[Acquired Creutzfeldt-Jakob disease (CJD)--Kuru, iatrogenic CJD, variant CJD].

Human prion diseases can be classified as sporadic, hereditary or acquired. The acquired forms are known to be caused by the transmission to human from human or animal, via medical appliances, oral intake or parenteral solutions. Usually, peripheral infection such as oral(Kuru) or parenteral (human pituitary hormones) transmission causes cerebellar degenerative form, and central nervous system infection such as neurosurgical treatment, dura mater grafts or corneal grafts transmission causes clinical features similar to sporadic form of Creutzfeldt-Jakob disease (CJD). The variant CJD (vCJD) is considered to be transmitted bovine spongiform encephalopathy(BSE) to human through dietary exposure. The early clinical features of vCJD are dominated by psychiatric symptoms, and minor number of patients have neurological symptoms from the onset. After about 6 months, there are frank neurological signs, including ataxia, cognitive impairment and involuntary movements.

Kuru: the old epidemic in a new mirror.

The kuru epidemic lasted almost a century; it started in 1901-1902, reached epidemic proportions in the mid-1950s, and disappeared in the 1990s. Kuru is the prototype member of a group of disorders known as transmissible spongiform encephalopathies (TSEs) or prion diseases. Recent data on the genetics and pathogenesis of TSEs contribute to a better understanding of the documented kuru phenomena, and vice versa, observations made during the kuru epidemic are immensely helpful in understanding the epidemic of variant Creutzfeldt-Jakob disease that is currently developing in Europe. The major goal of this review is to identify and illustrate these points.

A clinico-pathological study of a case of kuru.

Kuru was diagnosed in a 42-year-old Melanesian male from the Eastern Highlands Province of Papua New Guinea. The clinical features indicated predominant cerebellar degeneration together with widespread cortical neuronal dysfunction and involvement of the diencephalon, hippocampus and basal ganglia. Dementia was an early and prominent feature. The duration of clinical illness was about 12 months and atypically he spent the last 7 months in hospital allowing continuous assessment. At autopsy, spongiform encephalopathy was demonstrated, and inoculation of brain tissue into 4 squirrel monkeys and 1 capuchin monkey resulted in the development of kuru. This is the longest continuous study of kuru in a hospital setting to be recorded in the adult human subject. The virus isolated from the brain of this patient has been adopted as a standard reference strain of kuru for future use and repository.

Subacute spongiform encephalopathy with periodic paroxysmal activities: clinical evolution and serial EEG findings in 20 cases.

Evolution of both clinical and EEG abnormalities was analyzed in 20 (16 pathologically confirmed) patients suffering from subacute spongiform encephalopathy with periodic paroxysmal activities (PPA) on the EEG. Illness duration was less than 4 and greater than 17 months in 65% and 10% of cases, respectively. All data but EEG were utilized to assess 3 conventional clinical stages in 20 patients. The early clinical stage was characterized by gradual presentation of gait disturbances, mental deterioration, sensory or autonomic disorders. In contrast with other reports, no PPA were observed in 10 EEG recordings from 7 patients examined at the early clinical stage. Both clinical and EEG findings were not in contrast with a hypothetic subcortical onset of disease. Similar to recent data in the literature, early PPA appeared within 12 weeks of disease evolution in 88% of patients who underwent EEG recordings in the first 3 months of disease. Nonetheless, these early PPA always occurred at an intermediary stage, when our patients showed a marked worsening of the clinical picture. Focal, segmental and/or generalized myoclonic jerks were observed in 15%, 53% and 100% of cases at prodromal, intermediary and terminal stages respectively. Different kinds of PPA were observed: bi-tri-phasic periodic complexes (PC), periodic complexes with multiphasic configuration (PPC) and periodic polyspiking discharges (PPD). Abnormal "pacing" of PC by slowly repeated flashes was found in 4 patients presenting visual hallucinations or cortical blindness. Burst-suppression activity was frequently found at the terminal stage in decorticate patients.

The many faces of human prion diseases in Belgium and the world.

Prion diseases are rare neurodegenerative disorders that always lead to death and that can be transmissible under certain conditions. Although sporadic Creutzfeldt-Jakob's disease (CJD) is the best known human variant of these transmissible spongiform encephalopathies with an incidence of about 1 in 106 inhabitants, several other types of human prion disease have been described (e.g. Familial CJD, Gerstmann-Sträussler-Scheinker syndrome, Fatal Familial Insomnia,...). In 1996, a variant of CJD has been linked to the epidemic of bovine spongiform encephalopathy (BSE). Therefore, vigilance concerning prion diseases was increased throughout the whole of Europe. In Belgium, a comprehensive, nation-wide study has been conducted both retrospectively (1960-1997) and prospectively (1998-...) to identify prion disease patients. In 1998, a surveillance system has also been created to monitor the incidence of CJD and other prion diseases. Using data from both studies and the surveillance program, the occurrence and phenotype of all types of prion diseases in Belgium was investigated. The sporadic type of CJD was identified in 116 patients, while 4 suffered from a hereditary form. In our series, we could find no evidence for variant or iatrogenic CJD, neither for the more rare types of prion diseases.

Kuru and mad cow disease: understanding the prion theory.

A preponderance of evidence indicates that several neurodegenerative disorders are caused by prions: abnormally folded proteins that can induce abnormal folding in other normal protein molecules. Further, these "infections" can cross some species barriers.

From Creutzfeldt-Jakob disease to the mad cow epidemic.

Hans-Gerhard Creutzfeldt and Alfons Jakob independently authored clinical and pathologic descriptions of a new syndrome in the 1920s. This syndrome, which subsequently came to be named after them, was characterized by dementia, motor and coordination abnormalities, a fatal course, and pathologic findings of diffuse spongiform neuronal degeneration. Although it appeared for many years to be little more than a medical curiosity, Creutzfeldt-Jakob disease attained widespread attention by its pathologic similarity to kuru and bovine spongiform encephalopathy, "mad cow disease." Because there are sporadic, familial, and iatrogenic forms of Creutzfeldt-Jakob disease, it is considered to have both genetic and infectious aspects. Although its causation has for some time been ascribed to "slow viruses," the etiology of Creutzfeldt-Jakob disease is currently thought to be due to prions, small proteinaceous infectious particles that have genetic encoding. The debate regarding whether the appearance of atypical Creutzfeldt-Jakob disease can be linked to the epidemic of "mad cow disease" is currently unresolved.

The transmissible spongiform encephalopathies (prion diseases): a review for dental surgeons.

The transmissible spongiform encephalopathies (prion diseases) are a fatal group of neurological diseases characterised by the accumulation of an abnormal form of prion protein in the brain. In humans, these disorders occur in sporadic, acquired and familial forms. Outbreaks of bovine spongiform encephalopathy, predominantly in the United Kingdom, and the emergence of a clinically and pathologically distinct human prion disease, variant CJD, has generated much interest in the transmissible spongiform encephalopathies. As the agent is detectable in lymphoid and neural tissue in variant CJD, clinicians should be aware of the possibility of cross infection of the causative agent. This is particularly important because the abnormal prion protein is resistant to routine sterilisation procedures. This article reviews the transmissible spongiform encephalopathies, and summarises guidelines concerning prevention of crossinfection when treating patients with or at risk of developing prion disease.

[Encephalopathy caused by prions]. / Les encéphalopathies dues aux prions.

The concept of prion encephalopathy has emerged from such previous notions as slow virus infections, spongiform encephalopathies or transmissible dementias. The term prion (Prusiner, 1982) is now used in preference to unconventional agents. Proteins and genes of prions have recently been identified by molecular biology. Exactly how prion proteins are amplified in cells is still unknown. It has been demonstrated that amyloid deposits in scrapie-infected brain, Creutzfeldt-Jakob, Gerstmann-Straüssler and Kuru diseases are composed of prion proteins. Prion encephalopathies are good models to study some immunopathological mechanisms observed in the central nervous system in degenerative diseases or ageing.

Appearance of EEG changes reminiscent of a secondary generalized epilepsy in a rhesus monkey inoculated with a strain of kuru.

In a group of rhesus monkeys (Macaca mulatta) inoculated intracerebrally and intravenously with a strain (Enage strain rhesus L6 56) of kuru already passaged in rhesus monkeys, 1 monkey presented the typical EEG pattern of epileptogenic encephalopathy reminiscent of the Lennox-Gastaut syndrome. This observation provides no direct evidence for the viral origin of epilepsies of this type. It does, however, show that it is possible to induce an epileptogenic encephalopathy by an unconventional infectious agent.

Phenotype-genotype studies in kuru: implications for new variant Creutzfeldt-Jakob disease.

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt-Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future "epidemic curve" of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD "epidemic." The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.

Experimental kuru in the rhesus monkey: a study of EEG modifications in the waking state and during sleep.

EEG patterns recorded in the waking state and during sleep were studied in 6 rhesus monkeys inoculated with a strain of Kuru previously passaged in rhesus monkey (ENAGE strain, rhesus L6 56). The onset of the disease was confirmed by the appearance of various clinical signs in 4 monkeys 15 months after inoculation. At the 16th month, the first EEG modifications appeared during sleep, which became lighter. The waking EEG was abnormal during the mature phase of the disease; it was characterized by slow anomalies and scattered spikes. The sleep EEG still presented 3 stages of Slow Wave Sleep which, however, were totally unlike the physiological stages. REM sleep rapidly disappeared, as did the cyclic organization pattern. Irritative phenomena became very significant and, in particular, very frequent 'tonic seizures' were observed. Experimental Kuru thus appears, in the rhesus monkey, as an epileptogenic encephalopathy, which is differentiated from both the human disease and the experimental disease in the chimpanzee.

[Electrophysiology of transmissible encephalopathies]. / Electrophysiologie des encéphalopathies transmissibles.

The purpose of electrophysiological studies during the evolution of spongiform encephalopathies or prion diseases is to describe the changes of spontaneous or evoked electroencephalographic activity in natural and experimental diseases (natural and experimental scrapie, Kuru and Creutzfeldt-Jakob (CJ) disease in man and in different animal models) and to establish or to propose an action mechanism of the infectious agents. In the aim, the changes of electroencephalogram (EEG) and evoked potentials are described. Generally these modifications constitute an excellent and early marker of the initial phases of pathological mechanisms, replication of the agent and the cell membranes alterations. The changes of the sleep organisation occur generally later with the beginning of the clinical phase, just at the end of incubation period. The typical changes of EEG during the human CJ disease are rare in the experimental diseases. However, with animal models, it is possible to demonstrate the very univocal character of these diseases, creating pathophysiological modifications whose nature, origin and evolution are very comparable, with characteristic triade (loss of neurons, gliosis and spongiosis) and specific alterations of gabaergic, dopaminergic and inhibitory processes.