OCULAR MANIFESTATIONS OF THYROID

DISEASE: CURRENT CONCEPTS

BY Rober-t M. Day, M.D.

THIS S1hUDY was undertaken in an attempt to clarify some of the

problems which have arisen from the marked variability in the ocular
changes associated with thyroid dysfunction. The ocular signs may
be abrupt or insidious in onset, mild or severe, unilateral or bilateral,
more advanced about one eye than the other. They may appear long
before any evidence of thyrotoxicosis, with the onset of thyroid
dysfunction, or following its treatment. In addition, the pathogenesis
of these ocular signs is poorly understood, and there is no agreement
as to whether they represent one or two disease processes. A clearer
understanding of their nature is not only of academic interest, but also
of practical importance, for the clinician often has difficulty in in-
terpreting the significance of these ocular findings. This report is
divided into two portions: the first from the laboratory and the second
from the clinic. Both parts, however, have a similar purpose-to pro-
mote a better understanding of the orbital process which occurs in
association with thyroid disease.

PATHOGENESIS
Signs about the eyes have been recognized as part of the picture of
hyperthyroidism since the disease was first described as a clinical
entity over one hundred years ago (1, 2, 3, 4). Both changes in the lids
and exophthalmos have been observed, but a differentiation between
lid retraction and proptosis has often not been properly made. Many
thoughts concerning their pathogenesis have been proposed, and the
outstanding theories may be discussed under three main headings:
SMOOTH MUSCLE OVERACTION AND STRIATE MUSCLE UNDERACGION
Following Claude Bernard's (5) classic experiment in 1852, in which
lid retraction and exophthalmos in dogs were produced by stimulating
the cervical sympathetic nerves, sympathetic overactivity has been
TR. Amr. OPHTH. Soc., vol. 57, 1959
 Ocular Alan ifestations of Thlyriyoid Disease557;31
widely upheld as the cause of both the lid signs and exophtlhalmos.
Arguments in favor of this theory are: (a) increase in circulating
thyroxine, which occurs in thyrotoxicosis, is known to potentiate the
action of circulating epinephrine (6, 7), as well as to produce a
generalized myasthenia (8, 9); (b) weakness of the ocular recti
muscles in hyperthyroidism has been demonstrated by Wilson (10)
and others (11); and (c) contraction of orbital smooth muscle,
secondary to a relative sympathetic overaction, is believed to result
in lid retraction and exophthalmos. The latter is thought to be en-
hanced by loss of tone in the recti muscles. Hovever, there are certain
strong objections to this hypothesis. Suclh a theory demands the
demonstration of smooth muscle in the human orbit capable of these
effects, and such an anatomic demonstration has not been made. After
repeated dissections in man, Moore (12) and Whitnall (13) were able
to find only vestigial remnants of Muller's orbital smooth muscle in the
region of the inferior orbital fissure. Landstrom's muscle, which was
originally described as a cylindrical band of fibers running from the
septum orbitale to the equatorial region of the globe, is also rudi-
mentary in humans, and Whitnall and Beattie (14) felt that it did little
more than move the conjunctiva during horizontal movements of the
eye. It is, therefore, not surprising that Pochin (15) and Friedgood
(16) were unable to demonstrate a significant proptosis by stimulating
human cervical sympathetic nerves. Undoubtedly for the same reason,
Wagener (17) was able to demonstrate enophthalmos in only one of a
series of 94 cases of clinical Horner's syndrome. Although there is
some difference of opinion as to whether the lower lid is raised or
lowered in hyperthyroidism (18, 19), lid retraction is primarily con-
fined to the upper lid, and Pochin (15, 20) has shown that cervical
sympathetic stimulation in man results in a definite retraction of both
lids. Pupillary abnormalities, which should be expected in a state of
sympaticotonia, are conspicuously absent. Furthermore, upper lid re-
traction and exophthalmos are often much more marked in one eye
than the other (21), an unlikely result of generalized sympathetic
overactivity. Retraction of the upper lid tends to decrease following
control of the hyperthyroidism, but it may persist for many months
after re-establishment of the euthyroid state. This is a strong argument
against the view that the lid signs are secondary to a sympathicotonia
resulting from thyrotoxicosis. From these facts it may be concluded
that although the sympathetic nervous system may contribute to the
production of upper lid retraction and lid lag, it does not play a
primary role in the pathogenesis of exophthalmos.
574 Rober t M. Day
ALTERATIONS IN ORBITAL TISSUE

Numerous reports of the gross and microscopic pathologic changes

associated with thyroid ophthalmopathy have appeared in the litera-
ture. However, for a variety of reasons the complete picture has never
been adequately formulated. As a rule only the most severe cases
have been studied, and these studies have often been limited to
biopsy material. In addition, no one observer has been able to obtain
sufficient material to correlate the various degrees of clinical involve-
ment with the pathologic changes within the orbit.
Friedenwald (22) reported five cases of hyperthyroidism, pre-
sumably without eye signs, in which the extraocular muscles were
completely normal. Mulvaney (23), on the other hand, feels that there
is a pathologic picture characteristic of "thyrotoxic" exophthalmos.
The extraocular muscles are thin and pale, and their fibers show loss
of striation with fibrillation and fatty degeneration. The terminal nerve
fibers also undergo degeneration, the fat cells are increased in number,
and there is little evidence of round cell infiltration.
The reported descriptions (23, 24, 25, 26, 27, 28, 29, 30) of the
changes in the more severe forms of the disease process have shown
general agreement. The extraocular muscles are increased three to six
times in size, and at first appear pale and edematous, later becoming
fibrous and gritty. Histologically, the muscle fibers swell with a loss of
striation and become frayed. Interstitial edema appears and there is
proliferation and aggregation of round cells, most marked about
blood vessels. In the late stages the fibrils condense into dense scar
tissue. All of the retrobulbar orbital tissues, including the lacrimal
gland (31), are affected.
Various degrees of involvement of the orbital tissues may occur, and
the appearance of cellular infiltration in both the mild and severe
forms of the disease suggests that a common factor is responsible.
However, as Smelser (32, p. 474) has indicated, too few studies have
been made on the "mixed" types seen clinically to state that only one
disease process is operative.
Quantitative examinations by Rundle (27, 28, 33) and his co-workers
have shown that the microscopic appearance of the orbital tissues may
be misleading. Their studies of thyrotoxic patients with or without
eye signs indicate an increase in the orbital tissue weight as compared
with normal controls. This increase, 70 percent of which occurs in the
nonmuscle tissue, is primarily fat. On the other hand, in severe
exophthalmos the marked growth in orbital tissue bulk results solely
 Oculatr Manifestations of Thyr oid Disease 575
from enlargement of the muscles, where the water and dry fat-free
component may be 400 percent greater than normal. The bulk of the
nonmuscle tissue is not changed. The increase in the water content of
the muscles is proportional to the increase in the bulk of the muscle,
suggesting that the greater water content in the muscles is relative
rather than absolute. This occurs despite the histologic appearance of
frank edema. These authors interpreted their findings as indicating
two disease processes, but their results do not preclude the possibility
that the two sets of data represent extremes of the same disease
process.
The increase in water content is limited mainly to the orbital tissues
(34, 35, 36), and Rose (37, 38) has suggested that it may result from
a specific tissue hypersensitivity. Anatomic studies (13) and determina-
tion of the removal rate of radiosodium (39) have revealed no evidence
of venous obstruction as a possible cause of the edema. An increase
in the water-binding properties of the retrobulbar tissues in exophthal-
mos has been known for some time and the recent studies of Asboe-
Hansen and his co-workers have helped to explain this phenomenon.
On the basis of observations that mast cell granules stain like hya-
luronic acid and that mast cells are increased where an increase in
hyaluronic acid can be shown, they postulate that the mast cells
produce hyaluronic acid (40). Both the mast cells and hyaluronic
acid have been shown to be increased in experimental exophthalmos
in guinea pigs (41, 42). Inasmuch as the retrobulbar connective
tissue in humans with severe exophthalmos shows similar changes,
Wegelius (43) has suggested that replacement of the orbital fat by a
strongly water-binding connective tissue results in a mucinous edema,
increased intraorbital pressure, and exophthalmos. Such a course of
events would also explain the fullness of the lids and chemosis which
is seen clinically. Fibrosis, particularly of the extraocular muscles,
results in limitation of ocular motility and may account for the per-
sistence of exophthalmos after the acute edematous process has sub-
sided (25, 44, 45). However, all these findings fail to explain the
fundamental cause for these phenomena.
ENDOCRINE FACTORS
Only two years after Loeb and Bassett (46) identified the thyroid-
stimulating hormone (TSH) of the anterior pituitary gland, Schockaert
(47) produced exophthalmos in young ducks with adenohypophyseal
extracts. Since that time pituitary preparations rich in TSH have been
employed to produce experimental proptosis, most notably in the
576 Robert M. Day
guinea pig (41, 44, 48, 49, 50, 51). As Smelser (29) has demonstrated,
the orbital changes in these animals bear a great similarity to those
occurring in the severer forms of exophthalmos in man. Predominantly
by enlargement of fat and muscle, the orbital contents of the guinea
pig are increased 34 percent in weight. Edema occurs throughout the
orbits, and there is an invasion of lymphocytes which are often found
clumped together. This experimental exophthalmos persists during
anesthesia, after cervical sympathectomy, and even after death (52).
These experimental findings strongly suggest that the thyrotropic
hormone may play an important role in the production of the orbital
changes associated with thyroid disease. It is believed that the pituitary
and thyroid glands are related cybernetically. Purves and Griesbach
(53) have shown that as the level of thyroxine falls there is an in-
crease in TSH secretion until the thyroid hormone level rises, and
this in turn suppresses the release of TSH. In addition, Dobyns and
Rawson (54) demonstrated that both the proptotic and the thryroid-
stimulating effects of anterior pituitary gland extracts are lost after
they are incubated with thyroid tissue. Experimental guinea pig
exophthalmos, induceoI by TSH, tends to be inhibited by thyroid
hormone (55) and iLs intensified by thyroidectomy (41, 50, 52, 55).
According to this line of reasoning, it is not surprising that human
exophthalmos is most frequently encountered after the treatment of
thyrotoxicosis (56, 57), whether by surgery, antithyroid drugs, or
irradiation.
The evidence that TSH is the cause of clinical exophthalmos, how-
ever, is not conclusive. The administration of TSH to humans is not
necessarily followed by exophthalmos (58), a fact which might be
explained by an intact thyroid gland. Although the methods of bio-
assay for TSH are not too reliable (53, 59, 60, 61), both high and low
serum levels have been found in severe exophthalmos. Furthermore,
high levels of TSH occur in hypothyroidism (53, 62) and yet
exophthalmos is rare in this condition. Finally, Means (63) and others
(36) agree that the administration of thyroid preparatiors have little
effect on the severe orbital changes in man.
Both the corticosteroids and the sex hormones have also been postu-
lated as factors in the production of the severe orbital process, but at
the present time there is no clear-cut evidence that they play a major
role (64).
More recently it has been suggested that another pituitary hormone
might be the causative agent (65). This hormone, whiich has been
called EPS or exophthalmos-producing substance, is closely related
 Octular Mfanifestations of Thyyroid Disease 5'77
to but distinct from TSH. Dobyns and Steelman (66) separated these
two hormones by their differential solubility in trichloracetic acid, and
found that the TSH but not the EPS fraction had a marked stimulating
effect uipon the thyroid of a day-old chick; while the EPS fraction, but
not the TSHI, produced a definite exophthalmos in Fundulus hetero-
clittus (Atlantic minnov or killifish). This experimental exophtlha'lmos
was the same as that produced in these fish by cruder TSH preparations
(67, 68, 69) where the orbits became edematous with some round cell
infiltration. Carrying these studies further, Dobyns and Wilson (70)
injected the serum of women with progressive exophthalmos in killifish
and felt that the resulting degree of increase in the intercorneal dis-
tance of the fish might be correlated with the stage and severity of the
patients' ocular picture. More recently, the common goldfish (Caras-
sius aturatus) has been claimed to respond to the injection of human
serum in a manner similar to the Atlantic minnow (71).

LABORATORY STUDY

The report that exophthalmos could be produced in the common

goldfish, as well as in the killifish, with the serum of patients with
thyroid ophthalmopathy was of great potential interest. As the prop-
tosis in the fish was said to correlate with the severity of the patient's
orbital changes, a laboratory method appeared to be available for
determining whether human exophthalmos represented one or two
disease processes. If there were two diseases, it seemed reasonable to
assume that there might be one group of patients whose sera would
be without effect and another group whose sera would produce
exophthalmos in fish. If one disease process were operative, one could
postulate a gradual shading of response from very mild to very severe.
In addition, it was hoped that this test might afford a method for
following the progress of a patient's ophthalmopathy. With these pur-
poses in mind, the following experiment was undertaken.
The goldfish was chosen for study because it is universally available
at all seasons of the year and is easy to maintain. The killifish, on the
other hand, has the disadvantage of being available only along the
coastline during the summer months.
MIETHOD
Specimens of Funtdulus heteroclitts, 7 to 10 eni. in length, vere
obtained from the Harlem River in Nev York City, and specimens of
Carassiis auiratuts, measuring 7 to 8 cm., wvere ptirchased at a local
578 Robert M. Day
pet shop. They were kept in a standard 20-gallon laboratory fislh tanlk.
Brackish water was employed for the killifish, whereas city tap water,
to which declorination tablets were added, was utilized for the gold-
fish. The water was changed twice weekly and was contintuously
aerated and filtered through glass wool and carbon by means of a
siplhon pump. The fislh were fed once daily with a commercial fisl
food containing chlortetracycline. Each fish was marked witlh colored
threa(ds passed through the lower lip and through the base of the dorsal
tail fin. Two threads were found advisable since a thread occasionally
became dislodged during the course of an experiment.
Mleasurements of intercorneal distance were made with the fish
placed in a standard, circular aquarium bowl (fingerbowl) measuring
115 mm. in diameter by 50 mm. in depth. The bowls were filled
approximately two-thirds with water and the fish were immobilized
by wedging strips of wet gauze on each side. The measurements were
made with a Boley gauge (micrometer), and were recorded to 0.1
mm., employing a vernier scale. The readings were made monocularly
with a loop, the caliper being above the surface of the water and the
fish's head below. A series of seven measurements was taken on each
occasion, and the mean of these readings was taken as the final
measurement.
In order to test the reliability of this method of mensuration, three
goldfish were measured over a three-week period, each fish receiving
0.25 c.c. of 0.45 percent salt solution three times daily for three days
eaclh week. On the first fish a series of 21 and on the other two a
series of 18 measurements were made. In the first instance, the readings
of intercorneal distance resulted in a mean of 15.1 mm. with a (r of
0.13, in the second a mean of 12.8 mm. with a o- of 0.14, and in the
third of 15.6 mm. with a u of 0.15. A zone of nonsignificance repre-
sented by mn ± 2.5 r gave a variation of single readings from the mean
of 2.2 percent, 2.7 percent, and 2.4 percent, respectively. Therefore,
any variation greater than 3 percent may be interpreted as significant.
This is in agreement with published statements that any increase
greater than 5 percent in intercorneal distance in fish represents true
exophthalmos (72, p. 163).
Injections were malde intraperitoneally through the dorsal vent with
a tuberculin svringe and a #27 gauge needle. These injections had to
be made with care. In evatluating the ability of the goldfish to witlh-
stand the injections and the handling three times a day, it was found
that three out of four fish were killed by careless insertion of the
needle.
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580 Robert Al. Day
TABLE 2. F UNDULUS HEROCLITUS E1XPERIMENTrS

TSH Armour 317-51-R

(0.25 mg. = 0. 25 c.c.) Saline 0. 4-5 %
Red Green Yellow Blue Orange White Black Brown Pink Purple
AMay6,I.958 11.7 11.7 13.8 11.0 11.4 12.7 14.4 11.3 11 .9 II .:3
11.9 11.4 13.8 11.0 11.4 12.8 14.4 11.1 12.0 11 .4
11.8 11.5 13.9 10.9 11.4 12.7 14.3 11.3 12.0 11.7
12.0 11.6 13.9 11.1 11.5 12.9 14.3 11.2 11.9 11.4
12.0 11.7 14.0 10.8 11.4 12.7 14.4 11.2 11.9 11.4
11.9 11.5 14.0 11.1 11.4 12.7 14.0 11.3 12.0 11.5
12.0 1]1.3 14.0 11.0 11.6 12.9 14.0 11.4 12.0 11. .3
Average 11.9 11.5 13.9 11.0 11.4 12.8 14.3 11.3 12.0 11.4

A.M. 10:20 10:30 10:40 10:55 11:05 11:15 11:25 11:35 11:45 11:55
Injection (c.c.) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25

A.M. 1:40 1:40 1:40 1:45 1:30 1:45 1:45 1:25 1:25 1:30
Injection (c.c.) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25

P.M. 3:50 3:55 4:00 4:05 4:10 4:15 4:25 4:20 4:30 4:35
12.4 12.1 14.0 12 .8 11.8 13.0 14.4 11.4 12.0 11.5
12.6 12.2 14.0 12.8 11 .7 13.0 14.1 11.3 12.3 11.7
12.4 12.2 14.4 12.7 11.9 12.8 14.0 11.4 12.1 11 .6
12.8 12.4 14.3 12.7 11.9 12.8 14.3 11.5 12.2 11.7
12.7 12.4 14.2 12.8 11.9 12.7 14.1 11.5 12.1 11.5
12.8 12.:3 14.3 12.7 11.8 12.7 14.1 11.8 12.3 11.8
12.7 12.:3 14.4 12.6 11.9 12.8 14.2 11.8 12.4 11 . 9
Average 12.6 12.3 14.2 12.7 11.8 12.8 14.2 11.5 12.2 1 1. 7

P.M. 3:55 4:00 4:05 4:10 4:15 4:20 4:30 4:25 4:35 4:40
Injection (c.c.) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25

A.M. 8:05 8:25 8:15 8:55 8:00 8:45 8:35 8:30 8:40 8:10
Mary 7,11958 12.5 11.6 14.6 12.2 12.2 12.6 14.0 11.0 12.4 11 .6
12.3 11.4 14.8 12.2 12.2 12.3 14.0 11.0 12.0 11 .9}
12.2 11.5 14.5 12.3 12.1 12.4 14.2 11.0 12.0 11.9
12.3 11.7 14.6 12.3 12.2 12.4 14.1 11.0 12.0 11.8
12.3 11.6 14.5 12.4 12.4 12.4 14.0 11.3 12.0 11.5
12.4 11.6 14.6 12.5 12.0 12.3 14.0 11.2 12.1 11 .7
12.5 11.5 14.6 12.5 12.2 12.3 14.2 11.1 12.3 11.6
.Avcrage 12.4 11.6 14.6 12.3 12.2 12.4 14.1 11.1 12.1 1 1.7

A%.M. 8:10 8:30 8:20 9:00 8:05 8:50 8:40 8:35 8:45 8:15
Injection (c.c.) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25
12:15 12:05 12:20 12:40 12:05 12:15 12:50 12:30 12:40 12:35
 Manlifestation.s of
Ocutlarl IhItyoi(l Disease 581
TABI.E 2 (coiitinnlle(l)

TSH A rmour 31 7-51-R

(0.25 mg. = 0.25 c.c.) Saline 0.45 %
Red Green Yellow Blute Orange White Black Brown Pink Purple
Injection (c.c.) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25) 0.25 0.25
P.M. 3:4() 3:45 4:00 3:55 3:35 4:20 4:10 4:25 4:3() 4:05
12.9 12.7 13.7 12.9 12.3 12.4 14.0 11.1 12.2 11.9
13.0 12.4 14.0 12. 7 12.1 12.4 14.3 11.2 12.0 11.4
13.0 12.7 13.7 12.9 12.1 12.3 14.3 11.3 12.1 11. 6
13.0 12.8 14.0 12.9 12.1 12.5 14.3 11.2 12.1 11.6
13.2 12.4 13.9 13.0 12.1 12.5 14.0 11.1 12.1 11.7
13.3 12.6 14.0 12.9 12.3 12.4 14.1 11.3 12.2 11.4
13.3 12.8 13.8 12.9 12.0 12.5 14.3 11.1 12.2 11.8
.\veragc 13.1 12.6 13.9 12.9 12.1 12.4 14.2 11.2 12.1 11.7
Resuilt. .\11 5 Fundulus heroclituts treated with TISH developed a sigit-iicanat exoph-
thtldmos; nionie of the 5 controls had a signiticant change.

Five different beef pituitary preparations were employed, each one

of whlichl was known to produce a definite exophthalmos in guinea
pigs (73). Each was also known to be rich in thyroid-stimulating
lhormone ( 73). The powdered preparations were dissolved in 0.45
percent saline. The one exception to this was the Beef Pituitary 58
(Omaha') which, being very rich in salt, was dissolved in distilled
water. The tri-iodo-thyronine was dissolved in 0.45 percent salt
solution made alkaline to pH 8 with sodium carbonate, while the
controls were injected with 0.45 percent saline.
Serum from patients was obtained by centrifuging the clotted blood
shortly after it was drawn. It was then frozen until used. Both patients
were women who had been treated for hyperthyroidism, the first by
thyroidectomy and the second by radioactive iodine. They were both
considered to be euthyroid, and both had the increasing symptoms of
tearing and lid swelling, as well as the signs of chemosis, extraocular
muscle involvement, and proptosis characteristic of the severe, ad-
vancing form of thyroid ophthalmopathy. Control serum was obtained
from patients with ocular disease, but no evidence of thyroid
dysfunction.
A series of preliminary injections was first made in the Fundulus
leteroclituts, in an attempt to confirm the validity of the experimental
*This extract was prepared by Dr. George K. Smelser according to the method
described by him (29), and the pituitary glands were obtained from the slaughter
lhouse of Armour and Company, Omaha, Nel.
582 Rober t Al. Day
metlhod employed. Thiree different Armouir thiyroid-stimulating hormone
preparations were utilized. The results are summ'arized in Table I,
and a representative protocol is given in Table 2. Nineteen (79 per-
cent) of 24 killifish injected developed a significant exophthalmos
within 24 hours, while no instance of proptosis was noted in the 15
controls (Figure 1).
Pilot experiments employing varying dosages of TSH as well as
varying number of injections were then undertaken in Carassitus
auratus. The minimum dosage employed was comparable to that
wlhich lhas been reported to give positive results in Funduluts lhetero-
clitus (66, 67). This was followed by a series of more definitive
experiments.

FICURE 1
..
Exophthalimic Ftundulus heteroclitus on the left receix ed injections of beef anterior
pitmiitary. Normal control on the right.

RESULTS
A total of 62 goldfish were injected, in addition to 17 controls.
(Tables 3 and 4) Of the 62, 45 received various TSH preparations,
three received serum from a hypothyroid patient, four were injected
with sertim from a thyrotoxic individu.il, six received serum from
patients with severe ophthailmopathy, and four received tri-iodo-
thyronine. Only five goldfish developed a significant exophthalmos.
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 Ocular Manifestationis of Thyroid Disease S8S
All five of these positive results were obtained with preparations of
Armour pituitary, and positive results occurred with all three Armour
extracts employed. No exophthalmos resulted from the administration
of hypothyroid or hyperthyroid human serum. Tri-iodo-thyronine also
failed to produce any proptosis, as did the sera from the two patients
with acute, active advancing ophthalmopathy.
DISCUSSION

In all the biologic sciences it is less difficult to propose an explana-

tion for an observed phenomenon than it is to explain why some
expected result did not occur. In this study, however, several possible
explanations for the failure of the fish to respond are apparent.
The development of exophthalmos in 10 percent of Carassius auratus
injected with TSH is not significant. It correlated closely with the
experience of Olivereau (74) who produced exophthalmos in one of
14 goldfish by the injection of Salnio salar pituitary, but felt that this
was meaningless as a similar effect could be produced by the injection
of salmon brain or casein.
The response of the goldfish to Armour pituitary preparations alone
is also without real meaning. Only 15 percent of those receiving the
Armour extracts developed proptosis, whereas all the TSH prepara-
tions used were known to be highlv potent in producing exophthalmos
in guinea pigs.
Only a relatively small number of fish were injected with human
serum, but the total lack of response to this stimulus indicates that the
test is, at least, not sufficiently sensitive to be of clinical value in
evaluating any individual patient.
The method employed in determining the intercorneal distances was
subject to some interpretation, and demanded objectivity on the part
of the observer. Such a possible objection would be more valid if
positive results were being reported. However, in this study all in-
jections and measurements were performed by the author and, as
pointed out above, the measurements were shown to be reproducible.
It was repeatedly observed throughout the course of this experiment
that when a fish became ill and less vigorous, it developed an
enophthalmos. Such an event could conceivably mask any exophthal-
mic effect. This again seems unlikely, because most of the fish which
showed a decrease in intercorneal distance expired within a few hours,
while those which lived remained vigorous and showed no significant
change in the intercorneal measurement.
One factor which was not evaluated was the possibility of a seasonal
variation. Johnson (75) has stated that the killifish is more responsive
5`8 6 Rober't AI. Dayl
during periols of sextual activity, while Dobyns hals felt that it Nvas
more responsive during the fall (76). Nevertheless, a species differ-
ence remains the most plausible explanation for the failure of the gold-
fish to become exophthalmic in response to endocrine stimulation.
Excluding the proptosis which results from orbital ttumors or para-
sitic infestations, exophthalmos in animals has been observed under a
variety of conditions. Exophthalmos from abnormal orbital develop-
ment has been produced with tlhyroxine in Gamnbusia (77) and with
desiccated thyroid in immature poeciliid fish (Xiphophorus) (78).
However, the fact that these fish were smaller than normal controls
suggests that the eyes were simply too large for the orbits. Thyroid-
ectomy, the administration of cortisone (79), or hypophysectomy
(80) results in apparent exophthalmos in young rats, for the normal
growth of the eyeball is not hindered, while there is a marked in-
hibition of head and body growth. In contrast, an apparent enophthal-
mos has been produced in salmon by the administration of thyroid and
thyroxine (81). This is relative rather than actual, for an increase in
the intraorbital tissue, as well as in the tissues about the eye, produces
an illusion of enophthalmos.
Those states in which exophthalmos has been shown to result from
an increase in the retrobulbar tissue mass have characteristically been
associated with histologic evidence of hyperplasia in the thyroid gland.
Such a change has been observed not only in Futndulus heteroclitus
(67), but also in many other species. Il 1928 a great number of young
trout, hatched in a Wisconsin fishery, developed bilateral exopbthal-
mos, became ill, and died (82). The proptosis was associated with
hyperplasia of the thyroid cells and its extent was closely correlated
with the degree of hyperplasia. Furthermore, these abnormalities could
be prevented by the addition of small amounts of iodine to the water.
Methyl cyanide produces a chronic, bilateral exophthalmos in pre-
pubertal rabbits, and the degree of proptosis is proportional to the
degree of thyroid hyperplasia produced (83). This exophthalmos
apparently depends on thyroid insufficiency, for thyroidectomy hastens
the onset and increases the extent of the proptosis, and the administra-
tion of iodine to rabbits with intact thyroids prevents the development
of exophthalmos (84). Intact guinea pigs do not develop exophthalmos
from anterior pituitary extracts until thyroid hyperplasia is evident
(48). The exophthalmos occurs more often in the refractory state after
the animals are no longer made thyrotoxic by the injections (44) and
it persists indefinitely when the injections are continued for a long
time (49). Extensive studies have confirmed the observation that various
 Ocular Manifestations of Thyroid Disease 587
TSH preparations are more effective in producing proptosis when ad-
ministered to thyroidectomized guinea pigs (41, 50, 51, 55). Although
it is well recognized that the human thyroid is hyperplastic in the
toxic phase of Graves' disease, there is Imdirect evidence that this may
also be .true in the euthyroid phase of the disease. Werner (85) has
shown that in frank thyrotoxicosis, with a high 24-hour radioactive
iodine uptake, the uptake is not lowered by the administration of
tri-iodo-thyronine. In the normal human with an uptake in the normal
range, the uptake is decreased by tri-iodo-thyronine. However, in the
patient with thyroid ophthalmopathy and in whom all thyroid tests
indicate a euthyroid state, the normal radioactive iodine uptake is not
depressed by tri-iodo-thyronine. The nature of this thyroid dysfunction
is not known, but it is likely that it consists, at least in part, in thyroid
hyperplasia.
All this evidence points to the conclusion that exophthalmos resulting
from an increase in the retrobulbar tissue mass is associated with
hyperplastic changes in the thyroid gland. The fact that Carassius
auratus does not develop exophthalmos in response to anterior pitui-
tary injections is probably best explained on a species difference. From
the thyroid viewpoint, there is good evidence that such a species dif-
ference does exist, and that in some respects the goldfish is unique.
Gorbman (86) injected pituitary preparations from fish, frogs, chickens,
and sheep into guinea pigs, lizards, salamanders and goldfish and
measured the response in thyroid cell height. He found that lizard
and guinea pig thyroids did not respond to fish pituitary, although this
substance did produce a definite effect in goldfish. This suggests a
definite species specificity. Antithyroid drugs are known to produce
a hyperplasia in the thyroid cells of Fundulus heteroclitus as well as
in most fresh and salt-water fish (32, p. 156), whereas Fortune (87)
has demonstrated that the goldfish thyroid is very unresponsive.
Among fresh-water fish, Berg and Gorbman (88) found that the
thyroid gland of Carassius auratus is unique in not being an active
collector of radioactive iodine. Even the administration of TSH does
not cause the goldfish thyroid to accumulate as much radioiodine as
the average fresh-water fish. Whereas marine fish in an iodine-rich
environment concentrate 2-3 percent of tracer doses of 1131 in their
thyroids, fresh-water fish in iodine-poor environment are able to con-
centrate up to 30 percent. The radioiodine turnover of fresh-water
fish can be reduced to a rate similar to salt-water fish by the addition
of iodine to the water. Euryhaline fish, such as Fundulus heteroclitus,
can shift rapidly from one type of response to the other depending on
vu88 Robert M. Day
the environment, but the strictly marine varieties suclh as Fundulus
majalis are less adaptable.
From these observations one is able to conclude with Fortune (87)
that the thyroid gland of Carassius auratus is very inactive, an un-
tusual feature which perhaps results from the prolonged artificial
selection to which it has been subjected. This inactivity seems to hold
the key to the negative results reported, and consequently it appears
that the goldfish is Inot a suitable subject in which to study the ocular
manifestations of human thyroid disease.

CLINICAL EVALUATION

Inasmuch as no simple, reliable laboratory test for evaluating

thyroid ocular changes is available, a clinical investigation was under-
taken. The ocular signs in 200 patients were analyzed to determine
whether they fell into one or two groups. Although many recent
authors have indicated that the orbital changes are in reality different
manifestations of one disease process (32, p. 467; 63; 89-92), docu-
mentation of such a theory has been lacking.
CLINICAL PICTURE
Numerous ocular signs have been described in aissociation witl
thyroid dysfunction:
Name given to sign Sign
Enroth's Swelling of the lids
jellinek's Increased pigmentation of the lids
Dalrymple's Retraction of the upper lid
Kocher's Increased upper lid retraction oin attentive gaze
Von Graefe's Lid lag
Mean's Globe lag on upward gaze
Griffith's Lag of the lower lid on upwvard gaze
Boston's jerky lid lag
Stellwag's Inifrequent blinking
Roseinbach's Tremor of closed lids
Gifford's Difficulty in everting the upper lid
joffroy's Absence of forehead wrinkling oni upward gaze
Knies' Unequal dilatation of the pupils
Loewi's Pupillary dilatation with weak epinephrinie soluition-.s
Cowen's jerky pupillarv contractioni to consenisual light
Mobius' Weakness of convergence
Ballet's Palsy of one or more extraocular muscles
Suker's Poor fixation on lateral gaze
Riesman's Bruit audible over the closed eye
 Ocular Manifestations of Thyroid Disease 589
Most of these are of limited value, for although they undoubtedly
occur, their clinical interpretation is difficult. For the purpose of this
study six signs of thyroid ocular involvement were selected. Each was
felt to be not only characteristic of this disease, but also to be subject
to critical, clinical evaluation.
RETRACTION OF THE UPPER LID (DALRYMPLE'S SIGN). Normally with
the eyes in the primary position, the border of the upper lid rests at
or slightly above the upper border of the pupil. However, when it
rests just below,, at the level of, or above the limbus, true retraction
of the upper lid can be said to be present. It is extremely important
that the patient be relaxed in evaluating this sign, for voluntary staring
will also produce upper lid retraction and may lead to a false interpre-
tation. It is this retraction of the upper lid which produces the charac-
teristic stare of hyperthyoidism, and may lead to the illusion of
exophthalmos. It was described as far back as 1849 by Cooper (4) who
attributed the original description to Dalrymple. As previously men-
tioned, there is no agreement as to the mechanism of the lid retraction.
Some have claimed that it results from spasm of the striated levator
palpebrae superioris muscle, while others have felt that it was pro-
duced by overaction of the smooth palpebral muscle of Muller. In an
attempt to reconcile these opposing views, Adler, Scheie, and Dennis
(93) have suggested that the levator is weakened not only by the
deposition of fat, but also by the circulating thyroxine which sensitizes
the smooth muscle of the lid to circulating epinephrine and increases
its tone (89).
LID LAG (VON GRAEFE S SIGN). This sign consists of a failure of the
upper lid to maintain its relative position with respect to the globe
as the eyes are moved progressively downward. It may not become
apparent until the gaze is directed well below the horizontal. As in
evaluating retraction of the upper lid, the patient must be relaxed, for
voluntary lid lag may be -produced by staring. It was first described
in 1864 by Von Graefe (94) who felt that it might be one Iof the
earliest signs of hyperthyroidism. The pathogenesis of this sign is
also not understood, but is undoubtedly similar to that of upper lid
retraction.
FULLNESS OF THE UPPER LID (ENROTH'S SIGN,). A diffuse, persistent
fullness, which is more marked in the upper lids and does not pit on
pressure, is frequently associated with the severer forms of thyroid
ophthalmopathy. It is a frequent cause of cosmetic complaint by the
patient. This type of swelling was particularly noted in 1897 by
Mackenzie (95), and it probably results from the widespread orbital
edema with its high mucin content (43).
590 Robert M. Day
CONJUNCTIVAL INJECTION. A deep injection of the globes, especially
temporally and less frequently nasally, is often seen in association with
thyroid disease. Enlarged vessels may be visible and their appearance
suggests that they result from venous stasis secondary to increased
tissue pressure within the orbit. However, they persist after the acute
process has subsided and studies with radiosodium have failed to
demonstrate evidence of passive congestion (39). Goldzieher (96),
as far back as 1900, called attention to conjunctival hyperemia, and
it was noted later by Ohlemann (97) and Sattler (98, p. 107).
LIMITATION OF EXTRAOCULAR MOVEMENT. Although isolated extra-
ocular muscle palsies are rare (99), a limitation of movement of the
globe is frequently seen. Characteristically, there is at first a limitation
of elevation, followed later by a limitation of lateral movement, and the
eye may eventually become fixed in depression. The globes are held
in position mechanically and cannot be moved passively with forceps
(100).This loss of function results from the changes in the muscles
already described. However, Breinin (101) has recently produced
electromyographic evidence that there may also be a neurogenic factor.
In 12 patients with the orbital abnormalities of thyroid dysfunction,
he found only one with an innervational pattern of myopathy, while
a neurogenic palsy pattern occurred in most instances.
CHEMOSIS. As the ocular signs of thyroid disease progress, the con-
junctiva at first appears glassy, then water-logged, and finally a frank
chemosis appears. This may be so marked that the conjunctiva actually
prolapses between the lids. It is known that mucopolysaccharides with
marked hydrophilic properties are increased within the orbital tissues
in this condition (43) and it is most likely that the chemosis is an
obvious manifestation of this change.
METHOD
These six signs were evaluated in a series of 200 patients, all of
whom were knoNvn to have, or to have had, some form of thyroid dys-
function. There was considerable variation in the time of onset of the
thyroid abnormality, its treatment, and the toxicity at the time of the
examination. The distribution of these patients by age, sex, and race
is summarized in Table 5. This distribution is similar to that usually
reported for Graves' disease, where its occurrence is approximately
4.5 times as common in women as in men, and the peak occurrence in
women is in the third and fourth decades and in a slightly older age
group in men (32, pp. 427-428). Each patient had ocular signs or
symptoms of sufficient severity for him or for his internist to seek an
 Ocular Alanitfestaitions of Thyroid Disease
TrABL, .5. D)ISTRIBUTION OF PATIlENTS BY AGE, SE,X, ANI) RACE.

NVumnber of patients
Sex and age, White Negro
Female
15-25 16 7
26--35 30 8
36-45 :34 8
46-55 :30 2
56---65 13 1
(66 75 4
roTrAL 127 27

Mfale
15-25 2 0
26-35 8 ,)
36-4;5 9 2
46557)4#(
5;6 6.5 13 0
66-75 0 0
T'OTAL 39

ophthalmic opinion. They were selected in no other way. Therefore,

the over-all incidence of the ocular signs in the presence of thyroid
disease is not available from this study. All the signs were recorded as
they appeared at the time of the initial examination. No attempt was
made to follow the progress of the ocular changes.
Each patient was arbitrarily classified as having either the mild or
the severe type of eye change. A diagnosis of the former was made
when the patient had no subjective ocular complaints and presented
only upper lid retraction, with or without lid lag. Severe change,
however, was diagnosed whenever the patient complained of lid
swelling, increased lacrimation or a "sandy" sensation about the eyes
and on examination the orbits showed evidence of one or more of the
last four signs (upper lid fullness, conjunctival injection, extraocular
muscle involvement, and chemosis) critically evaluated in this study.
It must be emphasized that this separation was arbitrary and resulted
from the over-all clinical, ocular examination.
An attempt was made to evaluate the significance of the patient's
ocular symptoms. However, as symptoms are by definition subjective,
it was felt that the results obtained were not sufficiently reliable to be
of value.
592 Robei-t Al. Day
In addition to the above signs, a measurement of the degree of
relative exophthalmos in each eye was made with the Hertel exophthal-
mometer. The measurements were recorded to the nearest 32 mm.
RESULTS

The percentages of patients in both the mild and the severe group
showing each of the six ocular signs evaluated are summarized in
Table 6. By far the most common sign is retraction of the upper lid,
occurring in over 90 percent of both groups. Lid lag, on the other
hand, was evident in only about one-third of the patients. The last
four signs were naturally found more frequently in the severe than in
the mild group. However, their occurrence became less as they repre-
sented increasing severity of the ocular process. Thus, lid fullness and
deep conjunctival injection were more common than extraocular muscle
involvement and chemosis.
'TABLE 6. PEftCENTA;E, OF 200 PATIENTS SHOWING EACHI OF T'rHE
OCULAR SIGNS EV'ALUATED

Mild orbital changes Severe orbital changes

(86 patients) (114 patients) TIotal
No. % vo. % No. %
Lid retractioni 85 98.8 103 90.3 188 94.0
Lid lag 3.3 38.3 34 29.8 67 33.5
Lidi fullniess 13 15.1 95 83.3 108 54.0
Inljectionl :30 34.8 97 85.0 127 63.5
EOM involvenienit 3 :3.4 81 71.0 84 42.0
Chemosis 0 0 26 22.8 26 13.0

Althouglh clinical signs are not subject to exact mathematical

interpretation, the total number of signs exhibited by each patient
was determined. This was done in an attempt to present an over-all
picture of the group. It was found that .35 patients slhowed only one
sign, 42 showed two, 44 slhowed tlhree, 47 showed four, 27 showed five,
and 5 showed six signs. The majority of patients, therefore, demon-
strated two, three, or four signs.
For the purposes of evaluating the Hertel exophthalmometer read-
ings, the patients were divided into four groups according to the most
severe ocular sign. Those patients with lid retraction associated with
or without lid lag, but no other signs, were placed in Group I. If they
demonstrated lid fullness or deep conjunctival injection, regardless of
 Ocullar NiManifestaltions of Thyroid Disease5593s
the position of the lids, they were placed in Grouip II. Group III was
composed of those with extraocular muscle involvement, but no con-
junctival edema, and Grouip IV was reserved for those with chemosis.
The average exophthalmometer readings for the more prominent eye
are listed for each group in Table 7. The degree of relative exophthal-
mos is greater on the average as each group represents more severe
ocular involvement. However, the range of readings within each
group is wide.
TABLE 7. HFRTEI. E'XOPHTHALMOMElTE.R. RrE,ADING,S ON THE
M1ORtE, PROMINENT EYE GRO(JPED ACCORDING T'O 'HE
-MOST SEVERE OCULAR SIGN

Average Range
Group Number (mm.n) (mmt-.)
Group I: Lid retractioni
or lid lag 46 18.6 14.5-25.5
Grouip II: Lid fullness or
bulhar injection 62 20.5 14.5-29.0
Grouip III: ExtraocLular mtiscle
involvement 66 21.4 16.5-31.5
Group IV: Chemosis 26 22.5 13.5-29.5

A statistical evaluation of the exophthalmometer readings' reveals an

over-all mean of 20.6 mm. with a standard deviation of 3.31. As 66
percent of the patients had a measurement which fell within m ± c,
96.5 percent a reading which fell within in ± 2 a, and 98 percent
within mn ± 2.5 a, the measurement as a whole may be said to represent
a normal curve. Such a normal distribution is suggestive that these
patients represent a single group, at least as far as the Hertel exoph-
thalmometer readings are concerned.
DISCUSSION
Within recent years Mulvany (23) has been the outstanding pro-
ponent of the concept that the orbital changes associated with thyroid
dysfunction represent two separate disease processes. According to his
Group IV, with a mean of 22.5 mm. and with a = 3.59, has a statistically sig-
nificant greater degree of exophthalmos on the average than Group I, with a mean
of 18.6 mm. and with a = 2.80. The ratio of the difference between the two means
and the standard error of this difference in means is equial to 4.7.
In a similar fashion a combination of Grouips II, III, and IV with a mean of
21.2 and a = 3.21 has a significantly greater exophthalmos on the average than
does Group I. The value for the ratio in these cases is 5.3.
,594 Robei-t AL Day
ideas, the eye manifestations are divisible into two distinct types:
"thyrotoxic" and "thyrotrophic." The former represents the milder
form of eye involvement and consists of lid retraction and an exoph-
thalmos which is more apparent than real. These signs are thought to
result from sympathetic overactivity secondary to the hyperthyroidism.
The "thyrotrophic" variety consists of edema and infiltration of the
orbital structures producing a marked exophthalmos, and the thyroid-
stimulating hormone of the pituitary gland is said to be the etiologic
agent.
Means (63), on the other hand, classifies Graves' disease into three
types, but feels that eaclh is probably a different phase of the same
disease process. Thus, there are: (i) classic Graves' disease with oph-
thalmopathy, thyrotoxicosis, and goiter; (ii) Graves' disease with thy-
rotoxicosis but no ophthalmopathy; (iii) hyperophthalmopathic
Graves' disease with hyper-, eu-, or hypothyroidism. Mann (89) classi-
fies her patients differently into three groups, but feels that each group
shades into the others. She thinks of them as: (i) primary deficiency
of thyroxine with compensatory excess of thyrotropic hormone; (ii)
primary excess of thyroxine as an initial symptom, followed by thyroid
failure or thyroidectomy and replacement by excess thyrotropic hor-
mone; (iii) excess thyroxine and thyrotropic hormone arising simul-
taneously. Both of these classifications are attempts to arrive at a
unifying concept, rather than to describe a series of clear-cut disease
entities. Those favoring a unitarian concept have felt that the differ-
ences between the mild and severe forms of the orbital process could
be explained by the abruptness of the onset, the severity of the process,
or by the relative activities of the various endocrine factors involved
(23).
The results of this study suggest that the division of the clinical
picture of thyroid ocular dysfunction into two distinct and mutually
exclusive groups is arbitrary and cannot be supported on clinical
grounds. Thus, lid retraction occurs in almost as high a percentage of
patients with "thyrotrophic" as with "thyrotoxic" type of eye change.
As this is the characteristic sign of the latter, it seems unnecessary to
postulate a different etiology to explain this one sign. Two-thirds of
the patients demonstrated two, three, or four signs, and did not fall
into the typical mild or severe groups. Rather they were of the "mixed"
types, and in the majority of instances the division into two clinical
categories is difficult.
Analysis of the exophthalmometer measurements leads to a similar
conclusion. The measurements have a normal distribution, which im-
plies that they belong to one population. The finding that the patients
 Ocular Manifestations of Thyroid Disease 595
with the milder ophthalmopathy have significantly less exophthalmos
on the average than those with the more severe signs does not neces-
sarily mean that they belong to a separate group. Rather, it suggests
that as the severity of the orbital process increases, the exophthalmos
increases.
The wide range of exophthalmometer readings in each group makes
it apparent that the degree of proptosis is not necessarily indicative of
the severity oi the eye changes in any one patient. In evaluating a
thyroid ocular problem it is not sufficient to measure only the exoph-
thalmos. Rather, the whole ocular picture must be carefully assessed
and one may conclude with Sattler that "the value of exact ophthal-
mometer measurements is that they provide a record of the changes
in the degree of protrusion which occurs during the course of the
illness" (98, p. 35).
Lid lag occurred in approximately one-third of the 200 patients
studied, a figure much lower than would be expected from the litera-
ture (18). This relatively low incidence undoubtedly resulted from
the care with which it was evaluated. It was only recorded as present
when the patient was completely relaxed and the possibility of volun-
tary lid lag was eliminated. Failure to have the patient relaxed may
well account for the fact that it has been reported to occur in 14
percent of patients without any evidence of thyroid dysfunction- ( 102).
The unitarian concept is in accord with the pathlogic changes in the
orbital structures to which reference has already been made. Although
enough studies have not been carried out to reach definite conclusions,
there is no clear-cut evidence that two distinct types of pathologic
change occur. This concept also correlates with orbitonometry studies
made in Graves' disease. There is a gradual variation in the orbital
tension from normal to abnormally high in association with exoph-
thalmos and the results cannot be separated into two distinct groups
(103). Measurements of the removal rate of radiosodium from the
orbital fat in patients with thyroid dysfunction have also failed to
produce evidence of two definite types of orbital change (39). Ater-
man's report (104) on experimentally produced exophthalmos also
supports this unitarian view. He found that the exophthalmos could
be of all degrees of severity without varying its method of production,
and concluded that the difference was one of degree and not of the
nature of the process involved. Clinical studies have led to similar
interpretations. In a recent evaluation, summarizing ten years of ex-
perience with radioiodine, Werner et al. (105) carefully analyzed the
ocular problem. They found that in a series of 525 patients, 92 had
mild eye signs before treatment, and six of these developed severe
et-0 Robert M. Day
ophthalmopathy following 1131 therapy. They concluded that separating
their patients with orbital involvement into two separate groups was
meaningless from a prognostic point of view.
The significance of this study lies mainly in its clinical implication
of a single disease process developing in the orbit in association
with thyroid dysfunction. At one extreme, and almost universally, there
is upper lid retraction. If the orbital disease progresses, lid fullness and
conjunctival injection appear, and then as it becomes more severe,
extraocular muscle involvement develops and chemosis occurs. Rarely
it may go-on to corneal ulceration or optic nerve involvement (106,
107, 108). The incidence of these various signs of orbital infiltration
decreases as each sign indicates increasingly severe orbital involvement.
This is in accord with the relatively infrequent occurrence of the very
severe type of eye change (109; 32, p. 476).
The unitarian concept implies that the ocular signs may progress,
even though severe changes are rare. It implies that one examination
during which only mild ocular signs are found does not eliminate the
possibility of severe changes occurring at a later date. Although abso-
lute proof is lacking, many clinicians, such as Sloan (110), believe that
severe orbital changes may be precipitated by too rapid control of
thyrotoxicosis. The concept of a single disease process emphasizes the
importance of treating with extreme caution any hyperthyroid patient
who shows more than the mildest eye signs.

SUMMARY AND CONCLUSIONS

1. The various theories of the pathogenesis of the eye manifestations

of thyroid dysfunction are briefly reviewed.
2. A significant exophthalmos was produced in Fundulus heteroclitus
(the Atlantic minnow) with several extracts of the anterior pituitary
gland.
3. No significant exophthalmos could be produced in Carassius
auratus (goldfish) with extracts of the anterior pituitary gland or with
the serum from patients with progressive orbital disease associated
with thyroid dysfunction.
4. Carassius auratus does not appear to be a favorable subject in
which to bioassay the exophthalmos-producing substance in human
serum.
5. The failure of Carassius auratus to respond to exophthalmos-pro-
ducing substance is ascribed to a species difference.
6. As no satisfactory laboratory test is available, six clinical signs
 Ocular Manifestations of Thyroid Disease 597
and the exophthalmometer measurements were carefully analyzed in
a series of 200 patients with thyroid ocular disease.
7. The ocular changes associated with thyroid dysfunction occur in
varying degrees of serverity.
8. The degree of exophthalmos is not necessarily indicative of the
severity of the ocular involvement.
9. The division of the ocular manifestations of thyroid disealse into
twvo distinct groups cannot be made on clinical grounds.
REFERENCES
1. lPlarry, C. H1., Collections from the Unpublislhed medical Writinigs of tlec
Late Caleb Hillier Parry. London, Underwood, 1825.
2. Graves, R. J., Palpitation of the heart witlh enlargemenit of the thyroid
gland, London Med. & Surg. J. (Renshaw), 7:516, 1835.
3. Von Basedow, C. A., Exophthalmuis durch Hypertrophie des Zellgewebes in
der Augenhohle, Wchschr. f. d. ges. Heilk., 6:197, 1840.
4. Cooper, W., On protrusion of the eyes, in connexion with anemia, palpitation
and goiter, Lancet, 1:551, 1849.
5. Bernard, C., Legons sur la physiologie et la pathologie du systeme nerveux.
Paris, J. B. Bailliere et Fils, 1858.
6. Blau, N. F., and H. McNamara, Sympathetic activity after prolonged ad-
ministration of thyroxin, Proc. Soc. Exper. Biol. & Med. 27:997, June, 1930.
7. Gellhorn, E., and J. Feldman, The influence of the thyroid on the vago-
insulin and sympathetico-adrenal systems, Endocrinology 29:467, 1941.
8. Ayer, J. B., J. H. Means, and J. Lerman. Simulation of progressive muscutlar
atrophy by exophthalmic goiter, Endocrinology, 18: 701, 1934.
9. Fagin, I. D., R. W. Pagel, and H. H. Sand, Exophtlhalmic ophthalmoplegia:
Report of a case with thyrotoxicosis of unusuially long duration, Am. J.
Ophth., 27: 504, 1944.
10. Wilson, L. B., quoted by W. A. Plummer and R. M. Wilder, Etiology of
exophthalmos, constitutional factors with partictular reference to exophthal-
mic goiter, Arch. Ophth., 13:833, 1935.
11. Rundle, F. F., and C. WV. Wilson, Ophthalmoplegia in Craves' disease, Clin.
Sc., 5:17, 1944.
12. Moore, F. R., Discussion on the diagnostic significance of proptosis. Tr.
Ophth. Soc. U. Kingdom 43:215, 1923.
13. Whitnall, S. E., The Anatomy of the Human Orbit and Accessory Organs of
Vision, p. 88, 2nd ed., London, Oxford University Press, 1932.
14. Whitnall, S. E., and J. Beattie, Exophthalmos: An anatomical criticisimi of
the theories of its causation; together with results of experiments on the
cat, J. Anat., 68:146, 1933.
15. Pochin, E. E., Ocular effects of sympathetic stimulation in man. Clin. Sc.
4:79, 1939.
16. Friedgood, H. B., Exophthalmos: Clinical applications of studies in experi-
mentally induced exophthalmos of anterior pituitary origin, J. Clin. Endoc-
rinal., 1:804, Oct., 1941.
17. Wagener, H. P., Enophthahlos in Hormier's syndromice, Amii. J. Oplitlh., 177:
209, March, 1934.
18. Holloway, T. B., WV. E. Fry and H. A. Wentworth, Octiular signsi in one lhuin-
dred uinselected calses of goiter, J.A.M.A., 92:35, Jan. 5, 1929.
598 Robert M. Day
19. Wybar, K. C., Endocrine exophthalmos, Tr. Ophth. Soc. U. Kingdom,
73:639, 1953.
20. Pochin, E. E., The mechanism of lid retraction in Graves' disease, Clin. Sc.,
4:91, June 5, 1939.
21. Kisner, WV. H., and H. Mahorner, Unilateral exophthalmos: An early sign
in thyrotoxicosis, Surg., Gynec. and Obst., 84:326, March, 1947.
22. Friedenwald, J. S., Orbital myositis and choked disc in exophthalmic
goitre, Ann. Surg., 96:995, Dec., 1932.
23. Mulvany, J. H., Exophthalmos of hyperthyroidism; differentiation in
mechanism, pathology, symptomatology, and treatment of 2 varieties, Am.
J. Ophth., 27:589, 693, 820, 1944.
24. Naffziger, H. C., Progressive exophthalmos following thyroidectomy: Its
pathology and treatment, Ann. Surg., 94:582, 1931.
25. Naffziger, H. C., and 0. W. Jones, The surgical treatment of progressive
exophthalmos following thyroidectomy, J.A.M.A., 99:638, 1932.
26. Naffziger, H. C., Pathologic changes in the orbit in progressive exophthal-
mos, with special reference to alterations in extra-ocular muscles and optic
disks, Arch. Ophth., 9:1, 1933.
27. Rundle, F. F., and E. E. Pochin, The orbital tissues in thyrotoxicosis: A
quantitative analysis relating to exophthalmos. Clin. Sc., 5:51, Aug. 7, 1944.
28. Rundle, F. F., L. R. Finlay-Jones, and K. P. Noad, Malignant exophthalmos:
A quantitative analysis of the orbital tissues, Australasian Ann. Med., 2:128,
Nov. 1953.
29. Smelser, G. K., A comparative study of experimental and clinical exophthal-
mos, Am. J. Ophth., 20:1189, Dec. 1937.
30. Burch, F. E., The exophthalmos of Graves' disease, Minn. Med., 12:668,
1929.
31. Reese, A. B., Dacryadenitis in hyperthyroidism, Arch. Ophth., 13:855, 1935.
32. Werner, S. C., The Thyroid: A Fundamental and Clinical Text, New York,
Hoeber-Harper, 1955.
33. Pochin, E. E., and F. F. Rundle, Deposition of adipose tissue between
ocular muscle fibres in thyrotoxicosis, Clin. Sc., 8:89, 1949.
34. Moore, R. F., A note on the exophthalmos and limitation of the eye move-
ments of Graves's disease, Lancet, 2:701, 1920.
35. Means, J. H., The nature of Graves disease with special reference to its
ophthalmic component, Am. J. M. Sc., 207:1, 1944.
36. Falconer, M. A., and W. S. Alexander, Experiences with malignant exoph-
thalmos: Relationship of the condition to thyrotoxicosis and to the pituitary
thyrotropic hormone, Brit. J. Ophth., 35:253, 1951.
37. Rose, E., Exophthalmos associated with disturbances in the pituitary-
thyroid axis: The clinical problem, Arch. Ophth., 48:657, Nov., 1952.
38. Hedges, T. R., and E. Rose, Hyperophthalmopathic Graves's disease: Clini-
cal observations in nineteen cases, Arch. Ophth., 50:479, Oct., 1953.
39. Day, R. McC., and S. C. Werner, Removal rate of radiosodium (Na24) from
human orbit in Graves's disease and in health, Arch. Ophth., 52:85, July,
1954.
40. Asboe-Hansen, G., The origin of synovial mucin Ehrlich's mast cell-a secre-
tory element of the connective tissue. Ann. Rheumatic Dis., 9:149, 1950.
41. Ludwig, A. W., N. F. Boas, and L. J. Soffer, Role of mucopolysaccharides in
pathogenesis of experimental exophthalmos, Proc. Soc. Exper. Biol. & Med.,
73:137, Jan., 1950.
42. Asboe-Hansen, G., and K. Iversen, Influence of thyrotophic hormone on
connective tissue: Pathogenetic significance of mucopolysaccharides in ex-
perimental exophthalmos, Acta Endocrinol., 8:90, 1951.
 Ocular Manifestations of Thyroid Disease 599
4.3. NVegelius, O., G. Asboe-Hansen, and B. A. Lamberg, Retrobulbar connective
tissue changes in malignant exophthalmos, Acta Endocrinol., 25:452, 1957.
44. Aird, R. B., Experimental exophthalmos and associated myopathv induced
by the thyrotropic extract. Arch. Ophth., 24:1167, 1940.
45. Ridley, H., Discussion on the management of endocrine exophthalmos, Proc.
Roy. Soc. Med., 45:243, April, 1952.
46. Loeb., L., and R. B. Bassett, Effect of hormones of anterior pituitary on
thyroid gland in the gtuinea pig, Proc. Soc. Exper. Biol. & Med., 26:860,
June, 1929.
47. Schockaert, J. A., Hyperplasia of thyroid and exophthalmiios from treatment
with anterior pituitary in young duck, Proc. Soc. Exper. Biol. & Med., 29:306,
Dec., 1931.
48. Marine, D., and S. H. Rosen, Exophthalmos in thyroidectomized guinea
pigs by thyrotropic substance of anterior pituitary, and the mechanism in-
volved, Proc. Soc. Exper. Biol. & Med., 30:901, April, 1933.
49. Friedgood, H. B., Experimental exophthalmos and hyperthyroidism in
guinea pigs: clinical couirse and pathology, Bull. Johns Hopkins Hosp.,
54:48, Jan., 1934.
50. Smelser, G. K., Experimental production of exophthalmos resembling that
found in Graves' disease, Proc. Soc. Exper. Biol. & Med., 35:128, 1936.
51. Paulson, D. L., Experimental exophthalmos in the guinea pig, Proc. Soc.
Exper. Biol. & Med., 36:604, 1937.
52. Smelser, G. K., The role of the cervical sympathetic ganglia and Muller's
orbital muscle in experimental exophthalmos, Am. J. Ophth., 22:1201, Nov.,
1939.
53. Purves, H. D., and WV. E. Griesbach, Thvrotropic hormone in thyrotoxicosis,
malignant exophthalmos and myxoedema. Brit. J. Exper. Path., 30:23, Feb.,
1949.
54. Dobyns, B. M., and R. Rawson, A comparison of exophthalmos and tissue
changes induced by active and inactivated thyrotropic hormone, Endocrin-
ology, 49:15, 1951.
55. Smelser, G. K., Treatment of experimentally produced exophthalmos with
thyroxin and other iodine compounds. Am. J. Ophth., 21:1208, Nov., 1938.
56. Dobyns, B. NI., The influence of thyroidectomy on the prominence of the
eyes in the guinea pig and in man, Surg., Gynec., & Obst. 80:526, May,
1945.
57. Ruedemann, A. D. (in discussion), C. E. G. Shannon, and W. Hunt, The
hyperophthalmopathy of Graves's disease, Tr. Am. Ophth. Soc., 45:240,
1947.
58. Simkin, B., and P. Starr, Failure of short-term administration of thyrotrophic
hormone to produce exophthalmos in man, Proc. Soc. Exper. Biol. & Med.,
84:99, Oct., 1953.
59. Smelser, G. K., Chick thyroid responses as a basis for thyrotropic hormone
assay, Endocrinology, 23:429, Oct., 1938.
60. Galli-Mainini, C., Effect of thyroid and thyrotropic hormones upon oxygen
consumption (QO,) of the thyroid of the guinea pig, Endocrinology, 29:674,
Nov., 1941.
61. D'Angelo, S. A., and A. S. Gordon, The simniltaneous detection of thyroid
and thyrotropic hormones in vertebrate sera, Endocrinology, 46:39, Jan.,
1950.
62. McCullagh, E. P., A. D. Ruedeim1aIni, and XVr. J. (ardner. Exophthalmos of
Graves' disease following pituitary irradiation, orbital decompression and
electrocautery to the pituiitary gland, Tr. Am. Assoc. Study Goitre, 15-32,
1946.
600 Robei-t Al. Day
63. Means, J. H., Hyperophthalmopathic Graves' disease, Ann. Int. Med.,
23:779, Nov., 1945.
64. Wybar, K. C., The nature of endocrine exophthalmos, Adv. Ophth., 7:119,
Basel/New York, S. Kargel, 1957.
65. Adams, D. D., The presence of an abnormal thyroid stimulating horimione in
the serum of some thyrotoxic patients, J. Clin. Endocrinol., 18:699, July,
1958.
66. Dobyns, B. NI., and S. L. Steelmiian, The tlhyroid stimutlating lhormllolne of the
anterior pituitary as distinct from the exophthalmos producing substance,
Endocrinology, 52:705, June, 1953.
67. Albert, A., The experimnental production of exophthalnmos in Fundulus by
means of anterior pituitary extracts, Endocrinology, 37:389, Dec., 1945.
68. Pickford, G. E., The response of hypophysectomized male killifish to pro-
longed treatment with small doses of thyrotropin, Endocrinology, 55:589,
Nov., 1954.
69. Brunish, Robert, The production of experimiiental exophthalimlos, Endocrin-
ology, 62:437, April, 1958.
70. Dobyns, B. M., and L. A. Wilson, An exophthalmos producing substance in
the serum of patients suffering from progressive exophtlhalmiios, J. Clin.
Endocrinol., 14:1.393, Nov., 1954.
71. Barraquer, J., and J. M. Canadell, Exophthalmic factor of humiian serumii,
Arch. chilenos oftal., 13:54, Jan.-June, 1956.
72. Pickford, G. E., and J. W. Atz, The Physiology of the Pituitary Glanid of
Fishes. New York, New York Zoological Society, 1957.
73. Smelser, G. K., personal communication.
74. Olivereau, M., quoted by Pickford and Atz (72), p. 164.
75. Johnson, L. V. (in discussion), J. M. McLean, and E. W. D. Norton, Uni-
lateral lid retraction, American Ophthalmological Society, Whlite Sulphuir
Springs, \W. Va., May 28, 1958.
76. Dobyns, B. M., quoted by Pickford and Atz (72), p. 162.
77. Rizzo, L., quoted by Pickford and Atz (72), p. 162.
78. Grobstein, C., and A. W. Bellamy, Some effects of feeding thyroid to immllna-
ture fishes, Proc. Soc. Exper. Biol. & Med., 41:363, June, 1939.
79, Boas, N. F., and R. 0. Scow, Apparent exophthalmos in the rat following
cortisone treatment or thyroidectomy, Endocrinology, 55:148, Aug., 1954.
80. Essex, H. E., Exophthalmos in hypophysectomized and cortisone-treated
albino rats, Am. J. Physiol., 181:375, May, 1955.
81. LaRoche, G., and C. P. Leblonde, Effect of thyroid preparations and iodide
on salmonidae, Endocrinology, 51:524, Dec., 1952.
82. Hamre, C., and M. S. Nichols, Exophthalmia in trout-fry, Proc. Soc. Exper.,
Biol. & MIed., 26:63, Oct., 1928.
83. Marine, D., A. W. Spence, and A. Cipra, Production of goiter and exoplh-
thalmos in rabbits by administration of cyanide, Proc. Soc. Exper. Biol. &
Med., 29:822, April, 1932.
84. Marine, D., S. H. Rosen, and A. Cipra, Further studies on the exophthalmos
in rabbits produced by methyl cyanide, Proc. Soc. Exper. Biol. & Med.,
30:649, Feb., 1933.
85. Werner, S. C., Euthyroid patients with early eye signs of Craves' disease:
their response to L-triiodlotlhyronine aind thyrotropin, Am. J. M\Ied., 18:608,
1955.
86. Gorbman, A., Suitability of the conininoni goldfislh for assaly of thyrotropic
hormone, Proc. Soc. Exper. Biol. & Mled., 45:772, Dec., 1940.
87. Fortune, P. Y., An inactive thyroid gla.nd( in Ca(rassitis auirattus, Nature, Lould.,
178:98, July 14, 1956.
 Octilair Manifestations of Thtyroid Disease 601
88. Berg, 0. A., and A. Gorbnian, Normal and altered thyroidal function in
domesticated goldfish, Cara.ssiuts auiratus, Proc. Soc. Exper. Biol. & Med.,
86:156, May, 1954.
89. Mann, I., Exophthalmic ophthalmioplegia and its relation to thyrotoxicosis,
Am. J. Ophth., 29:654, June, 1946.
90. Irvine, A. R., Jr., Exophthalmos: from the standpoint of the ophthalmologist,
California Med., 80:75, Feb., 1954.
91. DeVoe, A. C., The orbit: A review of the literatuire for 1953, Arch. Ophth.
52:461, Sept., 1954.
92. Rose, E., Endocrine aspects of exophthalmos, Arch. Ophth., 56:668, Nov.,
1956.
93. Adler, F. H., H. C. Scheie, and R. Dennis, Thyrotropic exophthalmos from
viewpoint of the ophthalmologist, J. Michigan M. Soc., 48:852, Jully, 1949.
94. Von Graefe, A., Ueber Basedow'sche Krankheit, Deuitsche Klinik, 16:158,
1864.
95. Mackenzie, H., On oedema in Graves's disease, Edinbuirgh MI. J. (N.S.),
1:401, 1897.
96. Goldzieher, W., Therapie der Augen Krankheiten, vol. II, p. 415. Leipzig,
Veit, 1900.
97. Ohlemann, M., Ueber Augen Symptome beim Mlorbus Basedowii, Arch. f.
Augenh., 66:43, 1910.
98. Sattler, H., Basedow's Disease. English translation by G. W. Marchand and
J. F. Marchand. New York, Grune and Stratton, 1952.
99. Woods, A. C., Ocular changes of primary diffuse toxic goitre: A reviewv,
Medicine, 25:113, May, 1946.
100. Dunnington, J. H., and R. N. Berke, Exophthalmos duie to chronic orbital
myositis, Arch. Ophth., 30:446, Oct., 1943.
101. Breinin, G. M., New aspects of ophthalmoneurologic diagnosis, Arch. Ophth.,
58:375, Sept., 1957.
102. Jackson, W. P. U., Observations of the general incidence of certain signs
usually connected with thyrotoxicosis, with special reference to "lid lag"
(von Graefe's sign), South African M. J., 24:582, 1950.
103. Kearns, T. P., J. W. Henderson, and S. F. Haines, Clinical orbitonometry
in Graves' disease, Am. J. Ophth., 36:45, 1953.
104. Aterman, K., Exophthalmos: Its relation to adrenocortical function, Acta
Endocrinol. Suppl. 20, Kobenhavn, Mlunksgaard, 1954.
105. Werner, S. C., B. Coelho, E. H. Quimby, and R. McC. Day, Ten year
results of IPs" therapy of hyperthyroidism, Buill. New York Acad. Med.,
33:768, 1957.
106. Igersheimer, J., Visuial changes in progressive exophthalmos, Arch. Ophth.,
53:94, Jan., 1955.
107. Hedges, T. R., Jr., and H. G. Scheie, Vistial field defects in exophthalmos
associated with thyroid disease, Arch. Ophth., 54:885, 1955.
108. Wagener, H. P., Lesions of the optic nerve in exophthalmos of endocrine
origin. Am. J. M. Sc., 232:226, 1956.
109. Ryan, H., Thyroidectomy and thyrotropic exophthalmos (exophthalmic oph-
thalmoplegia): A review of 1001 thyroidectomies, Brit. J. Ophth., 33:769,
Dec., 1949.
110. Sloan, L. W., Surgical treatment of hyperthyroidism, New York J. MIed.,
51:2897, 1951.