Detecting chloroquine retinopathy: electro-oculogram versus colour vision

Aim: To investigate the relative sensitivity and specificity of two tests of retinal function (the electro-oculogram (EOG) and a computerised colour vision test) in screening for ocular toxicity caused by chloroquine and hydroxychloroquine. Methods: 93 patients with rheumatic diseases receiving long term chloroquine and hydroxychloroquine therapy were followed for an average of 2.6 years. Clinical examination, an EOG, and a quantitative test of colour vision were carried out every 6 months. Results: Mild fundus changes were observed in 38 patients. Four patients developed typical bull’s eye maculopathy, three of whom had received 250, 365, and 550 g total dose of chloroquine, and one 1500 g of hydroxychloroquine. Statistical analysis of all patients showed that for those with no fundus changes or stippled pigmentation a number showed elevation of tritan threshold, so that if macular stippling is a sign of mild retinopathy the test on tritan changes has a 64% sensitivity and 63% specificity for an upper threshold value of 7%. All four patients with bull’s eye lesions showed a marked disturbance of tritan colour vision, with a threshold of 14.8%, a sensitivity of 75%, and a specificity of 94%. For protan colour vision a threshold of 10% gives 75% sensitivity and 91% specificity. By contrast, neither an absolute nor a relative EOG reduction was a valid criterion for early or late chloroquine retinopathy. In advanced retinopathy an Arden coefficient (AQ) <180% yields 50% sensitivity and 54% specificity. When AQ <160% is the threshold, sensitivity does not increase but specificity rises to 82%. Occurrence of marked corneal deposits on clinical examination yields 50% sensitivity and 90% specificity in this situation. Conclusion: Screening for chloroquine retinopathy can be improved by using a sensitive colour test. Disturbance of the tritan axis appears to occur first. A normal test result on computerised colour testing virtually excludes any retinopathy by antimalarials. The EOG is of little diagnostic value.

[1]  A. Steiger,et al.  Lack of correlation between melanin affinity and retinopathy in mice and cats treated with chloroquine or flunitrazepam , 2004, Albrecht von Graefes Archiv für klinische und experimentelle Ophthalmologie.

[2]  Bernstein Hn.  Chloroquine ocular toxicity. , 1967 .

[3]  A. M. Potts.  FURTHER STUDIES CONCERNING THE ACCUMULATION OF POLYCYCLIC COMPOUNDS ON UVEAL MELANIN. , 1964, Investigative ophthalmology.

[4]  R. Yee,et al.  Current practices for monitoring ocular toxicity related to hydroxychloroquine (Plaquenil) therapy. , 1994, The Journal of rheumatology.

[5]  P. Grützner.  Acquired color vision defects secondary to retinal drug toxicity. , 1969, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde.

[6]  P. Becker,et al.  Visual function and long-term chloroquine treatment. , 1994, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[7]  Experimental chloroquine retinopathy. , 1986, Ophthalmic research.

[8]  J. François,et al.  EXPERIMENTAL CHLOROAQUINE RETINOPATHY. , 1964, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde.

[9]  J. François,et al.  Experimentally induced chloroquine retinopathy in rabbits. , 1967, American journal of ophthalmology.

[10]  H. Kolb,et al.  A preliminary study of the effect of chloroquine on the rat retina. , 1970, Archives of ophthalmology.

[11]  S. Bishara,et al.  Evaluation of several tests in screening for chloroquine maculopathy , 1989, Eye.

[12]  R. Burde,et al.  Static perimetry in chloroquine retinopathy. Perifoveal patterns of visual field depression. , 1984, Archives of ophthalmology.

[13]  U. Nylander.  OCULAR DAMAGE IN CHLOROQUINE THERAPY , 1966, Acta ophthalmologica.

[14]  H. Kolb,et al.  Anticipation of chloroquine retinopathy. , 1962, Lancet.

[15]  A. M. Potts,et al.  In vitro inhibition of protein synthesis in the retinal pigment epithelium by chloroquine. , 1974, Investigative ophthalmology.

[16]  P. Gouras,et al.  Chloroquine retinopathy; a report of eight cases with ERG and dark-adaptation findings. , 1963, Archives of ophthalmology.

[17]  P. Mills,et al.  Assessment of the retinal toxicity of hydroxychloroquine. , 1982, Transactions of the ophthalmological societies of the United Kingdom.

[18]  R. Hitchings,et al.  Color vision defects in ocular hypertension and glaucoma. Quantification with a computer-driven color television system. , 1988, Archives of ophthalmology.

[19]  G. V. Lith,et al.  Interpretation of the electro-oculogram of patients taking chloroquine , 1980, Documenta Ophthalmologica.

[20]  P. Sfikakis,et al.  Retinal toxicity in long term hydroxychloroquine treatment. , 1996, Annals of the rheumatic diseases.

[21]  H. Black,et al.  Left ventricular systolic performance during upright bicycle exercise in patients with essential hypertension. , 1983, The American journal of medicine.

[22]  M. Easterbrook.  Current concepts in monitoring patients on antimalarials. , 1998, Australian and New Zealand journal of ophthalmology.

[23]  G. Duncker,et al.  Chloroquine-induced lipidosis in the rat retina: functional and morphological changes after withdrawal of the drug , 1996, Graefe's Archive for Clinical and Experimental Ophthalmology.

[24]  Percival Sp.  The ocular toxicity of chloroquine. , 1967 .

[25]  A. Richter,et al.  Erfassung morphologischer Hornhautveränderungen infolge Chloroquintherapie mit Hilfe der konfokalen In-vivo-Mikroskopie , 1997, Der Ophthalmologe.

[26]  G. Arden.  Comparison of new psychophysics and perimetry with electrophysiological techniques in the diagnosis of glaucoma. , 1993, Current opinion in ophthalmology.

[27]  R. Carr,et al.  EARLY CHLOROQUINE RETINOPATHY: CLINICAL AND FUNCTIONAL FINDINGS. , 1964, Archives of ophthalmology.

[28]  R. D. Wood,et al.  Differences in the retinotoxic action of chloroquine and phenothiazine derivatives , 1970, The Journal of pathology.

[29]  P. Gouras,et al.  Chloroquine retinopathy. Early detection by retinal threshold test. , 1966, Archives of ophthalmology.

[30]  Eberhart Zrenner,et al.  Standard for clinical electro-oculography , 1993 .

[31]  B. S. Fine,et al.  Chloroquine toxicity in the human eye. Histopathologic observations by electron microscopy. , 1972, American journal of ophthalmology.

[32]  J. Kelsey,et al.  Changes produced by light in the standing potential of the human eye , 1962, The Journal of physiology.

[33]  J. Heckenlively,et al.  Hydroxychloroquine and Retinal Toxicity , 1983 .

[34]  R. M. Broekhuyse,et al.  THE EOG IN RHEUMATOID ARTHRITIS , 1983, Acta ophthalmologica.

[35]  M. Easterbrook,et al.  Detection of color vision defects in chloroquine retinopathy. , 1999, Ophthalmology.

[36]  P. Gouras,et al.  THE EOG IN CHLOROQUINE AND OTHER RETINOPATHIES. , 1963, Archives of ophthalmology.

[37]  M. Easterbrook,et al.  The use of Amsler grids in early chloroquine retinopathy. , 1984, Ophthalmology.

[38]  A. Kampik,et al.  [Color vision in relation to age: a study of normal values]. , 1999, Klinische Monatsblatter fur Augenheilkunde.

[39]  Arden Gb.  Comparison of new psychophysics and perimetry with electrophysiological techniques in the diagnosis of glaucoma. , 1993 .

[40]  M. Easterbrook.  Is corneal deposition of antimalarial any indication of retinal toxicity? , 1990, Canadian journal of ophthalmology. Journal canadien d'ophtalmologie.

[41]  S. Percival,et al.  Chloroquine: Ophthalmological Safety, and Clinical Assessment in Rheumatoid Arthritis , 1968, British medical journal.

[42]  F. Weinstock,et al.  OCULAR COMPLICATIONS OF CHLOROQUINE. A SERIES AND CASE PRESENTATION WITH A SIMPLE METHOD FOR EARLY DETECTION OF RETINOPATHY. , 1964, American journal of ophthalmology.

[43]  M. Easterbrook.  Ocular effects and safety of antimalarial agents. , 1988, The American journal of medicine.

[44]  Scott Perry,et al.  Color vision testing with a computer graphics system: Preliminary results , 1988, Documenta Ophthalmologica.

[45]  Renate Lüllman-Rauch.  Lipidosis of the Retina Due to Cationic Amphiphilic Drugs, Rat , 1991 .

[46]  J. François,et al.  Experimental chloroquine keratopathy. , 1965, American journal of ophthalmology.

[47]  R. Carr,et al.  Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. , 2002, Ophthalmology.

[48]  H. Bernstein.  Chloroquine ocular toxicity. , 1967, Survey of ophthalmology.

[49]  M. Easterbrook.  Detection and prevention of maculopathy associated with antimalarial agents. , 1999, International ophthalmology clinics.

[50]  G. V. van Lith,et al.  Clinical importance of the electro-oculogram with special reference to the chloroquine retinopathy. , 1976, Bibliotheca ophthalmologica : supplementa ad ophthalmologica.

[51]  A. Silman,et al.  Royal College of Ophthalmologists guidelines: Ocular toxicity and hydroxychloroquine , 1998, Eye.

[52]  C. Cursiefen,et al.  [Chloroquine-induced bull's eye maculopathy without electrophysiologic changes]. , 1997, Klinische Monatsblätter für Augenheilkunde.

[53]  G. Krohel,et al.  Hydroxychloroquine. Seven-year experience. , 1982, Archives of ophthalmology.

[54]  G. V. Lith,et al.  Ophthalmological examination of patients taking chloroquine , 1980, Documenta Ophthalmologica.

[55]  U. Kellner,et al.  Multifocal ERG in chloroquine retinopathy: regional variance of retinal dysfunction , 2000, Graefe's Archive for Clinical and Experimental Ophthalmology.

[56]  A. Mackenzie,et al.  Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. , 1983, The American journal of medicine.

[57]  M. Marmor,et al.  Standard for clinical electro-oculography. International Society for Clinical Electrophysiology of Vision. , 1993, Documenta ophthalmologica. Advances in ophthalmology.

[58]  W. Jaeger.  [Acquired colour-vision-deficiencies caused by side-effects of pharmacotherapy (author's transl)]. , 1977, Klinische Monatsblatter fur Augenheilkunde.

[59]  H. Bernstein.  Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. , 1983, The American journal of medicine.

[60]  S. Jezequel,et al.  Binding of drugs to eye melanin is not predictive of ocular toxicity. , 1998, Regulatory toxicology and pharmacology : RTP.

[61]  C. J. Walter.  RETINOPATHY FOLLOWING CHLOROQUINE THERAPY , 1961, The Medical journal of Australia.

[62]  S. Ryan,et al.  Long-term course of chloroquine retinopathy after cessation of medication. , 1979, American journal of ophthalmology.

[63]  A. Cambiaggi.  Unusual ocular lesions in a case of systemic lupus erythematosus. , 1957, A.M.A. archives of ophthalmology.

[64]  H. Kolb,et al.  Chloroquine retinopathy in the rhesus monkey. , 1978, Investigative ophthalmology & visual science.

[65]  H. Kolb.  Electro-oculogram findings in patients treated with antimalarial drugs. , 1965, The British journal of ophthalmology.

[66]  H. Bernstein.  Ocular safety of hydroxychloroquine. , 1991, Annals of ophthalmology.

[67]  G. Duncker,et al.  Chloroquine-induced lipidosis in the rat retina: a functional and morphological study. , 1995, Ophthalmologica. Journal international d'ophtalmologie. International journal of ophthalmology. Zeitschrift fur Augenheilkunde.

[68]  B. Lundh,et al.  Colour contrast sensitivity in cataract and pseudophakia. , 2000, Acta ophthalmologica Scandinavica.

[69]  G B Arden,et al.  Does occupational exposure to argon laser radiation decrease colour contrast sensitivity in UK ophthalmologists? , 1995, Eye.