Search

A typical case of Creutzfeldt-Jakob disease is described. Two unusual morphological features—namely, `kuru-like' plaques in the cerebellum and coarsely vacuolated neurones in the striatum—are further similarities between Creutzfeldt-Jakob disease and kuru.

Creutzfeldt-Jakob disease (CJD) may present itself with cerebellar signs initially and in the course of the disease. In addition to the classical triad of morphological changes, i.e. status spongiosus, neuronal loss and astrocytic proliferation, in the cerebral cortex and basal ganglia, there may be cerebellar involvement with selective loss of the granule cells with associated astrocytic gliosis or sponginess and relative sparing of the Purkinje cells. Occasional systematized degeneration of the paleocerebellum, “kuru-like” plaques in the cerebellum and chromatolytic neurons in the striatum are similarities between CJD and kuru. Among 17 proven cases of CJD cerebellar onset with or without mental changes was present in 47%, and cerebellar ataxia in the course of the disease was prominent in 75%. Cerebellar lesions were noted in 81%, and were more severe and advanced than cerebral involvement in 5 cases with cerebellar onset. Kuru plaques were not seen. CJD presenting with ataxia and cerebellar symptoms constitutes about 17% of all cases of CJD reported to date, and should be considered in the differential diagnosis of cerebellar disease in middle-aged patients. The similarities and dissimilarities of this subtype of CJD to kuru and other transmissible slow virus spongiform encephalopathies in man and animals are discussed.

Spongy degeneration of the cerebral grey matter is reported in 3 unrelated boys dying at the ages of 15 and 16 months and 3 years. Some of the neuropathological changes in the cases presented here and in other similar cases are like those in Creutzfeldt-Jakob disease and in kuru, conditions which have recently been transmitted to monkeys. The aetiology of spongy degeneration in children is not known, and it would be worth while to find out whether the disease is transmissible.

Brain gangliosides from chimpanzees infected with the viruses of kuru and Creutzfeldt-Jakob disease were isolated and subjected to quantitative and TLC analysis. Decreases of 40% and 25%, respectively, were found in total gray matter gangliosides. White matter of kuru showed a decline of 23%, whereas white matter of Creutzfeldt-Jakob disease showed an increase in total gangliosides amounting to 20% on a wet weight basis and 34% related to dry weight. TLC patterns were relatively normal for Creutzfeldt-Jakob disease except for possible slight decrease in G1, G2 and G2A. The kuru pattern was abnormal with marked increase of G3A in both white and gray matter and slight elevation of G5 and G6. G2A did not increase, which marked a major difference from the previously reported pattern of subacute sclerosing panencephalitis (SSPE).

TS*URU is a fatal neurological disorder found only among the Fore and their **■ immediate neighbours in the Eastern Highlands of Australian New Guinea.1 Recently I had the opportunity to revisit the kuru region after an absence of six years.2 This paper describes (i) some modifications in the Fore theory of kuru ; (2) new patterns of social grouping and behaviour that may influence the epidemiology of the disease ; and (3) a hitherto unreported symptom in the terminal phase.

The status spongiosus in the cerebral cortex of mice affected with two different strains of scrapie virus corresponded to focally swollen perikaryal cytoplasm of nerve cells and astrocytes, to swollen neuronal and astrocytic processes and to membrane-bounded vacuoles within pre- and postsynaptic neuronal terminals. The swollen cytoplasm contained uniformly dispersed, finely granulo-filamentous material. A few enlarged dendrites were filled with fragments of membranes or 350 A wide vesicular and tubular structures suggestive of virus particles. Ruptured plasma membranes and curled fragments of membranes were seen around cleared cytoplasmic regions and within membrane-bounded vacuoles. Neurons or astrocytes that lined affected cells or processes frequently showed similar changes. Confluence of swollen cells or processes occurred after dissolution of their adjacent plasma membranes. Astrocytes reacted to the injury by proliferation whereas nerve cells degenerated. The findings are compared to those seen in other subacute spongiform virus encephalopathies, i. e., mink encephalopathy, Kuru and Creutzfeldt-Jakob disease. The characteristic vacuolar degeneration of nerve cells in these diseases which is associated with fragmentation and accumulation of plasma membranes is discussed with reference to the peculiar properties of the scrapie virus.

For more than a decade of investigation, the clinical and pathologic features of kuru, a subacute, fatal, progressive degenerative disease of the central nervous system, have remained constant; the disease remains confined to the Fore linguistic group and the neighbors with whom they intermarry. Dramatic changes, however, have taken place in the sex and age incidence of the disease, which has nearly disappeared among children. This has probably been the direct result of socioenvironmental changes taking place since 1957 in the kuru region. In the laboratory, the disease has been transmitted from a number of cases to the chimpanzee after an incubation period of 2 years. The simplest hypothesis that accommodates these findings, without stretching the other known factors, is that a conditionally infectious agent (slow virus), which demands the proper genetic and socioenvironmental background for transmission, causes the disease. The sociological phenomenon best able to explain the sex and age distribution of kuru, its historical spread, and its more recent changing pattern, is cannibalism.

Now that kuru and Creutzfeldt–Jakob disease have been transmitted to four species of New World monkeys, spider monkeys (Ateles geoffroyi), capuchin monkeys (Cebus sp.), squirrel monkeys (Saimiri sciurens), and woolly monkeys (Lagothrix lagothica), these more readily available animals may replace the chimpanzee in the laboratory study of these two subacute degenerative diseases of the human brain.

1.1. A clinical, pathological and epidemiological study has been made of 200 cases of a new neurological illness occurring in natives of the Fore linguistic and cultural group in the Eastern Highlands of New Guinea and in their immediate tribal neighbors who intermarry with them. This appears to be related to the group of heredofamilial progressive degenerative disorders of the central nervous system. Since the onset of investigations over 350 patients have now been studied. 2.2. Kuru causes the death of about 1 per cent of the affected population each year. In some communities the present incidence of Kuru reaches 5 to 10 per cent, and over 50 per cent of all deaths have been from Kuru in certain areas. 3.3. The disorder principally affects adult females, but almost one-quarter of the cases are in children of both sexes. Rarely, adult males are involved. The disease is generally fatal in six to nine months. The occurrence of mild, remitting forms of the disease is discussed. 4.4. The illness is apparently restricted to the Fore people, some 11,000 in number, and to only those portions of their tribal neighbors, the Auiana, Usurufa, Kanite, Iate, Keiagana, Kimi, Kamano and Iagaria, who are immediately adjacent to the Fore-Kuru region—an estimated additional population of 6,000. 5.5. Neurohistological examination of fifteen of the twenty-nine brains thus far obtained from Kuru patients has revealed a widespread neuronal degeneration, myelin degeneration and astroglial and microglial proliferation. The cerebellum and extrapyramidal system are most severely affected. There are also changes in the anterior horn cells, inferior olives, thalamus and pontine nuclei. In addition, plaque-like anistropic bodies resembling senile plaques are found in the cerebellum, sometimes in the basal ganglia and cerebral cortex. Occasional perivascular cuffings with mononuclear cells are found. Gross and microscopic pathological study of other tissues from twenty-four patients have thus far shown no specific lesions. 6.6. Acute meningoencephalitis, with a mononuclear pleocytosis in the cerebrospinal fluid, has been discovered in the region but it has been impossible to establish any relationship between this infection, presumably viral, and Kuru. 7.7. No antecedent encephalitic or meningoencephalitic illness or any other acute infectious disease has been identified in the study of Kuru and no nutritional or toxic factor has been incriminated as of possible etiological significance in the disorder. If the degeneration of Kuru is a postinfectious phenomenon the antecedent illness must be so mild or subtle as to escape detection by the natives and ourselves. 8.8. A congenital, familial tremor which does not greatly interfere with a normal life in native society has been found and is easily differentiated from the rapidly progressive degeneration seen in Kuru. 9.9. Extensive search for toxic factors which might be of etiological significance in Kuru, in diet, water, pica, smoke, materials used in body painting and in native salt preparations and medicines has been unsuccessful. Toxic trace metals have not been found in analyses of tissues from Kuru patients. The fact that Kuru has developed in natives from the Kuru region after long residence in alien environment with Kuru-free populaces, far outside the Kuru region, markedly limits the toxic possibilities. The possibility of a genetically determined intoxication with substances normally present in diet or metabolism is discussed. 10.10. A genetic predisposition is strongly suggested and the evidence for it is summarized, but the ethnic-environmental variables that are operating in the pathogenesis of Kuru have not yet been determined.

Forty-seven strains of virus have been isolated from sterile long maintained tissue explants from chimpanzees suffering from experimental kuru. Many are new simian viruses, and none have been demonstrated to be a cause of the kuru syndrome.

VIRAL agents are usually thought of as infectious units that cause acute illness. Recently, however, it has become clear that certain types of viruses are associated with delayed and persistent illness. This relation is best documented for a variety of progressive Central-nervous-system illnesses, including Kuru,1 Creutzfeld–Jakob disease,2 subacute sclerosing panencephalitis (SSPE)3 and progressive multifocal leukoencephalopathy.4 In all these conditions a viral etiology has Abbreviations Used dsRNA: double-stranded RNA mRNA: messenger RNA PFU: plaque-forming unit SSPE: subacute sclerosing panencephalitis ssRNA: single-stranded RNA been strongly indicated. Of particular interest is the isolation of a measles-like virus from the brains of patients with . . .

The kuru annual mortality statistics in the years succeeding 1964 revealed a continuing decline in juvenile cases, and a slight reduction in adult female and adolescent deaths. The adult male annual mortality-rate has continued to rise. Changes in the incidence of kuru have not been associated with alterations in its geographical extent. The geographical distribution and chronological sequence of the changes in kuru incidence accord with the theory of transmission of an infectious particle by cannibalism. The present studies also suggest that genetic factors play no important role in the predisposition to kuru.

A few years ago when European contact was established with the Fore and their tribal neighbours living in a remote part of the Eastern Highlands District of Australian New Guinea (Figure i), it was found that these people were heavily afflicted with a rapidly progressive and fatal neurological disorder not known elsewhere. This disease, which the Fore call kuru (trembling), is of unknown aetiology but the clinical and pathological features suggest an abiotrophy or a toxic factor as causative agent (Zigas and Gajdusek, 1957 ; Simpson, Lander and Robson, 1959 ; Fowler and Robertson, 1959 ; Gajdusek and Zigas, 1959). Because many adult females but relatively few males die from kuru, the population shows unusual features in respect of the sex and age distribution, birth and death rates, etc. (Bennett, 1961). This article is concerned with the study of more extensive population records than have been available hitherto and examines in particular how the population statistics and patterns are changing and how they vary with locality.

The neuropathological findings in 3 cases of Creutzfeldt-Jakob disease are described. The triad of morphological changes, i.e. neuronal loss, status spongiosus of the grey matter and proliferation and hypertrophy of fibrous astrocytes with or without microglial reaction, conforms to the typical pattern of pathology described in the literature. Degeneration of the cerebellum places these cases in the cortico-striato-cerebellar variant of the disease. The distribution of the lesions within cerebrum and cerebellum, with a more severe involvement of phylogenetically older portions, is unusual. In the cerebrum cortices belonging to the limbic system and the striatum were the most severely affected, whilst in the cerebellum the vermis and flocculo-nodular lobe bore the brunt of the pathological process. A similar distribution of the lesions is generally found in kuru. Further similarities with kuru are pointed out i.e. the occurrence of swollen, chromatolytic neurones predominantly within the infragranular layers of the cerebral cortex, of coarse intracytoplasmic vacuolation in many of the large striatal nerve cells and of “kuru” plaques within the cerebellum. Similarities and differences between the two diseases are discussed.

There has recently been a marked increase in interest on the part of research workers and clinicians in the role of viruses in autoimmune diseases. Much of the stimulus for this has come from laboratories working on analogous or similar diseases of animals in showing that immunologic aberrations triggered by viral infections can cause glomerulonephritis and arteritis. There is a feeling by some that these and other chronic diseases of man, such as rheumatoid arthritis and systemic lupus erythematosus, which have defied analysis, may prove to be virus-induced.