinography (mfERG), melanin-related near-infrared fundus autofluorescence (NIA), lipofuscin-related fundus autofluorescence (FAF) and spectral domain OCT (SDOCT) are all able to detect early stages of chloroquine toxicity with loss of the outer nuclear layer thickness being the earliest indicator. 45 Kellner also reports that this may begin with the vascular supply of the drug to the retinal ganglion cells. 46
In 2010 Pasadhika reported on three groups of patients. Group I displayed observable chloroquine fundus toxicity, Group II chronic chloroquine use with no observable fundus alterations, and Group III as a normal control group. On SD-OCT 87.5% of Group I showed peripapillary RNFL thinning in at least one quadrant whereas Groups II and III did not. On evaluating macular scans compared to Group III, Group I demonstrated significant thinning of the inner, outer and full thickness retina, Group II has significant thinning of only the inner retina. 47
Another 2010 report with a large cohort (60 females) further assessed the use of sophisticated testing technology for early diagnosis of hydroxychloroquine toxicity in patients with no ophthalmoscopic evidence of toxicity. Multifocal electroretinography (mfERG) demonstrated reduced ring 2 response in these patients. GDxVCC RNFL evaluation was statistically thinner than controls especially in the nasal and temporal areas. Visual fields with 10-2 were useful in the early detection but were a less sensitive tool. 48
A 2002 report addressed “at risk issues” and cited the following: high daily dosage, long duration of intake, high body fat, liver or kidney disease, concomitant retinal disease, age over 60 years. 3 There are, however, conflicting reports that there is variability of the retinotoxic changes associated with cumulative dosage. 49 A recent retrospective study in 51 patients being treated with hydroxychloroquine and chloroquine re-evaluated the potential risk factors. Age and duration continued to be the major risk factors with smoking being negligible and BMI not being an issue. 50 Another recent report emphasized that risk is associated with dosage and duration and that even when toxicity is recognized with visual fields and mfERG progression occurs. This group also pointed out that by use of SDOCT, the photoreceptor inner/outer segment junction demonstrated interruption in the perifoveal area accompanied by perifoveal collapse of the outer retinal layers. 51
FIGURES 2-6 ILLUSTRATE THE APPLICATION OF THE CURRENT TECHNOLOGY ON A RELATIVELY YOUNG PATIENT WITH SLE WITH A CUMMULATIVE DOSAGE OF OVER 1 MILLION mg.
Figure 2 The parafoveal area that is prone to retinotoxictiy. This is the “bullseye” zone described in the past. In this case there is a suggestion of RPE change in this zone but only under high magnification.
Figure 3 Using SDOCT to analyze full retinal thickness reveals the retinal thinning in the 1 to 1.5 mm zone of retinotoxicity.
Figure 4 The Ganglion Cell Complex TM Optovue, Inc map of SDOCT further demonstrates the thinning of the inner retinal/ganglion cell complex.
Figure 5 While the photoreceptor integrity line is ultimately affected in retinotoxicity, this retinal cross section shows no demonstrable affectation of the PIL.
Figure 6 The OS 10-2 visual field demonstrates no defect.
The “New Guidelines”
Because of technological advances and the relative availability of this technology, more sophisticated approaches to the management of the patient taking cholorquine or hydroxychloroquine may be utilized. These more sophisticated approach facilitate earlier detection. While the retinotoxicity is relatively rare, the consequences are significant. These updated guidelines were highlighted in the recent Marmor report.22 These guidelines have been echoed in subsequent reports. 52
The first step in the process should be the education of the patient regarding the potential issues associated with the medication. The patient must be engaged in the process and the discussion should be documented in the chart. The patient should also have a determination of liver and kidney function prior to initiation of treatment. The status of the liver and kidneys should offer guidance regarding adjustment of dosages.
The restyled guidelines also mandate an examination prior to the initiation of hydroxychloroquine. While the primary physician should be aware of the new guidelines a general letter to the local doctors would be appropriate.
Assess the patient and carefully chart document regarding:
- Question visual complaints including near vision
- Obtain a thorough medical history with emphasis on liver and kidney disorders more common in SLE
- Document the Duration and Dosage of hydroxychlorquine
- Best corrected visual acuities
- Biomicroscopic evaluation of corneal epithelium for vortex deposits as a possible harbinger of retinal toxicity
- Careful dilated ocular examination paying attention to pigmentary abnormalities in macula and periphery and retinal vasculature
- Visual field evaluation with 10-2 or other VF test of equal resolution (2 degrees) with attention to pattern deviation. Paracentral defects occur most often with 10-2 testing. 53 It has been suggested that microperimetry will reveal early functional change. 54 It has likewise been reported that Preferential Hyperacuity Perimetry (PHP) as well as Frequency Doubling Technology (FDT) may also be a useful adjunct for testing of patients suspicious of toxicity. 55-56
Apply at least one of the following specialized tests or obtain a consult to do so:
- Spectral Domain OCT assessing inner and outer retinal thickness and inner/outer segment (PIL) juncture in the perifoveal region with emphasis on the 1-1.5 mm zone from the fovea. Pavafoveal thinning of retinal tissue precedes RPE damage affecting the inferotemporal quadrant first. 57
- Fundus autofluorescence imaging to reveal subtle RPE defects and early photoreceptor damage.
- Multifocal Electroretinogram to assess for localized paracentral depression appears to show changes prior to observable structural changes. But there is the caution that considerable work must be done in this area. 58-60
Note that the following are no longer recommended for early detection of hydroxychloroquine and chloroquine retinotoxicity:
- Fundus photography
- Time Domain OCT
- Fluorescein angiography
- Full-field ERG
- Color vision testing
- Amsler grid
- 24-2 Visual field testing
After establishing baseline screening for toxicity on an annual basis should be continued no later than 5 years after starting the medication. 22 This recommendation must, however, be modified based on the patient’s existing medical situation.
Step 5 is a minimal recommendation and annual examinations after baseline determination would be judicious. Should early toxicity be detected and the drug discontinued, it is important to remember that even with discontinuation, the condition has the potential to progress and appropriate follow-up is indicated. It would likewise be judicious to communicate all findings and recommendations in writing to the primary care physician with a copy to the dispensing pharmacist.
Hydroxychloroquine and chloroquine has become a mainstay in the DMARD management of inflammatory disease. While very effective, the use of the medication carries the risk of retinotoxicity that is most directly tied to pre-existing retinal disease and cumulative dosage. The current science supports the fact that by the time ophthalmoscopic changes are noted, that the retinotoxicity has already created significant compromise. The origin of the toxicity is related to early loss of retinal tissue in the inner and outer layers in the perifoveal zone with subsequent compromise of the photoreceptor inner segment/outer segment junction.
Figure 7 Focus on the Zone
To effectively screen for these changes the new guidelines recommend utilization of both a careful eye examination and employment of one of the following clinical tools: Spectral Domain OCT assessing inner and outer retinal thickness and inner/outer segment juncture in the perifoveal region,
autofluorescence imaging to reveal subtle RPE defects and early photoreceptor damage, or multifocal electroretinogram (mfERG) to assess for localized paracentral depression. While the retinotoxicity may progress in spite of early detection and discontinuation of the drug, the progress will have been truncated. The final important message is that pre-existing liver and/or kidney disease will result in toxicity at a lower cumulative dosage as the drug will not be effectively cleared
The message must get out to the pharmacists and the primary care physicians regarding this issue. The new guidelines afford us an opportunity to intervene sooner to prevent loss of vision. Non-adherence to these guidelines begs the medico-legal question.
- Bernstein HN. Chloroquine ocular toxicity. Surv Ophthalmol 1967; 12: 415–447.
- Levy GD, Munz SJ, Paschal J, et al. Incidence of hydroxychloroquine retinopathy in 1207 patients in a large multicenter outpatient practice. Arthritis Rheum 1997; 40: 1482–1486.
- Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002; 109:1377–1382.
- Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res 2010;62:775– 784.
- Lyons JS, Severns ML. Detection of early hydroxychloroquine retinal toxicity enhanced by ring ratio analysis of multifocal electroretinography. Am J Ophthalmol 2007;143:801–809.
- Mavrikakis I, Sfikakis PP, Mavrikakis E, et al. The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal. Ophthalmology 2003;110:1321–1326.
- Warsy AS, Medani H, El-Hazmi MA, et al. Liver function profiles in Saudi nationals with systemic lupus erythematosus. J Islamic Acad Sci. 1991;4:58-62.
- The Royal College of Ophthalmologists - Hydroxychloroquine and Ocular Toxicity Recommendations on Screening – October 2009)
- Dubois EL, Tuffanelli DL : Clinical manifestations of systemic lupus erythematosus. Computer analysis of 520 cases. JAMA. 1964;190:104-111.
- Kofman S, Johnson GC, Zimmerman HJ : Apparent hepatic dysfunction in lupus erythematosus. Arch Intern Med.1955;95:669-676.
- Rothfield N : Systemic lupus erythematosus. Clinical and laboratory aspects. In: Arthritis and Allied Conditions. Ed by D McCarty. Philadelphia, Lea and Febiger, pp 691-715, 1979.
- Miller MH, Urowitz MB, Gladman DD, et al : The liver in systemic lupus erythematosus. Q J Med. 1984;53:401-409.
- Gibson T, Myers AR : Subclinical liver disease in systemic lupus erythematosus. J Rheum. 1981; 8:752-759.
- Altomonte L, Zoli A, Sommella L, et al. Concentration of bile acids as an index of hepatic damage in systemic lupus erythematosus. Clin Rheumatol. 1984;3:209-212, 1984.
- Runyon BA, La Brecque DR, Anuras S : The spectrum of liver disease in systemic lupus erythematosus. Report of 33 histologically proved cases and review of the literature. Am J Med. 1980;69:187-194.
- Rees EG, Wilkinson M : Serum proteins in systemic lupus erythematosus. Br Med J. 1959 5155:795-798.
- Pollak VE, Mandema E, Doig AB, et al. Observations on electrophoresis of serum proteins from healthy North American Caucasian and Negro subjects and from patients with systemic lupus erythematosus. J Lab Clin Med. 1961. 58:353-365.
- Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993;23(2 Suppl 1): 82-91.
- Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat Rev Immunol. 2006;6:823-835.
- Hennessey EJ, Parker AE, O’Neill LA. Targeting Toll-like receptors: emerging therapeutics? Nat Rev Drug Discov. 2010;9:293-307.
- Lenert PS. Classification, mechanisms of action, and therapeutic applications of inhibitory oligonucleotides for Toll-like receptors (TLR) 7 and 9. Mediators Inflamm. 2010;2010:986596.
- Marmor MF, Kellner U, Lai TYY, et al. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118:415-422.
- Bernstein HN, Ginsberg J. The pathology of chloroquine retinopathy. Arch Ophthalmol. 1964;71:238–245.
- Sundelin SP, Terman A. Different effects of chloroquine and hydroxychloroquine on lysosomal function in cultured retinal pigment epithelial cells. APMIS. 2002;110:481–489.
- Mahon GJ, Anderson HR, Gardiner TA, McFarlane S, Archer DB, Stitt AW. Chloroquine causes lysosomal dysfunction in neural retina and RPE: implications for retinopathy. Curr Eye Res. 2004;28:277–284.
- Duncker G, Schmiederer M, Bredehorn T. Chloroquine induced lipidosis in the rat retina: a functional and morphological study. Ophthalmologica 1995; 209: 79–83.
- Duncker G, Bredehorn T. Chloroquine-induced lipidosis in the rat retina: functional and morphological changes after withdrawal of the drug. Graefes Arch Clin Exp Ophthalmol 1996; 234: 378–381.
- Rosenthal AR, Kolb H, Bergsma D, et al. Chloroquine retinopathy in the rhesus monkey. Invest Ophthalmol Vis Sci 1978; 17: 1158–1175.
- Gonasun LM, Potts AM. In vitro inhibition of protein synthesis in the retinal pigment epithelium by chloroquine. Invest Ophthalmol 1974; 13: 107–115.
- Ivanina TA, Sakina NL, Lebedeva MN, Borovjagin VL. A study of the mechanisms of chloroquine retinopathy. II. Chloroquine effect on protein synthesis of retina. Ophthalmic Res 1989; 21: 272–277.
- Ivanina TA, Sakina NL, Lebedeva MN, Borovyagin VL.A study of the mechanisms of chloroquine retinopathy. I. Chloroquine effect on lipid peroxidation of retina. Ophthalmic Res 1989; 21: 216–220.
- Hallberg A, Naeser P, Andersson A. Effects of long-term chloroquine exposure on the phospholipid metabolism in retina and pigment epithelium of the mouse. Acta Ophthalmol (Copenh) 1990; 68: 125–130.
- Yoshida T, Fukatsu R, Tsuzuki K, et al. Amyloid precursor protein, A beta and amyloid-associated proteins involved in chloroquine retinopathy in rats-immunopathological studies. Brain Res 1997;764:283-288.
- Nebbioso M, Grenga R, Karavitis P. Early detection of macular changes with multifocal ERG in patients on antimalarial drug therapy. J Ocul Pharmacol Ther 2009;25:1-10.
- Bonanomi MTBC, Dantas NC, Medeiros FA. Retinal nerve fibre layer thickness measurements in patients using chloroquine. Clin Experiment Ophthalmol 2006;34:130-136.
- Kahn JB, Haberman ID,Reddy S. Spectral-Domain Optical Coherence Tomography as a screening technique for chloroquine and hydroxychloroquine retinal toxicity. Ophthalmic Surg Lasers Imaging. 2011;11:1-5.
- Chen E, Brown DM, Benz MS, et al. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clin Ophthalmol. 2010; 4: 1151–1158.
- Lowes M. Peripheral visual field restriction in chloroquine retinopathy. Report of a case. Acta Ophthalmol (Copenh) 1976; 54: 819–826.
- Butler I. Retinopathy Following the use of chloroquine and allied substances. Ophthalmologica 1965; 149: 204–208.
- Easterbrook M. Detection and prevention of maculopathy associated with antimalarial agents. Int Ophthalmol Clin 39:49–57.
- Vavvas D, Huynh N, Pasquale L, Berson EL. Progressive hydroxychloroquine toxicity mimicking low-tension glaucoma after discontinuation of the drug. Acta Ophthalmol 2010;88:156-157.
- Weiner A, Sandberg MA, Gaudio AR, et al. Hydroxychloroquine retinopathy. Am J Ophthalmol 1991;112: 528–534.
- Rodriguez-Padilla JA, Hedges TR III, Monson B, et al. Highspeed ultra-high-resolution optical coherence tomography findings in hydroxychloroquine retinopathy. Arch Ophthalmol 2007;125:775–780.
- Stepien KE, Han DP, Schell J, et al. Spectral-domain optical coherence tomography and adaptive optics may detect hydroxychloroquine retinal toxicity before symptomatic vision loss. Trans Am Ophthalmol Soc 2009;107:28–34.
- Kellner S, Weinitz S, Kellner U. Spectral domain optical coherence tomography detects early stages of chloroquine retinopathy similar to multifocal electroretinography, fundus autofluorescence and near infrared autofluorescence. Br J Ophthalmol 2009;93:1444–7.
- Kellner U, Kellner S, Weinitz S. Chloroquine retinopathy: lipofuscin-and melanin-relatedfundus autofluorescence, optical coherence tomography and multifocal electroretinography. Doc Ophthalmol 2008;116:119-127.
- Pasadhika S, Fishman GA. Effects of chronic exposure to hydroxychloroquine or chloroquine on inner retinal structures.Eye (Lond) 2010;24:340–6.
- Xiaoyn MA, Dongyi HE, Linping HE. Assessing chloroquine toxicity in RA patients using retinal nerve fibre layer thickness, multifocal electroretinography and visual field test. Br J Ophthalmol 2010;94:1632-1636.
- Ruther K, Foerster J, Berndt S, et al. Chloroquine/hydroxychloroquine: variability of retinotoxic cumulative doses. Ophthalmologe 2007;104:875-879.
- Bergholz R, Schroeter J, Ruther K. Evaluation of risk factors for retinal damage due to chloroquine and hydroxychlorine. Br J Ophthalmol 2010;94:1637-1642.
- Michaelides M, Stover NB Francis PJ, Weleber RG. Retinal toxicity Associated With Hydroxychloroquine and Chloroquine. Arch Ophthalmol 2011;129:30-39.
- Costedoat-Chalumeau N, Ingster-Moati I, Leroux G, et al. Critical review of the new recommendations on screening for hydroxychloroquine retinopathy. Rev Med Interne 2012;33:265-267.
- Anderson C, Blaha GR, Marx JL. Humphrey visual field findings in hydroxychloroquine toxicity. Eye (Lond) 2011;25:1535-1545.
- Angi M, Romano V, Valldeperas X, et al. Macular sensitivity changes for detection of chloroquine toxicity in asymptomatic patient. Int Ophthalmol 2010;30:197-197.
- Anderson C, Pahk P, Blaha GR, et al. Preferential hyperacuity perimetry to detect hydroxychloroquine retinal toxicity. Retina 2009. 29:1188-1192.
- Tanga L, Centofanti M, Oddone F, et al. Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine. Graefes Arch Clin Exp Ophthalmol 2011;249:715-721.
- Marmor MF. Comparison of screen procedures in hydroxychloroquine toxicity. Arch Ophthalmol 2012;130:461-469.
- Aliferis K, Mermoud C, Safran AB. Multifocal electroretinography in follow-up of patients treated with hydroxychloroquine. J F Ophtalmol 2011;34:468-475.
- Farrell DF. Retinal toxicity to antimalarial drugs: chloroquine and hydroxychloroquine: a neurophysiologic study. Clin Ophthalmol 2012;6:377-383.
- Adam MK, Covert DJ, Stepien KE, Han DP Quantitative assessment of the 103-hexagon multifocal electroretinogram in detection of hydroxychloroquine retinal toxicity. Br J Ophthalmol 2012;96:723-729.
About the Author(s)
Dr. Alexander (1948-2016) was a 1971 graduate of Indiana University School of Optometry. He served in the US Navy then served as a Professor at the University of Alabama Birmingham School of Optometry. Larry contributed to a number of chapters in textbooks and has published three editions of Primary Care of the Posterior Segment, as well as contributed to the professional literature. He also lectured extensively in the area of ocular and systemic disease. His areas of special interest included dysfunctional tear syndrome, glaucoma and macular degeneration. His lessons are the basis for this site and he will be dearly missed.