treating thyroid deficiency

treating thyroid deficiency:

Thyroid History

extracts in date order from 1892 - 1989
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1892 A Case of Myxoedema Successfully Treated by Massage and Hypodermic Injections of the Thyroid Gland of a Sheep Wallace Beatty M.D. Senior Assistant Physician to the Adelaide Hospital Dublin British Medical Journal March 12, 1892 Vol. I, p544 - 545

p 544
.... I need hardly say that I could not hold out much hope that any treatment would succeed ; still, as I had read that some cases of myxoedema were fairly curable by massage, I suggested that a consultation should be held with a view to the consideration of this treatment.

p 545
.... The extract so prepared from the two lobes of one thyroid gland was given in three parts, with two days' interval between. The patient experienced no unpleasant sensations. I have continued the injections, and have given up to the present (February 13th, 1892) the extracts of five thyroid glands. Each extract I have given in three separate injections within a week after its preparation. The time between the administration of each set of injections has varied from four to ten days.
The effect of the injections has been really marvellous. A marked improvement in the patient's condition was noticeable within one week, so much so that her husband, who saw her on December 15th for the first time since her admission to the hospital, was delighted with the change in his wife's condition. He told me that he could not have believed the change possible. She left the hospital on December 16th, and returned home. Massage was continued for seven weeks longer, the patient, however, being permitted to go about the house, and to take short walks daily our-of-doors.
The improvement has steadily progressed. Now she is practically cured ; the face looks natural, the skin of the face is now no longer thickened, but is thin and wrinkled ; the eyelids are not swollen ; the lips are natural ; the tongue is of natural size ; speech is rapid and easy ; the hands are no longer clumsy, she can give a hearty and firm "shake-hands ;" her movements are active ; her hair, which had become thin, is now growing thickly ; her memory has returned ; menstruation is natural. No physician, seeing her now for the first time, could recognise the case as one of myxoedema.

1892 A Case of Myxoedema with Insanity Treated by Injection With Extract of Thyroid Gland Ernest C. Carter, M.B., M.R.C.P. Pathologist to the County Asylum, Whittingham, Lancashire BRITISH MEDICAL JOURNAL April 16th, 1892

P805
The results reported to have been obtained in cases of myxoedema by injection of an extract of thyroid gland have been sufficiently favourable to justify a more extensive trial, while the small number of published cases may possibly render the following record of some interest. The account published by Dr. George R. Murray, of Newcastle-on Tyne, in the BRITISH MEDICAL JOURNAL, October 10th, 1891, suggested its application in a case which seemed likely to furnish a good test of the efficacy of this treatment under favourable circumstances.
....
p806
..... REMARKS.- The rapid progress of improvement in the bodily and mental condition of this patient is strongly corroborative testimony to the value of this method of treatment. She had been an inmate of the asylum for four years. Undoubtedly the amelioration of bodily condition was much more distinct than that of the mental; for while one could not well say that there were any obvious morbid physical conditions after the course of treatment, and certainly none characteristic of myxoedema, the patient's intellectual powers remained in a degree impaired. She was still partially demented, with a tendency to emotionalism. The injections were stopped on account of failure in the supply of fresh thyroids, or possibly a further improvement might have taken place; but the long establishment of mental symptoms makes it more than probable that irreparable degenerations have taken place in the cells of the brain cortex.

.... The accompanying illustration of the patient's appearance after treatment is reproduced from a photograph, for which I am indebted to Dr. Wallis, our superintendent. It was taken during a phase of mild exaltation. It shows well the restoration of the wrinkles on the forehead and around the eyes and mouth. The lips still appear thick, but it may be mentioned that the patient is a Scotswoman of originally coarse features. Unfortunately I am unable to contrast her appearance at the beginning and end of treatment. Her photograph in the typically myxoedematous condition was taken, but I have tried in vain to secure a print.

1892 Remarks on the Treatment of Myxoedema with Thyroid Juice, With Notes of Four Cases by G.R. Murray, B.A., M.B.Cantab., M.R.C.P. Lond Sixtieth Annual Meeting of the British Medical Association held in Nottingham July 26th, 27th, 28th, and 29th. Proceeding of the Sections Pathology Professor Victor Horsley M.B., F.R.C.S., F.R.S., President The Pathology and Treatment of Myxoedema , Lecturer on Bacteriology and Comparative Pathology in the University of Durham College of Medicine: Pathologist to the Hospital for Sick Children Newcastle-on-Tyne British Medical Journal Aug. 27, 1892

p449
PROFESSOR VICTOR HORSLEY has so conclusively shown by his own original work and by the experimental and clinical evidence brought forward in a recent paper that myxoedema is due to the loss of function of the thyroid gland that further evidence in support of this view may seem scarcely to be necessary. The evidence which I wish to bring before you has however a double interest, for it both supports this view of the causation of myxoedema and shows how, by a practical application of this knowledge, the condition of patients suffering from this disease can be considerably improved.
In health the thyroid gland plays an important part in keeping the blood in a normal condition and in maintaining the natural metabolism of the tissues. This is shown by the changes which take place when it is lost and myxoedema comes on. This function of the thyroid gland is probably carried on to a considerable extent by means of its secretion, which is carried into the blood.
If this really be so, we ought to be able in a case of myxoedema to remove those symptoms which are due to the loss of this secretion only, by introducing the secretion from a healthy thyroid gland into the body of the patient in such a way that it can be slowly absorbed by the lymphatics and carried into the circulation as in health.
In the case of animals, G. Vassale and E. Gley have both shown that injections of thyroid extract remove the acute symptoms which follow thyroidectomy in dogs. Brown-Séquard and d'Arsonval, reasoning from these results, suggested last year that injections of an extract of the thyroid gland of a sheep in a well-marked case of myxoedema with such satisfactory results that other cases have been treated in the same way.

.... As a rule, eXXV of the extract have been injected with antiseptic precautions beneath the skin of the interscapular region once a week. in some cases it may be better to give a smaller injection of eX to eXV more frequently. The injection is given slowly, so that five minutes are occupied in injecting eXXV. This is advisable, as occasionally some peculiar symptoms have immediately followed a rapid injection. These were flushing, nausea, and stabbing pain in the lumbar region. Once there was also loss of consciousness and general tonic muscular spasm for a few seconds. When given slowly, the injection can be stopped if the patient begins to flush. No pressure should be made on the seat of injection, as it seems probable that these symptoms are due to a too rapid entrance of the extract into the circulation.

p 450
These cases show that thyroid extract can to a very considerable extent supply the place of the natural secretion which has been lost in myxoedema. A patient's condition can be much improved and the improvement can be maintained as long as the treatment is continued.
.... The disadvantages of this means of treatment may, I think, with care be overcome. The unpleasant symptoms which occasionally follow an injection may be obviated by injecting slowly, at the rate of 2 or 3 minims a minute. The danger of causing an abscess may be reduced to a minimum by strict aseptic precautions and by having the extract sterilised.
The cases with signs of cardiac degeneration should either not be selected for treatment, or they must be specially warned not to take any unusual exercise when the improvement takes place.

1892 LETTER - THE SUBCUTANEOUS INJECTION OF THYROID JUICE IN MYXOEDEMA E. HURRY FENWICK BMJ SEPT 10, 1892 Vol. II p613

SIR, - As Dr. Murray and I initiated and have worked at the above subject quite independently of each other, I may perhaps be allowed, on the experience of three cases, to corroborate his conclusions on the value of the injection of thyroid juice in some cases of myxoedema.
,,,,With the fresh unsterilised juice which I have always employed no abscesses have as yet resulted, though fourteen patients have been injected. The sheep are very carefully selected, and all thyroid which are dry, tough, very small, or those which present the slightest appearance of suppuration are rejected. Some of the foreign sheep are overdriven, in others I have found localised thyroid abscess. - I am, etc., E. HURRY FENWICK

1892 FOUR CASES OF MYXOEDEMA TREATED BY INJECTIONS OF THYROID EXTRACT BY G. E. HALE, M.B., B.C. CANTAB., House Physician, St. George's Hospital BMJ DEC. 31, 1892 Vol. II, p1428 - 1429

p1428
HAVING had the opportunity of treating four cases of myxoedema with injections of thyroid extract, in the manner recommended by D. George Murray, it seemed that a record of them, at a time when the treatment has been recently under discussion, might be of some value.
CASE I. Advanced Myxoedema (15 years standing) : Marked improvement under Treatment. - Mrs C. B., aged 45, had been a confirmed sufferer for about fifteen years, and on a previous occasion an in-patient at St. George's Hospital, but no treatment had produced any alleviation of her symptoms. In 1889, she became too weak to leave her room, and had not done so for three years previously to the present admission.
On January 5th, when she became an in-patient for the second time, she was in an extremely advanced stage of the disease. Her physical strength was at such a low ebb that she could hardly walk alone : the senses were blunted, and all movements slowed to a remarkable degree. There was no dropsy. Perspiration had been absent for some time. She had not menstruated for ten years.
....CASE II. Myxoedema in Early Stage : Great Improvement. - Mrs. R., aged 46, had first noticed symptoms of the disease early in 1890. She was admitted into the hospital in January 1891, when she stated that she had altered so much in face that her friends failed to recognise her. The question of thyroid transplantation was considered and negatived. There was no change in her condition during her stay. Her hair was then beginning to fall off. This patient was not admitted into the hospital for treatment, but attended weekly as an out-patient to have the injections performed. She was, at the commencement of the treatment of April 5th, a well-marked case, whose only peculiarity was that she was subject to profuse perspirations.
....CASE III. Myxoedema of Seven Years' Duration : Marked Improvement. - Mrs M. B., aged 54, had been a sufferer from myxoedema for seven years, and was once a patient in St. George's Hospital for a few days, but had never derived any permanent benefit from medical treatment. At the time of the commencement of the treatment she was a very well marked case, having much oedema of the face and legs, chilliness, red nose, red patches on either cheek, and her speech so greatly affected as to be unintelligible to strangers, while her weakness incapacitated her from fulfilling her household duties. Her menopause took place in 1897.

p1429
CASE IV. Myxoedema in Early Stage : Slight Improvement. - A.N., female, aged 27, had, when admitted as an in-patient in February, shown symptoms of the disease for a year and a-half, but did not present a very characteristic appearance. The treatment was begun early in March, and injections of eXXV were made weekly for three months. The injection on May 30th was followed by pain and selling at the seat of puncture, and that on June 4th by an abscess, which healed kindly after incision. She then had no treatment for seven weeks. In July, August, and September she underwent another course of injections at the Atkinson Morley Convalescent Hospital. The result may be briefly summarised as follows : No improvement in strength or in appearance has taken place, and she still feels as cold as before, but her speech has become brisker, and her fingers more nimble in the use of the needle, which menstruation has reappeared regularly. According to the patient's account diuresis took place during the treatment, but the phenomenon was not confirmed by observation.
It will thus be seen that an improvement - decided in the first three cases, slight in the fourth - followed the adoption of the treatment. The cases have not been long enough under observation to discuss the permanency of the improvement, but at present it seems as if a period of more than three or four weeks' abstention from the injections was sufficient to produce a certain amount of deterioration. In the first and fourth cases the red blood corpuscles were counted before and after the commencement of the treatment, but no appreciable difference was found in the estimations. It is unfortunate that the diuretic properties of the remedy were not known by me in time to permit of the urine being measured daily in the two cases treated as in-patients, but it will have been noticed that three of the four patients asserted that their urine was unusually profuse during the administration of the injections.
The unpleasant symptoms following the injections may be summarised as (1) inflammation which may terminate in abscess, (2) giddiness and headache, (3) faintness, (4) loss of power in the upper extremities. The best method of obviating these has yet to be elucidated ; in the above cases no unpleasant symptoms have occurred if the injection has been made at two spots instead of one, but the employment of this method has not been sufficiently tested even in the above cases to more than suggest its further trial. Dr. Murray now recommends that the extract should be sterilised by the pressure of liquefied carbonic acid gas at 40 atmospheres, whereas that used in the above cases was rendered aseptic by the addition of a minute quantity of carbolic acid (about 1 in 600). It will be seen that two of the above patients had been sufferers from the disease for some years, and the fact that both have been greatly relieved tends to disprove Dr. Michell Clarke's theory that the injection treatment must be adopted at a very early stage of the disease to produce any good effects.

1892 A CASE OF MYXOEDEMA TREATED WITH GREAT BENEFIT BY FEEDING WITH FRESH THYROID GLANDS HECTOR W.G. MACKENZIE, M.D.CANTAB., F.R.C.P., Assistant Physician to the Brompton Hospital for Consumption and to the Royal Free Hospital; Medical Registrar to St. Thomas's Hospital BRITISH MEDICAL JOURNAL October 19th, 1892

p940
The account published recently in the BRITISH MEDICAL JOURNAL by Dr. Murray and others regarding the treatment of myxoedema by means of subcutaneous injections of an extract of the thyroid gland testify so unmistakably to the beneficial effect resulting therefrom that the method will probably receive a more extensive trial. This mode of treatment is not, however, free from objection. First, it requires the most scrupulous care in the preparation of the extract, the demand for which is never likely to be so great as to enable it to be supplied when manufacturers under the ideal conditions at less than an almost prohibitive price, and few medical men have the time to devote to its preparation themselves. Secondly, the application of the remedy sometimes produces alarming immediate symptoms, such as loss of consciousness and tonic spasm; and remoter effects, such as indurated swellings and abscesses at the seat of injection, have followed the use of even the most carefully prepared extract. When it is remembered that these injections have to be personally administered for the remainder of the patient's life by the medical attendant, these risks, however slight in regard to a single application may appear, become immensely magnified when a long series has to be taken into account.
These objections are of great moment as regards the future use of this plan of treatment, although not in least detracting from the value and interest of the results which have so far been obtained.
The method of treatment I have been employing is altogether so very much simpler and safer, and so very easily carried out, and the results in the case in which I have tried it have been so striking and encouraging, as well as interesting, that I am induced to publish a short account of it, in order that others may have an opportunity of putting it to the test. The method consists essentially in administering by the mouth either the fresh thyroid glands themselves or a freshly-prepared extract. It is obvious that this mode of treatment can be perfectly easily carried out. No elaborate antiseptic precautions have to be taken. There is no more difficulty in getting thyroids, once it is explained what is wanted, than there is in getting kidneys. All the dangers attending hypodermic injection are avoided.
When I first started with the treatment I was sceptical as to whether any effect at all would result, and I therefore commenced by giving my patients two whole sheep's thyroid at a time. This amount, however, I consider more than is necessary or advisable, as it is easy to nauseate.

p941
.... To sum up the effects observed in this case: (1) A marked acceleration of the pulse and rise of temperature proportional to the quantity of thyroid given, these persisting for some time after the administration is discontinued. (2) A general diminution of the swelling and amelioration of all the symptoms accompanying myxoedema.
In the administration it has been found that it is less nauseating when given with a little brandy. In another case, as I have already mentioned, I should be inclined to commence the treatment with either one thyroid every other day or half a thyroid every day. If it is found that this is well tolerated and does not produce any marked effect, the dose can be easily increased. The method is one which experience will no doubt much improve on; but it will be a great advance if further observation confirms what has been observed in this case - that a remedy, easily obtained, taken by the mouth should produce marked improvement in a disease hitherto intractable except by hypodermic and somewhat risky injections.

1892 A CASE OF MYXOEDEMA TREATED BY TAKING EXTRACT OF THYROID BY THE MOUTH E.L. FOX, M.D., M.R.C.P., Plymouth BRITISH MEDICAL JOURNAL October 28th, 1892

p941
.... The disadvantages of having to treat cases of myxoedema by continued hypodermic injections are many and obvious. I was therefore induced to try the effect of thyroid extract when taken by the mouth. I directed the patient how to prepare a glycerine extract of half a sheep's thyroid, on much the same lines as laid down by Dr. Murray. Of the extract thus prepared she was to take half one hour before breakfast and the remainder one hour before supper, and to continue doing so twice a week.
.... I have reported this case, as the method of administrating the remedy is simple in the extreme, and in my case, at all events, the result has been satisfactory. If I had another case to treat I should begin with small doses of the minced gland, as that seems to be more potent gives less trouble in preparation, and is preferred by the patient.

1892 A CASE OF MYXOEDEMA WITH INSANITY TREATED BY THE SUBCUTANEOUS INFECTION OF THYROID EXTRACT Cecil F. Beadles M.R.C.S., L.R.C.P., Assistant Medical Officer Colne Hatch Asylum BRITISH MEDICAL JOURNAL Dec. 24th, 1892

p1386
The following is a further case of myxoedema treated by the method first proposed by Dr. George Murray, which is followed by such remarkable results, and has now been shown to be so successful. We all owe, I think, to Dr. Murray our best thanks for pointing this out.
M.B., a single woman, aged 50, was admitted on April 26th, 1892, upon the medical certificate which ran as follows: "She is suffering from mania. She destroys her clothes, and she also imagines that she has done some terrible crime for which there is no forgiveness. These mental symptoms are common in the third stage of myxoedema, from which she is suffering."
Mr. John R. Lunn, medical superintendent of St. Marylebone Infirmary, kindly informs me that the patient had been several times in that institution with delusions and religious melancholia. Mr. Lunn supplies me with the following brief notes of her

past history:
July, 1885. Always had good health: only ailing twelve months. First commenced in the big toes with intense pain, which was followed by swelling in the wrist. Is said to have slept in a damp bed in March, 1884, since which she has been able to attend to her calling, and has been for the most part confined to her bed. There is swelling and thickening of the lower end of the femur, with grating in the joints: both knees can be bent. Phalangeal joints enlarged and thickened. Complains of intense pain in all the joints. No nerve symptoms; pupils react to light; reflexes normal; catamenia stopped.
September, 1887. No change, with exception of religious delusions at times. December. Since last account the patient has remained in the same condition, not getting either worse or better, but on two occasions she had paroxysms of religious mania. In these paroxysms on the first occasion she imagined the porter who cleaned the windows had bowed to the crucifix, and she threw herself flat on the floor and refused to move until the arrival of one of the medical officers. She completely recovered from this attack, but about a month afterwards she had another religious frenzy, calling out loudly, and falling on her knees before the medical officer. Between the fits she is the same as usual. April 18th. Patient seems better and does not have delusions.
April 20th, 1888. Discharged improved. Readmitted October 29th, 1891.
On admission into Colney Hatch the patient was in impaired health, suffering from advances myxoedema. Nothing could be found out from her regarding her past life. She appeared to have no relatives or friends living. Her religion was Roman Catholic. If asked a question, she made no attempt to answer it, but always made the sign of the cross and said "Send me the priest." When asked if she was married she replied "Yes, to the cross." When the priest visited her she took no notice of him. She took not the slightest interest in anything that was going on around her.

p1387
.... October 15th. No further injections have been given. The swelling and pain of the shoulder passed off in a couple of days, but she complained of pain in her joints when the weather was damp, and her wrists were still tender. The temperature remains about normal. There was a systolic cardiac murmur, but this was less loud than before treatment was commenced. The pulse was 54. She passed a considerable amount of urine now, specific gravity 1010, acid, no albumen or sugar. She had recently increased in weight, and was now 9st. 4lbs., but she had not the oedematous appearance, and it is possible that the increase in weight was due to an increase in fat. New hair was growing on the scalp and eyebrows, she was less grey and was looking very well. She stated that she used to be very active when a cook. She was very cheerful and grateful for what had been done. The improvement in her mental condition had been as great, or greater, as that of the myxoedema with which it was associated.
I have to thank Dr. Seward, Medical Superintendent, for allowing me to treat the patient in the manner described; and the Committee for their liberality in providing the necessary thyroid extract.

1893 CLINICAL REMARKS ON CERTAIN CHANGES OBSERVED IN THE URINE IN MYXOEDEMA AFTER THE ADMINISTRATION OF GLYCERINE EXTRACT OF THYROID GLAND. BY WILLIAM M. ORD, M.D., F.R.C.P., Physician and Lecturer on Medicine at St. Thomas's Hospital; AND EDMUND WHITE, B., SC. LOND. BMJ JULY 29, 1893 Vol. II, p 217

A PATIENT suffering from myxoedema was admitted to St. Thomas's Hospital on April 19th, 1893. After careful daily examination of the food and the urine, she began, on May 1st, to take 20 drops of a glycerine extract of the thyroid body of the sheep daily.

....We beg to present the following conclusions as the result of the treatment and observations in this case : 1. That the urine is increased in volume.
2. That the nitrogen excreted in the urine exceeds the total quantity of nitrogen in the food.
3. The phosphoric acid and chlorine elimination are practically unaffected.

4. That the increased nitrogenous excretion is chiefly in the form of urea. 5. That the body weight is rapidly diminished.
6. That the temperature of the body is raised.

1893 THE MENTAL SYMPTOMS OF MYXOEDEMA AND THE EFFECT ON THEM OF THE THYROID TREATMENT AUG. 26, 1893 Vol. II, p454 - 464

p463
DR CLOUSTON referred to the fact that in almost every fully reported case of myxoedema, from Sir William Gull's classical case onwards, mental changes in the patient of a pathological nature were noticed, though they did not necessarily amount to insanity. He reported on the mental symptoms in nine cases of myxoedema, one man and eight women, that had been sent to the Royal Edinburgh Asylum on account of their insanity. The mental symptoms of these cases differed greatly. One had the symptoms of suicidal melancholia, one was simple melancholia, and the other seven were cases classified as mania on their first admission.

p464

The effect of the treatment was manifest within the first month of treatment - in mental impairment.

....The mental improvement went on pari passu with the disappearance of the bodily symptoms until the general enfeeblement disappeared ; the general sense of well-being became normal, the memory improved, the delusions disappeared, the affection for husbands and children returned, and the volition and originating power became gradually normal.

General Conclusions.- 1. The mental functions of the brain are always affected in myxoedema. 2. In a very large proportion of the total number of cases of the disease the mental disturbances are so severe as to amount to insanity. 3. Though in the "sane" stage, the mental symptoms of most cases closely resemble each other, being characterised by slowness of mental action and lethargy, in the insanity they differ entirely. 4. Common sensation and the special senses, as well as all the mental faculties, were in a marked pathological state. 5. The attacks had mostly an acute period, which was succeeded by a condition closely resembling a mild dementia with delusions of suspicion. 6. Under thyroid treatment, which was found to be best carried out slowly by small doses of one-sixteenth of a thyroid, both cases got well within six months, mental defect gradually disappearing, the whole mental powers acquiring strength, and the normal enjoyment of life being restored.

1893 DISCUSSION ON THE PATHOLOGY OF THE THYROID GLAND BMJ SEPT. 23 1893 Vol. II, p676 - 678

p677
III. JOHN THOMSON, M.D., Extra Physician, Royal Hospital for Sick Children, Edinburgh.
DR. JOHN THOMSON showed lantern slides of photographs illustrating the appearance before and after thyroid feeding in three cases of sporadic cretinism, aged respectively 5, 18, and 22 years. In all of them the progress had been remarkable. The main points of improvement were as follows :-
(1) The growth of the skeleton, in the young child, was very greatly accelerated, and in the older patients, who had not grown for fourteen and seventeen years respectively, it recommenced and proceeded actively for several months. (2) There was a rapid disappearance of the abnormal swelling, characteristic of the disease from all parts of the body in which it was met with. This was most strikingly seen in the face - the skin became sort and rosy like a child's, the features lost their bloated outline and became more natural in their conformation, and the muscles of expression were allowed freer play. In the same way the abnormal snoring ceased, the voice became more natural, and the articulation more precise. (3) The temperature became normal, and the patient ceased to complain of chilliness. (4) During the first two or three months there was, along with the emaciation, considerable muscular debility, but afterwards this passed off, and the muscles became much stronger than before. The appetite also improved, the bowels became regular, and the health was better in every way. (5) The mental progress was very difficult to gauge. There was certainly a distinct advance in mental capacity in all the cases. The parents and friends, however, were apt to over-estimate it, owing to the immense improvement which took place in the power of expressing mental action due to the recovered facial movements, the improved articulation, and the livelier gestures. Another important point was, that as the mental and bodily torpor of the disease passed off, the patients evidently acquired a capacity for enjoying life which was formerly quite unknown to them.

1893 HUNTERIAN SOCIETY F. GORDON BROWN, M.R.C.S., President, in the Chair. Wednesday, October 25th, 1893. BMJ DEC 9, 1893 P1275
THYROID TREATMENT IN MYXOEDEMA AND SKIN DISEASE.
DR. ARTHUR DAVIES read a paper on Thyroid Gland and its Therapeutic Value in Myxoedema and certain Skin Affections. He first briefly discussed the different theories as to the function of the thyroid gland, and showed that from experimental and clinical evidence the most important of these was that one which connected the function of the gland with the metabolism of the body. The results of transplantation of the thyroid gland by Kocher and Van. Esselberg, and the able experimental investigations of Horsley were alluded to. He then described the great therapeutic advance made by Dr. George Murray, who most successfully carried out the injection of the thyroid juice in a case of myxoedema. The disadvantages were also dwelt on - namely, (1) loss of consciousness, (2) tendency to syncope, (3) acceleration of pulse rate, (4) abscesses and indurations, (5) nausea, (6) flushings, (7) tonic spasms, (8) stabbing pains in the lumbar region.

1894 A REPORT ON SOME RECENT CASES OF "MALIGNANT" INDIAN SYPHILIS TREATED WITH THYROID EXTRACT BY J. DUNCAN MENZIES, M.B., SURGEON, R.N. [COMMUNICATED BY THE DIRECTOR-GENERAL R.N.] BMJ JULY 7, 1894 Vol. II, p12

DURING the homeward voyage from Bombay in H.M.S. Euphrates I had an opportunity of studying the therapeutic action of thyroid extract in a few bad cases of syphilis. The patients were all invalids, lying in the military hospital, having been sent down from their respective stations for change to England. They were all in a very weak, sickly state, the disease being complicated by malarial fever, bowel complaints, etc. All mercurial and alterative treatment was suspended for the time, in order to watch the effect of the remedy.

....The patient, when placed under my care on April 4th, was in a miserable corrupt state, his body being covered with foul, discharging, malodorous sores. On April 10th desquamation was noticed after 10-grain doses of extract. The old scars were actually peeling, and his general condition began to improve. The crusts over the ulcers became detached, leaving flat, pigmented, healthy granulation areas. On April 14th a large ulcer on the left hip was closing. On April 17th the dose was

increased to 20 grains. Pulse 96 ; no untoward symptoms. On April 20th the face was desquamating freely ; an ulcerated patch involving the right upper eyelid showed pink granulations. The sores were dressed with simple ointment. On April 22nd the dose was reduced to 15 grains, as there had been slight diarrhoea on the previous day. The patient continued to gain strength, and was discharged on April 27th.

Remarks.- This was my best case. No recurrence of the eruption took place. Old cicatrices took on a healthy action, and the pigmentation in a great degree disappeared. I should like to draw attention to the following considerations : 1. The exceptional virulence of the poison. 2. The undeniable value of thyroid extract given alone, without any mercurial preparations. 3. The hygroscopic and absorbent properties of the powdered extract. I have found it useful for insufflation and dusting purposes. "Tabloids" are very susceptible to moisture. Three other cases came under my notice : (a) Rupial ulcers of face and arms. (b) Ozaena, with ulceration of nasal passages. (c) Hereditary syphilitic patient with a broken down gumma of calf. These men also decidedly progressed under the new treatment. I am inclined to regard the remedy as a powerful skin tonic and adjuvant to the mercurial and alternative treatment of syphilis.

1894 CYST IN THE THYROID GLAND : REMOVAL : CURE. BY W. THELWALL THOMAS, F.R.C.S., Assistant Surgeon, Royal Infirmary, Liverpool : Demonstrator of Surgery, University College, Liverpool. BMJ DEC 1, 1894 Vol. II, p1231
IN July, 1894, Dr. Barlow, of Prescott, sent Mrs. S. T., aged 30, to the infirmary, on account of a swelling in the neck which resisted local treatment. She was very anaemic, and had noticed the lump for two years ; it steadily increased in size, and for twelve months caused severe pain during the swallowing of solid food. There was no history of any tumour in her family. ,....The case illustrates what has been recently made out, namely, that all local swellings in the thyroid gland, be they in the lateral lobes or in the isthmus, are composed of adenomata, simple or cystic, and are encapsuled, like an adenoma of the breast ; and further, that in the cystic variety the wall is not vascular. In the non-cystic adenomata the wall is very vascular, so that by carefully working around the capsule no serious haemorrhage may be feared ; they thus differ from the true parenchymatous goitre, in which the vessels are greatly enlarged and very thin, bleeding very readily on slight interference.

1895 MEMORANDA : MEDICAL, SURGICAL, OBSTETRICAL, THERAPEUTICAL, PATHOLOGICAL, ETC. A CASE OF MYXOEDEMA TREATED WITH THYROID EXTRACT BMJ MARCH 30, 1895 Vol. I, p697

M. A., single, aged 45, first consulted me in August, 1894. She complained of swelling of the whole body, breathlessness on exertion, etc. She attributed her illness to exposure to cold and wet during menstruation about eleven years ago. Her condition had gradually become worse until the time of coming under my notice.
She presented a general oedematous appearance, especially well marked in the connective tissue around the eyes, also in the lips and hands. The face was pale and waxy, with a circumscribed malar blush. The lips were swollen and translucent. her tongue was also swollen and appeared too large for her mouth, otherwise the alimentary system was normal. No trace of thyroid gland was to be felt. The first sound of the heart was faint but there was no murmur. The respiratory and urinary systems were normal. The skin was dry and harsh, the hair was very scanty. She had had complete amenorrhoea for about eleven years, while during the year previous to its entire cessation menstruation had been very irregular. Her speech was slow and thick and her memory was almost completely gone. Her movements were very slow and her gait uncertain and tottering. The diagnosis was myxoedema.

She was put on thyroid extract tabloids (B., W., and Co,) commencing with one half daily and gradually increasing to three a day.
From the first I noticed an improvement which has gradually increased until now the oedema has entirely disappeared. Her speech has lost its thickness, her memory has returned, and menstruation is now quite regular ; in fact my patient says that "she feels as well to-day as ever she did in her life."

I consider this case worthy of publication owing to the prolonged amenorrhoea and the return of menstruation under treatment at so late a period in life.
MATTHEW ELDER, M.B., C.M.Edin. Walls, Shetland.

1895 ON SOME TUMOURS OF THE THYROID GLAND BY ALFRED SQUARE COOKE, M.R.C.S. L.S.A., Surgeon to the Stroud General Hospital. BMJ June 8, 1895 Vol. I, p1262

p1262
I propose only to give a few notes concerning three cases of operation on the thyroid gland, which I have performed or assisted in performing during 1894. It is well known that goitre is very prevalent in the neighbourhood of Stroud ; but, notwithstanding this, I have never yet come across a case of either malignant, tuberculous, syphilitic, or hydatid goitre. In that neighbourhood, at least, the great majority of cases are cystic in character, yet extremely varied in their minor characteristics.
Apart altogether from the great inconvenience and unsightliness of these tumours, they acquire an importance which compelled attention to them from the fact that they were a constant danger to life. This danger was caused by the lateral pressure which they exercised at times upon the trachea, narrowing it even to occlusion.

p1263

As the result of my experience in these cases I would suggest that the observation of the following seven rules would greatly facilitate the successful completion of an operation :
1. Give chloroform as ether engorges the already enlarged veins.
2. Observe scrupulous cleanliness, have plenty of assistance, and many forceps and ligatures handy.

3. Take plenty of time.
4. After exposure of the cyst use only directors and fingers for dissecting, and keep close to the cyst wall.
5. Keep the fingers and wound moist with an antiseptic solution sufficiently weak not to irritate the sensitive and important nerves sometimes exposed, and, as far as possible, keep the parts in their normal position.
6. Partially evacuate a large cyst before removal to assist the later stages of the operation.
7. Insert a small drainage tube before sewing up for fear a collection of serum should press upon and occlude the trachea. The possible dangers which must be kept in mind and guarded against are three in number ; they are :
1. The wounding of large distended vessels.
2. The wounding of large nerves.
3. Cellulitis after the operation.
The after-treatment is quite as important as the operation. It also might be summed up under three heads :
1. Dust the wound with antiseptic powders, and apply gentle but firm pressure with a pad of antiseptic wool over the cavity left.
2. Keep the head and neck absolutely at rest for some days by pillows, sand bags, or splints.
3. Keep a careful watch that no retained serum causes pressure upon the trachea.
I consider the following are the indications that the tumour need removal :
1. If the tumour be steadily increasing in size.
2. If there be troublesome pressure upon the trachea, oesophagus, or nerves.
3. That the tumour be so placed as to render impossible a possibly necessary tracheotomy.
4. If the patient strongly urge its removal because of its unsightly appearance, or its interference with the movements of the head.

1895 A DISCUSSION ON THE SURGICAL TREATMENT OF CYSTS, ADENOMATA, AND CARCINOMA OF THE THYROID GLAND AND ACCESSORY THYROIDS. I. HENRY T. BUTLIN, F.R.C.S., Surgeon to St. Bartholomew's Hospital. BMJ OCT 12, 1895 Vol. II, p901 - 903

p901
Towards the end of March I received a letter from the officers of the Section to ask me to take the place of Professor Annandale, upon whom they had relied to introduce the subject of the surgical treatment of cysts, adenomata, and carcinoma of the thyroid gland and accessory thyroids, and who had, after long negotiations, reluctantly felt obliged to decline, as it was uncertain whether he would be able to attend our meeting. I cannot say I willingly accepted the task, for I was fairly frightened by the list of those who were to take part in the discussion, most, if not all, of whom know far more of the subject than I do ; but time was growing short, it was necessary that someone should undertake to open the debate, and I agreed to do so, because it was represented to me that if I had no claim to be the wisest, at least I must admit to be one of the oldest of those set down to speak.

p902
Here, for example, is a simple cyst in which only fluid was found. Here is a solid tumour which is formed of tissue resembling the structure of the thyroid gland. Here is a cyst in which an adenoma has grown, and here is an adenoma which contains a cyst. And here is another in which the cyst again contains a solid glandular growth. And here are larger complex tumours, in which the changes and relations of cysts and adenomata are rung in and out until the pathologist becomes confused in his attempt to assign the proper value to their component parts. But to the surgeon they all present some common features; they are innocent tumours, separate and generally easily separable, enclosed in distinct capsules, and for the most part growing in the midst of sufficiently healthy thyroid glands - glands which are certainly no more diseased than the mammary glands in which we find corresponding tumours.
It is difficult to understand why we have been so slow to become acquainted with these facts. Our ignorance of them is reflected in our nomenclature. We still speak of a cyst, simple or proliferous, of the thyroid gland as a "cystic goitre," which may be translated into "cystic enlargement of the thyroid gland ;" and of mixed solid and cystic tumours as "cystic adenomatous goitres," terms which seem to imply that there is some general affection of the thyroid gland, instead of a tumour in the substance of the thyroid gland.
....With a better knowledge of the conditions to be dealt with a more reasonable and appropriate surgery has grown up. Cysts and adenomata are removed precisely by the same method as is employed for their removal from many other parts of the body ; indeed, much more easily than from some parts of the body, on account of the readiness with which they can be separated from the tissues of the thyroid gland. I need not describe the operation further than to say that the tumour is exposed by a free incision ; that the structures over it, including a layer of the thyroid gland itself, are divided until the capsule of the tumour is apparent. The capsule can almost always be readily distinguished by its bluish tint, compared with the redder colour of the thyroid gland, with which it may be confounded. From this point the knife is used as little as possible ; the tumour is separated, generally quite easily, from the surrounding tissues with the finger, aided by an occasional

touch with the knife or scissors to some firm band which will not yield. The haemorrhage is temporarily arrested with clamp forceps, and, after the removal of the tumour, the vessels are tied with catgut. The wound is treated precisely in the same manner as any other wound of the neck or body.

p903
To my mind, there is one great objection to the treatment of cysts and adenomata of the thyroid gland by excision or enucleation - the scar. And in the cases of young subjects I can never reconcile myself to it. At the present time we are so enamoured of our art and so pleased with our achievements in surgery that without hesitation we cut wounds which leave long scars in the neck, white and fine and perfect as scars, but cruel disfigurements in the eyes of the patients and their friends.
To avoid such scars I have, in a certain number of cases, employed Morell Mackenzie's method of treating cysts by injection. This method, which I believe to be excellent in suitable cases, has fallen much into disuse, partly because of its uncertainty, partly because it is not free from danger, and is sometimes very long-lasting and tedious ; and partly because the method of treatment by enucleation is at present in vogue, for we have our fashions in surgery as in our dress and manners. ....And in order to do so with the best prospect of success and with the least danger, I have again quite recently studied the accounts of cases to discover, if possible, the conditions which have led to failure, and the causes of danger or of death : for it is said that in some cases repeated injections have failed to cure the disease, and in other cases an injection has been immediately or quickly followed by death, presumably from thrombosis or embolism, or the entrance of air into a vein, or there has been paralysis of a vocal cord and permanent affection of the voice, or diffuse suppuration has occurred in the tissues around the thyroid, and this has sometimes led to death.
I believe that failures and danger are largely to be ascribed to the treatment of improper cases, and the selection of fit cases has been rendered unduly difficult by our confused knowledge of the pathology of tumours and enlargements of the thyroid gland.
....In spite of careful selection of cases for injection, it is probable that some cases will end in failure, for it is not possible invariably to gauge the fitness of the individual case. It may then be necessary to excise the disease. I should have thought that an operation undertaken under such circumstances would prove to be very difficult. I have never myself performed it, but other surgeons have done so, and their reports do not tell of greater difficulties or dangers than are met with in ordinary cases.
Of other methods of treatment of cysts and adenomata of the thyroid gland I have had no experience, nor have I any inclination to adopt them, unless a better account is given of them to-day than I have learned from reading.
It will be seen, Sir. that I have not dealt with parenchymatous enlargements of the thyroid gland, whether simple or containing cysts. To have done so would lead to long and probably discursive discussion. You, Sir, in your good judgement, defined the subject for discussion in such a manner as to exclude all true goitres. And I have thankfully availed myself of your definition, for it saved me from dealing with matters in which perhaps I should have gone beyond my depth.

1895 A DISCUSSION ON THE SURGICAL TREATMENT OF CYSTS, ADENOMATA, AND CARCINOMA OF THE THYROID GLAND AND ACCESSORY THYROIDS. III. W. W. KEEN, M.D., LL.D., Professor of Surgery, Jefferson Medical College, Philadelphia ; Surgeon to Jefferson College Hospital BMJ OCT 12, 1895 Vol. II, p904

PROFESSOR KEEN drew attention to the fact that on the Continent of Europe thyroid operations were done without the use of anaesthetics except in children under 15 and in very nervous patients. He was much struck with the very slight pain of the operation. When no anaesthetic was given there was less haemorrhage since the respiration was less embarrassed, and the patient did not cough when coming to. Also during the ligation of the inferior thyroid artery the patient was induced to talk in order that it might be seen whether the recurrent laryngeal nerve was included in the ligature. Professor Kocher, whose practise he was describing, made a transverse incision convex downwards so as to get at the thyroid better, and leave a well- concealed scar. Dr. Keen thought the scars in Mr. Butlin's cases very slight. He suggested the use of Halstead's subcuticular suture for the purpose of obviating unsightly scars. This is effected by a moderately stout silver wire carried backwards and forwards across the face of the cavity beneath the skin. The wound is slightly puckered at first, but when the suture is removed, in some cases after as long as three weeks, almost no visible scar is left. There is no invasion of the ligature by the epidermal streptococci. Dr. Keen's own personal trouble in these cases was haemorrhage. Much attention is paid to this in Switzerland, every bleeding point (artery, vein, or tissue) being seized in pressure forceps and subsequently, if necessary, ligatured. Thus not more than 2 ozs. of blood are lost during the operation. Professor Kocher, after his first incision, cuts right down to the tumour, tying every source of bleeding. He then goes for the tumour, commencing his extirpation at the upper part, which he can often wipe clean from the surrounding tissues. He next ties the superior thyroid artery and vein, and then goes right down to the thyroidea ima. He finally feels for and ligates both inferior thyroid arteries in succession, then removes the tumour. Dr. Keen assented to Mr. Butlin's statement that in diseases of the thyroid the treatment should rest on a pathological basis.

1895 A DISCUSSION ON THE SURGICAL TREATMENT OF CYSTS, ADENOMATA, AND CARCINOMA OF THE THYROID GLAND AND ACCESSORY THYROIDS. VI. JAMES BERRY, B.S., F.R.C.S., Surgeon, Royal Free Hospital BMJ OCT 12, 1895 Vol. II, p904 - 905

p904
MR. BERRY said : I think it ought to be clearly borne in mind that the great majority of cases of goître that we meet with in practice require no surgical treatment. I cannot help thinking that of late years operations for goître have been performed a little too often, sometimes when they were really not necessary. In my own practice I operate only on a small minority of cases that come under my notice. There should, in my opinion, always be some definite reason for the operation other than the mere presence of a tumour. That reason in most cases is dyspnoea. I find from my notes that my operations for the removal of goître have been 36 in number, and that in 31 of these cases the operation was undertaken on account of dyspnoea, often dyspnoea of a severe and paroxysmal nature. In one case dysphagia was the cause of operation, in another a septic sinus that had followed injection of a large cystic goitre performed a year previously at another hospital ; in 3 cases only have I operated merely for deformity ; in 2 of these the patients were young ladies exceedingly anxious to be rid of a deformity which prevented them from wearing low dresses.
There are two main classes of operation by which removal may be effected, and these two classes are essentially different. One is extirpation of a part of the gland together with its glandular capsule, an extraglandular operation ; the other is enucleation of a localised tumour, whether cyst or adenoma, from within the thyroid gland in which it lies embedded, an intraglandular operation.
p905
A few words in conclusion upon the complications of operations upon goître. By far the most serious are sepsis and haemorrhage. Of the former it is not necessary to say much. It is of course all important that the operation should be strictly aseptic, and I have pleasure in stating that I have never lost a patient from suppuration or other septic complication following an operation for goître. In one case some suppuration was followed by a slight attack of pneumonia, and caused much anxiety for about three weeks, the patient then making an excellent recovery ; this was a case of extirpation of a large bilateral parenchymatous goître. Haemorrhage, especially venous haemorrhage, I have found occasionally to be troublesome. This has especially been the case with some enucleations. I consider that haemorrhage is less serious in cases of extirpation, because every vessel should be seen, and tied or clamped before it is cut. In all my later cases of extirpation, the loss of blood has been quite trivial, and I hardly ever see spurting from any artery except the most minute. With enucleation the case is somewhat different. In the great majority of cases there is very little bleeding, but sometimes, especially in the case of large tumours and tumours in young subjects, the haemorrhage may be very alarming. It is best dealt with by rapidly completing the enucleation, and then temporarily drawing the bottom of the wound forward with a pair of forceps. Of wound of the recurrent nerve a grave complication by no means unknown, I have fortunately had no personal experience.

1896 ENLARGED THYROID : DISAPPEARANCE OF GLAND FOLLOWED BY MYXOEDEMA. BY T. F. HUGH SMITH, F.R.C.S., Farningham, Kent. BMJ JAN 4, 1896 Vol. I, p14 - 15
The patient, H. C., was born in Kent. Her paternal grandfather and a paternal aunt both died "dropsical." Her father died aged 56 from endocarditis. Her mother's father and two uncles died with "dropsy." Of the patient's own brothers and sisters, six died in infancy ; of two brothers living one suffers from rheumatism and alopecia the family came out of Norfolk into Kent.

H. C., aged 26, enjoyed good health until she was aged 17, when enlargement of throat and prominence of eyeballs were noticed. There was also present a hurried jerky manner both in speech and in the movements of the limbs.
....At the age of 21 the catamenia appeared, and at the same time the general health improved. During the past four years the hair of the head has been coming out ; for three years a dry harsh condition of the skin has been noticed ; speech has become less distinct than formerly and slower in character ; a feeling of coldness is constantly complained of ; the appetite has been indifferent, and constipation has been the rule.

In March, 1893, the condition of the patient was as follows : The expression of the face was vacant ; there was an appearance as of oedema under the eyes and a fulness under the chin. The face and neck were sallow and pigmented, with a flush over the cheeks. The eyelids met together when closed (formerly the eyeballs were partially exposed). The skin of the hands was hard, dry, and thickened. The tongue was enlarged ; speech was slow and rather indistinct. There was no albumen in the urine. The heart and lung sounds were normal. The temperature was 96.4°. Constipation was present.
Although there existed ten years earlier considerable enlargement of the whole gland, the substance of the thyroid body could not be detected either by sight or by palpation.
Towards the end of March, 1893, dried sheep's thyroid was given in 5-grain doses twice daily ; the weight of the patient being 10 st. 9 lbs., and her pulse 84.
....On September 18th the patient appeared to be in a normal state of health. She had worked in the fields since July.
In this case a condition resembling Graves's disease existed six or seven years prior to the appearance of the first symptoms indicating the onset of myxoedema.
The clinical history of the case seems to justify the conclusion that complete atrophy of the thyroid followed the well- marked general enlargement of the gland which was observed and verified ten years ago.

1896 AFTER HISTORY OF THE FIRST CASE OF MYXOEDEMA CURED BY THYROID EXTRACT. BY GEORGE R. MURRAY, M.A., M.B.CAMB., M.R.C.P.LOND., Health Professor of Comparative Pathology in the University of Durham ; Pathologist to the Hospital for Sick Children, Newcastle-on-Tyne. BMJ FEB. 8, 1896 Vol. I, p 334 - 335

....myxoedema can be cured, and that it does not return when the use of the remedy is continued. It is necessary, however, to be quite clear as to terms. Myxoedema is a symptom or combination of symptoms of loss of the function of the thyroid gland. In the idiopathic form it is a symptom of chronic interstitial thyroiditis, just as anasarca may be a symptom of renal disease of ascites of hepatic disease. Thus the myxoedema can be cured, although the chronic interstitial thyroiditis still remains. As myxoedema is thus a symptom of thyroid inadequacy, it not only occurs as a result of removal or of fibrosis of the thyroid gland, but also in rare cases in consequence of other diseased conditions of the gland.

....In myxoedema which accompanies fibrosis of the thyroid gland, we cannot restore the gland to its normal condition, but we can restore the patient to health if no incurable complication has arisen. For example, a gentleman, aged 44, who had suffered from myxoedema for about two years and a-half, was sent to me three years ago. At that time he suffered from well-marked myxoedema. He could scarcely walk half a mile, and could undertake no work. Under treatment by thyroid extract, rapid improvement took place, so that in six weeks the myxoedema had almost entirely disappeared. Five months later he wrote to say that he was "quite cured."

....In order to show that patients remain free from nyxoedema as long as they take thyroid extract and without any increase in the dose, a short reference must be made to the first case in which the treatment was adopted. This patient was a woman, aged 46, who had suffered from myxoedema for four or five years. There was well-marked swelling of the face, hands, and feet ; dry skin, without perspiration ; loss of hair, subnormal temperature, langour, slowness of speech and action. It is now four years and a-quarter since the treatment was first commenced in April, 1891. She gradually lost all the symptoms of myxoedema, which, however, partly returned on two occasions when the use of the remedy was discontinued for a time. She has for long been free from myxoedema, and is so now. The swelling has gone, and the skin is soft and moist ; the hair has grown again, the temperature is normal, and she leads an active live as the wife of a working man. She continues to take one drachm of thyroid extract during each week. As this case remains well at the end of more than four years, it is evident that as long as she continues to take the extract she will not have myxoedema, even if she lives for another twenty years. This continuance of good health in the adult gives us all the more reason to expect that cretins, if treated early and continuously, will also grow up and develop into normal adults. It will, of course, take years to prove this, but I have brought forward these observations, as they help to show that in cretinism it is well worth while to persevere with the treatment year by year with this object in view.

1896 TENDENCY TO BENDING OF THE BONES IN CRETINS UNDER THYROID TREATMENT. BY T. TELFORD-SMITH, M.A., M.D., Medical Superintendent Royal Albert Asylum, Lancaster. BMJ SEPT. 12, 1896 p 645 Vol. II

ONE of the most marked among the many other signs of development produced in cretins during the administration of thyroid preparations is the rapid increase of growth in stature which takes place, an effect which is all the more striking when we remember than in these cases growth is almost at a standstill previous to treatment.
.... As a point in the practical treatment of these cases, I have found that during thyroid treatment this rapid growth of the skeleton leads to a softened condition of the bone, resulting in a yielding and bending of those which have to bear weight ; and as cretins under treatment become much more active and inclined to run about, this tendency to bending has to be guarded against.

....Cretins under thyroid treatment should therefore be watched for any commencing bending of the bones of the legs ; and if such appears, the child should for a time be hindered from walking, or the legs supported by light splints. As an additional means of assisting the rapid bone and other growth, the diet should be generous, and the child should get plenty of sunlight and open air.

1896 NOTES ON A CASE OF SPORADIC CRETINISM. BY W. H. GEORGE, M.R.C.S.ENG., L.R.C.P.EDIN. BMJ SEPT. 12, 1896 Vol. II p 647 - 647

THE successful treatment of sporadic cretinism by the thyroid method is such an established fact that the repetition of instances may well appear superfluous and unnecessary.
....R.S., a female, aged 12, first came under observation on May 7th, 1894, when her physical characteristics were those of a marked case of cretinism

....The child is the elder of a family of two, the other child being perfectly healthy and intelligent. The present condition is stated to have existed since birth, the labour being apparently normal in every respect. The child had never learnt to speak, and did not attempt to utter any sounds. The height was 2 feet 9 inches, not having increased perceptibly for six years. The tongue was habitually protruded, and there was constant dribbling of saliva. There was no sign of any permanent teeth, the incisors being notched and the molars carious. The anterior fontanelle was still patent, and the abdomen very protuberant, with a small umbilical hernia. As shown in the illustration (Fig 1), the left foot was in a condition of semi-talipes.

The parents were both in good health
....The child was at once placed on thyroid treatment, receiving 5 gr. (in Burroughs and Wellcome's tabloids) daily. Owing to distance exact observations could not be made, and the mother was instructed to give one tabloid daily when it could be taken without marked constitutional disturbance, hence about twenty-four tabloids were taken in six weeks at first, but the full number as time went on. In rather less than five weeks afterwards the dull phlegmatic condition was disappearing. A

brighter expression was seen in the face, and dawning intelligence was shown in the child's increased observation and attention to its surroundings.
....On December 21st, the abdomen was becoming less prominent. The child was found to be cutting a permanent molar, and was able to say, "Dada," "Mamma," and "butter," the words appearing to indicate definite ideas, and not being repeated in parrot-like fashion.
On January 23rd, 1895, a remarkable change was visible in its general condition, as shown in the third photograph (Fig. 3). The height had increased to 2 feet 11 inches. There was entire absence of the vacuous expression originally noticed. Speech was very distinct, and the vocabulary was increasing daily. The hernia had practically disappeared, and the abdomen was nearly of a natural size, whilst the extremities were firm and plumply rounded. By June another half an inch had been gained in stature, and the child was able to talk fairly well.
Even had no mental progress been made, the successful result of the treatment physically alone is worthy of record. Indeed, it is difficult to realise that the first photograph can be that of the same individual as the attractive, intelligent-looking child shown in the third.
It is to be regretted that a fatal attack of diphtheria prevented the further observation of the case.

1896 A DISCUSSION ON SPORADIC CRETINISM IN THIS COUNTRY AND ITS TREATMENT. A LANTERN EXHIBITION OF CRETINS ILLUSTRATING THE EFFECTS OF THYROID TREATMENT. I. - W. RUSHTON PARKER, M.A., M.D., Honorary Surgeon, Kendal Hospital BMJ SEPT 12, 1896 Vol. II p 615 - 617
p615

....3. A striking diminution of several hideous deformities, especially of the lordosis in the lumbar spine, of the bulky head, of the ugly sinking of the bridge of the nose, and sometimes of the rickety curvatures of the legs. Many of the pictures, however, showed little or no improvement in the deformity of the legs, owing to the softening of bones produced by thyroid extract and to the fact that the majority of cretins were allowed an undue use of their legs during treatment.

4. A rapid and very striking increase of intelligence occurred, as was well shown by comparing the dull, stupid, heavy, listless, often idiotic countenance before treatment with the bright, cheerful, pleasing expression which soon took its place. It was stated that no other disease existed the treatment of which lent itself so admirably to photographic display, and that the treatment of cretinism by thyroid extract was one of the greatest triumphs of modern therapeutics.
Dr. Parker added that there appeared to be at least three pathological varieties of cretinism. The first variety is embryological, due to non-development or partial development of the thyroid body, and analogous to any other malformation from deficiency, such as absence or arrested development of uterus, ovaries, testicles, etc., acardia, acephalism, anancephalism, etc. A second variety is due to atrophy of the thyroid parenchyma, occurring occasionally after some serious illness in childhood, and analogous to the atrophy of the testicles after mumps. A third variety is due to goîtrous degeneration of the thyroid body. Though the etiology and pathology of these varieties are quite distinct, the symptoms appear to be identical, and to be due solely to the degree to which the function of the thyroid body is lost, and the youthfulness of the patient in whom the loss of function occurs.

1896 A DISCUSSION ON SPORADIC CRETINISM IN THIS COUNTRY AND ITS TREATMENT. A LANTERN EXHIBITION OF CRETINS ILLUSTRATING THE EFFECTS OF THYROID TREATMENT. II. - TELFORD- SMITH, M.D., Medical Superintendent, Royal Albert Asylum, Lancaster. BMJ SEPT 12, 1896 Vol. II p 617 - 618 p616

THE THYROID TREATMENT OF CRETINISM AND IMBECILITY IN CHILDREN.
....There are, however, among idiots generally many cases showing defects, both of body and of mind, of a more or less similar character to those found in cretins, so that, to those at least who have to deal with large numbers of idiots, the wider question is inclined to occur : Does defective function of the thyroid enter as an appreciable factor into the causation of idiocy? and if so, may not some degree of improvement, similar to that produced in cretins, be looked for in other cases during the administration of thyroid preparations. Borneville has shown, by a table he published of the weights of the thyroid in different cases of idiocy, that there is a considerable variation in the size of the gland. May there not also be variation in the completeness with which it fulfils its functions?
Idiots belonging to the so-called Mongol type are those who most nearly resemble the cretin, both in physical aspect and in mental character. In idiots of this type we get the stunted growth, the dull heavy expression, with open mouth and thick lips ; the slow deliberate movement, and hoarse, guttural and monosyllabic speech ; the mental apathy, and lack of spontaneity ; the sluggish circulation and sensitiveness to cold. A thickened condition of subcutaneous tissue is often found, with dulled cutaneous sensibility. The skin is coarse and dry, the hair short and thin. First and second dentition are delayed. As far as palpation enables one to judge, the thyroid gland is subnormal in size. Pseudo-lipomata I have not found. The temperature is always subnormal, ranging between 96.5° and 97.5°.
p617
....I have for over two years been trying the effects of thyroid treatment in cases of Mongol idiocy, and, put briefly, my experience is as follows :
Improvement of a physical and mental kind takes place. This varies inversely as the age of the patient. The improvement is not nearly so marked nor so rapid as in the case of the cretin. The temperature reacts, but only slightly ; it cannot be kept at normal. There is some improvement in the condition of the skin ; it desquamates but does not become normally smooth. Tarsal ophthalmia (marginal blepharitis), which in these cases is almost chronic, improves considerably, and in some cases is

cured. Growth improves, but does not react in anything like the rapid manner seen in cretinism. The mental condition of the child improves ; the apathy is less pronounced ; the patient becomes more active and spontaneous in his movements ; he plays more like other children, and joins in the simple amusements or employments going on around him ; he even works voluntarily. His speech is less thick and guttural, and he talks and chatters to a more normal extent. His mental reflexes all seem more active, and there is a decided advance on the patient's previous rather vegetable existence.

p 618
....I have found extreme bowing to the legs to take place during treatment, and I have had to place the patient in bed, and I would warn those treating cases to be on their guard against this complication.
In conclusion, I think that in cases of Mongol idiocy thyroid treatment should be pursued, the earlier the better. Caution should be observed in the dose, as the heart is undersized and weak in these patients. A small dose administered daily with dinner, and increased very carefully, will act best (from half to three 5-gr. tabloids daily). The temperature, weight, and state of general nutrition should be watched in all cases. In many cases of mental apathy and disinclination to movement or speech in idiot children not otherwise cretinoid, I think treatment with thyroid is well worth a trial.
If in these children we can, even to a small degree, improve cerebration, and make movement more spontaneous, the work of training them and developing them in an educational manner is considerably assisted.

1896 A DISCUSSION ON SPORADIC CRETINISM IN THIS COUNTRY AND ITS TREATMENT. A LANTERN EXHIBITION OF CRETINS ILLUSTRATING THE EFFECTS OF THYROID TREATMENT. III. - JOHN THOMSON, M.D., F.R.C.P.Edin., Edinburgh. BMJ SEPT 12, 1896 Vol. II p 618 - 619
p618

ONE of the next things wanted in our study of the thyroid treatment of cretinism is a clearer idea of the amount and exact nature of the improvement to be hoped for. Now, the improvement of cretins under thyroid is a much less simple thing than that of ordinary myxoedematous adults. In cretins the treatment not only clears away the characteristic deformity and dulness, but also lets loose on the patient some at least of the natural impulses of growth which were in abeyance in his former thyroidless condition.

...DISTRIBUTION OF THE GROWTH
In the child, the degree of growth of the different parts of the body seemed in all respects normal. In the older cretins, however, there were certain marked peculiarities. For instance, the hands and feet in all the four were very characteristically broad and dwarfed at the beginning of the treatment. In the two adult patients these have changed very little in character, while in the adolescents they have grown very long and become much more natural in shape.
Another point is rather curious. When a normal child gets taller we find that the lower limbs grow considerably faster than the trunk and upper limbs do, and consequently that the centre of the body changes from the umbilicus in infancy to the pubes in adult life. Now the young cretin grew normally in this particular. In the adolescents the growth of the upper and lower limbs was very nearly the same, while in the two adults the arms grew more than the legs.
3. COMPLICATIONS
(a). Increase of Spinal Curvature. - In two of my cases - the older of the adolescents and the younger of the adults - there was very severe lateral curvature, and in both, especially the former, this increased considerably under the treatment. In these two, therefore, the mere increase in height was not a reliable index of the growth of the body.
(b). Bowlegs. - In both the adolescents the growth of the bones was accompanied by such softness that the increased standing and walking led to great bending of the legs which closely resembled that commonly produced in rickets. In the boy, who walked much more than usual soon after the beginning of the treatment, the bending of the legs was noticed within three months. It has increased greatly (Fig. 1), but has never gone far enough to interfere much with his power of walking. In the girl, who was very long in beginning to walk, and did not do so freely until she had got very heavy, the bending only began in the second year. When it did begin, however, it was very extreme in amount (Fig. 2) and rapid in development, and it has crippled her to a very serious extent.
Possibly this tendency to bowlegs may be due to too large doses of thyroid or to some other indiscretion in the treatment. It certainly seems likely to constitute a troublesome complication in the management of adolescent cretins.
p619
....What the pathology of these soft bones is I shall not venture to decide. When one sees the bent limbs, the enlarged epiphyses, and sometimes a sort of rosary on the chest wall, along with profuse sweating, nocturnal restlessness, and muscular debility, one naturally asks oneself whether, in restoring to these adolescents the growing capacities of babyhood, we have not also given them back the liability to rickets which they had left far behind them. It seems quite probable that this may be so.
4. THE HAIR OF THE HEAD
The hair was affected differently in the older and younger cases. In the child and in the two adolescents the characteristic coarse hair was rapidly replaced by softer and finer hair of a somewhat duller shade. In the adults, after more than two years' treatment, there was practically no change in its character or colour.
5. THE MENTAL IMPROVEMENT.
The mental change is exceedingly difficult to estimate and also, indeed, to define ; I shall, therefore, only attempt to speak of a few points which seemed tolerably distinct in my cases.
p 620
....There was, however, also evidence of some real mental improvement in all my five cases with the doubtful exception of

the oldest one. It was not distinctly perceptible until the sixth or eighth month, or later. About that time the weight was beginning to increase again, and the bodily functions of all sorts were becoming more vigorous and normal. The mental improvement seemed, therefore, part of a general upward move, and although it was very slight it was permanent and progressive.

....The patients became more inquisitive, more independent and enterprising, more "naughty," as the parents said, and they were more inclined to play actively, for example, they began to dress and undress their dolls which formerly they just sat and looked at.
Lastly, as the natural result of the greatly increased activity of mind and body the abnormal shyness when present passed off, the irritability lessened, and there was a remarkable increase in the patient's capacity for happiness. From being dull, morose, and self-centred, they became in a varying degree bright, happy, and sociable.

1896 A DISCUSSION ON SPORADIC CRETINISM IN THIS COUNTRY AND ITS TREATMENT. A LANTERN EXHIBITION OF CRETINS ILLUSTRATING THE EFFECTS OF THYROID TREATMENT. IV. - VICTOR HORSLEY F.R.C.S., F.R.S., Surgeon to the National Hospital for the Paralysed and Epileptic. BMJ SEPT 12, 1896 Vol. II p 620

MR. VICTOR HORSLEY showed a photograph of a rare and well-marked specimen of intrauterine cretinism. The child was stillborn and the case corresponded with the description of foetal rickets. The changes in the bones had been investigated by Hofmeister and von Eiselsberg, who found a great similarity to those of ordinary rickets, and studied them in reference to the removal of the thyroid of animals at birth. Cretins whose bones showed signs of softening should be kept lying down as they would be in ordinary rickets. Grafting thyroid into the peritoneal cavity was only a temporary measure equivalent to injection of thyroid material, in no way constituting a real transplantation of the gland, which should be effected by imbedding the gland in connective tissue.

p621
Dr. OLIPHANT NICHOLSON (Kirkcaldy) said that, with regard to the etiology of cretinism, it would be interesting to acquire more information on the geographical distribution of the disease, and compare the geological formation of the specially affected areas ; also their situation and peculiarities. At present the data were insufficient to enable us to say whether or not the geology of a district had anything to do with the occurrence of cretinism, and if the disease was in any way connected with the presence of an excess of soluble salts of lime or iron in the drinking water one would expect to find a large number of cases in London and along the valley of the Thames. But if specially affected cretinous districts were mapped out all over the globe, or even over the British Isles, one might find some common element existing as a possible factor in the causation of the disease. Then any relation between ordinary goître and cretinism should be more carefully studied, and it might be found that a specially goîtrous district was also a cretinous one. Some thirty years ago at Penrith in Cumberland, simple goître was a fairly common disease, and now it was a comparatively rare one, possibly because the town was supplied with river water, while formerly the inhabitants were much more dependent on well water containing a large percentage of lime salts from the red marls and limestones of the district. Goître was, however, still not uncommon in the country villages along the Eden valley, and cretins would seem to be found oftener in the English lake district that in any other part of Britain.

1897 BIRMINGHAM AND MIDLAND COUNTIES BRANCH OF THE BRITISH MEDICAL ASSOCIATION. C. W. SUCKLING, M.D., in the Chair. Friday, November 27th, 1896. PATHOLOGICAL AND CLINICAL SECTION. BMJ JAN. 9, 1897
THYROTOMY PERFORMED THREE TIMES ON ONE PATIENT.

MR. BARLING showed sections from a case of epithelioma of the larynx. The patient first came under observation in July, 1892, when thyrotomy was performed and a large quantity of simple papillomatous growth was removed. Two years later thyrotomy was again performed for recurrence, and this time sections of the growth showed that it was altering its nature, there being distinct, though few, cell nests. In April, 1895, a permanent tracheotomy tube was inserted, as cicatricial stenosis now existed, which was not relieved by intubation ; but at this time there was no recurrence. In July, 1896, the patient again presented himself, with pain and swelling of the neck and a good deal of fixation of the larynx. At this time the larynx was occupied by growth, which was attached widely on both sides, and parts of which were necrosing. The diagnosis now made was epithelioma, which had probably perforated the thyroid cartilage and invaded the soft tissues around. In a few days, however, it was evident that pus was forming in the neck, and as soon as this was let out the infiltration rapidly disappeared and the larynx again became movable. Thyrotomy was performed a third time, and a considerable amount of growth removed, which was entirely confined within the larynx. After this was extirpated, the remaining soft parts within the cavity were cleared out with scissors and the galvano-cautery was freely applied. The growth this time proved to be definite epithelioma. On each occasion the patient, a stout man aged 54 at the present time, made a good recovery, and was well as recently as two months ago. Hahn's tube was used at all the operations, and was replaced by an ordinary cannula the same day.

1897 PROGRESS REPORT OF A MYXOEDEMATOUS SPORADIC CRETIN. BY J. LOCKHART GIBSON, M.D.EDIN., M.R.C.S.ENG., Brisbane BMJ MAY 29, 1897 Vol. I p 1340 - 1342
p1340

....The series of photographs then published showed the myxoedematous sporadic cretin first getting steadily more myxoedematous, and then, after thyroid grafting, steadily improving. The improvement continued for some months after the last photograph published, and then became stationary. It seemed probably that sufficient of the gland which had been grafted into the peritoneal cavity had not survived for the boy's needs, and that thyroid feeding would prove the truth or fallacy of this surmise. He was put therefore, on thyroid tabloids (Burroughs, Wellcome), and began to improve further. It has, however, never been possible to give him many tabloids, as an excessive dose at once induces marked irritability of temper and diarrhoea. He has been taking lately one tabloid daily, and this is the largest daily dose he will bear.
p1341
....He had before the last report lost all signs of myxoedema, though remaining a cretin. He is steadily losing his cretinism, and is now a really intelligent looking, sturdy little boy.
....His height is now 3 feet 3 inches. At the end of 1892 it was just below 33 inches. I think of making a further endeavour to graft thyroid gland, as the outlook of thyroid feeding for the rest of his life is not a satisfactory one.

1897 REMARKS ON TUMOURS AND ENLARGEMENTS OF THE THYROID GLAND TREATED SURGICALLY. BY F. T. PAUL, F.R.C.S., Surgeon to the Liverpool Royal Infirmary BMJ JUL 3. 1897 Vol. II p 1 - 7 p1
HAVING during the last few years operated upon twenty-three cases of various forms of enlargement of the thyroid gland, I hope it may prove of interest to give a short sketch of the cases so treated. They arrange themselves in three groups - tumours, parenchymatous goître, and exophthalmic goître ; of the first 12 cases, of the second 5 cases, and of the last 6 cases. Tumours and parenchymatous goître are frequently confounded - a reasonable error, since structurally they are often identical, and not rarely are present together. Even Graves's disease in its early stages may be difficult to distinguish from some cases of tumour, as several similar symptoms may be presented by each before exophthalmos is fully developed. Here pathological anatomy is of service to us. The structural changes in Graves's disease are in a way unique, being neither inflammatory, degenerative, nor neoplastic, but more evolutionary as in the lactating mamma. This serves to distinguish it from all other affections of the thyroid. The pathological anatomy explains, too, on the theory that the symptom-complex of Graves's disease is due to the toxic secretions of the altered gland, how it is that similar symptoms may be met with in totally different affections of the gland, if the tissue changes are in any way allied.
GENERAL STRUCTURAL CHANGES
The remarks contained in this paper are based upon the cases operated on, together with some half dozen cases of cancer. A careful examination has been made of each specimen, and whether speaking generally or in regard to a special point, I wish to be understood as referring to the results obtained from the examination of my own material, and not as quoting from the work of others, with which in most instances these results are in accord.
....The epithelium : New gland follicles originate in three ways. 1. By the enlargement of old follicles, and the budding into them of branching epithelial growths from their walls until a complete lobule takes the place of what was previously only a follicle. (Fig. 9.) This intrafollicular hypertrophy is characteristic of Graves's disease, except that it is closely mimicked by typical thyroid carcinoma. 2. By the development of new follicles from gland cells lying between the old follicles (Fig. 4.) This intrafollicular mode of growth is usual in parenchymatous goître and adenomata. 3. By the budding growth of foetal thyroid (Fig. 6.), sometimes met with in adenoma, and possibly originating in "rests," or parathyroid tissue.
....MINUTE STRUCTURE AND CLASSIFICATION OF THE ADENOMATA.
Without pretending that these twelve cases of thyroid adenoma cover the entire field, I believe I am fortunate enough to include amongst them what are probably the leading types of innocent glandular growth in this organ. They remind one of other and better known adenomata in their general characters, but they present special features of which the following are amongst the more important :- 1. Their structure is generally purely glandular. 2. They are often multiple. 3. They are frequently cystic. 4. Haemorrhages into them are very common. At first one is inclined to divide them into two chief groups, the cystic and the solid, but such a classification is unscientific, as the cysts are not derived from distended follicles, but except in rare instances are produced by the continuous breaking down of the walls of the follicles, until more or less of the tumour is converted into a cyst.
p2
....STRUCTURAL CHANGES IN PARENCHYMATOUS GOÎTRE.
These, so far as my cases go, resemble the appearances seen in colloid adenoma, though the colloid matter is more limited to the interior of the follicles. The epithelium is flattened, and droplets of clear secretion are absent, or almost absent. (Fig. 7.) The gland, though so large, appears to be functionally quiet. Sometimes the collections of colloid are very large, apparently owing to the coalescence of several follicles.
....STRUCTURAL CHANGES IN EXOPTHTHALMIC GOÎTRE.
These are very different. They are characterised by the evident activity of the gland epithelium. When thyroidectomy has been performed at an early stage of the disease plenty of colloid matter is found in the follicles, and it would seem that the first effect of the increased activity of the gland is to distend the enlarging follicles with colloid matter. (Figs. 9. and 11.) The process however does not rest here at all, for the lining epithelium continues to grow and multiply, being in some instances shed into the follicles till they are full of cells, but generally the growth takes a villous character protruding into the enlarged follicle, and growing, branching, and coalescing again, until what was originally a single vesicle becomes a definite lobule composed of glandular acini lined with columnar epithelium and containing only a clear secretion and no colloid matter. (Figs. 9. and 10.)

....Perhaps there are colloid, catarrhal, and villous forms, all mere structural varieties or different stages of a pathological change indicating greater secreting energy. The colloid form is not like colloid but like mucous adenoma.
....In regard to the vascularity of the gland in Graves's disease, as I have already stated, I am of opinion that it is decidedly greater than in other forms of goître, and I have seen some specimens in which the vascularity was in excess of what should be required to meet any increased functional activity sufficient I should say to constitute a condition which might present the clinical features of a vascular tumour. (Fig. 8.) In considering this matter it should be remembered that surgical specimens may differ considerably from post-mortem specimens, since the evolutionary changes tend to end in sclerosis, and therefore the more advanced the disease beyond the full development of the affection, the less likely it is to show excessive vascularity.

RELATION OF STRUCTURAL CHANGES TO SYMPTOMS.
The theory that the symptoms in Graves's disease are due to toxic products derived from the abnormally abundant secretion of the gland, receives confirmation from a study of the structural changes in adenoma and parenchymatous goître.
p4
SURGICAL TREATMENT.
I now come to deal with the surgical treatment. This may be divided into cutting operations and other methods, such as counter-irritants, setons, drainage, and injections. In regard to these latter it is not necessary, nor does time permit me to go into detail respecting them. They are either less efficient or more dangerous than the former, and I have not recently made use of them. Of the major operations there are four varieties:- Thyroidectomy, partial and complete; ligature of the thyroid arteries ; exothyropexy, or exposure of the gland with the object of inducing atrophy ; and enucleation. Complete thyroidectomy is very rarely employed. It may sometimes be used in cancer involving the whole gland, though there are few places in which cancer is less remediable by operation than in the thyroid. In no other affection do I think it either desirable or justifiable to completely extirpate the gland.
p5
....Enucleation is the simplest of the operations. It is employed for the removal of all innocent tumours of the thyroid, most of which are encapsuled and shell out easily. In such cases an incision is made, either across the neck in the line of the skin folds as recommended Kocher of obliquely as is more usual and generally more convenient. Superficial veins if in the way are divided, the expanded throat muscles displaced or partly divided if necessary, and the surface of the gland exposed. The capsule is now incised and the tumour shelled out, which is generally done without difficulty, and without haemorrhage. Haemorrhage is never troublesome in the smaller cases. When the tumour is very large the remains of the gland are lost sight of, and the operation is practically the same as thyroidectomy for parenchymatous goître.
....No doubt, one should be very careful of the recurrent laryngeal nerve, but I very rarely see it during the operation, and have certainly never injured it. As regards the isthmus I used to ligature before dividing it, but this is not often necessary. In exophthalmic goître thyroidectomy is undoubtedly a more serious operation, and I never undertake any but quite early cases without a feeling of anxiety. There are three reasons for greater difficulty in Graves's disease :- 1. The patients are much less fitted to bear a serious operation. 2. The gland usually has no tendency to shell out, but requires dissecting from the neighbouring tissues. 3. The haemorrhage is much more difficult to control.
....In regard to these cutting operations enucleation is simple and in every way satisfactory. It may always be recommended with the same confidence that we would recommend excision of an adenoma of the breast. Thyroidectomy is a more severe operation. In small parenchymatous goîtres it is quite straightforward, and almost devoid of danger ; but it becomes both difficult and dangerous in large or awkwardly situated goîtres. In exophthalmic goître it is certainly dangerous, and is perhaps not to be recommended in advanced cases, at any rate until the milder measures of division or removal of the isthmus or exothyropexy have been tried and failed. It is assumed, though I rather doubt it, that either of them would render a subsequent thyroidectomy more easy and safe.
p6
CONCLUSIONS.
To sum up the results of the treatment, we have it first as a fact that in twelve cases, tumours weighing up to 3⁄4 lb. were removed, and in eleven cases, portions of the gland, some of considerable size, were removed without a fatality. Healing was rapid in all, only a few patients being under surgical treatment more than about a fortnight. There were six cases of adenoma in which the patients complained of constitutional symptoms, and in all of them young, active, gland tissue was present ; and six in which the symptoms were nil or of mechanical obstruction only. In these the tumour was very small, colloid, fibrous, or almost entirely cystic, that is to say, they were tumours in which there was little or no active secreting epithelium. The patients suffering from mechanical obstruction only were of courses entirely relieved by the operation, whilst those suffering from both mechanical and constitutional symptoms were cured of the former and relieved or very much improved in regard to the latter. I consider the operation for the removal of thyroid adenoma a complete success and worthy to be recommended in all cases. Of the five cases of parenchymatous goître only two have been operated on sufficiently long to pronounce an opinion. These were a class of cases in which I was not at all disposed to urge operation, unless the mechanical interference was such as to render relief imperative, as there are no constitutional symptoms ; but if the result obtained in these two is maintained - that is perfect health and atrophy of the opposite lobe - I shall be willing to go further in parenchymatous goître than my original position. If a patient can be relieved of the unsightly mass without serious danger, and without risk of myxoedema, why should it not be done to improve appearance? Finally, in regard to exophthalmic goître, I consider the operation in these cases as still on its trial. At best, perhaps it is only worthy of a position like that we accord to operations for cancer. It is a case of treating symptoms. No doubt a very proper thing to do when nothing better is available, but never

altogether satisfactory. In regard to the danger of thyroidectomy in Graves's disease, although my six cases have recovered, I certainly do not shut my eyes to the fact that this element has to be contended with. It is present in every case in which the disease is at all advanced, and, though experience helps us to meet it, I feel sure, from what I have seen, that we may all expect on occasion to have to reckon unsuccessfully with it. In regard to the results, they seem to be satisfactory. This is a new disease to the surgeon, and my previous acquaintance with it is slight. The immediate effect of the operation is a marked amelioration in all the symptoms. In some cases the first improvement is so decided, little short of remarkable, that I think there can be no doubt it is directly due to removal of thyroid tissue. If one only followed such cases for a month one would observe the results as "cures ;" but, after the temporary rapid improvement, the progress may be slow, and up to the present the whole of the symptoms have not completely disappeared in a single case. I feel one must wait three or four years before passing a final judgement, both on the score of permanency as to benefits obtained, and as to the possibility of encouraging a tendency to myxoedema. The six cases have all been unquestionably benefited.

p7
....In adenoma the success is all one could wish, and I believe one might almost say the same in regard to parenchymatous goître ; but in Graves's disease the circumstances are different, and I should be sorry if, by painting the results in too glowing colours, I encouraged anything like reckless operating in so serious a condition.
NOTES. Since this was written the improvement has been very marked in all the cases of Graves's disease.

1897 MEMORANDA : MEDICAL, SURGICAL, OBSTETRICAL, THERAPEUTICAL, PATHOLOGICAL, ETC. BMJ JULY 31, 1897 Vol. II p274
REGROWTH OF HAIR IN MYXOEDEMA UNDER TREATMENT WITH THYROID TABLOIDS.
IN THE BRITISH MEDICAL JOURNAL OF January 6th, 1894, I published an account, with illustrations, of the treatment of an old case of myxoedema with thyroid extract. The portraits, which were reproduced from photographs, showed the striking change that had been effected by five weeks' treatment.

I now supplement my paper of that date with the accompanying portraits, which represent the same patient, a woman aged 66, as she appeared before any treatment was attempted and as she appeared after taking two thyroid tabloids daily for fifteen months.
I would ask the question. Does not the remarkable influence of thyroid extract upon hair growth suggest that the thyroid gland in its function is largely occupied with nutrition of the skin?

THOS. F. RAVEN, M.R.C.S., L.R.C.P. Broadstairs.

1898 LETTER: THE DOSAGE OF LIQUID THYROIDEI GEORGE MURRAY, BMJ, JUL 23rd 2:273-284. 1898
p 273
THE DOSAGE OF LIQUID THYROIDEI, B.P., 1898.
SIR,- Dr Robert Hutchison's excellent paper in the BRITISH MEDICAL JOURNAL of July 16th on "The Pharmacological Action of the Thyroid Gland" will I am sure be read with interest by many. There is, however, one statement with regard to the dosage of liquor thyroidei with which I am unable to agree. Liquor thyroidei is simply the original liquid thyroid extract devised and described by me in 1901, which the new Pharmacopoeia Committee has paid me the compliment of adopting, unaltered in strength or composition as an official preparation. The dose recommended in the Pharmacopoeia is 5 to 15 minims, which are the proper limits of an ordinary dose for an average adult. Dr. Hutchison thinks this dose is too small, and that it would be better to give the dose as 15 to 60 minims. These doses are certainly too

p274
large, as doses ranging from 30 to 60 minims are likely to produce unpleasant effects, even if given only once daily. I have constantly used this preparation for more than seven years, and have found that 10 minims of it given once daily is quite sufficient to maintain an adult who has suffered from myxoedema in good health. Thus, for example, my first case of myxoedema, who has now been treated with liquor thyroidei for more than seven years, is maintained in continual good health by this amount.
It seems, therefore, that this amount (10 minims) contains as much thyroid secretion as is daily formed an poured into the blood by the healthy gland. In some cases it appears to be even less than this, for in another case 5 to 7 minims was found to be the suitable daily dose, larger doses producing increased frequency of the pulse, etc. When this patient ultimately died from cardiac disease, microscopical examination showed that the whole of the thyroid gland was converted into fat and fibrous tissue, not a trace of glandular structure being left. In this case no secretion at all can have been formed by the diseased gland, so that the 7 minims were equivalent to the maximum amount of normal thyroid secretion. It is thus evident that the dose given by the Pharmacopoeia is the right one. Of course this dose may be increased or repeated more frequently if it is desired, and produce a condition of thyroidism, but such doses are really toxic and beyond the ordinary range.
In conclusion, I may mention that in my opinion liquor thyroidei gives better results in treatment than the dried preparations of the gland, so many of which are now used in the form of powders and tablets. -I am, etc.,
GEORGE MURRAY, M.A., M.D., F.R.C.P. Newcastle-on-Tyne, July 18th.

1898 THE ITALIAN MEDICAL CONGRESS IN TURIN. BMJ OCT. 15, 1898 Vol. II p 1175 - 1178
p1175
....To one who has watched the work of the Italian medical schools during the past few years, who has watched the rapid

absorption of German exact methods by Italian native genius, and who has seen the new teaching bear fruit in the rapid springing up of modern hospitals, modern laboratories, modern schools, and modern methods, the fervent aspiration expressed by Signor Baccelli is no chimera. An English physician who takes a sincere interest in Italy's welfare recently gave utterance to an analogous expression of opinion - that the revival or resurrection of Italian vigour will take place through the influence exercised by the medical schools. In Italy the medical schools are all under Government control ; their constitution is throughout the same ; their professors are promoted from one university to another, and the resulting consolidation enables the medical profession to carry weight, and make its influence felt far beyond the academic precincts. p1177

....THYROID SERUMTHERAPY.
Professor CARLO FORLANINI also referred to a case of myxoedema which improved under treatment by thyroid extract, but succumbed with graver symptoms of permanent arterial hypertension which supervened in the course of the disease. He considered this hypertension to be a form per se, independent of venal influences, and maintained by an arterial constriction due to excess of muscular tone in the peripheral arteries. Arterial tone was maintained by the internal secretion of certain glands, the action of which was to increase tension - glands such as the suprarenals, the thyroid, and others. He expressed the suspicion, based on various considerations, that in the case in question the fatal hypertension was the effect of overtoning with thyroid extract. He referred in support of this opinion to another case of miyxoedema in which treatment by thyroid extract, together with improvement of all the symptoms, determined a notable increase of arterial tension, which previously had been low.

1898 CLINICAL SOCIETY OF LONDON. Friday, October 28th, 1898 JOHN LANGTON, F.R.C.S., President, in the Chair. p 1431 - 1432
p 1432
....MYXOEDEMA IN A CHILD

Dr. BERTRAM ABRAHAMS showed a case of myxoedema in a child, aged 7. She was unable to walk until five years of age. When 6 1/2 years she rapidly became fat, her tongue grew large, and in ten weeks she became helpless and unable to feed herself. She was put on treatment with thyroid extract, and within thirty days her weight fell from 44 lbs. to 33 lbs., and she became more active and was able to go to school. The treatment was left off by her parents and the symptoms returned. There was a curious induration of the muscles of the calf resembling that of muscular pseudo-hypertrophy, probably due to the deposition of mucin. The child began with cretinic symptoms, and then developed symptoms of myxoedema. Her pulse was at first only 66 ; after treatment with thyroid extract it rose to 108.

1899 MYXOEDEMA TREATED WITH "COLLOID" MATERIAL. BY ROBERT J. M. BUCHANAN, M.D.VICT., M.R.C.P.LOND., Honorary Assistant Physician, Hospital for Diseases of the Chest, Liverpool. BMJ JUNE 17, 1899 Vol. I p 1460 - 1462
p 1460

THE following case was treated with "colloid" material from the thyroid gland prepared according to Dr. R. Hutchison's formula.
J. F., aged 54, on January 7th, 1898, when first seen by me, complained of weakness, lassitude, pains in the limbs, uncontrollable sleepiness, and loss of memory. There was nothing special in his family history with the exception that his mother had died, aged 49, of what had been termed "dropsy." His only illness had been due to a carbuncle in 1896, followed by an abscess in the left side of the neck. There was no history of venereal disease.

p 1461
....On January 225th, 1898, he commenced treatment with "colloid" material, taking one palatinoid at night. The dose was gradually increased to four in twenty-four hours by February 22nd, it was then reduced to two, and by June to one in twenty- four hours. No symptoms of "thyroidism" arose during the treatment. The result was a rapid disappearance of all symptoms and a return to normal health. The hair during the treatment fell off ; the absolute baldness was followed by a thick crop of brown hair, which required cutting on three occasions before June. The pulse and temperature returned to normal ; the skin also, with normal perspiration ; the mental inactivity disappeared ; inflection and modulation of the voice returned, all the movements became easy, and walking was no trouble. The body weight gradually sank. Sleepiness disappeared, and the appetite increased almost to voracity. So distressing had been his condition before treatment that he was unable to attend to his daily business in anything like a satisfactory manner, but since treatment he has followed hi occupation with increasing pleasure and good results. At the present time (May, 1899) he remains in excellent condition, taking a daily dose of one or two palatinoids of the "colloid" material. His appearance has so altered that he has repeatedly to explain to his customers that he is the same person the knew before, and that the stout old gentleman with the white hair was not his father, who had, as they believed, died of "dropsy."

1899 MEMORANDA : MEDICAL, SURGICAL, OBSTETRICAL, THERAPEUTICAL, PATHOLOGICAL, ETC. ACUTE THYROIDITIS : SUPPURATION : OPERATION, RECOVERY BMJ JUNE 17, 1899 Vol. I p 1462
G. G., a French Canadian, aged 39, always healthy, both parents living, visited me on April 13th. He complained of a swelling outside the throat, also of stiffness of the neck. He stated that on April 8th he had been in the sugary gathering sap, and upon returning home first noticed the swelling. It rapidly increased and gave him some inconvenience, though swallowing did not incommode him, nor was inspiration embarrassed. Still, he was compelled to hold his head in one

position, as tuning it from side to side pained him considerably.
Examination disclosed an enlargement of the thyroid gland. There was a thickening of the tissues in the region of this structure extending downwards to the clavicles, and laterally to the borders of the mastoid muscles. The gland was hard to the touch, and slightly painful on pressure.
He visited me on the two following days. Tenderness was increasing, there was no rise in temperature, and the patient did not complain of chills. He suffered, however, from headache, stiffness of the neck, and loss of appetite. On April 16th he summoned me to attend him at his house. I found him in much the same condition, but he was vomiting, and showed symptoms of marked constitutional disturbance - coated tongue, foetid breath, and insomnia. The temperature was 102.5°. Some fluctuation could now be detected. I was satisfied that suppuration had taken place, and operated the following morning without administering an anaesthetic. A large quantity of stinking pus escaped. This gave immediate relief. An hour after my departure the patient declared he was very hungry, and demolished a plateful of beans and bacon.
This case appears to be to be interesting inasmuch as the disease is not frequently met with, and we have also a clear history of the causation, namely, exposure to cold. As a rule I believe thyroiditis is usually associated with infectious diseases or traumatism. In this instance, however, a history of neither was present.
R. H. PHILLIMORE, M.D.
Cookshire, Que., Canada.

1908 System of Medicine, Murray, G. R.; Allbut, C.; Rolleston, A. D. Macmillan and Company, London, 1908 Chapter 6
DISEASE OF THE THYROID GLAND
By Prof. GEORGE MURRAY, M.D., F.R.C.P.

p 355
Natural Course and Prognosis. - The course of the disease and the duration of life have been so entirely changed by the present method of treatment that it is necessary to describe shortly the natural course of myxoedema when palliative treatment only was available. The natural course of the disease was very slow, so that a patient might be incapacitated by the disease and yet survive for years. Thus, in a series of 320 cases, which I collected from various sources, the disease lasted for less than five years in 147, for five to nine years in 90, for ten to fourteen years in 50, for fourteen to nineteen years in 20, whilst 13 cases lived more than twenty years. As many of these cases were alive at the time they were recorded, the duration given here does not represent the full duration of the disease in all cases. The general tendency of the disease was to get progressively worse, though the condition sometimes remained stationary for several years, and temporary improvement, especially during warm weather, was not uncommon. Death not infrequently occurred from some acute disease, such as influenza, pneumonia, or bronchitis, which the patient was unable to resist. Cardiac failure from chronic degeneration of the myocardium, granular kidney with arteriosclerosis, cerebral haemorrhage, and insanity were the immediate cause of death in some cases, and in others death was apparently due to the progressive degeneration entailed by the disease itself. The prognosis was, therefore, gloomy, as no prospect of recovery could be held out. A certain amount of relief could be afforded by palliative treatment, and the course of the disease might be slow, but sooner or later it was certain to progress to a state of chronic invalidism with a fatal termination.
Since the introduction of the treatment of the disease by thyroid extract, its course has been profoundly modified. All the symptoms of the malady can be removed by the administration of sufficient doses of the extract, and they do not return if the supply is adequately maintained. Provided the treatment is started early and maintained throughout, a patient with myxoedema may now live as long as any one else. Thus, my first case is still alive and well though it is more than seventeen years since she first began the treatment, simply because she continues toe take the extract without intermission. In the case of educated people this good result may naturally be expected, but hospital patients are apt to be intermittent in their attendance, and relapses will occur from time to time from interruption of the treatment. As soon as treatment is resumed, however, the sympotms again disappear. The prognosis now is therefore very good, as with continuous and adequate treatment good health may be enjoyed for many years. If the case be one of long standing, in which either chronic degeneration
p 356
of the myocardium or renal disease was present before the commencement of treatment, the prognosis must be framed according to the degree of these complications.
Diagnosis. - In cases of fully developed myxoedema the appearance of the patient is so striking that the diagnosis can usually be made immediately on inspection (vid Fig. 5). Such cases are now rarely seen, and the diagnosis, which has now to be made in the early stages of the malady, may sometimes be rather difficult. Careful attention to the presence of the symptoms already described as occurring in the early stages of the disease will aid the formation of a correct opinion. The colour of the complexion, the shape and expression of the face, the dryness of the skin, associated with loss of hair and the presence of hallucinations, are all valuable indications of the development of the malady. From ordinary obesity, with which or course it may be combined, the translucency of the swelling of the eyelids, the state of the skin and hair will usually distinguish it. Adiposis dolorosa is sometimes mistaken for myxoedema, but in this disease the swelling does not affect either face, hands, or feet, and is due to the formation of irregular masses of fat in various parts of the body, which are painful and tender on pressure. In acromegaly the face is long and oval instead of being rounded as in myxoedema, and the enlargement of the face, hands, and feet is due to a definite increase in size of the bony and other structures, and not merely to the thickening of the subcutaneous tissues by the solid oedema. in early cases in which the presence of myxoedema or of

benign hypothyroidism is suspected, but the diagnosis is not certain, recourse may be had to the therapeutic test. If the patient be given fully doses of thyroid extract for three or four weeks the symptoms will greatly diminish or disappear if they are due to myxoedema ; if no improvement takes place it may be safely concluded that they are due to some other cause.

Treatment. - In the treatment of myxoedema the deficiency of thyroid secretion must be made good by the internal administration of some suitable preparation of the thyroid gland containing the secretion in an active form. This treatment is conveniently divided into two stages, the object of the first being to remove entirely all the symptoms of the malady, and of the second to maintain the patient in health, for it must always be remembered that abandonment of the treatment at any time will sooner or later be followed by a return of the symptoms of the disease. the two official preparations of the thyroid gland may be most conveniently employed. These are the original thyroid extract, liquor thyroidei, and dry thyroid, thyroideum siccum, 1 grain of the latter being equivalent to 6 minims of the former. In most cases the liquor gives the best results, but it should be freshly prepared once a fortnight. It should be prescribed undiluted, and the patient be instructed to measure out the required dose in a mimim-glass and add a dessertspoonful of water. The dry thyroid may be given as a powder or tablet, and should be employed in relatively larger doses than the extract. It is
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advisable to begin the treatment of a case with a dose of 5 minims of the extract or 2 grains of the powder each night at bedtime. This dose may be gradually increased up to 10 or 12 minims unless the pulse is unduly accelerated. The full dose should be maintained until the first stage of the treatment is accomplished and the symptoms have disappeared. During the second stage, which lasts during the rest of the patient's life, a daily dose should be given which is just sufficient to maintain good health without any recurrence of the symptoms. This permanent dose varies in different cases, according to the amount of thyroidal atrophy present, from 5 to 15 minims. As a rule a daily dose of 10 minims of the extract or from 3 to 5 grains of the powder will be found to fully adequate. If the disease has reached an advanced stage, and especially if any symptoms of cardiovascular degeneration are present, rest in bed should be enjoined during the first stage of the treatment, as there is a risk of cardiac failure if any increased effort be made at too early a period of convalescence. Fortunately, at the present time the disease is usually recognised at an early stage, so that this precaution is now rarely necessary.
Under the influence of this treatment the symptoms of myxoedema all gradually disappear, and the change in the appearance of the patient is striking. This is well illustrated by Figs. 5 and 6. In this case the disease had probably been developing for some fifteen years before
p 358
treatment was commenced at the age of 48. The gradual diminution of the myxoedematous swelling is accompanied by loss of weight, which may amount to as much as two or even four stones. The skin becomes moist and soft, and hair begins to grow afresh. The temperature rises to the normal level, both mental and physical activity are restored, and mental symptoms may entirely disappear. In women who have not reached the menopause menstruation is re-established. In short, the symptoms entirely disappear and the patient recovers, remaining free from all symptoms of myxoedema as long as the treatment is continued.

1911 Text-Book of Operative Surgery ... Third English edition by Emil Theodor Kocher, Adam & Charles Black: London, 1911
B. SURGERY O F THE NECK
p 446

....(d) Surgery of the Thyroid Gland
49. Indications for and Results of Operation for Goitre. The greatest umber of tumours of the thyroid gland which call for surgical interference are of an innocent character. They are all included under the old term "goitre," the amount of mechanical interference with respiration depending on the relative position of the tumour. Too little attention has been paid to the altered character of the heart's action, associated with a simple goitre, which, although partly due to mechanical causes, is also greatly benefited by surgical treatment.
p 447
In addition, the question of surgical interference has also to considered in Basedow's disease, as well as in inflamed and malignant goitres ; in the former case early operation affords the most speedy and certain chance of success.
As a rule, a portion of the gland is excised in diseased conditions of the thyroid. In inflammatory goitres the treatment consists in incision, while in vascular goitres and in Basedow's disease, ligature of the vessels is undertaken. Apart from these minor operations (we have treated a great number of vascular goitres by ligature of the vessels), we have up to the present [footnote: Careless treatment with iodine is now more dangerous than excision of the thyroid] performed excision of 3333 occasions.
The remarkable advances that have been made in wound-treatment are probably more conspicuous in this than in any other branch of surgery, notwithstanding the difficulties and the complicated nature of the operation.
As we stated in a communication delivered at the German Surgical Congress, only three deaths occurred in 904 operations for simple goitre (in our third series of a thousand cases), the fatal termination in each case being attributable to cachexia, existing paralysis of both recurrent laryngeal nerves, and lesions of the heart and kidneys. If we bring up the total to 1000 by including 96 cases from our fourth series of a thousand, the percentage mortality of 0.4 per cent is obtained. In the 333 cases of our fourth thousand cases we have only lost one patient, who suffered from a high degree of dyspnoea associated with bronchitis and emphysema.

One may, therefore, conclude that in the various forms of colloid goitre, operative treatment, if carried out on definite lines, is free from danger and should therefore be undertaken in all cases where medicinal treatment has failed, or - as happens in a large number of cases - has actually proved harmful. In many cases medical treatment is hopeless from the beginning.
The iodine treatment is of no use, for instance, in the cystic goitres. It does harm in all cases where "goitre-heart" is present either in a mild or more severe degree, as well as in the inflammatory forms, while if offers no prospects of success in large nodular or in malignant goitres, especially in the latter where the favourable time for radical cure is allowed to elapse.
All goitres should be operated on when they are nodular, cystic, or becoming adherent, especially in the case of adults ; when they extend into the thoracic inlet, or compress the trachea, and, lastly, when there is the least suspicion of malignancy, i.e. from the character of their growth, their hardness, irregularity, and fixation.
Notwithstanding these wide indications, however, one must bear in mind that here, as in all operations elsewhere, there is a limit fixed, beyond which surgery treads on uncertain ground.
50. Conditions influencing Extirpation of a Goitre. Notwithstanding all aseptic precautions and improved technique, we may lose our patients after excision of the thyroid when one or another of the following conditions exist :-
1. When there has been marked tracheal stenosis of long duration with constant emphysema and bronchitis, which, by causing imperfect oxygenation of the blood in the lungs, has interfered with the functions of other organs, especially the heart, the latter becoming dilated as a result of emphysema.
2. When the cardiac tone has been weakened by other causes, e.g. by general adiposity, with fatty heart ; by atheroma, especially of the coronary arteries, with resulting myocarditis ; by all conditions of venous stasis which have led to marked dilation of the right side of the hart, with irregular, weak and rapid pulse.
3. Where there is marked interference with the venous circulation, e.g. by a goitre pressing on the large vessels at the inlet of the chest, especially if thrombosis has occurred.
All these conditions are characterised by severe dyspnoea (Which is frequently more marked and more troublesome than would be expected from the existing enlargement) and by deep cyanosis of the face, and occasionally of the hands, and, finally, by oedema of the face, hands, and feet. The puffiness of the face is often very striking.
p 448
4. Where the entire thyroid is in a state of diffuse follicular colloid degeneration, with the healthy gland tissue reduced to a minimum. Such goitres are often of large size, and surround the trachea as a dense mass which is very slightly movable, having a firm nodulated consistence. To excise them is a difficult and bloody operation. Acute tetany may set in, and cannot always be combated by administering thyroid preparations. It is best, under these circumstances, to begin by ligaturing the vessels of supply to the gland, and, later on, when the tumour has diminished in size, to perform a unilateral excision.
5. In debilitated patients suffering from Basedow's disease, with extreme emaciation, irregularity of pulse, and a high degree of tachycardia. Even although we refrain from using either a general anaesthetic, or any antiseptic, these patients occasionally die in a few days, the wound remaining perfectly healthy. Here also preliminary ligature of the arteries is the rule, excision being performed later, if there are any indications of pressure on the trachea.
6. Where the goitre in inflamed, the inflammation involving the capsule and the structures adjacent to it. Removal of the thyroid in an acute inflammatory condition exposes the patient to the danger of a spreading wound infection ; and if the goitre is in a state of chronic inflammation, its removal is often attended with severe haemorrhage and shock (recurrent paralysis).
In those numerous cases where the above dangers ( which are chiefly due to undue delay in operation) do not exist, we aim at a rapid, sure, and successful cure by operation under the following conditions:-
1. By avoiding all antiseptics, both in preparing the patient and during the operation and by using the strictest aseptic precautions. [footnote - The precautions we take to prevent infection have been already stated in the discussion of wound- treatment, where we showed how infection from the nose and mouth is guarded against by stretching a cloth transversely on a hoop between the neck and the head. Bungener has attempted to simplify this measure by using a small hoop hung over the ears and fixed to the chin.]
2. By substituting novocain and adrenalin for a general anaesthetic. nervous and sensitive patients with healthy lungs and heart may be anaesthetised with a mixture of air and ether (Braun's method) without hesitation. Vomiting during and after the operation often prevents primary healing by causing restlessness and secondary venous haemorrhage, and by soiling of the dressings
3. By using a large incision properly placed. We recommend our symmetrical "collar incision" as shown in Fig. 283. This incision leaves a scar which is hardly perceptible, while it gives plenty of room, and has the great advantage of enabling one to determine, in doubtful cases, which lobe is causing the greater amount of compression. We would especially warn the beginner against using small incisions which interfere with the arrest of haemorrhage, and make it more difficult to remove more deeply-seated processes of the tumour. Our angled incision is to be preferred only in difficult highly-situated and adherent goitres, as it then greatly simplifies their removal.
4. By careful ligature of the chief arteries and veins (superior and inferior thyroid artery and veins, thyroid ima vessels, and the accessory veins), and at the same time by freeing the goitre within its fibrous capsule. This is the only way in which one can guard against severe loss of blood during the operation, against injury to the recurrent laryngeal nerve, reactionary haemorrhage, and especially against tetany as the result of interference with the parathyroids which are related to the lower poles of the gland. Special care must be taken, if the removal of both lower poles is indicated, not to interfere with the parathyroids.
5. By preserving the sterno-laryngeal muscles along with their nerve-supply. If they are not preserved, the deformity, which

results from the sinking-in of the soft parts is considerable. We enter in the middle line between the muscles and detach p 449
them, if necessary, from their upper insertions. In this way their nerve supply remains uninjured, while the principle of muscle "disinsertion" is carried out (cf. Küttner's and Quervain's flap incisions). The divided muscles should always be carefully re-sutured.

p 467
....62. Excision of Exophthalmic Goitre (Basedow's Goitre). To the present time we have operated on 200 cases of Basedow's disease (including 10 cases of stuma vasculosa and 60 of a mild type) with a mortality of 4.5 per cent, this mortality being higher than in other forms of goitre. We have, however, learned how to overcome the operative risks, which are almost entirely dependent on the condition of the heart, i.e. toxic myocarditis.
Excision should not be undertaken when the disease is advanced, i.e. when the pulse, besides being rapid, is also small and irregular, or when the heart is dilated and oedema is present. If there is sever thyro-intoxication, the slightest excitement causing acceleration of the heart's action (180 beats or more per minute) with an increase in the dilation, it is advisable to begin by ligaturing one, or possibly two, arteries, and to postpone the excision till the patient's condition shows distinct improvement.
Even then the operation is attended with considerable responsibility and requires the utmost caution. The large vessels are very readily torn, and the goitre is exceedingly vascular, even the external capsule bleeding freely, while it is often firmly adherent. Operation is thus a matter of greater difficulty, and attended with greater haemorrhage than is the case even in malignant goitres. The result, therefore, really depends for success on the most careful arrest of hemorrhage.
All antiseptics and anaesthetics are a source of danger owing to the toxic conditions present in these cases. The success of operative treatment in Basedow's disease depends on the patient's being seen by the surgeon at an early stage, as with early operation brilliant results can be obtained.
The angled incision is, as a rule, preferable and every vessel must be ligatured, without, however, losing time in extirpating the goitre. The separation of the outer capsule is often attended by so much bleeding that one has to dislocate the goitre rapidly and secure the main vessels. No practitioner, unless he has had considerable experience in goitre operations, should venture on a excision for Basedow's disease.
p 469
66. Transplantation of the Thyroid Gland. Transplantation of the thyroid gland in individuals with deficient thyroid secretion gives permanent results in comparatively few cases. Schiff performed the first intraperitoneal operation, while we originally transplanted thyroid gland-tissue in man under the skin of the neck in the autumn of 1883, since which date Bircher and Horsley have made a special study of the subject.
One of the most interesting transplantations of recent times, which has been
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verified by numerous experiments, is Payr's transplantation into the spleen. We have selected numerous sites, e.g. the subcutaneous tissues, both surfaces of the peritoneum, and also the capsule of the thyroid and large veins and arteries. The subserous layer of the peritoneum and the spleen seem to be the best sites in which the transplanted piece of thyroid gland- tissue will grow and act as a substitute for the absent function. Recently we have followed up the suggestion made by Albert Kocher, and have transplanted thyroid tissue into the medullary cavity of the tibia.

1914 Memoranda : MEDICAL, SURGICAL, OBSTETRICAL. A NOTE ON THE PRESCRIBING OF THYROID SUBSTANCE. BMJ JUNE 20, 1914 Vol. I p 1351
p1351
....while there is but one pharmacopoeial preparation of thyroid, the "thyroideum siccum," there are numerous other preparations on the market, and many of these are labelled as the equivalent of so much fresh gland. In the absence of explicit instructions it is thus possible for the physician to prescribe a dose of thyroid substance which he intends to be fresh thyroid, while the chemist interprets his prescription as meaning "thyroideum siccum." The reverse may as easily occur.

In the second place the Pharmacopoeia gives no statement of the relationship which thyroideum siccum is to bear to the fresh gland.
....Some firms standardize their thyroid products in terms of iodine. This may be a good test, but until it is proved that the therapeutic activity of fresh thyroid corresponds to its iodine content it is unwise to rely upon it.

In conclusion I wish to emphasize the importance of making it clear whether we mean fresh or dry thyroid in our prescriptions, and in the case of dry thyroid it is well to have some knowledge of its relation to the fresh substance. ALEXANDER GOODALL, M.D., F.R.C.P.Edin., Assistant Physician to the Royal Infirmary, Edinburgh.

1914 ROYAL SOCIETY OF MEDICINE. SECTION OF THERAPEUTICS AND PHARMACOLOGY. The Therapeutic Value of Hormones. BMJ JAN. 24, 1914 Vol. I p 196 - 197
AT a meeting on January 20th, Dr. W. HALE WHITE, President, being in the chair, Professor G. R. MURRAY opened a discussion on the therapeutical value of hormones. He said that our knowledge of the ductless glands had increased rapidly in the last few years, but it was difficult to distinguish between advance and more theorizing. There was a tendency to claim too great a therapeutic value for some of the hormones. The internal secretions of certain glands contained one or more hormones. Many glands consisted of two parts endowed with different functions. Hormones regulated metabolism in two directions, for whilst some stimulated it, others exercised a controlling or inhibitory effect. It was probable that an internal

secretion might contain different hormones, and it was also probably that one hormone might supplement or supplant another. In some cases, as in that of the internal secretion of the pancreas, one could not administer the hormone in a form in which it was therapeutically active. These agents might be put to four chief therapeutical uses : (1) Treatment of a disease which was caused by a destructive lesion of the gland by which the hormone was secreted ; (2) when there was a physiological demand for its increased secretion ; (3) when its known physiological action was of service although it was known that the gland which secreted it was normal ; and (4) empirically. he illustrated these points by reference to thyroidal hormones. As an example of their use under (1) he cited their administration in myxoedema and cretinism. It was essential to make sure that the preparation was physiologically active. The dose should be regulated by the effect produced, and not by any hard and fast rule. It was important that treatment should be continuous. Simple goitre provided an example of their use under group (2), but he thought that special care should be taken to exclude cases of Graves's disease. Under (3) thyroidal hormones might be used to stimulate metabolism, as in obesity. And lastly, as examples of its use under (4) he instanced its unexplained action in such conditions as nocturnal enuresis, rickets, and rheumatoid arthritis. He then spoke of suprarenal hormones, regarding Addison's disease as due to their deficiency. In his experience, suprarenal extracts did not replace the normal secretion, though some observers had noted recoveries after their use. They were nevertheless useful because of their physiological effect, and were thus employed in haemorrhage. They were valuable also in asthma, and were used for Graves's disease, but in the last condition he had not found them to be of much value. Concerning the pituitary gland, he said that its atrophy was known to be associated with adiposo-genital dystrophy. Good results had been claimed for pituitary extract, but it was apparently of no value in acromegaly. It was used, however, for post-partum haemorrhage, and stimulated mammary and renal activity. Ovarian extract had been said to be of value in the symptoms of the premature climacteric following removal of the ovaries, and for those of the normal climacteric. Concerning the value of ovarian and testicular extracts, he thought that judgement must be reserved. Preparations from the islets of Langerhans had not yet led to any beneficial effect in diabetes. The whole question was a very difficult one, and he would not further confuse it by referring to the combined use of hormones of more than one gland.

....Dr. LEONARD WILLIAMS said that his chief experience had been with thyroid extract, but that he had had some with that of the pituitary gland. He had formerly been afraid of administering pituitary extract because of its pressor effect, but had found that this was not produced when it was given by the mouth. He had obtained good results from its use in at least two cases of amenorrhoea. He pleaded for the disuse of the term "thyroid excess" for Graves's disease. Symptoms of Graves's disease were not those of simple excessive secretion, and often the signs of hypothyroidism could be detected in that disease. One of the functions of the thyroid gland was to fix the calcium salts, and in Graves's disease he had found calcium chloride or calcium lactate of great value. He also employed small doses of thyroid extract.

Dr. H. H. DALE said that treatment by means of hormones could be arranged under two heads : (1) Substitution therapy ; (2) treatment of symptoms through the knowledge of the physiological action of the hormone employed. Apart from the thyroid extracts, the extracts of the ductless glands were useful chiefly as drugs.
....The CHAIRMAN said that many people took an excess of thyroid extract for myxoedema. Another point upon which there was no information was what to do in the case of pregnancy in a myxoedematous woman. In that condition the thyroid normally enlarged. Was it proper treatment to give more thyroid then than before? In obesity, thyroid often started a loss of fat when diet alone had filed. When once the obesity had begun to diminish, diet alone might in such cases be sufficient. Pituitary extract was the best means of inducing a quick rise in low blood pressure, but it was disappointing as a diuretic. He considered that the effect of adrenalin in asthmatic attacks was remarkably successful.

1914 OUR PRESENT KNOWLEDGE OF THE THYROID GLAND ; WITH A PRELIMINARY REPORT ON A CASE OF THYROID GRAFTING. BY MARCUS MAMOURIAN, F.R.C.S.E., ASSISTANT SURGEON, THE DISTRICT INFIRMARY AND CHILDREN'S HOSPITAL, ASHTON-UNDER-LYME. BMJ NOV. 14, 1914 Vol. II p 824 - 826

p824
THE work that has been done on the thyroid gland within recent years has acquired enormous dimensions, but, remarkably enough, the clinical, operative, and pathological observations and physiological investigations constitute a perfectly congruous study of wide practical applicability and interest which concerns almost every branch of medical science.
In a comprehensive survey of this subject it is of advantage to refer, first of all, to a few developmental points.
1. Development.
....In some instances a mass or masses of thyroidal substance fail to coalesce with the main gland, and are known as "accessory thyroids." Our study of the development of the thyroid not only throws light upon the anatomical peculiarities already indicated, but it also explains certain pathological conditions which are met with in the neck, such as the vascular tumour which grows at the base of the tongue (lingual thyroid) and the cysts in the middle line of the neck, both being thyro- glossal in origin, and which are liable to be mistaken for the cystic enlargements of the hyoid bursae and dermoids, but the latter are rarely situated mesially, as they are attached, as a rule, to the great cornu of the hyoid, the styled, or the mastoid processes.
2. Anatomy.
....Physiology
....It is now conclusively proved that the thyroid has a profound influence on the metabolism of growth, specially with regard to calcium and nervous tissues ; that it affects sexual functions, as evidenced by its increased activity during menstruation,

pregnancy, and lactation and the retrogressive changes observed in the genitalia in experimental thyroid inefficiency ; that it is concerned in the glycogenic work of the liver by its inhibitory action upon the pancreas, the pancreatic hormone being the principal stimulus to the sugar-producing cells of the liver ; further, it influences the circulation by virtue of its vaso-dilator property, and the fact that the gland receives part of the blood supply from two cerebral vessels (the vertebrals) points to the probability of its having a bearing on intracranial blood pressure. There is also what Gley terms its neurochemical relationship with the other ductless glands, the parathyroids, the pituitary, the suprarenals, the ovaries, and the thymus, which is pretty constantly in a condition of hyperplasia in cases of Graves's disease.

Such substances as have been chemically obtained have not shown the potency of the gland extract, and of which may be mentioned Bubnow's thyro-protein, which acts in the manner of an enzyme ; Fraenkel's thyro-antitoxin - a significant term suggestive of the view, now held by many workers, that the thyroid secretion possesses the property of neutralizing toxins, and that in Graves's disease this defensive element is absent or impaired ; Roos and Bauman's thyro-iodine, which also contains a trace of phosphorus. In Hutchinson's opinion the iodine and phosphorus containing substance is the active one. 3. Pharmacology and Therapeutics of the Gland Extract.

Allusion has already been made to the vaso-dilator effect of the gland's secretion. Accordingly, the extract lowers the blood pressure. It produces tachycardia, diuresis and its prolonged administration brings on glycosuria.
....Thyroid medication may be said to occupy the foremost place in organotherapy. The brilliant results obtained by the exhibition of this drug in myxoedema are well known.

p825
....In parenchymatous goitres, especially those associated with myxoedema, there is no better treatment than thyroid extract. No case should be submitted to operation without a trial of this remedy in preference to iodine and iodides, which bring about local adhesions and render the work of the surgeon difficult. Thyroid extract is a potent remedy in cases of nocturnal incontinence in children, in obesity ; but in the latter condition its use is not free from risk, as, in addition to its depressing effects upon the circulation, it may cause wastage of albuminous substances. It has been recommended in the treatment of rheumatoid arthritis, spasmodic torticollis, and adenoids. It has been used successfully in recurrent mammary cancer.
....The extract has a field of usefulness in cardio-renal conditions with high arterial tension, especially when the nitrite group of drugs has proved of no avail. It has been used in dermatology in conditions characterized by keratosis and in post- operative tetany (but the parathyroid extract is to be preferred). It is one of the most useful drugs in gynaecological conditions, notably menstrual derangements, and as a preventive of an early menopause. Its employment in Graves's disease has proved worse than useless.
4. Pathology and Treatment.
Myxoedema.- Reference has already been made to this condition, which results from congenital absence, atrophy or parenchymatous degeneration of the gland. Three types are recognized - (a) the infantile, with its interesting geographical distribution, (b) the adult (Gull's disease), and (c) the post-operative. there is no difficulty, as a rule, in recognizing a cretin with the stunted body, bloated face, flat nose, puffy eyelids, the scanty hair, and the striking mental sluggishness.
Goitre.- This term is applied generally to enlarged thyroids, but enlargement may be brought about by a variety of structural changes ; thus we have the parenchymatous (cystic or colloid), the fibrous adenomatous, and the vascular - terms which are descriptions in themselves. There is no correlation between the dimensions that he gland may attain and the constitutional effects produced.

p826
....Graves's Disease.- The cardinal signs of exophthalmos, tachycardia, and tremor make the diagnosis of this condition easy. The ocular signs are well known. The etiology of the disease is obscure. The main issues are (a) that it is a neurosis, (b) that it is the result of perverted secretion or hypersecretion, (c) that it is due to sepsis.
....The relation of hyperthyroid states to tuberculosis has been studied by Professor G. R. Murray, who holds the view that there is some sort of antagonism between the two conditions, as these patients rarely die from tuberculosis, and even if a focus be present it remains quiescent as long as the hyperthyroidism continues.
....The treatment of Graves's disease still remains on an unsatisfactory basis. The bulk of the cases are still being treated with bromides and iodides. Kocher thinks well of phosphorus, and the Mayos and Thurstan Holland of x rays. The late A. Gibson claimed to have cured most of his cases by suprarenal gland extract, but the experience of others is very disappointing. Moebius's serum has not been a success. Pychlan recently reported a case which was cured by the administration of the milk of a thyroidectomized woman.

1915 Exophthalmic Goitre Leonard Williams M.D., M.R.C.P. Physician to the French Hospital, Physician to the Metropolitan Hospital The Practitioner January 1915 Special Number on Internal Secretions Part I

p94
It is proverbially ill to give a dog a bad name, but it is "milching mallecho" to do the same by a disease. The dog you can always hang, but the disease, though it may not hang you, is liable to hang your patient, because its name has obscured its real character. (secret and insidious mischief (Hamlet, III., 2))

In the nomenclature of disease there are many instances of bad names, among the most conspicuous of which is that which heads this paper. The malady has been christened and rechristened and christened again. in this country it occasionally bears

the name of Graves, the celebrated Dublin physician who described it in 1835. On the Continent it is usually called after Basedow, who redescribed it five years later. According to Sir William Osler, however, the credit really belongs to a physician of the City of Bath, Caleb Hillier Parry, who had called attention to it ten years before Graves. The name of the distinguished orismologist, who first called it exophthalmic goitre is unfortunately lost to fame.

In the later Victorian days, when reason pure and unimaginative was triumphantly but respectably ascendant, the practice of calling a disease after the person most prominently associated with it, came to be severely regarded. It was in consonance with pure reason that a disease should be called by a descriptive title, for what more reasonable than a name which proclaims a aetiology? Also, it was entirely in consonance with the proverbial generosity of scientists towards one another to ensure that no undue distinction should attach to him whose clearer vision had rescured an entity from the scrap heap of nescience. The pioneer is always a nuisance; he deranges pedagogic calm.

From this Pride's Purge of personalities in official nomenclature. Addison's disease was almost alone in escaping, and the simple dignity of "Graves's disease" became submerged under the pompous, pretentious and as it now turns out, almost wholly irrelevant cacology of "exophthalmic goitre."
Altogether irrelevant the name is not, for it fixes upon the two superficially most salient features in a typical cases. Inasmuch, however, as the disease may, and often does, exist without either ocular prominence or thyroid enlargement, the title cannot be said to suggest the aetiology, which is, in truth, still a great mystery. To attain to a solution we must divest out minds of such shallownesses as exophthalmos and goitre, and turn our attention to deeper things.

The latter-day endeavours in this direction have been laudable, but unfortunate. In our desire to simplify the complexities of internal secretory problems we have taken each individual endocrinic gland and have indicted it either with the brutality of excess or the cowardice of insufficiency. Just as the older oculists acknowledged myopia and hypermetropia, but could not realise astigmatism, so seemingly are we unable to imagine the existence of a disturbance which is neither a pure excess nor a pure inadequacy. Thus it has come about that Graves's disease is now in serious danger of suffering yet another christening, more misleading than any of the others, a sort of adult total immersion from which it shall issue forth, freed from former terminological heresies and clad in the simple, unsullied garment of "hyperthyroidism."

Against this threatening catastrophe I desire to enter a protest. Whatever it may be, or may not be, Graves's disease is not a pure hyperthyroidism. I have never seen a case, and I do not believe that there has ever been one, which to careful observation did not reveal the existence of some symptom or symptoms which proclaimed the presence of thyroid insufficiency side by side with those of the obvious thyroid excess. Moreover, real hyperthyroidism, a hyperthyroidism, that is, which has been artificially induced, does not succeed in evoking the picture of exophthalmic goitre. So far as I am aware it has never been claimed that thyroid enlargement has been effected and although cases are on record in which ocular protrusion has been provoked in this way, such cases are extremely rare It is indeed no longer possible to speak of proptosis as the result of hyperthyroidism, for Maurice of Lyons has shown that this symptom denotes an excessive action, not of the thyroid, but of the suprarenals. Little, then, as I love "exophthalmic goitre," I dislike "hyperthyroidism" more.

p103
To treat the patient and not the disease is, of course, one of the therapeutic aphorism which we serve in speech and neglect in practise, bur he who neglects it in the presence of Graves's disease will fail where he might succeed. An enormous number of drugs have been recommended as useful by an enormous number of more or less competent clinicians. Some of these drugs are useful in certain stages, and where certain symptoms predominate; but many of them are useless, and some are altogether and utterly bad.

p104
It is entirely in accordance with the spirit of the age that the surgeon should have come to regard the goitre of Graves's disease as a suitable field for his activities. He asserts that medical treatment is a failure; that surgical treatment is substantially free from risk; and produces brilliant results. When confronted with statistics to show that satisfactory and lasting benefits are obtained by the physician, he replies airily that, "it is very doubtful whether all these cases were true examples of Graves's disease." No such reservation is necessary in the case of the statistics adduced on the surgical side, for it is not possible that a surgeon's diagnosis of medical disease could ever be at fault. And what are the advantages of which the patients are to derive from these surgical deeds of derring-do? For an answer let us hearken unto the words of one of their latest and most persuasive advocates, "Usually within a month or six weeks of operation, the patients are able to get about in comfort, but exertion is followed by an increase in the pulse, and by a certain amount of dsyspnoea. The exophthalmos is more slowly recovered from, and although this may be considerably decreased, even within a fortnight of the operation, the eyes at once become prominent when the patient is excited." Here, indeed, are results so truly marvellous as to justify almost any risks. The operation is successful, but thereafter exertion is unfortunately attended with tachycardia and dyspnoea, and the slowly receding exophthalmos is rude enough to reappear as soon as the patient is excited. Verily, the mere physician must hide his head in the presence of such brilliancy.
And are they permanent, these staggering successes? It would seem not. Here (Fig. A) is a portrait of a young woman, the scar of whose operation is quite visible in the picture, on whom an operation was performed about three years before the photograph was taken. She had risked much, but she does not appear to have gained much. A more perfect example of the classical features of the disease it would be difficult to find. And she is not a single spy; scattered over Europe there must be battalions of them.
The truth is, these operative procedures in Grave's disease represent the heroic application of loose conclusions from

insufficient data. In spite of all that it is possible to urge in their favour, it must be obvious to any thinking person that, so far as their immediate consequences are concerned, these operations are by no means free from serious danger. From the above quotation it is equally obvious that the best obtainable results are but "dérisoires" and do not in any case exceed those which may be confidently expected of careful medical treatment. Where, then, is the excuse for operative measures?

If it could be established that the real seat of the disease was in the thyroid, it would be possible on theoretical grounds to justify interference with this gland. But so far from such a proposition being established, the evidence points strongly, even overwhelmingly, in the direction of showing that the thyroid is merely an unwilling agent in the production of the symptoms, and reflects, reluctantly enough, a disturbance which originates elsewhere.

1920 Prevention of Simple Goitre in Man Fourth Paper David Marine, O. P. Kimball Archives of Internal Medicine part 25 Cleveland

p661
In previous publications we have outlined the plan of prevention, presented the data of the incidence of thyroid enlargements as determined by annual surveys of all new pupils in the Akron public schools, and the results of the prophylactic use of sodium iodid for nineteen months. The present paper deals with the data obtained at the fourth general examination made October 13-17, 1919, together with summaries and conclusions based on observations extending over a period of thirty months.

p668
In the practical application of the preventive treatment, one must keep in mind the three periods when simple thyroid enlargements most commonly occur, viz., (1) fetal, (2) adolescence and (3) pregnancy.
(1) Prevention of goitre in mother and fetus is as simple as that occurring during adolescence. Practically, it would seem that it is a charge or responsibility of individual members of the medical profession supplemented with public education,.
(2) The prevention of goitre of adolescence, on the other hand, should be a public health measure under state, county or municipal control. The existing systems of organization of the schools, public and private, is sufficient to handle all the details without additional aid or expense. Education of the pupils would be combined with the actual administration so that after leaving school they could continue the treatment, if necessary. Physicians in industrial medicine could render an important service in this field. Thyroid enlargement is approximately ix times as frequent in girls as in boys. It is a social economic question each community must decide whether it will include both sexes. Likewise, as to the age of beginning and stopping the use of iodin. In this climate probably the maximum of prevention, coupled with the minimum of effort, would be obtained by giving it between the ages of 11 and 17 years. As applied to our schools it would mean beginning with the fifth grade.
Manner and Form of Administration.- As previously stated, iodin is taken up by the thyroid gland when given by mouth, by inhalation, or by external application. Weith reports favorable therapeutic effects from inhalation of iodin as carried out by suspending a wide mouthed bottle containing a 10 per dent. tincture of iodin in the school room. Waste and lack of control of amounts taken are the most obvious objections. Similar objections hold in case of external application. Some form of oral administration seems most practical and economical. The addition of iodin or a salt of iodin to the water supply as we have done in preventing goiter in fish might be considered. There are obvious objections to such a plan. It would entail enormous waste. It is applicable only when there are installations, i.e., in towns and cities, and depending on the chemical impurities in water interactions might throw out the iodin. The most feasible oral method would seem to be the individual administration of definite small amounts, either in solution or as tablets. The cheapest salt, sodium iodid, could be given in either form. Manufacturing pharmacists state that sodium iodid could be prepared very cheaply in tablet form protected from the action of water and light. For private use, the well known U.S.P. preparations, syrup of ferrous iodid and syrup of hydriodic acid are excellent.
Amounts of Iodin to be used.- An ounce of syrup of ferrous iodid or hydriodic acid given over a period of from two to three weeks and repeated twice yearly would seem ample. As a public health measure, we have used 2 gm. of sodium iodid given over a period of two weeks and repeated twice yearly. This dosage has prevented enlargement of the thyroid in more than 99 pre cent. of the children in this mildly goiterous district. It is our opinion that much smaller amounts would suffice for healthy children and healthy pregnant women, provided the period of taking was prolonged, i.e. 1 gm. sodium iodid distributed over a month would accomplish as good thyroid effects as 2 gm. given over a period of two weeks.
The prevention of thyroid enlargement in individuals with other diseases or residing in extremely goiterous districts, as in some glacial valleys of Alaska and British Columbia; certain districts in the Alps and Himalayas, might require larger amounts of iodin for normals than above indicated. Our data of the clinical condition of four of the five cases that enlarged during the administration of 2 gm. of sodium iodid, twice yearly, suggest that in infections (chronic catarrhal or suppurative tuberculosis, syphilis, etc.,) and possibly also in conditions like chlorosis, osteomalacia, lymphatism and exophthalmic goiter, such amounts might no control the thyroid growth. In such conditions there may be a greatly increased demand for the thyroid hormone or the organism's ability to store iodin in the thyroid may be impaired. There is a great deal of clinical evidence for the first view and none at present in support of the second.

p671 SUMMARY

Observations on the prevention of simple goiter in man on a large scale have extended over a period of thirty months. The results show tat it may be prevented very simply and cheaply in normal individuals. While thyroid enlargements of adolescence are more common, they are not more important than those occurring in mother and fetus. Prevention of adolescent goiter is properly a public health problem, while the prevention of fetal and maternal thyroid enlargements is largely a responsibility of individual physicians. the presence of pathologic conditions may modify the result of the prophylactic treatment in individual cases. While such instances are rare they are important and merit detailed reports.

1940 EDITORIAL: AUTHORITY, OBSERVATION, AND EXPERIMENT JULY 20, 1940 Vol. II p 88 - 89
Authority, Observation and Experiments in Medicine. By W. W. C. Topley M.D., F.R.C.P., F.R.S. Linacre Lecture, 1940, Cambridge ; University Press
p88
....Prof. Topley particularly dislikes the double label, "The Science and Art of Medicine," and has some pungent criticisms to make on the loose application of the word "art." In so far as that label is used to shelter "the didactic assertion of inadequately tested working hypotheses" from criticism he is justified in his contention that "a physician who, regarding himself as an artist, fails to realise that he is performing a series of peculiarly difficult experiments, is not likely to add greatly to his own knowledge or that of others." Nevertheless, if the term "art" is interpreted to mean the method of approach to the patient, and inducing him to consent to the adoption of appropriate measures, it is a convenient one.
...."No physician would now observe and treat his patients, in all their ills, guided only by his trained but unaided senses." On the other hand, he utters a strong protest against the growth of the pernicious habit of relying upon a collection of second-hand information to construct a diagnosis : "All concerned must be in constant personal touch and know enough of one another's methods to talk a common language." He does not refer, however, to a still more lamentable practice which is on the increase - the piling up by a certain type of laboratory worker, often not medically qualified, of a mass of biochemical statistics from which he draws far-reaching conclusions as to the metabolic disorders of a patient without an ordinary clinical examination. The mass of figures is doubtless intended to impress the patient that he has been very scientifically investigated, whereas many of them are superfluous and quite irrelevant. This is pseudo-science, which is as much to be condemned as the behaviour of a clinician who spurns laboratory aid.
The imperfect sympathy sometimes shown by the laboratory worker towards the clinician's difficulties may be attributed to his not being confronted by the dilemma between scientific controls and the immediacy of human suffering that clamours for relief.

1942 BASAL TEMPERATURE VERSUS BASAL METABOLISM BRODA BARNES, M.D. DENVER JAMA 119:1072,1942

p1072
Basal temperature is defined here as the body temperature taken under conditions which are usually considered as necessary for determining basal metabolism. That is to say, the individual should have had a good night's rest, no food for twelve hours and no exercise or excitement. Unless the patient is in the hospital or the test is run in the home a true basal metabolic rate is not obtained, for the exercise of dressing and going to the laboratory will have an appreciable influence on the oxidative rate. The half hour or hour rest is a poor compromise for basal conditions. This is not the most serious criticism of the determinations of basal metabolism, however. Many more errors are made when the patient is unable to relax because of nervous tension. Although the normal person would not be excited by such an examination, the person needing such a test is not normal and many of them are unable to relax after repeated tests.

....It is well established clinically that the hyperthyroid patient has an elevated body temperature. Thus is appears from the experimental data and from clinical observations that body temperature might serve as an index of thyroid activity in hypothyroidism.
There is considerable disagreement in the literature as to whether all patients with low metabolic rates are hypothyroid. There is no doubt that starvation will lower the metabolic rate. This must be taken into consideration when malnutrition is so prevalent even in our own country. The extreme effect of starvation on metabolism is illustrated by Benedict's patient, who fasted thirty-one days. The metabolism fell 30 per cent. It is interesting to note that the body temperature remained relatively constant during this entire period. Hence it seems that body temperature might well distinguish between cases of inanition and those of true hypothyroidism. Other instances in which the metabolic rate goes down have not been followed, but at present it seems that the body temperature can be safely used.

The present group includes some patients with neurasthenia, chronic nervous exhaustion, arthritis and other diseases which are not generally considered to occur with hypothyroidism. The initial low temperature and the improvement seen when the temperature is elevated by thyroid therapy indicate that further work should be done in this field.

p1073
Very few patients with subnormal temperatures fail to respond to thyroid therapy, both as to relief of symptoms and as to elevation in temperatures.
....Another group of cases in which body temperature would be useful is illustrated by the following:
A woman aged 22 had been very nervous and underweight for several years. She suffered from palpitation of the heart, had a

pulse rate of 110, blood pressure of 155 systolic and 100 diastolic, a fine tremor of the hands and hyperactive reflexes. Prior to entrance to the university her basal metabolic rate was +18 per cent, and she had been advised to have a thyroidectomy. She had refused the operation. Her body temperature was 97.6 F. The basal metabolic rate was found to be +8 per cent. The curve was smooth, but observations during the test left no doubt that she was not relaxed. She was given phenobarbital, 1⁄2 grain (0.03 Gm.) three times a day for one week and the metabolic rate was then found to be -8 per cent. She was started on thyroid therapy 1⁄2 grain daily and seen at weekly intervals, The dose was gradually increased to 2 grains (0.13 Gm.) daily. Over a period of sixty days the blood pressure gradually fell to 115 systolic and 85 diastolic, the pulse rate came down to 84 and the hyperactive reflexes became normal. The body temperature gradually rose. The nervousness and tremor of the hands improved.

The therapeutic results would leave no doubt in the mind of the physician or the patient that what had appeared to be a classic hyperthyroid syndrome was in reality hypothyroid in causation. The body temperature was the only criterion on which a correct diagnosis might have been made.
That such cases are not rare is indicated by 6 additional cases that I have observed during the past twelve months. In 5 of these an operation had been performed, and the subsequent history left no doubt of a mistaken diagnosis.

....The procedure followed at present for the diagnosis of subnormal body temperature is as follows: The patient places a thermometer and book by his bedside. When he awakens in the morning the thermometer is left in the mouth without interruption for ten minutes by the block (the use of the book is obvious). It will be found that in the absence of a cold or other infection the daily variation in one's temperature is comparatively slight. The menstrual cycle causes about 1 degree variation with the low point at the time of ovulation and a gradual rise to a peak occurring a day or two before menstruation. It will be necessary to determine the basal temperature in a number of cases before setting a standard. Hence the tentative standard set here may be modified slightly by more data, but it will serve as a safe working range for the present. It is based on observations on patients without symptoms as well as on patients with symptoms which were relieved by adequate doses of thyroid over long periods. For the male the basal temperature seems to be near 98.0 F. For the female the average for the entire period has been found to be about 98.0 F. with the low point at the time of ovulation at 97.5 and the peak near 98.5.

p1074
SUMMARY
1. From a study of over 1,000 cases the results indicate that subnormal body temperature is a better index for thyroid therapy than the basal metabolic rate.
2. The differential diagnosis between hypothyroidism and hyperthyroidism is sometimes difficult. In 7 cases reported the diagnosis was wrong, in 5 of which an operation had been performed. The temperature was subnormal in each case.

1945 THYROID HYPERPLASIA AFTER PROLONGED EXCESSIVE DOSAGE WITH THIOURACIL BY J. B. DONALD, L.R.C.P.Ed. Clinical Tutor, Royal Infirmary, Edinburgh AND D. M. DUNLOP, M.D., F.R.C.P.Ed. Professor of Therapeutics and Clinical Medicine, Edinburgh University BMJ JAN. 27, 1945 Vol. I p 117 - 118
p 117

During the past year we have treated with thiouracil a total of 31 patients suffering from thyrotoxicosis. The results obtained are very similar to those noted by other workers. They are on the whole most encouraging, and comparable to those produced by successful thyroidectomy.
....It seems to be the general experience of other workers that thiouracil in therapeutic doses does not as a rule affect the size of the goitre significantly, but Himsworth (1944) has reported three cases in which the goitre increased considerably in size as the result of treatment with thiouracil - an effect which he attributes to overdosage.

There seems to be general agreement that the optimum dosage during the initial period of treatment should be 0.6 g. daily. This dosage should be kept up for from three to four weeks, at which time a fall in the basal metabolic rate has usually become significant. No increased effect is obtained by doubling the dose, as any additional quantity appears to be immediately excreted in the urine. There is as yet no definite consensus of opinion as to the dose required for maintenance treatment. There can be little doubt that 0.2 g. daily is adequate.

....We have latterly treated a number of patients with a maintenance dose of 0.1 g. daily, and it is our impression that this dose is quite sufficient. One case, through a misunderstanding, received an excessively large maintenance dose for a period of five and a half months.
Case Record
A female patient, aged 33, suffering from classical thyrotoxicosis, had experienced her first symptoms one year before admission to hospital. A small primary goitre was present. She was treated
p118
with 0.6 g. of thiouracil daily for 20 days, and was then given a maintenance dose of 0.2 g. daily for a week.
....By the firth month this symptoms had become pronounced, and a swelling of the neck was reported. The patient was immediately sent for, and on readmission, five and a half months after her discharge, was found to have a very large soft goitre. This was associated with a mild degree of myxoedema. Her weight had increased by one stone since discharge from hospital, her B.M.R. had fallen to -20 and her blood cholesterol had risen from 220 to 266 mg. per 100 c.cm. Her white blood count of 5,600 showed no significant alteration. Thiouracil was immediately stopped, and in two weeks' time she felt considerably better, her B.M.R. having risen from -20 to -3.
....Comment

It is thought worth while to record this case as providing another instance to those noted by Himsworth of thiouracil causing a great enlargement of the goitre in a previously thyrotoxic patient. It gives practical proof of the theoretical assumption that if the pituitary is stimulated to produce excess thyrotrophic hormone by overdosage with thiouracil an increase in the size of the goitre will occur similar toe the hyperplasia of the thyroid produced in experimental animals by thiourea and its derivatives, and by sulphaguanidine. A rapid and significant enlargement of the goitre in a patient under treatment with thiouracil may thus be evidence of overdosage.

1945 THE INTEGRATION OF MEDICINE BY F. M. R. WALSHE, M.D., D.Sc., F.R.C.P. (Being an abridgement of the Annual Oration of the Medical Society of London, May, 1945) BMJ MAY 26, 1945 Vol. I p 723 - 727
p723
In the course of discussion upon the future and development of medicine two themes recur with melancholy iteration - namely, that specialism is an evil, and that it is inevitable.

p724
....As has been aptly said, once we seek to go beyond the basic elements of medicine as we know it, we tend to know more and more of less and less. thus it happens that those responsible for the training of our successors too often find themselves imparting unrelated categories of information and partial and often conflicting generalizations culled from different fields of medicine, and it is becoming nobody's business, and seems less and less within anyone's capacity, to teach medicine as a whole, or to build into a coherent body of knowledge the several contributions of the specialists.
It is therefore because ours is a useful rather than a liberal profession that we have been forced to face the situation created by the accumulation around us of more, and more diverse information than we can digest and assimilate. Hughlings Jackson was clearly aware of this, over 50 years ago, when he said that "we have multitudes of facts, but we require, as they accumulate, organizations of them into higher knowledge ; we require generalizations and working hypotheses. The man who puts two old facts into new and more realistic order deserves praise as certainly as does the man who discovers a new one. There is an originality of method." But in this, as in much else, Jackson was before his own time and ours ; ....Nevertheless, by whatever channel this awareness of the disorderly state of our science has reached us, we are at least generally agreed that we cannot indefinitely go on as we are, and that something must be done to bind the broken foundations of modern medicine and to make it something more than a congeries of ingenious techniques and unrelated fragments of knowledge. This, at any rate, however gained, is something gained.
Integration Keeps Pace With Differentiation
The thought that I am trying to develop will be familiar to many of you. It is summed up in the aphorism so familiar to neurophysiologist, "Integration keeps pace with differentiation." This is a fundamental principle in the evolution of the nervous system, and I cite it because I believe it to have a vital meaning for us in my present connexion. We owe its original formulation to the now disregarded genius of Herbert Spencer, from whom it was taken and so fruitfully employed by Hughlings Jackson. Derived anew from this latter source, it became a guiding inspiration in Sherrington's monumental contributions to experimental physiology, and its influence may be seen in the title he gave in his classic work of 1906, The Integrative Action of the Nervous System. Yet it is not so much with integrative action of the nervous system in respect to the organism as a whole that I am now concerned as with the development within that system, as it becomes progressively more differentiated, of structures and functions designed to control and to unify the several parts and to make them into a harmonious whole. In short, integration does, as an observed fact, keep pace with differentiation in the evolution of that system.
....Let us now replace the term "differentiation" by "observation" and the term "integration/" by "interpretation and synthesis." Observation leads to the increase and differentiation of information, while interpretation and synthesis are its integration into ordered knowledge, and I suggest that in the process of scientific thinking interpretation and synthesis must keep pace with observation if a coherent body of knowledge is to be forged. From this we pass easily and naturally to the notion that there is a rhythm in scientific thought, the two elements observation and interpretation alternating.
p725
I sometimes doubt whether one is justified in recording in print a new observation unless one also seeks to indicate what it holds, and to apply the inductive process to it. One should not fling a raw fact on to paper in public, as a keeper flings a chunk of raw meat to a tiger. I believe that in medicine we have a unique advantage in this respect over the purely experimental scientist, in that medicine, while becoming increasingly an experimental, has long been and must continue largely to be an observational science. In its observational aspect it deals with a supremely difficult material under conditions that make constant demands upon intuition and judgement. Nature is not interested in scientific method, and the experiments she provides for us in the guise of disease and injury we have to take as we find them ; we cannot subject them to the necessary but artificial simplification that is the essence of a good experiment. We are therefore forced to think, to synthesize, and to interpret our evidence to a point rarely necessary in the designed laboratory experiment. While, therefore, we must welcome the increasing role of experiment in the study of medicine, we must be on our guard not to be infected by the distrust of ideas characteristic of much experimental work, but continue to use the intellectual assets which experience of clinical observation gives every good doctor.
p727
In short, what I am proposing is that a humane education is an invaluable asset to any youth embarking upon the study of medicine. I am aware that I raises the banner of a forsaken cause wen I say this ; but nevertheless, twenty-five years of clinical teaching have fully persuaded me that wen I find a clinical clerk who can stand up and read at a ward visit a case

history that is a well-ordered, lucid, and fluently expressed account of the patient and his situation, that student will almost invariably be found to have had a sound education, and not a mere course of instruction of the polytechnic order, a utility education.
....Conclusion

What I have had to say is somewhat remote the medicine that presents itself to us in our daily lives. Yet as we grow older the urge to lift our eyes from the details of the little plot in which each of us labours becomes ever stronger, and we are impelled to look round upon the wider field of natural knowledge as a whole. Some may even feel the pull towards some philosophy of knowledge, towards those common truths to which all science must be obedient. Man does not live by facts alone, but craves also for generalizations, and the desire for some philosophy of knowledge burns, if with varying intensity, in all of us. Looked at in this spirit, how untidy and in places how overgrown the field of medicine seems to be ; in other places how bare, how precariously balanced the whole upon the uncertain

p727
foundations of biological knowledge! So it must remain until we develop a wider and deeper consciousness of what constitutes ordered knowledge, and by what cycle of thought it is to be achieved.
Yet to feel some discontent with medicine as we find it does not imply any lack of pride in its achievements, nor any diminished sense of privilege in seeking to serve it. If one is a critic, it is, I trust, in the spirit expressed by Milton when he says, "For he who freely magnifies what hath been nobly done, and fears not to declare as freely what might be done better, gives ye the best covenant of his fidelity."

1945 THYROID AND SEX FUNCTION BMJ DEC. 1, 1945 Vol. I p 772

Thyroid extract is often used clinically in treating sex disorders in women, though the rationale of this is not clear. We know little more than that the thyroid gland has some connexion with sex, since disturbances in sex unction accompany thyroid disease. On the experimental side Engle has recently established that thyroid deficiency in monkeys results in amenorrhoea, and that a course of thyroid treatment given for 10 days (20-60 mg. of thyroid substance daily) brings on menstrual bleeding 1-19 days after the last administration, followed by one or two further bleedings at normal cyclic intervals, even though there had been as many as 200 days of amenorrhoea preceding the treatment. ....If these findings are confirmed there is little doubt that more account must be taken of the part played by the thyroid gland in the regulation of sex function. But at the moment the picture is by no means clear.

Yale J. biol. Med., 1944, 17, 59
Endocrinology, 1944, 34, 90
J. Endocrinol., 1945, 4, 109
1971 FUNDAMENTALS OF INTERNAL MEDICINE A Physiological and Clinical Approach to Disease ROBERT P. McCOMBS, B.S., M.D., F.A.C.P. Professor of Medicine, Tufts University School of Medicine; Senior Physician, New England Medical Center Hospital

FOURTH EDITION, 1971 YEAR BOOK MEDICAL PUBLISHERS • INC. 3 EAST WACKER DRIVE • CHICAGO
p 613....CLINICAL CONSIDERATIONS
Laboratory aids in diagnosis of thyroid disorders.- BASAL METABOLIC RATE.- This test has been widely used, but as it is generally done in office or hospital practice it is not a reliable guide to the diagnoses of hyperthyroidism or myxedema. In the overt cases, no laboratory confirmation is necessary, but in the doubtful case, treatment should not be instituted solely on the basis of an abnormal BMR.

Basal metabolism, as it is ordinarily determined, is a measure of the heat produced by the body under basal conditions (patients at rest in the fasting state). It is determined by measuring the amount of oxygen consumed in a definite period. Corrections must be made for room temperature and barometric pressure. If the height and weight of the patient are known, the surface area of the body can be calculated from standard tables. The number of calories per square meter of body surface per hour is the common denominator in comparing energy production. Normals have been established for the various age groups. The final determinations are usually expressed as percentages of the mean normal values. The figures usually given as "normal variations" are +10 to -10 per cent. In clinical practice, however, these standards must be taken with considerable latitude. In hospitals, normal values considerably be

p614
low the "accepted" standards will be found to be the rule (+5 to - 15 or -20 per cent). This probably occurs because the "standards" were established from ambulatory healthy individuals, whereas hospitalized patients may be debilitated and have usually rested (often under sedation) for at least 12 hours prior to the test. It must also be remembered that the perfectly normal individuals may have basal metabolic rates moderately above or below the "normal" limits.
There are technical factors that must be taken into consideration. Leaks in the apparatus and gas leaks due to perforation of an ear drum may give falsely high readings. Hysterical hyperventilation and sighing also are apt to increase the apparent oxygen consumption. An inspection of the tracing made during the test, noting the evenness of breathing and any discrepancies in the rate of oxygen utilization, usually will serve to disclose these artifacts.
Elevation of the basal metabolic rate is regularly observed in hyperthyroidism. The rate is also increased by pregnancy, fever, hematologic disorders (anemia, leukemia and polycythemia), diabetes insipidus, malignant disease, pulmonary diseases and heart failure.
Depression of the metabolic rate is found in hypothyroidism. Other causes of abnormal depression of the metabolic rate are: nephrosis, hypopituitarism, Addison's disease, prolonged cachexia from any cause (such as starvation, terminal malignancies

and anorexia nervosa).

1973 Discriminant Value of Thyroid Function Tests DAVID B. BARNETT, ANTHONY A. GREENFIELD, PETER J. HOWLETT, JENNIFER C. HUDSON, ROBERT N. SMITH BMJ 1973, 2, 144-147
Summary
Different thyroid function tests permitted a final classification of 204 consecutive patients with suspected thyroid disorders into three populations (thyrotoxic, euthyroid, and hypothyroid). Linear discriminant analysis was applied to all test results (10 variates) on adjacent population pairs. Two in-vitro tests (serum protein bound iodine (P.B.I.) and triiodothyronine (T-3) uptake values) gave good separation of thyrotoxic from euthyroid patients and fairly good distinction of hypothyroid patients. If a 131uptake figure was then added to the in-vitro results most patients (95.55%), including these initially classified as equivocal, were correctly diagnosed. Other tests, including clinical questionnaires, were poor discriminants. Two new techniques of utilizing the test data were devised. firstly, the data from the two in-vitro tests were also displayed graphically, and oblique boundary lines derived form the discriminant functions gave better separation of patients than previously used limits or mathematical expressions of "free thyroxine." Secondly, a nomogram incorporating the best four discriminants was designed as a diagnostic aid and proved to be the best means of interpreting the tests.

Discriminant analysis of this kind can be used in the interpretation of diagnostic tests in any branch of medicine, and it allows the best use to be made of the available data.
Introduction
A clinician needs a screening test to decide whether suspicion of a thyroid disorder is substantiated or not and then requires confirmatory tests before any treatment is begun. The present study was undertaken to decide the best single test or combination for these purposes, and, if possible, to select in-vitro tests which avoid radiation exposure.

p 146
Discussion
Tests of thyroid function are needed which without undue risk or inconvenience accurately separate patients with thyrotoxicosis or hypothyroidism from those who are euthyroid. Most physicians and their colleagues in medical physics would like to reduce the number of radioiodine tests; there has been some disquiet about the radiation risk to all concerned. In fact, these requirements were fulfilled when linear discriminant analysis chose a combination of in-vitro tests as the best two discriminants. In this series of patients 127 out of 204 were euthyroid and really needed no further investigation with consequent radiation exposure.
In judging the results of thyroid function tests it is customary to rely on so-called "normal" ranges and limits of each test, which immediately restricts the discriminant value of any combination of tests because each is effectively taken as a single variate. When these test results are contradictory or borderline it is also difficult to decide which is the best discriminant. In this study the clinicians attempted to collate 10 parameters concurrently and to give appropriate weightings when these tests diverged from each other, but some patients were categorized as "equivocal." This approach was clearly inferior to at least one brand of multivariate analysis which considered several variates in combination and chose the best discriminants without reference to the "normal" range of test values. The optimum combination of tests placed these "equivocal" patients in the correct diagnostic category and this was supported by long-term clinical observation. The addition of more variates to the best three tests increased the errors and this explained our difficulties in trying to collate all test results.
....Discriminant analysis can be applied in any situation where several parameters attempt to identify two or more populations but its use in medicine has been limited. Firstly, it can select those tests which place patients into the correct diagnostic category with least risk of error. Many clinicians have difficulty in accepting this radical change in their interpretation of a group of tests, but the evidence from this and other studies can convince them.
This study has identified the best thyroid function tests for routine clinical use and led to the construction of simple desktop diagnostic aids for interpreting the laboratory test data. We would recommend the combination of serum P.B.I. and T-3 uptake measurements using either of the commercial kits as a screening procedure. the new boundaries would indicate any borderline patients and these together with patients in the thyrotoxic or hypothyroid sections would require further assessment. Physicians usually request confirmatory evidence from a 131I uptake test before instituting life-long thyroxine replacement or before destructive therapy (thyroid surgery or radioiodine treatment) and the nomogram with the discriminants displayed is the best way of interpreting three tests.
(these as in original article)

1973 LETTER Discriminant Value of Thyroid Function Tests JAMES CROOKS BMJ 1973, 2, 488

....Though I accept the conclusions of the authors that the combination of serum protein-bound iodine and triiodothyronine uptake tests is at present the most effective routine laboratory-based method of arriving at the diagnosis of thyrotoxicosis, I regret their implied denigration of clinical evidence as part of the diagnostic process. I also regret that they did not include the results of a therapeutic trial of the various methods of treating thyrotoxicosis in their paper since, in terms of the practicality of patient care, this is a more acceptable diagnostic criterion than that provided. - I am, etc.,

JAMES CROOKS
Department of Pharmacology and Therapeutics, University of Dundee
1. Crooks, J., Murray, I. P. C., and Wayne, E. J., Quarterly Journal of Medicine, 1959, 28, 211 2. Billewicz, W. Z., et al., Quarterly Journal of Medicine, 1969, 38, 255

1973 Treatment of Hypothyroidism: A Reappraisal of Thyroxine Therapy DAVID EVERED, E. T. YOUNG, B. J. ORMUSTON, RUTH MENZIES, P. A. SMITH, REGINALD HALL BMJ 1973, 3, 131-134
p131
Summary

Twenty-two subjects with hypothyroidism have been studied in detail before and during replacement thyroid therapy with L- thyroxine (T-4). All subjects were stablized on the minimum dose of T-4 which was necessary to suppress their serum thyroid-stimulating hormone (TSH) concentration to normal, and on this dose most subjects had a normal or impaired TSH response to thyrotrophin-releasing hormone (TRH). The daily dose of T-4 required to suppress TSH was 0.1 mg (13 subjects), 0.15 mg (six subjects), and 0.2 mg (three subjects). It was shown that all subjects were euthyroid on these doses and, using a range of thyroid function tests, that they were normal in all respects when compared with a group of euthyroid controls, with the exception of a small group who had a marginally raised serum triiodo-L-thyronine (T-3) concentration. It has been shown that those subjects who required the larger doses of T-4 had a more advanced degree of thyroid failure than those who where stabilized on 0.1 mg T-4 daily. it is concluded that conventional doses of t-4 (0.2-0.4 daily) are often associated with subclinical hyperthyroidism.

Introduction
It is generally accepted that all patients with symptomatic hypothyroidism require treatment, and L-thyroxine (T-4) is now used almost exclusively in the management of patients with hypothyroidism. The dose recommended by the major textbooks of medicine (Selenkow and Ingbar, 1970); Stanbury, 1967; Strong, 1968) and endocrinology (Ingbar and Woeber, 1967; Hall et al., 1969; Means et al., 1963) lies between 0.2 mg and 0.4 mg daily, and there is general agreement that 0.3 mg daily is the average replacement dose. IT is well known that the serum thyroxine concentration is raised on this dose and in the past it has been assumed that since the patient was receiving only T-4, and no replacement with the metabolically more potent triiodo-L-thyronine (T-3), that this was essential to maintain the euthyroid state (Ingbar and Woeber, 1968). Cotton et al., (1971), however, found that the serum thyroid-stimulating hormone (TSH) concentration can be restored to normal with much smaller doses of T-4. It has also recently been shown that there is considerable extrathyroidal conversion of T-4 to T-3 (Pittman et al., 1971; Sterling et al., 1970) and that raised serum T-3 levels are found in athyreotic subjects receiving T-4 only (Braverman et al., 1970). These findings raise the possibility that many subjects on replacement therapy with T-4 are mildly hyperthyroid but this state escapes detection in view of the insensitive methods available for the clinical assessment of thyroid status (Larsen, 1972). Goolden and his colleagues (191) provided some support for this view by showing that the red cell sodium concentration which is increased in hyperthyroidism is also raised in subjects receiving 0.3 mg T-4 daily. The availability of a wide range of precise diagnostic techniques has made it possible to test this hypothesis and to study the thyroid hormone requirements of a group of unselected patients with hypothyroidism.
Patients, Materials, and Methods
Twenty-two consecutive patients with untreated symptomatic hypothyroidism attending an endocrine clinic were studied. The diagnosis of symptomatic hypothyroidism was accepted in all patients who presented with symptoms consistent with hypothyroidism and were found to have a raised serum TSH concentration (Evered et al., 1973).. Seventeen of the patients had developed hypothyroidism spontaneously, three after 131I therapy and two after partial thyroidectomy for hyperthyroidism. None of the subjects had overt ischaemic heart disease.
p134
....The results of this study suggest that many subjects have received excessive doses of T-4 in the past, inducing a state of mild hyperthyroidism which is generally not clinically apparent. These findings confirm the isolated findings which have been reported previously (Braverman et al., 1970; Cotton et al., 1971; Goolden et al., 1971) which suggested that conventional doses of T-4 for replacement therapy were often excessive. It is not possible to be certain whether this state of mild hyperthyroidism is detrimental to the patient - but the disadvantages of untreated mild hyperthyroidism, particularly in relation to the skeleton and the cardiovascular system in the elderly, are well known. There would, therefore, seem to be a good prima facie case for establishing patients with hypothyroidism on the optimal dose of T-4.
It is, of course, not possible to investigate all patients with hypothyroidism in such detail. It is, however, possible to stabilize all patients on thyroid hormone replacement therapy by increasing the dose of T-4 until the serum TSH concentration falls within the normal range. Experience with this study has shown that patients' symptoms are abolished at this dose. Replacement therapy can also be controlled by following the serum thyroxine concentration (measured by direct or indirect means in the absence of the facilities for estimating serum TSH concentration.

1973 LETTER: Discriminant Value of Thyroid Function Tests J. VESTERDAL JØRGENSEN BMJ 1973, 3, 170

....From these data the authors postulate that their boundary lines have a grater discriminatory power than a free thyroxin index calculated on the basis of serum protein-bound iodin and T-3 uptake. however, these differences are not statistically significant (P> 0.05 ). Therefore it still remains to be shown whether linear discriminant analysis is superior to free thyroxine index in this respect - but certainly, this problem is subtle in comparison to the problem of supplying the clinical with self-explanatory laboratory data - for example, in the form of "cartoons." - I am, etc.,

J. VESTERDAL JØRGENSEN

1973 LETTER: Treatment of Hypothyroidism P. B. S. Fowler BMJ 11 August 1973 Vol. IV p 352 - 353
p352
....The authors state that after adequate treatment "the serum cholesterol and triglyceride concentrations were very similar to

those recorded in a group of control subjects" and two lines later, "the raised level of serum triglyceride concentration after treatment is unexplained." The two statements are contradictory and the first is incorrect.
....The fasting triglyceride level is a more accurate reflection of the abnormal lipid pattern in preclinical hypothyroidism than the serum cholesterol, but we have shown that even the serum cholesterol can be raised years before overt hypothyroidism occurs and is a characteristic finding in preclinical hypothyroidism. Patients with overt myxoedema have probably undergone a process of natural selection in regard to their abnormal lipids. Those with hypercholesterolaemia in the stage of preclinical hypothyroidism are prone to die of coronary artery disease, leaving those with less abnormal lipids to become myxoedematous.

....The abnormal lipid pattern is the first change to occur as hypothyroidism develops and the last to disappear on treatment, or remains the sole abnormal finding on inadequate therapy as shown in the data presented by Dr. Evered and his colleagues. ....The conclusions regarding T-4 dosage, reached as a result of the excellent work by Dr. Evered and his colleagues, are in conflict with mine, based on simpler tests done on a great number of patients. Dr. Evered and his colleagues will warn that over-treated hypothyroid patients will suffer from fragile bones and I will continue to warn that under-treated hypothyroid patients may die of coronary artery disease. - I am, etc.,

P. B. S. FOWLER
Charing Cross Hospital (Fulham), London W. 6
1. Fowler, P. B. S., and Swale, J., Lancet, 1, 1077
2. Fowler, P. B. S., and Swale, J., and Andrews, H., Lancet, 1970, 2, 488 3. Lewis, B., and Krikler, D. M., Lancet, 1971, 1, 1295

1998 Bone Changes in Pre- and Postmenopausal Women with Thyroid Cancer on Levothyroxine Therapy: Evolution of Axial and Appendicular Bone Mass E. Jodar (*), M. Begona Lopez (*), L. Garcia, D. Rigopoulou, G. Martinez, F. Hawkins(1) Service of Endocrinology, University Hospital 12 de Octubre, Madrid, Spain Osteoporosis International Volume 8 Issue 4 (1998) pp 311-316

Abstract: The effects of suppressive doses of levothyroxine (LT 4 on bone mass are controversial. Our aim was to evaluate the effects on axial and appendicular bone mineral density (BMD) and bone metabolism of long-term LT4 suppressive

therapy in women by means of cross-sectional and longitudinal studies, and also to assess the potential influence of menopausal status and LT4 dose. Seventy-six women (aged 47 + 13 years, 37 pre- and 39 postmenopausal) on suppressive therapy (67 + 34 months duration, mean LT4 dose 168 + 41 mg/day) from our Thyroid Cancer Unit without previous hyperthyroidism or concomitant hypoparathyroidism were studied. Serum TSH, T3 free T4, calcium, phosphorus, alkaline phosphatase, BGP, iPTH and urinary calcium (uCA) were measured. BMD was measured by dual-energy X-ray absorptiometry (DXA) at lumbar spine, femoral neck, Ward's triangle, ultradistal and distal third radius and expressed as a Z-score. In a subset of 27 women aged 46 + 15 years (14 pre- and 13 postmenopausal) a second densitometry scan was performed 27 + 5 months later. Patients on suppressive therapy showed a small reduction in BMD at the distal third radius (Z-score: 70.77 + 0.98; 95% confidence interval: 71.11, 70.44) without differences between pre- and postmenopausal women. Significant relations with the regimen of suppressive therapy and bone turnover markers were detected except at the lumbar spine. In the longitudinal study a significant although mild reduction in femoral neck BMD was found that correlated with prior T3 and iPTH. In conclusion, our data show a small detrimental effect of cautious LT4 suppressive therapy on bone mass assessed by DXA; it remains to be established whether this increases the prevalence of fractures.

Thyroid cancer (*) The contributions of Esteban Jodar and Maria Begona Lopez are equal and the order of authorship is arbitrary. (*) The contributions of Esteban Jodar and Maria Begona Lopez are equal and the order of authorship is arbitrary.

1999 Syndromes of resistance to thyroid hormone: Clinical considerations Vlaeminck-Guillem, V.; Wemeau, J.L. Revue de Medecine Interne, Vol: 20, Issue: 12, 1114-1122, 1999
Abstract (English):
Introduction. - Syndromes of resistance to thyroid hormone correspond to variable clinical states which are usually transmitted as autosomal dominant traits and characterized by the lack of sensitivity of target tissues to triiodothyronine (T3). The diagnosis has to be performed in order to offer an appropriate therapy.

Current knowledge and key points. - Clinical states range between two extremes: the generalized form, with global euthyroidism, and the predominantly pituitary form, with thyrotoxicosis. Surprisingly, these various clinical situations are usually determined by the same genetic defect, i.e., an anomaly of one of the two alleles of the gene encoding the thyroid hormone receptor TRâ. High levels of circulating thyroid hormones in the presence of detectable thyroid stimulating hormone (TSH) levels is the characteristic biological feature. Pituitary thyreotropic adenoma, another etiology of inappropriate secretion of TSH, needs thus to be ruled out. No treatment is required in case of generalized resistance to thyroid hormone, whereas two specific drugs (TRIAC and D-T4) appear to be useful in the predominantly pituitary form. Future prospects and projects. - Mechanisms of resistance have been well documented, therefore allowing better understanding of T3 action on its nuclear receptor. Several transcriptional cofactors or corepressors have been identified and have to be investigated to explain the intriguing inter- and intra-familial, and even intra-individual, phenotypic variability. New insights should, furthermore, be gained from these studies to precisely determine how therapeutic agents work in

resistance to thyroid hormone.

1989 LETTER: JAMA October 6, 1989 Vol 262, No. 13
Treatment with Thyroid Hormone
To the Editor. - In reference to the editorial by Dr Cooper, practitioners who continue to use thyroid extract despite criticism from their colleagues do so for a good reason: it sometimes works better than other thyroid preparations. ....After changing to an equivalent (or sometimes slightly less than equivalent) dosage of desiccated thyroid, these symptoms improve considerably.
....Dr Cooper's discussion about the indications for thyroid hormone therapy also deserves comment. The claim that thyroid hormone should be used only to treat hypothyroidism presupposes that conventional thyroid function tests are sensitive enough to detect most cases of hypothyroidism. In fact, free thyroxine index and thyrotropin measurements will frequently fail to detect hypothyroidism documentable by thyrotropin-releasing hormone stimulation tests. In one study of patients with depression due to hypothyroidism, the diagnosis would have been missed half the time if thyrotropin-releasing hormone stimulation tests had not been done. . ... These studies suggest that free thyroxine index and thyrotropin measurements are not sensitive indicators of hypothyroidism.
The basal axillary temperature teste, as described by Barnes and Galton, is being used successfully by many clinicians. A subnormal axillary temperature often predicts a beneficial response to thyroid hormone therapy, even if results of standard thyroid function tests are normal. ,,,,One must therefore wonder even about the sensitivity of the thyrotropin-releasing hormone stimulation test.
Alan R. Gaby, M
Pikesville, Md
1. Cooper DS. Thyroid hormone treatment: New insights into an old therapy. JAMA 1989;261: 2694 - 269
2. Waas SH. Diiodotyrosine in treatment of Graves's disease Lancet. 1941; 2: 34 - 37
3. Gold MS, Pottash ALC, Extein I. Hypothyroidism and depression: evidence from complete thyroid function evaluation JAMA 1981; 24: 1919 - 1922
4. Stoffer SS. Menstrual disorders and thyroid insufficiency: intriguing cases suggesting an association. Postgrad Med 1982; 72(2): 75 - 82
5. Al-Khader AA, Aber GM. The relationship between the idiopathic oedema syndrome' and subclinical hypothyroidism. Clin Endocrinol. 1979; 10: 271 - 279
6. Barnes BO, Galton L. Hypothyroidism: The Unsuspected Illness, New York, NY: Crowell; 1976

1989 JAMA October 6, 1989 Vol 262, No. 13

In reply. - Dr Gaby raises several issues that deserve comment.
First, he suggests that desiccated thyroid has medicinal properties beyond those of thyroxine itself, and criticizes my branding desiccated thyroid obsolete. It is ironic that he would consider the large fraction of the iodine in desiccated thyroid existing as diiodotyrosine (or other iodinated compounds) to be an advantage, since such compounds are metabolically inert. Indeed, one of the main reasons for rejecting desiccated thyroid is its lack of standardization and frequent low hormonal content, which often lead to suboptimal therapy. This can be potentially disastrous, especially in patients with thyroid carcinoma. There is absolutely no evidence that desiccated thyroid alleviates symptoms due to hypothyroidism that are not reversed with pure levothyroxine sodium.
....I would hope that the readers of JAMA will continue to diagnose hypothyroidism using standard thyroid function tests and serum TSH measurements, treat only when hypothyroidism is confirmed biochemically, and then use only synthetic levothyroxine sodium.
David S. Cooper, MD
Sinai Hospital of Baltimore (Md)
The John Hopkins University School of medicine
1. Oppenheimer JH. Thyroid hormone action at the cellular level. Science 1979; 203: 971 - 979
2. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-thyroxine therapy in subclinical hypothyroidism: a double- blind, placebo-controlled trail. Ann Intern Med. 1984; 101: 18 - 24.

2001 AACE Press release: January 18, 2001
New Campaign Urges People to "Think Thyroid" at Critical Life Stages and Get Tested
JACKSONVILLE, FL, January 18, 2001
January is Thyroid Awareness Month
New York, NY - January 18, 2001 - Fewer than fifteen percent of Americans correctly identified the post childbirth (postpartum) period, menopause, or over 60 years of age, as key life stages when thyroid disease often strikes, according to a national survey released today by the American Association of Clinical Endocrinologists (AACE). To combat this lack of awareness, AACE is launching a new campaign, "The Neck's Time is Now," to educate Americans about the pivotal times, from birth to advanced age, when people are at increased risk for developing a thyroid disorder. Americans need to "think thyroid" and see their doctor for a TSH (thyroid stimulating hormone) blood test when: pregnant women go for their first prenatal visit; following pregnancy if postpartum depression strikes; a child's growth or behavior patterns change; mood swings and other symptoms of menopause persist despite hormone replacement therapy; fatigue, depression and

forgetfulness plague older Americans. The thyroid is a butterfly-shaped gland located in the neck, just below the Adam's apple and above the collarbone. Left untreated, thyroid disease causes serious long-term complications such as elevated cholesterol levels and subsequent heart disease, infertility, muscle weakness and osteoporosis. Thyroid disease affects more than 13 million Americans, yet more than half remain undiagnosed.

"The millions who remain undiagnosed reflect the widespread lack of awareness of this serious, but easily treatable condition. While more than half of the respondents can tell you their blood pressure, and more than one in five can identify their cholesterol (39%) and glucose levels (21%), only fifteen percent know their thyroid function - even though the thyroid gland influences these levels, according to the AACE survey. "For the millions of Americans affected by thyroid disease, it is important that they learn to recognize and evaluate the subtle signs and symptoms that can be significant markers of thyroid disease for themselves or for a loved one," says Paul Jellinger, M.D., F.A.C.E., President of AACE and Clinical Professor at the University of Miami School of Medicine.
Detecting and Understanding TSH
"Despite the critical need for detecting thyroid disorders early to avoid serious complications, the survey also revealed that almost 60 percent of Americans have never been tested for a thyroid condition. An overwhelming majority of survey participants (85 percent) failed to know the most common, gold standard measure of thyroid function - the TSH test. The TSH is a simple yet highly sensitive blood test that enables physicians to detect even slight abnormalities in thyroid function. It determines the level of thyroid stimulating hormone which regulates thyroid hormone production, indicating whether the thyroid gland is overactive (hyperthyroid), underactive (hypothyroid) or normal (euthyroid).
"AACE encourages patients whose TSH is outside the normal range (.5-5.0 uU/ml) to see an endocrinologist for treatment and thyroid disease management. Even though a TSH level between 3.0 and 5.0 uU/ml is in the normal range, it should be considered suspect since it may signal a case of evolving thyroid underactivity. The new thyroid stimulating hormone test is sensitive enough to detect both hypothyroid and hyperthyroid conditions. "TSH tests play a vital role in helping physicians diagnose and manage thyroid disorders," says Hossein Gharib, M.D., F.A.C.E, a Vice-President of AACE and Professor of Medicine at the Mayo Medical School. "Constant monitoring of a patient's TSH level is critical in early detection and treatment of thyroid disease."
The Neck's Time is Now: Thyroid Through the Ages
There are several principal life stages at which the risk for developing a thyroid disorder increases. Because of the advanced prevalence of thyroid disease, AACE advises TSH testing during the following times:
Birth through Adolescence: Effects on Mental and Physical Growth
One out of every four to five thousand babies born in the U.S. has hypothyroidism. Fortunately, screening for hypothyroidism is done routinely in North America on all newborns by administering a heelpad test to uncover cretinism, a growth and mental disorder brought on by a lack of thyroid hormone.
Parents need to be aware that thyroid disorders may also appear later in their child's development. A change in a child's growth rate is sometimes the only evidence that thyroid trouble is present because children are less likely to complain of feeling sick or to ask for help. Hyperthyroid children will rapidly outgrow new clothes, while hypothyroid children may mysteriously stop growing. But difficulty concentrating and inattentiveness in school, unexplained change in grades, hyperactivity, or unexplained daytime fatigue, may all be symptoms of an underlying thyroid condition. Children who come from families with a history of thyroid disease are especially likely to develop thyroid disorders.
The Reproductive Years: Effects on Pregnancy
Women who are unable to conceive should have their thyroid function assessed since thyroid disorders can impair fertility. In addition, recent studies have shown that untreated thyroid disease during pregnancy may negatively impact a child's psychological development, resulting in a lower I.Q. score and a decrease in motor skills, attention, language and reading abilities. Other studies suggest that pregnant women with hypothyroidism have a four-times greater risk for miscarriage during the second trimester. In fact, six out of every 100 miscarriages may be associated with autoimmune thyroid disease during pregnancy. AACE advises expectant mothers to take a TSH test before pregnancy or as part of the standard prenatal blood work.
The symptoms of thyroid illness are often vague and hard to recognize, especially when they are present after a woman gives birth. In many cases, the symptoms are mistaken for other conditions such as depression. In reality, many new mothers who are diagnosed with postpartum depression may actually be suffering from a common but seldom diagnosed thyroid disorder known as postpartum thyroiditis. During this time, women may suffer from an increased heart rate, insomnia, anxiety, as well as depression. This condition usually occurs during the first few weeks after the baby is born, and can continue for up to a year. A TSH test will pinpoint postpartum thyroiditis and medication will return thyroid function to normal, and often reverses the depression.
Midlife: Menopause Doesn't Have to Mean "Pause"
One in three women over the age of forty still experience the common symptoms of menopause despite treatment with hormone replacement therapy (HRT), according to AACE data. In fact, common menopausal symptoms - mood swings, depression, sleep disturbances, fatigue, forgetfulness, weight gain, change in hair, skin, and nails - could actually be signs of an underlying thyroid condition. AACE recommends that all women over forty have a TSH test since studies have shown that 10 percent of women in this age group have undiagnosed thyroid disease.
The Senior Years: Aging Without Feeling Aged
For some older people, the golden years of life are not what they expected, due to the onset of symptoms such as fatigue, depression, forgetfulness, insomnia, and changes in appetite and weight. Most seniors erroneously assume that these feelings

are a natural part of aging, when in fact these may be signs of an underlying thyroid condition. Seniors who report these symptoms to their doctors may be misdiagnosed with depression or even mild dementia. AACE underscores that aging, in the absence of disease, should not automatically be associated with the above symptoms. Since incidence of thyroid disease increases with age, and almost 20 percent of women over the age of sixty have some form of thyroid disease, TSH testing is particularly important for this age group.
The American Association of Clinical Endocrinologists and the Neck CheckTM:
While the TSH blood test is the most sensitive and accurate diagnostic tool, as a first step, AACE recommends that patients perform a simple self-examination called the Thyroid Neck CheckTM. This self-exam, unveiled by AACE in 1997, will help Americans detect an enlarged thyroid gland. If a patient finds an abnormality, they should speak with a physician about getting tested and treated for thyroid disease.
The American Association of Clinical Endocrinologists (AACE) was established in 1991 and is the country's largest professional organization of clinical endocrinologists. Its membership consists of more than 3,500 clinical endocrinologists devoted to providing care for patients with endocrine disorders. The association strives to improve the public's understanding and awareness of endocrine diseases and the added value of the clinical endocrinologist in the diagnosis and treatment of these diseases.

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