Kuru

(The previous number of these Transactions, 1Iol. 57, .No. 2, was published on 29th March, 1963.

ORDINARY MEETING of the ROYALSOCIETYOFTROPICALMEDICINEANDHYGIENE, held at M a n s o n H o u s e , 26 P o r t l a n d P l a c e , L o n d o n , W.1,

on Thursday, 21st February, 1963, at 7.30 p.m. The President : SIR GEORGE MCROBERT, C.I.E., M.D., F.R.C.P., in the Chair.

PAPER

KURU BY

D. CARLETON GAJDUSEK National Institute of Neurological Diseases and Blindness, National Institutes of Health, Bethesda, Maryland, U.S.A.

T h e plague of kuru upon the Fore people has attracted the wonder, curiosity, sympathy, and imagination of both the lay and the medical world since Dr. Vincent Zigas and I first described the new disease in 1957 and since, in the wake of our reports, the lay press brought sensational notoriety to the tragic plight of the group of Melanesians who were the sole victims of this dreadful scourge, by irresponsibly dubbing it the "laughing death." Kuru is a Fore word for the shivering and trembling associated with fear or cold, and the name is applied by the Fore people themselves to the rapidly progressive acute, degenerative disorder of the central nervous system, fatal in all but a few of the cases in less than a year from its onset. T h e disease is restricted in its occurrence to members of the Fore cultural and linguistic group inhabiting one small region of the interior highlands of Australian New Guinea, and to their immediate tribal neighbours with whom they intermarry*. T h e patients are predominantly women and children of both sexes, and only rarely adult men. It presents an unprecedented situation of an entire population (a sub-culture of Melanesians) afflicted by a lethal disease reaching hyperendemic proportions, predisposition to which may be determined by a rather simple genetic mechanism. * Before entry of the Australian administration into the Fore region in 1952, the Fore-speaking natives had no name for themselves as a people and instead referred to different sub-groups of themselves by various names, such as: Pamusa kina, Keia kina, and Yanarisa kina ("forest people"). The name Fore kina, or Pore kina, they used to refer to the people living between the Aziana and Lamari Rivers who spoke a language distinct from theirs, and whom they occasionally visited. Administrative officers mistakenly used this name for them, and they have now accepted this designation as have their neighbours. The true Fore (Pore) kina, who also recognized themselves as such, were the people now called, with similar inaccuracy, the Awa. Some Fore refer to Iresa, Abomatasa and Awarosa groups of Fore, which all have close relation with the Awa, as Fore kina, as well.

152

Ktrau

In this lecture I propose to describe briefly kuru and its pattern of occurrence, and to outline the status of investigations of the disease. I shall try to present some explanation for the intense theoretical interest which the disease has awakened in many branches of science. I also intend to discuss some of the problems and concepts bearing on our current attempts to isolate a virus or demonstrate an inborn error of metabolism, and discover a toxin or a deficiency state, a latent infection, or a hypersensitivity reaction which may underlie kuru pathogenesis. Kuru is, primarily, a disease of motor co-ordination with ataxia somewhat akin to the trunkal ataxia of midline cerebellar lesions. Its clinical course is remarkably uniform. Excitement of any sort causes exaggeration of the involuntary movements, which disappear in sleep. The onset is insidious, without antecedent febrile illness. The patient himself is aware of his clumsiness in walking before others notice it. The subsequent course of the disease can be divided into three clinical stages: in the first stage, while the patient is still ambulatory, there is a fine irregular tremor akin to shivering, accompanied by a progressive locomotor ataxia, occasional myoclonic jerks, and emotional lability which is predominantly euphoric. In the second stage, the patient requires a stick for locomotion and later can walk only when supported by others. Tremors are still coarse and irregular, and choreiform and athetoid movements and myoclonic shock-like jerks are present. Dysarthria appears, and emotionalism with easily provoked inordinate laughter persists. Strabismus develops, often accompanied by nystagmoid eye jerks; tendon jerks are usually hyperactive, and there may be sustained ankle clonus. In the third stage the patient becomes sedentary, unable to walk even with support. He is dragged from the low kunai grass house to sit outdoors. Later, when he loses balance even when sitting, he is left inside, aphonic, and with dysphagia leading to starvation. Decubitus ulcers develop and terminal bronchopneumonia is frequent. The patient in this terminal stage often rolls into the house fire and is fatally burned, he may aspirate secretions, or roll over and suffocate. Muscle tone may be normal or may alternate between rigidity and flaccidity. There is no sensory disturbance; muscle fibrillations appear only late;in the disease. No outsiders from the kuru region have yet developed kuru after residence in the region, or upon close association with kuru victims. The genealogies of all kuru patients yet studied and all human ecological and epidemiological investigations continue to support the hypothesis that predisposition to kuru is determined by a single gene, dominant in the female only, which produces fatal disease in homozygous individuals of both sexes in childhood and in the heterozygous female carriers in adult life, but is usually non-penetrant in the heterozygous male carriers. This simplest serviceable genetic hypothesis cannot be proved; however, no case yet offers evidence to refute it, although genetic explanation of such a high incidence may seem highly improbable where the disease has attained staggering proportions in the South Fore region, more than decimating the original population each decade. For such a situation to arise, carriers of the hypothetical kuru gene must possess a distinct genetic advantage in the region, for unless such carriers were more fit than non-carriers, loss of the gene through death of non-reproductive homozygotes would have prevented the attainment of its present high frequency in the society. Random gene drift in the small population isolates of the region could hardly account for its wide-spread high frequency throughout most of the South Fore population of over 7,000. However, other genetically dependent alternatives remain, as, for example, the possibility that the kuru-predisposing non-lethal genetic constitution may have silently mounted to a high frequency in the population without associated disease as a balanced polymorphism which then became suddenly lethal with some

D. CAIRLETON GAJDUSEK

153

change in environmental factors, in the presence of which this genetic constitution was no longer innocuous. Certainly, the kuru situation is not in equilibrium today, nor has it probably ever attained equilibrium in the past. TttE ECOLOGY AND HUMAN BIOLOGY OF KURU

Kuru has now been under intense medical surveillance for a period of six years, and over 1,000 patients have been studied from the time of onset to their death. The boundaries of kuru occurrence are now known with moderate certainty. The disease occurs in 159 census units (complexes of hamlets grouped together for the purpose of yearly administrative enumeration of the population) of the Fore people and eight surrounding linguistic groups in the Eastern Highlands region of East New Guinea (Figs. 1 and 2). These hamlets are spread over an area of over 1,000 square miles and comprise a total population of over 35,000. T h e Fore themselves live on the Purari side of the Ramu-Purari Divide, principally on the eastern watershed of the YaM River and the western watersheds of the Lamari River. Th ei r hamlets and gardens lie between 4,000 and 7,500 feet above sea level. T h e northern hamlets lie in the higher valleys, usually at 6,000 to 7,000 feet, and the southern hamlets in the lower valleys at 4,000 to 4,500 feet. T h e region lies to the east of the Mt. Michael massif (12,500 feet) and is densely forested, with moss-covered rain forests at the higher elevations (above 9,500 feet). Kunai grass (Imperata sp.) covers many of the lower slopes, and in its extent indicates the degree of slash-burn agriculture in the past. T h e region is, and has been, more sparsely settled than is the case in the wide kunai-covered valleys of the Highlands to the north of the Ramu-Purari Divide. T h e current population density of approximately 30 per sq. mile, somewhat higher in the north Fore than in the south, is under that for many New Guinea Highland areas. Some kuru-afflicted hamlets of other linguistic groups lie in the northern, Ramu, side of the Divide among the Kamano and Usurufa people, and some kuru-afflicted hamlets in the Gimi are located on the western watershed of the Yani. However, the disease does not extend southward across uninhabited lower sago forests to the Yar-Pavaian population in Papua, nor does it cross the Lamari River to the Awa and Kukukuku populations which border the Fore on the east. It is of considerable interest that the disease extends in high incidence to hamlets at the borders of this sharp eastern and southern discontinuity of kuru occurrence, whereas northward and westward the incidence falls off gradually to low levels. T h e Abomatasa hamlets of the South Fore are unusual, however, in their exceptionally low kuru incidence among South Fore census units.

Since the entire population of the kuru region and surrounding hamlets of the adjacent linguistic groups is enumerated annually, all individuals are seen and accounted for each year. Virtually all of the last 1,000 patients who have developed kuru have been seen by medical investigators, often repeatedly, while they were still well and before the onset of their first symptoms of kuru. Many dozens of cases of kuru have developed and followed the typical course to death in individuals who have for several years been well known to the investigators and under careful medical surveillance. There have even been several cases in Fore male youths who have been living, working, and eating in the households of Europeans for months to years before the first onset of their symptoms. Some of these individuals and a few Fore labourers have developed kuru while living far from the extreme boundaries of the kuru region. A few have proceeded to fatal termination without ever returning to the previously established boundaries of kuru occurrence. Most significant of these cases are in those who have had prolonged residence (up to six years) outside of the region of previous kuru occurrence before the onset of their symptoms. In addition, a few cases have developed in individuals who have worked as labourers for many months to over a year in the New Guinea coastal lowland plantations where they have had no contact with the flora and fauna of the kuru region, and where few of the ecological or dietary conditions in their homeland prevailed. These patients are of particular significance in that they rule out the possibility of acute

154

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FIG. I. Cultural and linguistic groups in and surrounding the kuru region in the Eastern Highlands of Australian New Guinea. The population in hamlets affected by kuru in each group is given.

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D. CARLETON GAJDUSEK

155

toxic or infectious aetiology and make even chronic toxicity or deficiency states highly improbable. Mortality figures vary from hamlet to hamlet and native area to native area throughout the kuru region. They are presented on the map of the kuru region in Figure 3, and in greater detail in the Table. Mortality figures are calculated as cases per 1,000 population per annum. It is now possible to compare kuru mortality figures for the years 1957 to date. Because of differing incidence of the disease throughout the region, the figures must be analyzed by small native areas and the number of cases each year in any given census unit is often sufficiently small to permit wide random variability from year to year. It would thus seem preferable to analyze mortality figures at 2-yearly intervals, i.e., 1957-58, 1959-60, 1961-62, in order to investigate whether significant change in kuru incidence has occurred during the past six years of continued change in Fore culture under the impact of Western civilization. When this is done it is apparent that although there have been wide variations in mortality in given census units over whole native areas, the mortality has remained much the same as it was in the more primitive, pre-contact type culture which prevailed when kuru studies were initiated.

Fro. 3.

Mortality by tribal area in the kuru region. Figures are calculated as patients per 1,000 per a n n u m from data covering the 6-year

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The South Fore population under 16 years of age has a male to female sex ratio of 1.14 : 1, while the sex ratio of adults greater than 16 years is 1.87 : 1. In some Fore hamlets a 3 : 1 over-all sex ratio is found. In Figure 4 the varied over-all male : female sex ratio throughout the kuru region is plotted by native area. It will be seen by comparison with Figure 3 that the sex ratio is most shifted in favour of males where kuru prevalence is highest. In the 14 months up to August, 1962, there were 371 births in the South Fore as opposed

150

D. CARLETON GAJDUSEK

TABLE. Male : Female sex ratio, kuru mortality and per cent. recovery from kuru, 1957-1962. Location

Male : Female

Mortality

Per cent. recovery

South Fore Atigina Kamikina Ifufurapa Ilesa Purosa

1.7 1.5 1.6 1.5 2.0

22.9 16.0 16.8 11.1 25.9 1.6

2.9 9.8 10.4 15.6 4.0 7.1

18.6

North Fore Aga Awande Okasa O farina Ibusa Wantakabarasa

13.4 10.8 11.9 5.0 4.8 5.6

1.1 0.9 1.4 1.3 1.2 1.1 1.2

9.1 16.0 2.4 3.2 14.0 10.5 9.4

6.4

Keiagana Kigupa Taramo Hogateru Yagaria

0.7 1.2 2.5 6.6

1.1 1.1 1.0 1.2 1.1

15.4 14.3 23.1 11.1 16.0

1.7

Gimi Hepavina Negibi Mani A'ibu Raro

11.7 0.3 0.0 2.7 0.8

1.4 1.1 1.0 1.2 1.0 1.2

Kanite Kio Kemiu Arnufi

18.2 71.4 100 11.7 0

0.8 2.6 1.0

1.2 1.1 1.1

19.0

3.2 0 10.5 0

1.1

1.6

7.1

1.0

0.3

0.0

1.2

0.5

0.0

Usurufa

1.1

1.0

0.0

Auyana

1.0

0.1

0.0

Yagaria

1.1

0.4

0.0

Kamano Yate Iatebi Kauna Numugar

1.4 0.9 0.3

1.5 1.2 1.1

D.

CARLETON

157

GAJDUSEK

to 271 deaths, making a net increase of 11.9 per 1,000 per annum. The South Fore are increasing in number, in spite of the ravages of kuru, The explanation of the distorted sex ratio in areas of maximal kuru incidence lies in the fact that kuru is predominantly a disease of women. In Figure 5 the age and sex distribution of the 1,265 patients with kuru studied since the beginning of 1957 (127 "recovered" cases are excluded) is plotted. THE PAST HISTORY OF KURU AND ITS IMPLICATIONS

Knowledge of the past history of kuru and the date of its first appearance obviously could influence greatly our thinking about its pathogenesis. Reliable data affirming its sudden appearance or rapid spread in new regions, which could not be explained by genealogical analysis, would be strong evidence that the disease is not completely genetically determined. On the other hand, even extensive evidence that kuru was a new illness would not rule out a genetically determined susceptibility to some environmental factor, or peculiar constellation of factors. A silent genetically susceptible hearth might develop in the population and first become evident only after historical changes in environmental factors. Thus, a genetically determined susceptibility or intolerance to a toxin, to an otherwise normal metabolite, or even genetically determined thresholds (i.e., requisite relative concentrations of nutrients) might make dietary alterations, innocuous to an ordinary population, become suddenly dangerous or lethal to such a susceptible population. Other possible genetically mediated mechanisms of pathogenesis must be considered in kuru. Such mechanisms as occur in genetically controlled idiosyncracies to drugs or to hypersensitivity phenomena and genetically mediated susceptibility to infectious agents remain open possibilities.

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FIG. 4. Male: Female ratio in each tribal area of the kuru region. T h e close correlation of these ratios with the mortality data presented in Figure 3 is of interest.

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It is unfortunately impossible to reconstruct a fully reliable past history in the kuru region, where traditional and genealogical memory is shallow, rarely existing for five generations, and where myth, legend, and past history blend imperceptibly together in the only recent past. There have been no outside observers, and the cultures have kept no written record of any sort. However, even in the recent past since observations have been recorded by Europeans and, especially, since 1957, when documentation of all cases of kuru began, there is ample evidence of kuru occurring for the first time in new communities on the periphery of the region, and of the recent increase in incidence in certain peripheral communities. Civilized contact itself has been responsible for the increased movement of the populace which has led to some of this spread. Careful interviewing of the natives has yielded reliable, easily cross-checked accounts of the progressive spread and increase of the incidence of kuru in many communities in the decade, or two decades, before the arrival of the white man. In the high-incidence central region, and in some of the peripheral communities also, accounts of kuru go back much longer to 40 years or more. But we have been unable to obtain accounts of earlier cases except in a very few instances. I have interpreted this as the result of waning memory for the past, particularly in view of the small number of informants over 60 years of age, and in view of the unreliability of adult informants in reporting events which occurred before their own late adolescence. On the other hand the anthropologists, Robert and Shirley Glasse, working in the South Fore region during the past two years, are convinced that in the communities they have studied

D. CARLETON GAJDUSEK

159

kuru made its first appearance only some 40 years ago. They trace native accounts of kuru in Uwami in the Keiagana region to some 50 years ago or more, followed by spread to the Awande and Kasokasa groups of Fore some 40 years ago, with a spread about 35 years ago into Atigina and Purosa native areas of the South Fore. They claim that kuru has been present for only the past 20 years in most of the North Fore hamlets, and only for the past 12 years in Paid in the south-western part of the Fore area. Were there a reliable history such as that which they have constructed for the Uwami, Kamira and Wanitabi groups for the entire kuru region, we might conclude that kuru could not be fully genetically mediated. However, even were such data available, a genetic hypothesis of aetiology could still be maintained by espousing genetically determined susceptibility to environmental factors. Two examples of such mechanisms--purely hypothetical--are given: Recent changes in Fore diet, such as that created before European entry by the diffusion of corn into the region, may have upset a nutritional balance in a population already in balanced polymorphism for a trait which provides idiosyncratic pathological reaction to an otherwise normal nutrient. This would be quite parallel to the phenylketonuric's intolerance to phenylalanine. Throughout many regions of the interior of New Guinea the native population has survived under conditions of marked salt deprivation, with very minimal intakes of sodium and extremely high potassium intake. Native salts are often found to contain more potassium chloride, and potassium carbonate, and calcium carbonate than sodium chloride; and enormously high potassium:sodium ratios are found in casual urine specimens. Prolonged sodium deprivation with an intake of near-toxic levels of potassium may lead to compensatory shift in adrenal cortical function. Under such conditions there would be a selective advantage to any mutation which could lead to better homeostasis in the face of such high potassium and low sodium intake. The balanced polymorphism resulting from the introduction and survival of such a mutant might yield a high incidence of persons intolerant of more usual high sodium and lower potassium intake. Trade salt (NaC1) introduction from European contact--since salt is one of the first trade items introduced by government officers, missionaries, and miners as an item of exchange and payment--would then constitute the type of environmental change one sought to account for the strangely high incidence of kuru on a genetic basis. There is little or no evidence for either of these two specific suggested bases for kuru, but they offer realistic examples of the kind of situation for which we have been searching. AETIOLOGICAL HYPOTHESES

I have obviously been stressing possible means of maintaining a genetic hypothesis of kuru pathogenesis, not, however, from any particular desire to defend such a hypothesis, but from the necessity of conceding that all observations to date fit the simple genetic hypothesis stated above. Only the difficulty of explaining how the high requisite gene frequency could have arisen provides cause for doubt. Furthermore, all the other aetiological possibilities that we have entertained are beset by observations which make them even more unlikely than the genetic mechanism. None the less, we are investing our maximum effort in kuru investigation in an attempt to discover a virus aetiology, and in biochemical investigations aimed at uncovering any metabolic derangement which might put us on the track of an inborn error of metabolism and its associated enzyme deficiency, or some toxic or deficiency state; and in immunological and serological studies aimed at discovering a hyper-

160

KURU

sensitivity or autoimmune mechanism, perhaps in relation to a latent infectious agent. It would thus be in order to enumerate explicitly here the various aetiological possibilities which we have considered: 1) infection (including post-infectious reaction); 2) toxin; 3) deficiency; 4) hypersensitivity (immune reactions); 5) psychological reaction, probably hysterical; 6) genetic predisposition. These will now be considered in more detail. 1)

Infection

Investigations of kuru principally attempt to establish the aetiology and define its pathogenesis. Of the various aetiological possibilities, the studies most vigorously pursued are those aimed at uncovering an infectious agent underlying the pathogenesis. Infectious aetiology might represent: a) actively progressing infection, either very slow in progress with a long incubation period, or sudden activation of latent, silent infection; or b) a neurotoxic response from a distant focus of infection, as seen in tetanus (or from an exogenous focus, as in botulism); or c) a state of hypersensitivity or auto-immunity bearing a relationship to the micro-organism similar to that of post-encephalitic Parkinsonism to the virus of von Economo's encephalitis, or rheumatic diseases to the streptococcus; or d) a slowly progressive degenerative process, such as Hotchin has described in mice infected with lymphocytie choriomeningitis virus in infancy which, after developing immune tolerance, suffer from persistent tolerant infection. Furthermore, the possibility of genetic interaction with infectious processes must be considered. This could operate either at a level of a) genetic transmission of the agent in a fashion akin to the genetic transmission of temperate viruses in bacteria, but still unknown in mammalian cells; or b) susceptibility determined by pure genetic factors to a transmissible, widely disseminated infectious agent. Genetic transmission may be mimicked by nongenetic mechanisms such as a) transovarial transmission, as described for certain rickettsia and viruses in ticks, b) transplacental infection, which may occur with spirochaetes, toxoplasms, and viruses, c) venereal .infection, or d) transmission of a milk factor during lactation. This wide variety of possibilities clearly suggests that infectious aetiology should not be glibly dismissed as a possibility. The clinical and laboratory findings and histopathology of the disease fail to suggest an infection or an auto-immune hypersensitivity. The patient remains afebrile; cerebrospinal fluid shows no pleoeytosis or elevated protein, even late in the disease; there is no elevation of the erythrocyte sedimentation rate or alteration in peripheral haematology. Certain helminthic infections, particularly those with larval migrans, and certain fungal and spirochaetal and protozoal infections are difficult to demonstrate histopathologically and may fail to have pathological findings suggestive of infection. Furthermore, the possibility of a microbiak toxin such as the neurotoxins well known from bacteria, fungi, and rickettsia, must be considered. All these possibilities, however, seem remote in view of the epidemiological observations of kuru cases occurring in patients absent for many years from the ecology of the kuru region, and the failure to find, thus far, any cases of contact infection in natives from remote regions who are in intimate contact with kuru region natives or living in the kuru region itself. The man-years of such contact and residence of potential "susceptibles" are rapidly mounting beyond values which should already have yielded cases of kuru. Of all the infectious possibilities, the most likely seems to be that of a slow or latent virus infection either congenitally or genetically transmitted, or an infectious agent widely disseminated, but with genetically determined susceptibility. Recent developments in cancer virology offer numerous examples of such latency with apparent genetic control.

D. CARLETON OAJDUSEK

161

Hadlow in 1959 first drew our attention to the similarities between kuru and scrapie. Both the clinical features of the disease and the histopathological lesions found in the nervous system in scrapie are much like those found in kuru. Scrapie is an incurable disease of sheep, fatal within one to 12 months. It has been known in Europe for centuries and in England since 1720. Sheep breeders have traditionally considered it a hereditary disease of the central nervous system. Parry has now presented impressive data to support the hypothesis that the naturally occurring disease is hereditary and determined by a simple mendelian recessive gene. However, three decades ago Gordon and his Co-workers established the transmissible and filterable nature of the scrapie agent, and experimental transmission by intracerebral or subcutaneous inoculation of brain or visceral tissue from scrapie or pre-scrapie sheep is clearly possible. The experimental disease occurs only after a prolonged incubation period ranging from one to five years in various breeds of sheep, and from 7 to 18 months in goats. In the past two years Chandler has shown that the disease from goats may be transmitted to laboratory mice of many breeds and we and others have confirmed this; Chandler and we have succeeded subsequently in transmitting a scrapielike encephalomyelitis to mice by injection of brain material from sheep with naturally occurring scrapie. Further parallels between scrapie and kuru have become evident in an uncanny array; thus, many epidemiological features appear alike in the two diseases: small limited loci of high incidence of scrapie occur, and they are limited by breeding pattern; natural scrapie is apparently determined by genetic mechanisms (the scrapie trait segregating as a recessive mendelian agent); sudden epidemic-like high incidence of scrapie in one generation occurs in flocks previously thought to be scrapie-free; clinical features of the two diseases are strangely akin; and recent neuro-histological studies have revealed yet further remarkable similarities between kuru and scrapie, besides these which Hadlow first noted. Thus, Beck, Daniel, and Parry have recently demonstrated extensive hypothalamic lesions in scrapie with evidence of grossly disturbed neurosecretory activity, with large amounts of neurosecretory substances deposited in the neural portion of the pituitary stalk and even in the glandular pars tuberalis. There is also a deficiency of neurosecretory material in the neural lobe of the pituitary. The supraoptic, paraventricular, ventro-medial nuclei, the lateral hypothalamic area, the nucleus reuniens and manlmilary bodies frequently demonstrate severe neuronal lesions. Similar hypothalamic lesions have been found by these workers in kuru specimens, and this finding further emphasizes the previously noted analogy between kuru and scrapie, and strongly supports the need for more penetrating neuroendocrine and biochemical studies in kuru. 2) and 3) Toxin or Deficiency A nutritional survey of the Fore and dietary balance studies were done in 1957 on kuru victims and their families in collaboration with Mrs. Lucy Hamilton Reid. The Fore diet was found to be superior to that of many surrounding kuru-free groups. Fore men and boys share food and eat together with the women and younger children far more often than do the males in many other New Guinea societies, although they practice the sex segregation in sleeping and living which prevails in New Guinea Highland communities. Lists and collections of over 400 zoological and botanical specimens used by the Fore people as foods, condiments, body paints, medicines, etc., were prepared. The consistency of use, or excessive use of these specimens by patients who had later developed kuru was checked. Similar employ of these specimens by people of surrounding linguistic groups was noted. No

162

Krrau

item of the collection appeared to be used regularly, exclusively, or excessively by individuals who developed kuru, and all items were found to be similarly used by at least one surrounding kuru-free populace. These findings, taken with the discovery of the onset of kuru in individuals fully removed from contact with the ecology of the kuru region, considerably dampened our enthusiasm for toxicological studies. Although a number of the specimens of the wild flora and fauna used by the Fore were found to possess interesting pharmacological activity, and some, such as certain varieties of the edible heart of grass, were rich in alkaloids, none of these items appear to have relation to kuru pathogenesis. , Because of the clinical and, to some extent, pathological analogy between kuru and certain heavy metal poisonings--mainly those with manganese, copper and mercury--trace metal analyses of tissues from kuru patients (blood, urine, cerebrospinal fluid, and autopsy material) were carried out with failure to detect any trace metal or usual elements in abnormally high concentration. Similar analysis was carried out on garden soil, drinking water, stones used in mumu pit cooking, and native salt preparations. Kuru patients early and late in the disease were treated with massive doses of dimercaprol and of calcium disodium versenate without alteration in the patients' condition or change in their subsequent course. Trace metal studies on urine before and during therapeutic trials revealed an increased excretion of copper, but no more than would be expected in normal individuals so treated. Finally, the disease in kuru victims removed totally from the known region of kuru occurence at the onset of their symptoms has proceeded to fatal termination in the same time patterns which we observe in the Fore hamlets. The course and clinical picture have remained unaltered by the change in environment and the provision of a near-European diet heavily fortified with vitamins and mineral supplements. This has likewise been true of the pattern of kuru in those victims who have first developed the disease after prolonged absence from the kuru region and have not returned to their homeland during the course of their illness. 4) Hypersensitiz'ity (Immune Reaction) Early in kuru investigations we entertained such a n outlandish hypothesis as the possibility that, in the course of ritual cannibalism (the consumption of dead relatives, particularly by women and children as an act of respect and mourning) the infantile gut may have permitted passage of undenatured homologous brain antigens which might have initiated a state of auto-sensitization. Kuru symptomatology might then have been initiated by further ingestion of human brain at a later date by the hypersensitized individuals. Search for autoimmune complement-fixation antibodies to human brain antigen in sera from kuru patients has yielded negative results, and, more recently, Dr. Philip Paterson of New York University has failed to demonstrate serologically brain antibodies in kuru sera. On the other hand, early in kuru investigations, Dr. Cyril Curtain and I demonstrated the presence of an abnormally high level of ~-globulin in kuru sera, and this finding has been further confirmed. The possibility of a strange form of auto-immunization and hypersensitivity reaction thus remains, and Sir Macfarlane Burnet, interested in this possibility, is examining thymus glands from autopsies performed on kuru victims. 5) PsychologicalReactions and the Problem of Recovery from Kuru The clinical symptoms and signs of kuru clearly point to organic brain disease. The neuropathological findings in the disease are sufficient evidence to rule out any psychotic or hysterical-type reaction as a likely explanation for this illness. They consist of: a) wide-

D. CARLETON GAJDUSEK

163

spread neuronal degeneration, b) myelin loss, predominantly in spinocerebellar and cordcospinal tracts, c) intense astroglial and microglial proliferation, d) scattered perivascular cuffings with mononuclear elements, and e) presence of anisotropic, plaque-like bodies in over half the cases. These findings, while each in itself non-specific, are present in a pattern not seen in many other diseases and certainly not suggestive of any psychosis-like reaction. There have been a number of recoveries from kuru, including a few in patients who had progressed to moderately advanced disease. Since early 1957, 127 patients have been diagnosed as kuru victims who are now considered to be well. They constitute 9.1 per cent. of all cases diagnosed in this period. There have been yet further recoveries, but these have been in individuals whose disease has again exacerbated and finally terminated fatally. No patients who have developed neurological signs such as dysphagia, strabismus, ankle clonus, altered deep tendon reflexes, or muscular fasciculations, have recovered. A number of patients, including a few children, have had an exacerbating and remitting course with a total duration of disease of over two years from onset to death. There has also been a rare patient with very mild, slowly progressive disease which has dragged on for over three years. However, fewer than 10 per cent. of the patients with early symptoms of kuru recover, and of this 10 per cent. many suffer recrudescence of their disease and eventually die of kuru. Many of those who recover completely (no more than 9 per cent. of all patients) have undoubtedly suffered from hysterical mimicry of the kuru syndrome, as is evidenced by their sudden dramatic recovery, overnight or in a single day, from the advanced clinical picture into which they plunged with unusual rapidity, without the usual slow, insidious onset. There may be among the surviving patients a few who have recovered without sequelae from true kuru, but we have no way of establishing this possibility. In the map in Figure 6 the percentage of all kuru cases diagnosed in the past six years, and now surviving without disease, is plotted by linguistic and tribal group. The Table shows that surviving recoveries constitute 19.0 per cent. of the Gimi patients, 16.0 per cent. of the Keiagana, 9.4 per cent. of the North Fore, and only 7.1 per cent. of the South Fore--an interesting reversal of the order of mortality data. Furthermore, this trend is preserved into the tribal groups of the South Fore: in the high-incidence Purosa and Atigina tribal areas only 4.0 per cent. and 2.9 per cent. of the patients, respectively, are now surviving as recovered kuru patients. I can offer no explanation for this observation. 6) Genetic I have already discussed several aspects of the problem of a purely genetic determination of kuru in the introduction to this paper. Since we cannot yet dismiss this possibility, it requires further discussion. The existing high incidence of kuru, particularly the unusually high incidence in the South Fore hamlets, raises serious doubt as to the possibility of a genetically determined lethal trait reaching such staggering frequency in a population where homozygous individuals are lost before reproductive age and heterozygous carriers, at least the females, die earlier than their non-carrier age mates. The situation would seem to demand a remarkable genetic advantage associated with the kuru trait, and the mechanism of random gene drift, as discussed by Sewell Wright, would be required to have played a very improbably intense role. Extensive search for some biological advantage at a morphological or biochemical level associated with the kuru trait has failed to suggest any such phenomenon. In sheep, Dr. Parry of Oxford has noted that a peculiar distribution of hypertrophic muscles and unusual muscle formation preceding the development of scrapie tends to favour the chance

164

FIG. 6. Kuru recoveries by tribal area calculated as percentage of all kuru cases diagnosed in the area from 1957 to 1962 inclusive. Recoveries include still remitted victims of true kuru, patients with hysterical mimicry of kuru, and other misdlagnosed patients.

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of a pre-scrapie animal being selected for breeding stock in stock shows. We are reminded of the musculature condition in man early in pseudohypertrophic muscular dystrophy. No such obvious advantage has been observed in kuru. However, as discussed above, infectious, toxic, deficiency, or hypersensitivity factors may operate with genetic dependence. As illustration of this possibility: pharmacologists and geneticists have recently been aware of altered drug responses associated with hereditary defects. This is particularly true in the case of barbiturate sensitivity in porphyruria, primaquine sensitivity, and the genetically determined idiosyncrasy apparently present in favism. There is, in addition, a group of inherited metabolic disorders with biochemical defects causing pathological responses to constituents of normal foods. In these cases normal dietary components become toxic at otherwise normal levels. There are yet other inborn errors of metabolism in which the specific enzyme defect leads to an accumulation of toxic levels of otherwise normal metabolites, or to toxic responses to normal levels of metabolites. Thus, phenylalanine is harmful in phenylketonuria; copper in Wilson's disease; and galactose, sucrose, leucine, and gliadin in other inborn errors of metabolism. Crigler-Najjar syndrome in children, with specific suppression of an ether-type glucuronate formation, may result in idiosyncratic hypersensitivity of such patients to a wide variety of agents which undergo substantial glucuronide conjugation during detoxification and excretion. Early in the clinical studies on kuru we noted that women suffering from kuru often became pregnant after the onset of their disease and still went on to deliver normal infants, although they were in advanced disease at the time of delivery. As our clinical experience with kuru increased, we obtained the impression that pregnancy, particularly in its later

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165

stages, distinctly retarded the otherwise rapid progress of the disease, and that kuru seemed to remain stationary in many women in late pregnancy and early lactation, then suddenly to accelerate its course to fatal termination after the first few months of lactation. Menstrual cycle, conception, foetal development, parturition, and lactation all seemed to be unimpaired by kuru. We noted no alterations in secondary sexual character in child, adolescent, and adult patients. Although an adiposity unusual among the Fore often appeared in patients as their ataxia began to limit their physical activity, we have seen no other clinical signs of endocrine disturbance. Therapeutic trials of androgens (testosterone propionate and methyltestosterone), given orally and intramuscularly in high dosage, failed to arrest the usual course of the disease in the early stages in either adult or child patients. In fact, in a few instances, where high androgen dosage was employed, there was such an acceleration of the usual course of kuru that we hesitated to continue such therapeutic trials. Groping clinically, we employed estrogens in high dosage with the same effect, namely, young male and female patients deteriorated even more rapidly than might otherwise have been expected. The number of patients who showed this ominous deterioration on either androgenic or estrogenic steroids has been too few to be conclusive, yet we dare not further pursue such clinical trials of these agents. This suggestive observation, together with the still inconclusive laboratory data indicating abnormal serum steroid levels, would lead one to speculate on the possibility of an already dangerous steroid load being augmented by either androgenic or estrogenic steroids. On the other hand, high dosage therapy with cortisone, ACTH, and delta-1hydrocortisone, used to toxic levels in 1957 and 1958, failed to alter the course of the disease. Whatever aetiology is eventually assigned to kuru, whether it be a specific one-gene one-enzyme defect and a balanced genetic polymorphism which alone determines the disease, or whether a transmissible virus, a hyperimmune mechanism, or a toxin is eventually demonstrated, the disease cannot be adequately explained without accounting for the remarkable age and sex distribution of patients. Thus, the failure of cases to occur before about 4½ years of age, and their appearing in maximal incidence in early childhood, with disease in the youngest patient very much the same clinically as in the sexagenarian, present a unique pattern demanding explanation. Furthermore, the unique shift from a nearly equal sex ratio in child patients to an adult pattern of an overwhelming preponderance of women (14 per male patient in the 20 to 40 year age-range and 72 per male patient at ages over 40) requires complete causal elucidation before kuru pathogenesis is understood. The age-sex distribution is so unusual and constant a feature of the epidemiology of this illness that we have been tempted to look to it for clues as to aetiology and pathogenesis. It has suggested endocrine studies both in search for aetiology and in therapeutic trials. Since the disease does not interfere with conception or pregnancy, and since there are no changes in secondary sexual characters which we have noted, attention has been directed toward the androgenically and estrogenically silent steroids and to the pituitary hormones. Clinical observation of ameliorative effects on kuru symptoms of pregnancy and early lactation, the therapeutic observation of untoward response to estrogens and androgens, the pathological findings of hypothalamic secretory disturbances in kuru specimens, the findings of unusually high growth hormonal levels in cold acetone preserved pituitary glands from the kuru area, and, finally, the preliminary observation of unusual levels of compound B in kuru sera, all suggest a further pursuit of neuro-endocrine relationships in investigations on kuru.

166

KURU

BIBLIOGRAPHY BECK, E., DANIEL, P. i . & PARRY, H. B. (1962). Hypothalamic and cerebellar system degeneration m sheep with serapie. 4th Int. Congr. Neuropath., 4, 269. BENNETT, J. H., GRAY, A. J. & AURICHT, C. O. (1959). T h e genetical study of kuru. Med. ft. Aust., 2, 505. , RHODES, F. A. & ROBSON, H. N. (1958). Observations on kuru. 1. A possible genetic basis. Aust. Ann. Med., 7, 269. , - &- (1959). A possible genetic basis for kuru. Amer. ft. hum. Genet., 11, 169. CURTAIN, C. C., GAJDUSEK, D. C. & ZmAS, V. (1961). Studies on kuru II. Serum proteins in natives from the kuru region of New Guinea. Amer. ft. trop. Med. Hyg., 10, 92. FOWLER, M. & ROBERTSON, E. (1959). Observations on kuru. III. Pathological features in five cases. Aust. Ann. Med., 8, 17. GAJDUSEK, D. C. (1962). Kuru: an appraisal of 5 years of investigation. Eugen. Quart., 9, 69. & REID, Lucy Hamilton (1961). Studies on kuru. IV. T h e kuru pattern in Moke, a representative Fore village. Amer. ft. trop. Med. Hyg., 10, 628. & ZIGAS, V. (1957). Degenerative disease of the central nervous system in New Guinea. T h e endemic occurrence of "kuru" in the native population. New Eng. ft. Med., 257, 974. & (1959). K u r u : clinical, pathological and epidemiological study of an acute progressive degenerative disease of the central nervous system among natives of the Eastern Highlands of New Guinea. Amer. J. Med., 26, 442. - & ~ (1961). Studies on kuru. I. T h e ethnologic setting of kuru. Amer. J. trop. Med. Hyg., 10, 80. - - , - & BAKER, J. (1961). Studies on kuru. I I I . Patterns of kuru incidence: demographic and geographic epidemiological analysis. 1bid., 10, 599. GLASSE, R. M. (1962). T h e spread of kuru among the Fore: a preliminary report. June. (Mimeographed) Public Health Dept. Port Moresby, Papua. I-IADLOW, W. J. (1959). Scrapie and kuru. Lancet 2, 289. KLATZO, I., GAJDUSEK, D. C. & ZIGAS, V. (1959). Pathology of kuru. Lab. lnvest., 8, 799. MORRIS, J. A. & GAJDUSEK, D. C. Encephalopathy in mice following inoculation of scrapie sheep brain. Nature, Lond. (in press). PARRY, H. B. (1962). Scrapie: a transmissible and here.ditary disease of sheep. Heredity, 17, 75. REID, LucY H. & GADJUSEK, D. C. Studies on kuru. V I I . Nutritional status of the Moke Fore. Amer. ft. trop. Med. Hyg. (in press). SIMMONS, R. T., GP~YDON, J. J., ziGas, V., BAKER, LOlS L. & GADJUSEK, D. C. (1961). Studies on kuru. V. A blood group genetical survey of the kuru region and other parts of PapuaNew Guinea. 1bid., I0, 639. - - , , - - , - & - (1961). Studies on kuru. VI. Blood groups in kuru. Ibid., 10, 665. SIMPSON, D. A., LANDER, H. & ROBSON, H. N. (1959). Observations on kuru. II. Clinical features.

Aust. Ann. Med., 8, 8. ZIGAS, V. & GAJDUSEK, D. C. (1957). Kuru: clinical study of a new syndrome resembling paralysis agitans in natives of the Eastern Highlands of Australian New Guinea. Med. J. Aust., 2, 745.

167

DISCUSSION Dr. H. E. W e b b : William Shakespeare wrote, " T o gild refined gold, to paint the lily, . . . is wasteful and ridiculous excess." I think these words would apply both to the quality of Dr. Gajdusek's paper and to his photography. One hundred and twenty-seven patients with kuru have recovered, this being 9.1 per cent. of all cases diagnosed during the period. A few lines later is written, " Many of those who recover completely (no more than 9 per cent. of all patients) have undoubtedly suffered from hysterical mimicry of the kuru syndrome." I wonder if there have been any cases of kuru which recovered, and had unequivocal C.N.S. signs which could not be mimicked. I would have felt that, by the very nature of the disease and its histopathology, recovery was unlikely, but arrest of the disease process possible. In such a primitive people it must be very difficult to get accurate information on such points as this which would stand statistical analysis. I have been convinced that kuru is at any rate partially genetically determined. If there is another factor it appears very unlikely to be due to a toxin, deficiency or change in dietary habit, because of occurence of the disease in those removed totally from the known region of kuru and the normal dietary habits practised there. I favour strongly the idea of kuru's having a similarity to scrapie. As Dr. Gajdusek has said, " Parallels between scrapie and kuru have become evident in uncanny array." The fact that both may have some relation to other human demyelinating conditions, such as disseminated sclerosis, must be of the greatest importance. It is known that one human brain from a subject suffering from an acute stage of disseminated sclerosis has caused in sheep a scrapie-like illness. This, as yet, has not been repeatable. But the possibility that it may be, makes the work on kuru and on scrapie even more important. Naturally occurring scrapie appears to be the result of an infecting " a g e n t " that is able to cause disease in certain genetically determined breeds of sheep. The agent has been shown to be able to cross the placental barrier in sheep. The fact that goats and mice can develop the disease after inoculation appears to confirm the infective-agent theory. It seems that a similar situation is possible in kuru. An " agent " passes through the placenta to the foetus and the females, being more genetically suitable, have a higher incident of the disease. That contacts of all the Fore people have not developed the disease may well be because the agent is transmissible only by inoculation or by transplacental passage into a suitable genetic type. It would be interesting to know what animals have been used for isolation attempts, and how long they have been kept under observation particularly in view of the long incubation of scrapie in sheep of up to five years. Mice inoculated with tissues from sheep suffering from scrapie, and brain emulsions from goats infected with the scratching type of scrapie, may not develop symptoms during life, but if killed their brains show lesions histopathologically similar to those seen in the donor animals. It would also be interesting to know if postmortems have been done on any Fore people, thought to be free of kuru, dying of unassociated causes, to see if they have any pathological changes in the central nervous system. This would seem to be an important point. If by any chance the " infective-agent " theory is right for kuru, as it appears to be for scrapie, then the whole problem of " latency " of viruses must be further considered. I

168

DISCUSSION

believe that both in scrapie and kuru some form of slow, chronic antigen-antibody reaction may take place in the central nervous system tissue, and as yet techniques have not been developed able to show this. I think some important negative information could be obtained by using techniques for suppressing antibody production in these animals susceptible to scrapie before inoculating them, to see if there is delay or even prevention of the histopathological lesions. Mrs. E. B e c k : Similarities between the pathological changes in kuru and those in sheep affected with scrapie have been mentioned by various authors. The most striking likeness is the occurrence of wide-spread non-specific changes such as various types of neuronal degeneration and astrocytic proliferation which, however, may occur as a tissue reaction to a wide range of noxious stimuli. In kuru, as well as in scrapie, such non-specific changes may be so severe as to obscure system degenerations which constitute the main pathological effects and which explain many of the clinical signs in either condition. A further similarity between kuru and scrapie, a similarity which may eventually give the clue to the metabolic error " which Dr. Gajdusek has mentioned, is the occurrence of vacuolated neurons. This is a neuronal reaction which is very rarely encountered in the central nervous system and, as far as I am aware, has been described only in the anterior horn cells of patients suffering from porphyria, or from tetanus, and in the inferior olives after a lesion of the central tegmental tract. Experimentally vacuolated neurons have been produced by Einarson and Telford (1960) in vitamin E deficient mice. In scrapie the distribution of these vacuolated cells in certain brainstem nuclei strongly suggests that they express an atypical form of retrograde reaction of the cell to damage of its axon within the degenerated cerebellum. For vacuolated neurons are mainly found in those nuclear groups which have either afferent or efferent connexions with the cerebellum ; moreover they often lie side by side with cells showing the classical central chromatolysis. The same holds for the distribution of vacuolated neurons within the brainstem of kuru patients. In the disease which is transmitted experimentally to goats and mice the cells react in an identical way. One wonders what may be the factor responsible for this clearly atypical form of retrograde reaction. "

Dr. C. E. G o r d o n S m i t h : Dr. Gadjusek is clearly one of the harbingers of a new kind of virology. Medical virologists have been lagging considerably behind veterinary virologists in recognizing the existence of chronic virus infections like scrapie. Medical virology has been concerned largely with the acute virus infections which are rapidly followed by the development of antibody and the disappearance of the infection. The mechanism of latent infections has been closely studied in recent years and viruses which multiply very slowly have been found in the tumours of chickens and other experimental animals. The resemblances between kuru and scrapie are sufficiently striking to make it clear that we must embark on studies of kuru and other central nervous system diseases to see whether they might be caused by viruses To do this a great many new ideas and techniques are going to be needed. Some idea of the scale of such work has been given by Dr, Gajdusek. Dr. H. K a l m u s : If I may make a few remarks as a geneticist, I should say that the epidemiological aspect of Dr. Gajdusek's fascinating paper reminded me most forcibly of Bittner's milk factor which is transmitted by the milk of mice to their offspring, causing them t o develop mammary cancer later in life. Several distinct genetical factors are implicated in

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this transmission from mother to child, and they determine whether in fact cancer will develop or not. Now if one may interpret the familial distribution of kuru in an analogous way, two approaches seem possible. The one would be whether in fact kuru is more likely to be transmitted through the maternal line than through the paternal line, and the other, perhaps more practical if feasible, would be to try to prevent kuru by taking new born Fore babies off the breast and bottle-feed them. It might then be possible after a few years to see whether the incidence of the disease has been decreased. Dr. R. F. F o r t u n e : A case of an infam, who had a blue sclera and a hare-lip, born to a mother while she was suffering from kuru was noted--and also a case of spasm in leg muscles noted while a girl was lying extended and incapable of moving herself. A chance that the sera of patients who had recovered from an attack of kuru might, perhaps, be of use in case an antigen relevant to the disease was found was mentioned, and the statistics of the incidence of the disease were confirmed.