- Email: [email protected]
Ocular Complications of Chloroquine*
J O H N F. M O R G A N A N D J O S E P H C. H I L L
774
8. Dow Corning Medical Materials Data. Bull. 14-003, 1963. 9. Kirkegaard, R. S.; Silicone fluids in the long-term management of ocular prosthesis. Seminar, Jan. 4, 1961, Dept. Ophth., College of Med., Iowa City, Iowa. 10. Thygeson, P., and Kimura, S. J.: Chronic conjunctivitis. Tr. Am. Acad. Ophth., 67:494-517, 1963.
OCULAR A
COMPLICATIONS
SERIES A N D CASE PRESENTATION
O F
CHLOROQUINE*
W I T H A SIMPLE
METHOD FOR
EARLY DETECTION OF RETINOPATHY ROBERT A . Ν ο ζ ι κ , M . D . , F R A N K J. W E I N S T O C K , M . D . , A N D P A U L J. V I G N O S , JR., M . D . Cleveland, Ohio
Several recent reports of irreversible ret
defects gave abnormal responses to the H R R
inal changes following chloroquine therapy
pseudoisochromatic color vision plates
have suggested to some physicians that the
gave normal
drug may be too dangerous for clinical use.
D-15
For
defective form perception resulting from the
this reason, the true incidence o f the
retinopathy should be determined.
responses to the
but
Farnsworth
color discs. T h e y based this loss on
pericentral or central scotoma rather than on
Three series have been published. A 2.9
a true color loss. In the more advanced cases
percent incidence of retinopathy in 170 cases
abnormal responses were also noted with the
was reported by H o b b s , et al.' in 1961. Abels,
Farnsworth D-15 test.
et al.^ in 1963 found no positive cases out o f
T h e next most characteristic feature was
52 patients, whereas Henkind and Rothfield,^
found
also in 1963, found 13 percent o f 56 patients
"doughnut-shaped"
showed chloroquine retinopathy.
in
the
retina
where
or
the
so-called
"bulls-eye" macula
has been described as consisting o f a central
In 1959 Hobbs** suggested the possibility
hyperpigmented zone surrounded by a rela
of a direct relationship between the develop
tively depigmented ring which, in turn, is
ment o f retinopathy, the dose of chloroquine
surrounded by a hyperpigmented ring. A l s o
and the length of time on treatment. T o date,
described have been arteriolar
the patients in almost all reported cases had
disc pallor and peripheral
been taking the drug for at least one year.
turbances.
A
narrowing,
pigmentary dis
review o f the literature revealed that
Vague symptoms such as blurred vision,
the most characteristic finding o f chloroquine
decreased vision, halos, photophobia, color
retinopathy was a pericentral ring scotoma
blindness, night blindness and "seeing spots
which may progress to a central scotoma.
before the eyes" have been recorded.
This may be followed later by peripheral
Reversible corneal changes causing blurred
field constriction and, finally, an extension to
vision, halos a n d / o r decreased corneal sen
the periphery o f the central scotoma.
sation occur with a reported incidence o f
Recent work by Okun and his associates' showed that patients with early visual field * From the Division of Ophthalmology, Depart ment of Surgery, and the Department of Medi cine, Western Reserve University. Presented be fore the Cleveland Ophthalmology Club, Novem ber 12, 1963.
seven^ to 73^ percent. W e shall not discuss the keratopathy in detail. PURPOSES
The purposes o f this paper are threefold: 1. T o determine
the
chloroquine retinopathy.
true
incidence of
OCULAR COMPLICATIONS OF TABLE
TABLE 3
1
TOTAL DOSAGE OF MEDICATION (CHLOROQUINE EXCEPT WHERE NOTED)
AGE DISTRIBUTION Age (yr.)
No. Patients
1-20 21-40 41-60 61-80 81-90
5 11 21 11 2
TOTAL
50
retinopathy. 3. T o find a simple screening method for retinopathy
which may be used by the practitioner. DESCRIPTION OF SERIES
series
consists
chloroquine and
of
14* 15 6 7t 4 3t 1
30-100 101-200 201-300 301-400 401-500 501-576 Hydroxychloroquine (90 gm.)
dosage o f treatment to the development o f
early detection o f chloroquine
No. Patients
Grams
50
TOTAL
2. T o investigate the relationship o f time-
Our
775
CHLOROQUINE
Average total dosage: 208 gm. * One patient also had 33 gm. of hydroxychloro quine. t One patient also had 216 gm. of hydroxychloro quine. uine. Í One patient also had 39 gm. of hydroxychlloroquine.
of medication are shown in Tables 2 and 3.
49 patients
on
one patient on h y d r o x y
chloroquine for nine months or more. These
T h e average daily dose o f medication and the
duration
of
treatment
are
found
in
Tables 4 and 5.
50 patients (11 males and 39 females, with
T h e symptoms were mainly of a rather
an age range o f 13 to 85 years [table ] ) were
nonspecific nature (table 6 ) . O n l y one eye
drawn
of
consecutively from
the
University
one patient showed a significant visual
Hospital Arthritis, Muscle and Dermatology
decrease ( 2 0 / 5 0 ) , and that eye was myopic
Clinics as well as from the private practice o f
( — 9 . 5 D . s p h . ) , anisometrophic compared to
one of us ( P . V . ) . W e ( R . N . and F. W . )
the other eye (— 0.5D. s p h . ) , and had a small
performed a thorough ocular examination in
posterior subcapsular cataract. O n l y one pa
cluding visual fields and color vision testing,
tient demonstrated pericentral ring scotoma,
using the H R R plates at a distance o f 40 cm.
and one showed a superior nasal sector defect
and free fixation. T h e Farnsworth D-15 test
which appeared on the tangent screen but not
was used in cases where H R R defects were
on the perimeter.
found. A n y questionable o r suspicious find ings were checked by repeat examinations. The systemic diagnosis and total dosage
TABLE
TABLE 2
Milligrams (per day)
No. Patients
less than 100 100-199 200-299 300-399 400-499 Hydroxychloroquine (250 mg.)
2 11* 28t 7 1 1
SYSTEMIC DIAGNOSES OF PATIENTS Diagnosis Rheumatoid arthritis Polymyositis Systemic lupus erythematosus Discoid lupus erythematosus Sarcoidosis Dermatomyositis Rheumatoid spondylitis TOTAL
No. Patients 31 2 10 3 1 2 1 50
4
AVERAGE DAILY DOSE OF MEDICATION
TOTAL
50
* Includes one patient who also received hydroxy chloroquine. t Includes two patients who also received hy droxychloroquine
776
R O B E R T Α. N O Z I K , F R A N K J. W E I N S T O C K , A N D P A U L J. V I G N O S , JR. TABLE
5
feet.
TOTAL DURATION OF TREATMENT
T h e fundus
picture,
as well as the
clinical symptoms, was important but sec
Months
No. Patients
9-23 24-35 36-47 48-59 60-71 72-75 Hydroxychloroquine (12 mo.)
23* 8 12* 2 2» 2 1
ondary in establishing
the diagnosis. It is
important not to attribute every macular pig ment abnormality to chloroquine nor to ex trapolate "rings" in each suspicious macula. C A S E REPORT
Using these criteria we have found one case of chloroquine retinopathy in our series
TOTAL
50
of 50 patients.
Average—29 months * One patient also received hydroxychloroquine.
The mild H R R defects were all errors on the first screening plate ( 1 9 5 6 series). This is felt b y some authorities to be within nor mal limits if n o other plates are missed.* T h e severe H R R defects were in both eyes o f one patient and will be discussed more fully later. N o typical or even suggestive corneal lesions
of
chloroquine
keratopathy
were
noted on slitlamp examination. N o "dough nut" or "bulls-eye" maculas were seen, al though six eyes showed pigmentary disper sion o f the foveal light reflex (table 7 ) .
This patient was a 58-year-old white woman with a history of joint pain since five years of age. The condition was diagnosed as rheumatoid arthri tis in 1950 when she was 45 years of age. She had been treated intermittently with systemic steroids, aspirin, phenylbutazone, methyltestosterone, stilbesterol and snake venom. When first seen by us early in 1963 she had been on continuous chloro quine therapy of 250 mg. per day for almost six years. A t the time of her first visit her visual acuity was 15/30-1-3 in the right eye and 15/20 — 2 in the left eye. On the H R R color vision test she gave incorrect responses to eight of the first nine plates with the right eye and the first seven plates with the left eye. The Farnsworth test was normal, as were the visual field tests to the 1/1,000 and TABLE 7 SIGNS
DISCUSSION A N D CONCLUSIONS
W e have used as principal evidence of
Sign
early or developing chloroquine retinopathy the onset of a pericentral ring scotoma in a patient on continuous chloroquine treatment, with peripheral field constriction as a subse quent
development. T h e combined H R R -
Farnsworth testing was used to supplement the examination f o r the pericentral field deTABLE
6
SYMPTOMS Symptom Diminished or blurred vision Halos Diminished night vision Floaters or spots Photophobia Color blindness TOTAL
No. Patients 3 4 1 3 4 0 15
1. Decreased visual acuity 2. Diminished corneal sensation 3. Visual field abnormalities a. Pericentral ring b. Sector defect c. Concentric constriction 4. Color abnormalities a. Mild H R R b. Severe H R R c. Farnsworth 5. Slitlamp abnormalities a. Old corneal scars b. Punctate staining c. Cataracts 6. Fundus abnormalities a. Arteriolar sheathing b. Arteriolar narrowing c. Grade I arteriosclerosis d. Grade II arteriosclerosis e. Grade III arteriosclerosis f. Loss of foveal reflex g. Drusen h. Chorioretinal scars i. Peripheral retinal degeneration j . Choroidal sclerosis k. Cytoid body
No. Eye 1 2 1 1 4 10 2 0 3 2 9 1 24 6 1 1 6 2 2 11 4 1
777
OCULAR COMPLICATIONS OF CHLOROQUINE the 3/330 white test objects. The fundus examina tion showed only bilateral breaking up of the fo veal light reflex, with peripheral arteriolar nar rowing but no "bulls-eye" macular configuration. Six weeks later the examination was essentially the same. Six weeks after this, however, a definite and consistent pericentral ring scotoma of the right eye appeared inside the central five degrees with the 1/1,000 white test object (fig. 1). There was no regression of visual acuity or change in HRR-Farnsworth testing. The fundi showed slight increase in macular pigment clumping and arterio lar narrowing. The diagnosis of chloroquine retin opathy was made and the drug was discontinued. Five weeks later, visual acuity was 20/20 — 2 in each eye and on H R R testing at this time the patient missed only the first two plates with the right eye and the first plate with the left eye, a marked improvement over previous examinations. The pericentral field defect of the right eye disap peared to the 1/1,000 white test object and only an inconstant superonasal fragment remained to the 1/2,000 white object (fig. 2 ) . Although there was still some breaking up of the foveal reflex in each eye, less macular pigment appeared to be present than on the previous examination.
On reviewing the literature w e find this to be the first reported case in which chloro quine retinopathy has been demonstrated to develop while the patient was under observa tion, thus providing an unique opportunity to evaluate early diagnosis and prognosis. W e found that the combined H R R - F a r n s w o r t h testing worked very well in anticipating our
3W/330 Coi^eration - ö o o d Reliability-Fair Fixation — Qood V A S c OD 15/20-1
LK.
8-Ζ4-β3
-IW/1000 3W/1000 (OS)
Fig. 1 (Nozik, Weinstock and Vignos). Fields for L. K. on August 24, 1963.
Cooperíáioa - Good Kálkbiüty
- (rood
LK. 10-5-63
nxatlon - öood YASc 03
2Ό/Ζ0-Ζ ZO/ZO-Z
IW/ZOOO
Fig. 2 (Nozik, Weinstock and Vignos). Fields for L. K. on October S, 1963.
patient's retinopathy, since the test showed abnormal findings before definite visual field or fundus changes occurred. It seems reason able, therefore, to suggest that patients w h o are to be started on chloroquine be given a complete ophthalmologic examination and, perhaps, yearly follow-up examinations. T h e internist could use the H R R test as part o f his routine monthly o r six-week checkup and, if any abnormality develops, refer the patient to the ophthalmologist. It is also interesting and encouraging to note the regression o f the visual field and H R R defects after their early detection and the subsequent discontinuation o f chloro quine ; this is in contrast to the majority o f cases in the literature in which the retino pathy usually continued to progress. These cases, however, were more advanced than the one just presented. T h e total dosage o f chloroquine received by the one patient with a positive case o f retinopathy was 525 g m . over a period o f 70 months. In comparison with the other cases in our series this was about t w o and one-half times the average total dose o f 208 gm. received b y the other patients in our series and the duration o f treatment was about two and one-half times longer than the series average o f 29 months. One additional case o f chloroquine retino pathy not included in o u r series has been seen. This patient received a total o f 404 gm.
778
R O B E R T Α. Ν Ο Ζ Ι Κ , F R A N K J. W E I N S T O C K , A N D P A U L J. V I G N O S , JR.
o f chloroquine over a period o f 20 months, with an average daily dose o f 660 mg. W h i l e
SUMMARY i
^
series of 50 patients on chloroquine
the length o f treatment was relatively short,
treatment were
the
plications due
total dose was high when compared to
the average o f our series.
examined
for
ocular
com-
to this drug. T h e r e were no
casts o f corneal complications. O n l y one case
Both o f these cases support the suggestion
showed
retinopathy.
jgtered over
period o f
time. These
results suggest that the use o f
low-dosages
in
(an
which
average
dosage total dose
details of
were
540
gm.
with 43 months as the average total duration of
therapy
and
the
average
daily
dose
420mg.).i.3-=-'-i« incidence
can
be
drawn,
more and
larger
admin-
^he drug, as in most o f the patients o f this series, contributed to the
l o w incidence o f
ocular side-effects. 2. Very
early chloroquine retinopathy is
reversible if the drug is discontinued. 3. T h e
Before definite conclusions as to the true
a long
was
a
thy. T h e y also agree with the time-dosage reliterature
chloroquine
individual
dosage relationship in chloroquine retinopa-
given
of
this
j^rge
lationship found in 37 positive cases in the
amount
In
o f some authors that there is a direct time-
H R R test is recommended as
a
simple screening test f o r early detection o f chloroquine retinopathy,
series must be studied, using consistent, welldefined criteria f o r positive
findings.
University
Hospitals(6).
REFERENCES 1. Hobbs, H. E., Eadie, S. P., and Somerville, F.: Ocular lesions after treatment with chloroquine. Brit. J. Ophth., 45 :284-297, 1961. 2. Abels, D. J., O'Keefe, T. N., Smith, D., Gutow, R., Falls, H. F., and Duff, I. F.: Antimalarials and their ocular complications. Arthritis and Rheumatism, 6:258, 1963. 3. Henkind, P., and Rothfield, N. F.: Ocular abnormalities in patients treated with synthetic antimalarial drugs. New England J. Med., 269 :433-439, 1963. 4. Hobbs, H. E., Sorsby, Α., and Freedman, A . : Retinopathy following chloroquine therapy. Lancet, 277:478-480, 1959. 5. Okun, E., Gouras, P., Bernstein, H., and Von Sallmann, L . : Chloroquine retinopathy: A report of eight cases with ERG and dark-adaptation findings. A M A Arch. Ophth., 69:59-71, 1963. 6. Steimholtz, R., and Kearns, T . : H - R - R pseudoisochromatic plates; As a diagnostic aid in retro bulbar neuritis of multiple sclerosis. Am. J. Ophth., 41:833-837, 1956. 7. Ellsworth, R. T., and Zeller, R. W . : Chloroquine (Aralen) induced retinal damage. A M A Arch. Ophth., 66 :269-272, 1961. 8. Fuld, Η . : Retinopathy following chloroquine therapy. Lancet, 2:617-618, 1959. 9. Mayer, W . : Chloroquine retinopathy. Am. J. Ophth., 53 -.769-774, 1962. 10. Penner, R., and Somers, K . : Bilateral macular degeneration associated with chloroquine therapy. Am. J. Med., 54:381-385, 1962. 11. Richards, R. D., and Wilson, W . R . : Retinopathy associated with chloroquine phosphate therapy. Am. J. Med., 31:140-143, 1961. 12. Sachs, D. D., Hogan, Μ. J., and Engleman, E. P.: Chorioretinopathy induced by chronic administra tion of chloroquine phosphate. Arthritis and Rheumatism, 5:318-319, 1962. 13. Sataline, L. R., and Farmer, H . : Impaired vision after prolonged chloroquine therapy. New Eng land J. Med., 266:346-347, 1962. 14. Smith, J. L . : Chloroquine macular degeneration. A M A Arch. Ophth., 68:186-190, 1962. 15. Sternberg, T. H., and Laden, E . : Discoid lupus eryhthematosus: Bilateral macular degeneration due to chloroquine. Arch. Dermat & Syph., 79:116-118, 1959. 16. Wilson, W . : Retinopathy during chloroquine therapy. Brit. J. Ophth., 45:756-758, 1961.
774
8. Dow Corning Medical Materials Data. Bull. 14-003, 1963. 9. Kirkegaard, R. S.; Silicone fluids in the long-term management of ocular prosthesis. Seminar, Jan. 4, 1961, Dept. Ophth., College of Med., Iowa City, Iowa. 10. Thygeson, P., and Kimura, S. J.: Chronic conjunctivitis. Tr. Am. Acad. Ophth., 67:494-517, 1963.
OCULAR A
COMPLICATIONS
SERIES A N D CASE PRESENTATION
O F
CHLOROQUINE*
W I T H A SIMPLE
METHOD FOR
EARLY DETECTION OF RETINOPATHY ROBERT A . Ν ο ζ ι κ , M . D . , F R A N K J. W E I N S T O C K , M . D . , A N D P A U L J. V I G N O S , JR., M . D . Cleveland, Ohio
Several recent reports of irreversible ret
defects gave abnormal responses to the H R R
inal changes following chloroquine therapy
pseudoisochromatic color vision plates
have suggested to some physicians that the
gave normal
drug may be too dangerous for clinical use.
D-15
For
defective form perception resulting from the
this reason, the true incidence o f the
retinopathy should be determined.
responses to the
but
Farnsworth
color discs. T h e y based this loss on
pericentral or central scotoma rather than on
Three series have been published. A 2.9
a true color loss. In the more advanced cases
percent incidence of retinopathy in 170 cases
abnormal responses were also noted with the
was reported by H o b b s , et al.' in 1961. Abels,
Farnsworth D-15 test.
et al.^ in 1963 found no positive cases out o f
T h e next most characteristic feature was
52 patients, whereas Henkind and Rothfield,^
found
also in 1963, found 13 percent o f 56 patients
"doughnut-shaped"
showed chloroquine retinopathy.
in
the
retina
where
or
the
so-called
"bulls-eye" macula
has been described as consisting o f a central
In 1959 Hobbs** suggested the possibility
hyperpigmented zone surrounded by a rela
of a direct relationship between the develop
tively depigmented ring which, in turn, is
ment o f retinopathy, the dose of chloroquine
surrounded by a hyperpigmented ring. A l s o
and the length of time on treatment. T o date,
described have been arteriolar
the patients in almost all reported cases had
disc pallor and peripheral
been taking the drug for at least one year.
turbances.
A
narrowing,
pigmentary dis
review o f the literature revealed that
Vague symptoms such as blurred vision,
the most characteristic finding o f chloroquine
decreased vision, halos, photophobia, color
retinopathy was a pericentral ring scotoma
blindness, night blindness and "seeing spots
which may progress to a central scotoma.
before the eyes" have been recorded.
This may be followed later by peripheral
Reversible corneal changes causing blurred
field constriction and, finally, an extension to
vision, halos a n d / o r decreased corneal sen
the periphery o f the central scotoma.
sation occur with a reported incidence o f
Recent work by Okun and his associates' showed that patients with early visual field * From the Division of Ophthalmology, Depart ment of Surgery, and the Department of Medi cine, Western Reserve University. Presented be fore the Cleveland Ophthalmology Club, Novem ber 12, 1963.
seven^ to 73^ percent. W e shall not discuss the keratopathy in detail. PURPOSES
The purposes o f this paper are threefold: 1. T o determine
the
chloroquine retinopathy.
true
incidence of
OCULAR COMPLICATIONS OF TABLE
TABLE 3
1
TOTAL DOSAGE OF MEDICATION (CHLOROQUINE EXCEPT WHERE NOTED)
AGE DISTRIBUTION Age (yr.)
No. Patients
1-20 21-40 41-60 61-80 81-90
5 11 21 11 2
TOTAL
50
retinopathy. 3. T o find a simple screening method for retinopathy
which may be used by the practitioner. DESCRIPTION OF SERIES
series
consists
chloroquine and
of
14* 15 6 7t 4 3t 1
30-100 101-200 201-300 301-400 401-500 501-576 Hydroxychloroquine (90 gm.)
dosage o f treatment to the development o f
early detection o f chloroquine
No. Patients
Grams
50
TOTAL
2. T o investigate the relationship o f time-
Our
775
CHLOROQUINE
Average total dosage: 208 gm. * One patient also had 33 gm. of hydroxychloro quine. t One patient also had 216 gm. of hydroxychloro quine. uine. Í One patient also had 39 gm. of hydroxychlloroquine.
of medication are shown in Tables 2 and 3.
49 patients
on
one patient on h y d r o x y
chloroquine for nine months or more. These
T h e average daily dose o f medication and the
duration
of
treatment
are
found
in
Tables 4 and 5.
50 patients (11 males and 39 females, with
T h e symptoms were mainly of a rather
an age range o f 13 to 85 years [table ] ) were
nonspecific nature (table 6 ) . O n l y one eye
drawn
of
consecutively from
the
University
one patient showed a significant visual
Hospital Arthritis, Muscle and Dermatology
decrease ( 2 0 / 5 0 ) , and that eye was myopic
Clinics as well as from the private practice o f
( — 9 . 5 D . s p h . ) , anisometrophic compared to
one of us ( P . V . ) . W e ( R . N . and F. W . )
the other eye (— 0.5D. s p h . ) , and had a small
performed a thorough ocular examination in
posterior subcapsular cataract. O n l y one pa
cluding visual fields and color vision testing,
tient demonstrated pericentral ring scotoma,
using the H R R plates at a distance o f 40 cm.
and one showed a superior nasal sector defect
and free fixation. T h e Farnsworth D-15 test
which appeared on the tangent screen but not
was used in cases where H R R defects were
on the perimeter.
found. A n y questionable o r suspicious find ings were checked by repeat examinations. The systemic diagnosis and total dosage
TABLE
TABLE 2
Milligrams (per day)
No. Patients
less than 100 100-199 200-299 300-399 400-499 Hydroxychloroquine (250 mg.)
2 11* 28t 7 1 1
SYSTEMIC DIAGNOSES OF PATIENTS Diagnosis Rheumatoid arthritis Polymyositis Systemic lupus erythematosus Discoid lupus erythematosus Sarcoidosis Dermatomyositis Rheumatoid spondylitis TOTAL
No. Patients 31 2 10 3 1 2 1 50
4
AVERAGE DAILY DOSE OF MEDICATION
TOTAL
50
* Includes one patient who also received hydroxy chloroquine. t Includes two patients who also received hy droxychloroquine
776
R O B E R T Α. N O Z I K , F R A N K J. W E I N S T O C K , A N D P A U L J. V I G N O S , JR. TABLE
5
feet.
TOTAL DURATION OF TREATMENT
T h e fundus
picture,
as well as the
clinical symptoms, was important but sec
Months
No. Patients
9-23 24-35 36-47 48-59 60-71 72-75 Hydroxychloroquine (12 mo.)
23* 8 12* 2 2» 2 1
ondary in establishing
the diagnosis. It is
important not to attribute every macular pig ment abnormality to chloroquine nor to ex trapolate "rings" in each suspicious macula. C A S E REPORT
Using these criteria we have found one case of chloroquine retinopathy in our series
TOTAL
50
of 50 patients.
Average—29 months * One patient also received hydroxychloroquine.
The mild H R R defects were all errors on the first screening plate ( 1 9 5 6 series). This is felt b y some authorities to be within nor mal limits if n o other plates are missed.* T h e severe H R R defects were in both eyes o f one patient and will be discussed more fully later. N o typical or even suggestive corneal lesions
of
chloroquine
keratopathy
were
noted on slitlamp examination. N o "dough nut" or "bulls-eye" maculas were seen, al though six eyes showed pigmentary disper sion o f the foveal light reflex (table 7 ) .
This patient was a 58-year-old white woman with a history of joint pain since five years of age. The condition was diagnosed as rheumatoid arthri tis in 1950 when she was 45 years of age. She had been treated intermittently with systemic steroids, aspirin, phenylbutazone, methyltestosterone, stilbesterol and snake venom. When first seen by us early in 1963 she had been on continuous chloro quine therapy of 250 mg. per day for almost six years. A t the time of her first visit her visual acuity was 15/30-1-3 in the right eye and 15/20 — 2 in the left eye. On the H R R color vision test she gave incorrect responses to eight of the first nine plates with the right eye and the first seven plates with the left eye. The Farnsworth test was normal, as were the visual field tests to the 1/1,000 and TABLE 7 SIGNS
DISCUSSION A N D CONCLUSIONS
W e have used as principal evidence of
Sign
early or developing chloroquine retinopathy the onset of a pericentral ring scotoma in a patient on continuous chloroquine treatment, with peripheral field constriction as a subse quent
development. T h e combined H R R -
Farnsworth testing was used to supplement the examination f o r the pericentral field deTABLE
6
SYMPTOMS Symptom Diminished or blurred vision Halos Diminished night vision Floaters or spots Photophobia Color blindness TOTAL
No. Patients 3 4 1 3 4 0 15
1. Decreased visual acuity 2. Diminished corneal sensation 3. Visual field abnormalities a. Pericentral ring b. Sector defect c. Concentric constriction 4. Color abnormalities a. Mild H R R b. Severe H R R c. Farnsworth 5. Slitlamp abnormalities a. Old corneal scars b. Punctate staining c. Cataracts 6. Fundus abnormalities a. Arteriolar sheathing b. Arteriolar narrowing c. Grade I arteriosclerosis d. Grade II arteriosclerosis e. Grade III arteriosclerosis f. Loss of foveal reflex g. Drusen h. Chorioretinal scars i. Peripheral retinal degeneration j . Choroidal sclerosis k. Cytoid body
No. Eye 1 2 1 1 4 10 2 0 3 2 9 1 24 6 1 1 6 2 2 11 4 1
777
OCULAR COMPLICATIONS OF CHLOROQUINE the 3/330 white test objects. The fundus examina tion showed only bilateral breaking up of the fo veal light reflex, with peripheral arteriolar nar rowing but no "bulls-eye" macular configuration. Six weeks later the examination was essentially the same. Six weeks after this, however, a definite and consistent pericentral ring scotoma of the right eye appeared inside the central five degrees with the 1/1,000 white test object (fig. 1). There was no regression of visual acuity or change in HRR-Farnsworth testing. The fundi showed slight increase in macular pigment clumping and arterio lar narrowing. The diagnosis of chloroquine retin opathy was made and the drug was discontinued. Five weeks later, visual acuity was 20/20 — 2 in each eye and on H R R testing at this time the patient missed only the first two plates with the right eye and the first plate with the left eye, a marked improvement over previous examinations. The pericentral field defect of the right eye disap peared to the 1/1,000 white test object and only an inconstant superonasal fragment remained to the 1/2,000 white object (fig. 2 ) . Although there was still some breaking up of the foveal reflex in each eye, less macular pigment appeared to be present than on the previous examination.
On reviewing the literature w e find this to be the first reported case in which chloro quine retinopathy has been demonstrated to develop while the patient was under observa tion, thus providing an unique opportunity to evaluate early diagnosis and prognosis. W e found that the combined H R R - F a r n s w o r t h testing worked very well in anticipating our
3W/330 Coi^eration - ö o o d Reliability-Fair Fixation — Qood V A S c OD 15/20-1
LK.
8-Ζ4-β3
-IW/1000 3W/1000 (OS)
Fig. 1 (Nozik, Weinstock and Vignos). Fields for L. K. on August 24, 1963.
Cooperíáioa - Good Kálkbiüty
- (rood
LK. 10-5-63
nxatlon - öood YASc 03
2Ό/Ζ0-Ζ ZO/ZO-Z
IW/ZOOO
Fig. 2 (Nozik, Weinstock and Vignos). Fields for L. K. on October S, 1963.
patient's retinopathy, since the test showed abnormal findings before definite visual field or fundus changes occurred. It seems reason able, therefore, to suggest that patients w h o are to be started on chloroquine be given a complete ophthalmologic examination and, perhaps, yearly follow-up examinations. T h e internist could use the H R R test as part o f his routine monthly o r six-week checkup and, if any abnormality develops, refer the patient to the ophthalmologist. It is also interesting and encouraging to note the regression o f the visual field and H R R defects after their early detection and the subsequent discontinuation o f chloro quine ; this is in contrast to the majority o f cases in the literature in which the retino pathy usually continued to progress. These cases, however, were more advanced than the one just presented. T h e total dosage o f chloroquine received by the one patient with a positive case o f retinopathy was 525 g m . over a period o f 70 months. In comparison with the other cases in our series this was about t w o and one-half times the average total dose o f 208 gm. received b y the other patients in our series and the duration o f treatment was about two and one-half times longer than the series average o f 29 months. One additional case o f chloroquine retino pathy not included in o u r series has been seen. This patient received a total o f 404 gm.
778
R O B E R T Α. Ν Ο Ζ Ι Κ , F R A N K J. W E I N S T O C K , A N D P A U L J. V I G N O S , JR.
o f chloroquine over a period o f 20 months, with an average daily dose o f 660 mg. W h i l e
SUMMARY i
^
series of 50 patients on chloroquine
the length o f treatment was relatively short,
treatment were
the
plications due
total dose was high when compared to
the average o f our series.
examined
for
ocular
com-
to this drug. T h e r e were no
casts o f corneal complications. O n l y one case
Both o f these cases support the suggestion
showed
retinopathy.
jgtered over
period o f
time. These
results suggest that the use o f
low-dosages
in
(an
which
average
dosage total dose
details of
were
540
gm.
with 43 months as the average total duration of
therapy
and
the
average
daily
dose
420mg.).i.3-=-'-i« incidence
can
be
drawn,
more and
larger
admin-
^he drug, as in most o f the patients o f this series, contributed to the
l o w incidence o f
ocular side-effects. 2. Very
early chloroquine retinopathy is
reversible if the drug is discontinued. 3. T h e
Before definite conclusions as to the true
a long
was
a
thy. T h e y also agree with the time-dosage reliterature
chloroquine
individual
dosage relationship in chloroquine retinopa-
given
of
this
j^rge
lationship found in 37 positive cases in the
amount
In
o f some authors that there is a direct time-
H R R test is recommended as
a
simple screening test f o r early detection o f chloroquine retinopathy,
series must be studied, using consistent, welldefined criteria f o r positive
findings.
University
Hospitals(6).
REFERENCES 1. Hobbs, H. E., Eadie, S. P., and Somerville, F.: Ocular lesions after treatment with chloroquine. Brit. J. Ophth., 45 :284-297, 1961. 2. Abels, D. J., O'Keefe, T. N., Smith, D., Gutow, R., Falls, H. F., and Duff, I. F.: Antimalarials and their ocular complications. Arthritis and Rheumatism, 6:258, 1963. 3. Henkind, P., and Rothfield, N. F.: Ocular abnormalities in patients treated with synthetic antimalarial drugs. New England J. Med., 269 :433-439, 1963. 4. Hobbs, H. E., Sorsby, Α., and Freedman, A . : Retinopathy following chloroquine therapy. Lancet, 277:478-480, 1959. 5. Okun, E., Gouras, P., Bernstein, H., and Von Sallmann, L . : Chloroquine retinopathy: A report of eight cases with ERG and dark-adaptation findings. A M A Arch. Ophth., 69:59-71, 1963. 6. Steimholtz, R., and Kearns, T . : H - R - R pseudoisochromatic plates; As a diagnostic aid in retro bulbar neuritis of multiple sclerosis. Am. J. Ophth., 41:833-837, 1956. 7. Ellsworth, R. T., and Zeller, R. W . : Chloroquine (Aralen) induced retinal damage. A M A Arch. Ophth., 66 :269-272, 1961. 8. Fuld, Η . : Retinopathy following chloroquine therapy. Lancet, 2:617-618, 1959. 9. Mayer, W . : Chloroquine retinopathy. Am. J. Ophth., 53 -.769-774, 1962. 10. Penner, R., and Somers, K . : Bilateral macular degeneration associated with chloroquine therapy. Am. J. Med., 54:381-385, 1962. 11. Richards, R. D., and Wilson, W . R . : Retinopathy associated with chloroquine phosphate therapy. Am. J. Med., 31:140-143, 1961. 12. Sachs, D. D., Hogan, Μ. J., and Engleman, E. P.: Chorioretinopathy induced by chronic administra tion of chloroquine phosphate. Arthritis and Rheumatism, 5:318-319, 1962. 13. Sataline, L. R., and Farmer, H . : Impaired vision after prolonged chloroquine therapy. New Eng land J. Med., 266:346-347, 1962. 14. Smith, J. L . : Chloroquine macular degeneration. A M A Arch. Ophth., 68:186-190, 1962. 15. Sternberg, T. H., and Laden, E . : Discoid lupus eryhthematosus: Bilateral macular degeneration due to chloroquine. Arch. Dermat & Syph., 79:116-118, 1959. 16. Wilson, W . : Retinopathy during chloroquine therapy. Brit. J. Ophth., 45:756-758, 1961.