Human prion diseases

Human prion diseases - detailed technical article.

Topics covered:

  • Essentials
  • Introduction
  • Historical perspective
  • Aetiology, genetics, pathogenesis, and pathology
  • Human prion diseases
  • The diagnosis of human prion diseases
  • Investigations in human prion disease
  • Further reading

Essentials 

Prion protein (for proteinacious infectious particle) is a membrane-associated glycoprotein present in all mammalian species. Its normal function is unknown, but in prion diseases (also known as transmissible spongiform encephalopathies) a post-translationally modified form of the protein, partially resistant to protease digestion, is deposited in the brain and associated—after long incubation periods—with neuronal dysfunction and death.

Particular prion diseases

Creutzfeldt–Jakob disease (CJD)—several forms are recognized: (1) Sporadic—a rare condition typically presenting in late middle age with a rapidly progressive dementia associated with a range of neurological signs, most commonly myoclonus of the limbs, cerebellar ataxia and rigidity. Few patients survive for more than 2 years. (2) Hereditary—dominant pattern of inheritance; age at death is typically 5 to 10 years younger than in sporadic disease. (3) Iatrogenic—exposures in or adjacent to the nervous system (e.g. neurosurgical instruments, dura mater grafts, corneal transplants) typically present in a similar manner to sporadic disease; peripheral exposure to infection (pituitary hormones) usually manifests with progressive cerebellar ataxia. (4) Variant—bovine spongiform encephalopathy (BSE) was identified in 1986 as a prion disease in cattle, with the favoured hypothesis being that contamination of feed, probably with tissues from the central nervous system of affected animals. Variant CJD is caused by transmission of BSE to humans. Typical presentation is with psychiatric symptoms, followed after a period of months by progressive ataxia, dementia, and choreiform or dystonic involuntary movements which often evolve into myoclonus. It is likely that the maximum number of cases will be no more than a few hundred, with the mean age at death being 30 years.

Kuru—in Papua New Guinea this disease was transmitted in the course of ritual cannibalism, which ceased by 1960, hence there have been no cases in people born after 1959. Typical presentation was with headache and limb pain, progressing to a cerebellar syndrome, with eventual immobility.

Investigation, treatment, and prevention

Investigation—there is no test for the presence of the infectious agent, hence diagnosis depends on the recognition of clinical characteristics, sometimes supported by (1) electroencephalography—periodic triphasic complexes are seen in 60 to 70% of cases of sporadic CJD and in some cases of iatrogenic CJD; (2) cerebrospinal fluid analysis—elevation of 14-3-3 protein in the cerebrospinal fluid is about 90% sensitive and specific for sporadic CJD, but less useful for variant CJD; (3) MRI—with appropriate imaging protocols, localized abnormalities may be seen in the caudate nucleus and putamen in sporadic CJD, and the pulvinar region of the posterior thalamus in variant CJD; (4) tissue biopsy of brain or tonsil.

Treatment and prevention—there is nothing that influences the clinical course of human prion diseases, nor any treatment to prevent the development of neurological disease after infection.

Read more: An alternative article about prion disease: Prion disease

Introduction

Prion diseases, also known as transmissible spongiform encephalopathies, are fatal disorders of the central nervous system affecting both humans and animals. The clinical features and patterns of occurrence of these diseases vary, but they are linked by a number of characteristics including experimental and natural transmissibility, shared neuropathological features, prolonged incubation periods measured in years, and the deposition of prion protein, which may be the causal agent, in the brain of the host. Prion diseases have become the subject of intense scientific and public interest because of the likelihood that they are caused by a novel disease mechanism and because of the implications for public health following the identification of a new human prion disease, variant Creutzfeldt–Jakob disease (vCJD), and the evidence that it is caused by the transmission to humans of a cattle prion disease, bovine spongiform encephalopathy (BSE).

There have been remarkable scientific advances in the understanding of prion diseases and it is hoped that this may lead to the identification of a diagnostic test in life for the presence of infection and to therapies to prevent the development of disease. Human prion diseases have attained a public notoriety disproportionate to the overall burden of disease caused by these rare conditions. However, the transmission an animal prion disease to humans has been a tragedy and the prolonged incubation periods characteristic of this group of diseases indicate that the eventual consequences of BSE for public health both in the United Kingdom and in other countries remain unpredictable.

Historical perspective 

Scrapie was first transmitted experimentally from sheep to sheep in 1936 and to laboratory mice in 1961, but laboratory transmission of human prion diseases was not achieved until 1966 (kuru) and 1968 (Creutzfeldt–Jakob disease, CJD). The seminal discovery that apparently neurodegenerative diseases were transmissible stimulated extensive research into the nature of the infectious agent and attempts to identify the source of infection in CJD. Table 1 sets out the principal prion diseases known to affect the brains of animal species and humans.

Aetiology, genetics, pathogenesis, and pathology

No bacterium or virus has been isolated in these diseases and there is no immunological response to infection. This is of central importance as there is, as yet, no serological test to identify the presence of infection during the incubation period of any prion disease. The transmissible agent is remarkably resistant to inactivation procedures, including those that disrupt nucleic acids. In 1982 Prusiner proposed that the protein deposited in the central nervous system (CNS) in these diseases was itself the causal agent. Purified infectious fractions of brain contain prion protein (for proteinacious infectious particle),which is a major, and perhaps the only, component of the infectious agent. This membrane-associated glycoprotein is present in all mammalian species. The normal function of prion protein is unknown. In prion diseases a post-translationally modified form of the protein, partially resistant to protease digestion, is deposited in the brain and is associated with neuronal dysfunction and death.

There is a range of experimental evidence supporting the hypothesis that the disease-associated form of prion protein is the causal agent in prion diseases, most notably a series of elegant studies in transgenic rodents and the recent description of synthetic infectious prions. Cellular expression of prion protein is necessary for the development of the neuropathological changes and the disease. Hereditary forms of human prion disease are associated with, and perhaps caused by, mutations of the prion protein gene. However, the occurrence of multiple strains of the infectious agent and the stability of the transmission characteristics of the bovine spongiform encephalopathy (BSE) agent in the laboratory after cross-species transmission are not readily explained by the prion theory. The importance of prion protein as a determinant of disease expression has become increasingly clear in human prion disease. The phenotype of different clinicopathological subtypes of CJD is related to the deposition in the brain of different types of prion protein, probably reflecting distinct tertiary protein structures, despite the identical amino acid sequences of the normal and disease-associated forms of prion protein.

Table 1 The spongiform encephalopathies
Disorder Species
Sporadic Creutzfeldt–Jakob disease Human
Inherited Creutzfeldt–Jakob disease (includes Gerstmann–Straussler–Scheinker and fatal familial insomnia) Human
Iatrogenic Creutzfeldt–Jakob disease Human
Kuru Human
Variant Creutzfeldt–Jakob disease* Human
Scrapie Sheep/goat/moufflon
Transmissible mink encephalopathy Mink
Chronic wasting disease Deer/elk
Bovine spongiform encephalopathy* Cattle
Feline spongiform encephalopathy* Cat/cheetah/puma/ocelot/tiger
Spongiform encephalopathy of captive exotic ungulates* Kudu/nyala/oryx/gemsbok/eland

* These disorders are associated with the same infectious agent (bovine spongiform encephalopathy).

In experimental transmission of prion diseases there are a number of key determinants of the efficiency of transmission, as judged by the incubation periods in recipient animals and the proportion of these animals that develop disease. The route of inoculation influences these variables. The intracerebral route is the most efficient. Intravenous, intraperitoneal, and oral routes are decreasingly efficient. The incubation period is inversely related to the infective dose, while the strain of the infectious agent influences both the incubation period and whether recipient animals develop disease. In some transmission studies, e.g. transmission of BSE to hamsters or transmission of scrapie to chimpanzees, recipient animals do not develop disease even after intracerebral inoculation of high levels of infectivity. Within-species transmission is more efficient than cross-species transmission and this ‘species barrier’ to transmission is influenced by characteristics of both the host and the infective agent. The relative homology of amino acid sequences of prion proteins between species is not the only determinant of the species barrier. The relative efficiency of transmission between species cannot be predicted.

After oral exposure, the agent replicates in the lymphoreticular system, including the spleen and lymph nodes, before entering the thoracic spinal cord or brainstem, probably via the autonomic nervous system, and then spreading caudally to the brain. Moderate levels of infectivity plateau in the lymphoreticular system and are not associated with organ dysfunction, while in the spinal cord and brain high levels of infectivity develop, e.g. 1012 infectious units per gram of brain in one model of hamster scrapie, leading to neuronal death and clinical disease. In some experimental and natural prion diseases, infectivity in the lymphoreticular system can be detected at about a third of the total incubation period by inoculation of tissues of the lymphoreticular system, such as spleen, into recipient animals. The implication is that, in the absence of an in vivo serological test for the presence of infectivity, animals or humans incubating a prion disease may harbour significant infectivity in some organs or tissues but cannot be identified as being infected. This has important implications for the control and public health implications of prion diseases.

Human prion diseases

Human prion diseases may be classified as sporadic, inherited, or acquired (Table 2).

Table 2 Human prion diseases
Sporadic Creutzfeldt–Jakob disease
Inherited Familial Creutzfeldt–Jakob disease Gerstmann–Straussler–Scheinker syndrome Fatal familial insomnia
Acquired
  • Iatrogenic Creutzfeldt–Jakob disease
  • Variant Creutzfeldt–Jakob disease
  • Kuru  

Sporadic CJD

Epidemiology

Sporadic CJD is a rare disease, with an annual incidence of about 1 case per million population. The disease occurs worldwide and the cause is unknown, with no convincing evidence of an environmental source of infection and in particular no proven link with the animal prion diseases. The regional clusters of cases identified in some countries are unusual and may reflect the chance aggregation of a rare phenomenon. Overall the geographical and temporal distribution of cases of sporadic CJD appear to be random and case–control studies have demonstrated no consistent risk factors for the development of disease, with no good evidence of an increased risk through occupation, dietary factors, or animal contact. The currently favoured hypothesis is that sporadic CJD is caused by a spontaneous mutation of prion protein to the abnormal form, which acts as a template for protein self-replication and eventual disease.

Clinical features

Clinically, sporadic CJD presents with a rapidly progressive dementia associated with a range of neurological signs, most commonly myoclonus of the limbs, cerebellar ataxia, and rigidity. Less common features include dysphasia, pyramidal or extrapyramidal signs, primitive reflexes, cortical blindness, and lower motor neuron signs. Despite the predominantly cortical neuropathology epilepsy is rare. The rapidity of the progression of neurological deficits and cognitive decline is distinct from most other causes of dementia and the mean survival is only about 4 months from clinical onset, although in about 10% of cases the illness is more prolonged and a small minority of patients survive for 2 years or more. Terminally there is often a state of akinetic mutism.

Although the clinical presentation in sporadic CJD is relatively stereotyped, a minority of cases present atypically, e.g. acutely mimicking stroke, with cortical blindness, or with an initially pure cerebellar syndrome.

The neuropathological characteristics of sporadic CJD include spongiform change, neuronal loss, and astrocytosis in the cerebral and cerebellar cortex, in accordance with the neurological signs seen in life. Neuropathological changes are widespread and deposition of prion protein can be detected with immunocytochemical techniques. In about 10% of cases there are cortical deposits of prion protein in the form of amyloid plaques. There is heterogeneity in the distribution and morphology of the neuropathological changes, which correlate in part with the clinical phenotype and with two isotypes of prion protein that can be distinguished on western blots of brain tissue.

Sporadic CJD is mainly a disease of late middle age with a mean age at death of 67 years. In most systematic studies males and females are affected with equal frequency.

The human prion protein gene is situated on chromosome 20 and contains a polymorphic region at codon 129, which expresses either methionine or valine. Methionine homozygosity (MM) at codon 129 increases susceptibility to sporadic CJD (Table 3). The genotype distribution in sporadic cases is MM 70%, valine homozygous (VV) 17%, and heterozygous (MV) 13% in contrast to the genotype distribution in the normal white population. There is accumulating evidence that the disease phenotype in sporadic CJD, as well as susceptibility, is influenced by an interplay between the codon 129 genotype and the prion protein type. The classic form of sporadic CJD, representing the great majority of cases, is associated with type 1 prion protein and an MM or MV genotype, whereas alternative combinations of prion protein isotype and codon 129 genotype are often associated with atypical phenotypes.

Hereditary prion diseases

Epidemiology

Familial clusters of CJD account for about 10% of all cases and within pedigrees there is a dominant pattern of inheritance. The paradox of a transmissible disease that is also inherited was clarified by the identification of a mutation at codon 102 of the prion protein gene in two families affected by Gerstmann–Straussler–Scheinker (GSS) syndrome, a condition known to be a human prion disease on the basis of the neuropathology and laboratory transmissibility. More than 30 prion protein gene mutations, including point and insertional mutations, have now been identified in familial CJD or GSS syndrome (Table 4), and all cases of hereditary human prion disease to date have been found to have a mutation of the prion protein gene. Fatal familial insomnia was first identified as a prion disease following the identification of a mutation at codon 178 of the prion protein gene in affected family members, and it was only later that transmission in the laboratory confirmed the status of fatal familial insomnia as a prion disease. The current hypothesis is that mutations of the prion protein gene lead to an instability in the structure of prion protein and an increased chance of a spontaneous transformation of prion protein to the abnormal self-replicating disease-associated form. With the exception of the prion disease associated with a mutation at codon 200 of the prion protein gene, all hereditary human prion diseases are fully penetrant.

The incidence of CJD in localized areas of Slovakia and in Libyan-born Israelis was discovered many years ago to be 60 to 100 times greater than expected. Possible explanations for these clusters included excessive dietary exposure to sheep scrapie and a high coefficient of inbreeding. Following the identification of the mutations of prion protein in human disease, genetic studies have shown that in both clusters there is a high population frequency of mutations at codon 200 of the prion protein gene, and that the excess of cases of CJD is due to an excess of familial cases, with an expected background incidence of sporadic cases.

Clinical features

Overall the age at death in hereditary prion diseases is about 5 to 10 years earlier than in sporadic CJD, but the duration of clinical illness is often more prolonged and the clinical features vary with the underlying mutation. With some mutations, notably the codon 200 mutation, the clinical course is similar to sporadic CJD, but cases of hereditary prion disease may present with ataxia, e.g. GSS syndrome, or with a highly atypical phenotype such as fatal familial insomnia in which the early clinical features include dysautonomia and insomnia. There may be variation in the clinical phenotype both within and between families even if these are associated with the same underlying mutation in the prion protein gene.

Table 3 Percentage of codon 129 genotypes in the normal population and in different forms of Creutzfeldt–Jakob disease, and in Kuru
  Genotype
MM MV VV
Normal population 39 50 11
Sporadic Creutzfeldt–Jakob disease 70 13 17
Iatrogenic Creutzfeldt–Jakob disease central 74 20 6
peripheral 48 21 32
Variant Creutzfeldt–Jakob disease 100 0 0
Kuru 30 45 25
Table 4 Inherited prion diseases—mutations of the prion protein gene
Creutzfeldt–Jakob disease phenotype
D178N-129V
V180I-129M
T183A-129M
E200K-129M
H208R-129M
V210I-129M
M232R-129M
Fatal familial insomnia phenotype
D178N-129M
Phenotype of GSS syndrome
P102L-129M
P102L-129M-219K
P102L-129V
P105L-129V
A117V-129V
Y145STOP-129M
F198S-129V
Q212P
Q217R-129V
Heterogeneous phenotype: insertional mutations
Ins 24 bp-129M
Ins 48 bp-129M
Ins 96 bp-129M
Ins 96 bp-129V
Ins 120 bp-129M
Ins 144 bp-129M
Ins 168 bp-129M
Ins 192 bp-129V
Ins 216 bp-129M

GSS: Gerstmann–Straussler–Scheinker. 

Neuropathologically there is great heterogeneity in hereditary prion diseases, and as with the clinical phenotype there is an overall relationship between the neuropathological features and the specific prion protein gene mutation, although there can be great variation within and between pedigrees. The neuropathology can be similar to sporadic CJD but in a significant proportion of hereditary prion diseases there is amyloid plaque formation and in fatal familial insomnia gliosis and neuronal loss may be restricted to the thalamus.

In some forms of hereditary prion disease the codon 129, genotype may influence clinical characteristics, including age at death and the neuropathology. Variation at this locus has a profound effect on the disease phenotype in association with mutations at codon 178 of the prion protein gene. Cases with a codon 178 mutation and a methionine at codon 129 of the prion protein gene develop fatal familial insomnia, whereas with valine at codon 129 the phenotype is similar to sporadic CJD.

Iatrogenic CJD

Epidemiology

CJD has been transmitted accidentally in the course of medical treatment by neurosurgical instruments, corneal grafts, cadaveric dura mater grafts, and human pituitary-derived hormones (Table 5). The presumption is that infection from individuals with CJD was transmitted to uninfected individuals via these procedures and there is strong circumstantial evidence that this has occurred. In the two transmissions by corneal grafts the donors died of sporadic CJD, and in the neurosurgical transmissions there was a clear temporal link between surgical procedures on CJD cases and patients operated on using the same instruments who subsequently developed CJD. It is presumed that some human dura mater grafts and human pituitary hormones came from individuals with CJD and there may have been cross-contamination in the production process, leading to dissemination of infection. Infection via human pituitary growth hormone has been demonstrated in laboratory transmission studies. All cases of iatrogenic transmission of sporadic CJD have involved surgical instruments, grafts, or hormonal products potentially contaminated by CNS tissue and, by implication, high levels of infectivity.

Clinical features

There is a distinction between the clinical features in iatrogenic CJD which depends on the route of inoculation. In exposures in or adjacent to the nervous system (neurosurgical instruments, dura mater grafts, and corneal transplants) most cases present with a progressive dementia similar to sporadic CJD. With a peripheral route of exposure to infection (pituitary hormones) there is a progressive cerebellar ataxia and cognitive impairment develops late in the clinical course, if at all.

The incubation period also varies according to the route of exposure to infection. With central exposure the mean incubation period ranges from about 18 months, similar to the incubation periods in primates after experimental intracerebral inoculation, to 6 years with dura mater grafts. With a peripheral route of exposure the mean incubation period is about 12 years, but may extend to over 30 years, which is similar to the extended incubation periods in kuru, a human prion disease also caused by a peripheral route of exposure to infection.

Table 5 Iatrogenic Creutzfeldt–Jakob disease worldwide
Mode No. of cases Mean incubation period (years) Clinical
Neurosurgery 4 1.6 Visual/cerebellar/ dementia
Depth electrodes 2 1.5 Dementia
Corneal transplant 2 15.5* Dementia
Dura mater 114 6 Visual/cerebellar/ dementia
Human growth hormone 139 12 Cerebellar
Human gonadotrophin 4 13 Cerebellar

 

* Range 1.5 to 26.5 years.

Homozygosity at codon 129 of the prion protein gene, either MM or VV, increases susceptibility to human growth hormone-related CJD and heterozygosity may lead to a more prolonged incubation period. In dura mater-related CJD 81% of cases have an MM genotype, similar to the proportion of sporadic cases with this genotype, but the codon 129 genotype does not influence the incubation period.

Measures to reduce the risk of iatrogenic transmission of CJD have been introduced in many countries. There are strict selection criteria for obtaining corneal grafts, recombinant growth hormone replaced human growth hormone in 1985, and human dura mater grafts have not been licensed in the United Kingdom since the early 1990s. 

Variant CJD

Epidemiology

Bovine spongiform encephalopathy was identified in 1986 as a novel prion disease in cattle in the United Kingdom, and is thought to have been caused by feeding cattle material contaminated with sheep scrapie or, perhaps, a previously unrecognized endemic prion disease of cattle. Bovine-to-bovine recycling of infection through cattle feed amplified the epidemic and there have now been over 180 000 cases of BSE in the United Kingdom. Small numbers of cases of BSE have been identified in other countries, mainly in Europe.

In 1996 10 cases of a novel form of human prion disease, variant Creuzefeldt–Jakob disease (vCJD), were identified in the United Kingdom and a causal link with BSE was proposed as this was a new disease occurring only in the United Kingdom, the country with the greatest potential human exposure to BSE. Up to January 2010 there have been 167 primary cases of vCJD in the United Kingdom, 25 in France, and a limited number of cases in some other countries (Table 6). The mean age at death in vCJD is 30 years (range 14–75 years) contrasting with a mean age at death in sporadic CJD of 67 years. The hypothesis that vCJD is caused by the BSE agent has been supported by the consistent disease phenotype, and in particular the neuropathology which is distinct from other human prion diseases, the failure to identify similar cases in the past either in the United Kingdom or elsewhere, and laboratory transmission studies that have shown a remarkable similarity between the transmission characteristics of BSE and vCJD in mice.

Table 6 Variant Creutzfeldt-Jakob disease worldwide
Country Total number of primary cases (Number alive) Total number of secondary cases: blood transfusion (Number alive) Cumulative residence in UK > 6 months during period 1980–1996
UK 167 (3) 3 (0) 170
France 25 (1) 1
Republic of Ireland 4 (0) 2
Italy 2 (1) 0
USA 3† (0) 2
Canada 1 (0) 1
Saudi Arabia 1 (1) 0
Japan 1* (0) 0
Netherlands 3 (0) 0
Portugal 2 (0) 0
Spain 5 (0) 0

† The third US patient with vCJD was born and raised in Saudi Arabia and has lived permanently in the United States since 2005. According to US case-report, the patient was most likely infected as a child when living in Saudi Arabia.

* The case from Japan had resided in the UK for 24 days in the period 1980–1996.

Cases of vCJD have been identified from throughout the United Kingdom, and risk factors include residence in the United Kingdom and an MM genotype at codon 129 of the prion protein gene. All the United Kingdom cases and some of the cases in other countries (see Table 24.11.5.6) had been resident in the United Kingdom during the 1980s to early 1990s, when human exposure to BSE was likely to have been maximal. However, many of the cases outside the United Kingdom had never visited the United Kingdom, implying that exposure to BSE must have occurred in the country of origin to indigenous BSE or export from the United Kingdom of cattle or food products. The favoured hypothesis is that transmission of BSE to humans was through contamination of food, probably with tissues from the CNS such as brain or spinal cord which are known to contain high levels of infectivity in cattle infected with BSE. All tested cases of vCJD to date have been MM homozygotes at codon 129 of the prion protein gene. This genotype is also present in about 70% of cases of sporadic CJD and may represent a susceptibility factor for the development of vCJD. Variation at this locus can, however, influence the incubation period and disease phenotype and it is possible that cases of human infection with BSE may yet be identified in individuals with a VV or MV genetic background.

The possible future number of cases of vCJD is unknown, but the outbreak in the United Kingdom peaked in 1999/2000 with a subsequent decrease in the annual number of deaths. Early predictions estimated a total of 100 to over 136 000 cases of vCJD in the United Kingdom, but recent estimates are more conservative, predicting a maximum of no more than a few hundred cases There are, however, a number of uncertainties that make accurate prediction problematic, including the mean incubation period of BSE in humans, the level of the species barrier between bovines and humans, and the possibility of future cases in a non-MM genetic background. The identification of three cases of vCJD and one subclinical infection caused by transmission of the infectious agent through blood transfusion has raised concerns about the possibility of other routes of secondary transmission, e.g. through contaminated surgical instruments.

Clinical features

The clinical features of vCJD are relatively distinct from other forms of human prion disease, including sporadic and iatrogenic CJD. Patients present with psychiatric symptoms, including depression, withdrawal, and anxiety, followed after a period of months by progressive ataxia, dementia, and choreiform or dystonic involuntary movements, which often evolve into myoclonus. The terminal stages are similar to sporadic CJD, but the overall duration of illness, median 14 months, is significantly more prolonged. The distinctive neuropathological characteristic of vCJD is the widespread deposition of prion protein in deposits with a halo of spongiform change, so-called florid plaques, throughout the cerebral and cerebellar cortex, in addition to the spongiform change, neuronal loss, and gliosis seen in other human prion diseases.

Kuru

Epidemiology

The transmissibility of human prion diseases was first demonstrated in 1966 with the transmission of a spongiform encephalopathy to chimpanzees 18 to 21 months after intracerebral inoculation of a brain extract from a patient who had died of kuru. This seminal experiment followed years of clinical, epidemiological, and anthropological research in the Fore region of Papua New Guinea where kuru was endemic. In the early 1960s kuru caused over half of all deaths in the affected population and there have been more than 3000 deaths from kuru in the at-risk population of 30 000 people.

The epidemiological characteristics of kuru are unusual with familial aggregation of cases and a high incidence of disease in women and children in the early years of the epidemic. Since 1960 there has been a decline in the incidence, particularly in women and children, and there have been no cases in children born after 1959. After extensive investigation into a possible genetic or toxic origin, anthropological research established that kuru was transmitted in the course of ritual cannibalism. As a mark of respect, relatives consumed affected individuals and virtually all tissues were consumed, including the brain and viscera. Although men took part in these rituals, women and children are thought to have consumed the internal organs such as the brain, which contained the highest levels of infectivity. It is also possible that there was transcutaneous transmission through rubbing of tissue on the skin. Detailed investigation of individual cannibalistic events has shown that a number of members of the same family, including those who came from different areas, developed kuru after attending a single cannibalistic rite. Ritual cannibalism ceased by 1960, explaining the subsequent decline in incidence of kuru, but there are still occasional cases with incubation periods exceeding 40 years. It is of interest that at the height of the epidemic many hundreds of women were affected by kuru during pregnancy and breastfed their children, but none of these children later developed kuru.

Clinical features

Clinically kuru presented with a cerebellar syndrome, initially truncal ataxia and titubation, followed by ataxia of gait and dysarthria. A prodromal phase of headache and limb pain was common and hypotonia was a prominent early feature. Involuntary movements such as myoclonus and rigidity of the limbs did not occur, in contrast to other forms of human prion disease. Terminally patients became immobile and communication was often impossible because of severe dysarthria. Dementia did not occur, and even in the terminal akinetic and mute state patients could obey simple commands. In children the clinical features were similar, but in the early stages there were often brainstem signs such as strabismus, nystagmus, and ptosis. The total duration of illness ranged from 12 months to 18 months in adults and 3 months to 12 months in children.

In kuru, neuropathological changes were most apparent in the cerebellum, consistent with the clinical features. Neuronal loss and intense cerebellar astrocytosis were uniform findings and about three-quarters of cases had amyloid plaque deposition, particularly in the granule cell layer of the cerebellum. The cerebral cortex showed mild spongiform change. The similarity of the neuropathology of kuru to scrapie was commented on by Hadlow in 1959, prompting the transmission studies which later demonstrated that kuru, similar to scrapie, was experimentally transmissible.

By using stored samples, analysis of the influence of the codon 129 polymorphism of the prion protein gene on susceptibility to kuru has shown that homozygosity, either MM or VV, increases susceptibility and that heterozygotes may have a more prolonged incubation period. The analysis of codon 129 genotype in kuru is complicated by the limited number of tested cases and the possible effect of the high mortality rate on the codon 129 distribution in a closed population.

The diagnosis of human prion diseases

Human prion diseases are rare, but the high public profile of CJD and vCJD has resulted in an increase in the number of cases in which the diagnosis of one of these diseases is suspected. Accurate diagnosis of any condition, including patients suffering from a human prion disease, is essential but the exclusion of a diagnosis is also important, particularly for a fatal and untreatable condition. Although symptomatic treatment, e.g. for involuntary movements, can be helpful in human prion diseases, there is currently no available treatment that influences the clinical course or any treatment to prevent the development of neurological disease after infection. An important objective is to improve diagnostic accuracy in human prion diseases and in particular to allow early diagnosis. In the absence of a test for the presence of the infectious agent, diagnosis depends on the recognition of the clinical characteristics of human prion diseases supported by a range of investigations, some of which have been developed in recent years. Diagnostic criteria for sporadic, iatrogenic, familial, and vCJD have been formulated and validated (Tables 7 and 8). In all human prion diseases a definite diagnosis can be made only by the examination of brain tissue, usually post-mortem.

In most cases of sporadic CJD the diagnosis is made in life because of the multifocal neurological deficits, the development of myoclonus, and in particular the rapidity in the progression of cognitive impairment. The clinical picture is distinct from more common forms of dementia. In forms of sporadic CJD with early focal neurological features, such as a cerebellar syndrome, the rapid evolution of other neurological deficits and dementia suggests the diagnosis of CJD. Diagnosis can be difficult in cases of sporadic CJD with atypical features such as long duration of illness, and in these cases investigations such as MRI of the brain can be helpful. There is increasing evidence that cases of sporadic CJD may be atypical if there is an underlying MV or VV codon 129 prion protein genotype.

Hereditary prion diseases are often suspected because of a family history of a similar disorder, but in a significant proportion of cases of CJD associated with a prion protein gene mutation there is a family history of another neurodegenerative disorder or no relevant family history. The gradual clinical progression in many forms of hereditary human prion disease makes accurate diagnosis difficult and the diagnosis may be recognized in life only after prion protein gene analysis. Genetic testing should be carried only out with fully informed consent.

Table 24.11.5.7 Diagnostic criteria for sporadic Creutzfeldt–Jakob disease
I Rapidly progressive dementia
IIA Myoclonus
IIB Visual or cerebellar problems
IIC Pyramidal or extrapyramidal features
IID Akinetic mutism
III Typical electroencephalogram
Definite Neuropathologically/immunocytochemically confirmed
Probable I + two of II + III
or
Possible + positive 14-3-3
Possible I + two of II + duration less than 2 years
Table 24.11.5.8 Diagnostic criteria for variant Creutzfeldt–Jakob disease
IA Progressive neuropsychiatric disorder
IB Duration of illness more than 6 months
IC Routine investigations do not suggest an alternative diagnosis
ID No history of potential iatrogenic exposur
IIA Early psychiatric symptoms*
IIB Persistent painful sensory symptoms
IIC Ataxia
IID Myoclonus or chorea or dystonia
IIE Dementia
IIIA Electroencephalogram does not show the typical appearance of sporadic Creutzfeldt–Jakob disease (or no electroencephalogram performed)
IIIB Bilateral pulvinar high signal on magnetic resonance scan
IVA Positive tonsil biopsy
Definite IA + neuropathological confirmation of variant Creutzfeldt– Jakob disease§
Probable I + four out of five of II + IIIA + IIIB
Probable I + IVA
Possible I + four out of five of II + IIIA

* Depression, anxiety, apathy, withdrawal, delusions.

† This includes both frank pain and/or unpleasant dysaesthesia.

‡ Generalized triphasic periodic complexes at approximately one per second.

§ Spongiform change and extensive deposition of prion protein with florid plaques, throughout the cerebrum and cerebellum.

The diagnosis of iatrogenic CJD depends on the identification of a relevant risk factor, e.g. previous treatment with human growth hormone, and an assessment of the neurological presentation. Most patients with growth hormone-related CJD present with a cerebellar syndrome, whereas after central iatrogenic exposure to infection the clinical picture is usually similar to that of sporadic CJD. The utility of specialist investigation in iatrogenic CJD is uncertain because of their rarity, but positive findings on MRI of the brain and/or the 14-3-3 CSF test may support the diagnosis.

The clinical picture in the later stages of vCJD is similar to that of sporadic CJD and, although the recognition of the diagnosis in the first cases of this new disease was difficult, the clinical phenotype is now well known and the diagnosis is usually apparent after neurological signs develop, often in young patients in an age group in which dementia is very unusual. Diagnosis in the early stages is, however, difficult as there is a period of many months in which the clinical picture is dominated by psychiatric symptoms, including depression, anxiety, and withdrawal. Clues to the possibility of vCJD include cognitive impairment, subtle gait ataxia, and persistent painful sensory symptoms in combination with the psychiatric symptoms.

Table 9 Clinical features of sporadic and variant Creutzfeldt—Jakob disease
Feature Sporadic CJD Variant CJD
Mean age at death 67 years 30 years
Median illness duration 4 months 14 months
Symptoms at onset:
 Cognitive impairment 70% 10%
 Psychiatric (depression, anxiety etc) <5% 70%
 Painful sensory symptoms <1% 20%
Signs during clinical course:
 Dementia 100% 100%
 Ataxia 80% 100%
Involuntary movements:
 Myoclonus 95% 70%
 Chorea <5% 50%
 Dystonia <5% 25%

The clinical features of sporadic and vCJD are compared in Table 9.

Investigations in human prion disease 

Many of the investigations carried out in suspected cases of human prion disease do not show any specific disease-related abnormality, but help to exclude other diagnoses, some potentially treatable. The interpretation of the results of investigations depends on the clinical picture because the sensitivity and specificity of surrogate markers for prion disease, such as 14-3-3 CSF analysis (see below), depend on clearly defining the characteristics of the patients in which the test has been carried out.

Routine haematological and biochemical tests are usually normal. About a third of cases of sporadic or vCJD may have minor abnormalities in liver function tests.

The EEG shows periodic triphasic complexes at about 1/s in 60 to 70% of cases of sporadic CJD and in some cases of iatrogenic CJD after central exposure to infection. These EEG changes are relatively specific, but similar appearances can be seen in hepatic encephalopathy, lithium or metrizamide toxicity, metabolic disturbance, and rarely in other forms of dementia such as Alzheimer’s disease.

There is no CSF pleocytosis in any form of human prion disease, but CSF protein is elevated in about a third of cases. Elevation of the 14-3-3 CSF protein, a marker for neuronal damage, has a sensitivity and specificity of about 90% in the diagnosis of sporadic CJD, but is less useful in the diagnosis of vCJD.

A CT scan of the brain is usually normal, but can show nonspecific cerebral atrophy. MRI of the brain shows a high signal on diffusion-weighted imaging (DWI) or FLAIR images in the caudate nucleus and putamen in about 70% of cases of sporadic CJD, but the sensitivity and specificity of these abnormalities have not been formally assessed. In vCJD about 95% of cases show a high signal on DWI or FLAIR images in the pulvinar region of the posterior thalamus and in the appropriate clinical context these abnormalities have a high sensitivity and specificity for the diagnosis of vCJD. To date all cases of vCJD classified as ‘probable’, a diagnosis requiring the abnormalities on MRI, that have come to postmortem examination have been confirmed as vCJD.

Table 10 Investigations in sporadic and variant Creutzfeldt—Jakob disease
Test Result Sporadic CJD Variant CJD
CSF 14-3-3 Positive 90% 50%
EEG Periodic triphasic complexes 65% <1%
Tonsil biopsy Positive for prion protein 0% 95%
MRI brain scan High signal in caudate putamen 70% 15%
(DWI/FLAIR) High signal in pulvinar <1% 95%

Brain biopsy can allow the confirmation of the diagnosis of a human prion disease in life, but this investigation has risks and is mainly carried out when there is a realistic possibility of an alternative diagnosis. Tonsil biopsy in vCJD can increase the likelihood of the diagnosis in life, but this procedure is also invasive and, although early diagnosis is important for the relatives of the patient and for clinicians, it does not benefit the patient. The outcome of investigations in sporadic and vCJD are shown in Table 10.

Further reading

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Bradley, et al. (2006). Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: Part 1. Folia Neuropathol, 44, 93–101. 

Brown P (2008). Transmissible spongiform encephalopathy in the 21st century. Neurology, 70, 713–22.

Cali I, et al. (2006). Classification of sporadic Creutzfeldt–Jakob disease revisited. Brain, 129, 2266–77.

Collee JG, et al (2006). Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: Part 2. Folia Neuropathol, 44, 102–10. 

Collinge J, et al. (2006). Kuru in the 21st century—an acquired human prion disease with very long incubation periods. Lancet, 367, 2068–74.

Collins SJ, et al. (2006). Determinants of diagnostic investigation sensitivities across the clinical spectrum of sporadic Creutzfeldt–Jakob disease. Brain, 129, 2278–87.

De Armond SJ, et al. (2003). Perspectives on prion biology, prion disease pathogenesis, and pharmacologic approaches to treatment. Clin Lab Med, 23, 1–41.

Mead S, et al. (2009). A novel protective prion protein variant that colocalizes with kuru exposure. N Engl J Med, 361, 2056–65.

Wadsworth JDF, et al. (2007). Update on human prion disease. Biochim Biophys Acta, 1772, 598–609.