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THE SIZE OF FOLLICLES IN NON-TOXIC GOITRE
175 TABLE EX-RESULTS OF BY
PATIENTS’
increased in size, and others continued to have pain while healing was proceeding actively. Such observations underline the need for using an objective method (as well as the subjective one) in assessing the effects of a new treatment for gastric ulcers.
TREATMENT ASSESSED SUBJECTIVELY
SYMPTOMS
(COMPARISON BETWEEN PATIENTS PHENOBARBITONE
WITHOUT AND TREATED WITH WITH AND WITHOUT ASCORBIC
AND
ACID)
No. of
cases
(for Treatment
group
0
1
with symptoms
scale see
text)
SUMMARY AND CONCLUSIONS A trial was undertaken to assess the factors influencing the rate of healing of gastric ulcers. Inpatient treatment on a regulated gastric diet was compared with outpatient treatment and advice to follow the diet on a prescribed sheet ; the effect of added phenobarbitone and ascorbic acid was also determined. Inpatient treatment led to a significantly quicker rate of healing, as judged by measurements of the ulcer crater in the radiograph, and seemed to be more effective in relieving symptoms. It is not known whether the therapeutic factor was rest in bed or the supervised diet.
2
unless the ulcer had healed to a, third of its size in one month. Phenobarbitone and Asoorbic Acid The results of treatment - with phenobarbitone and ascorbic acid are set’out in tables VIII and ix: Inspection of the tables is sufficient to indicate that neither drug exerted any beneficial effect on the rate of healing of the ulcers or on the patients’ symptoms.
- After discharge
from
hospital, healing usually c’on-
tinued, but the evidence that a course of inpatient treatment exerted any beneficial effect on the subsequent rate of healing is not conclusive. Unless the ulcer had healed to a third of its size in one month it was unlikely to heal completely in three. The giving of phenobarbitone and ascorbic acid did not increase the rate of healing.
DISCUSSION
We are grateful to Dr. F.- Avery Jones for his advice and for allowing us to treat patients referred to his- clinic ; to all members of the gastro-enterological and radiological departments, Central Middlesex Hospital, for practical help in the management of the cases ; and to Mr. P. Armitage, of the Medical Research Council’s Statistical Research Unit, for suggesting the use of the method of rank correlation.
In the investigation special care was taken to ensure that the patients had equal corifidence in all the treatments tested. All the patients were examined and treated throughout by one doctor, and -all were given what were superficially the same medicaments by mouth. This appeared to have the desired effect. Inpatient treatmentwith rest in bed and a " gastric " diet is seen to have produced better results than ambulant treatment with advice to diet according to a prescribed sheet. Whether this was due to the rest in bed or to the diet, which could be more strictly enforced in hospital, is not known. It has been suggested that even the modern gastric diet, so much more liberal than the old " slop " diets, is more restricted than is really necessary, and perhaps rest in bed was the essential therapeutic factor. Possibly the psychological effect of withdrawing the patients from their home surroundings was also beneficial. The rate of healing after discharge from hospital was little, if at all, greater than that in the control group of patients treated as outpatients throughout. Such advantage as did- accrue may, perhaps, be attributed to. the fact that some of- the series-A patients continued to. " " stay away from work for a period of convalescence (lasting one to three weeks} after discharge from hospital ; in contrast all the control patients-apart from the few who continued to have incapacitating pain-were working. The practical conclusion to be drawn is that those gastric-ulcer patients whose condition merits admission to hospital should be kept in hospital until healing is complete-that is, if it is believed that the patient’s prognosis is improved by securing healing of the ulcer. Healing may, however, continue with ambulant treatment, should it be impossible to keep the patient in
REFERENCES
Gill, A. M. (1947) Lancet, i, 291. Ivy, A. C., Grossman, M. I., Bachrach, W. H. (1950) Peptic Ulcer. London ; p. 914. Jones, F. A. (1949) Brit. med. J. ii, 1463. Kendall, M. G. (1948) Rank Correlation Methods. London ; p. 37.
THE SIZE OF FOLLICLES IN NON-TOXIC GOITRE SELWYN TAYLOR* M.A., M.Ch. Oxfd, F.R.C.S. LECTURER IN SURGERY, POSTGRADUATE MEDICAL SCHOOL OF LONDON, HAMMERSMITH HOSPITAL, LONDON
NON-TOXIC goitre is common in London, and a. careful observer will not take long in finding numerous examples if he looks about him in any of the city’s thoroughfares. It seems unlikely that a lack of iodine is primarily responsible, since the Londoner has traditionally included fish in his-diet. Latterly, strict rationing of meat for some ten years has increased the consumption probably sea food by people of all income of levels. In an attempt to follow the metabolism of iodine in this type of goitre, patients were given a tracer dose of radioactive iodine, and after thyroidectomy sections of the removed glands were placed in contact with photographic film. The resulting autoradiograms showed a hospital. patchy distribution of the isotope, intense blackening The proportion of ulcers which healed completely in being confined to a few discrete areas not necessarily the present series is small ; no more than 8 out- of 64 correlated with nodules, and the remainder of the gland were healed after a month’s treatment, and even after showing little evidence of iodine uptake (figs. 1-3).three months the total was only 17. These figures cannot, This is in sharp contrast to the iodine uptake seen in be however, compared with many other series, because the normal thyroid, where the autoradiogram presents most favourable ulcers, those which had healed between scattered throughout the entire gland (fig. 4). diagnosis in outpatients and the initial examination after blackening When a histological survey was made of these discrete admission, have been excluded. areas of iodine uptake, it was at once apparent The disparity between the relief of the patients’ showed. certain characteristics which distinsymptoms and the extent of healing of the ulcer is of that they them from the rest of the gland. The follicles guished interest. A certain parallelism exists, but it is notable * In that some patients had no symptoms while their ulcers receipt of a personal grant from the Medical Research Council. *
iodine-containing
’
-
176 microtome. The technique was difficult because nodular goitre is very variable in- consistence, the tissue is friable, and the col. To add to these loid shrinks.
difficulties, calcification was often encountered. The sections, 5-10 µ thick, were mounted on glass slides and placed in contact with "
pieces of Kodak ’X-ray film in light-tight containers. At 1 day, 8 days, and 16 days the films and developed, were removed
Fig. I-Nodular non-toxic goitre. (a) Section through a complete lobe of the thyroid showing multiple nodules. (b) Autoradiogram from this section, showing intense blackening due to uptake of radio-iodine in only a few of the nodules. were
of
a
smaller average diameter and
more
uniform in
size, and the cells comprising the follicle walls
The sections were then stained with hæmatoxylin and eosin. Areas in the sections which corresponded to the dense black. ening on the autoradiograms were examined microscopically witha X 6 eyepiece and 1{ in. objec. tive. With a graticule in the eye-piece the diameters of -100 follicles were measured, two sets of diameters at right-angles to each other beingrecorded. A control area on theslide was then chosen in -which the auto. radiogram showed minimal blackening, and a further 200 measurements were made. .
RESULTS
were
consistently
tall. The diameters of the follicles in active and non-active areas were measured in preparations made from non-toxic goitres removed at operation. METHOD
patient received 100 µC of I131 by mouth whilst fasting, andwithin 30-50 hours the neck was scanned by a method previously described (Taylor and Stewart 1951). The urine was collected during the first 48 hours, and the urinary excretion of 1131 determined (Arnott et al. 1949) as a measure of over-all thyroid function. All the patients investigated fell-within the normal range. Within 24 hours of scanning, thyroidectomy was performed, the amount of tissue removed being decided by the severity of the pathological process and the age of the patient. The excised thyroid tissue was weighed, and thin slices cut from each lobe were fixed in formol saline solution. The tissue was subsequently embedded in paraffin wax, and large sections were cut with a sledge
From a series of goitres investigated by this auto. radiographic technique, six were chosen for measurement in the manner described. They were selected because AVERAGE. DIAMETERS OF FOLLICLES IN NON-TOXIC GOITRE
The
Average diameter (µ) Case no.
Inactive follicles
Active follicles
pathological changes other than those of simple goitre. In addition those showing good on the autoradiograms and well-defined cell histologically were preferred, so as to make’ the task of measuring the follicles as simple as possible. The results of these measurements are presented in the accompanying table, from which it will
they showed so-called contrast
outlines
no
be seen that the average diameter of the inactive follicles is about two or three times that of the active-ones. In addition it is well shown in figs.5 an d 6 that the diameters of the active follicles are consistently small in eontrast= to the wide range of diameters of the inactive follicles. ; DISCUSSION
non-toxic goitre. (a) Section with one nodule detached during embedding paraffin wax. ,(b) Autoradiogram of section showing almost all the activity confined to the one nodule.
Fig. 2-Nodular in
The thyroid follicle, which is the secretory unit of the gland, has been the subject of much study in the past, and. its size has been investigated in norm and pathological states by many workers No-one, however, seems to have had the advantage of being able to relate size and function
as
has
now
been made
possible
177
by using autoradiography. Wilson (1927) made wax reconstructions of serial sections of ten thyroids and found that the normal thyroid follicle is more or less or budded, and has an average diameter of 300 µ. The follicles in normal thyroid tissue varied less in size than those examined in any variety of diseased gland. In diffuse colloid goitre they retained their normal shape but might increase from three to five times in size by passive dilatation, coalescence, or budding. In Graves’s disease Wilson described the follicles as having an average diameter ’of 417 µ. Jackson (1931) used a different technique ; he macerated small pieces of thyroid tissue- in 75% hydrochloric acid, which
discrete, round, oval,
readily correlated with the well-known habit of the thyroid to form nodules, the so-called adenomata. It might be
postulated that only follicles of a certain critical size suitable are
targets for thyroidstimulating
the
hormone (T.s.H.) of the anteriorr
pituitary.
Fig. 5-Distribution of follicles in active and inactive Note uniformly small follicles in areas of thyroid.
If this were active area and wide scatter of diameters in it would inactive area (case 1). leave unexplained the observation that such follicles are typically found grouped together. Possibly the distribution of blood-vessels in th’3 thyroid is partly responsible. From the diffusely scattered iodine uptake seen in autoradiograms of normal thvroid tissue it has been so
-
postulated that each follicle has a natural cycle of alternating
activity and rest. Williams Fig. 3-Non-toxic goitre.
(a) Section through lobe with many large follicles filled with colloid. (b) Autoradiogram of section showing blackening due to uptake of radio-iodine, mainly confined to one small area, not nodular but composed of uniformly small follicles.
produced a suspension of follicles. These were washed and placed in a type of counting-chamber where their diameters could be determined. His average size for follicles of normal thyroid was 163-24 : 1-17 . ; for Graves’s disease it was 16878 067 , and for simple - goitre 244-5 ± 160 µ. In the present study it was found that those areas of the gland which showed uptake of radioactive iodine presented follicles of remarkably uniform diameter. It is interesting that discrete islands of tissue should function in this way, and it is an observation which is
(1937, 1939, 1941, 1944) studied living thyroid tissue in animals by transillumination and also by trans-
plants made in a transparent
of follicles in active and inactive areas in case 2, showing smalter difference in follicle diameters in active and
Fig. 6-Distribution
chamber mounted in the rabbit’s ear:
inactive
areas. -
-
He described how each follicle passed cycle- of secretion, colloid release, partial through and recuperation. He reported that few collapse, follicles appeared active at any one time. From the present work it appears that in non-toxic goitre most of the thyroid follicles become incapable of taking part in normal thyroid function, and that small discrete groups of follicles are producing all the body’s requirements of thyroid hormone. A vicious circle may well be set up, for nodules exhibiting increased activity are likely to undergo central necrosis and hæmorrhage (Dobyns and Lennon 1948) ; thus area after area, of the gland may become exhausted and eventually a
go on to cyst formation.
not
Fig. 4-Apparently normal thyroid.
(a) Section through lobe (removed with a foetal adenoma). (b) Autoradiogram of section, showing fairly uniform scattering of blackening due to uptake ofradio-iodine.
known at what stage in It is the development of a goitre this restriction of function to discrete The surgical ,areas takes place.
specimens removed inthe-present
178 series showed gross enlargement and advanced pathological changes, and there have been no indications for excising small goitres which might show intermediate
continued at this level for at least seven days. This time was considered to be adequate because there is no cumulative effect and mephenesin is very rapidly metabolised and excreted ; hence the greatest effect should occur soon after taking the drug. Berger and Schwartz (1948) stated that the maximum benefit occurred after two or three days’ therapy. Frequent clinical examinations were made. If the patient claimed improvement, a control mixture was substituted for the active mixture without the patient’s knowledge. The mephenesin elixir contained 1 g. of mephenesin in 15 ml. of elixir and 35% ethyl alcohol V. in V. The control elixir was of identical composition except that it contained no mephenesin. 10 of the patients were also examined before and after intravenous injections of mephenesin (5% solution), and electromyographic studies were made in Dr. Philippe Bauwens’s department with the collaboration of Dr. A. T.
stages in the evolution of this condition. SUMMARY
Patients with non-toxic goitre were given tracer doses of radio-iodine, and autoradiograms were prepared from the tissues removed at thyroidectomy. The iodine uptake was mainly localised in small
discrete
areas.
The follicles in these active areas were smaller and oi a more uniform diameter than those in the remainder of the gland. to record my indebtedness to Prof. Ian was done, and to many colleagues, in particular Dr. I. Doniach of the department of pathology. The photomicrographs are the work of Mr. E. V. Willmott, F.i.B.P., F.R.P.S. Finally the technical assistance of Miss Margaret Tomlinson made this investigation possible.
It is
a
pleasure
Aird, in whose department this work
Richardson. ’
REFERENCES
EFFECTS OF ORAL MEPHENESIN
The results may be summarised
Arnott, D. G., Emery, E. W., Fraser, R., Hobson, Q. J. G. (1949) Lancet, ii, 460. Dobyns. B. M., Lennon, B. (1948) J. clin. Endocrinol. 8, 732. Jackson, J. L. (1931) Anat. Rec. 48, 219. Taylor, S., Stewart, F. S. (1951) Lancet, ii, 232. Williams, R. G. (1937) Amer. J. Anat. 62, 1. (1939) J. Morph. 65, 17. (1941) Anat. Rec. 79, 263. (1944) Amer. J. Anat. 75, 95. Wilson, G. E. (1927) Anat. Rec. 37, 31.
as :
No improvement Modification of neurological state, but with no true benefit to patient.......... Definite improvement .. ...... 2 ..........
cases 17
8 .
—
Of the 27 patients who received protracted treatment with mephenesin in the largest tolerated dose the absence of improvement was so obvious in 15 that it was unnecessary to use the control mixture at all. In 12 cases the control mixture was substituted, but in only 2 of these was there a relapse, and these alone can be claimed as showing genuine improvement :
—
—
THE EFFECT OF MEPHENESIN IN SPASTIC PARALYSIS D. R. LAURENCE Lond., M.R.C.P.
(1)
M.D. LECTURER IN
THERAPEUTICS, ST. THOMAS’S SCHOOL, LONDON
HOSPITAL MEDICAL
a
man,
aged 28,
with
a severe
Two
In 8 cases it alteration in
MATERIAL
with flexor spasms were not
was
considered that there
was a
definite
benefit to the patient. A single large dose of about 5 g. of mephenesin can produce changes similar to those produced by intravenous mephenesin, but the effects are less. The changes last up to two hours.
paraplegia (1), syringomyelia (1), familial spastic paralysis (1), and spastic cases of doubtful origin (3). patients were admitted to hospital, and 3 were Iw all cases the mephenesin as outpatients. was given orally as an elixir four times a day after meals, and again during the night if the patient complained of symptoms due to the spasticity. The dose was steadily increased, usually daily, until toxic manifestations appeared. It was then reduced by an amount corresponding to 05-10 g. of mephenesin per dose, and this was regarded as the largest tolerated dose ; this was 6-18 g. Treatment was a day, with an average of 10-5 g. a day.
patients
physical state during treatment with a mephenesin : previously easily elicited clonus was abolished and spasticity reduced, but without significat
collected. The cases were dissemi27 patients nated sclerosis (6), cerebrovascular accident (6), motorneurone disease (4), traumatic hemiplegia (2), spinalcord compression (2), cerebral tumour (1), syphilitic
METHODS
other
improved by mephenesin.
were
24
was
since the age of 8 years. He is classified above under cases of doubtful origin. He had good voluntary power underlying his spasticity and since taking mephenesin has had a reduction in spasticity and has found that his shoe toes wear out less quickly and that he can leave his house later in the mornings because he gets to the bus stop sooner. His gait is still very spastic. He takes 14-16 g. of mephenesin a day and has been doing so for a year. (2) The second was a man, aged 65, with a paraplegia due to spinal-cord compression caused by Paget’s disease. He had severe flexor and adductor spasms and cramps which were almost completely relieved for two hours after a dose of mephenesin. His wife says she can get his trousers on and off, usually a -difficult slow task, in half the time if he has had a dose of mephenesin shortly beforehand. He is no longer kept awake at night by painful spasms and cramps. He has taken about 10 g. of mephenesin a day for a year.
MEPHENESIN (’Myanesin’) was introduced by Berger and Bradley in 1946 when they showed that its principal action was depression of the spinal cord. It was later shown by Berger (1947), Henneman et al. (1949), and Kaada (1950) that the action was on the internuncial neurones. Thus polysynaptic neural circuits were depressed, and monosynaptic circuits remained unaffected at ordinary doses. Spasticity is a condition of hyperactive stretchreflexes with after-discharge and a tendency for impulses to irradiate in the spinal cord (Magoun and Rhines 1947). Therefore mephenesin might be expected to depress this hyperactivity and allow the patient to use what voluntary power he has to better advantage. It is still not clear what place mephenesin has in the treatment of spastic paralysis ; therefore the present investigation was undertaken.
treated
The first of these
spastic paraplegia
EFFECTS OF INTRAVENOUS MEPHENESIN .
-
Clinical.
S’pasticity was always much reduced or completely abolished for about half an hour. The effect was much more dramatic in the legs than in the arms. " Clonus was abolished or reduced to a few weak jerks where previously it had been brisk and sustained. Flexor spasms (2 cases) were hardly affected in one case, although spasticity was reduced ; in the other case they could not be elicited even on strong- stimub tion of the leg where before they had occurred apparently spontaneously.
PATIENTS’
increased in size, and others continued to have pain while healing was proceeding actively. Such observations underline the need for using an objective method (as well as the subjective one) in assessing the effects of a new treatment for gastric ulcers.
TREATMENT ASSESSED SUBJECTIVELY
SYMPTOMS
(COMPARISON BETWEEN PATIENTS PHENOBARBITONE
WITHOUT AND TREATED WITH WITH AND WITHOUT ASCORBIC
AND
ACID)
No. of
cases
(for Treatment
group
0
1
with symptoms
scale see
text)
SUMMARY AND CONCLUSIONS A trial was undertaken to assess the factors influencing the rate of healing of gastric ulcers. Inpatient treatment on a regulated gastric diet was compared with outpatient treatment and advice to follow the diet on a prescribed sheet ; the effect of added phenobarbitone and ascorbic acid was also determined. Inpatient treatment led to a significantly quicker rate of healing, as judged by measurements of the ulcer crater in the radiograph, and seemed to be more effective in relieving symptoms. It is not known whether the therapeutic factor was rest in bed or the supervised diet.
2
unless the ulcer had healed to a, third of its size in one month. Phenobarbitone and Asoorbic Acid The results of treatment - with phenobarbitone and ascorbic acid are set’out in tables VIII and ix: Inspection of the tables is sufficient to indicate that neither drug exerted any beneficial effect on the rate of healing of the ulcers or on the patients’ symptoms.
- After discharge
from
hospital, healing usually c’on-
tinued, but the evidence that a course of inpatient treatment exerted any beneficial effect on the subsequent rate of healing is not conclusive. Unless the ulcer had healed to a third of its size in one month it was unlikely to heal completely in three. The giving of phenobarbitone and ascorbic acid did not increase the rate of healing.
DISCUSSION
We are grateful to Dr. F.- Avery Jones for his advice and for allowing us to treat patients referred to his- clinic ; to all members of the gastro-enterological and radiological departments, Central Middlesex Hospital, for practical help in the management of the cases ; and to Mr. P. Armitage, of the Medical Research Council’s Statistical Research Unit, for suggesting the use of the method of rank correlation.
In the investigation special care was taken to ensure that the patients had equal corifidence in all the treatments tested. All the patients were examined and treated throughout by one doctor, and -all were given what were superficially the same medicaments by mouth. This appeared to have the desired effect. Inpatient treatmentwith rest in bed and a " gastric " diet is seen to have produced better results than ambulant treatment with advice to diet according to a prescribed sheet. Whether this was due to the rest in bed or to the diet, which could be more strictly enforced in hospital, is not known. It has been suggested that even the modern gastric diet, so much more liberal than the old " slop " diets, is more restricted than is really necessary, and perhaps rest in bed was the essential therapeutic factor. Possibly the psychological effect of withdrawing the patients from their home surroundings was also beneficial. The rate of healing after discharge from hospital was little, if at all, greater than that in the control group of patients treated as outpatients throughout. Such advantage as did- accrue may, perhaps, be attributed to. the fact that some of- the series-A patients continued to. " " stay away from work for a period of convalescence (lasting one to three weeks} after discharge from hospital ; in contrast all the control patients-apart from the few who continued to have incapacitating pain-were working. The practical conclusion to be drawn is that those gastric-ulcer patients whose condition merits admission to hospital should be kept in hospital until healing is complete-that is, if it is believed that the patient’s prognosis is improved by securing healing of the ulcer. Healing may, however, continue with ambulant treatment, should it be impossible to keep the patient in
REFERENCES
Gill, A. M. (1947) Lancet, i, 291. Ivy, A. C., Grossman, M. I., Bachrach, W. H. (1950) Peptic Ulcer. London ; p. 914. Jones, F. A. (1949) Brit. med. J. ii, 1463. Kendall, M. G. (1948) Rank Correlation Methods. London ; p. 37.
THE SIZE OF FOLLICLES IN NON-TOXIC GOITRE SELWYN TAYLOR* M.A., M.Ch. Oxfd, F.R.C.S. LECTURER IN SURGERY, POSTGRADUATE MEDICAL SCHOOL OF LONDON, HAMMERSMITH HOSPITAL, LONDON
NON-TOXIC goitre is common in London, and a. careful observer will not take long in finding numerous examples if he looks about him in any of the city’s thoroughfares. It seems unlikely that a lack of iodine is primarily responsible, since the Londoner has traditionally included fish in his-diet. Latterly, strict rationing of meat for some ten years has increased the consumption probably sea food by people of all income of levels. In an attempt to follow the metabolism of iodine in this type of goitre, patients were given a tracer dose of radioactive iodine, and after thyroidectomy sections of the removed glands were placed in contact with photographic film. The resulting autoradiograms showed a hospital. patchy distribution of the isotope, intense blackening The proportion of ulcers which healed completely in being confined to a few discrete areas not necessarily the present series is small ; no more than 8 out- of 64 correlated with nodules, and the remainder of the gland were healed after a month’s treatment, and even after showing little evidence of iodine uptake (figs. 1-3).three months the total was only 17. These figures cannot, This is in sharp contrast to the iodine uptake seen in be however, compared with many other series, because the normal thyroid, where the autoradiogram presents most favourable ulcers, those which had healed between scattered throughout the entire gland (fig. 4). diagnosis in outpatients and the initial examination after blackening When a histological survey was made of these discrete admission, have been excluded. areas of iodine uptake, it was at once apparent The disparity between the relief of the patients’ showed. certain characteristics which distinsymptoms and the extent of healing of the ulcer is of that they them from the rest of the gland. The follicles guished interest. A certain parallelism exists, but it is notable * In that some patients had no symptoms while their ulcers receipt of a personal grant from the Medical Research Council. *
iodine-containing
’
-
176 microtome. The technique was difficult because nodular goitre is very variable in- consistence, the tissue is friable, and the col. To add to these loid shrinks.
difficulties, calcification was often encountered. The sections, 5-10 µ thick, were mounted on glass slides and placed in contact with "
pieces of Kodak ’X-ray film in light-tight containers. At 1 day, 8 days, and 16 days the films and developed, were removed
Fig. I-Nodular non-toxic goitre. (a) Section through a complete lobe of the thyroid showing multiple nodules. (b) Autoradiogram from this section, showing intense blackening due to uptake of radio-iodine in only a few of the nodules. were
of
a
smaller average diameter and
more
uniform in
size, and the cells comprising the follicle walls
The sections were then stained with hæmatoxylin and eosin. Areas in the sections which corresponded to the dense black. ening on the autoradiograms were examined microscopically witha X 6 eyepiece and 1{ in. objec. tive. With a graticule in the eye-piece the diameters of -100 follicles were measured, two sets of diameters at right-angles to each other beingrecorded. A control area on theslide was then chosen in -which the auto. radiogram showed minimal blackening, and a further 200 measurements were made. .
RESULTS
were
consistently
tall. The diameters of the follicles in active and non-active areas were measured in preparations made from non-toxic goitres removed at operation. METHOD
patient received 100 µC of I131 by mouth whilst fasting, andwithin 30-50 hours the neck was scanned by a method previously described (Taylor and Stewart 1951). The urine was collected during the first 48 hours, and the urinary excretion of 1131 determined (Arnott et al. 1949) as a measure of over-all thyroid function. All the patients investigated fell-within the normal range. Within 24 hours of scanning, thyroidectomy was performed, the amount of tissue removed being decided by the severity of the pathological process and the age of the patient. The excised thyroid tissue was weighed, and thin slices cut from each lobe were fixed in formol saline solution. The tissue was subsequently embedded in paraffin wax, and large sections were cut with a sledge
From a series of goitres investigated by this auto. radiographic technique, six were chosen for measurement in the manner described. They were selected because AVERAGE. DIAMETERS OF FOLLICLES IN NON-TOXIC GOITRE
The
Average diameter (µ) Case no.
Inactive follicles
Active follicles
pathological changes other than those of simple goitre. In addition those showing good on the autoradiograms and well-defined cell histologically were preferred, so as to make’ the task of measuring the follicles as simple as possible. The results of these measurements are presented in the accompanying table, from which it will
they showed so-called contrast
outlines
no
be seen that the average diameter of the inactive follicles is about two or three times that of the active-ones. In addition it is well shown in figs.5 an d 6 that the diameters of the active follicles are consistently small in eontrast= to the wide range of diameters of the inactive follicles. ; DISCUSSION
non-toxic goitre. (a) Section with one nodule detached during embedding paraffin wax. ,(b) Autoradiogram of section showing almost all the activity confined to the one nodule.
Fig. 2-Nodular in
The thyroid follicle, which is the secretory unit of the gland, has been the subject of much study in the past, and. its size has been investigated in norm and pathological states by many workers No-one, however, seems to have had the advantage of being able to relate size and function
as
has
now
been made
possible
177
by using autoradiography. Wilson (1927) made wax reconstructions of serial sections of ten thyroids and found that the normal thyroid follicle is more or less or budded, and has an average diameter of 300 µ. The follicles in normal thyroid tissue varied less in size than those examined in any variety of diseased gland. In diffuse colloid goitre they retained their normal shape but might increase from three to five times in size by passive dilatation, coalescence, or budding. In Graves’s disease Wilson described the follicles as having an average diameter ’of 417 µ. Jackson (1931) used a different technique ; he macerated small pieces of thyroid tissue- in 75% hydrochloric acid, which
discrete, round, oval,
readily correlated with the well-known habit of the thyroid to form nodules, the so-called adenomata. It might be
postulated that only follicles of a certain critical size suitable are
targets for thyroidstimulating
the
hormone (T.s.H.) of the anteriorr
pituitary.
Fig. 5-Distribution of follicles in active and inactive Note uniformly small follicles in areas of thyroid.
If this were active area and wide scatter of diameters in it would inactive area (case 1). leave unexplained the observation that such follicles are typically found grouped together. Possibly the distribution of blood-vessels in th’3 thyroid is partly responsible. From the diffusely scattered iodine uptake seen in autoradiograms of normal thvroid tissue it has been so
-
postulated that each follicle has a natural cycle of alternating
activity and rest. Williams Fig. 3-Non-toxic goitre.
(a) Section through lobe with many large follicles filled with colloid. (b) Autoradiogram of section showing blackening due to uptake of radio-iodine, mainly confined to one small area, not nodular but composed of uniformly small follicles.
produced a suspension of follicles. These were washed and placed in a type of counting-chamber where their diameters could be determined. His average size for follicles of normal thyroid was 163-24 : 1-17 . ; for Graves’s disease it was 16878 067 , and for simple - goitre 244-5 ± 160 µ. In the present study it was found that those areas of the gland which showed uptake of radioactive iodine presented follicles of remarkably uniform diameter. It is interesting that discrete islands of tissue should function in this way, and it is an observation which is
(1937, 1939, 1941, 1944) studied living thyroid tissue in animals by transillumination and also by trans-
plants made in a transparent
of follicles in active and inactive areas in case 2, showing smalter difference in follicle diameters in active and
Fig. 6-Distribution
chamber mounted in the rabbit’s ear:
inactive
areas. -
-
He described how each follicle passed cycle- of secretion, colloid release, partial through and recuperation. He reported that few collapse, follicles appeared active at any one time. From the present work it appears that in non-toxic goitre most of the thyroid follicles become incapable of taking part in normal thyroid function, and that small discrete groups of follicles are producing all the body’s requirements of thyroid hormone. A vicious circle may well be set up, for nodules exhibiting increased activity are likely to undergo central necrosis and hæmorrhage (Dobyns and Lennon 1948) ; thus area after area, of the gland may become exhausted and eventually a
go on to cyst formation.
not
Fig. 4-Apparently normal thyroid.
(a) Section through lobe (removed with a foetal adenoma). (b) Autoradiogram of section, showing fairly uniform scattering of blackening due to uptake ofradio-iodine.
known at what stage in It is the development of a goitre this restriction of function to discrete The surgical ,areas takes place.
specimens removed inthe-present
178 series showed gross enlargement and advanced pathological changes, and there have been no indications for excising small goitres which might show intermediate
continued at this level for at least seven days. This time was considered to be adequate because there is no cumulative effect and mephenesin is very rapidly metabolised and excreted ; hence the greatest effect should occur soon after taking the drug. Berger and Schwartz (1948) stated that the maximum benefit occurred after two or three days’ therapy. Frequent clinical examinations were made. If the patient claimed improvement, a control mixture was substituted for the active mixture without the patient’s knowledge. The mephenesin elixir contained 1 g. of mephenesin in 15 ml. of elixir and 35% ethyl alcohol V. in V. The control elixir was of identical composition except that it contained no mephenesin. 10 of the patients were also examined before and after intravenous injections of mephenesin (5% solution), and electromyographic studies were made in Dr. Philippe Bauwens’s department with the collaboration of Dr. A. T.
stages in the evolution of this condition. SUMMARY
Patients with non-toxic goitre were given tracer doses of radio-iodine, and autoradiograms were prepared from the tissues removed at thyroidectomy. The iodine uptake was mainly localised in small
discrete
areas.
The follicles in these active areas were smaller and oi a more uniform diameter than those in the remainder of the gland. to record my indebtedness to Prof. Ian was done, and to many colleagues, in particular Dr. I. Doniach of the department of pathology. The photomicrographs are the work of Mr. E. V. Willmott, F.i.B.P., F.R.P.S. Finally the technical assistance of Miss Margaret Tomlinson made this investigation possible.
It is
a
pleasure
Aird, in whose department this work
Richardson. ’
REFERENCES
EFFECTS OF ORAL MEPHENESIN
The results may be summarised
Arnott, D. G., Emery, E. W., Fraser, R., Hobson, Q. J. G. (1949) Lancet, ii, 460. Dobyns. B. M., Lennon, B. (1948) J. clin. Endocrinol. 8, 732. Jackson, J. L. (1931) Anat. Rec. 48, 219. Taylor, S., Stewart, F. S. (1951) Lancet, ii, 232. Williams, R. G. (1937) Amer. J. Anat. 62, 1. (1939) J. Morph. 65, 17. (1941) Anat. Rec. 79, 263. (1944) Amer. J. Anat. 75, 95. Wilson, G. E. (1927) Anat. Rec. 37, 31.
as :
No improvement Modification of neurological state, but with no true benefit to patient.......... Definite improvement .. ...... 2 ..........
cases 17
8 .
—
Of the 27 patients who received protracted treatment with mephenesin in the largest tolerated dose the absence of improvement was so obvious in 15 that it was unnecessary to use the control mixture at all. In 12 cases the control mixture was substituted, but in only 2 of these was there a relapse, and these alone can be claimed as showing genuine improvement :
—
—
THE EFFECT OF MEPHENESIN IN SPASTIC PARALYSIS D. R. LAURENCE Lond., M.R.C.P.
(1)
M.D. LECTURER IN
THERAPEUTICS, ST. THOMAS’S SCHOOL, LONDON
HOSPITAL MEDICAL
a
man,
aged 28,
with
a severe
Two
In 8 cases it alteration in
MATERIAL
with flexor spasms were not
was
considered that there
was a
definite
benefit to the patient. A single large dose of about 5 g. of mephenesin can produce changes similar to those produced by intravenous mephenesin, but the effects are less. The changes last up to two hours.
paraplegia (1), syringomyelia (1), familial spastic paralysis (1), and spastic cases of doubtful origin (3). patients were admitted to hospital, and 3 were Iw all cases the mephenesin as outpatients. was given orally as an elixir four times a day after meals, and again during the night if the patient complained of symptoms due to the spasticity. The dose was steadily increased, usually daily, until toxic manifestations appeared. It was then reduced by an amount corresponding to 05-10 g. of mephenesin per dose, and this was regarded as the largest tolerated dose ; this was 6-18 g. Treatment was a day, with an average of 10-5 g. a day.
patients
physical state during treatment with a mephenesin : previously easily elicited clonus was abolished and spasticity reduced, but without significat
collected. The cases were dissemi27 patients nated sclerosis (6), cerebrovascular accident (6), motorneurone disease (4), traumatic hemiplegia (2), spinalcord compression (2), cerebral tumour (1), syphilitic
METHODS
other
improved by mephenesin.
were
24
was
since the age of 8 years. He is classified above under cases of doubtful origin. He had good voluntary power underlying his spasticity and since taking mephenesin has had a reduction in spasticity and has found that his shoe toes wear out less quickly and that he can leave his house later in the mornings because he gets to the bus stop sooner. His gait is still very spastic. He takes 14-16 g. of mephenesin a day and has been doing so for a year. (2) The second was a man, aged 65, with a paraplegia due to spinal-cord compression caused by Paget’s disease. He had severe flexor and adductor spasms and cramps which were almost completely relieved for two hours after a dose of mephenesin. His wife says she can get his trousers on and off, usually a -difficult slow task, in half the time if he has had a dose of mephenesin shortly beforehand. He is no longer kept awake at night by painful spasms and cramps. He has taken about 10 g. of mephenesin a day for a year.
MEPHENESIN (’Myanesin’) was introduced by Berger and Bradley in 1946 when they showed that its principal action was depression of the spinal cord. It was later shown by Berger (1947), Henneman et al. (1949), and Kaada (1950) that the action was on the internuncial neurones. Thus polysynaptic neural circuits were depressed, and monosynaptic circuits remained unaffected at ordinary doses. Spasticity is a condition of hyperactive stretchreflexes with after-discharge and a tendency for impulses to irradiate in the spinal cord (Magoun and Rhines 1947). Therefore mephenesin might be expected to depress this hyperactivity and allow the patient to use what voluntary power he has to better advantage. It is still not clear what place mephenesin has in the treatment of spastic paralysis ; therefore the present investigation was undertaken.
treated
The first of these
spastic paraplegia
EFFECTS OF INTRAVENOUS MEPHENESIN .
-
Clinical.
S’pasticity was always much reduced or completely abolished for about half an hour. The effect was much more dramatic in the legs than in the arms. " Clonus was abolished or reduced to a few weak jerks where previously it had been brisk and sustained. Flexor spasms (2 cases) were hardly affected in one case, although spasticity was reduced ; in the other case they could not be elicited even on strong- stimub tion of the leg where before they had occurred apparently spontaneously.