A C T A O P H T H A L M O L O G I C A VOL. 5 4 1976
Department of Ophthalmology (Heads: N . Ehlers and L. Corydon), Arhus Kommzrnehospital, University of Aarhus, Department of Physical Medicine k Rehabilation (Heads: /. Fossgren and M. R m k j e r ) , Arlius Amtssygehus, Denmark
PERIPHERAL VISUAL FIELD RESTRICTION IN CHLOROQUI NE RETlNOPATHY Report of a Case BY
MARTIN LOWES
Chloroquine compounds are known to cause a retinopathy which typically begins in the central fundus giving rise to a “bull’s eye” macula. Ultimately peripheral changes may become apparent. In the routine eye examination of such patients emphasis has been laid on the central area of the fundus. A case is presented where the retinopathy was not diagnosed until marked peripheral changes had occurred with peripheral pigment changes, attenuated retinal vessels, slight optic atrophy, peripheral visual field restriction and a subnormal electroretinogram. The typical “bull’s eye” changes were not apparent. Routine examination of the peripheral fundus by means of ophthalmoscopy and perimetry is necessary to avoid missing any such retinopathy.
Key words: chloroquine - resochin retinopathy - peripheral retina ophthalmoscopy - perimetry - visual field restriction - electroretinography.
Chloroquine was originally synthesised f o r use as an antimalarial agent. Page (1951) introduced mepacrine in the treatment of lupus erythematosus, and since then the synthetic antimalarial compounds have had an important role in the Received September 29, 1976.
819
Martin Lowes
treatment of a variety of collagenoses and skin diseases. T h e dosage, usually from 250-750 mg daily over a period of months to years, is many times in excess of that given for the short antimalarial course. Such long-term treatment can cause a characteristic retinopathy giving rise to a severe and permanent visual handicap. The retinotoxic effects were described by Hobbs et al. (1959), and have since been well documented by Nylander (1967). In spite of stopping the treatment the retinopathy may progress due to the pronounced accumulative properties of the drug in the melanin containing tissues of the eye (Rubin et al. 1963). The serious retinotoxic effects have led to the necessity of continuous ophthalmological control during chloroquine treatment. As far as the detection of the retinopathy is concerned, the emphasis has been laid on the central area of the fundus (Okun et al. 1963; Henkind et al. 1964; Carr et al. 1966; Percival k Behrman 1969). The present case illustrates that marked peripheral changes may occur before the characteristic central changes and stresses the necessity of evaluating the periphery of the fundus as well as the macula in patients treated with long-term doses of chloroquine compounds.
Case Report A ?I-year-old woman developed joint symptoms in March 1967 consistent with a diagnosis of rheumatoid arthritis. Treatment with a chloroquine compound (Resochin) was commenced in April 1971 because of a continued and considerable activity of the arthritis. A daily dose of 500 mg controlled the condition and was maintained until Msy 1975. The treatment was continuous except for 10 days in July 1971 and a 3-month period from May to July 1973 which caused a relapse. A total chloroquine dosage in the region of 700 g was given. Ophthalmological examination was performed regularly throughout the course of treatment. The patient was seen prior to treatment and a total of nine eye examinations were performed up to the time of diagnosis of the retinopathy. The patient began to experience fainting attacks in May 1975 and noted a defect in the upperiouter field of vision of the right eye. She was admitted to a general medical ward, and an eye examination was requested because of a suspected intracerebral tumour. Eye examination May 1975 Visual acuity was 1.0 right eye, and 1.0 left eye. Colour vision with lshihara plates was normal. Slit lamp examination revealed several thin, linear corneal opacities which had originally been observed 9 months previously. Ophthalmoscopy showed slight bilateral optic nerve atrophy with the right optic disc paler than the left. There was a marked narrowing of the retinal arterioles, especially involving the lower nasal branches. Peripherally, from the equator outwards, numerous, small, round and regular pigment aggregations were seen. These findings had not been described in the previous examinations. A few small pigment epithelium defects were
820
Chloroqzrine Retino f a t h y
Fig. 1 . Fluorescein angiography of right macula showing discrete pigment epithelium defects (36 seconds).
just visible in the region of the right macula. T h e left rnacula appeared quite normal. There were no characteristic “bull’s eye” changes, and no central pigment deposits. Fluorescein angiography of the right eye revealed a few small slightly confluent pigment epithelium defects in the macula area but no “bull’s eye” pattern (Fig. 1). There was an increase in the peripheral background choroidal flourescence with pigment aggregations (Fig. 2). Visual field examination with the Goldmann perimeter revealed restriction of the peripheral fields, especially involving the upper temporal quadrants. No definite scotomas could be elicited (Fig. 3a). Electrorctinography showed a subnormal but positive curve. Dark adaptation revealed a normal biphasic curve. A diagnosis of chloroquine retinopathy was made and treatment was immediatedly stopped. Eye examination October 1975
Visual acuity was 1.0 right eye. and 0.G7 left eye. Colour vision was normal. Slit lamp examination showed almost complete disappearance of the corneal deposits. Ophthalmoscopy was unchanged, the right macula remained unaltered, and the left inacula still appeared normal. Fluorescein angiography of the right eye revealed a few
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Martin Lowes
Fig. 2. Fluorescein angiography of the peripheral retina of right eye showing increased back. ground fluorescence and pigment aggregations (120 seconds).
more rcntral pigment cpithclium defects. Fluorescein angiography of the left eye showed a norinal macula without any sign of pigment epithelium defects. Visual field examination demonstrated increased peripheral field restriction with paracentral scotoinas (Fig. 3b). Electroretinography was of the negative (-) type.
Fig. 3a. Visual fields at the time of diagnosis of the retinopathy.
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Chloroquine Retinopathy
Fig. 3b. Visual fields G months after stopping chloroquine treatment.
Eye examination January 1976
Visual fields (Fig. 3c) showed some improvement with regression of the central scotomas. Electroretinography was again positive but still subnormal. Moreover, the patient’s hair which had become bleached under the chloroquine treatment had begun to return to its usual brown colour. Eye examination August 1976
Visual acuity and colour vision were normal. Oplithalmoscopy was unchanged. T h e retinal vessel attenuation, optic atrophy and peripheral pigmentation were unaltered. There was no “bull’s eye” pattern or pigment deposition in the central fundus. Visual fields showed disappearance of the paracentral scotomas for 1/4 objects, but otherwise largely unchanged peripheral field constriction (Fig. 3d).
Fig. 3c. Visual fields 9 months after stopping chloroquine treatment.
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Martin Lowes
Fig. 3d.
Visual fields 16 months after stopping chloroquine treatment.
Discussion In the case described a retinopathy developed in spite of regular ophthalmological control. The retinopathy was, however, uncharacteristic in that there was marked peripheral involvement without any “bull’s eye” pattern in the central fundus. Visual field examination revealed peripheral constriction. Central scotomas were not found at the time of diagnosis of the retinopathy. The visual field defects were first noted by the patient in connection with fainting attacks when admission to a medical ward led to examination of the entire visual fields and a diagnosis of chloroquine retinopathy. Follow-up of the patient has been carried out for 16 months and no definite “bull‘s eye” changes have become apparent, whereas the visual field constriction has largely remained unchanged. It is widely accepted that in chloroquine retinopathy the first changes occur in the central fundus. After describing some of the first cases of chloroquine retinopathy, Hobbs et al. (1959) were of the opinion that the retinopathy began with narrowing of the arterioles and retinal oedema, and later progressed to pigmentation both peripherally and centrally. However, Okun et al. (1963) found that pericentral scotoma was an early and constant feature, and that as the retinopathy progressed the peripheral field became constricted with extension of the scotoma. They maintained that the earliest fundus changes occur in the macula, and that these are followed by narrowing of the retinal vessels. Peripheral pigment changes were described as being a very late phenomenon. In a discussion concerning the early retinal changes, Henkind et al. (1964) observed that macular mottling was the first visible sign of chloroquine retino-
824
Chloroquine Retinopathy
pathy, and only one out of 14 patients with early retinopathy showed visible arteriolar narrowing. Crews (1969) has graded patients according to their fundus appearance on ophthalmoscopy: Grade 1 normal macula and fovea; grade 2 foveal reflex absent; grade 3 perifoveal pigmentation; grade 4 depigmentation; grade 5 bull’s eye macula; grade 6 optic atrophy and narrowed arterioles. Reliable scotoma could only be detected in grades 3-6. In the most advanced grade (6) peripheral constriction was also present. Carr et al. (1966) observed that although the earliest ophthalmoscopical changes were in the macula area, retinal profiles to red light indicated that some damage also occurs at the periphery. They felt, however, that in the early stages central damage is more severe than peripheral damage. Nylander (1967) found in a number of cases of slight retinopathy that a subnormal ERG was the first evidence in support of the diagnosis. The macula changes were then so discrete that they were not evaluated as pathologicaL He concluded that in certain cases it appeared that some involvement of the rods in the periphery could occur before any conspicuous macular lesions were demonstrable. In the present case ophthalmoscopy, perimetry and ERG examination revealed marked involvement of the peripheral fundus with pigment changes, narrowed arterioles and slight optic nerve atrophy. Fluorescein angiography showed minimal changes in the macula area with only a few pigment epithelium defects. The typical fluorescein angiography pattern with “bull’s eye” macula have been described by Kearns & Hollenhorst (1966). The ERG was interesting in that it was originally positive but subnormal, progressing to a negative (-) type before again reverting to a positive curve, implying some recovery of rod function. The normal dark adaptation curve is in agreement with other authors (Okun et al. 1963; Henkind et al. 1964; Carr et al. 1966) who have similarly found normal or only slightly reduced rod thresholds even in relatively advanced cases of chloroquine retinopathy. The present case demonstrates that by concentrating on the central fundus only there is a very real danger of missing the retinopathy. A normal central fundus may give a sense of false security. Practically, it is therefore important to routinely examine the peripheral fundus by means of ophthalmoscopy and perimetry in patients undergoing long-term treatment with chloroquine preparations. As regards the frequency of these control examinations, the patients need not be seen more than once during the first year of treatment, but should be examined more frequently as the total dose increases and exceeds 300 g (Nylander 1967).
825
Martin Lowes
References Carr R. E., Gouras P. & Gunkel R. D. (1966) Chloroquine retinopathy. Early detection by retinal threshold test. Arch. Ophthal. (Chicago) 75, 171-1 78. Crews S. J. (1969) Some aspects of retinal drug toxicity. Ophthalmologica 158, 232-244. Henkind P., Carr R. E. & Siege1 I. M. (1964) Early chloroquine retinopathy: Clinical and functional findings. Arch. Ophthal. (Chicago) 71, 157-165. Hobbs H. E., Sorsby A. & Freedman A. (1959) Retinopathy following chloroquine therapy. Lancet 2, 478-480. Kearns T. P. & Hollenhorst R. W. (1966) Chloroquine retinopathy. Evaluation by fluorescein fundus angiography. Arch. Ophthal. (Chicago) 76, 378-384. Nylander U. (1967) Ocular damage in chloroquine therapy. Actn ophthal. (Kbh.) SUPPI. 92. Okun E., Gouras P., Bernstein H. & von Sallmann L. (1963) Chloroquine retinopathy. A report of eight cases with ERG and dark-adaptation findings. Arch. Ophthal. (Chicago) 69, 59-71. Page F. (1951) Treatment of lupus erythematosus with mepacrine. Lancet 2, 755-758. Percival S. P. B. & Behrman J. (1969) Ophthalmological safety of chloroquine. Brit. J . Ophthal. 53, 101-109. Rubin M., Bernstein H. N. & Zvaifler N. J. (1963) Studies on the pharmacology of chloroquine. Recommendations for the treatment of chloroquine retinopathy. Arch. Ophthal. (Chicago) 70, 4 7 4 4 8 1 .
Author’s address: Dr. Martin Lowes, Department of Ophthalmology, Aalborg Sygehus, 9100 Aalborg, Denmark.
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Department of Ophthalmology (Heads: N . Ehlers and L. Corydon), Arhus Kommzrnehospital, University of Aarhus, Department of Physical Medicine k Rehabilation (Heads: /. Fossgren and M. R m k j e r ) , Arlius Amtssygehus, Denmark
PERIPHERAL VISUAL FIELD RESTRICTION IN CHLOROQUI NE RETlNOPATHY Report of a Case BY
MARTIN LOWES
Chloroquine compounds are known to cause a retinopathy which typically begins in the central fundus giving rise to a “bull’s eye” macula. Ultimately peripheral changes may become apparent. In the routine eye examination of such patients emphasis has been laid on the central area of the fundus. A case is presented where the retinopathy was not diagnosed until marked peripheral changes had occurred with peripheral pigment changes, attenuated retinal vessels, slight optic atrophy, peripheral visual field restriction and a subnormal electroretinogram. The typical “bull’s eye” changes were not apparent. Routine examination of the peripheral fundus by means of ophthalmoscopy and perimetry is necessary to avoid missing any such retinopathy.
Key words: chloroquine - resochin retinopathy - peripheral retina ophthalmoscopy - perimetry - visual field restriction - electroretinography.
Chloroquine was originally synthesised f o r use as an antimalarial agent. Page (1951) introduced mepacrine in the treatment of lupus erythematosus, and since then the synthetic antimalarial compounds have had an important role in the Received September 29, 1976.
819
Martin Lowes
treatment of a variety of collagenoses and skin diseases. T h e dosage, usually from 250-750 mg daily over a period of months to years, is many times in excess of that given for the short antimalarial course. Such long-term treatment can cause a characteristic retinopathy giving rise to a severe and permanent visual handicap. The retinotoxic effects were described by Hobbs et al. (1959), and have since been well documented by Nylander (1967). In spite of stopping the treatment the retinopathy may progress due to the pronounced accumulative properties of the drug in the melanin containing tissues of the eye (Rubin et al. 1963). The serious retinotoxic effects have led to the necessity of continuous ophthalmological control during chloroquine treatment. As far as the detection of the retinopathy is concerned, the emphasis has been laid on the central area of the fundus (Okun et al. 1963; Henkind et al. 1964; Carr et al. 1966; Percival k Behrman 1969). The present case illustrates that marked peripheral changes may occur before the characteristic central changes and stresses the necessity of evaluating the periphery of the fundus as well as the macula in patients treated with long-term doses of chloroquine compounds.
Case Report A ?I-year-old woman developed joint symptoms in March 1967 consistent with a diagnosis of rheumatoid arthritis. Treatment with a chloroquine compound (Resochin) was commenced in April 1971 because of a continued and considerable activity of the arthritis. A daily dose of 500 mg controlled the condition and was maintained until Msy 1975. The treatment was continuous except for 10 days in July 1971 and a 3-month period from May to July 1973 which caused a relapse. A total chloroquine dosage in the region of 700 g was given. Ophthalmological examination was performed regularly throughout the course of treatment. The patient was seen prior to treatment and a total of nine eye examinations were performed up to the time of diagnosis of the retinopathy. The patient began to experience fainting attacks in May 1975 and noted a defect in the upperiouter field of vision of the right eye. She was admitted to a general medical ward, and an eye examination was requested because of a suspected intracerebral tumour. Eye examination May 1975 Visual acuity was 1.0 right eye, and 1.0 left eye. Colour vision with lshihara plates was normal. Slit lamp examination revealed several thin, linear corneal opacities which had originally been observed 9 months previously. Ophthalmoscopy showed slight bilateral optic nerve atrophy with the right optic disc paler than the left. There was a marked narrowing of the retinal arterioles, especially involving the lower nasal branches. Peripherally, from the equator outwards, numerous, small, round and regular pigment aggregations were seen. These findings had not been described in the previous examinations. A few small pigment epithelium defects were
820
Chloroqzrine Retino f a t h y
Fig. 1 . Fluorescein angiography of right macula showing discrete pigment epithelium defects (36 seconds).
just visible in the region of the right macula. T h e left rnacula appeared quite normal. There were no characteristic “bull’s eye” changes, and no central pigment deposits. Fluorescein angiography of the right eye revealed a few small slightly confluent pigment epithelium defects in the macula area but no “bull’s eye” pattern (Fig. 1). There was an increase in the peripheral background choroidal flourescence with pigment aggregations (Fig. 2). Visual field examination with the Goldmann perimeter revealed restriction of the peripheral fields, especially involving the upper temporal quadrants. No definite scotomas could be elicited (Fig. 3a). Electrorctinography showed a subnormal but positive curve. Dark adaptation revealed a normal biphasic curve. A diagnosis of chloroquine retinopathy was made and treatment was immediatedly stopped. Eye examination October 1975
Visual acuity was 1.0 right eye. and 0.G7 left eye. Colour vision was normal. Slit lamp examination showed almost complete disappearance of the corneal deposits. Ophthalmoscopy was unchanged, the right macula remained unaltered, and the left inacula still appeared normal. Fluorescein angiography of the right eye revealed a few
821 53
Martin Lowes
Fig. 2. Fluorescein angiography of the peripheral retina of right eye showing increased back. ground fluorescence and pigment aggregations (120 seconds).
more rcntral pigment cpithclium defects. Fluorescein angiography of the left eye showed a norinal macula without any sign of pigment epithelium defects. Visual field examination demonstrated increased peripheral field restriction with paracentral scotoinas (Fig. 3b). Electroretinography was of the negative (-) type.
Fig. 3a. Visual fields at the time of diagnosis of the retinopathy.
822
Chloroquine Retinopathy
Fig. 3b. Visual fields G months after stopping chloroquine treatment.
Eye examination January 1976
Visual fields (Fig. 3c) showed some improvement with regression of the central scotomas. Electroretinography was again positive but still subnormal. Moreover, the patient’s hair which had become bleached under the chloroquine treatment had begun to return to its usual brown colour. Eye examination August 1976
Visual acuity and colour vision were normal. Oplithalmoscopy was unchanged. T h e retinal vessel attenuation, optic atrophy and peripheral pigmentation were unaltered. There was no “bull’s eye” pattern or pigment deposition in the central fundus. Visual fields showed disappearance of the paracentral scotomas for 1/4 objects, but otherwise largely unchanged peripheral field constriction (Fig. 3d).
Fig. 3c. Visual fields 9 months after stopping chloroquine treatment.
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Martin Lowes
Fig. 3d.
Visual fields 16 months after stopping chloroquine treatment.
Discussion In the case described a retinopathy developed in spite of regular ophthalmological control. The retinopathy was, however, uncharacteristic in that there was marked peripheral involvement without any “bull’s eye” pattern in the central fundus. Visual field examination revealed peripheral constriction. Central scotomas were not found at the time of diagnosis of the retinopathy. The visual field defects were first noted by the patient in connection with fainting attacks when admission to a medical ward led to examination of the entire visual fields and a diagnosis of chloroquine retinopathy. Follow-up of the patient has been carried out for 16 months and no definite “bull‘s eye” changes have become apparent, whereas the visual field constriction has largely remained unchanged. It is widely accepted that in chloroquine retinopathy the first changes occur in the central fundus. After describing some of the first cases of chloroquine retinopathy, Hobbs et al. (1959) were of the opinion that the retinopathy began with narrowing of the arterioles and retinal oedema, and later progressed to pigmentation both peripherally and centrally. However, Okun et al. (1963) found that pericentral scotoma was an early and constant feature, and that as the retinopathy progressed the peripheral field became constricted with extension of the scotoma. They maintained that the earliest fundus changes occur in the macula, and that these are followed by narrowing of the retinal vessels. Peripheral pigment changes were described as being a very late phenomenon. In a discussion concerning the early retinal changes, Henkind et al. (1964) observed that macular mottling was the first visible sign of chloroquine retino-
824
Chloroquine Retinopathy
pathy, and only one out of 14 patients with early retinopathy showed visible arteriolar narrowing. Crews (1969) has graded patients according to their fundus appearance on ophthalmoscopy: Grade 1 normal macula and fovea; grade 2 foveal reflex absent; grade 3 perifoveal pigmentation; grade 4 depigmentation; grade 5 bull’s eye macula; grade 6 optic atrophy and narrowed arterioles. Reliable scotoma could only be detected in grades 3-6. In the most advanced grade (6) peripheral constriction was also present. Carr et al. (1966) observed that although the earliest ophthalmoscopical changes were in the macula area, retinal profiles to red light indicated that some damage also occurs at the periphery. They felt, however, that in the early stages central damage is more severe than peripheral damage. Nylander (1967) found in a number of cases of slight retinopathy that a subnormal ERG was the first evidence in support of the diagnosis. The macula changes were then so discrete that they were not evaluated as pathologicaL He concluded that in certain cases it appeared that some involvement of the rods in the periphery could occur before any conspicuous macular lesions were demonstrable. In the present case ophthalmoscopy, perimetry and ERG examination revealed marked involvement of the peripheral fundus with pigment changes, narrowed arterioles and slight optic nerve atrophy. Fluorescein angiography showed minimal changes in the macula area with only a few pigment epithelium defects. The typical fluorescein angiography pattern with “bull’s eye” macula have been described by Kearns & Hollenhorst (1966). The ERG was interesting in that it was originally positive but subnormal, progressing to a negative (-) type before again reverting to a positive curve, implying some recovery of rod function. The normal dark adaptation curve is in agreement with other authors (Okun et al. 1963; Henkind et al. 1964; Carr et al. 1966) who have similarly found normal or only slightly reduced rod thresholds even in relatively advanced cases of chloroquine retinopathy. The present case demonstrates that by concentrating on the central fundus only there is a very real danger of missing the retinopathy. A normal central fundus may give a sense of false security. Practically, it is therefore important to routinely examine the peripheral fundus by means of ophthalmoscopy and perimetry in patients undergoing long-term treatment with chloroquine preparations. As regards the frequency of these control examinations, the patients need not be seen more than once during the first year of treatment, but should be examined more frequently as the total dose increases and exceeds 300 g (Nylander 1967).
825
Martin Lowes
References Carr R. E., Gouras P. & Gunkel R. D. (1966) Chloroquine retinopathy. Early detection by retinal threshold test. Arch. Ophthal. (Chicago) 75, 171-1 78. Crews S. J. (1969) Some aspects of retinal drug toxicity. Ophthalmologica 158, 232-244. Henkind P., Carr R. E. & Siege1 I. M. (1964) Early chloroquine retinopathy: Clinical and functional findings. Arch. Ophthal. (Chicago) 71, 157-165. Hobbs H. E., Sorsby A. & Freedman A. (1959) Retinopathy following chloroquine therapy. Lancet 2, 478-480. Kearns T. P. & Hollenhorst R. W. (1966) Chloroquine retinopathy. Evaluation by fluorescein fundus angiography. Arch. Ophthal. (Chicago) 76, 378-384. Nylander U. (1967) Ocular damage in chloroquine therapy. Actn ophthal. (Kbh.) SUPPI. 92. Okun E., Gouras P., Bernstein H. & von Sallmann L. (1963) Chloroquine retinopathy. A report of eight cases with ERG and dark-adaptation findings. Arch. Ophthal. (Chicago) 69, 59-71. Page F. (1951) Treatment of lupus erythematosus with mepacrine. Lancet 2, 755-758. Percival S. P. B. & Behrman J. (1969) Ophthalmological safety of chloroquine. Brit. J . Ophthal. 53, 101-109. Rubin M., Bernstein H. N. & Zvaifler N. J. (1963) Studies on the pharmacology of chloroquine. Recommendations for the treatment of chloroquine retinopathy. Arch. Ophthal. (Chicago) 70, 4 7 4 4 8 1 .
Author’s address: Dr. Martin Lowes, Department of Ophthalmology, Aalborg Sygehus, 9100 Aalborg, Denmark.
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