Acta Xediea Scandinavica. Vol. CSXVI, fasc. VI, 1947.

From The Medical Clinic of Karolinska Sjukhuset, Stockholm. Head: Professor Nenna Svartz.

Esophtlialnios as an Early Syiiiptoiii in Cases of‘ Hyperthyreosis.

BY

BO ANDERSSON.

a (Submitted for publication August 20, 1946.)

Exophthalmos holds a key position with regard to the etiology, pathogenesis and symptomatology of hyperthyreosis. Several clinicians from the last century, such as v. Basedow and Graves, considered exophthalmos to be an inevitable symptom. In 1835, in his description of this diesease, Robert Graves stated the main symptoms to be goitre, mental disturbances, tachycardia, asthe- nia and exophthalmos. v. Basedow, in his report from 1840, gave three principal symptoms, viz., goitre, exophthalmos and tachy- cardia. Later, the tremor symptom was added, merely mentioned by v. Basedow, but particularly stressed as an important symp- tom by Charcot and Marie.

However, further experience has shown that exophthalmos is by no means intrinsic. It is completely lacking in about every third case. This lead Plummer in 1913 to distinguish between two different forms of hyperthyreosis, viz., exophthalmic goitre and toxic adenoma. This differerentiation was criticized by many as being unnatural and confusing, particularly since transitional forms are far from infrequent. Plummer’s classification has, nevertheless, been fairly widely adopted.

Exophthalmos is, accordingly, an incalculable symptom and follows its own course. Even in cases where it is manifested, there is no parallelism between the degree of exophthalmos and hyper- thyreosis. In the majority of cases, a more or less pronounced

488 BO AXDERSSOK.

exophthalmos occurs simultaneously with the other symptoms of hyperthyreosis. It is, however, often only a late symptom. This, not least, is the reason why the correct diagnosis may frequently be overlooked for a long time. It is, no doubt, unusual to find exophthalmos appearing as an early symptom. I n a case observed a t our clinic, a marked exophthalmos preceded, for almost a period of a year, the other symptoms of hyperthyreosis. A de- scription seems justified in this connection, since cases of this type are of great interest, not least from a theoretical point of view, as contributing to the discussion regarding the relationship be- tween the hypophysis and the thyroid gland.

In September 1944, a chauffeur, aged 45 years, applied a t our Eye Policlinic owing to diplopia and left-sided exophthalmos. Apart from a sister who had a goitre without hyperthyreosis, no hereditary findings of any value in this respect. He had earlier always enjoyed good health. The morbid symptoms appeared during this military service in July 1944. He began to see the tree-tops double, in other words, he showed signs of doublesighted- ness when lifting the eyes upwards. At examination a t the Eye Policlinic in September 1944, a left-sided exophthalmos was ob- served, being so pronounced as to cause suspicion of a tumor forma- tion behind. Consequently, Kronlein’s operation was performed. The patient had previously been examined in the usual manner with, inter alia, roentgenography of the skull with negative results. Two metabolic examinations gave the following values: + 9 and + 11 per cent. He disclosed no subjective or objective symptoms of hyperthyreosis, i. e . no emaciation, no goitre, no tremor, no skin changes, no tachycardia, no nervousness. Surgery failed to con- firm the suspicion of a tumor. Ordinary adipose tissue was found. A microscopical examination of the retrobulbar tissue gave no indications of a tumor formation. The patient said he felt rather worse after the operation, with increased doublesightedness. However, towards the Spring and Summer of 1945, a gradual improvement occurred insomuch as the doublesightedness began to subside. Still, he was unable to find any decrease in the ex- ophthalmos. After July 1945, when he was feeling better than ever, a new deterioration set in. Not until then, that is t o say, almost a year after he had first noticed the doublesightedness, did other symptoms begin to appear. At this time, also the other eye started to protrude. Now, a gradually increasing nervousness troubled him which had not been felt before. Further, a disticnt and by

EXOPHTIIALMOS IN CASES OF HYPERTHYREOSIS. 489

degrees more embarrassing tremor appeared which was notice- able by the patient himself. Simultaneously, in spite of an in- creased appetite, he shortly commenced losing weight u p to al- most 20 kg. He was subjected to shortness of breath and palpita- tions. At a control examination at the Eye Policlinic, a definite hyperthyreosis was diagnosed. He was then admitted to the Medical Clinic in the middle of October 1945, with a typical pic- ture of hyperthyreosis with bilateral exophthalmos, tremor, emacia- tion, tachycardia of approximately 90 beats per minute, a soft, warm and damp skin, standard metabolism + 48 yo, blood chol- esterine 229 mg%, fasting blood sugar approx. 130 mg%, no glycosuria, lymphocytosis in the blood of 50 yo, on other occasions varying from 25 to 35 %. No roentgenological change of the sella turcica. The electrocardiogram showed left preponderance. Blood pressure 145/85. The absence of a supra- as well as intrathoracic goitre and of hypocholesterinemia was noteworthy. Double images were invariably seen when the eyes were directed above the hori- sontal plane, exophthalmometry - right 25 mm, - left 23 mm. At first methylthiouracil, 11% g daily, was administered for 12 days. This caused the metabolic rate to fall during 10 days from + 48 % to + 17 %, increasing after another week to + 30 yo, 9 change was made to radiological treatment of the hypophysis, applied once every day for a period of ten days. The patient was then discharged from the hospital. He was subjectively improved but his condition seemed 'unchanged from an objective point of view. After having consulted the colleagues at the Eye Clinic, he was permitted gradually to resume work to some extent, since no double images appeared when he was driving his car and kept his eyes directed downwards or straight ahead. After his discharge from hospital, he improved successively and, at a control examina- tion 2 months later, in December, 1945, he felt completely restored. Standard metabolism was then + 10 %, no skin symptoms, minimal finger tremor remained, had increased 3 kg in weight, pulse rate about 80 beats per minute. At a reexamination in May 1946, his exophthalmos was unchanged but he had otherwise no symptoms of hyperthyreosis. Standard metabolism equalled + 6 yo, the cholesterine value 255 mg%.

Exophthalmos is the only one of the several symptoms of hy- perthyreosis which does not form the direct result of an increased hormonal incretion from the thyroid gland. It has long been known that one or several extra-thyroidean endocrine factors are

490 BO ASDERSSON.

prerequisites for the occurrence of exophthalmos, inter alia, for the following reasons:

1. As a rule, exophthalmus cannot be produced by experimental means, as can hyperthyreosis otherwise, by the injection of large quantities of thyroxin in test animals.

2. The hyperthyreosis which is seen to occur in human beings after over-dosages of thyroidean preparations, e. g., for the pur- pose of losing weight, is generally not combined with exophthal- mos. However, Brain, among others, has described cases where exopthalmos appeared during thyroidean treatment.

3. The post-operative form, after thyroidectomy, of so-called malignant exophthalnios is not to be explained as the result of increased thyroxin incretion. Several cases of this kind have been reported where the other symptoms of hyperthyreosis have dis- appeared after the surgical intervention, even giving rise to a state of hypothyreosis where, this notwithstanding, the patient’s exophthalmos has either remained unchanged or increased. 4. Cases of acromegaly, the Cushing disease, encephalitis, etc.,

with simultaneous exophthalmos. 5. Cases where, in accordance with the case described by us

above, the exophthalmos precedes the occurrence of the classical hyperthyreosis.

Thus, while there is a general agreement regarding the imprac- ticability of conceiving exophthalmos as a symptom induced by the administration of thyroid, opinions distinctly diverge in at- tempts to explain its etiology and pathogenesis. Much has been written, many experiments performed and numerous theories propounded on this subject. No account will be given in the pres- ent paper of the partly conflicting results arrived at. Those par- ticularly interested in this subject may refer to the monograph published by John Hertz in 1943, entitled ))On goitre and allied diseaseso, where a comprehensive chapter with a great number of bibliographical references is devoted to this question.

Here only a few brief facts will be given concerning the rela- tionship between the hypophysis and the thyroid gland, being of significance for an understanding of the case reported above from our clinic.

As early as in 1889, Rogowitsch demonstrated that total thyroidectomy on mice caused secondary changes in the hypo- physis of the type compensatory hypertrophy. He thereby declared

EXOPHTHALMOS IK CASES OF HTPERTHYREOSIS. 49 1

the relationship between the hypophysis and the thyroid, In 1912, it was made clear that this w-as a matter of an interplay between these two glands. Cushing, a t this time, proved in experiments on dogs that involution of the thyroid gland set in after surgical removal of the hypophysis. The clinical counterpart of these animal experiments may be seen in Simnionds’ disease. The following may be inferred as a general rule with regard to the interplay between certain of the endocrine glands (as quoted from Means’ book on ))Thyroid and its disease))): ))Removal or destruction of an endocrine gland which makes a tropic hormone causes atrophy of the gland upon which that hormone acts. Also removal of an endocrine gland for which another gland makes a tropic hormone causes hyperactivity of the latter gland.)) In 1927-28, Uhlenhuth and Schwartsbach produced hypertrophic changes of the thyroid gland in axolotls by injecting an extract from the anterior lobe of the hypophysis. This was considered due to the hormone of the anterior lobe which, on account of the effects of it, was defined as the thyrotropic hormone (Wiesner 1930).

Thus, the thyrotropic hormone is capable of transforming the thyroid gland in a hyperthyreotic direction. Therefore, it is not particularly surprising to find that i t is also capable of producing exophthalmos in certain test animals. On the other hand, it is of special interest t o note that the thyrotropic hormone can give rise to exophthalmos even when the thyroid has been removed. As a matter of fact, the effect of producing exophthalmos has been ascertained to be more certain and more pronounced by means of this hormone in previously thyroidectomized cases. Judging from these experiments, i t would seem as though an antagonism exists between the thyrotropic hormone and the thyroxin. When both are administered simultaneously, the exophthalmic effect is said to fail t o come off. Moreover, many investigators are of the opinion that a thyroidean insufficiency is a prerequisite for obtaining a surplus of thyrotropic hormones capable of producing exophthalmos. The sexual glands have also been mentioned in this connection (Marine). According to several authors, the thyro- tropic hormone exerts a direct or indirect effect via the sexual glands and acts upon the sympathetic centre in the hypothalamus. This contention finds support in observations that exophthalmos cannot be produced on mice when the sexual glands have first been removed. However, these are mere theories, based prin- cipally on animal experiments. A strong impression is obtained

493 BO ANDERSSON.

from a perusal of the literature on this subject of the difficulties to be encountered in attempts to apply experiences from animal experiments to man. Judging from these experiments, for instance, one would be inclined to expect exophthalmos at hypothyreosis rather than at hyperthyreosis.

The pathogenesis of exophthalmos is, in spite of all theorization, still far from elucidated. Opinions have varied and the theories advanced are innumerable. At present, the conception most generally maintained is that edema and an increase of the retro- bulbar tissue are the immediate cause. We are, thus, back at the original viewpoint on this subject, though in a modified form, as laid down by v. Basedow, among others.

Since we are still so ignorant of the factors causing exophthalmos, attempts a t analysis of the present case must be very tentative. It is tempting to divide the hyperthyreoses into two groups, viz., a hypophysial hyperthyreosis and a primary thyrogeneous one, according to the occurrence or absence of exophthalmos. The mu- tual interplay between hypophysis-thyroid-hypophysis and the cooperation with other endocrine glands, however, undoubtedly puts such a simplified classification out of the question. In add- tion, etiology and pathogenesis are probably too complicated. I n spite of our limited knowledge, it would, perhaps, be justified to define the abovementioned case as an example of hypophysial hyperthyreosis where the primary cause of the disease is a hypo- physial disturbance with increased incretion of a thyrotropic hormone. For some reason or other (at first, hypofunction of the thyroid gland?), this gland has, evidently, contrary to custom, for a long time refused to respond to the thyrotropic hormone. Therefore, the transformation of the gland in a hyperthyreotic direction has failed to take place for some time. However, in this, as in so many other cases, the long, strictly unilateral exophthalmos seems inexplicable.

Summary. A case of hyperthyreosis is reported where a pronounced uni-

lateral exophthalmos preceded for a year the appearance of other symptoms of the hyperthyreosis. The exophthalmos becomes bilateral simultaneously with the development of a typical hyper- thyreosis. The hyperthyreosis is rapidly reduced by radiological treatment of the hypophysis but the exophthalmos remains prac- tically unchanged. In connection with the description of this

ESOPHTHALMOS IN CASES OF HPPERTHYREOBIS. 493

case, a brief account is given of some of the most important facts known concerning the etiology and pathogenesis of the ex- ophthalmos symptom as well as an attempt a t interpretation of the case in question.

References.

For details regarding the literature reference may be had to Borell: On the transport route of the thyrotropic hormone, the occur-

rence of the latter in different parts of the brain and its effect on the thyroidea, Sthlm 1945. - Cameron: Recent advances in endocrionoly, London 1945. - Hertz: On goitre and allied diseases, Copenhagen- London 1943. - ;Means: Thyroid and its diseases, Philadelphia-London 1937.