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Ocular chrysiasis correlated with gold concentrations in the crystalline lens during chrysotherapy.

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704
OCULAR CHRYSIASIS CORRELATED
WITH GOLD CONCENTRATIONS IN
THE CRYSTALLINE LENS DURING
CHRYSOTHERAPY
NORMAN L. GOTTLIEB and JAMES C . MAJOR
The eyes of 11 patients with rheumatoid arthritis
(RA) who received extended chrysotherapy (mean cumulative dose greater than 7 grams during a mean 6-year
period) were examined biomicroscopically. Minute reddish-purple particles were seen in the cornea (corneal
chrysiasis) in 5 and in the lens (lens chrysiasis) in 4
patients. Particulate deposits were absent in 11 other RA
patients who had not received gold treatment. Seven crystalline lenses from 5 gold-treated patients were removed
surgically because of incidental cataract formation and
analyzed for gold content using neutron activation analysis. Although the mean lens gold concentration was higher
in these patients than in non-gold-treated controls without
RA (0.0073 pg/grams versus 0.001 pg/grams), the absolute gold level was markedly lower than that found in 25
diverse tissues analyzed previously. This finding is compatible with the absence of clinical gold-related lens disease or visual impairment.
From the Arthritis Division, Department of Medicine, and
the Department of Ophthalmology, University of Miami School of
Medicine, Miami, Florida.
Supported in part by a training grant in arthritis and rheumatic diseases (NIH-AM05058). the Dade County Division of the
Arthritis Foundation, and the Oritt, Greenberg and Applebaum
funds.
Norman L. Gottlieb, MD.: Associate Professor of Medicine;
James C. Major, M.D.: Clinical Associate Professor of Ophthalmology.
Address reprint requests to Norman L. Gottlieb. M.D., Arthritis Division, PO Box 520875, Miami, Florida 33152.
Submitted for publication December 19, 1977; accepted in
revised form March 13, 1978.
Arthritis and Rheumatism, Vol. 21, No. 6 (July-August 1978)
Ocular findings associated with chrysotherapy
for rheumatoid arthritis (RA) and other disorders include corneal chrysiasis (1-4), and rarely blepharitis,
conjunctivitis, iritis, and marginal ulcerative keratitis
( I ) . Corneal chrysiasis, documented in 40% of 40 goldtreated RA patients in one series ( 5 ) , is demonstrated by
biomicroscopic examination and consists of numerous,
minute, yellowish-brown to violet glistening gold deposits, which are distributed irregularly throughout the
cornea at various depths and do not cause visual disturbance or other symptomatology. Gold also has been
identified in the bulbar conjuctiva and adherent to the
anterior lens capsule ( 6 ) .
To further define ocular changes possibly related
to gold, the eyes of 22 RA patients were examined by
slit-lamp microscopy. Eleven patients had received protracted chrysotherapy consisting of an initial course followed by maintenance treatment; the other 1 1 patients
had never received gold treatment. Subtle findings in the
crystalline lens, similar to those noted with corneal chrysiasis, were observed in several gold-treated patients, but
not in non-gold-treated subjects. These changes, not
previously described in association with chrysotherapy,
suggested that gold was deposited in the lens, as well as
in the cornea. To quantitate the magnitude of gold
deposition 7 crystalline lenses, obtained from 5 goldtreated RA patients who subsequently underwent cataract extraction, were analyzed for gold content using
neutron activation analysis. Results were compared to
lens gold concentrations in 3 non-RA patients who had
not received gold therapy.
705
OCULAR CHRYSIASIS
MATERIALS AND METHODS
Twenty-two patients with definite or classic RA according to the American Rheumatism Association criteria (7),
1 1 of whom received extended courses of chrysotherapy, underwent detailed ocular examination by an ophthalmologist.
Patients who were under the care of the author (NLG) and
who consented t o ophthalmoscopic examination were selected
for study if they had never received gold treatment, or if they
had received greater than 1.5 grams of gold compound. Patients in G r o u p l (Table l ; Lens Extracted) had one or more
visual symptoms (e.g. blurring of vision, loss of visual acuity);
subjects in Group 2 (Lens Intact) had no ocular symptoms.
The cornea and crystalline lens were carefully studied for
evidence of chrysiasis or other abnormalities, by use of a Zeiss
100-16 or Haag-Steit 900 biomicroscope. Non-gold-treated
RA patients had a mean age of 46 years (range: 26 to 67 years)
and a mean disease duration of 6 years (range: 0.5 to 18 years).
Nine patients were female, and all but 2 were Caucasian.
Pertinent characteristics of the gold-treated population and
chrysotherapy history are shown in Table 1. All patients received a minimum cumulative dose of 1500 mg of gold compound, the mean total dose being 7087 mg. Seven patients
were given aurothioglucose (Solganal), 2 (AB, C J ) aurothiomalate (Myochrysine), and 2 (EW, S K ) both compounds.
Seven crystalline lenses subsequently were extracted
from 5 of the above gold-treated patients (Table 1) because of
severe progressive visual impairment due to cataract forrnation. Lens extraction was performed in an operating room
during hospitalization, using standard surgical techniques and
a cryoprobe to lift the intact lens from the globe. The lenses
were placed immediately into acid-washed, preweighed 0.9 ml
volume polyethylene container capsules, which were sealed
and weighed with a Mettler balance. Capsules with enclosed
contents were placed in sterile glass containers and stored at
room temperature prior to gold analysis.
For purpose of control the lenses from 3 additional
patients without R A or a history of chrysotherapy, who suffered severe visual loss from cataracts, were analyzed for gold
content. This group consisted of 2 women and 1 man (DB),
whose ages were 69, 71, and 83 years, one of whom had
diverticulitis and hypertension (MP) and another diabetes
mellitus, hypertension, and arteriosclerotic heart disease (RW)
(Table 2). Lens specimens from these patients were handled as
described above.
To monitor extraneous contamination, two empty
container capsules were irradiated simultaneously. The gold
content of the blanks was 0.00005 and 0.0002 pg/specimen.
This compared favorably with earlier assays of 50 empty capsules (X f 1 SD = 0.0003 f 0.0003 Mg Au) (8). The mean
empty capsule gold content was subtracted from the lens gold
content before determining the gold concentration (Table 2).
To provide a baseline for comparison with tissue gold
levels reported previously (9-1 1) two ashed fecal specimens
with known gold concentration were also analyzed. Mean gold
content was 2.9 pg A d g r a m , slightly less than that obtained
when 41 aliquots were analyzed (2 1 SD = 4.6 f 0.5 pg Au/
gram) (12).
The gold concentration in the specified specimens was
measured using neutron activation analysis at Union Carbide
Corporation, Tuxedo, New York. All samples were irradiated
at the 0.5 ng sensitivity level. The coefficient of variation for
gold measurements was approximately 10% (12).
+
Table 1. Selected Clinical Characteristics of Gold-Treated Rheumatoid Arthritis Patients
Age
(Years)
Patients
I -Lens Extracted
AB
44
DM
56
ES*
70
EW*
69
CD
71
2-Lens Inlac1
DB
CJ
KD
AS
SK
GD
* Bilateral
t NA
48
71
34
59
34
66
lens extraction.
= not applicable.
Sex
M
M
F
F
M
F
F
F
F
F
M
Interval
between
Duration of
Last Gold
ChrysoCumulative Mean Gold Injection and
Duration of
RA
therapy
Gold Dose Dose/Year Lens Removal
(Years)
(Years)
(ms)
(mg)
(Weeks)
7
7
15
I2
20
17
7
10
12
7
7
6
0.6
5
6
13
4180
1995
9695
4450
10305
691
3325
1939
142
793
5
2
8
10
5
5
4735
I500
14410
15295
5060
6335
941
150
1801
I529
1010
1261
< I
146
161
1
I
NAt
NA
NA
NA
NA
NA
Gold Dose
(mg) X
Frequency
(Weeks)
50X 2
50-100x1
50X I
25X I
50X 2
50 X 3
50X 2
IOOX 4
50X I
50 X 2
50 X 2
Chrysiasis
Cornea
Lens
Lens
Cornea, Lens
Cornea
Cornea, Lens
Cornea
7 06
GOTTLIEB AND MAJOR
Table 2. Gold Concentrations in the Crystalline Lens of Controls and Rheumatoid Arthritis Patients
Given Chrysotherapy
Patient
Eye
Lens Weight
(ms)
Gold Content/
Specimen ( p g )
Gold Concentration
(&gram)*
I -Gold Treated
AB
DM
R
I78
244
217
228
153
159
260
0.0007
0.000I
0.004
0.003
0.0008
0.0004
0.003
0.0033
0
0.0179
0.0127
0.0045
0.0018
0.011 I
274
233
226
0.0002
0.0002
0.0003
0.0004
0.0022
ES
R
R
EW
L
R
L
CD
R
2-Non-Gold
DB
Treated Controls
MP
RW
L
R
L
0.0006
* Gold content of empty capsules (i = 0.0001 pg Au) subtracted from gold content of lens specimen
before gold concentration calculated.
RESULTS
Biomicroscopic corneal and lens examination
showed normal results in the 11 non-gold-treated RA
patients but trichiasis and early posterior subcapsular
cataracts were found in one patient each. N o deposits
suggestive of gold particles were observed in the corneas
or lenses. Results in the 1 1 gold-treated patients are
listed in Table 3. The corneas of five (ES, KD, AS, SK,
G D ) contained deposits compatible with gold particles.
The deposits were noted diffusely throughout the
cornea, with a preponderance posteriorly, near Descement’s level. Patients with corneal chrysiasis had more
than twice the mean cumulative gold dose than patients
without corneal gold (10,159 versus 4,528 mg; Table I ) ,
although overlap in total dosage was evident. The time
interval between cessation of treatment and slit-lamp
examination apparently was not the determinant of
corneal chrysiasis; one patient (ES) with corneal gold
had not received chrysotherapy in 3 years, whereas four
others were currently receiving various dosage schedules.
Gold deposits in the lens were seen in 4 patients
(CD, CJ, KD, SK; Table 3). The particles were of similar size, but were less numerous than in the cornea, and
therefore more difficult to define. No positive correlation between gold dose or interval since last gold injection and the presence of lens chrysiasis was observed.
Unexpectedly, there was no significant association between corneal chrysiasis and lens chrysiasis. Only
2 (KD, SK) of the 5 patients with corneal chrysiasis had
lens gold, and lens gold was found in 2 patients (CD,
CJ) without corneal chrysiasis.
There was no evidence that the presence of gold
particles in either the cornea or lens reduced visual
acuity. The best corrected vision was 20/25 or better in
all gold-treated patients with the following exceptions:
a ) one patient’s (CD) best corrected vision was 20/30
(right eye) and 20/40 (left eye); cataractous changes of
the right eye, and cystoid macular edema of the left eye
accounted for the visual loss; b) 2 other patients (EW
and CJ) had 20/30 (right eye) and 20/40 (left eye)
vision, due to cataract formation, and EW did not have
corneal or lens chrysiasis. Furthermore, there did not
appear to be an association between lens chrysiasis and
cataract formation (Table 1). Only one (CD) of 5 patients requiring cataract extraction had lens chrysiasis,
while 3 (CJ, KD, S K ) of the remaining 6 patients with
clear lenses had lens chrysiasis.
The lens gold concentrations in gold-treated RA
and in non-RA control patients are shown in Table 2.
The mean lens gold level was approximately seven times
higher in gold-treated patients (X = 0.0073 pg/gram)
than in control subjects X = 0.001 pg/gram), although
the difference was not statistically significant (P = 0.2),
using the Wilcoxon two-sample rank test. Furthermore,
the total lens gold content was negligible in both patient
groups, and 2 gold-treated patients (DM, EW [L]) had
lower values than one control (RW). Of the 5 patients
whose lens gold content was measured, only one (ES)
had corneal chrysiasis and one (CD) lens chrysiasis, as
determined biomicroscopically.
707
OCULAR CHRYSIASIS
Table 3. Biomicroscopic Findings in Gold-Treated Rheumatoid Arthritis Patients
Patient
AB
DM
ES
EW
CD
Interval
between
Last Gold
Injection and
Biomicroscopy
(Weeks)
< I
104
I56
1
<I
DB
CJ
3
78
KD
4
AS
1
SK
<I
GD
< I
* PSCC
=
Cornea
Lens
No gold
No gold
Dark purplish-red dusting at Descemet’s level
No gold; fingerprint dystrophy anteriorly
No gold; anterior crocodile shagreen
No gold
No gold
Minute iridescent particles in the central anterior stroma
near Bowman’s membrane; fine brick-red to reddishpurple nonluminescent particles at Descemet’s level
deposited centrally and diffusely
Minute iridescent particles in the central anterior stroma
near Bowman’s membrane; several less iridescent
particles in deeper stroma; diffuse layer of fine reddish
particles at Descemet’s level, concentrated peripherally
Fine dark purplish-red particles homogeneously deposited at Descemet’s level; a few similar deposits
anteriorly
Trace of dark-purplish dusting at Descemet’s level
PSCC’; early nuclear sclerosis; no gold
PSCC; no gold
PSCC; no gold
PSCC; no gold
PSCC; nuclear sclerosis; traces ofgold deposits in
anterior capsule of both lenses-greater on the left
No gold
PSCC; nuclear sclerosis; minute traces ofgold in anterior
suture lines of both lenses
Minute reddish-brown deposits in a stellate configuration, perhaps outlining the suture lines (ends of
individual lens fibers), which were subcapsular,
anterior and central
No gold
Polychromatic deposits in central subcapsular region
PSCC; no gold
Posterior subcapsular cataracts.
DISCUSSION
Gold particles were deposited in the corneas of
45% of this select group of patients who received pro-
tracted chrysotherapy for RA, as determined by biomicroscopy. These results confirm the work of Hashimoto
et al. (5) and others (13) who found corneal chrysiasis in
the majority of patients who received greater than 1.5
grams of gold compound. The slightly lower prevalence
of corneal gold in this study was not a consequence of
lower cumulative doses than those used in earlier studies, but may reflect cessation of treatment (3 cases) or
longer intervals between gold injections. Although corneal deposits reportedly (5) disappear within 3 to 5
months after discontinuation of chrysotherapy, deposits
compatible with gold were found at Descemet’s level in
one of our patients (ES) 3 years after termination of
treatment. This finding is in concert with the observation that superficial crystalline deposits regress within 2
months of cessation of therapy, whereas deeper deposits
may persist for many years (3).
Lens chrysiasis has not been reported previously,
although a few gold particles adherent to the anterior
lens capsule were noted in a single case report (6). The
prevalence of lens chrysiasis in this study was 36%.
However, because patients were selected on the basis of
having received protracted chrysotherapy, the frequency
of this finding in the general gold-treated population
remains to be determined. Others (1,3,5) investigating
the ocular deposition of gold have not observed this
phenomenon. Perhaps the relatively small number of
gold particles in the lens compared to the cornea, or the
relatively large cumulative gold doses these patients received, accounts for this discrepancy.
Despite the high cumulative gold doses administered, only miniscule quantities of gold were present in
the crystalline lens, when a sensitive technique of measurement was used. The highest gold concentration approached 0.02 pg/gram, a level many times below that
found in approximately 25 other human tissues analyzed
previously (9-1 l ) , including hair and nails (8). Perhaps
the low lens gold content is a function of the avascularity of this tissue or results from a paucity of as yet
undefined gold-binding sites. T o our knowledge ocular
GOTTLIEB AND MAJOR
708
studies of a similar nature have not been reported previously.
Corneal chrysiasis did not adversely affect visual
acuity, a finding in concert with other studies (1,5).
Similarly, lens chrysiasis did not appear to cause visual
disturbance. Although not specifically addressed in the
literature, chrysotherapy is not thought to be associated
with cataract formation. Our findings, in a small number of patients who received large cumulative gold
doses, did not define a positive correlation between lens
chrysiasis and cataracts. This preliminary observation
should be confirmed in a larger series of patients.
Perhaps the lens particles identified as gold
biomicroscopically are in fact some other substance.
This possibility cannot be ruled out entirely using the
present methodology, but could be resolved with electron probe x-ray analysis (14), a technique unfortunately not at our disposal. However, such particles were
not seen in non-gold-treated RA patients, the appearance of the lens and corneal particles was identical, and
similar particles in the conjunctiva have been identified
as gold by histochemical staining techniques ( 6 ) . The
quantitation of gold in the lens, cornea, or other components of the eye is not available in the literature. The
exceedingly low lens gold levels, coupled with the absence of visual field loss, reassure the clinician that this
structure is not likely to be adversely affected even with
prolonged chrysotherapy.
REFERENCES
1. Grant WM: Toxicology of the Eye. Second Edition.
Springfield, Illinois, Charles C Thomas, 1974, pp 530-533
2. Freyberg RA, Ziff M, Baum J: Gold therapy for rheumatoid arthritis. Arthritis and Allied Conditions. Edited by
J L Hollander, DJ McCarty. Eighth Edition. Philadelphia,
Lea & Febiger, 1972, pp 455-482
3. Thomas CI: The Cornea. Springfield, Illinois, Charles C
Thomas, 1955, pp 830-833
4. Berliner ML: Biomicroscopy of the Eye. Vol. I . New
York, Paul B. Hoeber, 1949, p. 387
5. Hashimoto A, Maeda Y, Ito H, Okazaki M, Hara T:
Corneal chrysiasis-a clinical study in rheumatoid arthritis patients receiving gold therapy. Arthritis Rheum
15:309-312, 1972
6. Roberts WH, Wolter JR: Ocular chrysiasis. Arch Ophthalmol 56:48-52, 1956
7. Ropes MW, Bennett GS, Cobb S, Jacox R, Jessar R: 1958
revision of diagnostic criteria for rheumatoid arthritis.
Bull Rheum Dis 9:175-176, 1958
8. Gottlieb NL, Smith PM, Penneys NS, Smith EM: Gold
concentrations in hair, nail and skin during chrysotherapy. Arthritis Rheum 17:56-62, 1974
9. Gottlieb NL, Smith PM, Smith EM: Tissue gold concentration in a rheumatoid arthritic receiving chrysotherapy.
Arthritis Rheum 15:16-22, 1972
10. Gottlieb N L , Smith PM, Smith EM: Gold excretion correlated with clinical course during chrysotherapy in rheumatoid arthritis. Arthritis Rheum 15:582-592, 1972
11. Gottlieb NL, Smith PM, Smith EM: Pharmacodynamics
of lelAu and lssAu labeled aurothiomalate in blood. Arthritis Rheum 17:171-183, 1974
12. Smith E M , Smith PM, Gottlieb NL: Verification of the
biological properties of Au- I95 labeled gold sodium
thiomalate by activation analysis. J Nucl Biol Med 19:3235, 1975
13. Rodenhauser JH, Behrend T: Art und Haufigkeit der Augenbeteilgung nach parenteraler Goldtherapie. DTSH
Med Wochenschr 94:2389, 1969
14. Ghadially FN, Oryschak AF, Mitchell DM: Ultrastructural changes produced in rheumatoid synovial membrane
by chrysotherapy. Ann Rheum Dis 35:67-72, 1976
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