ENDEMIC CRETINISM in the
JIMI VALLEY of
NEW GUINEA
- P.O.D. Pharoah, KB., B.S., B.Sc. STATEMENT
In 1966, discussions were held between Professor B.S. Hetzel, Dr. I.H. Buttfield and myself and the decision was made to set up a controlled trial on the effectiveness of iodised oil in the prevention of endemic cretinism. Subsequently a patrol to the Jimi valley was made in August 1966 by Dr. Buttfield in association with Mr. M.D. Brown of the Department of District Administration. On this patrol, the census was conducted and Dr. Buttfield determined the goitre gradings and supervised the administration of iodised oil. All subsequent field work and collection of samples described in this thesis was carried out by me.
Laboratory investigations, were performed at the Institute of Nuclear Medicine, the Middlesex Hospital, London, Prince Henry's Hospital, Melbourne, Laboratory Services Pty. Ltd., Melbourne and the Queen Elizabeth Hospital, Adelaide.
None of the material has been incorporated in any other thesis or been presented for the purpose of obtaining any other degree.
Some of the experimental data has been published in Proceedings of the 6th. International Thyroid Congress 1970, Lancet 1, 308, 1971., Papua New Guinea Medical Journal 14, 115, 1971., Papua New Guinea Institute of Human Biology Monograph Series No. 2, 109, 1971.
P.O.D. Pharoah. M.B., B.S., B.Sc. June 1972.
CONTENTS
Acknowledgements Index of tables Index of figures Chapter One Historical Introduction 1 Terminology Endemic cretinism and hypothyroidism Endemic cretinism and endemic goitre Chapter Two The Syndrome of Endemic Cretinism 10 Definition Cretinism in Europe Cretinism in Asia Cretinism in the Americas Cretinism in Africa Discussion
Chapter Three The Jimi valley and its Inhabitants 22 Introduction Geography History The People Housing Agriculture Animal Husbandry Diet Languages Health Services Educational Services Missions Economic Development Politics
Chapter Four Methodology 33 Chapter Five Endemic cretinism in the Jimi valley 39 Introduction Methods Results Neurological abnormalities Growth and Dentition Endocrinology Discussion Mental Retardation Deaf-mutism Growth Serum T4 and T3 Electrocardiography Summary Chapter Six The Relation between Cretinism and Endemic goitre 52 Introduction Methods Results Goitre rates Prevalence of cretinism Goitre prevalence in women who have borne children Goitre prevalence in cretins Correlation between goitre and cretin prevalence rates Discussion Summary Chapter Seven Endemic Cretinism and Iodine Deficiency 62 Introduction Methods Results Conclusion Chapter Eight The Recent Onset of Endemic Cretinism in the Jimi valley 68 Introduction Methods Results Ecological change consequent upon European contact Traditional salt and the pax sauna Salt preparation Salt analysis Discussion Summary Chapter Nine Maternal Thyroid Function and Cretinism 78 Introduction Methods Results Thyroid binding proteins TBG and TBPA Serum T4 Serum TSH Infant Mortality and the Maternal Serum T4 Discussion Summary Chapter Ten The Pathogenesis of Endemic Cretinism 86 Maternal hypothyroidism and endemic cretinism Foetal hypothyroidism and endemic cretinism Elemental deficiencies and endemic cretinism Pendred's syndrome and endemic cretinism Maternal rubella and endemic cretinism Protein malnutrition and endemic cretinism Summary Chapter Eleven Recapitulation and Conclusions 9S' Summary
Appendix Glossary of Abbreviations References ACKNOWLEDGEMENTS
The work described in this thesis was carried out while the author was employed by the Department of Public Health and later while on secondment to the Institute of Human Biology. I am indebted to Dr. R.F.R. Scragg, then Director of Public Health, who allowed my secondment and provided financial assistance to the Institute of Human Biology in order' that I may concentrate on the problem of endemic goitre and cretinism.
I also wish to express my thanks to many others without whose help this project could not have been carried out: To Dr. R.W. Hornabrook and Professor B.S. Hetzel who supervised the work and offered valuable advice. To Professor E.S. Williams, Drs. Y. Patel, P. Davoren and M. Wellby who performed the laboratory investigations. To Professor J.B. Stanbury for the determination of iodine content in the salt-water samples. To Dr. I.H. Buttfield who carried out the initial patrol instituting the trial of iodised oil and generously made all the census records available to me. To Mr. Raus Roga and others who accompanied and assisted me on numerous patrols. To the staff of the Anglican mission, Koinambe, the Nazarene mission Tsingoropa and the patrol post at Tabibuga who provided accommodation, stored samples and helped in many other ways. To the staff of the Institute of Human Biology who assisted with typing and the preparation of Figures and Tables. To Mr. M. Davis who arranged the printing of this thesis. To my wife and children who accepted my frequent absences from home with unfailing good humour. Last but not least, to the people of the Jimi valley for their co-operation, particularly to the women who often walked long distances to bring their children to me for examination. INDEX OF TABLES
Table 1. Regional variations in endemic cretinism. Table 2. Neurological abnormalities in endemic cretins. Table 3. E.C.G. voltages in cretins. Table 4. Serum thyroxine in cretins and normal female adults. Table 5. Village goitre rates. Table 6. Village visible goitre rates. Table 7. Prevalence of cretinism. Table 8. Goitre rates in trial and control populations. Table 9. Mortality of children born to iodine-supplemented and control women. Table 10. Classification of affected children in the iodised oil trial. Table 11. Eruption of deciduous teeth. Table 12. Annual incidence of cretinism. Table 13. Salt water analysis. Table 14. Events in the Jimi Table 15. Serum P.B.I. in iodine deficient areas. Table 16. Serum thyroid-binding proteins in non-pregnant and in treated and untreated pregnant women. Table 17. Serum thyroxine in treated and untreated pregnant women. INDEX OF FIGURES
Figure 1. Classification of cretinism. Figure 2. Map. Papua New Guinea and West Irian. Figure 3. Map. Languages of the Jimi valley. Figure 4. Map. The middle Jimi valley. Figure 5. Gathering of people during a survey. Figure 6. Severe head-lag in a cretinous infant. Figure 7. Normal child sitting erect. Figure 8. Cretin showing kyphotic spine. Figure 9. Standing posture in a cretin. Figure 10. Cretinous infant with a strabismus. Figure 11. Growth curve of cretins (males). Figure 12. Growth curve of cretins (females). Figure 13. Serum thyroxine levels in cretins and normal female adults. Figure 14. Serum triiodothyronine levels in cretins. Figure 15. Ages of cretins born since the trial in 1966. Figure 16. Eruption of deciduous teeth. Figure 17. Annual incidence of cretinism. Figure 18. The salt pool at Sangen. Figure 19. Serum thyroxine in pregnancy. Figure 20. Serum TSH in pregnant and non-pregnant women. Figure 21. Correlation between serum thyroxine and TSH. CHAFER ONE
HISTORICAL INTRODUCTION
Terminology
Endemic cretinism in New Guinea is a congenital syndrome of neurological damage in which the salient features are deaf-mutism, mental retardation, a diplegia and strabismus. It closely resembles the syndrome described from other areas of the world such as the Andes (Dodge et al., 1969) and the nervous type of cretinism described by McCarrison (1908) from the Himalayas. In its symptomatology it differs from sporadic cretinism in that the majority of cases are not hypothyroid.
The term cretin was first recorded in Diderot's Encyclopedie 1754 referring to "an imbecile who was deaf and dumb with a goitre hanging down to the waist". Earlier Platter (1602) had given a clinical description of the disease stating that - "many infants are wont to be afflicted: who besides their innate simplemindedness, the head is now and then misformed, the tongue immense and tumid, dumb a struma often at the throat, they show a deformed appearance and seated in solemn stateliness, staring and a stick resting be- tween their hands, their bodies twisted variously, their eyes wide apart, they show immoderate laughter and wonder at unknown things".
De Quervain and Wegelin (1936) discuss the possible derivation of the term cretin. The most likely origin is from "Christianus" or "Crestin" in the south-eastern French dialect, the afflicted person being referred to as a "pauvre chretien" or "bon chretien" because of their harmlessness or innocence. Other possible derivations include "Cretira" from the Rhaeto - romanic language as a colloquialism for an unfortunate creature, or from the Latin "creta" in reference to the chalk-like pallor of the skin.
Endemic cretinism and hypothyroidism
There is today considerable confusion over the concept of cretinism. Initially the term was used in reference to a condition peculiar to the Alps and the Pyrenees in which the salient features were mental and physical retardation and deaf-mutism. - 2
Subsequently, in Europe, the term was used in a wider sense to encompass the whole spectrum of mental retardation. Benda (1946) noted that many "cretins" in Swiss institutions would merely have been categorised as mental defectives in the U.S.A.
In contrast to the cretin of the European authors, cretinism in the English speaking countries has come to be equated with hypothyroidism. The Encyclopaedia Britannica (Landau 1966) describes cretinism as "a condition resulting from the failure of the thyroid gland to secrete its hormone from the time of intrauterine life or very early infancy". It further states that "the thyroid gland in endemic cretinism is incapable of secreting hormone". Webster's dictionary (1966) defines cretinism as "a congenital deficiency of thyroid secretion characterised by a stunted and malformed body and arrested mental development".
The aetiological association between hypothyroidism and cretinism commenced with Curling's description of Sporadic cretinism in 1850. In this he states: "In countries where cretinism and bronchocele prevail, it was long supposed that there is some connection between the defective condition of the brain and the hypertrophy of the thyroid In the foregoing cases we have examples of an opposite condition viz a defective brain or cretinism combined with an entire absence of the thyroid".
Although, in this description, the differing pathologies of the thyroid gland in endemic and sporadic cretinism are noted, no differentiation between the two syndromes is made on clinical grounds. Furthermore the term cretin is being used synonymously with a defective brain.
Fagge (1871) described four further cases of sporadic cretinism and compared it with endemic cretinism. He drew attention to the comparative findings in the two syndromes and wrote:
(a) Sporadic and endemic cretinism are attended with a deficiency of the mental powers. - 3
(b)Sporadic cretinism instead of being associated (like endemic cretinism) with a goitre, appears to be attended with a wasting or absence of the thyroid body. (c)Sporadic cretinism is not necessarily congenital.
Endemic cretinism is now largely a disease of remote under-developed areas with which Western medicine has little contact, whereas the number of cases of sporadic cretinism reported in the literature has progressively increased. Such change in emphasis has led to the equation of the term cretin with the sporadic hypothyroid variety. Most modern authoritative text books of medicine substantiate this e.g. both Harrison's Principles of Internal Medicine (Selenkow and Ingbar 1970) and Cecil and Loeb's Textbook of Medicine (Stanbury 1967) classify sporadic and endemic cretinism under the general heading of hypothyroidism. This school of thought was earlier expressed by Osler (1897) who stated that "the changes characteristic of cretinism, endemic as well as sporadic, result from the loss of function of the thyroid gland". This conclusion, though perfectly applicable to the sporadic variety of cretinism, cannot be applied to endemic cretinism.
That endemic cretinism may not necessarily be associated with hypothyroidism was first implicit in McCarrison's (1908) classification of the Himalayan cretins into the "nervous" and "myxoedematous" varieties. Subsequently Gordon (1922, 1938) reviewing the cases of sporadic cretinism in the United States literature was most precise in his distinction between endemic and sporadic cretinism. He suggested that the term "sporadic cretinism" be dispensed with in favour of the term "childhood myxoedema" because "cretinism as described in Europe is a clinically distinct entity from sporadic hypothyroid cretinism". These suggestions have gone unheeded and the confusion in terminology persists.
In summary, the initial descriptions of cretinism referred to a syndrome of deaf-mutism and mental and physical retardation. The disease occurred in areas of high goitre endemicity and frequently the cretins themselves had a goitre. Subsequently the sporadic hypothyroid variety - 4 of cretinism was described, it also had mental and physical retardation as major defects and was associated with an abnormality of the thyroid gland. The absence of endemic cretinism in the English speaking countries and the greater awareness of sporadic hyperthyroid cretinism led to the equation of the term cretin with hypothyroidism.
The differentiation between sporadic and endemic cretinism is important both clinically and aetiologically. The former is the result of hypothyroidism due to a congenitally absent thyroid gland, an inherent defect within the gland preventing normal thyroid hormone synthesis or damage to the gland e.g. by irradiation. Endemic cretinism shows regional variations in its symptomatology, the important point being that it is a syndrome of neurological damage manifested by mental retardation, abnormalities of hearing and speech, a congenital diplegia and strabismus, while hypothyroidism is present in only a minority of cases. The classification of cretinism is summarised in Figure 1.
Endemic cretinism and endemic goitre
The association that exists between endemic cretinism and goitre was first noted by Paracelsus (1567) who wrote - "but to speak of these creatures that they perchance also have defects of the body, that is they carry growths with them such as goitres and the like: this perhaps is not a characteristic of fools but also of others, however it fits most of them".
Although this recognition of an association between goitre and cretinism is often attributed to Paracelsus, it was implicit in the literature prior to Paracelsus e.g. the Reuner Musterbuch of 1215 depicts a figure with a large multilobed goitre, a stupid facial expression and brandishing a fool's staff in one hand. In 1220 the encyclopaedia of Jacques de Vitry describes large goitres in Burgundy. He notes deaf-mutism in the region and further states "Ex mutis et surdis, muti et surdi infantes procreantur" suggesting a familial tendency in the deaf-mutism (Mercke 1960). CLASSIFICATION OF CRETINISM
Congenital absence of the thyroid gland .
Enzyme defect causing hypothyroidism SPORADIC — ineffective thyroid present in all hormone synthesis. cases.
Damage to the thyroid gland e.g. by irradiation.
CRETINISM
Hypothyroid type.
ENDEMIC aetiology not firmly established but Nervous type a possibly related to A congenital syndrome of dietary iodine neurological damage manifested deficiency. by mental retardation, abnormalities of hearing and speech, a diplegia and strabismus.
Figure 1 -5
Endemic goitre is a problem of world wide importance, a fact emphasised by the extensive review of Kelly and Snedden (1960) on the prevalence and geographical distribution of endemic goitre. It is clear that almost no country is exempt from this condition. Areas with a high prevalence are determined by certain geological factors, they are:
1. Mountainous regions, e.g. The Alps, the Andean cordillera, the Himalayas and the mountain chain extending through Burma, Indonesia, New Guinea and the Phillipines.
2. Alluvial plains that have recently been the site of quaternary glaciation e.g. the Great Lakes basin of Canada and the U.S.A., Finland and the low lying Netherlands.
3. Areas where water supplies originate in limestone e.g. the Peak District and the Cotswolds in England and in parts of Colombia.
Historically, Langer (1960) indicates that references to goitre may be found in the literature of 4,000 years ago such as the early Hindu and Chinese writings. He notes that even in these times remedial measures for goitre included the Sargassum and Laminaria seaweeds, while in China preparation of pig and deer thyroids were used. In Europe the recognition of the geographical distribution of goitre predated the Christian era, the poet Juvenal in the 1st century B.C. remarking "Who wonders at a swelling of the neck in the Alps".
In 1811, Courtois isolated the element iodine from the seaweed Fucus vesiculosis when in the process of producing saltpetre for use in the Napoleonic wars. Previously Fucus vesiculosis had been used for the treatment of goitre and this prompted both Coindet (1820) and Prout (1834) to prescribe iodine for the treatment of goitre. Subsequently Coindet (1821) described iodism and the development of hyperthyroidism later called Jod-Basedow's disease which he ascribed to excessive dosage. In spite of his warnings the remedy fell into disrepute because of the toxic effects re- sulting from the excessively large doses used. Fear of iodine induced hyperthyroidism reached its zenith under the influence of Kocher (1833a). 6
Eggenberger (1928), reviewing the early literature, claims that up to 5,000 times the optimum dosage of iodine was used.
Interest in iodine was rekindled following Baumann's (1895) discovery that an acid hydrolysate of the thyroid gland contained 10% iodine. In 1927 Harington and Barger synthesised thyroxine and showed that iodine was an integral part of the active hormone.
It is now generally accepted that dietary iodine deficiency is the major cause of endemic goitre. Evidence supporting this comes fran a number of lines of investigation:
i) Endemic goitre occurs in areas of low soil iodine content and an inverse relationship can often be demonstrated between soil iodine and goitre prevalence (Roche and Lissitzky 1960).
ii) Urinary iodine excretion is low and thyroidal 1131 uptake is regularly elevated in areas of endemic goitre (Follis 1964).
iii) Experimentally, goitre may be produced in animals fed on a low iodine diet (Axelrod et al., 1955).
iv) The effectiveness of iodine in preventing goitre has been widely demonstrated. Although Boussingault (1833) advocated the use of iodised salt for endemic goitre prevention, it was not until the trial of Marine and Kimball (1920) in Akron, Ohio, that convincing evidence was produced of the effectiveness of iodine in goitre prophylaxis. Since then various measures to supplement the iodine intake have been introduced in many countries, they include iodisation of salt, bread and water supplies and the administration of iodide containing tablets and sweets. Following the observation that iodised oil remained in situ for prolonged periods after procedures such as bronchography and myelography, McCullagh (1963a) in New Guinea introduced the use of intramuscular iodised oil for goitre prophylaxis. Its long duration of action makes it particularly useful in those countries where other iodisation programmes are ineffective for reasons such as poor communications or low dietary salt intake. 7
The effectiveness of iodised oil as a prophylactic has been confirmed by many workers. (Buttfield et al., 1965, Fierro-Benitez and Stanbury 1968, Kevany et al., 1969, Pretell et al., 1969).
However, factors other than iodine deficiency are thought to be of aetiological significance in some areas. These include: a) Dietary goitrogens. Clements and Wishart (1956) incriminated a dietary goitrogen as a cause of seasonal epidemics of goitre among Tasmanian school children which could not be prevented by iodine administration. They postulated that the epidemics were related to the spring flush of goitrogen containing weeds in the pasture, the goitrogen subsequently appearing in the cows milk which was distributed to the school children. Attempts to isolate the goitrogen however, were unsuccessful.
In the Cauca valley of Columbia, endemic goitre still exists despite adequate iodine prophylaxis. It has been correlated with the source of drinking water which has been found to have a thiourea antithyroid like activity (Walmer et al., 1971, Gaitan et al., 1968, 1969).
Observations in the Congo indicate that goitrogenic factors distinct from an inadequate iodine supply exist (Ermans et al., 1969). Further investigations suggest that the goitrogenic substance may be a thiocyanate produced by the hydrolysis and detoxification of the glycoside Linamarin present in the cassava consumed by the local populace (Delange & Erman 1971). b) Infection. McCarrison's (1906) studies at Gilgit in the Himalayas drew attention to the progressive increase in goitre prevalence in successive villages down-river which he attributed to the progressive degree of pollution of the water. On the basis of this and other observations he concluded that a micro-organism was responsible for the disease. Doubt has since been cast on McCarrison's interpretation of the results since it has been shown that bacterial pollution effectively binds iodine making it unavailable for absorption, (Stanbury personal communication). 8 c) Mineral factors. The higher prevalence of goitre in areas where water sources originate in litestone has been appreciated for many years. Kelly and Snedden (1960) note that even as early as 1810, the disease was observed to be frequent in Bogota, Columbia among institutions which used well water of exceptional hardness for cooking. The Medical Research Council (Murray et al., 1948) in Britain reported that a dietary iodine level which may be adequate in a soft water area, is inadequate in an area where the water supplies are hard.
Experimentally, Taylor (1954) has found that calcium causes enhanced growth of the iodine-deprived rat thyroid. The postulated reasons for this were:
i) Iodine is bound by or forms a complex with calcium which prevents effective utilisation;
ii) Calcium prevents binding of iodine by the thyroid;
iii) Calcium increases renal excretion of iodine.
In addition to the enhancing effect of calcium on a low iodine intake as a cause of goitre, Kelly and Snedden (1960) note the work of the Russian workers who associate a high manganese - low iodine ratio in goitrogenesis.
Two points emerge:
a) Endemic goitre can largely be attributed to dietary iodine deficiency.
b) Endemic goitre is geographically associated with endemic cretinism.
This has led to the assumption that iodine deficiency is of importance in the causation of endemic cretinism (Wespi 1945, Stanbury and Querido 1957, Choufoer et al., 1965). This assumption is not universally accepted (Costa 1957, Clements 1958, Greenwald 1959, Koenig and Veraguth 1961) and -9- there is doubt concerning the role of iodine deficiency in the pathogenesis of endemic cretinism.
Several areas in New Guinea are recognised as being iodine deficient and having a high prevalence of endemic goitre (Buttfield and Hetzel, 1967, 1971, Choufoer et al., 1965). The use of intramuscular iodised oil introduced by McCullagh (1963a) and its ability to provide iodine over a prolonged period of time (Clarke et al., 1960, Buttfield and Hetzel, 1967, 1971), made eminently feasible the possibility of evaluating the effectiveness of iodine in preventing endemic cretinism.
A preliminary survey of the Jimi valley in the Western highlands of New Guinea had revealed that it was an area of iodine deficiency with a high prevalence of endemic goitre and cretinism (Buttfield, personal communication). Thus a situation was available in which it was possible to test the hypothesis that the administration of iodine can prevent endemic cretinism.
This thesis is concerned with the follow-up of a trial using iodised oil and evaluating its effectiveness in preventing endemic cretinism. The subject matter was initially obtained while the author was the District Medical Officer for the Western highlands of which the Jimi valley is a part. Later, while on secondment to the Institute of Human Biology, full-time study was devoted to the problem.
Retrospective observation revealed that appeared to be a spontaneous recent occurence of an epidemic of cretinism in the valley. The various factors possibly responsible for this phenomenon were investigated, and revealed that the likely cause of the epidemic was a significant change in the dietary iodine intake.
As a sequel to the iodised oil trial, investigations were also made concerning the mechanisms by which iodine deficiency could be related to the pathogenesis of endemic cretinism. In particular, serum thyroid hormone levels and thyroid binding proteins during pregnancy were determined. A comparison of these parameters in the iodine treated and the untreated populations was made.
An account of the clinical syndrome of endemic cretinism as seen in the Jimi valley is given and a review of the disease as reported from other areas of the world is made. CHAPTER TWO
The Syndrome of Endemic Cretinism Definition
Regional variations in the syndrome of endemic cretinism, particularly concerning hypothyroidism as a clinical feature, have perpetuated the difficulty in defining the syndrome.
In formulating a definition, the Pan American Health Organisation (1963) described an endemic cretin as: "An individual with irreversible changes in mental development, born in an endemic goitre area and exhibiting a combination of some of the following characteristics not explained by other causes.
1. Irreversible neuromuscular disorders 2. Irreversible abnormalities in hearing and speech leading in certain cases to deaf-mutism 3. Impairment of somatic development 4. Hypothyroidism
Although this definition successfully combines the clinical features of the syndrome as seen in all regions, it does little to demarcate the differences found in various countries. Such regional variations may be very marked with irreversible neuromuscular disorders and deaf-mutism on the one hand and hypothyroidism and impaired somatic development on the other. Dumont et al., (1969) postulate two distinct syndromes with different pathogenetic mechanisms or perhaps similar mechanisms operative at different periods of foetal life.
The following account reviews the manifestations of endemic cretinism in different areas of the world.
EUROPE
As described in Chapter 1, the earliest descriptions of endemic cretinism are from Europe, the condition constituted a problem of sufficient magnitude to have a Sardinian Royal Commission (1848) appointed to investigate it. The endemic cretin as defined by this commission was a person with signs of abnormal body development and structure associated with a more or less marked degree of idiocy, who was born in an area where several persons suffer such defects of body and mind and where endemic goitre is widespread. The cretins were classified into three groups:
a) those with vegetative faculties only b) those with vegetative and reproductive faculties c) those endowed with vegetative and reproductive faculties and capable of some communication through imperfect language carried on by words and gestures.
This classification implies a wide range of mental retardation and the reference to normal reproductive faculties in two classes would exclude severe hypothyroidism.
Costa et al., (1961a) discuss sporadic and endemic cretinism and state that the two are completely different morbid conditions. On the basis of 127 various parameters including PB I, radio131I uptake, basal metabolic rate and the electrocardiograph, they conclude that the endemic cretin is not usually hypothyroid. In a subsequent report on the cretins in the Piedmont of Italy (Costa et al., 1964), an area previously encompassed by the Sardinian Commission report (1848), the cretin is described as an individual with pronounced defects in body development suffering from characteristic nervous changes manifest by anomalies of gait, speech, hearing and a peculiar form of idiocy. Myxoedema is said to occur in only 8% of the cretins, even this figure would appear to be an overestimate allowing for the fact that a very selected group was investigated namely the inmates of certain special institutions, while endemic deaf-mutes were excluded. Furthermore the diagnosis of myxoedema was made on rather scanty evidence. A subnormal B.M.R. was obtained in 2 of 49 cases, only rarely the electrocardiograph showed bradycardia, low voltage and T wave inversion and never all in the same case and the mean PB127I for 65 cases was 5.6 ug%. The stature was noted to be smaller than normal but true dwarfism was uncommon while a normal or greater than normal stature was not exceptional. - 12 -
In Switzerland, de Quervain and Wegelin (1936) subdivided the cretins into groups, those with and those without a goitre. The latter were considered more typical as they showed the greatest degree of retarded growth and histopathology of the thyroid revealed atrophy and fibrosis. Seventy five percent of all cretins had some growth retardation, but only 7% were true dwarfs. Abnormalities of hearing or speech were present in all 111 cases reported by Wydler (1926), 42% were deaf-mutes, 32% were deaf but had understandable speech and 25% had abnormal speech but normal hearing. These findings are confirmed by de Quervain and Wegelin (1936).
Abnormalities consistent with a congenital diplegia were not common, being present in a few cases only (de Quervain and Wegelin 1936). These authors note a number of clinical differences between endemic cretinism and the cretinism of a congenital thyroid aplasia. In the endemic cretin:
a) Stature may be normal b) Myxoedema is not always present c) Sexual development may be normal
In the cretin with thyroid aplasia hearing is usually normal.
Laboratory investigations (Koenig and Veraguth 1961) have revealed a wide range in the radio-iodine uptake varying from definitely hyperthyroid to moderately hypothyroid with a parallel variation in the PBI. Only 3 out of 19 cases were clinically hypothyroid. These investigations however, were carried out on a group selected for their dwarfism and mental deficiency while those with large goitres were excluded. Such a selection would favour those with an atrophy of the thyroid gland and may therefore give a falsely high indication of the prevalence of hypothyroidism.
A clinical description of endemic cretinism in England was given by Norris (1847). His report from the village of Chisleborough in Somerset divided the cretins into four groups which included: - 13 - i) Four perfect idiots. ii) Seventeen partial idiots. All quite unable to articulate so as to be understood, with memories so deficient as to prevent their being entrusted in the simplest affairs of life, walking with an unsteady step and an unsteady waddling gait. iii) Five deaf and dumb, two who have been educated, are said to be possessed of remarkable quick parts; two uneducated of moderately quick parts and one an aged woman being but little removed from idiocy. iv) A majority of the whole population: viz. those with an obvious deficiency of intellect, of more than usually dull perception, or having a very marked impediment in their speech and I believe without a single exception affected with bronchocele.
It is clear that the cardinal features of the neurological type of cretin are being described i.e. deaf-mutism, mental retardation and an abnormal gait.
However, from this description it is not possible to infer that hypothyroidism is a feature. It is mentioned that the cretins are of short stature, in one instance an adult female 31 feet in height was described, raising the possibility that hypothyroidism was present during the years of active growth. Among the females, while difficult, deficient or absent menstruation was noted, it is also stated that some of the worst cases had borne children, which would negate hypothyroidism of any magnitude.
In summary, cretinism in Europe presents with hypothyroidism in a minority of cases only, probably less than 10%. The majority present with central nervous system abnormalities of which deaf-mutism and mental deficiency predominate but with a congenital diplegia also being occasionally present. - 14 -
ASIA
The earliest clinical description of cretinism in the Himalayas is that of McCarrison (1908). He subdivided the cretins into two types, "nervous" and "myxoedematous" with some cases presenting the clinical features common to both types. His clinical description of the myxoedematous type is incomplete merely stating that "it corresponds to that form of the affection met with in Europe and is described in any text book of medicine". He remarked that deaf-mutism is an almost constant accompaniment of both types of the disease and later confirms this observation noting that deaf-mutism occurred in 87% of all cases of cretinism. In the majority of cases the deafness was complete and in a minority only partial. The question then arises as to how many of McCarrison's cases were indeed myxoedematous. In this context it must be noted that myxoedema and the role of the thyroid was a medical topic of focal interest at the time. Gull (1873) had given his paper "On a cretinoid state supervening in adult life in women", a condition subsequently called myxoedema by Ord (1878). Reverdin (1882) had noted the consequences of total thyroidectomy and maintained that the changes resulting from it were identical to the myxoedema described by the English authors. In fact, he called the condition "myxoederre operatoire". Kocher (1883b) had also noted the changes following thyroidectomy which he termed "cachexia strumipriva" and drew attention to the relationship between this condition and cretinism. In 1883 the Myxoedema Commission of London had been appointed to investigate the relationship of myxoedema and allied conditions of the thyroid gland and published its report in 1888.
In the light of this gathering momentum of interest in the thyroid gland, it is possible that McCarrison's (1908) description of cretinism was biased towards hypothyroidism. This is substantiated by McCarrison's conclusion that defective thyroid function in the mother is the essential factor in the production of cretinism.
The clinical description he gives of "nervous" cretinism is more complete and remains a model of accuracy. The disability is described as pertaining more especially to the central nervous system. - 15 -
Deaf-mutism is as a rule complete, mentality is much disordered and there is a congenital diplegia with increased knee jerks and a spastic rigidity more severely affecting the lower limbs with a characteristic gait. A coarse nystagmus and internal strabismus were noted in some cases. Dwarfism is mentioned in one case only, a 24 year old subject with a height of 31 feet. In view of the statement that these cretins exhibit a complete or partial inability to stand upright, the accuracy of any measurement of height must remain doubtful.
Stott and Gupta (1934) also describe two groups, namely cretins and deaf-mutes. They use the term cretin to be synonymous with hypothyroidism and note that the cretins are of short stature, ranging in height from 3 feet 5 inches to just over 4 feet, show variable degrees of mental retardation and 50% are deaf-mutes. The deaf-mute group had abnormalities of posture and gait but were of normal height and only a few showed the clinical features of myxoedema.
Laboratory tests on the Himalayan endemic deaf-mutes were carried out by Raman and Beierwaltes (1959) and Srinivasan et al, (1964). The former found slightly lower serum Protein Bound Iodine (P.B.I.) and Butanol Extractable Iodine (BEI) levels in deaf persons compared with those not deaf. The latter investigators found no differences in radio thyroidal 1311 uptake, serum PB1311, BE131I and P-n127 I, between endemic deaf-mutes and normal clinically euthyroid persons from the same area.
Ibbertson et al., (1971), investigating a Sherpa population in Nepal, made clinical observations similar to those of Stott and Gupta (1934). They also equated cretinism with hypothyroidism and described two groups, cretins and deaf-mutes. The former were considered to be hypothyroid clinically but there was little in the way of laboratory investigation to substantiate the diagnosis. The four-hour and twenty-four hour radio 1311 uptake and peripheral indices of thyroid function such as serum cholesterol, ECG voltage and ankle reflex time gave poor confirmation of hypothyroidism. - 16 -
These parameters were not significantly different in the cretins as compared with the normal control population. The only parameter supporting the diagnosis of hypothyroidism was the serum PHI. This was significantly lower in cretins than in normal controls from the same area but both groups had low FBI's by western standards. Among the 28 cretins examined, 19 were deaf-mutes. The second group, with deaf-mutism as the predominant symptom, were clinically euthyroid, of normal stature and had laboratory parameters of thyroid function not significantly different from the normal population.
Summarising the syndrome in the Himalayas, most workers in this region have carried out their study with the preconception that a cretin is hypothyroid, The "nervous" cretins first described by McCarrison (1908) and subsequently by many others are euthyroid and have as their predominant manifestations mental retardation, deaf-mutism and a congenital diplegia. The myxoedematous cretins, though stated to be clinically hypothyroid, have scanty and unconvincing laboratory evidence to substantiate this fact,
THE AMERICAS
Endemic cretinism has been described in many South American countries, mainly from the Andean region but also from the Mato Grosso and Goias regions in the middle west of Brazil (Lobo et al., 1963, 1964, Rosenthal et al., 1969). In the latter studies 40 cretins were investigated, the clinical features observed being mental retardation, short stature and neuromuscular disorders. Spasticity was the typical neurological abnormality and attention was drawn to the clinical similarity between these cases and McCarrison's (1908) nervous cretinism. Hypothyroidism was not detected either on clinical examination or by laboratory investigation. 127 The serum PB I levels and the radio 131I uptakes were the same in cretins and non-cretins and the response to TSH was normal. Other investigations included pneumoencephalography and cytogenetic studies which were normal and electroencephalography which showed diffuse abnormalities. - 17 -
The clinical features of the syndrome as found in Ecuador have been described by Fierro-Benitez et al., (1969). The fundamental abnormality taken into account was mental deficiency and on this basis there were two types of cretin:
Type I Those with mental deficiency and severe impairment of hearing and speech Type II Those with mental deficiency, severe impairment of hearing and speech, short stature and motor abnormalities.
Type I occurred almost ten times as frequently as Type II. The classification implies that a short stature is not a feature of the first type and may be taken to indicate that hypothyroidism was not present during the years of active growth. In addition to those included in these groups there were other subjects with deaf-mutism, mutism, deafness and motor abnormalities who were not included as cretins, presumably because mental retardation was not obvious.
Dodge et al., (1969) investigated the neurological aspects of these cretins and, using the Leiter and the form-board item of the Gesell tests for psychological evaluation, found marked mental deficiency in all cases. Abnormalities of hearing and speech were present in 27 of the 28 examined, 17 were total deaf-mutes and 10 had some hearing deficit. Neuromuscular abnormalities were manifest in 23 cases by an impairment of walking, the gait being described as shuffling with a stooped attitude and slightly flexed knees; three of these cases were unable to stand or walk and had marked flexion contractures of the knees. Other features included spasticity, adductor spasm, increased tendon reflexes, ankle clonus and extensor plantar responses. It was concluded that the majority of cases had pyramidal tract dysfunction involving predominantly the lower extremities.
A propos thyroid function, Fierro-Benites et al., (1970) found no clinical evidence of hypothyroidism in 9 out of 10 cases while laboratory investigations revealed low normal serum hormone measurements and high - 18 -
i 131 rad o I uptakes, Harrison et al,, (1969), reporting on the serum thyroxine levels in 20 cretins, found an abnormally low level in one case only.
Stanbury et ale, (1954), investigating Endemic Goitre in the Mendoza province of Argentina, examined approximately 50 cretins, most of whom, were of short stature varying between 32 feet (106 cm) and 4 feet (122 cm) and almost all of whom were mute. A clinical diagnosis of hypothyroidism could not be made in any single case and this was substantiated in 13 subjects by a normal serum PBI.
In summary, the cretins of South America are almost always euthyroid both clinically and biochemically,hypothyroidism is present in less than 10%. The clinical syndrome closely resembles McCarrison's (1908) "nervous cretinism" with mental deficiency, deaf-mutism and pyramidal tract dysfunction being the cardinal features.
Cretinism and deaf-mutism is reported to occur in many of the Central American countries (Kelly and Snedden 1960) but the information available is scanty. In North America only Sporadic hypothyroid cretinism is found and Gordon (1938) draws attention to the lack of the endemic type, particularly in the goitre-belt region of the United States of America.
AFRICA
Descriptions of endemic cretinism in the Congo provide the most convincing evidence of hypothyroidism. The two areas most extensively studied are the island of Idjwi in Lake Kivu and the Uele region.
In the latter region Bastenie et al., (1962) and Dumont et al., (1963a) report on a series of 35 cases. They took as their minimal criteria for cretinism mental and growth retardation and a characteristic physical appearance. The clinical features of hypothyroidism - hoarseness, puffiness of the face and hands, coldness of the skin, sensitivity to . cold, sluggishness and swelling of the abdomen - were present in all cases though only nine showed a delayed relaxation of the ankle jerks. - 19 -
In this series there were five deaf-mutes and two who had a stiff spastic gait and muscle spasticity. Laboratory investigations supported the of hypothyroidism, both the PB127I and the radio 131I being significantly reduced in the cretins compared to the normal population. Also the radio iodine uptake failed to increase with TSH stimulation. The intensity of the hypothyroidism as indicated by these laboratory findings was said to correlate with the degree of both mental and growth retardation.
Radiologically the cretins showed features characteristic of hypothyroidism with delayed and irregular bone maturation and epiphysial dysgenesis of the femoral head.
The mechanics of the thyroid failure were also investigated (Dumont et al., 1963b). Significant defects in iodine concentration, organic binding and iodotyrosine coupling were excluded by a salivary-serum iodine ratio greater than one, no significant iodine discharge after thiocyanate administration and the appearance of radio-thyroxine in the serum after radio iodine administration respectively. It was concluded that hypothyroidism was due to thyroid damage and the suggestion made that involution of the gland had occurred secondary to excessive stimulation probably during foetal development and early infancy.
Similar studies have been carried out on the Idjwi Island cretins by Erman et al., (1969) and Delange et al., (1971). They described 99 cases of cretinism of wham 88 were clinically and biochemically hypothyroid, but had no neurological abnormalities. The remaining eleven cases were all clinically euthyroid. Nine were deaf-mutes and seven had a spastic diplegia. It was stated that there are two clinically distinct types of cretin to be found in this region.
The clinical and biochemical findings among these cretins were very similar to those of the Uele cretins, i.e. low PB1271, low radio 1311 uptake, low voltage QRS complexes and flattening of the T waves in the electrocardiogram and marked retardation in bone maturation with ,epiphysial dysgenesis. -20-
On the basis of the radiological appearances, it was thought that the hypothyroidism commenced towards the end of gestation or in the first year after birth. It is pertinent however, that the laboratory investigations were carried out on the hypothyroid cretins only and not on the clinically euthyroid neurological cretins.
An important difference between the myxoedematous cretins in the Congo and those in the Himalayas is the low radio 1311 uptake in the former (Dumont et al., 1963a, Delange et al., 1971) and the high values in the latter group (Ibbertson 1971). This suggests that thyroid atrophy is a feature of the African cretins.
In summary, the majority of endemic cretins in the Congo show unequivocal evidence of hypothyroidism but there is a minority group of euthyroid neurological cretins. Whether these two types are distinct syndromes with a different pathogenesis or whether there is an overlap in the symptomatology with a common aetiological factor active at perhaps different times of foetal or infant development, remains controversial and requires further investigation.
Discussion
It is only in descriptions of cretinism in the Congo that there exists acceptable evidence of significant hypothyroidism in the majority of cases. A review of the literature on endemic cretinism in all other countries reveals a minority with hypothyroidism while in sane endemics it is extremely rare, the majority being euthyroid but with typical neurological abnormalities.
Mental deficiency is common to both sporadic and endemic cretinism. Abnormalities of hearing and speech, a congenital diplegia and strabismus which are characteristic of the "nervous" type of endemic cretin are not usully found in the hypothyroid type.
Although some deafness is a common finding in myxoedema, it is an acquired deafness and not usually severe. Also it may be perceptive, - 21 -
conductive or mixed in type and may respond to treatment with thyroid extract (Howard and Lloyd 1956). In contrast, the deafness of endemic cretinism is congenital and predominantly perceptive in type (Ramalingaswami 1964, Costa et al., 1964, Fierro-Benitez et al., 1970). It is usually severe and is often total. Fierro-Benitez et al., (1970) found a hearing loss of over 70% in all seven oases examined. Dodge et al., (1969) examining 27 cases found 17 to be totally deaf-mute and the remaining ten to have only slight hearing. Even after the exclusion of all endemic deaf-mutes from their study, Costa et al., 1964 found a hearing loss of greater than 45% in almost half the cretins.
Although various neurological complications of hypothyroidism have been described (Nickel and Frame 1958, Watanakunakorn et al., 1965, Jellinek and Kelly, 1960), none of these complications resemble the neurological abnormalities of endemic cretinism.
In conclusion there appears to be two types of endemic cretinism, nervous and myxoedematous, a classification originally suggested by McCarrison (1908). The myxoedematous type closely resembles sporadic hypothyroid cretinism and is the predominant type in the Congo. The nervous predominates in most other endemics and cannot be related to clinical hypothyroidism in the adult or child though this does not exclude the possibility that hypothyroidism during foetal development may be responsible for the syndrome.
It has been suggested that the two types of the disease have different pathogenetic mechanisms or similar mechanisms operating at different times (Dumont et al., 1969). The hypothyroidism characteristic of the myxoedematous type is due to thyroid deficiency and is related to atrophy and fibrosis of the thyroid gland. However, the reason for this is not clear, though it may be due to a dietary goitrogen (Medical Journal of Australia, 1972).
Table 1 summarises the incidence of hypothyroidism, deaf-mutism and central nervous system defects such as diplegia and strabismus as reported from various countries. REGIONAL VARIATIONS IN ENDEMIC CRETINISM
Country, Hearing/speech C.N.S. defects Hypothyroidism reference abnormalities e.g. diplegia .
Switzerland DeQuervain &Wegelin 1936 100 % <10% 10-20% Koenig &Veraguth 1961 ...---,. Italy 80-90% • Present ?incidence <10% Costa at aI.1961a,b&1964 ..... Ecuador fierro—Benitez et el. 1969, 90% 70% 10 1970 Dodge at al. 1969
Brazil 80% 100% 10% Lobo at al. 1963 &1964
Africa Bastenie et al. 1962 10-15% 5 -10% 90% Dumont at al. 1963a&b
India MtCarrison 1908 80-90% '30-40% 50-60% Stott & Gupta 1931 Ibbertson at al.1971
a
TABLE 1 CHAPTER 3
THE JIMI VALLEY AND ITS INHABITANTS
Introduction
Politically the island of New Guinea is divided in two. The Western half, formerly Dutch New Guinea, was transferred to the Indonesian administration in 1962 and is now West Irian. The Eastern half combines Papua and New Guinea. Papua, formerly British New Guinea, was placed under Australian control in 1906. New Guinea including the islands of the Bismarck Archipelago and the Admiralty Islands remained as Kaiser Wilhelm Land, a German colony until 1918 when aLeagve of Nations mandate transferred it to an Australian administration. Papua and New Guinea were formally united under one administration following World War II by the Papua and New Guinea Provisional Administration Act of 1945.
Geography
New Guinea, lying to the north of Australia, is an island slightly smaller than Greenland and has an area of over 300,000 square miles. The most prominent physiographic feature is the central cordillera extending continuously from the Vogelkop in West Irian to the Owen Stanley range in Papua with peaks attaining heights of over 16,000 ft.
North of the central cordillera and running parallel with it, is the Northern Chain containing the Torricelli, Prince Alexander, Adelbert, Finisterre and Saruwaged ranges. Separating the central cordillera and the northern chain is a geological fault in which run three major valleys containing the Sepik, Ramu and Markham rivers. (Figure 2).
The Jimi valley in the western highlands is approximately 50 miles long and is part of the Sepik drainage system. The river has its source on the western slopes of Mt. Wilhelm (14,793 ft.), and flows in a north-westerly direction. After uniting with the Gai and Baiyer rivers it becomes the Yuat river which enters the Sepik basin. The Sepik river passes between the Torricelli and Adelbert ranges and enters the Pacific Ocean to the north. Manus Is. CC•:>"- •
New Bismarck Sea Ireland
PAPUA NEW GUINEA C2I and WEST IRIAN
Solomon Sea The Jimi valley (this thesis)
Gulf of Papua The Mulia valley (Choufoer et al. 1965, se) van Rhijn 1969).
The Huon peninsula (McCullagh 1963, Buttfield and Hetzel 1969). Torres Strait
Figure 2 - 23 -
In its lower reaches the valley floor is flat, lying at an altitude of 1200 ft. Here the country is sparsely populated, probably the result of malaria of high endemicity and migration of the people to more healthy areas. The upper and middle Jimi is a deeply incised valley and is more densely populated. The people live at altitudes varying from 2,500 to 6,000 ft., the highest settlements being on the western flank of Mt. Wilhelm.
To the north-east the Jimi is bordered by the Bismarck-Schrader mountain range which seperates it from the Simbai valley and the Ramu river system. To the south and south-west it is separated from the Wahgi valley by the Wahgi-Sepik divide. This range is part of the water shed for New Guinea, the Wahgi river eventually emptying into the Gulf of Papua to the south.
Climatically, seasonal variations in temperature are slight, the diurnal variation is from a minimum in the low 60's to a maximum in the high 70's (degrees fahrenheit). Rainfall is 110-140 inches per year, a wet and a dry season being recognised. However, even in the dry months May to October, the average monthly rainfall is over 5 inches while in the wet season the monthly rainfall may exceed 20 inches. Most of the rainfall occurs in the late afternoon or during the night.
The vegetation up to 3,000 ft. is classified as lowland rain forest and consists of five forest layers (three tree layers, a shrub and a ground layer). Over 3,000 ft. lower montane forest is found and is recognised by a reduction in structure to two tree layers and a change in the floristic composition. Interspersed throughout the valley are areas of grassland which are probably man-made and have little use in the native economy though they do have a potential for cattle and reafforestation (Robbins 1970).
Geologically the area is very active and is structurally controlled by large parallel faults. The valley is occupied by resistant flat-lying or gently dipping greywacke with sediments of the Mesozoic period and later intrusions of igneous bodies. -24-
History
One of the last areas in New Guinea to be contacted by the European was the Jimi Valley. It was first visited by the two gold prospectors Leahy and Taylor in 1933. This visit was very brief and touched only the lower Jimi during the course of a prospecting patrol to the Baiyer and Yuat rivers. The following year the two Schmidts, father and son, also traversed the lower Jimi and while building a bridge across the river, Schmidt junior was wounded by natives. (Souter 1963).
The upper Jimi was first explored by the Ashton brothers in 1934, however, the failure to find gold and the intervention of World War II ensured that the middle Jimi remained untouched by the European until 1953 except for an army patrol which is reputed to have crossed the area in 1944 en route from Mount Hagen to the north coast.
In July 1953 a patrol party led by patrol officer Walters left Minj in the Wahgi valley, crossed the Wahgi-Sepik divide and entered the Jimi valley with the express purpose of making contact with the people. The patrol reached Tabibuga the present administrative headquarters of the Jimi valley on July 26th 1953. Contact was first made with the people of Kwibun on the south side, subsequently the river was crossed and initial contact with the people of Kompiai, Kupeng, Kwima, Togban and Kwiop on the north side was made. It is recorded that this is the first time these people had seen the European, and in one area, Kupeng, the reception received by the patrol was hostile (Walters 1953).
In 1956 a patrol post was established at Tabibuga (middle Jimi) and is today the administrative headquarters for the valley. A second patrol post was opened at Kol (upper Jimi) in 1957 and the valley has gradually been brought under administrative control with regular patrolling by government officers. However a few outlying areas, particularly those further to the north in the Bismarck ranges were not contacted until as late as 1958. 725-
Until 1970 the only access to the valley was by light aircraft or on foot. The first airstrip to be constructed was at Tabibuga in 1959. Subsequently airstrips were completed at Kol and Ambullawah (upper Jimi), Koinambe (middle Jimi) and Ruti (lower Jimi). During the years of early development all supplies, building materials etc., were transported by aircraft from the adjacent Wahgi valley. Occasionally they were carried in on foot.
An internal vehicular road was built entirely by hand, the focal point being the Tabibuga patrol post. By 1966, there were 8 miles of road linking the villages of Kwibun, Tabibuga and Karap. This road was within the valley only and there was no road link with the outside world. Two vehicles, belonging to the Government and the Nazarene mission, were disassembled carried in on foot and reassembled for use on this isolated length of road. It was not until 1970 that the road was extended over the Wahgi-Sepik divide, a distance of 35 miles and linked with the main highway to the coast. This road link, traversing a pass of 7,000 ft. was constructed with human labour only; no road-building machinery being used - a major undertaking considering the rugged nature of the country. The driving force behind the road construction was the knowledge that significant economic development was unlikely unless vehicular access to the valley became available. At the time of writing the road is frequently closed to all traffic because of landslides or bridges having been washed away. There is as yet no vehicular access to the northern part of the valley, though progress towards this goal is rapidly being made. The road currently extends to the Jimi river itself and a bridge across the river is envisaged within the ensuing year.
The people
The total population of the valley numbers approximately 24,000, the majority being concentrated in the middle and upper valley. The villages, numbering about 40, each have between 250 and 1000 inhabitants and lie at altitudes varying from 1,500 to 6,000 ft. In this context, the term "village" needs qualification as a homestead type of existence is maintained with houses and gardens distributed throughout the valley. - 26 - There are no compact village settlements such as are found in most other areas of New Guinea. Rather there exist social groups each with its focal meeting point. Thus a village can be considered to consist of a social group with common interests and with whom administrative contact is made at a particular place. Any patrol passing through the area is accommodated in a native-material rest house erected specifically for that purpose and focally situated for ease of contact with each social group. Access between villages is by walking track only. The tracks are often very steep, a reflection of the rugged nature of the country. Rivers are either forded or crossed by bridges of bamboo and vines. The distance between villages varies from 1 to 4 hours walking.
The people are a short stocky dark-skinned race. The traditional dress of the adult male consists of a bark belt with string or bark hanging in front and a spray of leaves at the rear covering the buttocks. Young males are usually entirely naked until puberty when they adopt the adult dress. Females wear a string belt supporting string hangings at the front and rear and ornamental trappings such as bracelets on the arms and legs and bead necklaces. Traditional dress, particularly in the males, is now occasionally replaced by western style clothing, usually in various degrees of disrepair.
Housing
Houses vary in size from 7' x 20' to 10' x 35' with a height at the ridge pole of about 5'. They have dirt floors and are constructed of a light timber frame with walls of thatched pandanus leaves and roofs of thatched pandanus leaves or grass. This type of house is being superceded by a considerably taller structure with walls to a height of about 6' and a ridge pole height of 12'. The construction of the newer buildings is also of a light timber frame but the walls are of plaited bamboo and the roofs of thatched grass. Frequently the floor is also of plaited bamboo. Younger men, in particular those who have travelled outside the district, are adopting the new style of building.
In the centre of each house a fire burns almost continuously for cooking during the day and to keep the cold out at night. -27-
Segregation of the sexes is maintained with regard to housing, there being men's houses and women's houses. However young children of both sexes up to the age of about 8 years sleep with their mothers.
Agriculture
A slash and burn technique of shifting horticulture is practised. Gardens are made in areas of secondary forest with planting following immediately after the clearing and burning. Steel axes, bush knives and digging sticks are the only implements used A given area is planted once or perhaps twice with a cropping period of up to 2 years. The land is then allowed to lie fallow for approximately 12 years providing a cultivation cycle time of about 15 years and enabling secondary forest to re-establish.
A division of labour exists. Men are responsible for clearing and burning of the forest, fencing the garden (primarily to keep the pigs out), and the planting of certain crops e.g. banana, sugar cane and pit pit (Saccharum edule). The women plant the tubers and greens, do the weeding and carry out the harvesting of all crops.
Gardening pairs may overlap so that a woman may make a garden not only with her husband but with her own and her husband's unmarried brothers. Similarly a man may make a garden not only with his wife but with his and his wife's unmarried sisters (Rappaport 1967).
Animal Husbandry
Animal husbandry is limited to pigs, dogs, Chickens and cassowaries. Of these the pig is of greatest importance and occupies a special place in the social organisation of the community. The number of pigs owned represents the wealth and social standing of the owner in the community. Care of the animals is the responsibility of the women. Soon after weaning the piglet is constantly with its mistress, is given considerable attention and shares the same sleeping quarters. It is used as an item of exchange in ceremonies as diverse as the purchase of a bride or in the settlement of quarrels. -28-
The slaughter of pigs is reserved for ritual or ceremonial occasions so that the animal cannot be considered a regular source of protein food. A major feast is held when the size of the herd becomes sufficiently large to constitute a burden to the community. Such an occasion arises every 5 to 10 years and drastically reduces the size of the herd.
The animals serve a secondary purpose as "cultivating machines". They may be turned loose in gardens prior to the second planting, providing a form of tillage or they are allowed in abandoned gardens and utilise small tubers which otherwise would have been wasted. In abandoned gardens, the uprooting of herbaceous plants encourages secondary forest growth.
Diet
Tubers provide the staple foods and include sweet potatoes (Ipomea batatas), yams (Dioscorea esculenta), taro (Colocasia esculenta) and manioc (Manihot utilissima). These are supplemented by other vegetables e.g. peas, beans and cucumbers, fruits e.g. bananas and mangoes and nuts particularly the pandanus nut.
Animal protein is limited in supply though not in variety. The domesticated pig as stated previously does not provide a regular supply of protein. Other animal sources include feral pigs, birds, marsupials, rats, fish, lizards, snakes, frogs and spiders. Various taboos are associated with the consumption of animal food. They are most extensive for the adult male for whom the consumption of most animals except feral pigs and birds is proscribed. The least taboos apply to children and women who have borne children, they may consume any animal food. Adolescent girls and boys occupy an intermediate category in relation to the list of proscribed animal foods,
The most common mode of cooking is by roasting in the ashes of an open fire. Less commonly and usually reserved for festive occasions in the stone oven or "mu-mu". In this process, food wrapped in leaves, usually banana leaves, is surrounded by preheated stones in a pit dug in the ground. -29-
A covering of earth is placed over the top and allowed to remain for some 3 or 4 hours. More recently the introduction of saucepans has enabled food to be cooked by boiling.
Languages
Five languages are spoken in the Jimi valley. Of these only two are spoken in the area covered by this thesis, namely Gandja and Maring. Gandja has two dialects with only limited understanding between them. Maring has four dialects - Central, Eastern, Tsuwenki and Timbunke. The central dialect is understandable to all the other three but understanding within the other three is limited (Bunn and Scott 1963). Figure 3 is a map of the area showing the language boundaries.
• Melanesian Pidgin English is considered the lingua franca for the region, although, even as late as 1969, the numbers of Pidgin English speakers in the Jimi was very small and an interpreter had to be used. Increasing contact with the outside world, particularly through labourers returning after working on coastal plantations, is ensuring that the number of Pidgin speakers is on the increase. Now every village has its quota of Pidgin speakers and an interpreter is no longer necessary.
Health Services
The common diseases of the area include respiratory tract infections often exacerbated by the conditions of living in smoke-filled houses. Among adults cor pulmonale is probably the commonest cause of death. Malaria is seasonally epidemic, three species of human malaria being known to exist - Plasmodium falciparium, P. malariae and P. vivax. Among children gastroenteritis and malnutrition are common.
The basic unit for health services consists of an aid-post staffed by an orderly. One such unit is found for every 3 or 4 villages and serves about 2,000 people. Commonly the aid-post orderly is semi-literate in Pidgin English only and has been trained in the use of such drugs as penicillin, the sulphonamides and the antimalarials chloroquin and quinine.
Figure 3
LANGUAGES OF THE JIMI VALLEY ,,.rin.. ,vc%44' o -E, after BUNN and SCOTT (1963) ',, Ii• 4 , k,' k0 -,4,44444, , 6 V 7 1, ,,,,,,,....,5 'ye lr.
N
I, •• • : 1; • l ,..-. 9 -,.... • *g. K ARAM 9i, a • % i *. ir
• GIIMINJI 4,>/de,„,/ k//14 • •• /d,i7:4419*At hfr/ • • • • • *Ai /.7/ •,r1- y",//#/#1,, A • • • qpo,„,„ w • •YIMBOGEMA MEDLPA B°4'°P.suwEAl NKAI ymitnq 64 % f/i1/414 ( bet dpl , tw • 101APIA1 • "Wert ! Po o .KupENG • Awe* • • • • KWICP 701whfills • ammo • • • • /////m /V. 0 • • • • 4,, V • • . • • TAR IBUGA • KCRIOM • • • • r • • • • M°GINI • • YUWARAMUL `461)/kill//fri,,,,,e,"1:110`104 • • • Senik • •• lm. t.:4p. ..1, NARAK •.0.. /\•--- Mt. • .m it* I • - ' ,Prkvirk.,„/ Divide loluoliat , niV1)1 1'911' jfi ,11.r "milt • - 30 -
In addition he may suture and dress minor wounds. More sophisticated health centres have been developed at Tabibuga and Kol (Government), Koinambe (Anglican mission) and Tsingoropa (Nazarene mission). These are staffed by a more highly qualified Medical Assistant or Nursing sister. No medical officers are resident in the valley though visits to the health centres may occasionally be made by such personnel. Patients requiring more expert medical attention than is available at the health centre, particularly those requiring some form of surgery, are flown to the base hospital at Mount Hagen.
Educational Services
Education is provided at the primary level only, by both mission and government schools. Children requiring secondary education must leave the valley to attend schools elsewhere. Only during the past three or four years has the occasional child completed the course of primary education. Less than 30% of children eligible to do so attend primary schools.
Currently 6 students are completing Form 4 of secondary education and will then be eligible to seek tertiary education at, for example, the University of Papua New Guinea in Port Moresby or the Institute of Technology in Lae.
Missions
Various missions (Anglican, Roman Catholic, Lutheran and Nazarene) established themselves in the late 1950's and early 1960's and have actively contributed to the development of the area. By tacit agreement they have accepted certain territorial boundaries so that Anglican and Nazarene ddhom±naiionswork predominantly in the middle Jimi and the Roman Catholic and Lutheran missions in the upper valley. Besides routine evangelical work, they are concerned with the staffing and building of schools and the provision of health centres, aid-posts and infant and maternal welfare services. - 31 -
Economic development
The local economy was a subsistence one only until coffee was introduced as a cash crop in 1965, The success of this primary industry is evidenced by the number of native-owned trucks now seen regularly taking coffee from the Jimi to the commercial buyers in the Wahgi valley. In 1970-71 the coffee produced in the area was estimated to be about 70 tons.
Valuable timber stands have been found in the lower Jimi and are beginning to be exploited. Money raised from the sales of these stands was used to finance a cattle project on the grasslands of the lower Jimi which was commenced in 1970. The highlands labour scheme has been a further source of cash for the valley inhabitants. Young males are recruited to work on coastal plantations for a two-year period and return not only with cash but with some expertise and the trappings of western civilisation such as clothes and transistor radios.
Exploration of the area for mineral deposits has been carried out. Copper and gold have been found but have not proved to be a commercial proposition.
Politics
A local government council was formed in 1967, each village electing its own councillor. Initially the annual tax levied by the council was $A0.50 to $A1.00 per adult male and produced an income of $A2,000 for the fiscal year. By 1970-71 the tax had increased to $A2.00 to $A4.00 per adult male and produced an income of $A13,500 for the council. This was expended on projects such as road construction and maintenance, schools and aid-posts. These projects were eligible for a government subsidy so that the total council expenditure for 1970-71 was $A66,000.
The extent of change in the tax rate and the council income provides an indication of the progress made in the development of a cash economy. This is as yet in its infancy and is in contrast to the adjacent Wahgi valley - 32 - whose prosperity is more advanced and acts as a spur to the inhabitants of the Jimi valley.
In 1968 a member representing the Jimi was elected to the country's 100 member House of Assembly, a Parliament based on the Westminster system. CHAPTER FOUR
METHODOLOGY
A census of the Jimi valley was carried out by the Department of District Administration in 1966. The patrol visited 27 villages and recorded a population of 16,500. On this occasion, at each village, the name of every man woman and child was recorded on census sheets together with an estimate of each person's age. Age was estimated partly by updating the estimates made on previous censuses which had been conducted at approximately two yearly intervals since 1956. In this context it needs emphasis that the indigenous people have no means of recording time particularly as there are no marked seasonal variations during the year. Also the first European contact was in 1953. Prior to this date there are no well recognised temporal landmarks to which referral can be made in placing the date of birth as is possible in many coastal areas of New Guinea which have seen such major events as World War I and II. Because of this, the recorded ages are only estimates and allowance needs be made for the inaccuracies this implies.
Every person attending the census was examined for goitre and a grading made according to the technique of Perez, SoriMshew'and Munoz (1960) i.e.
Grade 0 The gland is not readily palpable. Grade 1 The gland is readily palpable with the head in the normal position but is not visible. It is readily visible with the head fully extended. Grade 2 The gland is readily visible with the head in the normal position. Grade 3 The gland is so greatly enlarged as to be readily visible as a prominent goitre at a considerable distance.
The goitre rate (GR) is the number of those with a Grade 1, 2 or 3 thyroid enlargement expressed as a percentage of the total number examined. The visible goitre rate (VGR) is similarly determined from those having Grade 2 or 3 thyroid enlargement. A controlled trial of iodised oil for the prevention of endemic cretinism was commenced by giving intramuscular -34- injections of either iodised oil containing approximately 400 mg, elemental iodine per ml. or normal saline to alternate families. Each member of the family received 4 ml. if aged 12 years or over and 2 ml, if under the age of 12 years. The nature of the injection given was recorded on the census sheet, note was also made of any woman who was obviously pregnant.
Subsequent follow up patrols have been carried out in July 1967, November, 1969, January, March and November 1970, January, May, August, November and December 1971 and February, May and June, 1972. Thirteen of the original twenty seven villages with a population of approximately 7,500 have been followed up. The villages concerned were Koriom, Kwiop, Togban, Tabibuga 1 and 2 and Kwibun in the Gandja linguistic group and Kwima, Kupeng, Kompiai, Tsuwenkai, Bokopai, Yimbogema and Koinambe in the Maring linguistic group. Figure 4 is a map of the area. A typical gathering of men, women and children during the survey is shown in Figure 5. At each visit, all mothers and children in the villages were assembled and checked against the census sheets. Infants born since 1966 were identified and their names and birth dates recorded. Birth dates were obtained from a variety of sources, primarily from the Anglican and Nazarene mission infant welfare records, but also from administration council records and from records kept by Indigenous aid-post orderlies stationed in some of the villages, The maternal and infant welfare clinics are conducted by the Anglican and Nazarene missions at approximately monthly intervals, so that the ages of the majority of the infants born since 1966 are accurate to within a month.
Every child was examined primarily for evidence of motor retardation, the milestones assessed were those of sitting, standing and walking. Motor retardation was taken to be present if these milestones were not attained by the ages of 12, 18 and 24 months respectively.
The parents of all children were questioned as to whether they considered that hearing and speech in each child was normal. If there was thought to be any abnormality of hearing or speech or if there was motor retardation, then a more formal attempt to assess deafness was made by Figure 4
Footpath Rest house • Airstrip in Gathering of people during a survey
Figure 5 -35- having the child's attention distracted, approaching from behind and noting if there was any response to a tuning fork, a snapping of fingers or a hand clap. Auriscopic examination of the ear drum was also carried out.
A squint if present was noted. A more careful assessment of the extraocular movements was made in those children who were retarded in their motor milestones or had abnormalities of speech and hearing.
On each occasion that a child was seen, the number of deciduous teeth that had erupted was recorded.
Studies on the endemic cretins born prior to 1966 were instituted by making enquiries at each village for abnormalities of hearing or speech in members of the population. Whenever a village was visited a request was made for anyone with such abnormalities to present themselves for clinical examination.
The presence of deafness and/or speech abnormalities was elicited mainly from the history which was taken in Pidgin English with an interpreter translating into the local dialect. In most cases a history of deafness was substantiated by observing the method of communication between the patient and other people e.g. whether mime or a raised voice was used.
Those in whom deafness was of late onset or in whom there was evidence of middle ear disease such as otitis media were excluded from the study.
Clinical examination was aimed primarily at detecting abnormalities of the central nervous system and evidence of hypothyroidism, particular attention was paid to the gait, sitting and standing postures, the external ocular movements, tendon reflexes, plantar responses, muscle tone and the presence of clonus, - 36 -
Standing height was determined using a Harpenden anthropometer, a metal box with a level top provided a platform on which the patient could stand.
Electrocardiographic records were obtained using a portable battery-operated Phillips Cardiopan 531A with a paper speed of 25 cms per second, Standard limb leads I, II, III, aVr, aVl, aVf and precordial leads V were recorded in each case, The mean QRS 1 to V6 deflection measured to the nearest millivolt was determined from three consecutive complexes in the limb leads I, II and III and precordial leads V and V 2 6° The mean T wave voltage was similarly determined for leads I and II,
The majority of the cretins were under 10 years of age at the time of the census in 1966, The significance of this observation is discussed in chapter 8. Owing to biennial census records having been kept since 1956, inaccuracies in the estimated age of each cretin are unlikely to be greater than two years, In February 1972, an independent assessment of age was made from the dentition,
As part of the trial of iodised oil, approximately half of the cretins received supplementary iodine in 1966, the remainder received saline or had no treatment.
Blood samples from cretins and women during pregnancy were taken during the 15 month period between November 1970 and February, 1972. Difficulty was experienced in the sampling of women in the first trimester of pregnancy as admission of pregnancy is not made until foetal movements are felt, In order to overcome this difficulty a series of women in the childbearing age who did not admit to being pregnant was also sampled. Subsequently a few of these women did prove to be in early gestation at the time of sampling. The selection of women sampled was narrowed by:
a) excluding unmarried women, it being rare for an unmarried woman to become pregnant; -37-
b) excluding women who had borne an infant within the previous two years. It is unusual for the birth interval between children to be less than two years.
The age of gestation at the time of sampling was determined from the date of birth of the child and assuming a 40 week gestatory period. This determination is liable to error as a result of pre- or post-mature birth but was found to be unavoidable.
Approximately equal numbers of these women had received either intramuscular iodised oil or saline in 1966. All blood samples were taken at least four years after the women were injected.
Women who were sampled and subsequently proved not to be pregnant were used for comparison with the pregnant group and also provided a range of normal values for comparison with the endemic cretins. The blood samples were withdrawn into plain 15 ml. Vacutainer tubes, allowed to clot and stand overnight and the supernatant sera transferred to sterile plastic tubes using a Pasteur pipette. The sera were then sent by runner to the Nazarene mission at Kwibun, a journey that took from 4 to 8 hours, and there stored in a deep-freeze kerosene refrigerator until completion of the patrol. Thus, samples withdrawn on one day were frozen by the latest on the evening of the following day.
Subsequently, the frozen sera were taken to the laboratory at Goroka where they were thawed and subdivided. The aliquots were then refrozen and sent by air to various laboratories.
Two sets of serum thyroxine (T4) analyses were made:
a) at the Institute of Nuclear Medicine, the Middlesex Hospital, London using a competitive protein-binding technique (Ekins et al., 1969). These results are quoted in ng/ml, the normal range for euthyroid adults being 45-115 ng/ml and for pregnant women 60-140 ng/ml; - 38 -
b) at Laboratory Services Pty. Ltd., Melbourne also using a competitive protein-binding technique (Murphy and Jachan 1965). These results are quoted in vg/100m1, the normal range for euthyroid adults being 2.5-7.0 vg/100m1 and for pregnant women 400-9.0 vg/100m1.
Duplicate analyses performed at the two laboratories on 31 samples showed a high degree of correlation, (correlation coefficient r=0.92).
Analyses for serum thyrotropin (TSH) were performed at the Middlesex Hospital, London by radioimmunoassay (Utiger 1965). The normal range is given as 0-3,0i U/ml. Serum triiodothyronine (f3) determinations were made at Prince Henry's Hospital, Melbourne using a competitive protein- binding technique (Patel et al., in publication). The normal range in males being 90-177ng/100m1 and in females 75-165ng/100m1.
Serum thyroxine binding globulin (TBG) and thyroxine binding pre-albumin (TBPA) determinations were made under the direction of Dr. M.L. Wellby at the Queen Elizabeth Hospital, Adelaide using the technique of Elzinga et al., (1961), with the modification by Roberts and Nikolai (1969). CHAPTER 5
ENDEMIC CRETINISM IN THE JIMI VALLEY
INTRODUCTION
Endemic cretinism has been described by both the Dutch and Australian workers in both West Irian and Papua New Guinea (Figure 2). In the Mulia Valley of West Irian Choufoer et al. (1965) describe mental deficiency, deaf-mutism and motor abnormalities as the most frequent defects. The motor abnormalities in young children are an inability to sit or stand, a sagging of the head and a characteristic extension and internal rotation of the legs suggestive of a diplegia. The adults have a characteristic gait and stance with flexed knees and flexion, adduction and internal rotation of the hips. Radiographic assessment of bone maturation and measurements of height were not significantly different between defectives and non-defectives and the authors conclude that hypothyroidism is not a feature of the syndrome as seen in the Mulia valley.
Subsequently, investigating the same population, van Rhijn (1969) found that 40% of the feebleminded individuals or "wimendeks" as they were known locally,were deaf and mute. Many others who were deaf though not mute nevertheless had some speech defect. Motor abnormalities were present in 40% and affected the lower limbs more than the upper, with hyperreflexia and occasionally extensor plantar responses. Thirty per cent had a convergent strabismus.
In New Guinea, McCullagh (1963) describes the syndrome in the Huon Peninsular as presenting with amentia (or hypomentia), partial or complete deaf-mutism and motor incoordination. He states that he did not see one case of classical cretinism by which he meant no case of hypothyroid cretinism. Buttfield and Hetzel (1969) also found deaf-mutism, neuro- muscular abnormalities and mental deficiency to be the commonest clinical features and no case of clinically obvious hypothyroidism was seen.
Being forewarned by the regional variations in the syndrome of endemic cretinism as noted in Chapter 2 and the existing controversy concerning hypothyroidism as a feature of the disease, a survey was made of the endemic cretins in the Jimi valley of New Guinea. -40-
METHODS
The elicitation of a history, the clinical examination and the laboratory procedures used are described in detail in the section on methodology (Chapter 4), - 41 -
RESULTS
A total of 124 patients with abnormalities of hearing and speech were examined on at least one occasion. This total is comprised of 74 males and 50 females i.e. a male/female ratio of 1.5. There were 100 patients under 10 years of age (60 male, 40 female), 22 were aged 11-20 years (14 male, 8 female) and 2 (both female) were over 20 years of age.
Neurological abnormalities a) Mental retardation
Owing to cultural and linguistic difficulties, no formal evaluation of mental ability was attempted. Nevertheless, the impression was obtained that a wide range of mental retardation was a feature of the syndrome and a few of those who had hearing/speech abnormalities may have had a normal intelligence. b) Hearing/Speech abnormalities
Speech was invariably affected in all those who had a severe, partial or complete deafness. There were 99 cases in this group, an incidence of 79.9%.
A second group constituted those who had partial hearing evidenced by the fact that a raised voice was able to be heard and in whom speech was not normal, being limited to a few words such as the names of siblings or common household items. There were 17 cases in this category, an incidence of 13.7%.
A third group was composed of those in whom speech was severely affected, amounting at times to mutism, but in whom hearing appeared to be normal. If a degree of deafness did exist it was disproportionate to the severity of the speech abnormality. There were 5 such cases (4.0%). - 42 - c) Neuromuscular abnormalities
In young infants there was a hypotonia and a delay in attaining motor milestones. Head control was poor and often drew attention to the infant who was being carried, because the head hung limply to one side. The lack of head control was also evident when the child was pulled to sitting from lying supine. In the normal child there is no head-lag after about 24 weeks (Illingworth 1970) but in the endemic cretin head-lag often persisted until over 12 months of age. Figure 6 shows a severely affected child over 21 years old with a very marked head-lag. The ability to sit upright in normal infants was attained by the age of 8 or 9 months and when sitting upright the spine was straight (Figure 7). In the cretin however, this motor milestone may be delayed for years and the child tended to sit forward supporting itself by its hands. Even when able to sit unsupported, there was usually a kyphosis of the thoraco-lumbar spine (Figure 8).
Crawling was also abnormal in the cretin. Characteristically the infant was unable to properly raise its pelvis from the floor and the hips were in abduction so that a frog-like posture was maintained. Furthermore, the crawling movements were ineffective.
When standing the posture adopted was with the legs apart and the knees and hips partially flexed (Figure 9). There was usually some internal rotation at the hips also. The gait was wide-based, stiff-legged and sometimes with a stamping quality to it. A kyphosis was sometimes present giving a stooping appearance which was accentuated by the flexion of the hips and knees.
The upper limbs were not as frequently affected as the lower, but when affected, the abnormality was manifest by a clumsiness of movement. An example of this was the inability to pick up a small object with the thumb and forefinger, rather the whole hand being used with a main-en-griffe posture.
Tone was variably increased in different muscle groups. The muscles predominantly affected were the quadriceps, hamstrings and adductors of the thighs, this was accompanied by pathologically brisk tendon reflexes. Severe head-lag in a cretinous infant Figure 6
Normal child sitting erect Cretin showing kyphotic spine
Figure 7 Figure 8 Standing posture in a cretin
Figure 9
Cretinous infant with a strabismus
Figure 10 - 43 -
A prolonged ankle clonus was rarely obtained but an unsustained clonus was common. In 40% of cases the plantar response was extensor.
In summary, the neuromuscular disturbance was that of a congenital diplegia and was present in 99 out of 124 patients (79.9%).
Strabismus occurred with sufficient frequency for it to be considered part of the syndrome. It was usually found in the more severely affected cases (Figure 10). In the majority of instances it was an internal strabismus: often it was transiently present and may alternate between one eye and the other. In one severely affected child a coarse nystagmus was also present. Of 124 cases, 28 had a strabismus (22.6%).
Table 2 provides a summary of the incidence of the neurological abnormalities.
Growth and dentition
The mean height for 127 normal adult males was 154.6 cm. S.D. ± 4.7 am. and for 227 normal adult females 145.3 am. S.D.± 5.1 cm. Although height measurements were made on all age groups, adequate numbers were not obtained to permit the construction of a growth curve during Childhood. As an alternative, the growth curve obtained by Malcolm (1970) for Bundi children (an adjacent valley to the Jimi), was used. He obtained mean adult heights of 156.3 ± 5.3 cm. and 147.7 ± 4.9 cm. for males and females respectively. These values are not significantly different from the values obtained in the Jimi valley. As the social and ethnic backgrounds for the Bundi and Jimi people are similar and the adult heights are not significantly different, it is assumed that the growth pattern is also comparable.
Figures 11 and 12 for males and females respectively, shows the mean heights,,the mean ± 1S.D. and the mean - 2S.D. plotted against age. Superimposed on the growth curves are the observations of height made on 49 male and 29 female cretins. NEUROLOGICAL ABNORMALITIES IN CRETINS
ABNORMALITIES OF SPEECH NEURO- TOTAL AND HEARING
Partial Speech Predominant MUSCULAR STRABISMUS Deaf - and Abnormality 124 mutism Hearing Loss of Speech DISORDERS
Number 9 9 17 5 9 9 3 2
Percentage 719 13.7 4.0 79.9 25.5
TABLE 2
MALES
...... -. .•• 0,• .. • ..... • • • ' / 160 • ° Saline injected m •.° I/ • Oil injected • / 0° I. •• / •0 s a • • • • • • • 1 • I . • • / 0 • • I • • ...... 1I . • .. 1 • • 0.• i • i • I • • III 1 • •• I I • 140 I . • I • • I 0 • I1 I I • / I Oe • I • • I •• e I• • 1 II • • 1 • I . • I I S • 1 s • I • 1 I *e II / • A • ••• I • I I i S •• 1 120 I : I1 SSS i S . 1 , . • ••.• I • • I II E .•I 0 • s I 5 el6 • I os o • f I s .■44, • I • w• t . • m e/ • - A I its • • • •• II • 1I • ••• • II I c9 I s ▪ 100 • IIS 1I •■ II • • II • 1I. il• I • U I 1 •• • — , •
I/ obs. • IV 1Ii 11% — I • • I I.I. • I I • of I • I • ir •• # • • • / • • I • • • I Mean 80 • I • 1 • 1 Mean ±1 SD ••••• • I • I • I Mean ±2 SD • If I I I I
12 16 20 24 AGE (years) Figure 11
FEMALES
Saline injected • Oil injected • ...... ‘"...... 0. • • • • ' 10 0 • ,.0 • . • • • , • • . 040 • • ..... , • • • , • , .. ■ ...... ••• '' 0 * • • ..... ' / • e•••• / • • • I • •• I I • • olo ** 140 / • • 0... I • • , / • • e „• • i • • e 1 • i I • • • • / I • • 1 I • 1 i . •• , ■1 ,• • 1 I • I / • • I , •• iI • •• I 120 i • t •• •, I ,t v•is ••,,• t • . , ••• • . .. aa 0 I • • ,/ • .1I 1 • E , / • 41 i O I • • / %no / • • / f ./ /i .: IV II • 1' 100 I • 1 • ii IN /I. • . A: I I I • a MIS A • 1 ( .7 II • I , df Xi , ,. : I 1 • , i Pi1 , . ... is, , • • I , • • I , • • I • • I • • , • • , ...... 11. ••• , Mean • I • I Mean ± 1 SD • • • • • • I • 1 • • Mean ± 2SD • I • I • I I I I I
12 16 20 AGE (years) Figure 12 -44-
Dental age was estimated in 39 cretins using the tables obtained by Barker (1965) for Papuan and New Guinean children. In only one case the dental age exceeded the estimated age recorded in the 1966 census. In 22 cases the discrepancy between the dental age and census age was less than one year. Of the remaining 16 cretins the dental age was one year less than the census age in 9, two years less in 5 and three years less in 2.
Endocrinology a) Clinical
In no case were the clinical features of hypothyroidism evident such as a large protruding tongue, dry puffy skin, umbilical hernia, low-set hairline or delayed relaxation of the ankle jerk. b) Electrocardiograph
The QRS voltage in leads I, II and III and precordial leads V2 and V6 are given in Table 3. In one case only the QRS complex in each of the three limb leads was 0.5 millivolts or less. In no instance was there flattening of the T waves in leads I and II. c) Serum T4 and T3
In 10 of 11 cretins who had received iodised oil four years previously, the serum T 4 levels were within the normal range of 2.5 - 7.0 ug/100 ml. The eleventh had a serum T of 7.1 ug/100 ml. The mean T 4 4 was 4.77 - 1.30 ug/100 ml and the range 2.9 - 7.1 pg/100 ml. In 19 normal adult females who had also received iodised oil, the mean serum T4 was 4.98 ± 1.57 ug/100 ml. with a range of 2.9 - 8.0 ug/100 ml. The values for the cretins and the normal adult females are not significantly different.
Of 18 endemic cretins who had not received supplementary iodine, 9 (50%) had a serum T 4 below 2.5 ug/100 ml. and the remaining 9 were within the normal range. The mean serum T4 was 3.05 ± 2.25 with a range of 0.3 - 6.9 ug/100 ml. In 35 untreated normal adult females the mean serum T4 was 2.55 t 1.39 with a range of 0.2 - 5.9 ug/100 ml. These values are TABLE 3
ELECTROCARDIOGRAPHIC VOLTAGES IN CRETINS
Standard limb leads Precordial QRS leads ( 33 patients) (29 patients) . Complex. I I II II I V2 V6 . , , , Mean 0.76 1.03 0.90 2.65 1.13 millivolts Range millivolts 0.3- 1.6 0.4-2.5 0.3-31 1.1 - 4.0 0.4- 2.7
TABLE 4
SERUM THYROXINE LEVELS IN CRETINS AND NORMAL FEMALE ADULTS
TREATED (IODISED OIL) •UNTREATED (SALINE)
NORMAL FEMALE NORMAL FEMALE CRETINS CRETINS ADULTSDULTS
Number of 11 19 18 35 cases
Mean serum T4 + SD 4.77+1.30 4.98 +1.57 3.85 ±2.25 2.55+1.39 P9/100m1
Range of serum T4 2.9-7.1 2.9-8.0 0.3-6-9 0.2-5.9 Ng/100m1 ,
Difference not significant Difference not significant -45-
not significantly different from the untreated cretins.
Table 4 is a comparison of serum T4 levels in treated and untreated cretins and normal female adults, the results being graphically illustrated in Figure 13.
The serum T 's in 4 of 5 cretins who had received iosided oil were 3 within the normal range. The fifth case, a female adult, had a below normal T3 (51 ng/100 ml.) but her serum T4 was normal (4.8 14/100 ml.).
In 10 of 12 cretins who had not received supplementary iodine, the serum T3 was within the normal range. The two cretins who had low T3's (47 and 63 ng/100 ml.) also had low T4's (0.5 and 0.8 pg/100 ml.). These results are shown in Figure 14, Figure 13
SERUM THYROXINE LEVELS IN CRETINS AND NORMAL FEMALE ADULTS
(Method of Murphy and Jachan 1965)
Horizontal lines indicate upper and lower limits of the normal range
TREATED UNTREATED (IODISED OIL) (SALINE ) Normal Normal
female Cretins female Cretins adults adults 8— 0
O
7 • 00 • a
O • • 6
O ❑ O •
0 ❑ ■
5 • 0 O • 8o ❑ 0 • a ■ 2 4 0 0 0 • 00 00 ■ LIJ • 0 • 0 a 3 O •
❑a ❑ • 2 000 •
000 0 • ❑ ❑ 1 • ❑ • 0 • • 00 • 0 • Figure 14
SERUM TRIIODOTHYRONINE LEVELS IN CRETINS Horizontal lines indicate upper and lower limits of the normal range
200 IODISED OIL SALINE
180
160 ■
140 • •
120 •
g 0 100 • 0 ■ cis ■ tY) 80
2 cc UJ 60 U) •
40
20 -46-
Discussion
Mental retardation
In the Pan-American Health Organisation definition of endemic cretinism (1963), mental deficiency is a sine qua non of the syndrome. This however, is open to discussion. No formal assessment of mental ability was attempted with the Jimi cretins, nevertheless the impression was obtained that some, albeit a minority, did perhaps have a normal intelligence. In many studies of endemic cretinism, mental deficiency has been the major feature essential to the diagnosis. This was so in the report by Fierro-Benitez et al. (1969), they describe a group of patients with abnormalities of hearing and speech or motor abnormalities yet do not classify them as cretins presumably because mental retardation was not an obvious clinical feature. Furthermore they state that some deaf-mutes had a normal intelligence. Similarly in the Piedmont and Mendoza studies (Costa et al. 1964, Stanbury et al. 1954), the inmates of certain mental institutions were studied excluding deaf- mutes, who were among the normal population.
The case that some endemic cretins may be of normal intelligence is also made by Choufoer et al. (1965). They found in two deaf-mutes that there was sufficient proof of a good intelligence, though the evidence for this was not given.
In the cretins of Somerset described by Norris (1847), two deaf-mutes are said to have been educated and possessed of remarkably quick parts.
In all these investigations formal testing of mental ability has not been carried out. This has often been due to wide cultural and linguistic differences between investigator and patient, added to which is the inherent difficulty of assessing mental ability in a deaf-mute.
The case for mental retardation being essential to the diagnosis of endemic cretinism must be regarded as unproven. Although the majority of endemic cretins are mentally retarded, proof is lacking that they are all - 47 - retarded, equally it is not proven that some are of normal intelligence. Thus, there appears to be a spectrum of mental ability ranging from gross imbecility to a normal or near normal intelligence. This may be of relevance in the role attributed to hypothyroidism during foetal development and in early childhood. In none of the reported studies on endemic cretinism has replacement therapy been given during the critical infant years, therefore if mental retardation is minimal in some cases, then hypothyroidism of any degree during the critical years of mental development can be excluded.
Deaf-mutism
The occurrence of deaf-mutism or hearing speech abnormalities as a feature of the syndrome of endemic cretinism is noted in the earliest literature (see Chapter 1) and is accepted by most authorities. However, in a goitre area, those who have as their sole defect an abnormality of hearing or speech are often not considered to be endemic cretins. Costa et al. (1964) did not study endemic deaf-mutes because "in the large majority of cases the endemic deaf-mute is not a cretin". Fierro-Benitez et al. (1969) classified endemic cretins as Type I or Type II but those with deaf-mutism, deafness, mutism and neuromuscular abnormalities alone were not classified as cretins.
In the foregoing description of cretinism in the Jimi valley, a spectrum of hearing/speech abnormalities ranging from total deaf-mutism to relatively minor defects of hearing and speech was observed.
The mutism that occurs is usually presumed to be secondary to the congenital deafness but in a minority the mutism appears to be out of proportion to the deafness. It can be inferred from the Andean report that a similar situation exists there (Fierro-Benitez et al. 1969). This being so, the cause of the mutism needs clarification. A hearing deficit not obviously apparent but which may become evident with more sophisticated testing is a possible explanation. Alternatively, mental deficiency is a common cause of speech retardation. Illingworth (1970) states that the commonest cause of delay in the development of speech is mental retardation -48-
and that speech is relatively more retarded in mentally backward children than are other fields of development. A combination of mental retardation and a partial hearing loss could also explain a mutism out of proportion to the hearing defect.
Growth
The height of endemic cretins has been another contentious point i.e. whether dwarfism is a feature of the syndrome. In an endemic area where overt hypothyroidism is evident, dwarfism is unequivocal and correlates with the degree of thyroid failure (Dumont et al. 1963). However, in those areas where the neurological form of the syndrome predominates, dwarfism is uncommon. Costa et al. (1964) in the Piedmont of Italy state that the stature of the cretins was on average smaller than normal ranging from 150 to 160 cm. but true dwarfism was uncommon and a normal or greater than normal stature was not exceptional. Choufoer et al. (1965) in West New Guinea found that the mean adult height of defectives was slightly below the mean of the normal population but the majority fell within the normal range. In the Andean study (Fierro-Benitez et al. 1969) two types of cretin were described, type I, the incidence of which was 10 times greater than type II, were of normal stature.
The height of the Jimi valley cretins need to be interpreted with caution because the age of each individual was not accurately known in the majority of cases. There appears to be some growth retardation, with 78% of cretins falling below the curve for the mean height of the normal population. Severe growth retardation i.e. a height less than the mean -2S.D. occurred in 12 of 48 male and 3 of 30 female cretins, an overall incidence of less than 20%. 50% of all cases fell within the normal range of the mean ± 1S.D. The incidence of growth retardation would be less if based on dental age rather than census recorded age.
If many of the cretins are of normal or near normal stature, then hypothyroidism of any severity during the growth period can be excluded. The minor growth retardation that occurs in some cretins could be related to other factors notably malnutrition. The mental deficiency and the -49 - reduced mobility secondary to the diplegia must constitute a. severe handicap in the growing Child's ability to fend for itself. Certainly overt clinical malnutrition is very common among the New Guinea cretins.
Serum T4 and T3
Althoughtheserum.T4 low in 50% of untreateduntated cretins, exactly the same pattern was observed in the normal female population and similar results have been reported from other iodine deficient areas (Srinivasan et al. 1964., Choufoer et al. 1963). Among those to whom supplementary iodine had been given, both cretins and normal female adults, the serum T4 values were normal. These results suggest that the cretins are no different from the normal population in respect to the serum T4. Furthermore any thyroid hormone deficiency that exists can be corrected by the administration of iodine indicating that the thyroid gland is capable of normal synthesis and has suffered no permanent sequelae as a result of the iodine deficiency.
Electrocardiograph .... y
The electrocardiograph was recorded in cretins solely as an indicator for hypothyroidism. Friedberg (1966) states that the main changes in the electrocardiogram characteristic of hypothyroidism are a flattening or inversion of the T wave particularly in standard leads I and II and a reduction in the voltage of the QRS complex. Douglas and Samuel (1960) assumed a low voltage to mean a QRS complex no more than 0.5 my in any of the standard leads and the sum of RS not higher than 0.9 um in precordial lead V and 0.7 my in V . Using these criteria, in no case was the T wave 2 6 less than 0,1 my in leads I or II, neither was the sum of RS lower than 0.9 my in V2 and 0.7 my in V6. The QRS complex was less than 0.5 my in all three standard leads in only one case.
Schlesinger and Landtman (1940) in 10 sporadic cretins prior to treatment, recorded mean QRS complexes of 0.47, 0.70 and 0.59 my in standard leads I, II and III respectively. These are considerably lower than the values of 0.76, 1.03 and 0.90 my obtained for the Jimi endemic cretins, the -50- latter are similar to the normal childhood values of 0,70, 1,10 and 0.94 quoted by Lepeschkin (1951).
Thus, excepting one possible case, there is no electrocardiographic evidence of hypothyroidism in the Jimi cretins at the time the recording was made. - 51 -
Summary
Endemic cretinism in the Jimi valley resembles the syndrome described from other areas of New Guinea (McCullagh 1963, Choufoer et al. 1965 and Buttfield and Hetzel 1969). It closely resembles the nervous cretinism described by McCarrison (1908) in the Himalayas and endemic cretinism in the Andes (Dodge et al, 1969, Fierro-Benitez et al. 1969).
The syndrome presents a wide spectrum ranging from the severely mentally deficient, total deaf-mute with a diplegia involving all four limbs and a gross strabismus to a person with only minor abnormalities of hearing and speech perhaps without even any deficiency of the intellect. Clinical hypothyroidism is not a feature of the syndrome. A low serum T4 occurs in some cases but is also present with equal frequency in the normal population. CHAPTER 6
THE RELATION BETWEEN CRETINISM AND ENDEMIC GOITRE
INTRODUCTION
Endemic cretinism is found in geographical association with endemic goitre; however a precise correlation between the two conditions has not been well documented. On occasions when epidemiological surveys of endemic cretinism and goitre have been made, there appears to be a direct relationship between the two conditions. Eugster (1938) in Switzerland found 0.6% cretins in places where the goitre incidence was 45-55%, but when the goitre rate was over 55%, then the prevalence of cretinism also increased to 1.0% or more. Similarly Buttfield and Hetzel (1969) found villages with visible goitre rates of 0-10, 11-30 and 30+% to have a cretin-prevalence of 0.9, 2.7 and 4.4% respectively. Trotter (1960) utilising the data of Greenwald (1957) from Peru and Argentina, showed a remarkable correlation between the prevalence of deaf-mutism and obviously visible goitres in various departments of those two countries.
A comparison of the correlation between goitre and cretinism in different countries is not generally valid because of a number of factors. a) there is no precise definition of endemic cretinism partly because of regional variations in the syndrome and the confusion in terminology; b) the criteria for assessing the prevalence of goitre have varied in different surveys e.g. goitre rates have been variously quoted in terms of palpably enlarged, visibly enlarged or visibly obvious goitres; c) some goitre surveys have been confined to a particular sector of the community e.g. military recruits or school children; d) only rarely are the coincident prevalence rates of goitre and cretinism quoted for the same communities. -53-
Although endemic cretinism has ohly been described where endemic goitre is prevalent, the latter has been found in areas without concomitant cretinism. The survey by Gordon (1922) of cretinism in the U.S.A. showed no increase where goitre is endemic. He also noted that not a single case of endemic cretinism as exists in Europe was to be found in North America. This was confirmed by Greenwald (1959) who found no significant differences in deaf-mutism in the inland states and provinces of the U.S.A. and Canada compared with those states and provinces immediately contiguous to the ocean.
In El Salvador, the goitre rate among 35,000 school children throughout the community varied fram 8.5 to 38.7% but deaf-mutism and cretinism were not observed (Kelly and Sneddon 1960). This is perhaps not surprising in view of the fact that any cretins are unlikely to have been attending school.
Anomalies in the epidemiological correlation between endemic goitre and cretinism in various countries may be a reflection of: a) inaccuracies in the recorded data due to surveys being conducted on selected groups in the community e.g. the discrepancy between goitre and cretinism in El Salvador; b) an insufficient degree of intensity of the goitre endemic; the assumption being that cretinism appears only when the goitre endemic becomes sufficiently severe; c) an insufficient duration of the goitre endemic; again an assumption being made that goitre must be present in the community for a generation or longer before cretinism appears; d) a subsidiary aetiological factor existstingin arlar6a af'endemiagoitre and cretinism which may influence the prevalence of one condition and not the other; e) a failure to diagnose endemic cretinism. -54-
In order to determine the correlation between endemic goitre and cretinism in the Jimi valley, an epidemiological study of the two conditions was commenced in 1966. -55-
METHODS
The assessment of goitre size in each individual was made by Dr. Ian Buttfield according to the technique of Perez, Scrimshaw and Munoz, (1960). Using the census records, the goitre and visible goitre rates in each village and in various sections of the population were determined as described in Chapter 4.
The assessment of the prevalence of hearing and/or speech abnormalities in the population was also described in Chapter 4. For epidemiological purposes, these prevalence rates were taken to indicate the prevalence of endemic cretinism. -56-
RESULTS
Goitre rates
Among a total population of 7,528 in 13 villages, there were 4,008 males and 3,520 females; 3,385 (84.5%) of the males and 3,326 (94.5%) of the females were seen in 1966 and a grading of their goitre size made.
The goitre and visible goitre rates for males and females in the age groups 0-9, 10-19, 20-39 and 40+ years in each village are given in Tables 5 and 6. These age groups represent very approximately the childhood, pubertal, and in females the child-bearing and post-child-bearing ages respectively. There is considerable variation in the goitre rate from village to village; for males the range is 1.4 - 18.9% and for females 15.9 - 50.0%. The highest rates are found among females of the 10-19 and 20-39 age groups. This is probably to be expected as it is among these groups that the greatest physiological demands are made of the thyroid i.e. during puberty and the child-bearing years. In males the highest goitre rate is in the 10-19 age group.
Goitre is considerably more frequent in females than in males at all ages except for the 0-9 age groups when there is no significant difference between the sexes.
Prevalence of cretinism
Although for epidemiological purposes the prevalence of hearing/speech abnormalities was taken to indicate the prevalence of endemic cretinism, among those clinically examined, the majority also had gross evidence of mental retardation and over 80% had signs compatible with a cerebral diplegia. (viz Chapter 5). From these figures the prevalence of cretinism per 1000 population was calculated for each village. This is shown in Table 7. As with the goitre rate, there is considerable variation from one village to the next ranging from 3.8 per 1000 to 33.3 per 1000. TABLE 5
% GOITRE RATE . , 0-9 10-19 20-39 40+ VILLAGE MEAN years years years years MFMF M F MFMF
Koriom 4.2 15.9 0.0 4.4 8.9 21.2 2.2 22.9 5 . 4 16.7
Kwiop 12.3 34.0 0.0 5.0 31.8 34.2 5.8 53.1 7.4 25.6
Togban 9.1 25.6 7.5 8.2 12.7 29.9 10.0 41.2 11.9 13.2
Kwima 11.5 33.9 7.0 11.0 21.7 44.5 2.9 40.3 2.6 32.1
Kupeng 12.1 29.3 2 . 4 16.0 19.3 45.5 15.5 35.2 3.8 11.5
Kompiai 6.5 23.6 4 . 6 5.5 12.6 35.3 1.7 33.1 4.3 8.3
Suwenkai 0.9 19.1 0.0 7.1 3.3 38.5 0.0 30.3 0.0 0.0
Bokopai 4.5 16.7 0.0 6 . 2 10.1 33.8 3.3 14.4 3.7 7.3
Yinbogema 5.5 23.2 12.5 0.0 6.9 44.4 1.9 25.0 4.8 12.5
Koinambe 1.4 18.7 0.0 4.2 5.4 36.4 0.0 20.5 0.0 4.2
Tabibuga 1 6.0 25.1 4 . 3 7.2 3.0 31.4 3.8 39.6 3.7 17.8
Tabibuga 2 10.8 37.6 7 . 5 6.1 22.0 55.8 7.6 44.2 7.5 38.2
Kwibun 18.9 50.0 22.1 16.1 32.0 58.9 14.8 67.9 4.8 46.0
All 8.8 29.2 6.5 8.6 17.3 40.0 5.7 42.3 3.9 21.0 Villages TABLE 6 . VISIBLE GOITRE RATE % 0 - 9 10 - 19 20 - 39 40+ VILLAGE MEAN years years years years M F M F M F M F M F
Koriom 2.4 5.1 0.0 0.0 4.4 15.2 0.0 6.3 5.4 0.0
Kwiop 7.1 26.7 0.0 5.0 15.9 29.0 3.8 40.8 7.4 18.6
Togban 2.8 15.6 0.0 3.5 2.7 17.5 4.5 26.1 1.9 9.4
Kwima 3.7 20.1 0.0 2.4 10.1 20.4 2.1 31.7 0.0 18.0
Kupeng 6.9 20.7 0.0 2.0 9.6 34.9 11.3 30.7 1.9 3.8
Kompiai 6.5 17.4 0.0 2.7 5.2 24.5 0.9 27.8 1.4 3.3
Suwenkai 0.9 14.8 0.0 3.6 3.3 25.0 0.0 21.2 0.0 0.0
Bokopai 2.4 6.7 0.0 0.0 5.1 10.8 2.2 10.0 1.9 2.4
Yimbogema 0.8 8.1 0.0 0.0 0.0 3.7 1.9 13.9 0.0 125
Koinambe 0.7 6.5 0.0 0.0 2.7 15.2 0.0 6.8 0.0 0.0
Tabibuga 1 2.3 12.6 0.0 0.0 5.8 17.6 1.3 21.6 2.5 8.2
Tabibuga 2 6.3 23.6 0.0 0.0 14.0 34.6 6.1 29.1 7.5 25.5
Kwibun 9.9 39.0 11.6 9.7 13.3 49.5 10.2 52.5 3.2 34.9 All 3.9 18.5 1.4 2.6 7.1 Villages 24.9 3.6 29.9 2.4 124 TABLE 7
PREVALENCE OF CRETINISM
TOTAL NUMBER PREVALENCE VILLAGE of per POPULATION CRETINS 1,0 0 0
KORIOM 3 6 6 6 1 6.4
KWIOP 3 4 1 7 20.5
TOGBAN 7 5 2 2 3 3 0.6
KWIMA 8 8 3 2 9 3 2.8
KUPENG 5 5 7 15 2 9.6
KOMPIAI 8 0 9 12 14.8
SUWENKAI 2 6 1 1 3.8
BOKOPAI 5 9 3 4 6.7
YIMBOGEMA 2 3 9 7 2 9.3
KOINAMBE 3 0 8 1 0 3 3.3
TABIBUGA 1 8 8 7 6 6.8
TABIBUGA 2 5 8 7 11 18.7
KWIBUN 94 5 20 21 .2
ALL VILLAGES 7,5 2 8 1 5 1 20.1 -57-
Goitre prevalence in women who have borne cretin children
Goitre grading was made in 128 women who had borne 131 cretin children; 11 had a Grade 1 goitre and 34 a Grade 2 goitre, i.e. a goitre rate of 35.2% and a visible goitre rate of 26.6%. The prevalence values are not significantly different from the goitre rate and visible goitre rate of 42.3% and 29.9% respectively of women in the 20-39 age group of the whole area under study. ( p > 0.20)
Goitre prevalence in cretins
Goitre size was determined in 124 cretins; 117 were in 0-9 age group of whom 4 had a Grade 1 goitre and 2 had a Grade 2 goitre, i.e, a goitre rate of 5.1% and a visible goitre rate of 1.7%. These prevalence values are not significantly different from the goitre rate and visible goitre rate of 7.5% and 2.0% respectively for the age group 0-9 years in the normal population. ( p > 0.15)
Among the 7 cretins of 10 years of age or more there.were two with a goitre of size Grade 1. The numbers are insufficient to make a valid comparison with the normal population.
Correlation between goitre and cretin prevalence rates
The goitre and visible goitre rates for females 20-39 years of age and in the population as a whole were taken for each village and the correlation between these parameters and the prevalence of cretinism determined. Correlation coefficients of 0.11, 0.07, 0.21 and 0.08 respectively were obtained, none of which are significant. - 58-
Discussion
The lack of correlation between the prevalence of goitre and cretinism in the foregoing study might suggest that the geographical association of these two conditions is a purely fortuitious one. This supposition is supported by the absence of cretinism in other goitrous regions e.g. Gordon (1922, 1938) found no case of endemic cretinism in the goitre belt of the U.S.A. On the other hand if the figures of Greenwald (1957) for the prevalence of deaf-mutism and goitre in Peru and Argentina are taken into account, there is considerable correlation in the prevalence of the two diseases. Eugster (1938) in Switzerland and Buttfield and Hetzel (1969) in the Huon peninsula of New Guinea also found an association between the goitre rate and the prevalence of cretinism.
However, the lack of statistical correlation between goitre rate and endemic cretinism prevalence in the Jimi valley need not necessarily imply that there is no causal association between the two conditions. Assuming that a single environmental factor is common to both cretinism and goitre and that other subsidiary factors also exist but do not effect both conditions equally, then a correlation might be expected if the status quo in relation to these factors had been maintained for a sufficiently long period of time. Alternatively, if these factors are in a state of flux and subject to recent change, then variations in the prevalence of either condition so produced may conceal any true relationship. Such may be the case in the Jimi valley where profound social and economic changes have occurred, particularly within the past 10-15 years. Furthermore, these Changes have not affected all villages equally e.g. some have vehicular access to the main road to the coast while others do not. Also the development of a cash economy, which has only commenced during the past 5 years, varies from village to village as is evidenced by a 100% differential in council tax rates that exists between villages.
The presence of a goitre in the cretin and its relationship to the syndrome itself does not appear to be of significance. The goitre rate in cretins was found to be no different from the goitre rate in the normal population of the same age group, an observation that has been confirmed -59- elsewhere. Buttfield (1965) found a visible goitre rate of 26% among 254 cretins. Although this was slightly higher than the 18% visible goitre rate among the normal population as a whole, most of the cretins were drawn from those villages with the higher goitre rates and it was thought that the goitre rate in the cretins was not different from that of the normal population in the same villages. Choufoer et al. (1965) found no obvious difference between goitre size in cretins and the rest of the population, but added the proviso that the number of cretins examined was too small for accurate comparison, McCarrison (1908) found a goitre in 88 of 203 cretins (44%) but did not give the goitre rate in the normal population. He notes however, that with the exception of two cases in which goitre was congenital, the thyroid enlargement occurred subsequent to and not prior to the appearance of cretinism and that the incidence of goitre among cretins increased with age as it does in the normal population. DeQuervain and Wegelin (1936) claim that the most severely affected cretins are those without a goitre.
It is usually accepted that the neurological type of endemic cretinism is a congenital defect. McCullagh (1963b) coined the term "Goitre associated congenital defect" in referring to the syndrome. Choufoer et al. (1965) refer to congenital defects when referring to the three features of endemic cretinism namely mental deficiency, deaf-mutism and motor insufficiency. Costa et al, (1964) state that the characteristic nervous changes develop during intrauterine life, while Eggenberger and Messerli (1938) are even more specific claiming that the deaf-mutism has its origin in the fourth month of foetal life, In view of the congenital nature of the defect, the presence of a goitre in the mothers of cretins may be relevant. Buttfield and Hetzel (1969) found an increased incidence of goitre among mothers et endemic cretins (76%) compared with the mothers of normal children. Eugster (1938) notes that in every case the mother of a cretin was affected by a goitre. McCarrison (1908) found a goitre rate of at least 86% among the mothers of endemic cretins, although again, he does not state the prevalence of goitre in the normal population. However he makes the pertinent observation that in endemic localities, goitre in the mother is one of the most essential conditions for the development of cretinism in the child. Observations in the Jimi valley do not confirm those from other areas. Again this does not necessarily imply that there is no relation between the presence of goitre in -60-
the mother and the neurological damage produced to the infant in utero. If cretinism develops during intrauterine life, then the aetiological agent must act during a specific and limited time. On the other hand, a goitre may develop gradually over a long period of time and also may fluctuate in its appearance in a given person, being more likely to appear during puberty or in pregnancy. Therefore any changes in the factor or factors aetiologically responsible for endemic cretinism or goitre may conceal epidemiological correlations between the two syndromes which could otherwise be apparent if the status quo was unchanged for many years. - 61 -
Summary
The epidemiological correlations between goitre rate and prevalence of cretinism, and the high incidence of goitre in the mothers of endemic cretins that have been reported from many different areas, are not confirmed by observations in the Jimi valley. This could be due to the profound social changes currently occurring in the valley. CHAPTER 7
ENDEMIC CRETINISM AND IODINE DEFICIENCY
INTRODUCTION
The important role played by dietary iodine deficiency in the pathogenesis of endemic goitre and the association of endemic goitre with cretinism has led to the incrimination of iodine deficiency in the pathogenesis of endemic cretinism.
Variation in the incidence of cretinism was noted prior to any measures of iodine prophylaxis. A declining incidence was reported by Malacarne (1801) by Parchappe and Lunier (1874) and by Cerletti and Perusini (1907). A steady downward trend can be seen in the statistics of the Sardinian Royal Commission (1848). In a letter to Fagge (quoted by Fagge 1871), Norris states that the cretins of Chisleborough which he had described in an earlier publication (Norris 1847), had almost died out. Parker (1896) confirms this, referring to the Chisleborough cases, he states that "one solitary cretin now survives of about 50 years of age, the march of civilisation having apparently stamped out the disease".
These examples all relate to foci of the disease in Europe but the downward trend has occurred in other countries also. Stott et al. (1930) record that the incidence of deaf-mutism in the United Provinces of India decreased by a half between the censuses of 1881 and 1921. Similarly the census figures for the Argentine republic quoted by Greenwald (1957) show a steady decline in the number of deaf mutes in all provinces of the republic between the years 1869, 1895 and 1914.
In these areas, a declining incidence of cretinism predates specific measures of iodine prophylaxis.
Evidence for a correlation between iodine prophylaxis and a decline in cretinism in Switzerlandwasgiven by Wespi (1945). Iodisation of salt was introduced independently in various Swiss cantons about 1922-1925 and the decline of deaf-mutism in each canton could be correlated with the extent of salt iodisation. However, this was a correlation in time only and it was -63- conceivable that factors other than that of salt iodisation could be held responsible. Koenig and Veraguth (1961) disputed these findings of Wespi, they stated that it was almost impossible to find any cretin born around the time when iodine prophylaxis was introduced and that all the cretins were born ten years or more prior to the introduction of iodine prophylaxis,
Clements (1958) also questions the relevance of iodine deficiency in the pathogenesis of endemic cretinism. He draws attention to the fact that cretinism does not occur with all goitre endemics and that consanguinuity as a result of intermarriage or epidemics of maternal rubella in isolated communities are other plausible explanations.
Thus, although iodine deficiency has been incriminated by some authors as the likely cause of endemic cretinism, this is still the subject of controversy and spontaneous variations in the prevalence of the syndrome have been recorded which cannot be directly correlated with variations in dietary iodine. Until recently no controlled trial of iodine prophylaxis on the prevalence of endemic cretinism had been carried out. Difficulties in controlling the use of measures such as iodised salt or iodide tablets were paramount. However, the introduction by McCullagh (1959) of a single intra- muscular injection of iodised oil and its proven effectiveness over a number of years (Clarke, et al. 1960, Buttfield and Hetzel, 1967, 1969, 1971.) made a controlled trial a feasible proposition. Buttfield and Hetzel (1971) had found that, 41 years after a single 4.0 ml dose of iodised oil, the treated group had a significantly higher serum PBI and urinary iodine excretion and a lower 24 hour radio-iodine uptake than the untreated control population. In the light of these results, a trial of iodised oil was instituted in the Jimi valley in 1966. A preliminary survey of the area had revealed a high incidence of endemic goitre and cretinism and 24 hour radio-iodine uptakes in 50 cases had shown a mean value of 60% (Buttfield, personal communication), - 614 -
METHODS
The administration of iodised oil to alternate families and the subsequent follow-up and assessment of children born into the trial are described in Chapter 4. Every child has been examined on many occasions between July 1967 and June 1972. The assessment and classification of each child was made without knowledge of whether the mother had received iodised oil or saline. When each child was examined the number of teeth that had erupted was recorded. -65-
RESULTS
The comparative male and female goitre and visible goitre rates in the oil injected and control groups are given in Table 8. There are no significant differences either in numbers or in goitre prevalence in these two groups.
The numbers of children who have died are given in Table 9. The combined mortality rate for all children born after the trial commenced in 1966 is 18.5%. If the treated and untreated groups are considered separately, the mortality rate is significantly higher in the latter (p<0.025). However these figures need to be interpreted with caution because no visits were made to the villages between July 1967 and November 1969. Children born and who died in this two and a half year period will not have been recorded so that the overall mortality rate of 185% is an underestimate. Presumably the unrecorded deaths will affect the treated and untreated groups equally and the significant difference in mortality may still be valid.
For the purpose of the trial, affected children have been divided into four groups as shown in Table 10.
Group I. Those presenting with the full syndrome of hearing and speech abnormality, abnormality of motor development, and strabismus.
Group II. Those with abnormalities of hearing, speech and motor development.
Group III. Those with a hearing or speech defect only.
Group IV. Those showing motor retardation with an abnormal gait.
An appendix at the end of the thesis gives a brief resume of the history and clinical features of each affected child,
TABLE 8 I GOITRE OIL SALINE
TOTAL MALES FEMALES TOTAL MALES FEMALES POPULATION POPULATION SIZE 3,1 8 0 1,535 1,645 3,063 1,476 1,587
GRADE 0 2 5 40 1383 1157 2463 1355 1108
GRADE 1 249 79 170 257 74 183
GRADE 2 391 73 318 343 47 296
G.R. 20.1% 9.9% 29.7% 19.6% 8.2% 30.2%
V.G.R. 12.3% 4.8% 19.3% 11.2% 3.2 18.7 %
1 TABLE 9
CHILDHOOD MORTALITY IN CONTROL AND TRIAL POPULATIONS
MOTHER'S TOTAL LIVING DEATHS STATUS BIRTHS CHILDREN
OIL 687 , 577 110
SALINE 62 6 495 131
NIL 62 48 14 TABLE 10
GROUP TREATED UNTREATED CONCEPTION CONCEPTION CONCEPTION CONCEPTION CLASSIFICATION TOTAL BEFORE TRIAL AFTER TRIAL TOTAL BEFORE TRIAL AFTER TRIAL I
Abnormalities of hearing or speech, 3 2 1 18 3 15 motor development and strabismus. r II Abnormalitiesof hearing or speech
and motor development. 3 3 0 13 2 11 ■ • In
Hearing or speech defect only. 2 2 0 4 2 2
& Delay in motor development
with an abnormal gait. 1 1 0 1 0 1 -66- The imprecise definition of endemic cretinism presents some difficulty in assessing the results of the trial, If, for epidemiological purposes, those patients in Groups I and II can be considered endemic cretins, then there are 6 cretins born to women who have had iodised oil out of a total 687 children. In 5 of these 6 cases, conception had occurred prior to the iodised oil injection. In the sixth case, the mother received the injection on October 6th 1966 and the birth date of the infant is recorded as August 1967 i.e. approximately 42-46 weeks later. However the lack of precision regarding the birth date raises the possibility that conception had occurred prior to treatment in this case also.
In the untreated group there are 31 endemic cretins out of a total of 688 children born since the trial commenced. In 5 of these 31, conception had occurred prior to the saline being given.
The ages of the cretins born to the oil and saline groups are graphically recorded in Figure 15.
The average number of teeth erupted at each month from the age of 7 to 26 months is shown in Table 11. Two groups of children are represented, Those whose mothers had oil and those whose mothers had saline. From these figures the regression equations obtained were:
Oil x = 0.78y + 8.07 (634 observations) Saline x = 0,76y + 9.09 (643 observations)
The regression equation for 55 observations made on cretin children was:
x = 0.72y + 13.1
The three equations are plotted in Figure 16.
The slopes of all three lines are almost identical, however, there is a slight delay in the eruption of deciduous teeth in the saline group compared to the oil and a marked delay in the eruption in cretinous children when compared to either the oil or the saline group. AGES OF CRETINS JUNE 1972
Observations above the horizontal line indicate cases of whom conception occurred prior to the commencement of the trial.
6 OIL SALINE
5 • .r■ 4 r
2
1
Figure 15 ERUPTION OF DECIDUOUS TEETH
OIL SALINE AGE NUMBER NUMBER NUMBER NUMBER OF OF OF OF (mon ths) OBSERVATIONS TEETH OBSERVATIONS TEETH
7 36 0.7 47 0.6 8 29 1.2 29 0.8 9 30 2.5 35 2.4 10 28 2.8 27 2.1 11 37 4.7 31 2.4 12 44 5.5 33 4.6 13 35 7.1 40 5.7 14 37 7.9 38 6.6 15 32 10.0 40 7.5 16 38 11.3 36 9.2 17 26 13.0 33 10.5 18 36 12.4 19 13.4 19 30 13.0 31 13.0 20 26 15.0 30 13.8 21 27 15.9 32 15.3 22 37 16.4 31 15.7 23 31 17.3 32 17.0 24 29 18.4 29 16.6 25 31 18.7 26 16.4 , 26 15 18.9 24 _ 18.0
TABLE 11 ERUPTION OF DECIDUOUS TEETH 28
26
24
22
"' 20 O E •-• 18
•
• — • Oil • • Saline • • Cretins
2 4 6 8 10 12 14 16 18 20 NUMBER OF TEETH
Figure 16 -67- Conclusion
The results of this trial indicate that the administration of iodised oil can prevent endemic cretinism, but it must be given prior to conception for it to be effective. The neurological damage that is characteristic of the syndrome in New Guinea appears to occur in early pregnancy, probably sometime in the first trimester.
It is local custom to withhold solid food until an infant has cut 3 or 4 teeth. The delay in appearance of the deciduous teeth apparent in many cretins may therefore be partly responsible for the malnutrition and retarded growth that sometimes occurs.
A discussion of the relevance of these results to the pathogenesis of endemic cretinism appears in Chapter 10.
1-` CHAPTER 8 ro THE RECENT ONSET OF ENDEMIC CRETINISM IN THE JIMI VALLEY
INTRODUCTION
Variations in the prevalence of goitre with ecological changes have been frequently documented. Most commonly a diminishing prevalence has been recorded, particularly with the introduction of iodine prophylaxis. (Eggenberger and Messerli 1938, Kimball 1946, Brush and Attland 1952, Sooch and Ramalingaswami 1965, McCullagh 1963a and Pretell et al. 1969). Increases in prevalence have also been recorded. In many European countries an increase in goitre prevalence followed both world wars and was usually attributed to dietary privations (Kelly and Sneddon 1960)e Other factors have also been incriminated. The recent appearance of endemic goitre in the north west of Nigeria was associated with a change in the water supply from surface to deep-well water (van Amelsvoort 1969). In Poland an increased prevalence of goitre coincided with the substitution of synthetic fertilisers for Chilean nitrate of soda, the latter containing a significant portion of iodine (Kelly and Sneddon 1960).
As discussed earlier in Chapter 7, a declining prevalence of cretinism has been reported from many countries but an increase in prevalence does not appear to have been recorded.
The following account is of the recent occurrence of the disease in the Jimi valley, the local populace maintain that the disease has been present only since the advent of European influence. If this is so, endemic cretinism has appeared since 1953 when the first patrol to the area was made (Walters 1953). -69- METHODS
For epidemiological purposes, the incidence of hearing and speech abnormalities has been taken to represent the incidence of cretinism, The year of birth of the cretins and all members of the normal population were determined from the census records as described in Chapter 4. -70- Results
A total of 148 people with hearing/speech abnormalities were recorded, of these 121 02%) were clinically examined. The remaining 27 (18%) were included in the study on the basis of hearsay evidence only, based on information obtained from village leaders and aid-post orderlies.
Among those clinically examined, the majority showed gross evidence of mental retardation and 80% had signs compatible with a cerebral diplegia (Chapter 5).
The prevalence of cretinism in the years prior to 1966 only have been recorded. In 1966 the controlled trial evaluating intramuscular iodised oil as a prophylactic for endemic cretinism was commenced. The results of this trial are reported in the previous chapter.
The epidemiological records show that the onset of cretinism post-dates the initial contact with the European. Table 12 gives the total number of subjects and the number of cretins born in each year. From these figures the prevalence of cretinism per annum was determined and has been plotted as a histogram as shown in Figure 17.
Prior to 1953 there was only an occasional case of hearing/speech abnormality, an incidence of approximately 0.1%. A sharp rise in prevalence commenced in the late 19501 s and by 1965 over 15% of the children born in that year were affected.
The local people confirm the epidemiological findings. One councillor from a severely affected village - Kwima - remarked that the disease had only occurred since the white man came to the valley, that it was present in the children of the present generation only and had not occurred in his parents or his own generation. This view was universally substantiated in every village visited.
Ecological change consequent upon European contact
Minor changes in food preparation have occurred. Previously food was either roasted in the ashes of an open fire, or an oven of heated stones ANNUAL INCIDENCE OF CRETINISM
YEAR NUMBER TOTAL INCIDENCE of of of BIRTH CRETINS POPULATION CRETINISM ( %)
1966 15 140 10.7 1965 25 162 15.4 1964 25 179 14.0 1963 13 102 12.7 1962 20 176 11.4 1961 23 173 13.3 1960 12 168 7.1 1959 3 145 2.1 1958 1 221 0.5 1957 0 139 0.0 1956 2 202 1.0 1955 2 182 1.1 1954 1 206 0.5 1953 0 233 0.0 1952 0 230 0.0 1951 0 173 0.0 1950 0 258 0.0 1949 1 253 0.4 1948 1 217 0.5 1947 1 195 0.5 pre 1947 _ 3 3727 0.1
TABLE 12 Figure 17
16
EAR Y
ER 12 E P G TA RCEN PE
IIIMMITITItmuirrt 1 I I 1946 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 AND BEFORE
YEAR OF BIRTH - 71 - was used. The introduction of metal saucepans now permits the preparation of food by boiling, nevertheless the former two methods predominate even today and the use of saucepans is uncommon.
Some new vegetables have been introduced e.g. tomatoes, peas and beans, but the staple yams, sweet potato and taro are unchanged. The primitive slash-and-burn horticulture is also unchanged with land being used for one or two cycles and then remaining fallow for about 15 years.
It is difficult to explain the recent onset of endemic cretinism on the strength of these relatively minor changes. However, a total change has occurred in the type of salt consumed by the people of the Jimi valley.
Following the first contact with the European in 1953 many further patrols were made to the area. It was the usual procedure for each patrol to carry in rock salt which was used in exchange to purchase food for members of the patrol. The subsequent development of the area and the opening of government and mission stations, allowed for ease of access to the introduced rock salt so that traditional methods of salt production lapsed completely.
Traditional salt and the pax salina
Traditionally salt used to be obtained from salt springs in the Simbai Valley which lies parallel and to the north of the Jimi Valley. The two valleys are separated by the Bismarck mountain range, Figure 2. There used to be at least three salt springs in the Simbai at Tumbi, Sangen and Gai. The former two are still in existence - the spring at Gai has been obliterated by a landslide.
The Jimi people obtained salt either by an exchange of goods, e.g. stone axes and pigs, with the Simbai valley inhabitants, or they would themselves travel to the salt springs and remain there for a period of four to six weeks. On these occasions salt would be prepared in commercial quantities not only for their own use but for trade into the Wahgi valley further to the south. The crossing of the Simbai valley by the Jimi people must have necessitated a pax sauna (Clarke, 1971) because it entailed entering country having people of a different language. -72- Salt preparation
The method of salt production was enthusiastically described by a number of the older men who vied with each other in the telling. It entailed the construction of ovens in the immediate vicinity of the salt spring. An oven consisted of a pyramid made of river stones and was approximately two feet in height with a fire beneath. On top of the pyramid was a large disc-like stone which supported a container of banana leaves surrounded by clay. Water from the spring was continuously evaporated in this container so producing a large circular slab of salt.
Production in commercial quantities is no longer maintained even by the Simbai people. Small quantities for private use are still occasionally made or the water is used for cooking only by those living in the immediate vicinity of the spring.
This traditionally produced salt was used at all times and not merely for festive occasions. Moreover, all members of th,lcommunity used to partake of it. One old man told of how, in times past, a woman might wrap a small quantity of the salt in a leaf and attach it to an armlet round her wrist. Then, when working in the garden, if her infant became fractious she would attempt to pacify it by wetting her finger with saliva, dipping it in the salt and applying it to the infant's tongue.
Salt analysis
In November 1971 the journey from the Jimi valley to the salt springs at Tumbi and Sangen was undertaken. This entailed a two day walk crossing the Bismarck range, descending to and crossing the Simbai river and ascending into the range forming the northern wall of the Simbai valley. The two springs are approximately 12 hours walking distance apart and arise in an area of volcanic activity as evidenced by the strong odour of hydrogen sulphide in the vicinity. The pool formed by each spring is about six feet in diameter and only a few inches deep. The Sangen pool is shown in Figure 18.
Collection of the saline samples was made in plastic containers previously washed with deionised water. One container was refilled with The salt pool at Sangen
Figure 18 -73- deionised water and used as a control. The samples collected were:
1. Tumbi A. Water from the pool at Tumbi. 2. Tumbi B. Water from Tumbi as it emerged fran the ground and immediately before it entered the pool. This was "fresh" in contrast to the sample fran the pool itself which is subject to surface evaporation. 3. Sangen A. Water fran the pool at Sangen. 4. Sangen B. Water and sediment from the floor of the pool which was agitated and then filtered.
A small quantity of salt prepared from the Sangen spring for private.. use by one of the villagers was also obtained for analysis.
Iodine determinations were made at the Boston Medical Laboratories by the courtesy of Professor J.B. Stanbury. A modification of the Zak wet ash method was used
Chloride was estimated by titrating with a standard solution of gayer nitrate using potassium chromate as an indicator, and sodium by direct aspiration into a flame photometer. The total salt value was obtained by the addition of the sodium and chloride values. The analysis results are given in Table 13.
The historical sequence of changes that have occurred in the Jimi valley is given in Table 14. Read in conjunction with Figure 17, the time relationship between the various changes and the onset of the epidemic of cretinism can be correlated. TABLE 13
SPRING WATER TOTAL SALT IODINE IODINE /SALT SAMPLE (Parts per million) (Parts per million) RATIO
TUMBI A 15,800 4.4 1 : 3590
TUMBI B 14,200 9 .8 1 : 1450
- SANGEN A 19,500 6.0 1 : 3250
0•1■1■P
SANGEN B 18,300 4.2 1 : 4350
DEIONISED CONTROL 99 Not detected
Prepared salt contained iodine 189.1 micrograms per gram; i.e. iodine/salt ratio 1 : 5300 TABLE 14 EVENTS IN THE MIDDLE JIMI VALLEY
YEAR EVENT
1953 Initial contact with the European (Walters 1953)
1956 Establishment of patrol post at Tabibuga
1958 Closure of salt ovens in the Simbai valley
1959 Completion of airstrip at Tabibuga
1960 Anglican and Nazarene mission work started
1965 Trade stores opened
1966 Local government council formed
1970 Vehicular link with road to the coast completed - Discussion
It is possible that the recent onset of endemic cretinism is an apparent and not a real phenomenon. The introduction of health services, particularly the Infant and Maternal Welfare Services provided by the missions, may now ensure survival of affected infants whereas previously they died. There are, however, cogent arguments invalidating this supposition. The assumption that affected infants do not survive to adulthood in a socially primitive situation is not borne out in many other areas of the world and in particular in other equally primitive areas of New Guinea. McCullagh (1963b) and Buttfield and Hetzel (1969) investigated the cretins of the Huon peninsula, most of whom were adults. Even more pertinent is the report by Choufoer et al. (1965) who state that when missionaries entered the Mulia Valley of West New Guinea for the first time in 1958, they were struck by the high incidence of defectives in the population, many of whom were adults.
An alternative possibility concerns the practice of infanticide. Affected infants who previously may have been killed, would now be allowed to survive consequent upon the new tenets of law and order. That infanticide was once practised is recognised but it was reserved almost exclusively for instances of multiple births, this being considered a characteristic of animals and not worthy of humans. In order to put a stop to this practice, a government subsidy used to be awarded to the parents of twin children. The people themselves vehemently deny that cretinous children were deliberately killed, a denial supported by the considerable parental care and attention bestowed on these children. Furthermore, there is no disgrace attached to the parents of an affected child.
If changes in patterns of mortality are unable to account for an apparent recent onset of cretinism, then it must be a real phenomenon.
The degree of iodisation of salt introduced in various countries as a prophylactic for endemic goitre has varied considerably. The range has been from 1 part iodine to 10,000 parts salt in the U.S.A. and Canada to 1 part iodine to 200,000 parts salt in Poland (Matovinovic and Ramalingaswami, 1960). Traditionally prepared salt used in the Jimi valley -75- with 1 part iodine to 5,300 parts salt is almost twice as highly iodised as the most highly iodised commercial salt and therefore must have provided a rich source of dietary iodine.
Querido (1971a) has collated urinary iodine excretion values from various areas and has estimated that the critical level of urinary iodine excretion in a oammunity below which endemic cretinism is likely to be present is in the range 15 - 20 pg per day. This quantity of iodine would be provided by approximately 100 mg of the traditional salt.
Natural sources of salt in many localities are known to be relatively rich in iodine. In Columbia certain salt deposits were recognised as effective in preventing goitre. It was this property that led Boussingault (1831) to recommend the iodisation of domestic salt supplies for the prophylaxis of endemic goitre.
Eggenberger and Messerli (1938) record that the county of Vaud in Switzerland used to be goitre-free and that the goitre-free area was determined by political not geological boundaries. This was attributed to the fact that the county was supplied with salt from the mine at Bex and was naturally iodised at 1 part per 100,000 parts salt. Since 1900 the demand for more highly refined and therefore less highly iodised salt increased and this was accompanied by an increase in goitre prevalence.
Fierro-Benitez et al. (1969) record the use of a natural salt having a high iodine content in two Peruvian villages, in these villages goitre and cretinism is almost non-existent. In contrast, other villages using salt of a low iodine content have an incidence of goitre and cretinism as high as 54.4% and 8.2% respectively.
When the inhabitants of a non-giotre area move into an area of goitre and cretinism, then cretinism may occur in the succeeding generations (McCarrison, 1908; Querido, 1971b). Kicic et al. (1961) reported a severe focus of endemic cretinism subsequent to the migration of a whole community to form a new settlement. The foregoing report, however, is probably unique in recording the recent onset of cretinism that can be attributed to a relatively minor change which has altered a delicate -76- ecological balance. It provides circumstantial evidence that the withdrawal of a potent source of dietary iodine has precipitated an epidemic of cretinism in the community. If read in conjunction with the effectiveness of intramuscular iodised oil in preventing endemic cretinism (Chapter 7), iodine deficiency is linked even more firmly to the pathogenesis of the syndrome of endemic cretinism. - 77- SUMMARY
A description is given of a recent epidemic of cretinism which post- dates the coming of the European to the Jimi valley. It can be related to a change in the type of salt used. Prior to European influence, natural salt having a high iodine content was obtained by the evaporation of water from saline volcanic pools. The introduction of an uniodised rock salt and its ease of acquisition by the indigenous population resulted in the dying out of traditional methods of salt production. Thus the withdrawal of a rich source of dietary iodine correlated with the commencement of an epidemic of cretinism. CHAPTER 9
MATERNAL THYROID FUNCTION AND ENDEMIC CRETINISM
INTRODUCTION
In chapter 6, the efficacy of a single intramuscular injection of iodised oil in the prevention of endemic cretinism is described. The evidence presented suggests that the damage occurs during foetal development. In Chapter 7, circumstantial evidence is presented indicating that the withdrawal of a rich source of dietary iodine precipitated an epidemic of cretinism. Thus iodine deficiency is strongly implicated in the pathogenesis of the syndrome of endemic cretinism.
It has been postulated that intra-uterine hypothyroidism, either maternal or foetal, consequent upon iodine deficiency is of importance in the pathogenetic mechanism (Stanbury et al., 1954; Choufoer et al., 1965; Querido, 1969; Fierro-Benitez et al., 1970). In many areas of severe iodine deficiency low serum PBI values have been reported in the normal, clinically euthyroid population. Some examples are given in Table 15. Pretell and Stanbury (1971) investigated the effect of chronic iodine deficiency on maternal and foetal thyroid hormone synthesis. They found that 27 out of 45 pregnant iodine deficient women had a serum T4 below the normal range.
This discrepancy between the clinical and biochemical findings may be due to a number of factors:
a) a relative increase in the metabolically more active triiodothyronine. b) a depression of the thyroid protein binding concentrations. c) acceleration of peripheral thyroxine metabolism.
In order to investigate the role of maternal-hypothyroidism in the aetiology of endemic cretinism, a study was made of thyroid function during pregnancy and the infants born as a result of these pregnancies subsequently followed up. A comparison of thyroid function between women who had TABLE 15
Authors Area Mean Serum PSI Range
Tocacchi 3.10 1.90 - 5.20 Fierro-Benitez et al. 1970 Peru La Esperanza 3.20 1.80 - 5.80
Ibbertson et al. 1971 Nepal 2.86 0-5-7-80
Choufoer et al . 1963 West New Guinea 1.90 0-30- 4.80
Srinivasin et al. 1964 India (Himalayas) 2.04 0-90- 2.88 -79- received supplementary iodine in the form of an iodised oil injection and the control saline injected group was also made. -80-
METHODS
The selection of women for sampling, the collection of serum samples and the techniques used for the various analyses are described in the section on methodology (Chapter 4). - 81 -
RESULTS
THYROID BINDING PROTEINS TBG AND TBPA
Serum TBG and TBPA for the non-pregnant, the pregnant iodised oil and the pregnant saline groups are shown in Table 16. There is no significant difference between the two pregnant groups for either parameter. Both pregnant groups had a significantly higher TBG than the non-pregnant group.
The serum TBPA is lower in pregnancy. This difference is significant for the pregnant saline versus non-pregnant (p < 0.01) but is not significant for the pregnant oil versus non-pregnant.
SERUM T14
The mean serum T4 during pregnancy in the iodised oil and the control saline group is given in Table 17. The difference between the two means is highly significant (p < 0.001). The range of serum T4 is shown in Figure 19. Those women who had received supplementary iodine all had a serum T4 within or above the normal range. In contrast, over 50% of those who did not receive supplementary iodine had a serum T4 below the lower limit of normal.
SERUM TSH
Serum TSH levels were determined in 68 women, 14 of whom were pregnant. The values obtained are shown in Figure 20. Sixty per cent have an elevated TSH (upper limit of normal 3.0 uU/m1.) and 5 cases had a TSH > 50uU/ml, If the serum TSH is plotted against the serum 114 (Figure 21) the greatest elevations of TSH occur when the serum T4 is abnormally law.
INFANT MORTALITY AND THE MATERNAL SERUM T 4
If the lower limit of normal of serum T 4 during pregnancy is 6Ong/m1., then a severe reduction in the serum T 4 may be arbitarily defined as being less than 3Ong/ml. There were 9 women who fell into this category i.e. had SERUM THYROID BINDING PROTEINS IN NON-PREGNANT AND IN TREATED AND UNTREATED PREGNANT WOMEN 1•• - Number of Group T B G T B PA Observations Mean ± SD Range Mean *SD Range Ng/100m1 pg/100m1 pg/IOOmI pg/100m1 , - Non-pregbant 23 untreated 27.7±3.8 20-35 166'81131. 133-188 4 - Pregnant untreated 15 59-1±10.2 40-79 (saline) 154.1±12.5 123-179
Pregnan t treated 14 53.2 ±6.9 44 -66 159.9+174 137-190 (Iodised oil) •
TABLE 16 SERUM THYROXINE LEVELS IN PREGNANCY
Number Mean -± SD Range of cases ng/ml ng iml
Iodised Oil 20 128.1 ± 22.9 94-167
Saline 32 59.8 ±35.8 5 -154
TABLE 17 Figure 19
SERUM THYROXINE VALUES IN PREGNANCY
(Method of Ekins et al.1969 )
Horizontal lines indicate upper and lower limits of the normal range
IODISED OIL SALINE 180
- 160 • •
140 :e • •
120 i• • • s : I - 100 • . i • tb • .....c • • a .v. 80 II III I- II II 2 m I cc 14.1 to 60 • I 40 a •
20 I i Log TSH p lliml 40 20 10 30 50 2 4 3 5 6 9 8 7 FM SERUM TSHINPREGNANTANDNON—PREGNANTWOMEN Horizontal lineindicatesupperlimitofnormalrange Pregnant ❑❑❑ 0 ❑ ❑ 0
Figure 20 Non-pregnant ■■■ CORRELATION BETWEEN SERUM T4 AND TSH
50 Pregnant A
A Non-pregnant •
40
A A
• 20
10 A • •A
• • • A • • AA • A • • • A A • • A • •• A •• • A A AA • AA • AA A • A A A • •
20 40 60 80 100 120 140 160 T4 ngiml
Figure 21 -82-
a serum T 4 < 3Ong/ml. at the time of sampling during pregnancy. Two of these pregnancies terminated in a stillbirth, in another 2 the infants succumbed immediately after birth, and in 5 the infants still survive, i.e. a perinatal mortality of 4 out of 9.
There were 34 women whose serum T was greater than 3Ong/ml. at the 4 time of sampling during pregnancy. Among these there were 3 neonatal deaths and 31 infants still survive.
The difference in perinatal mortality rates in the two groups i.e. those in whom the maternal serum T4 was greater than 3Ong/ml. and those in whom it was less than 30ng/ml. is highly significant (p > 0.01). - 83 -
DISCUSSION
The mean serum TBG value of 27 ug/100 mi. found in non-pregnant female adults in the Jimi valley, is slightly in excess of the mean value of 20 14/100 ml. that is usually reported (Oppenheimer, 1968; Murphy, 1971). The effect of oestrogens in augmenting serum TBG is well established (Dowling et al., 1956; Engbring and Engstrom 1959). The rise in TBG reported in the foregoing results is therefore physiological and similar in degree to that found elsewhere. The mean TBG levels in pregnancy in the treated and untreated women were 59.1 and 53.2 ug/100 ml. respectively and fall within the range 50-60 ug/100 ml. normally quoted (Ingbar and Woeber, 1968). The serum TBPA values also fall within the normal range of 150-300 14/100 ml. quoted by Ingbar and Woeber (1968).
Thus there are no major differences in TBG and TBPA levels in the present series when compared with the series reported elsewhere. Furthermore there are no significant differences in these parameters when the treated and untreated groups of pregnant women are compared. Therefore it is unlikely that hormone binding abnormalities can be incriminated in the pathogenesis of endemic cretinism.
levels in the The elevation in serum TSH and reduction in serum T4 untreated group closely resemble the results obtained by Pretell and Stanbury in Peru (1971). The fact that both TSH and T4 are within the normal range in those women who have received iodised oil suggests that abnormalities in these parameters are secondary to iodine deficiency and not due to any inherent defect in the thyroid gland. The correlation of an elevated TSH with abnormally low serum T4's indicates a normal thyroid- pituitary feedback mechanism.
The normal serum T4 levels in the iodine supplemented group four years after injection confirms the findings of Buttfield and Hetzel (1971), who found normal serum PBI's 42 years after a single 4.0 ml. dose of intra- muscular iodised oil. This dose can therefore be considered effective in correcting iodine deficiency for a minimum period of four years. The results assume greater significance when consideration is given to the fact -84- that those investigated were in the child-bearing age, many of wham had one or two children in the intervening period, i.e. when the physiological demands for iodine could be regarded as being at a maximum.
An abnormally low serum T4 in the mother during pregnancy was accompanied by a significant increase in the perinatal mortality rate. -85-
SUMMARY
1. A comparison of women who have received supplementary iodine with an untreated control group showed no differences in the serum levels of the thyroid binding proteins.
's and high serum TSH's were corrected by the 2. Low serum T4 administration of iodine.
correlated with a high serum TSH. 3. A low serum T4
4. A single 4.0 ml. dose of intramuscular iodised oil was sufficient to correct the iodine deficiency for a minimum period of four years.
5. The perinatal mortality rate was significantly higher in children born to women with an abnormally low serum T4 when compared to children born to women with a normal serum T4° CHAPTER 10
THE PATHOGENESIS OF ENDEMIC CRETINISM
A number of authors have indicated that the nervous type of endemic cretinism is a congenital defect. McCullagh (1963b) called the syndrome "Goitre-associated congenital defect". Eggenberger and Messerli (1938) state that the deaf-mutism has its origin in the fourth month of foetal life, although evidence supporting this statement is not given. Costa et al,, (1964) remark that endemic cretinism seems to develop during intrauterine life and to be related to the parental environment. The trial of iodised oil reported in Chapter 7 supports the view that the neurological damage of endemic cretinism is an intrauterine event. The recent epidemic of cretinism which followed the withdrawal of a rich source of dietary iodine (Chapter 8), further linked the pathogenesis of the disease to iodine deficiency.
If iodine deficiency during foetal development is incriminated in the pathogenesis of the syndrome, then the mechanism by which it exerts its pathogenic effect needs elucidation.
MATERNAL HYPOTHYROIDISM AND ENDEMIC CRETINISM
The premise that maternal hypothyroidism may be of pathogenic importance receives some support fran the results reported in Chapter 9, in that a degree of hypothyroidism does undoubtedly occur. Fifty per cent of those women who did not receive supplementary iodine had serum T4 values below the normal range, while 9 out of 31 cases had a T4 of less than 30 ng/ml. These results accord with the low PBI values found in other iodine deficient areas (Table 15), and the low serum T4 values during pregnancy found by Pretell and Stanbury (1971). Although a biochemical hypothyroidism occurs, it may not necessarily be implicated in the pathogenic mechanism. Animal experimentation shows a strikingly increased incidence of abortion or foetal resorption associated with maternal hypothyroidism. Nevertheless, thyroidectomised animals are able to conceive and bear normal young (Chu 1944; Jones et al,, 1946; Krohn and White 1950, Krohn 1951). -87-
It is a well recognised fact that it is rare for a myxoedematous female in the child-bearing age to conceive or, if conception occurs, for the pregnancy to proceed to term if the hypothyroidism is untreated (Barnes, 1965). Parkin and Greene (1943) reported on nine pregnancies in six hypothyroid women. There was one stillbirth, three aborted, in three cases no details concerning the infants is noted, and there were two normal children. Hodges et al., (1952) recorded six pregnancies in a myxoedematous woman, two infants died (details not given), there was one mongol, another child was mentally dull and two children were normal. Lister and Ashe (1955) also record the birth of a normal child to a myxoedematous woman untreated during the first four months of her pregnancy and irregularly treated thereafter. Koenig (1968) has surveyed the literature on the subject. In 74 hypothyroid women he records 110 pregnancies, of these 30 aborted, there were 49 normal infants and 28 had congenital abnormalities. Thus, conception in a myxoedematous woman is accompanied by a greater than usual number of abortions, stillbirths and developmental anomalies. Nevertheless, in no instance did the developmental anomaly resemble the syndrome of endemic cretinism. The pregnancy wastage in hypothyroidism is confirmed by the Jimi valley results. There is a significantly higher perinatal mortality of children born to women with a very low T4 (arbitrarily determined as below 30 ng/m1.) compared with children born to women with a normal T4. This is perhaps also reflected in'the higher mortality rate among children born to women in the saline versus the oil injected group as discussed in Chapter 6.
Radiological examination of athyreotic infants reveals the absence of ossification centres normally present in the full term baby (Anderson, 1961). Also, the ultimate intellectual development of these infants is often disappointing in spite of early and adequate replacement therapy (Cooke and Man, 1956: French and van Wyk, 1964). This suggests that intrauterine hypothyroidism occurs if foetal thyroid hormone synthesis is deficient and that the placental transfer of maternal hormone is inadequate to compensate the foetal deficit.
The transfer of maternal thyroxine and tri-iodothyronine across the placenta has been studied in experimental animals and in humans -88-
(Myant, 1958a and b, 1964; Osorio and Myant, 1960). The foetal/maternal ratio for both hormones was low, particularly in the early stages of pregnancy and it was thought possible that thyroid hormone was not required for the early stages of foetal development.
The similarity in binding protein levels between the iodised oil and control group, and the normal rise in TBG during pregnancy, makes it unlikely that binding abnormalities are of aetiological importance in endemic cretinism.
Two salient points emerge:
a) Placental transfer of maternal thyroid hormone is poor and is insufficient to compensate a foetal deficit if it exists.
b) Maternal hypothyroidism in pregnancy, though it may result in a greater incidence of developmental anomalies, does not produce the same clinical syndrome as endemic cretinism.
Therefore, although a biochemical hypothyroidism may exist in an area of severe iodine deficiency, it is difficult to adequately explain the pathogenesis of endemic cretinism on the basis of maternal hypothyroidism.
FOETAL HYPOTHYROIDISM AND ENDEMIC CRETINISM
Foetal hypothyroidism secondary to iodine deficiency has been suggested as a possible cause of endemic cretinism (Choufoer et al., 1965). However, this is also untenable for a number of reasons:
1) Pretell and Stanbury (1971) found a poor correlation between in an iodine deficient area and concluded that maternal and cord blood T4 iodine deficiency in the mother does not result in hypothyroidism in the foetus.
2) The most severe degree of foetal hypothyroidism might be expected when there is congenital athyreosis, yet such infants do not present the -89 - clinical features of endemic cretinism.
3) There is evidence, both embryological and physiological, that the foetal thyroid does not commence functioning until about the twelfth week. Follicle formation begins at about the twelfth or thirteenth week (Norris, 1916; Cooper, 1924) and thyroidal accumulation of administered radioactive iodine also commences at about this time (Chapman et al., 1948; Hodges et al., 1955). If, therefore, the neurological damage of endemic cretinism occurs in the first trimester, then it is unlikely that foetal hypothyroidism can be accounted responsible.
ELEMENTAL DEFICIENCIES AND ENDEMIC CRETINISM
If both foetal and maternal hypothyroidism cannot be implicated in the pathogenesis of endemic cretinism, then consideration needs to be given to; the possibility that elemental iodine, apart flum its role in hormcnogenesis, may be necessary for foetal neurological development. Iodide is actively transported across the placenta from the mother to the foetus and reaches a concentration in foetal blood several times that in maternal blood (Hall and Myant, 1956; Logethetopoulos and Scott, 1955, 1956; Costa et al., 1965). It may even be of significance that the mammalian ovary has a high iodine content in the follicular phase (Brown-Grant, 1961). In the human, 12 to 60 hours after an injection of 1131, a follicular fluid to serum con- centration ratio of 1.13 was obtained (Kaulla et al., 1958).
An analagous situation in respect to an elemental deficiency occurs in sheep and cattle. Pastural copper deficiency during gestation causes mal-development of the foetal central nervous system producing the syndrome of swayback which is characterised by an ataxia (Bennetts and Chapman, 1937). The pathological lesion is a myelin aplasia with cavitation of the cerebral white matter. The myelin aplasia also affects the long tracts of the spinal cord (Howell et al., 1964). Unfortunately there is virtually nothing known of the neuropathology of the central nervous system in endemic cretinism so that a comparison of the lesions is not possible.
Similarly, manganese deficiency in gestational pigs (Plumlee et al, 1956) -90- and rats (Shils and McCollum, 1943) resulted in the offspring having a central ataxia. It is preventable if manganese supplements are given during the first half but not the second half of gestation (Hurley et al., 1958).
If elemental iodine deficiency is of importance in foetal development, then the sequence of events leading to a deficiency in the foetus would be: Low dietary iodine diminution in hormone synthesis -4- increased production of TSH ÷ increased uptake of iodine by the maternal thyroid. Thus the maternal thyroid would compete with the placenta for available iodine. By contrast in hypothyroidism due to, for example, a thyroiditis, although serum TSH may be grossly elevated, the thyroid is unable to respond to the stimulus and so does not compete with the placenta for iodine. Thus the increased avidity of the thyroid for iodine under conditions of iodine deficiency effectively deprives the placenta and foetus of iodide. Conceivably a foetal iodide deficiency may also result from a malfunctioning of the placenta in which the active transport of the ion is involved.
PENDRED'S SYNDROME AND ENDEMIC CRETINISM
The association of congenital deafness with goitre was described by Vaughan Pendred (1896). The thyroidal defect is an abnormality of organic binding of iodine (Morgans and Trotter 1958; Fraser et al., 1961). The hearing defect is a congenital nerve deafness, more marked in the high tones than the low (Fraser et al., 1960)c Essentially the same abnormality in hearing has been found among the endemic cretins (Costa et al., 1964; Fierro-Benitez et alc, 1970)0
If foetal iodide deficiency is of importance in the pathogenesis of endemic cretinism, it is possible that foetal iodide deficiency is also of importance in the pathogenesis of the hearing defect in Pendred's syndrome. In order for this hypothesis to be tenable it must be assumed that the thyroidal defect in Pendred's syndrome is associated with the same defect in other organs, Thus a foetal iodide deficiency may be produced at more than one level cog. - 91 -
a) If the defect lies in the placenta, the active transport of iodide from mother to foetus may be limited. b) If the defect is in the embryonal cells of the developing ear and its central connections then the ability of these cells to utilise iodine may be affected.
Should any of these possibilities prove to be the case, then the deaf-mutism of endemic cretinism may be considered the phenotype of the genetically determined Pendred's syndrome.
There are anomalies in this hypothesis, the mental deficiency, the diplegia and the strabismus of cretinism do not occur with Pendred's syndrome. This may be explained by differences in degree or timing of the iodide deficiency.
If the difference is one of degree, in Pendred's syndrome it may be postulated that active placental transport of iodide is affected, but mental deficiency does not occur because sufficient iodide traverses the placenta by passive diffusion. Alternatively the timing of the insult may be important. If mental deficiency and diplegia are dependent on iodine deficiency in the earliest stages of development prior to significant placental development, then these symptoms would be absent in Pendred's syndromes as they would not be dependent on active placental transfer. It must be reiterated that these suggestions are hypothetical and will need experimental confirmation.
MATERNAL RUBELLA AND ENDEMIC CRETINISM
The association of iodine deficiency in the mother with neurological damage to the foetus is analagous to the congenital defects produced by maternal rubella infection. Defects of hearing with deaf-mutism are common to both syndromes. A squint which occurs in approximately 25% of endemic cretins (Chapter 4) was also present in a number of cases of the rubella syndrome reported by Sheridan (1964).
Analogy between endemic cretinism and the rubella syndrome can also be - 92 - drawn in the time relationship between the insult and the damage produced. The trial of iodised oil described suggests that the neurological damage of cretinism occurs early in pregnancy. Similarly in maternal rubella infection the first trimester appears to be the critical period. In women developing clinical rubella during the first sixteen weeks of gestation, major congenital anomalies were found in 23.8% of the children and minor anomalies in 19.5% (Pitt and Kiir 1965a, b). No major defects resulted from infection which occurred in the second and third trimesters. This was confirmed by Tartakow (1965), however he also found 13.4% and 14.3% o of children with minor anomalies following infection in the second and third trimesters respectively.
If iodine deficiency in early pregnancy does cause neurological damage to the foetus, the question arises whether variations in the clinical syndrome are due to differences in degree, in timing, or in the duration of the insult. It is not possible to draw any conclusions concerning this from the iodised oil trial, with rubella the timing of the infection is of importance in the type of congenital anomaly produced. Cataracts occur almost exclusively with infection during the first eight weeks of gestation, major cardiac anomalies in the first nine weeks and deafness with infection up to the fifteenth week.(Sheridan 1964; Pitt and Keir 1965 a and b). Furthermore, the earlier the infection the greater the likelihood of multiple defects. In view of this, the timing of the iodine deficiency may be important in the type of neurological damage produced.
PROTEIN MALNUTRITION AND ENDEMIC CRETINISM
Although the iodised oil trial shows that iodine administration in a community can prevent endemic cretinism, this does not necessarily mean that iodine deficiency is solely responsible for the syndrome. It is possible that the deficiency acts in conjunction with other factors. As endemic cretinism is today so much a disease of under-privileged communities, the possibility that protein malnutrition is a secondary factor cannot be denied. A number of studies have assessed the effects of malnutrition in infancy on intellectual development, most suggest that permanent intellectual impairment may be produced by protein malnutrition -93- in early infancy. Stoch and Smythe (1963, 1967) following two groups of Children found marked differences in both physical and mental development in the group grossly malnourished in infancy compared to the well-nourished group. Similar results have been obtained by other workers (Winick and Rosso 1969; Latham and Cobos 1971; Chase and Martin 1970; Latham et al, 1969), they all suggest that poor mental development is associated with, though not necessarily caused by, malnutrition.
The association between intrauterine malnutrition and brain development has been investigated in experimental animals. Total brain weight and brain cellularity are decreased by foetal malnutrition (Chase et al., 1971; Zamenhof et al., 1968). The deficit in the numberrof brain cells is most severe if the malnutrition is maintained post-natally until weaning i.e. if malnutrition exists throughout the entire period of brain cell proliferation (Winick 1970).
Protein malnutrition occurring during the years of active brain growth may therefore be partially responsible for the mental retardation found in endemic cretinism. However, the other features of the syndrome namely, deaf-mutism, a diplegia and strabismus are not described with protein malnutrition. If an aetiological role is to be ascribed to protein malnutrition, it must be a secondary one only acting in conjunction with iodine deficiency. -94-
SUMMARY
In an area of iodine deficiency changes in serum T4 and TSH may occur which are consistent with the diagnosis of hypothyroidism. However, neither maternal nor foetal hypothyroidism can adequately explain the pathogenesis of the syndrome of endemic cretinism. The possibility is raised that foetal deficiency of iodide is of pathogenetic importance and that the deaf- mutism of endemic cretinism is the phenotype of the genetically determined Pendred's syndrome.
Similarities between endemic cretinism, rubella embryopathy and certain elemental deficiencies in animals is noted. The possibility that maternal protein malnutrition may play a secondary role to iodine deficiency in the pathogenesis of endemic cretinism is also discussed. CHAPTER 11
RECAPITULATION AND CONCLUSIONS
Endemic cretinism is a disease of world-wide distribution occurring mainly in mountainous regions and geographically associated with endemic goitre. The earliest accounts of the syndrome are to be found in the literature from the Alpine countries, and in these accounts mental deficiency and deaf-mutism are the defects most frequently mentioned.
In the late 19th and early 20th centuries, there was a gathering momentum of interest in the thyroid, particularly in the symptoms and signs referable to hypofunctioning of the gland. The application of the term cretin to the early descriptions of congenital or juvenile hypothyroidism, together with the gradual disappearance of the endemic variety from many countries consequent upon socio-economic development, led to the equation of the term with hypothyroidism. However, in most areas where endemic cretinism prevails, the disease constitutes a congenital neurological syndrome with abnormalities of hearing and speech, mental deficiency, a diplegia and strabismus as the salient features, while hypothyroidism is rare.
The Jimi valley in the Western Highlands of New Guinea has a population of 24,000 and is an area of iodine deficiency evidenced by the high goitre rate, high thyroidal radio 1311 uptakes (the mean 24 hour 1311 uptake in 50 cases was 60%, Buttfield - personal communication). Endemic cretinism is common in the area and presents a wide spectrum varying from the severely mentally deficient, totally deaf and mute diplegic with a strabismus, to minor abnormalities of hearing and speech with a variable deficiency of the intellect. Clinical hypothyroidism is not evident though a low serum T4 occurs in 50% of cases and indicates that there is a biochemical hypothyroidism. However, a similar reduction in Tit is to be found in the normal population and is not characteristic of the cretins.
The relationship between iodine deficiency, endemic goitre and endemic cretinism led to the hypothesis that iodine deficiency is causally associated with endemic cretinism. To test this hypothesis, in 1966 a controlled trial of intramuscular iodised oil was commenced in the Jimi valley. As a result of this trial it was found that the oil was effective in preventing the disease but had to be given prior to conception. -96-
The neurological damage of cretinism appears to occur during early foetal development.
Epidemiological evidence is presented which suggests that cretinism is of recent onset in the Jimi valley. This is confirmed by the people themselves who claim that the onset of the disease post-dates the coming of the white man in 1953. Circumstantial evidence indicates that the recent onset may be related to a change in the type of salt used. Prior to European influence, salt having a very high iodine content was manufactured from volcanic springs in an adjacent valley. Subsequently a non-iodised rock salt was introduced and superseded traditional salt production. Thus, the syndrome of endemic cretinism is very closely linked to iodine deficiency.
In a village to village survey there was a failure to correlate the prevalence rates of goitre and cretinism. Cretinism is the result of iodine deficiency during a precise and limited period of foetal development, whereas goitre is the result of a more prolonged deprivation and may be variably affected by other factors also. The lack of correlation between cretin and goitre prevalence rates may be explained by the relatively recent onset of dietary iodine deficiency so that a constancy in these prevalence rates had not been attained.
The pathogenic mechanism by which iodine exerts its effect on foetal development was investigated. Although maternal hypothyroidism may exist during gestation and be responsible for an increase in the perinatal mortality rate, it cannot adequately account for the syndrome of endemic cretinism. The possibility is raised that elemental iodine, apart from its role in hormonogenesis, may be necessary for foetal neurological development and that the deaf-mutism of cretinism may be the phenotype of the genetically determined deaf-mutism in Pendred's syndrome.
In animals, gestational deficiencies( Of certain elements e.g. copper and manganese are known to adversely affect the development of the offspring. The similarity between these syndromes and that of endemic cretinism is noted. - 97 -
The normal serum T4 and TSH levels in the iodine supplemented women compared to the low T4 and high TSH values in the control group four years after treatment, indicates that a single intramuscular 4 ml. dose of iodised oil (containing approximately 400 mg elemental iodine per ml.) is effective for amininum period of four years. This assumes greater significance when consideration is given to the fact that sampling was done of women in the child-bearing age many of whom had had one or two children in the intervening period, i.e. during a time of greatest physiological demands on the iodine stores. -98-
SUMMARY
1. The syndrome of endemic cretinism in the Jimi valley of New Guinea presents a wide-spectrum with abnormalities of hearing and speech, mental deficiency, a diplegia and strabismus.
2. The disease is closely linked to iodine deficiency. An epidemic of cretinism was precipitated by the withdrawal of a rich source of dietary iodine and the disease can be prevented by iodine supplementation.
3. Iodine deficiency exerts its pathogentic effect during early gestation.
4. A single intramuscular injection of 4 ml. of iodised oil is effective for a minimum period of four years. APPENDIX
CLINICAL SUMMARY OF CRETINS BORN IN THE IODISED OIL TRIAL
* Denotes that conception had already occurred prior to the commencement of the trial. GROUP I Abnormalities of hearing and/or speech, abnormalities of motor development and strabismus.
IODISED OIL
Case 1. WAGI KURAM. Female, born December 1966. Last examined when aged five years and four months. Mentally defective deaf-mute, unable to sit upright. An upper motor neurone lesion involving the arms and legs was present with spasticity, ankle dkonus, pathologically brisk tendon reflexes and extensor plantar responses. She had a convergent strabismus which fluctuated from one eye to the other. The mother was approximately 32 weeks pregnant at the time she received iodised oil.
Case 2. MEKPAI KOMBERAM. Female, born August 1967, died October 1970. Last examined when aged two years and eight months at which time she was unable to either sit or crawl. Her legs were hypotonic but became rigidly extended with the feet in plantar flexion when she was lifted. She was deaf and mute and had a convergent strabismus which fluctuated from one eye to the other. The mother was injected with iodised oil on 6th October 1966, The date of birth of the child is noted in the council records as August 1967, This would be when the mother first presented the child at the Council office , The true date of birth may be earlier than actually recorded.
* Case 3. GANDE ORUKA. Male, born January 1967. He commenced walking aged three years, When last seen aged four years four months he walked with a stiff, unsteady gait and was mute though not totally deaf. His mother claims that he can hear but that he has no speech at all. There was a transient strabismus of either eye. The mother was approximately 26 weeks pregnant when she received iodised oil. GROUP I Abnormalities of hearing and/or speech, abnormalities of motor development and strabismus.
SALINE
Case 1. BER MIND. Male, born 4th November 1967. Deaf and mute, he has pathologically brisk ankle and knee jerks, an unsustained ankle clonus and extensor plantar responses. Walking commenced sometime after three years and four months of age. A transient inward and upward squinting of either eye occurs.
Case 2. GONA WAREBO. Female, born 30th January 1969. (Figure 6). She was last examined when aged three years and five months. At the time she was unable to sit and had a marked head lag when pulled up from the lying to the sitting position. The tendon reflexes in both arms and legs were pathologically brisk and she had a transient convergent strabismus. The parents stated that the child was deaf and mute. She appeared mentally retarded.
Case 3. MEMAL PAKO. Female, born 26th September 1968, died about September, 1971. She was last examined when aged two years and eight months. She was deaf and mute, had a convergent strabismus and was unable to sit unsupported. Both plantar responses were extensor. Case 4. GENT WANDJU. Male, born 13th June, 1969. (Figure 10). Last examined when aged two years and five months. He was deaf and mute, had a convergent strabismus and appeared mentally retarded. The tendon reflexes in both arms and legs were excessively brisk, the plantar responses extensor and he was unable to sit upright.
Case 5. MEKO KONDARI. Male, born 5th February, 1968. Last examined aged four years and two months at which time he was unable to walk. He was deaf and mute and had a transient convergent strabismus of either eye. The motor milestone of sitting had not been attained until he was over two years old.
Case 6. ROY KIND. Male, born 24th March, 1970. At twelve months of age he was unable to sit and there was a pronounced head-lag when pulled from the lying to the sitting position. By twenty months he was able to sit but the spine was kyphotic and he could not stand unaided. The parents state that he is deaf and mute. He has a convergent strabismus.
Case 7. GOPI WEM. Male, born 19th September, 1969. He was unable to sit upright aged fourteen months but had attained this milestone by the age of nineteen months. At two years and two months he could neither stand nor walk, was deaf, mute and had an intermittent convergent strabismus.
Case 8. AIGUMP MENINGA. Male, born 15th November, 1967. A severely affected child who is a mentally defective deaf-mute with a convergent strabismus. The legs are spastic and the tendon reflexes in both upper and lower limbs are pathologically brisk. At four years eight months of age he is unable to walk. Case 9. LANGE TALI. Male, born 14th September, 1968. At nineteen months he was unable to sit upright and when last seen aged three he was just starting to walk. The parents stated that neither speech nor hearing was normal. A convergent strabismus of the left eye was present.
* Case 10. BANG KOMBEK. Male, born December, 1966. This child was first seen aged three years and four months when walking was established though the gait was unsteady. When last seen aged four years eleven months, he was mute though partial hearing at least was present. He had a convergent strabismus of the left eye. The mother was thirty weeks pregnant when the trial commenced.
Case 11. NUMDI WERNDE. Male, born 10th April, 1966. A spastic, deaf-mute. The knee and ankle jerks are pathologically brisk and the plantar responses extensor. He was not able to sit upright until over four years of age and he is unable to stand unsupported. He has a transient strabismus involving either eye.
* Case 12. ARNOLD RENUWAI. Male, born 19th March, 1967. Unable to sit until over three years of age and walking commenced between the ages of four years and four years and nine months, The gait is abnormal, there is a pronounced strabismus and he is a deaf-mute. The mother was sixteen weeks pregnant when the trial commenced.
Case 13. KAME BOLT. Male, born about December, 1967. When examined aged three years six months, he was just able to p# but could neither stand nor walk. The ankle and knee jerks were pathologically brisk. He had a convergent strabismus and was deaf and mute. Case 14. SINGAN KUNIJ. Female, born 8th July, 1970, died March, 1972. When last seen aged nineteen months she was unable to sit upright and had a strabismus. She had not developed any speech and the mother thought the child was deaf.
* Case 15. KISIPA TEMBERA. Male, born February, 1967, died November, 1970. A severely affected child who was unable to sit aged three years. He was deaf, mute and had a convergent strabismus. The mother was about 24 weeks pregnant when the trial commenced.
Case 16. WONGA TUMBI. Male, born October, 1968. Sitting not attained until over thirteen months of age. Walking commenced at about two years but the gait was unsteady. He had a strabismus of the left eye and the parents complained that speech was not normal.
Case 17. SANIYA WANDINE. Male, born 29th June, 1970. When last examined aged eighteen months he was unable to sit upright or to crawl and had a transient strabismus of either eye. He appeared to hear a handclap.
Case 18. KORAMA ATIPEPE. Female, born January, 1970. She was unable to sit until over fifteen months old and when last examined aged two years one month, she could neither stand nor walk. She had strabismus which fluctuated from one eye to the other and had not yet developed any speech. GROUP II Abnormalities of hearing and/or speech and motor development.
IODISED OIL
* Case 1. TOWOLI WUNDA. Female, born 13th December, 1966. Sitting was delayed until after three years of age and walking until four years. The gait at four years and nine months was unsteady, stiff and wide-based and she was deaf and mute. The mother was 30 weeks pregnant when she received iodised oil„
• Case 2. MENAMBA PENPEN. Male, born 7th November, 1966. A mentally retarded child who at four years ten months was unable to walk or stand and had spasticity of the lower limbs with pathologically brisk tendon reflexes and extensor plantar responses. He was also deaf and mute. The mother was 34 weeks pregnant when she received iodised oil.
* Case 3. BEBE WOURA: Female, born 4th April, 1967, died November, 1970. She was last examined one week before she died. At this time, aged three years seven months she was unable to sit unsupported and was deaf and mute. The mother was thirteen weeks pregnant when she received iodised oil_ GROUP II Abnormalities of hearing and/or speech and motor development.
SALINE
Case 1. MOLT KABAL. Male, born 13th March, 1968. Unable to sit until almost two years of age, and walking commenced at three years. The gait was unsteady and spastic and the knee and ankle jerks were pathologically brisk. When last examined aged four he had no speech but was not totally deaf.
Case 2. BELEI MONTS. Male, born 16th November, 1968. Sat at one year three months of age and walked at two years and five months. The gait is spastic. When last seen aged three years and three months, he was mute though not totally deaf.
Case 3. GURUPI KORIN. Male, born July, 1967. Unable to walk or stand until over three years six months of age. The gait is spastic and the knee and ankle jerks are excessively brisk. He is deaf and mute.
Case 4. DIMBON WANDJU. Male, born 9th December, 1968. Brother of GENT WANDJU (Group I, Saline Case 4). Deaf and mute. He was unable to sit until over two years of age and at the last examination aged three years six months he had a pronounced kyphosis when sitting. The left ankle and knee are fixed due to scarring from an extensive burn which partly accounts for his inability to walk, nevertheless the tendon reflexes in the right leg are pathologically brisk. * Case 5. ALIS NGGAU. Female, born April, 1967. She was first seen when aged two years seven months when walking was established but the gait appeared abnormal. The tendon reflexes in the leg were excessively brisk and the plantar responses extensor. She is partially deaf and her parents indicate their wishes to her by signs. When examined aged five, she had a purulent otitis media of the right ear. She did not commence talking until she was five years old. The mother was about ten weeks pregnant when the trial commenced.
Case 6. DEN AMBUNGA. Male, born October, 1969. Sitting not achieved until over thirteen months old. When last examined aged two years eight months he was unable to walk and on sitting there was a pronounced kyphosis. He had no speech and appears not to hear when his mother calls to him.
Case 7. GABRIEL GARAGA. Female, born 7th November, 1968. Deaf and mute. Sitting not achieved until over two years old and at two years ten months was unable to stand or walk.
Case 8. AILA NANGNI. Female, born 15th April, 1968. Walking started aged three and when last examined aged three years eight months the gait was unsteady and stiff and she was unable to negotiate a step. Speech was not normal.
Case 9. GOS YUBUKUAI. Male, born 21st February, 1968. Deaf and mute. He was unable to sit until aged two and walk until after three years of age. He was last examined aged four years four months when the gait was wide-based and stiff. * Case 10. KEP GEWT. Male, born November, 19660 He was first seen when aged three. He could walk but the gait was broad-based and unsteady. The mother complained of the child's inability to talk and this remains the major complaint, though hearing appears fairly normal. The mother was approximately 32 weeks pregnant at the time the trial commenced.
Case 11. JON KUMBA. Male, born 10th February, 1968. Commenced walking aged three years two months. At the last examination aged three years nine months, the gait was spastic and unsteady and the ankle and knee jerks were excessively brisk, The parents stated that speech was not normal though they thought hearing was allright.
Case 12, BON NDAP, Male, born 6th December, 1969, He was unable to sit until two years five months old. The tendon reflexes in the legs were excessively brisk and the plantar responses extensor. He appeared mentally retarded and was mute.
Case 13. TEP MALAGA. Female, born 26th February, 1969. Sitting commenced after the age of fourteen months. When last examined aged three years four months, she was unable to walk and could not crawl properly. The parents stated that her speech was abnormal. GROUP III Abnormalities of hearing and/or speech only.
OIL
* Case 1. WABLI DIWA. Male, born 15th January, 1967. This child was last seen when he was five years old. The parents have always complained that his speech was not normal, though he appeared to hear and understand what was said. There has been no evidence of any motor retardation. His mother received iodised oil when she was 24 weeks pregnant.
* Case 2. REMI RAREN. Male, born 18th January, 1967. He was last examined aged four years ten months. He is mute but can hear a tuning fork. His mother received iodised oil when she was 24 weeks pregnant. GROUP III Abnormalities of hearing and/or speech only.
SALINE
* Case 1. BOAR MEBEBE. Male, born 5th March, 1967. He was first seen when aged two years and eight months when walking was already established and the gait appeared normal. When last seen aged five years three months, he was mute and his parents communicated with him by using signs. His mother was 18 weeks pregnant when the trial started.
* Case 2. KUNAI PIN. Male, born Mardh, 1967. Aged four years two months he had no speech and at least a partial hearing loss. His mother was 18 weeks pregnant when the trial started.
Case 3. AP GUROMP. Male, born 21st July, 1967. Motor milestones were normal but when seen aged three years ten months he was mute and partially deaf.
Case 4. INMOL BAN. Male, born 24th March, 1968. He commenced walking at 23 months. When last examined aged two years eight months, the gait appeared normal. The parents complained that speech was not normal though there is no grossly evident hearing loss. GROUP IV Abnormalities of motor function only.
OIL
* Case 1. PORO ANGGUWAI. Male, born December, 1966. Motor milestones were retarded. He was unable to sit until over twelve months old and did not walk until nearly three years old. The gait was unsteady and speech retarded. When the child was five years old, the parents stated that speech had improved and was normal. There does not appear to be any gross hearing loss. His mother was approximately 20 weeks pregnant when given iodised oil. GROUP IV Abnormalities of motor function only.
SALINE
Case 1. TIMOLO KABUR. Female, born 20th October, 1967. Did not commence walking until over three years of age. When seen at three years and six months, the gait was unsteady and spastic and she tended to fall after every few steps. On sitting there was a marked spinal kyphosis. There did not appear to be any deficit of hearing or speech. GLOSSARY OF ABBREVIATIONS
BEI Butanol extractable iodine PBI Protein bound iodine TBG Thyroid binding globulin TBPA Thyroid binding prealbumin T 3 Triiodothyronine T4 Thyroxine TSH Thyroid stimulating hormone or thyrotropin ECG Electrocardiogram GR Goitre rate VGR Visible goitre rate REFERENCES
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