JUVENILE
THYROTOXICOSIS
Results
of Treatment
in 30
Cases
By RICHARD F. ALLEN, M.D., EDWARD ROSE, M.D., D
ELIZABETH KIRK ROSE, M.D. Philadelphia
TABLE 1
Follow-up in Years
Results
Case Sex Race
r’
Age at
Pu-berty
Opthal- Treatment- of
mopathy and
Con-Years Duration servative Total
Treat-ment
After
Comply-tion of Treat-ment
Comments
I AB F W 9 ?
Group 1 (Cases 1-3) Received Irradiation Only
+ 400 r 3/H S 0 19-9/H
CB F C H 13 + 400 rX 6/H S Q
400 r X
1-6/H Hypothyroidism after treatment.
Thyroid nodule appeared H yr.
later.
3 ES F W 14 13+ 0 3600 r 8/H S 9-i/H 8-6/H
4AGF F W’ 13
5EBR F \V 7
6 AQ F \V ii
7 1.5 F \V 11
38
D
IVERGENT views exist regarding therelative merits of conservative therapy
and thyroidectomy in juvenile
thyrotoxi-cosis. In 1941, Black and Webster,’
review-ing the literature and their own therapeutic
results in 26 such patients under the age of
18, concluded that nonsurgical treatment had proved impractical. However, since the
introduction of antithyroid compounds in
1943, conservative management has been
more generally favored.”3 The purpose here is to report the results of various types of treatment in 30 thyrotoxic children whose symptoms began prior to 15 years of age, and who have been treated under the authors’ supervision between 1928 and
From the Department of Pediatrics of the Uni-versity of Pennsylvania School of Medicine and the Endocrine Section, Medical Clinic of the Hos-pital of the University of Pennsylvania, Phila-delphia.
(Received for publication Dec. 8, 1953.)
1951. All but 2 of these 30 patients were under observation for 2 years or more, 17 for more than 5 years, 10 for more than 9 years.
The authors have consistently followed
a conservative policy in the treatment of
juvenile thyrotoxicosis, resorting to
thyroid-ectomy only after conservative measures
have failed or when their continuation has
seemed impractical. Prior to 1943 their
treatment of choice comprised external
irradiation of the thyroid, with or without
stable iodine. Since 1943 they have
em-ployed antithyroid compounds, sometimes
accompanied by, or alternating with stable
iodine.
In accord with their general policy re-garding the avoidance of radioactive iodine in young persons, the authors have not em-ployed it therapeutically in thyrotoxic chil-dren, because they do not believe that sufficient time has elapsed to exclude the
1)A’rA IN 30 CASES OF JUVENILE TIIYuoToxIcoSIS
Group 9 (Cases 4-15) Received Irradiation and Stable Iodine
13+ Ei00 r 3/H F IQ-5/II H-f/H
H+ 0 %800r 4-5/H S H-i/H 7-8/H
14 + 4400 rX 10/H S Q4-6/H 3-8/H
Q400 rX
13 + 1600 r .5 5-3/H 4/H
Age Age Treatment-
Ophthal-and
Case Sex Race at at
mopathy Years’ Duration
Onset Puberty
8 LSV
9 MWW
10 PH
ii AH
It 115
13 \‘S
14 AS
Comments
F F F F F F F
15 FSG F VS 14 17 + lSOOrX4 t-3/lt
Group 3 (Cases 16-to) Received Thiouracil Compounds Only
16 LG F Vi 54 - 0 M Q-t/lt S 3-1/it 6/it
17 RB M C 6 - + M 10/it R t 0
Relapsedafter6mo.onPT.Inre-PT 6/It mission after 10 mo. on M. when
last seen 5-t-5t.
18 WH M C 74 - + M S-i/it R S-i/it 0 Still under treatment. Social and behaviour problem.
19 KK F W 4-9/it - + M 2-6/it t-iO/lt 0 Relapse after M. Still under
treat-PT 4/it R ment with P’F.
to JS F W 10-9/it - + M 1-9/it R 1-9/it 0 Still under treatment. In remission
on small dose of M.
ti JL M W’ 10
Group 4 (Cases 21-30) Received Thiouracil Compounds and Stable Iodine
normal + PT 1-7/it S 4-6/it 2-il/it
22 BJS F W 94 134 + PT 1-2/12 S 6-10/it 5-8/it
ts MB M Vs ii normal + PT t-6/it S 6-6/it 7/it Relapsed after P’F and again after
MT 1-2/it M.
M 1-9/it
24 CE F C 7 it4 0 PT i-li/it S 7 4
MT i/it
ts LRM F \\ 9 1t4 + MT 1-i/it S 2-7/it 1-6/it Diabetes mellitus appeared during
therapeutic remission. Mild
hypo-thyroidism later.
t6 DR M W ii normal + PT i-li/it S 2$/it 4/it In remission on PT but
thyroid-ectomy done because of large
goiter.
t7 Bi) F C it it-8,’it + AT 3/it S 6-5/it 1-4/it In complete remission i-4/it yr.
PT 3-5/it after stopping M. Irregular in
M 5/it clinic attendance. Jaundice and
re-lapse after AT.Leucopenia and
ye-lapse after PT. Dose of M
prob-ably small and irregular.
28 BA F WI 13 13 + PT F 2-9/it 9/it In remission 9 mo. after
thyroid-M ectomy. Sensitive to PT, M. and I.
t9 MI F W 104 14 + T 9/it F 6-7/it i-i/it Relapsed after T, again after AT.
AT 5/it Later preoperative M.
M 2/it
30 SF F \V 3 - + MT i-iO/it R 3-6/it 0 Still under treatment with M,
M 1-7/It beginning remission. Goiter
en-larging.
T-Thiouracil MT-Methylthiouracil
AT-Aminothiozole M-Methimazole
PT-Propylthiouracil I-Stable Iodine
5L.SV received pituitary irradiation for hyperophthalmopathic syndrome.
S-Satisfactory R-Remission
F-Failure
TABLE 1-Corainued
W 84 11+ + 3700r i-i/H
W Ft 13+ 0 40rXt /H
780 r
\V 5 14 + 600 rXt /1t
C 8 13 + 800r 6/H
W’ 14 13 0 ltOOrXt 3/H
\V 13+ 11 + t800r 4/it
\V 14 13 0 1900 rXt 6/It
Results Follow-up in Years of
Con- After
servatis’e
Comple-Treat- Total tion of
meat
Treat-ment
S 9-3/It 8-t/lt
S tl-8/It ti-S/it
S 16-t/lt 16
S 8 6 Previous hemithyroidectomy but
8till toxic when first seen.
F 4-6/it li/it Thyroidectomy after failure to
re-spond to irradiation.
F 4/It 4/it Cardiac death prior to
thyroidec-tomy. See protocol.
F 3-11/it 1-t/lt Recurrence after t
hemithyroid-ectomies. No response to
sube-quent irradiation. Emotional and
social problems.
F tt it 1-lyperthyroidism relieved after
second thyroidectomy but
anor-exia nervosa with psychosis
Total
Maximum Minimum Median
23-8/12 4/12 4-10/12
3-6/12 1-9/12 2-10/12
* Not included is the cardiac death (Case 13) at 4/12 yr.
40 R. F. ALLEN, E. ROSE AND ELIZABETH KIRK ROSE
* B.D. (Case 27) isin incomplete remission, 1-4/12 yr. after termination of therapy.
TABLE 2
SUMMARY OF DATA IN ‘30CASES OF JUVENILE THYROTOXICOSIS
1. Sex 2. Race
3. Ophthalmopathy 4. Age at onset
25 female
24 white
23 present
under 5 yr. (5-9 yr.)
11
No. of Years 5 male
6 Negro 7 absent
(10-14 yr.)
17
5. Follow-up No. of Cases
After conclusion of treatment
Still under treatment
possibility of late untoward sequelae.
The authors have encountered no
chil-dren with toxic nodular goiter, but would consider thyroidectomy the treatment of choice in such cases because of the po-tential risk of carcinoma.
Data pertaining to these cases and the
results of treatment are shown in tables
1 to 4.
The antithyroid compounds used in the patients have included thiouracil,
methyl-thiouracil, amino-thiozole, propylthiouracil and methimazole. At present methimazole is employed as the drug of choice, propyl-thiouracil being substituted when sensitivity
reactions require a change of medication.
The initial daily dose of methimazole in
children varies from 15 to 60 mg. and of
propylthiouracil from 150 to 450 mg.,
given in 3 equal doses at 8 hour intervals. The total daily dose is gradually reduced as remission develops. The objective is to
TABLE 3
RESULTS OF MEDICAL TREATMENT IN 30 CASES OF JUVENILE THYROTOXICOSIS
Group Treatment Number
. Satis-factory
Still , 1nder
.
‘1reatment
,
Ijnsati.s-factory
1. Irradiation 3 3 0 0
2. Irradiation plus stable 12 7 0 5 COMMENTS
iodine 2-Required thyroidectomy for
permanent remission (Cases 12 and 15)
1-Required thyroidectomy after
failure of previous surgery
(Case 14) 1-Death (Case 13)
3. Antithyroid compounds 5 1 4 0
4. Antithyroid compounds 10 6* 1 3 Required thyroidectomy for
per-plus stable iodine manent remission (Cases 26, 28,
29)
TABLE 4
END RESULTS OF 30 CASES OF
JUVENILE THYROTOXICOSIS
Permanent remission 23
Conservative treatment 18
Conservative treatment plus surgery 5
Still under treatment 5
Failures 2
Fotal 30
maintain full remission without hypothy-roidism for about one year. Daily main-tenance doses of methimazole have varied from 5 to 15 mg. and of propylthiouracil
from 25 to 50 mg. Stable iodine and desic-cated thyroid have been used as adjuncts
in the treatment of ophthalmopathic
corn-plications and of undesirably large goiters.
Family understanding and cooperation
are of great importance in managing the emotional stresses inherent in a protracted
therapeutic program.
Contrary to reports4 of delayed puberty in thyrotoxic children, the authors found
no evidence of such tendency in these
patients. In a longitudinal study of growth
using Wetzel grids in nine of the patients, no definite relationship was evident be-tween the state of thyroid function and the rate of growth and development.
Because of their unusual interest, details of two patients who died are presented below.
CASE REPORTS
Case 13: V.S., a white girl, aged 14 yr., was first seen with the clinical picture of severe
Graves’ disease with marked exophthalmos and a rather large diffuse goiter. Typical symptoms
had begun 8 mo. previously and had continued to progress despite 2 courses of iodine pre-scribed by her family physician. She had lost
6.4 kg. There was no history to suggest
rheu-matic infection or congenital heart disease. The cardiac rate was accelerated and slight cardiac enlargement was apparent on percussion but
the rhythm was normal and no murmurs were
heard. There were no signs of congestive heart
failure. Basal metabolic rate was plus 45%.
Thyroid irradiation was begun 1 wk. after
admission and totaled 2800 roentgens by the end of 4 mo. Six weeks after admission, her basal metabolic rate had fallen to + 24% and during the next 6 wk. she gained about 4.1 kg. She was not seen in the outpatient clinic for 2
mo., although during this interval she returned to the Department of Radiology several times
for treatment. Chest RG, taken because of a
cough, showed marked generalized cardiac en-largement particularly to the left and pos-teriorly, suggesting to the radiologists the p05-sibility of a double mitral lesion; there was evidence of passive congestion in both lungs.
She returned to the outpatient clinic where it was obvious that her condition had worsened and that she was in congestive heart failure.
Irradiation therapy was suspended and she
was immediately hospitalized with the hope
that she could be successfully prepared for
thyroidectomy. Examination on admission
showed slight cyanosis and a suggestion of icterus. She was orthopneic, with regular cardiac rhythm and tachycardia ranging from 140 to 150/mm. No murmurs were heard. The heart showed marked generalized enlargement
(
86% above predicted normal area in the ortho-diagram). The ECG showed regular sinustachycardia with inverted T-waves in leads
II and III (no chest leads). Congestive heart failure was manifested by basal pulmonary rales, marked hepatomegaly, edema of depend-ent parts and possible ascites. There was moder-ate irregular fever. A program of medical treat-ment was begun, including compound solution of iodine. The patient’s general condition re-mained unchanged except for a slight progres-sive increase in fever, pulse and respiratory rate, until the morning of her third hospital day, when she suddenly died following a severe episode of coughing with cyanosis. Necropsy was not permitted.
Comment: This case is of particular interest because of the possibility that the patient may have succumbed to heart failure due solely to thyrotoxicosis. Although necropsy data are
lack-ing and the configuration of the heart was
considered by the radiologist somewhat sug-gestive of a mitral lesion, there was no history to suggest rheumatic disease, congenital
42 R. F. ALLEN, E. ROSE AND ELIZABETH KIRK ROSE
admitted to exist, Likoff and Levine5 have described 7 cases. The authors are not aware of any reported instance of death from purely thyrotoxic heart failure in a patient as young as this.
Case 15: F.S.G., a white female, was first
seen at age 14 yr. with moderately severe
Graves’ disease accompanied by exophthalmos and diffuse goiter. Subtotal thyroidectomy was followed by incomplete remission. During the next 10 yr. her condition fluctuated with per-sistent exophthalmos, tachycardia, scanty ir-regular menses and increasing emotional
mal-adjustment, despite a weight gain of 27.2 kg.
Intermittent administration of iodine and
sev-eral courses of thyroid irradiation failed to produce a sustained remission. A second sub-total thyroidectomy at 24 yr. of age, was fol-lowed by. permanent remission of the thyrotoxi-cosis, although exophthalmos persisted. Dur-ing the next 12 yr. there developed progressive
anorexia, inanition, weight loss and psychic
and emotional disturbances. Scanty irregular menstruation continued. Her later course was marked by recurrent cutaneous oral and urinary
infections. She was extensively studied and treated in several local hospitals besides this one. These studies showed extreme inani-tion, hypoproteinemia, hypochloremia, alkalosis and nutritional edema. She was negativistic
and refused to eat or to cooperate in attempts at psychotherapy. Thyroid function, measured by uptake of radioactive iodine, was normal. Urinary gonadotrophins, which had been
ele-vated in 1947, were absent in 1949. The pa-tient died in another hospital in 1951 in an advanced state of inanition, the clinical pic-ture conforming to that of anorexia nervosa.
Necropsy revealed marked atrophy of the
liver, spleen, kidneys, pancreas, ovaries and adrenals; the thyroid remnant contained an adenomatous nodule but was otherwise atrophic; the anterior pituitary was atrophic
but showed no other pathologic process. No
histologic examination of the brain was
re-ported.
Comment: This case presents the possibility
that psychic factors may have constituted a
common etiologic background for the thyrotoxi-cosis and the subsequent anorexia nervosa. It
is of interest in connection with the recent
ob-servations of Ham et al.#{176}concerning the etio-logic role of psychic and emotional disturb-ances in Graves’ disease, and also because it
confirms the existence of both anterior pituitary and target gland atrophy in anorexia nervosa.
DIscussIoN
In the group of patients receiving thyroid
irradiation with or without stable iodine
(
see table 3), satisfactory remissions were obtained in 10. The five failures include the patient who died in congestive heart failure; one patient in whom thyroidectomy had previously failed and two who were op-erated on successfully after the failure of irradiation and iodine.The average dose of irradiation was esti-mated as approximately 3800 r in air in the
patients with satisfactory results and
ap-proximately 2120 r in air in the patients classified as failures.
Among the 15 patients receiving anti-thyroid compounds with or without stable iodine, six have been in remission for from 6/12 to 5 8/12 years following cessation of therapy. The condition of one patient (Case 27), who has cooperated poorly, fluctuated for one year after withdrawal of therapy but has been satisfactory for the past three months. Four patients are still under
treat-ment at time of writing. One of these (Case
30) is improved, but not yet in full re-mission after 33 years of treatment. Three others (Cases 18, 19 and 20) are in full remission on small maintenance doses of
methimazole or propylthiouracil after
1-9/12, 2 10/12 and 3 1/12 years,
respec-tively. Another patient (Case 17) was in
complete remission on a small maintenance dose of propylthiouracil after two years of treatment, but has been lost to follow-up for the past two years.
Two patients (Cases 28 and 29) were
sub-jected to thyroidectomy after conservative
treatment had failed (see below). One
pa-tient (Case 26) was operated on in another city 10 months after leaving the authors’ observation (see below).
Seven of the patients were subjected to
thyroidectomy at some time during the
seen by the authors and subsequently
re-sponded well to irradiation and stable iodine. Another (Case 14) had failed to im-prove following two hemithyroidectomies in this hospital and subsequently also failed to respond to irradiation and stable iodine;
her problem was complicated by serious
emotional and social factors. One patient (Case 26) had a successful subtotal
thyroid-ectomy in another city 10 months after
leaving the authors’ supervision; during this interval he had apparently remained in re-mission on propyithiouracil and operation was performed because of the persistence
of a large goiter. The remaining four
pa-tients were subjected to thyroidectomy
be-cause conservative therapy failed to
pro-duce sustained remissions. Two of these (Cases 12 and 15) had received irradiation and stable iodine and the other two (Cases 28 and 29) had failed to respond to anti-thyroid compounds and stable iodine ad-ministered for 2 and 1 1/12 years,
respec-lively. Satisfactory remissions are known to have followed thyroidectomy in these four patients for 11/12, 12, 9/12 and 1 1/12
years, respectively.
It is possible to evaluate the results of conservative therapy in 24 patients and among these patients treatment was
suc-cessful in 17 or 70.8%. Good results were
obtained in 10 of the 15 patients irradiated
and in 7 of 9 patients receiving antithyroid compounds. None of the patients became myxedematous but two (Cases 2 and 25) developed mild hypothyroidism after ir-radiation and methyithiouracil, respectively. Thyroidectomy was successful in 5 of the 6 patients in whom it could be evaluated.
The results of nonsurgical therapy in this group of juvenile patients are approximately
comparable to those reported in all age groups7’8 following both irradiation and the use of antithyroid compounds.
The authors feel that thyrotoxic children without nodular goiters should be given the benefit of a long trial with antithyroid com-pounds before resorting to thyroidectomy, despite the fact that the over-all results from nonsurgical therapy (exclusive of
radioactive iodine) do not compare
favor-ably with those to be expected from
thy-roidectomy,#{176} in patients of all ages. Among the reasons for such a conservative policy
may be included the preservation of an
anatomically intact thyroid for adjustment
to the endocrine stresses of puberty and the remaining growth period, and the low incidence of post-therapeutic myxedema.
SUMMARY
Results of treatment are presented in 30 thyrotoxic children whose symptoms ap-peared prior to age 15 years.
Fifteen patients received thyroid irrad-ation with or without stable iodine and 15 received prolonged treatment with anti-thyroid compounds, with or without stable iodine.
Among the 24 patients in whom the final
results of treatment could be fairly assessed,
satisfactory remissions were obtained in 17
(70.8%). Approximately similar results were obtained in those who were irradiated and in those who received antithyroid com-pounds.
Satisfactory remissions were obtained in 5 of the 6 patients subjected to thyroid-ectomy.
Two cases of unusual interest are de-scribed. Reasons for the present conserva-tive policy in the treatment of juvenile thyrotoxicosis are stated.
ACKNOWLEDGMENT
The authors are indebted to Dr. F. H. Harvie for permission to include D. R. (Case 26) in this report.
REFERENCES
1. Black,
J.
B., Jr., and Webster, B., Hyper-thyroidism in adolescent,J.
Clin. Endo-crinol. 1:859, 1941.2. Blattner, R.
J.,
Comments on current litera-ture: Hyperthyroidism,J.
Pediat. 40:679, 1952.3. Eckel,
J.,
Conference on therapy: Manage-ment of thyrotoxicosis, Am.J.
Med. 10: 497, 1951.4. Wilkins, L., Diagnosis and Treatment of
44 R. F. ALLEN, E. ROSE AND ELIZABETH KIRK ROSE
Adolescence, Springfield, Ill., Charles C Thomas, Publisher, 1950, p. 108.
5. Likoff, W. B., and Levine, S. A., Thyrotoxi-cosis as sole cause of heart failure, Am.
J.
M. Sc. 206:425, 1943.6. Ham, G. C., Alexander, F., and Carmichael, H. T., Psychosomatic theory of thyrotoxi-cosis, Psychosomatic Med. 13:18, 1951. 7. Harris,
J.
H., Radiation treatment ofhyper-thyroidism, Am.
J.
Roentgenol. 38:129, 1937.8. Solomon, D. H., Beck,
J.
C., VanderLaan,W. P., and Astwood, E. B., Prognosis of hyperthyroidism treated by antithyroid drugs, J.A.M.A. 52:201, 1953.
9. Ravdin, I. S., Rose, E., and Maxwell,
J.
D., Treatment of thyrotoxicosis, J.A.M.A. 140:141, 1949.SPANISH ABSTRACT
Tirotoxicosis Juvenil
Resultados del Tratamiento en Treinta Casos
El objeto del presente trabajo es informar los resultados de diversos tipos de tratamiento en 30 niflos tiroideos cuyas manifestaciones se pre-sentaron antes de los 15 aflos de edad. Se ha seguido una polItica conservadora, recurriendo a la tiroidectomla cuando aqu#{233}llaha fracasado. Antes de 1943 el tratamiento consistla en ra-diaci#{243}nexterna de la tiroides, adicionada de administraci#{243}n de yodo en algunos de los casos. Despu#{233}sde esa fecha se utilizaron compuestos antitiroideos, adicionados ocasionalmente de yodo estable o bien altern#{225}ndolo con #{233}l;estos
compuestos han incluldo el tiouracil,
metil-tiouracil, aminotiozole, propiltiouracil y
meti-mazole. La dosis promedio de radiaci#{243}n se
es-tim#{243}en 3800 r en los pacientes con resultados
satisfactorios y alrededor de 2120 r en los
con-siderados como fracasos. Los resultados de la terap#{233}utica no quir#{241}rgica en este grupo de pa-cientes son comparables a los ya publicados para grupos de todas las edades, tratados tanto con radiaci#{243}n como con compuestos tiroideos.
Los autores consideran que los ni#{241}os tiroi-deos sin bocio nodular deben recibir un tra-tamiento prolongado con compuestos antitiroi-deos; se les practicar#{225} tiroidectomla como iil-timo recurso pues debe tenderse a conservar la gl#{225}ndula anat#{243}micamente intacta para su ajuste a los esfuerzos end#{243}crinos de Ia pu-bertad y el resto del perlodo de crecimiento, adem#{225}sde haberse observado en estas condi-ciones una baja incidencia de mixedema post-tiroideo.
Debido al inter#{233}sde dos de los casos estu-diados, los autores los describen m#{225}s amplia-mente; el primero por Ia posibilidad que mostr#{243} de haber fallecido por insuficiencia cardiaca
debido exclusivamente a Ia tirotoxicosis y el segundo por Ia posibilidad de que Ia tirotoxico-sis y una anorexia nerviosa subsecuente, fueron
determinadas por factores psiquicos.
En resumen, se presentan dos grupos de 15 pacientes cada uno, tratados por radiaci#{243}n y compuestos antitiroideos respectivamente; en ambos se agreg#{243}yodo en algunos casos. Se obtuvieron remisiones satisfactorias en 17 de los 24 pacientes que han logrado ser observados por tiempo prolongado, siendo los resultados similares con ambos tratamientos. En 5 de 6 pacientes tratados quithrgicamente tambi#{233}nse observaron remisiones satisfactorias.
c/o Dr. Edward Rose, Hospital
