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Prions are recognized as misfolded, pathologic isoforms of the normal mammalian prion protein, which can uniquely cause infectious inherited or spontaneous disease. They are agents of transmissible spongiform encephalopathies (TSEs). The normal, benign, host-encoded forms of PrP are denoted PrPC, and the infectious disease-associated, misfolded conformers are designated PrPTSE. Earlier it was hypothesized that TSEs were caused by a new type of “slow virus” that was too small to purify but had virus-like phenotypes such as transmissibility and heritability. This was the predominantly held theory until 1982, when Stanley Prusiner proposed that the causative agent was exclusively a protein. He solidified the “protein-only” hypothesis which had been developing and termed the agent proteinacious infectious only, or prion. Prion diseases are a family of inevitably fatal neurodegenerative disorders affecting a variety of mammalian species, including human diseases such as Creutzfeldt-Jakob disease (CJD), variant CJD (vCJD), Kuru, Fatal Familial Insomnia (FFI) and Gerstmann-Straussler-Scheinker Syndrom (GSSS). Animal prion diseases include chronic wasting disease (CWD) in North American deer, elk and moose; scrapie in sheep and goats, bovine spongiform encephalopathy (BSE: “mad cow” disease) in cattle, and transmissible mink encephalopathy (TME) in mink. These diseases are characterized by long incubation periods, spongiform degeneration of the brain and accumulation of an abnormally folded isoform of the prion protein, designated PrPSc, in brain tissue. The unusual nature of prions has created a formidable challenge for detection and study of the agent. Studies have shown prions to adsorb strongly to soil components, remain infectious and persist for years. Indirect transmission most likely occurs through incidental and geophagic ingestion of soil or other contaminated fomites, as well as deer sign-post behavior such as scraping and marking overhanging branches.

The human prion diseases comprise Creutzfeldt–Jakob disease, variably protease-sensitive prionopathy, Gerstmann–Straussler–Scheinker disease, fatal familial insomnia, and kuru. Each is a uniformly fatal rare neurodegenerative disease in which conformational changes in the prion protein are thought to be the central pathophysiologic event. The majority of cases of human prion diseases occur worldwide in the form of sporadic Creutzfeldt–Jakob disease and a minority of around 10–15% are associated with mutations of the prion protein gene, termed PRNP, in the forms of genetic Creutzfeldt–Jakob disease, Gerstmann–Straussler–Scheinker disease, and fatal familial insomnia. Prion diseases are also transmissible and occur in iatrogenic and zoonotic forms (iatrogenic Creutzfeldt–Jakob disease and variant Creutzfeldt–Jakob disease respectively), adding a public health dimension to their management. Despite having a high public profile, human prion diseases are both rare and heterogeneous in their clinicopathologic phenotype, sometimes making a diagnosis challenging. A combined clinical, genetic, neuropathologic, and biochemical approach to diagnosis is therefore essential. The intensive study of these diseases continues to inform on neurodegenerative mechanisms and the role of protein misfolding in more common neurodegenerative diseases such as Parkinson disease and Alzheimer disease.

The first of several pivotal moments leading to current understanding of human transmissible spongiform encephalopathies (TSEs) occurred in 1959 when veterinary pathologist W.J. Hadlow first recognized several similarities between scrapie-a slow infection of sheep caused by an unusual infectious agent-and kuru, a fatal exotic neurodegenerative disease affecting only people of a single language group in the remote mountainous interior of New Guinea, described two years earlier by D.C. Gajdusek and V. Zigas. Based on the knowledge of scrapie, Gajdusek, C.J. Gibbs, Jr., and M.P. Alpers soon initiated efforts to transmit kuru by inoculating kuru brain tissue into non-human primates, that-although requiring several years-ultimately proved successful. In the same year that Hadlow first proposed that kuru and scrapie might have similar etiology, I. Klatzo noted that kuru's histopathology resembled that of Creutzfeldt-Jakob disease (CJD), another progressive fatal neurodegenerative disease of unknown etiology that A.M. Jakob had first described in 1921. Gajdusek and colleagues went on to demonstrate that not only the more common sporadic form of CJD but also familial CJD and a generally similar familial brain disease (Gerstmann-Straussler-Scheinker syndrome) were also transmissible, first to non-human primates and later to other animals. (Other investigators later transmitted an even rarer brain disease, fatal familial insomnia, to animals.) Iatrogenic CJD (spread by human pituitary-derived hormones and tissue grafts) was also transmitted to animals. Much later, in 1996, a new variant of CJD was attributed to human infection with the agent of bovine spongiform encephalopathy; vCJD itself caused an iatrogenic TSE spread by blood transfusion (and probably by a human-plasma-derived clotting factor). Starting in the 1930s, the scrapie agent was found to have a unique constellation of physical properties (marked resistance to inactivation by chemicals, heat and radiation), eventually interpreted as suggesting that it might be an unconventional self-replicating pathogen based on protein and containing no nucleic acid. The work of S.B. Prusiner led to the recognition in the early 1980s that a misfolded form of a ubiquitous normal host protein was usually if not always detectable in tissues containing TSE agents, greatly facilitating the diagnosis and TSEs and understanding their pathogenesis. Prusiner proposed that the TSE agent was likely to be composed partly if not entirely of the abnormal protein, for which he coined the term "prion" protein and "prion" for the agent. Expression of the prion protein by animals-while not essential for life-was later found to be obligatory to infect them with TSEs, and a variety of mutations in the protein clearly tracked with TSEs in families, explaining the autosomal dominant pattern of disease and confirming a central role for the protein in pathogenesis. Prusiner's terminology and the prion hypothesis came to be widely though not universally accepted. A popular corollary proposal, that prions arise by spontaneous misfolding of normal prion protein leading to sporadic cases of CJD, BSE, and scrapie, is more problematic and may serve to discourage continued search for environmental sources of exposure to TSE agents.

Background: Kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia are a group of transmissible, progressive, and ultimately lethal neurodegenerative disorders caused by prion diseases. Prion disease may present in sporadic, inherited, and acquired forms. Fewer new cases of CJD are presenting themselves compared to the 1990’s when a surge of cases was recognized after an extended incubation period following dura mater and growth hormones replacement up to 25 years before. Currently, prion disease affects approximately 1 - 2 persons per million worldwide annually. In recent years, however, variant CJD has been associated with transfusions, making the possibility of transmission through operative procedures, blood, and tissue donations a real concern. Since the emergence of variant CJD, prion disease has become a considerable public health threat, not only because of their mysterious pathogenesis, but the lack of treatment options, limited diagnostic availability, and emerging transmission routes. Active surveillance of human prion diseases is critical for disease control and prevention considering the limited options for therapeutic and prophylactic interventions. Due to the risk to public health, CJD surveillance systems are now established in many countries; especially developing countries and deployed military units where healthcare is poor and infection control measures in the field are difficult to maintain. Several long-term multinational cooperative projects are on-going as well as reporting systems which protect military families from purchasing bovine in endemic countries. Objective: This paper reviews the epidemiological characteristics of various human prion diseases, infection control issues, current disinfection processes as well as recommended processes, and active surveillance systems in different countries. Conclusions: Prion disease represents a continued public health concern due to its insidious nature. Current practice continues to advance finding better ways at diagnosing earlier. Treatment options are still far from being anything but palliative. Prevention remains the primary component to neutralizing the spread of non-inherited forms of prion disease.

Since J. Cuille and P. L. Chelle successfully transmitted scrapie between sheep by experi- mental inoculation in 1936 and D. C. Gajdusek kuru and Creutzfeldt-Jakob disease to chimpanzee in 1966 and 1968, respectively, the nature of the agents causing these " slow virus diseases " remains a mystery. In 1982, S. Prusiner called them " PRIONs " (for " PROteinaceous INfectious particles ") because they appeared lacking the nucleic acids that would classify them viruses. Although infectious or genetic mechanisms were seldom found, most of the rare human PRION diseases appeared " sporadic ". They shared many clinical and neuropathological properties with human neurodegenerative diseases (slow development, prominent nervous system involvement, amyloid deposits, paucity of immune response) the mechanism of which was not considered usually infectious. In 1991, H. Braak showed, in Alzheimer's disease brain, the low spreading of neuropathological tau associated lesions along anatomic pathways. They appear long before the clinical signs. The abnor- mally misfolded proteins characteristics of many neurodegenerative diseases are thought to aggregate after an initial seeding. This leads to their cell-cell transmission and dissemina- tion through neuronal and extra-neuronalpathways, which unexpected extent is under study. Whether the seeding is infectious or not remains debated. This new paradigm for unders- tanding their natural history and phenotypic diversity, which has already led to assess the diagnostic value of skin biopsy, should open the door to new therapeutic approach.

Prion diseases or transmissible spongiform encephalopathies (TSEs) are fatal protein-misfolding neurodegenerative diseases. TSEs have been described in several species, including bovine spongiform encephalopathy (BSE) in cattle, scrapie in sheep and goats, chronic wasting disease (CWD) in cervids, transmissible mink encephalopathy (TME) in mink, and Kuru and Creutzfeldt-Jakob disease (CJD) in humans. These diseases are associated with the accumulation of a protease-resistant, disease-associated isoform of the prion protein (called PrP(Sc)) in the central nervous system and other tissues, depending on the host species. Typically, TSEs are acquired through exposure to infectious material, but inherited and spontaneous TSEs also occur. All TSEs share pathologic features and infectious mechanisms but have distinct differences in transmission and epidemiology due to host factors and strain differences encoded within the structure of the misfolded prion protein. The possibility that BSE can be transmitted to humans as the cause of variant Creutzfeldt-Jakob disease has brought attention to this family of diseases. This review is focused on the TSEs of livestock: bovine spongiform encephalopathy in cattle and scrapie in sheep and goats.

We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain.

"Bovine spongiform encephalopathy", "scrapie", as well as Creutzfeldt–Jakob disease and kuru belong to a group of related neurological conditions termed "transmissible spongiform encephalopathies". These diseases are based on the LD 50 measurement whereby saline brain homogenates are injected into experimental animals and when 50% of them develop symptoms, this is considered as transmission of the disease, but the gold standard for diagnosis is autopsy examination. However, an untenable assumption is being made in that saline brain homogenates do not cause tissue damage but it is known since the time of Pasteur, that they give rise to "post-rabies vaccination allergic encephalomyelitis". This is the fundamental flaw in the diagnosis of these diseases. A way forward, however, is to examine infectious agents, such as Acinetobacter which show molecular mimicry with myelin and elevated levels of antibodies to this microbe are found in multiple sclerosis patients and animals affected by "bovine spongiform encephalopathy".