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Thyroid Hormones and Human Mental Development
Thyroid Hormones and Human Mental Development A. QUERIDO, N. BLEICHRODT and R. DJOKOMOELJANTO
Department of Medicine, University of Leiden, Leiden, Department of Industrial and Organizational Psychology and Test Development, Free University of Amsterdam, Amsterdam (The Netherlands) and Department of Medicine, Diponegoro University, Semarang (Indonesia)
INTRODUCTION There is abundant experimental evidence that thyroid deficiency in the neonatal period causes impaired development of the central nervous system. The studies were mainly done in rats, and especially the work of Eayrs and of Balizs deserves to be mentioned (e.g. Eayrs, 197 1 ; Balizs, 1976). The techniques applied were histological, biochemical and behavioral, while EEG studies were also carried out. Biochemically, attention was given to nucleic acids, to various enzymes, and to the deposition of the myelin sheath. Interpreting these data in terms of the human situation is difficult, however, in part because of the differences in the state of brain development at birth between experimental animals and humans. There are also a few studies available on primates, such as those reported by Holt et al. (1973) using the macaque as the animal model for study. Thyroidectomy was done through injection of radioactive iodine halfway through pregnancy (days 7 1-88). The authors concluded that overall RNA and protein synthesis is depressed in the fetal brain in the absence of thyroid hormone. Even with the monkey, however, there is still a large difference from the human in the timing of the period of rapid brain development relative to the moment of birth. Before going into detail about what is known about the relationships between thyroid function and mental development in the human, a few basic facts should be mentioned. The thyroid in the human fetus is considered to start functioning around 10-1 2 weeks. According to Dobbing (1974, 1975) neuronal multiplication in humans occurs mainly from 10 to 1 8 gestational weeks. Transfer of thyroid hormones from the mother to the fetus seems to be negligible (Goslings, 1975), which is in agreement with the experience that hypothyroid mothers can give birth to normal infants. On the other hand, it is well known that children born with congenital defects of the thyroid (congenital athyreosis, dystopic hypoplasia, or thyroid enzyme defects) reveal a varying degree of mental deficiency in a high percentage of cases. Normal thyroid function during the second and third trimester of pregnancy is therefore a prerequisite for normal mental development. It is important, finally, to recognize what happens to the central nervous system after birth. Human brain cells as a total population continue multiplication well into the second postnatal year, and rapid myelination continues for even longer (Dobbing, 1975). It is against the background of these facts that we will discuss the effect of thyroid hormones on human mental development.
338 FORMS OF CRETINISM Knowledge about the relationship of thyroid hormones to mental development has very practical significance. There are two important areas of health care where this problem is present, and which are currently being intensively studied. These relate, respectively, to two different models of pre- and postnatal development in the presence of an inadequate supply of thyroid hormones. The first model is at present the concern of the industrially developed countries. Techniques have been developed for the recognition of congenital hypothyroidism at birth (sporadic cretinism), a condition which is known to be present in 1 out of 5000 babies. The aim here is to immediately institute adequate substitution therapy, the hope being to prevent irreversible mental retardation in these babies. Aside from humanitarian reasons, there is also the aspect that adequate prevention of mental retardation gives important economic benefits. The second model is mainly the concern of the developing countries, and addresses itself to the problem of preventing endemic goiter and cretinism in regions of severe iodine deficiency (which is still widespread throughout the world). Also in this situation there are two aspects: viz. the humanitarian problem, and the creation of conditions which enable optimal socioeconomic development in such countries. As indicated in Fig. 1 , the two models present quite different conditions and problems. I
I1
ZNVIRONMENT WITH ADEQUATE IODINE SUPPLY
ENVIRONMENT WITH SEVERE IODINE SHORTAGE
r--l
PREGNANT MOTHER
PREGNANT MOTHER
TtiYROID
THYROID
THYROID
ENDEMIC CRETINISM
CONGENITAL HYPOTHYROIDISM (SPORADIC CRETINISM)
Fig. 1.
Both conditions have in common fetal hypothyroidism during pregnancy, as shown by Tilly et al. (1974) through umbilical cord blood analysis, and through analysis of bone development in severe endemic goiter. In both conditions, we also find evidence that thyroid hormones are needed for normal mental development, and for the prevention of neurological abnormalities as well. In severe congenital hypothyroidism, neurologic signs such as spasticity, tremor and hyperactive deep tendon reflexes are present. In endemic cretinism, besides these abnormalities, squinting, hearing loss and spastic paresis are also seen with high frequency. SPORADIC CRETINISM Let us focus first on congenital hypothyroidism. Since the classic article of Smith et al. (1957), early recognition of the syndrome and the administration of adequate thyroid
339 substitution therapy, have been strongly advocated in order to achieve optimal prevention of mental retardation. From the results of their studies (see Fig. 2 ) , it is clear that in 10 out of 22 severe hypothyroid cases, early treatment (before 6 months of age) achieved I.Q. values of 90 or greater. This is much better than in the large group of severe congenital hypothyroidism, where treatment was done between 6 months and 1 year of age, and in which only 15% reached the same favorable I.Q. score. Of 32 patients with mild hypothyroidism on the other hand, 41% acheved an I.Q. of 90 or greater despite the fact that the average age at the institution of therapy was 3 years. Similar results have been obtained by others (e.g. Van Gemund and Laurent de Angulo, 1971). I.Q.
50 50 69 70-89 90
-
Percentage 100 80
79
22
32
17 cases
-
60 LO
-
20
-
SEVERE CONGENITAL TOTAL GROUP
SEVERE CONGENITAL ADEOUATE RX 0-6 no.
MILD CONGENITAL
ACQUIRED
Fig. 2. The mental prognosis of the patients with severe cretinism, given adequate therapy before 6 months of age (second column), is contrasted with the total results in the three categories of hypothyroidism. (From Smith et al., 1957.)
From the above data it can be concluded that the prevention and reversibility of damage caused by thyroid deficiency depend upon the degree of hormone depletion, and also on the time of starting replacement therapy. The latter aspect is highly relevant for the great effort being presently developed to institute routine screening for hypothyroidism at birth. The idea behind this is that the frequency of congenital hypothyroidism is 1 per 5000 births, and that screening cost and effort (aside from the benefits to the affected children) has a very good cost-benefit ratio with regard to the prevention of institutionalization. It remains to be seen, however, whether treatment from birth onwards will increase the favorable results already attained.
ENDEMIC CRETINISM The second model, that of endemic cretinism through iodine deficiency, is more complicated and far more difficult to study. It has in common with congenital hypothyroidism that the deficiency is present both prenatally and (in a great number of cases) also post-
340 natally. How serious the deficiency in both of these periods actually is, however, depends mainly upon environmental factors. In endemic cretinism, the final result depends upon the level of iodine supply because the thyroid is able to synthesize thyroid hormones. After birth, the infant depends directly upon the environment for its iodine supply. I have seen many places where 10% of the population is severely retarded because of iodine deficiency. Is this the result of prenatal damage, or of postnatal hypothyroidism? Technically, it is not feasible to study the effect of thyroid substitution therapy after birth, because areas which are recognized as being severely iodine deficient should receive adequate iodine prophylaxis, either through iodization of salt or (temporarily) with injections of iodized oil. The second aspect is the difficulty of adequately measuring intelligence performance; the great influence of socioeconomic development for the expression and development of intelligence should also be taken into consideration (see Fig. 3). POOR SANITARY HIGH DISEASE CONDITIONS -LEVEL
POOR PHYSICAL GROWTH (MALNUTRITION) LOW, UNSTABLE INCOME
INADEQUATE NUTRITION
\
LOW EDUCATIONAL LEVEL
MENTAL DEVELOPMENT
P
P FACTORS WITH A POSSl8LE M V E R S E INFLUENCE ON MENTAL DEVELOPMENT
Fig. 3. Factors with a possible adverse influence on mental development. (From WHO chronicle, 1974.)
We have the privilege of an ongoing cooperation between the Leiden Medical Faculty and the Medical Faculty of Diponegoro University, in Semarang, for studies of the effect of severe iodine deficiency on populations in Central Java. In these severely iodine deficient areas, both endemic goiter and endemic cretinism are widespread. Endemic cretinism is characterized by abnormalities of the central nervous system, such as mental deficiency, squinting, deafness, neuromotor abnormalities and spasticity (for review see Querido, 1975). These abnormalities of the central nervous system are seen in different combinations, and to a different degree, in a relatively limited number of persons. However, the entire population has been exposed to iodine deficiency during pregnancy and thereafter. The question therefore rises whether in the socalled normal, noncretinous, part of the population there exist a number of persons who are subnormal in mental development, but who escape observation because school education is not obligatory and social adaptation is rather easy. To study this problem, the Leiden Medical Faculty and the Diponegoro University in Semarang obtained the cooperation of the Psychology departmmts of the Free University of Amsterdam and the Universitas Indonesia in Djakarta.* Two villages were chosen for
* We gladly acknowledge the assistance and cooperation of the members of the project team in Djakarta: Drs. Saparinah Sadli, Sudirgo Wibono and Engelien Bonang.
34 1
comparison (Gowok and Lonjong). A number of characteristics of these villages relevant for the study are given in Table I. TABLE I PARAMETERS OF LONJONG (LONJONG) AND GOWOK (SENGI) Lonjong
Inhabitants Farmers Distance Magelang Altitude Distance to main road Schools Primary school at distance
489 99% 23 km 600 m 1 km 0 1 km
Goiter rate (OB up) Protein-bound iodine pg%
3% 4.9 (‘76) (3.4 -6.6) 41.5 (‘73) 40.9 (‘76) normal
Urinary excretion of iodine pg/g creatinine TSH pU/ml
Gowok
411 100% 30 km 600 m 5 km 0 4 km
5 8% 3.4 (1.2-5.9) 18.9 18.4
Based on the experience of the Psychology departments of the Free University, Amsterdam, and of Unpad Bandung, a battery of tests was chosen, which can arbitrarily be divided into two sets. One is directed mainly towards the testing of factors of general intelligence, and is therefore strongly sensitive to educational experience. The second group of tests was directed more towards non-intelligence factors such as motor skills, concentration and perceptual capacity. The tests were tried out in small villages with test leaders who were M.A. students of the Psychological Faculty of Universitas Indonesia, and were especially trained for this project. After the try-out, a definite choice of tests was made for different age groups. Translation of the tests into Javanese had t o be carried out, after which the battery was tried out in a rural area near the villages Gowok and Lonjong. Only after all of this were the definitive observations carried out. In Table I1 and 111 an impression is given of the composition of the test battery.
TABLE I1 TESTS USED IN GOWOK AND LONJONG (1976). GENERAL INTELLIGENCE .
Fluency Visual memory Learning names Exclusion Quantity Discs Verbal meaning
Form board Memory span Progressive matrices Hidden patterns Block design Mazes Exclusion B. Components
342 TABLE 111 TESTS USED IN GOWOK AND LONJONG (1976). NON INTELLIGENCE FACTORS (MOTOR SKILLS, CONCENTRATION OR PERCEPTUAL CAPACITIES) Pinboard (finger dexterity) Throwing balls Balance Reaction time Choice reaction time Tapping Figure comparison
The subjects in the two villages were divided into the following three age groups: 6-8 years, 9-12 years, and 13-20 years. In Gowok, the cretins were not included among the subjects to be tested. For their identification we used the presence of 2 out of 3 diagnostic characteristics: mental retardation, hearing loss, and neuromotor abnormalities. In this report we will present only the average results obtained. We will first discuss the tests directed mainly towards general intelligence. In the youngest age group, that of 6-8 years, there was (to our astonishment!) no significant difference between the results attained in Gowok and in the control village. In the other age groups, most of the results in Gowok were below those attained in the control village. Close analysis of the educational background, however, revealed some essential differences between the population of the two villages in these age groups; we therefore are not inclined to attach any special meaning to these results (Table IV). TABLE IV NUMBER EXAMINED PERSONS, AVERAGE AGE AND AVERAGE EDUCATIONAL LEVEL FOR 3 AGE GROUPS
Gowok
Lonjong
6-8 years 9 - 12 years 13-20 years 6-20 years
Number
Age
Education
Number
Age
Education
40 41 58 139
7.2 10.5 15.6 11.7
0.4 2.6 4.1 2.5
21 41 44 106
7.1 10.6 16.1 12.2
0.1 0.3 0.6 0.4
When it comes to the results of the second set of tests (more directed towards nonintelligence factors, such as motor skills, concentration and perceptual capacity - which we consider t o be less dependent on educational background) we did find clearcut differences in all age groups, and usually at the 1% level of significance (Table V). Four of the tests (pinboard, tapping test, reaction time and choice reaction time) are considered to be ‘perceptualmotor abilities’. Factors such as finger dexterity, manual dexterity and response orientation are also involved here. In the test of ‘figure comparison’ (which also showed differences in outcome) ‘perceptual speed’ was studied. in addition. Thus, we did indeed find significant differences in the second group of tests between the two communities, i.e. the severely iodine-deficient village, Gowok, and the control village, Lonjong. These results pose many questions: are such differences reversible; are the dif-
343 TABLE V SUMMARY OF DIFFERENCES OF TEST RESULTS IN LONJONG AND GOWOK Su btests
16. Pinboard 17. Throwing balls 18. Balance 19. Single reaction time 20. Choice reaction time 2 1. Tapping 22. Figure comparison
6-8 y r
9-12 y r
13-30 y r
** -
** ** ** ** ** ** **
** ** ** **
-
*
-
** Significant at 1% level.
* Significant at 5%level. - Not significant.
ferences the consequence of prenatal or of postnatal conditions; is an anatomical substrate demonstrable (e.g. degree of dendritization or myelination, or number of cells)? CONCLUSIONS As was stated in the beginning, there are similarities between congenital hypothyroidism and endemic cretinism with respect to the periods during which the development of the central nervous system is exposed to hypothyroidism, prenatally as well as postnatally. Both conditions are subject, for instance, to a variable degree of hypothyroidism. The fact is recalled that the people with mild congenital hypothyroidism seen by Smith e t al. (1957), and treated either early or late, end up in 41% of the cases with an I.Q. of 9 0 or better. We naturally ask ourselves whether cases of mild hypothyroidism which did not achieve an I.Q. of 90 or more, if seen in Gowok would all have been classified as cretins. If so (which we doubt), our observations on general intelligence in Gowok would be in line for the two conditions. If, however, this should not be the case, we are left with no explanation for the failure to find any instances of mild retardation in Gowok. We are now in the process of analyzing individual results, in relation to the biochemical parameters of hypothyroidism. Unfortunately, to our knowledge no studies using differentiated tests comparable to those reported here have been made in congenital hypothyroidism. Such studies will be very necessary in the near future, because of the high hopes being placed on the early diagnosis of this condition.
ACKNOWLEDGEMENT The support of the Netherlands Foundation for the Advancement of Tropical Research
(WOTRO)Grant: W 94-3 1 , is gratefully acknowledged. REFERENCES
Balizs, R. (1976) Hormones and brain development. In Perspectives in Brain Research, Progress in Brain Research, Vol. 45, M.A. Comer and D.F. Swaab (Eds.), Elsevier, Amsterdam, pp. 139-159.
344 Dobbing, J. (1974) The later development of the brain and its vulnerability. In Scientific Foundations of Pediatrics, J.A. Davis and J. Dobbing (Eds.), Heinemann Medical Books, London, pp. 565-577. Dobbing, J. (1975) Normal brain development in human. In Brain Development and Thyroid Deficiency, A. Querido and D.F. Swaab (Eds.), North-Holland, Amsterdam, pp. 7-1 1. Eayrs, J.T. (1971) Thyroid and the developing brain: anatomical and behavioural effects. In Hormones in Development, M. Hamburgh and E.J.W. Barrington (Eds.), AppletonCenturyCrofts, New York, pp. 345-355. Gemund, J.J. van and Laurent de Angulo (1971) The effects of early hypothyroidism on I.Q., school performance, and electroencephalogram pattern in children. In NormalandAbnormal Development of Brain and Behaviour, G.B.A. Stoelinga and J.J. van der Werff ten Bosch (Eds.), Leiden University Press, pp. 299-313. Holt, A.B., Cheek, D.B. and Kerr, G.R. (1973) Prenatal hypothyroidism and brain composition in a primate, Nature (Lond.), 243: 413-414. Querido, A. (1975) Endemic cretinism - a continuous personal educational experience during 10 years, Postgrad. med. J., 51: 591-599. Smith, D.W., Blizzard, R.M. and Wilkins, L. (1957) The mental prognosis in hypothyroidism of infancy and childhood. A review of 128 cases, Pediatrics, 19: 1011-1022. Thilly, C., DeLange, F., Camus, M., Berquist, H. and Ermans, A.M. (1974) Fetal hypothyroidism in endemic goitre : the probable pathogenic mechanism of endemic cretinism. In Endemic Goiter and Cretinism: Continuing Threats t o World Health, Sci. Publ. No. 292, Pan American Health Organization, Washington, D.C., pp. 121-128. W.H.O. Chronical(1974) Malnutrition and Mental Development, W.H.O., Geneva, pp. 95-102.
345 DISCUSSION BALAZS: I suppose that the basic question you are asking us is how reversible are the changes in the central nervous system when a metabolic insult, such as abnormal thyroid state or undernutrition, has been inflicted during development. The literature on animal experiments is quite confusing, so I am not at all surprised that the evaluation of the human situation is even more complicated. There is no unambiguous answer to the question. If brain maturation is assessed in terms of biochemical or structural parameters it is frequently observed that metabolic imbalance, including thyroid deficiency, results in a severe retardation. The emphasis here is on retardation, since most of the parameters are restored more or less t o normal after proper treatment. For example, Eayrs (1971) has found that the structural changes in the thyroid deficient cerebral cortex are reversible to a great extent after implementing replacement therapy at different times after birth. However, unless animals are rehabilitated within a relatively short time after birth, the behavioral impairments persist. So it seems that there is a discrepancy between the reversibility of the physical and the behavioral changes: the plasticity of the system, in terms of structure and biochemistry, is greater than the plasticity of the system in terms of behavior. This leads us to an important question: what are the proper estimates for correlating the structure and biochemistry of the brain with behavior? Cragg has studied the effect of undernutrition and thyroid deficiency on the number of synapses per nerve cell in the cerebral cortex. In the current repertoire of neuroanatomy, this estimate is probably the nearest to ‘higher nervous function’. However, Cragg has pointed out that, since there are about lo4 synapses per neuron, it is very difficult to appreciate the implication of even a marked deficit. Thus we have real problems when we try to choose the proper physical correlates of behavior; the estimates we are presently using are far from ideal. QUERIDO: In the beginning of this week Dr. Dobbing claimed that there is one insult for which you cannot compensate, and that is an early insult after birth in the human when cerebellar cell division is still going on. This would result in what they call ‘clumsy people’. My question is whether, on the basis of our data, you would call the people from the village with endemic cretinism ‘clumsy people’, and whether you would expect a reduced cell number in the cerebellum. BALAZS: Well, the evidence is quite good that, even in man, neurogenesis does occur in the cerebellum in the postnatal period. However, the important question here is: how far will even a deficit of 10-30% in granule cell numbers influence the functioning of the neuronal circuits in the cerebellum? There is a real chance that the effect will be relatively small as a result of the great redundancy of cells and circuits in the CNS. I really don’t think that deficit in cell number on its own could explain the impairment of behavioral performance. SWAAB: But this is arguing the other way round. Dr. Querido has shown clumsiness, which presumably means that that the cerebellum must be affected seriously in one way or another. BALAZS: Yes, but the defect is not necessarily, or exclusively, due to a deficit in cell numbers. It may be something else, e.g. balance of neuronal circuits, and I would put my money on the ‘something else’ as the major factor. SWAAB: One question about the set-up of this kind of experiment: I think the better you look at villages, the greater the chance that you will find a difference, for example in school distance or something else. It seems impossible to get two villages that are absolutely similar in all parameters except iodine intake. Would it not be easier to develop an experiment in such a way that performance of individuals is related t o their TSH-levels, PBI, etc.? QUERIDO: First of all, we are going t o do that with the individual data we have now. I mean, in addition to calculating the average, we are going to study the individual correlations. The problem, however, is that the data on thyroid function give only a snapshot. A certain hormone level does not tell you how the thyroid gland was functioning some years ago. BLOM: Were you giving iodine to the people in the affected village after the observations? And if so, are you doing a followup study on the results?
346 QUERIDO: Together with Dr. Djokomoeljanto we are carrying out prophylaxis in that area and we plan to come back in 5 years time for a follow-up study. However, it is not so simple to mobilize this effort again and to get the same cooperation. Moreover, the people would have to stay in the same village. Dr. Djokomoeljanto is currently doing the follow-up of our prophylaxis program in another village in Java, by measuring the correction of the iodine metabolism. It turned out that after 3 years part of the original population had moved to Sumatra. For an extensive followup we should, in addition, have a similar group of investigators again, and that will also be difficult. The doctoral students of the University of Indonesia were remarkable young men and women, They stayed in such villages for weeks, and they were playing and singing with these children when they had done a good job during the day. There was a very impressive relationship between the testing group and the population, and it would be difficult to get such a group again. SWAAB: If there is indeed plasticity in the brain, such a relationship would influence your experiments! QUERIDO: They did it in both the ‘experimental’ and the control villages. BALAZS: Your data give a very optimistic outlook. If iodine was the only crucial factor, one would also have expected a significant difference in the 6-8-year-old group. I suppose that the degree of education, probably even in the control village, was not very high. Nevertheless, it seems that education has influenced performance in the intelligence tests in a positive way. This means that, at least in man, the social environmental stimulation must have a very important role. This brings me back to the plasticity of the central nervous system, and to the different means with which one can try to rectify an abnormal situation. It would appear that, even if physical alterations lead to a handicap, there is a chance of correct behavioral performance, to some extent, by the proper intervention. QUERIDO: Yes, I agree; it resembles the data of Davenport e t al. (1976). He enriched the environment of rats exposed perinatally to thiouracil and changed in that way the behavior in a positive sense. DE CROOT: I was wondering about another disadvantage in the village with iodine deficiency. One would expect that the parents too had a lower educational level because of the iodine deficiency, and that this would have also a negative influence on the next generation, since their possibility to stimulate the children would be less. QUERIDO: Well, that is the general problem when measuring I.Q. everywhere in the world. It is, as you know, still a major issue at present. REFERENCE Davenport, J.W., Gonzalez, L.M., Carey, J.C., Bishop, S.B. and Hagquist, W.W. (1976) Environmental stimulation reduces learning deficits in experimental cretinism, Science, 191: 578-579.
Department of Medicine, University of Leiden, Leiden, Department of Industrial and Organizational Psychology and Test Development, Free University of Amsterdam, Amsterdam (The Netherlands) and Department of Medicine, Diponegoro University, Semarang (Indonesia)
INTRODUCTION There is abundant experimental evidence that thyroid deficiency in the neonatal period causes impaired development of the central nervous system. The studies were mainly done in rats, and especially the work of Eayrs and of Balizs deserves to be mentioned (e.g. Eayrs, 197 1 ; Balizs, 1976). The techniques applied were histological, biochemical and behavioral, while EEG studies were also carried out. Biochemically, attention was given to nucleic acids, to various enzymes, and to the deposition of the myelin sheath. Interpreting these data in terms of the human situation is difficult, however, in part because of the differences in the state of brain development at birth between experimental animals and humans. There are also a few studies available on primates, such as those reported by Holt et al. (1973) using the macaque as the animal model for study. Thyroidectomy was done through injection of radioactive iodine halfway through pregnancy (days 7 1-88). The authors concluded that overall RNA and protein synthesis is depressed in the fetal brain in the absence of thyroid hormone. Even with the monkey, however, there is still a large difference from the human in the timing of the period of rapid brain development relative to the moment of birth. Before going into detail about what is known about the relationships between thyroid function and mental development in the human, a few basic facts should be mentioned. The thyroid in the human fetus is considered to start functioning around 10-1 2 weeks. According to Dobbing (1974, 1975) neuronal multiplication in humans occurs mainly from 10 to 1 8 gestational weeks. Transfer of thyroid hormones from the mother to the fetus seems to be negligible (Goslings, 1975), which is in agreement with the experience that hypothyroid mothers can give birth to normal infants. On the other hand, it is well known that children born with congenital defects of the thyroid (congenital athyreosis, dystopic hypoplasia, or thyroid enzyme defects) reveal a varying degree of mental deficiency in a high percentage of cases. Normal thyroid function during the second and third trimester of pregnancy is therefore a prerequisite for normal mental development. It is important, finally, to recognize what happens to the central nervous system after birth. Human brain cells as a total population continue multiplication well into the second postnatal year, and rapid myelination continues for even longer (Dobbing, 1975). It is against the background of these facts that we will discuss the effect of thyroid hormones on human mental development.
338 FORMS OF CRETINISM Knowledge about the relationship of thyroid hormones to mental development has very practical significance. There are two important areas of health care where this problem is present, and which are currently being intensively studied. These relate, respectively, to two different models of pre- and postnatal development in the presence of an inadequate supply of thyroid hormones. The first model is at present the concern of the industrially developed countries. Techniques have been developed for the recognition of congenital hypothyroidism at birth (sporadic cretinism), a condition which is known to be present in 1 out of 5000 babies. The aim here is to immediately institute adequate substitution therapy, the hope being to prevent irreversible mental retardation in these babies. Aside from humanitarian reasons, there is also the aspect that adequate prevention of mental retardation gives important economic benefits. The second model is mainly the concern of the developing countries, and addresses itself to the problem of preventing endemic goiter and cretinism in regions of severe iodine deficiency (which is still widespread throughout the world). Also in this situation there are two aspects: viz. the humanitarian problem, and the creation of conditions which enable optimal socioeconomic development in such countries. As indicated in Fig. 1 , the two models present quite different conditions and problems. I
I1
ZNVIRONMENT WITH ADEQUATE IODINE SUPPLY
ENVIRONMENT WITH SEVERE IODINE SHORTAGE
r--l
PREGNANT MOTHER
PREGNANT MOTHER
TtiYROID
THYROID
THYROID
ENDEMIC CRETINISM
CONGENITAL HYPOTHYROIDISM (SPORADIC CRETINISM)
Fig. 1.
Both conditions have in common fetal hypothyroidism during pregnancy, as shown by Tilly et al. (1974) through umbilical cord blood analysis, and through analysis of bone development in severe endemic goiter. In both conditions, we also find evidence that thyroid hormones are needed for normal mental development, and for the prevention of neurological abnormalities as well. In severe congenital hypothyroidism, neurologic signs such as spasticity, tremor and hyperactive deep tendon reflexes are present. In endemic cretinism, besides these abnormalities, squinting, hearing loss and spastic paresis are also seen with high frequency. SPORADIC CRETINISM Let us focus first on congenital hypothyroidism. Since the classic article of Smith et al. (1957), early recognition of the syndrome and the administration of adequate thyroid
339 substitution therapy, have been strongly advocated in order to achieve optimal prevention of mental retardation. From the results of their studies (see Fig. 2 ) , it is clear that in 10 out of 22 severe hypothyroid cases, early treatment (before 6 months of age) achieved I.Q. values of 90 or greater. This is much better than in the large group of severe congenital hypothyroidism, where treatment was done between 6 months and 1 year of age, and in which only 15% reached the same favorable I.Q. score. Of 32 patients with mild hypothyroidism on the other hand, 41% acheved an I.Q. of 90 or greater despite the fact that the average age at the institution of therapy was 3 years. Similar results have been obtained by others (e.g. Van Gemund and Laurent de Angulo, 1971). I.Q.
50 50 69 70-89 90
-
Percentage 100 80
79
22
32
17 cases
-
60 LO
-
20
-
SEVERE CONGENITAL TOTAL GROUP
SEVERE CONGENITAL ADEOUATE RX 0-6 no.
MILD CONGENITAL
ACQUIRED
Fig. 2. The mental prognosis of the patients with severe cretinism, given adequate therapy before 6 months of age (second column), is contrasted with the total results in the three categories of hypothyroidism. (From Smith et al., 1957.)
From the above data it can be concluded that the prevention and reversibility of damage caused by thyroid deficiency depend upon the degree of hormone depletion, and also on the time of starting replacement therapy. The latter aspect is highly relevant for the great effort being presently developed to institute routine screening for hypothyroidism at birth. The idea behind this is that the frequency of congenital hypothyroidism is 1 per 5000 births, and that screening cost and effort (aside from the benefits to the affected children) has a very good cost-benefit ratio with regard to the prevention of institutionalization. It remains to be seen, however, whether treatment from birth onwards will increase the favorable results already attained.
ENDEMIC CRETINISM The second model, that of endemic cretinism through iodine deficiency, is more complicated and far more difficult to study. It has in common with congenital hypothyroidism that the deficiency is present both prenatally and (in a great number of cases) also post-
340 natally. How serious the deficiency in both of these periods actually is, however, depends mainly upon environmental factors. In endemic cretinism, the final result depends upon the level of iodine supply because the thyroid is able to synthesize thyroid hormones. After birth, the infant depends directly upon the environment for its iodine supply. I have seen many places where 10% of the population is severely retarded because of iodine deficiency. Is this the result of prenatal damage, or of postnatal hypothyroidism? Technically, it is not feasible to study the effect of thyroid substitution therapy after birth, because areas which are recognized as being severely iodine deficient should receive adequate iodine prophylaxis, either through iodization of salt or (temporarily) with injections of iodized oil. The second aspect is the difficulty of adequately measuring intelligence performance; the great influence of socioeconomic development for the expression and development of intelligence should also be taken into consideration (see Fig. 3). POOR SANITARY HIGH DISEASE CONDITIONS -LEVEL
POOR PHYSICAL GROWTH (MALNUTRITION) LOW, UNSTABLE INCOME
INADEQUATE NUTRITION
\
LOW EDUCATIONAL LEVEL
MENTAL DEVELOPMENT
P
P FACTORS WITH A POSSl8LE M V E R S E INFLUENCE ON MENTAL DEVELOPMENT
Fig. 3. Factors with a possible adverse influence on mental development. (From WHO chronicle, 1974.)
We have the privilege of an ongoing cooperation between the Leiden Medical Faculty and the Medical Faculty of Diponegoro University, in Semarang, for studies of the effect of severe iodine deficiency on populations in Central Java. In these severely iodine deficient areas, both endemic goiter and endemic cretinism are widespread. Endemic cretinism is characterized by abnormalities of the central nervous system, such as mental deficiency, squinting, deafness, neuromotor abnormalities and spasticity (for review see Querido, 1975). These abnormalities of the central nervous system are seen in different combinations, and to a different degree, in a relatively limited number of persons. However, the entire population has been exposed to iodine deficiency during pregnancy and thereafter. The question therefore rises whether in the socalled normal, noncretinous, part of the population there exist a number of persons who are subnormal in mental development, but who escape observation because school education is not obligatory and social adaptation is rather easy. To study this problem, the Leiden Medical Faculty and the Diponegoro University in Semarang obtained the cooperation of the Psychology departmmts of the Free University of Amsterdam and the Universitas Indonesia in Djakarta.* Two villages were chosen for
* We gladly acknowledge the assistance and cooperation of the members of the project team in Djakarta: Drs. Saparinah Sadli, Sudirgo Wibono and Engelien Bonang.
34 1
comparison (Gowok and Lonjong). A number of characteristics of these villages relevant for the study are given in Table I. TABLE I PARAMETERS OF LONJONG (LONJONG) AND GOWOK (SENGI) Lonjong
Inhabitants Farmers Distance Magelang Altitude Distance to main road Schools Primary school at distance
489 99% 23 km 600 m 1 km 0 1 km
Goiter rate (OB up) Protein-bound iodine pg%
3% 4.9 (‘76) (3.4 -6.6) 41.5 (‘73) 40.9 (‘76) normal
Urinary excretion of iodine pg/g creatinine TSH pU/ml
Gowok
411 100% 30 km 600 m 5 km 0 4 km
5 8% 3.4 (1.2-5.9) 18.9 18.4
Based on the experience of the Psychology departments of the Free University, Amsterdam, and of Unpad Bandung, a battery of tests was chosen, which can arbitrarily be divided into two sets. One is directed mainly towards the testing of factors of general intelligence, and is therefore strongly sensitive to educational experience. The second group of tests was directed more towards non-intelligence factors such as motor skills, concentration and perceptual capacity. The tests were tried out in small villages with test leaders who were M.A. students of the Psychological Faculty of Universitas Indonesia, and were especially trained for this project. After the try-out, a definite choice of tests was made for different age groups. Translation of the tests into Javanese had t o be carried out, after which the battery was tried out in a rural area near the villages Gowok and Lonjong. Only after all of this were the definitive observations carried out. In Table I1 and 111 an impression is given of the composition of the test battery.
TABLE I1 TESTS USED IN GOWOK AND LONJONG (1976). GENERAL INTELLIGENCE .
Fluency Visual memory Learning names Exclusion Quantity Discs Verbal meaning
Form board Memory span Progressive matrices Hidden patterns Block design Mazes Exclusion B. Components
342 TABLE 111 TESTS USED IN GOWOK AND LONJONG (1976). NON INTELLIGENCE FACTORS (MOTOR SKILLS, CONCENTRATION OR PERCEPTUAL CAPACITIES) Pinboard (finger dexterity) Throwing balls Balance Reaction time Choice reaction time Tapping Figure comparison
The subjects in the two villages were divided into the following three age groups: 6-8 years, 9-12 years, and 13-20 years. In Gowok, the cretins were not included among the subjects to be tested. For their identification we used the presence of 2 out of 3 diagnostic characteristics: mental retardation, hearing loss, and neuromotor abnormalities. In this report we will present only the average results obtained. We will first discuss the tests directed mainly towards general intelligence. In the youngest age group, that of 6-8 years, there was (to our astonishment!) no significant difference between the results attained in Gowok and in the control village. In the other age groups, most of the results in Gowok were below those attained in the control village. Close analysis of the educational background, however, revealed some essential differences between the population of the two villages in these age groups; we therefore are not inclined to attach any special meaning to these results (Table IV). TABLE IV NUMBER EXAMINED PERSONS, AVERAGE AGE AND AVERAGE EDUCATIONAL LEVEL FOR 3 AGE GROUPS
Gowok
Lonjong
6-8 years 9 - 12 years 13-20 years 6-20 years
Number
Age
Education
Number
Age
Education
40 41 58 139
7.2 10.5 15.6 11.7
0.4 2.6 4.1 2.5
21 41 44 106
7.1 10.6 16.1 12.2
0.1 0.3 0.6 0.4
When it comes to the results of the second set of tests (more directed towards nonintelligence factors, such as motor skills, concentration and perceptual capacity - which we consider t o be less dependent on educational background) we did find clearcut differences in all age groups, and usually at the 1% level of significance (Table V). Four of the tests (pinboard, tapping test, reaction time and choice reaction time) are considered to be ‘perceptualmotor abilities’. Factors such as finger dexterity, manual dexterity and response orientation are also involved here. In the test of ‘figure comparison’ (which also showed differences in outcome) ‘perceptual speed’ was studied. in addition. Thus, we did indeed find significant differences in the second group of tests between the two communities, i.e. the severely iodine-deficient village, Gowok, and the control village, Lonjong. These results pose many questions: are such differences reversible; are the dif-
343 TABLE V SUMMARY OF DIFFERENCES OF TEST RESULTS IN LONJONG AND GOWOK Su btests
16. Pinboard 17. Throwing balls 18. Balance 19. Single reaction time 20. Choice reaction time 2 1. Tapping 22. Figure comparison
6-8 y r
9-12 y r
13-30 y r
** -
** ** ** ** ** ** **
** ** ** **
-
*
-
** Significant at 1% level.
* Significant at 5%level. - Not significant.
ferences the consequence of prenatal or of postnatal conditions; is an anatomical substrate demonstrable (e.g. degree of dendritization or myelination, or number of cells)? CONCLUSIONS As was stated in the beginning, there are similarities between congenital hypothyroidism and endemic cretinism with respect to the periods during which the development of the central nervous system is exposed to hypothyroidism, prenatally as well as postnatally. Both conditions are subject, for instance, to a variable degree of hypothyroidism. The fact is recalled that the people with mild congenital hypothyroidism seen by Smith e t al. (1957), and treated either early or late, end up in 41% of the cases with an I.Q. of 9 0 or better. We naturally ask ourselves whether cases of mild hypothyroidism which did not achieve an I.Q. of 90 or more, if seen in Gowok would all have been classified as cretins. If so (which we doubt), our observations on general intelligence in Gowok would be in line for the two conditions. If, however, this should not be the case, we are left with no explanation for the failure to find any instances of mild retardation in Gowok. We are now in the process of analyzing individual results, in relation to the biochemical parameters of hypothyroidism. Unfortunately, to our knowledge no studies using differentiated tests comparable to those reported here have been made in congenital hypothyroidism. Such studies will be very necessary in the near future, because of the high hopes being placed on the early diagnosis of this condition.
ACKNOWLEDGEMENT The support of the Netherlands Foundation for the Advancement of Tropical Research
(WOTRO)Grant: W 94-3 1 , is gratefully acknowledged. REFERENCES
Balizs, R. (1976) Hormones and brain development. In Perspectives in Brain Research, Progress in Brain Research, Vol. 45, M.A. Comer and D.F. Swaab (Eds.), Elsevier, Amsterdam, pp. 139-159.
344 Dobbing, J. (1974) The later development of the brain and its vulnerability. In Scientific Foundations of Pediatrics, J.A. Davis and J. Dobbing (Eds.), Heinemann Medical Books, London, pp. 565-577. Dobbing, J. (1975) Normal brain development in human. In Brain Development and Thyroid Deficiency, A. Querido and D.F. Swaab (Eds.), North-Holland, Amsterdam, pp. 7-1 1. Eayrs, J.T. (1971) Thyroid and the developing brain: anatomical and behavioural effects. In Hormones in Development, M. Hamburgh and E.J.W. Barrington (Eds.), AppletonCenturyCrofts, New York, pp. 345-355. Gemund, J.J. van and Laurent de Angulo (1971) The effects of early hypothyroidism on I.Q., school performance, and electroencephalogram pattern in children. In NormalandAbnormal Development of Brain and Behaviour, G.B.A. Stoelinga and J.J. van der Werff ten Bosch (Eds.), Leiden University Press, pp. 299-313. Holt, A.B., Cheek, D.B. and Kerr, G.R. (1973) Prenatal hypothyroidism and brain composition in a primate, Nature (Lond.), 243: 413-414. Querido, A. (1975) Endemic cretinism - a continuous personal educational experience during 10 years, Postgrad. med. J., 51: 591-599. Smith, D.W., Blizzard, R.M. and Wilkins, L. (1957) The mental prognosis in hypothyroidism of infancy and childhood. A review of 128 cases, Pediatrics, 19: 1011-1022. Thilly, C., DeLange, F., Camus, M., Berquist, H. and Ermans, A.M. (1974) Fetal hypothyroidism in endemic goitre : the probable pathogenic mechanism of endemic cretinism. In Endemic Goiter and Cretinism: Continuing Threats t o World Health, Sci. Publ. No. 292, Pan American Health Organization, Washington, D.C., pp. 121-128. W.H.O. Chronical(1974) Malnutrition and Mental Development, W.H.O., Geneva, pp. 95-102.
345 DISCUSSION BALAZS: I suppose that the basic question you are asking us is how reversible are the changes in the central nervous system when a metabolic insult, such as abnormal thyroid state or undernutrition, has been inflicted during development. The literature on animal experiments is quite confusing, so I am not at all surprised that the evaluation of the human situation is even more complicated. There is no unambiguous answer to the question. If brain maturation is assessed in terms of biochemical or structural parameters it is frequently observed that metabolic imbalance, including thyroid deficiency, results in a severe retardation. The emphasis here is on retardation, since most of the parameters are restored more or less t o normal after proper treatment. For example, Eayrs (1971) has found that the structural changes in the thyroid deficient cerebral cortex are reversible to a great extent after implementing replacement therapy at different times after birth. However, unless animals are rehabilitated within a relatively short time after birth, the behavioral impairments persist. So it seems that there is a discrepancy between the reversibility of the physical and the behavioral changes: the plasticity of the system, in terms of structure and biochemistry, is greater than the plasticity of the system in terms of behavior. This leads us to an important question: what are the proper estimates for correlating the structure and biochemistry of the brain with behavior? Cragg has studied the effect of undernutrition and thyroid deficiency on the number of synapses per nerve cell in the cerebral cortex. In the current repertoire of neuroanatomy, this estimate is probably the nearest to ‘higher nervous function’. However, Cragg has pointed out that, since there are about lo4 synapses per neuron, it is very difficult to appreciate the implication of even a marked deficit. Thus we have real problems when we try to choose the proper physical correlates of behavior; the estimates we are presently using are far from ideal. QUERIDO: In the beginning of this week Dr. Dobbing claimed that there is one insult for which you cannot compensate, and that is an early insult after birth in the human when cerebellar cell division is still going on. This would result in what they call ‘clumsy people’. My question is whether, on the basis of our data, you would call the people from the village with endemic cretinism ‘clumsy people’, and whether you would expect a reduced cell number in the cerebellum. BALAZS: Well, the evidence is quite good that, even in man, neurogenesis does occur in the cerebellum in the postnatal period. However, the important question here is: how far will even a deficit of 10-30% in granule cell numbers influence the functioning of the neuronal circuits in the cerebellum? There is a real chance that the effect will be relatively small as a result of the great redundancy of cells and circuits in the CNS. I really don’t think that deficit in cell number on its own could explain the impairment of behavioral performance. SWAAB: But this is arguing the other way round. Dr. Querido has shown clumsiness, which presumably means that that the cerebellum must be affected seriously in one way or another. BALAZS: Yes, but the defect is not necessarily, or exclusively, due to a deficit in cell numbers. It may be something else, e.g. balance of neuronal circuits, and I would put my money on the ‘something else’ as the major factor. SWAAB: One question about the set-up of this kind of experiment: I think the better you look at villages, the greater the chance that you will find a difference, for example in school distance or something else. It seems impossible to get two villages that are absolutely similar in all parameters except iodine intake. Would it not be easier to develop an experiment in such a way that performance of individuals is related t o their TSH-levels, PBI, etc.? QUERIDO: First of all, we are going t o do that with the individual data we have now. I mean, in addition to calculating the average, we are going to study the individual correlations. The problem, however, is that the data on thyroid function give only a snapshot. A certain hormone level does not tell you how the thyroid gland was functioning some years ago. BLOM: Were you giving iodine to the people in the affected village after the observations? And if so, are you doing a followup study on the results?
346 QUERIDO: Together with Dr. Djokomoeljanto we are carrying out prophylaxis in that area and we plan to come back in 5 years time for a follow-up study. However, it is not so simple to mobilize this effort again and to get the same cooperation. Moreover, the people would have to stay in the same village. Dr. Djokomoeljanto is currently doing the follow-up of our prophylaxis program in another village in Java, by measuring the correction of the iodine metabolism. It turned out that after 3 years part of the original population had moved to Sumatra. For an extensive followup we should, in addition, have a similar group of investigators again, and that will also be difficult. The doctoral students of the University of Indonesia were remarkable young men and women, They stayed in such villages for weeks, and they were playing and singing with these children when they had done a good job during the day. There was a very impressive relationship between the testing group and the population, and it would be difficult to get such a group again. SWAAB: If there is indeed plasticity in the brain, such a relationship would influence your experiments! QUERIDO: They did it in both the ‘experimental’ and the control villages. BALAZS: Your data give a very optimistic outlook. If iodine was the only crucial factor, one would also have expected a significant difference in the 6-8-year-old group. I suppose that the degree of education, probably even in the control village, was not very high. Nevertheless, it seems that education has influenced performance in the intelligence tests in a positive way. This means that, at least in man, the social environmental stimulation must have a very important role. This brings me back to the plasticity of the central nervous system, and to the different means with which one can try to rectify an abnormal situation. It would appear that, even if physical alterations lead to a handicap, there is a chance of correct behavioral performance, to some extent, by the proper intervention. QUERIDO: Yes, I agree; it resembles the data of Davenport e t al. (1976). He enriched the environment of rats exposed perinatally to thiouracil and changed in that way the behavior in a positive sense. DE CROOT: I was wondering about another disadvantage in the village with iodine deficiency. One would expect that the parents too had a lower educational level because of the iodine deficiency, and that this would have also a negative influence on the next generation, since their possibility to stimulate the children would be less. QUERIDO: Well, that is the general problem when measuring I.Q. everywhere in the world. It is, as you know, still a major issue at present. REFERENCE Davenport, J.W., Gonzalez, L.M., Carey, J.C., Bishop, S.B. and Hagquist, W.W. (1976) Environmental stimulation reduces learning deficits in experimental cretinism, Science, 191: 578-579.