The Blood-Retinal Barrier in Chloroquine Retinopathy

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Investigative Ophthalmology & Visual Science, Vol. 30, No. 8, August 1989 Copyright Association for Research in Vision and Ophthalmology The Blood-Retinal Barrier in Chloroquine Retinopathy ichael.

1 Investigative Ophthalmology & Visual Science, Vol. 30, No. 8, August 1989 Copyright Association for Research in Vision and Ophthalmology The Blood-Retinal Barrier in Chloroquine Retinopathy ichael. Raines, Sarish K. Dhargava, and Emanuel S. Rosen Chloroquine retinopathy can result in devastating loss of vision. To date, there are no effective and reliable methods of detecting the toxicity at an early stage when retinopathy may be reversible. Chloroquine is deposited in the retinal pigment epithelium, which forms part of the blood-retinal barrier (BRB). By vitreous fluorophotometry we have shown that there is breakdown of the BRB in chloroquine retinopathy. However, in asymptomatic patients who had received varying amounts of hydroxychloroquine (up to 1067 g), the BRB remained intact. Invest Ophthalmol Vis Sci 30: ,1989 Since ocular toxicity was first ascribed to chloroquine and its derivative hydroxychloroquine in the 1950s 1 there have been many reports in the literature concerning the more devastating toxic manifestation of retinopathy. 2 " 12 The retinopathy ranges from fine mottling of the macular region and loss of the foveal light reflex to the classic bull's-eye maculopathy with concentric rings of hyperpigmentation and hypopigmentation. Detection of the retinopathy in the early stages is imperative as cessation of the drug at this stage may arrest the progress of the condition and also may allow resolution to normal pretreatment levels Chloroquine toxicity affects the retinal pigment epithelium, as shown by light and electron microscope studies. 1 " 16 Vitreous fluorophotometry is a technique of high sensitivity that is used to assess the blood-retinal barrier (BRB) This is comprised of the outer BRB, formed by the tight junctions between the retinal pigment epithelial cells, and the inner BRB, formed by the tight junctions between the endothelial cells of the retinal blood vessels. 19 ' 20 We therefore undertook to examine by vitreous fluorophotometry a group of patients with known chloroquine retinopathy, and also a group who had received various amounts of hydroxychloroquine, to assess the blood-retinal barrier and to remark on the technique of fluorophotometry as a clinical detector of the condition. aterials and ethods Patients were selected from the diagnostic index of the retinal photographic department of the anches- rom the anchester Royal Eye Hospital, anchester, England. Submitted for publication: August 16, 1988; accepted ebruary 23, Reprint requests:.. Raines, RCS, Birmingham and idland Eye Hospital, Church Street, Birmingham, B3 2NS England. ter Royal Eye Hospital with the diagnosis of chloroquine retinopathy. The notes of 18 patients were found and their case histories were reviewed. After exclusion of other ocular or systemic conditions that could affect the fluorophotometric readings such as diabetes, systemic hypertension, posterior vitreous detachment and intraocular inflammation, there were four patients remaining. One refused further investigation and one was untraceable. Two patients with definite chloroquine retinopathy therefore underwent vitreous fluorophotometry. After similar exclusion criteria, a further 12 patients attending the ophthalmology department were examined. These latter patients had received various doses of hydroxychloroquine over various different times and all were asymptomatic. Informed written consent was obtained from all patients. Examination of patients included medical history, Snellen chart visual acuities, slit-lamp examination of the ocular anterior segment, Amsler grid testing, color vision testing with Ishihara pseudoisochromatic plates, ophthalmoscopy under full mydriasis, fundus photographs, fluorescein angiography and vitreous fluorophotometry. Vitreous fluorophotometry was performed using the luorotron aster (Coherent, Palo Alto, CA). The technique has been described in detail elsewhere 1721 and will be briefly explained here. Both eyes were dilated with tropicamide 1% and phenylephrine 10% to attain maximum dilatation and cycloplegia. A baseline background scan was performed on each eye to assess the natural fluorescence of the eye. Sodium fluorescein was injected intravenously at the antecubital fossa in a dose of 1 mg/kg/body weight. Standard fluorescein angiography was then performed. Between 3 and 5 min postinjection a further scan, termed the bolus scan, was performed on each eye to account for any chorioretinal spread function that may occur. This scan is used in the final calculation to minimize the influence of 1726 Downloaded rom: on 11/02/2016

2 No. 8 THE DRD IN CHLOROQUINE RETINOPATHY / Raines er ol 1727 the fluorescein in the choroid-retina on the readings taken in the vitreous. A final measurement scan was performed at 60 min post-injection. Venepuncture was performed, in the opposite arm to the fluorescein injection, between 5 and 10 min post-injection, and also at the end of the examination. Ten milliliters of blood was obtained on each occasion. Exact times of scans and venepuncture, following fluorescein injection, were recorded. Plasma fluorescein levels were measured using the special plasma adapter supplied with the luorotron. or analysis the pre-injection scan was subtracted from the measurement scan, as only low levels of fluorescein leakage were identified. This maneuver minimizes the contribution of natural fluorescence, which comes predominantly from the lens. The value offluorescencebetween 2 mm and mm anterior to the retina was taken. This has been shown to be relatively free of interference from the chorioretinal spread function. 17 The plasma values were incorporated into a recognized computer algorithm to attain the plasma fluorescein integral, and a final posterior vitreous penetration ratio (pr) for the eye was obtained from these data. 22 The penetration ratio is a measure of the integrity of the BRB. Penetration ratios obtained were compared to those found in a group of 20 age- and sex-matched normal controls. Results All patients had a diagnosis of rheumatoid arthritis and all were receiving or had received chloroquine or hydroxychloroquine before cessation of therapy. By ophthalmoscopy and fluorescein angiography, only the two patients with retinopathy (cases 1, 2) had any fundal abnormality. This abnormality was in the form of a bull's-eye or partial bull's-eye with almost complete loss of macular pigment (igs. 1-). Amsler grid testing showed striking scotomas around and including fixation in these two patients, and Ishihara color vision testing demonstrated complete loss of color discrimination. Vitreous fluorophotometry showed elevated penetration ratios (Table 1). The remaining patients (cases 3-1) who were at risk of developing retinopathy had been exposed to hydroxychloroquine therapy ranging from 7 months to 12 years (mean = 5.09 years). The total dose exposure ranged from 92 g to 1067 g (mean = 9.6 g). All parameters in these patients were normal (Table 1) except two who had corneal verticillata (cases 12, 1). The penetration ratios in these patients at risk of retinopathy (average pr = 2.25 ± 0.7 X 10" 6 min" 1 ) were not significantly different (P = 0.87 unpaired t-test), from our group of normal age matched individuals (average pr = 2.22 ± 0.60 X 10" 6 min" 1 ). We calculated the daily dose of hydroxychloroquine and adjusted this for actual body weight. Of all the patients in the study only one (case 1), who did have retinopathy, had received a daily dose in excess of that recommended as a safe daily dosage, namely 6.5 mg/kg body weight/day (Table 2). Discussion Chloroquine and hydroxychloroquine have been used in the treatment of the connective tissue diseases since the 1950s. The pharmacokinetics, physiological effects and the metabolization of chloroquine and hydroxychloroquine are all similar. 23 Retinal toxicity was first confirmed in 1959' and since then there have been many reports in the literature of such toxicity. 2 " 12 This retinopathy ranges from subtle pigmentary stippling at the macula, loss of the foveal reflex, through to the classical bull's-eye appearance which consists of stippled hyperpigmentation of the macula surrounded by a ring of hypopigmentation that is further surrounded by a ring of hyperpigmentation. Rarely, the arterioles may become attenuated and granularity of the peripheral fundus may appear together with optic disc pallor. The term premaculopathy was introduced to define mild asymptomatic pigmentary changes at the macula that were almost always reversible with cessation of the chloroquine. These changes include pigmentary stippling, diminished foveal light reflex and paracentral scotoma to a red test target. The visual acuity is never affected and visual symptoms are rarely present. It is at this stage of toxicity that diagnosis is important, as discontinuation of the drug may result in reversal of the abnormality. ' However, there is no one technique that can reliably detect the toxicity. Several procedures have been advocated, including repeated ophthalmoscopy, measurement of visual acuities, color photographs, 2 visual field evaluation, 810 EOG, 25 ERG, 26 fluorescein angiography, 27 Amsler grid testing, photostress testing, 30 and color vision testing. 31 Usually a combination of tests are used to establish the diagnosis and often serious visual impairment has occurred by the time of diagnosis. It is known that there is a disturbance of the retinal pigment epithelium in chloroquine toxicity that is evident early on with electron microscope studies This initially usually takes the form of curvilinear cytoplasmic inclusions. Chloroquine is known to be highly concentrated in the pigmented ocular tissues, binding to melanin, and remains there for prolonged periods of time even after cessation of therapy. 32 ' 33 Some authors have suggested that the drug initially Downloaded rom: on 11/02/2016

3 INVESTIGAT!VE OPHTHALOLOGY G VISUAL SCIENCE / August Vol. 30 AhnSLP RECORDING CHART ig. I. Care I, right eye. (A) luorescein angiogram, and (B) Amsler chart demonstrating complete bull's-eye maculopathy. I. 2. Case 1, left eye. (A) luorescein angiogram, and (B) Amsler chart demonstrating complete bull's-eye maculopathy. Downloaded rom: on 11/02/2016

No. 8 THE BRl3 IN CHLOROQUINE RETINOPATHY / Roines er 01 ig. 3. Case 2, right eye. (A) luorescein angiogram, and (B) Amsler chart demonstrating partial bull's-eye maculopathy. ig.. Case 2, left eye.

4 No. 8 THE BRl3 IN CHLOROQUINE RETINOPATHY / Roines er 01 ig. 3. Case 2, right eye. (A) luorescein angiogram, and (B) Amsler chart demonstrating partial bull's-eye maculopathy. ig.. Case 2, left eye. (A) luorescein angiogram, and (B) Amsler chart demonstrating partial bull's-eye maculopathy. Downloaded rom: on 11/02/

5 1730 INVESTIGATIVE OPHTHALOLOGY & VISUAL SCIENCE / August 1989 Vol. 30 Table 1. Clinical details Case R Visual acuity L Amsler grid Ishihara plates Ophthalmoscopy and fluorescein angiography luorophotomelry penetration ratio (X10~ 6 min ' ) R L * = Amblyopia. 6/12 6/12 6/5 3/60 6/2 6/18* 6/18* 6/18 * t t tt t t = Normal. Bull's-eye Bull's-eye t destroys photoreceptors and ganglion cells and later involves the retinal pigment epithelium. 16 However, others have suggested that chloroquine may first interfere with the metabolism of the retinal pigment epithelium and cause secondary photoreceptor degeneration. 115 If the metabolism of the retinal pigment epithelium is disrupted then this may manifest itself as a breakdown of the blood-retinal barrier, as the retinal pigment epithelium forms the outer fraction of this barrier. Vitreous fluorophotometry has been used to assess the integrity of the BRB and has been shown to be a sensitive, quantifiable and reproducible method of detecting abnormalities. The BRB is formed by both the retinal pigment epithelium and the endothelial cells of the retinal vessels. The methods used to date Table 2. Chloroquine dosages Case Age (yrs) Sex Total dose (g) Duration (yrs) Weight-adjusted daily dose (mg/kg body weight/day) are unable to distinguish between abnormalities of these two components. Similarly, at present it is not possible to distinguish between different diseases on the basis of vitreous fluorophotometry results alone. The subject has recently been reviewed 18 and patients with forms of macular dystrophy that can affect the retinal pigment epithelium, including Stargardt's disease, familial drusen and fundus albipunctatus, have shown normal vitreous fluorophotometry values. However, the technique has not been performed in all forms of macular dystrophy yet. Our study shows that there is breakdown of the blood-retinal barrier in established cases of chloroquine retinopathy. However, in those patients at risk of retinopathy we could find no abnormality of the BRB. In these same patients we were unable to detect an abnormality with the other forms of investigation. Therefore, despite chloroquine binding to melanin and accumulating in the retinal pigment epithelium, which we can assume, it appears to have no detectable effect on the BRB when all other parameters are normal. It is acknowledged that retinopathy can occur with total doses of 100 g 5 and all but two of our patients had received substantially more than this amount. When the dose is adjusted for actual body weight none of our at-risk patients exceeded the suggested safe daily dose of 6.5 mg/kg body weight/day. 3 However, one of our patients who did have retinopathy had received an adjusted daily dose of less than the recommended safe amount. Chloroquine retinopathy is less common now than it used to be, since the risks of treatment are known, but there is still a need for a reliable test to detect early Downloaded rom: on 11/02/2016

6 No. 8 THE DRD IN CHLOROQUINE RETINOPATHY / Raines er ol 1731 retinopathy. The BRB is not compromised prior to the signs and symptoms of retinopathy. If the symptoms of chloroquine retinopathy are a result of breakdown of the BRB, then vitreous fluorophotometry may be a sensitive method of detecting early retinopathy, but at present it appears to show no advantages over other forms of investigation. This may, however, indicate that the primary damage from chloroquine is to structures other than the retinal pigment epithelium. Key words: chloroquine, vitreous fluorophotometry, blood-retinal barrier, retinopathy Acknowledgments We would like to thank Dr. R. B. Clague for refering cases and 12. The authors have no commercial interest in the luorotron. References 1. Hobbs HE, Sorsby A, and reedman A: Retinopathy following chloroquine therapy. Lancet 2:78, Voipio H: Incidence of chloroquine retinopathy. Acta Ophthalmol :39, Nylander U: Ocular damage in chloroquine therapy. Acta Ophthalmol :335, Rynes RI: Ophthalmological safety of long term hydroxychloroquine sulfate treatment. Am J ed 75(1A):35, Bernstein HN: Ophthalmologic considerations and testing in patients receiving long term antimalarial therapy. Am J ed 75(1A):25, arks JS: Chloroquine retinopathy: Is there a safe daily dose? Ann Rheum Dis 1:52, Johnson W and Vine AK: Hydroxychloroquine therapy in massive total doses without retinal toxicity. Am J Ophthalmol 10:139, Hart W, Burde R, Johnston GP, and Drews RC: Static perimetry in chloroquine retinopathy: Perifoveal patterns of visual field depression. Arch Ophthalmol 102:377, Arden GB and Kolb H: Antimalarial therapy and early retinal changes in patients with rheumatoid arthritis. Br ed J 1:270, Percival SPB and Behrman J: Ophthalmological safety of chloroquine. Br J Ophthalmol 53:101, Percival SPB and eanock I: Chloroquine: Ophthalmological safety, and clinical assessment in rheumatoid arthritis. Br ed J 3:579, ills PV, Beck, and Power BJ: Assessment of the retinal toxicity of hydroxychloroquine. Trans Ophthalmol Soc UK 101:109, Crews SJ: Chloroquine retinopathy with recovery in the early stages. Lancet 2:36, Bernstein HN and Ginsberg G: The pathology of chloroquine retinopathy. Arch Ophthalmol 71:238, Ramsey S and ine BS: Chloroquine toxicity in the human eye: Histopathologic observations by electron microscopy. Am J Ophthalmol 73:229, Rosenthal AR, Kolb H, Bergsma D, Huxsoll D, and Hopkins JL: Chloroquine retinopathy in the rhesus monkey. Invest Ophthalmol Vis Sci 17:1158, Zeimer RC, Blair NP, and Cunha-Vaz JG: Vitreous fluorophotometry for clinical research: II. ethod of data acquisition and processing. Arch Ophthalmol 101:1757, Raines : Vitreousfluorophotometry.Seminars in Ophthalmology 1:153, Shiose Y: Electron microscope studies on blood retinal and blood aqueous barriers. Jpn J Ophthalmol 1:73, Shakib and Cunha-Vaz JG: Studies on the permeability of the blood retinal barrier: IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood retinal barrier. Exp Eye Res 5:229, Zeimer RC, Blair NP, and Cunha-Vaz JG: Vitreous fluorophotometry for clinical research: I. Description and evaluation of a newfluorophotometer.arch Ophthalmol 101:1753, Cunha-Vaz JG, Gray JR, Zeimer RC, ota C, Ishimota B, and Leite E: Characterization of the early stages of diabetic retinopathy by vitreous fluorophotometry. Diabetes 3:53, ackenzie AH: Pharmacologic actions of -aminoquinoline compounds. Am J ed 75:5, Cruess A, Schachat AP, Nicholl J, and Augsburger JJ: Chloroquine retinopathy: Is fluorescein angiography necessary? Ophthalmology 92:1127, Arden GB, riedmann A, and Kolb H: Anticipation of chloroquine retinopathy. Lancet 1:116, Schmidt B and uller LW: Electroretinographic examinations following the application of chloroquine. Acta Ophthalmol 70(Suppl):25, Kearns TP and Hollenhorst RW: Chloroquine retinopathy. Arch Ophthalmol 76:378, Easterbrook : The use of Amsler grids in early chloroquine retinopathy. Ophthalmology 91:1368, Easterbrook : The sensitivity of Amsler grid testing in early chloroquine retinopathy: Trans Ophthalmol Soc UK 10:20, Carr RE, Henkind P, Rothfield N, and Siegel I: Ocular toxicity of antimalarial drugs. Am J Ophthalmol 66:738, Nozik RA, Weinstock, and Vignos P: Ocular complications of chloroquine. Am J Ophthalmol 58:77, Bernstein HN, Zvaifler N, Rubin, and ansour A: The ocular deposition of chloroquine. Invest Ophthalmol 2:38, Okun E, Gouras P, Bernstein HN, and Von Sallmann L: Chloroquine retinopathy: A report of eight cases with ERG and dark adaptation findings. Arch Ophthalmol 69:59, ackenzie AH: Dose refinements in long term therapy of rheumatoid arthritis with antimalarials. Am J ed 75:8, Downloaded rom: on 11/02/2016

Chloroquine retinopathy:

Annals of the Rheumatic Diseases, 1982, 41, 52-58 Chloroquine retinopathy: J. S. MARKS Is there a safe daily dose? From the Rheumatism Research Centre, Royal Infirmary, Manchester M13 9 WL SUMMARY Published