Close patient observation and electroencephalography play an important role in the diagnosis of rare diseases. Presentation of a case of Creutzfeldt-Jakob disease

Creutzfeldt–Jakob disease is a rare, progressive spongiform encephalopathy caused by infectious proteins called prions. It is characterised by rapidly progressive dementia accompanied by cerebellar, visual, extrapyramidal, and pyramidal symptoms, as well as myoclonus and mutism in later stage of the disease. The most common type is sporadic Creutzfeldt– Jakob disease, accounting for 85% of all cases. Treatment of the disease is symptomatic. An important role in making the diagnosis is attributed to the observation of the patient and electroencephalography, showing characteristic cyclical discharges. We present the case of a patient whose first symptoms were psychiatric in nature, and who was diagnosed with Creutzfeldt–Jakob disease based on careful observation, presence of myoclonus, and repeated electroencephalography examinations in which typical 1–2 seconds of sharp and slow wave discharges appeared. By presenting this case of severe progressive encephalopathy, we would like to highlight the fact that even in the age of modern diagnostic methods, electroencephalography, which has been in use for many years, may be crucial in the diagnostic process. We would also like to point out that the initial symptoms of Creutzfeldt–Jakob disease may suggest a psychiatric disorder.

Dealing With Deadstock: A Case Study of Carnivore Conflict Mitigation From Southwestern Alberta

Livestock deaths are an unfortunate reality for livestock producers and dead livestock (i.e., deadstock) disposal options can have implications beyond the ranch itself. In Alberta, Canada, natural disposal (i.e., disposing of the carcass in a manner that allows for scavenging) has increased since the 2003 detection of bovine spongiform encephalopathy (BSE) in Canadian cattle. Prior to BSE, rendering companies removed deadstock for free. However, rendering companies started charging producers to remove deadstock to offset costs associated with new regulatory requirements enacted by the Canadian Food Inspection Agency, which has resulted in increased on-farm natural disposal of deadstock. This increase has ecological implications because deadstock are a major attractant for large carnivores. Carnivores feeding on deadstock are often near other agricultural attractants such as stored grain and feed, silage, and living livestock, which can exacerbate conflict potential and pose a risk to human safety. To help mitigate conflicts associated with deadstock, the Waterton Biosphere Reserve's (a local non-profit) Carnivores and Communities Program (CACP) supported expansion of community deadstock removal efforts beginning in 2009, including reimbursement of on-farm removal costs, bear-resistant deadstock bins, and a livestock compost facility (operational 2013–2014). Here, we present an evaluative case study describing the development, implementation, and results of the deadstock removal program, including the compost facility. We tracked the number of head of livestock removed each year, the number of participating landowners, the average cost per head, and total program costs. We also used an online survey to assess participants' perspectives of the deadstock removal program and future needs. To date, the CACP has removed >5,400 livestock carcasses, representing between 15.1 and 22.6% of available carcasses in the program area, and 67.3% of livestock owners indicated they currently use the deadstock removal program to dispose of deadstock. Average cost to compost an animal was significantly less than other removal methods ($36.89 composting vs. $79.59 non-composting, one-tailed t-test, unequal sampling variances: t = 4.08, df = 5.87, p = 0.003). We conclude by discussing both ecological and social implications for deadstock removal as a conflict mitigation measure and make suggestions for future management considerations.

Differential Accumulation of Misfolded Prion Strains in Natural Hosts of Prion Diseases

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of neurodegenerative protein misfolding diseases that invariably cause death. TSEs occur when the endogenous cellular prion protein (PrPC) misfolds to form the pathological prion protein (PrPSc), which templates further conversion of PrPC to PrPSc, accumulates, and initiates a cascade of pathologic processes in cells and tissues. Different strains of prion disease within a species are thought to arise from the differential misfolding of the prion protein and have different clinical phenotypes. Different strains of prion disease may also result in differential accumulation of PrPSc in brain regions and tissues of natural hosts. Here, we review differential accumulation that occurs in the retinal ganglion cells, cerebellar cortex and white matter, and plexuses of the enteric nervous system in cattle with bovine spongiform encephalopathy, sheep and goats with scrapie, cervids with chronic wasting disease, and humans with prion diseases. By characterizing TSEs in their natural host, we can better understand the pathogenesis of different prion strains. This information is valuable in the pursuit of evaluating and discovering potential biomarkers and therapeutics for prion diseases.

Prion infections of animals: safety of food and medicinal raw materials of animal origin. Up-to-date data

Prion infections of humans and animals are absolutely fatal. The cellular prion protein retains its antigenicity during the transition to the prion isoform; therefore, animals affected by prions do not respond to them with defensive reactions in the form of inflammation and the production of antibodies, which makes it difficult to diagnose the disease in vivo. In affected animals, prions accumulate in the nervous, lymphoreticular and muscle tissues and are released into the environment, in which they remain for many years. The resistance of prions to physical and chemical factors does not allow them to be inactivated in food by heat or radiation. Zoonoticity has been proven only for the causative agent of bovine spongiform encephalopathy, to which sheep, goats and pigs are susceptible. Sheep scrapie and chronic wasting deer disease occur widely in natural conditions in the form of enzootics and are similar in many characteristics. The zoonotic nature of their pathogens has not been proven.

RT-QuIC detection of pathological prion protein in subclinical goats following experimental oral transmission of L-type BSE

Objective The spread of bovine spongiform encephalopathy (BSE) agent to small ruminants is still a major issue in the surveillance of transmissible spongiform encephalopathies (TSEs). L-type bovine spongiform encephalopathy (L-BSE) is an atypical form of BSE with an unknown zoonotic potential that is transmissible to cattle and small ruminants. Our current knowledge of bovine atypical prion strains in sheep and goat relies only on experimental transmission studies by intracranial inoculation. To assess oral susceptibility of goats to L-BSE, we orally inoculated five goats with cattle L-BSE brain homogenates and investigated pathogenic prion protein (PrPsc) distribution by an ultrasensitive in vitro conversion assay known as Real-Time Quaking Induced Conversion (RT-QuIC). Results Despite a prolonged observation period of 80 months, all these animals and the uninfected controls did not develop clinical signs referable to TSEs and tested negative by standard diagnostics. Otherwise, RT-QuIC analysis showed seeding activity in five out of five examined brain samples. PrPsc accumulation was also detected in spinal cord and lymphoreticular system. These results indicate that caprine species are susceptible to L-BSE by oral transmission and that ultrasensitive prion tests deserve consideration to improve the potential of current surveillance systems against otherwise undetectable forms of animal prion infections.

Creutzfeldt - Jakob Disease in South West Sydney 2014-2020: An Unusually High Incidence of a Rare Disease

Introduction Creutzfeldt - Jakob Disease (CJD), a spongiform encephalopathy, caused by a transmissible misfolded cellular prion protein is a rapidly progressive, debilitating neuro-degenerative disorder with no effective treatment. The estimated global incidence is at 1/ million inhabitants. This retrospective study examined the incidence of CJD in South Western Sydney Local Health District (SWSLHD) from 2014 to 2020. Background SWSLHD had an estimated population of 1,038,534 in 2020, with CJD data being limited. Methods New South Wealth (NSW) Health-Information-Exchange (HIE) database, for all admissions with CJD diagnoses in SWSLHD, between 2014–2020, was reviewed according to World Health Organization (WHO) diagnostic criteria, consistent with the Australian national CJD registry. Only probable CJD cases were included. Incidence was calculated based on the projected SWSLHD population. Results 35 patients, diagnosed with CJD, were identified. Each was evaluated by two independent investigators, including clinical presentation; MRI; EEGs; 14-3-3; and RT-QUIC results, before assigning CJD-probable status. Four failed the CJD criteria and were excluded. Of the 31 CJD-probable cases, most (59%) were male and older (37% range 61-70 years). The incidence rate peaked at 9/million in 2017 and was above 2/million, throughout the seven years, with an average of 4.859/million/year. Conclusions The incidence of CJD, in SWSLHD, exceeds the national average of 1/million. Cost-effective, adequate diagnostic and screening tools, implementable over a large population, will become increasingly essential.

Reduced SOD2 expression does not influence prion disease course or pathology in mice

Prion diseases are progressive, neurodegenerative diseases affecting humans and animals. Also known as the transmissible spongiform encephalopathies, for the hallmark spongiform change seen in the brain, these diseases manifest increased oxidative damage early in disease and changes in antioxidant enzymes in terminal brain tissue. Superoxide dismutase 2 (SOD2) is an antioxidant enzyme that is critical for life. SOD2 knock-out mice can only be kept alive for several weeks post-birth and only with antioxidant therapy. However, this results in the development of a spongiform encephalopathy. Consequently, we hypothesized that reduced levels of SOD2 may accelerate prion disease progression and play a critical role in the formation of spongiform change. Using SOD2 heterozygous knock-out and litter mate wild-type controls, we examined neuronal long-term potentiation, disease duration, pathology, and degree of spongiform change in mice infected with three strains of mouse adapted scrapie. No influence of the reduced SOD2 expression was observed in any parameter measured for any strain. We conclude that changes relating to SOD2 during prion disease are most likely secondary to the disease processes causing toxicity and do not influence the development of spongiform pathology.

Variant CJD: Reflections a Quarter of a Century on

Twenty-five years has now passed since variant Creutzfeldt-Jakob disease (vCJD) was first described in the United Kingdom (UK). Early epidemiological, neuropathological and biochemical investigations suggested that vCJD represented a new zoonotic form of human prion disease resulting from dietary exposure to the bovine spongiform encephalopathy (BSE) agent. This hypothesis has since been confirmed though a large body of experimental evidence, predominantly using animal models of the disease. Today, the clinical, pathological and biochemical phenotype of vCJD is well characterized and demonstrates a unique and remarkably consistent pattern between individual cases when compared to other human prion diseases. While the numbers of vCJD cases remain reassuringly low, with 178 primary vCJD cases reported in the UK and a further 54 reported worldwide, concerns remain over the possible appearance of new vCJD cases in other genetic cohorts and the numbers of asymptomatic individuals in the population harboring vCJD infectivity. This review will provide a historical perspective on vCJD, examining the origins of this acquired prion disease and its association with BSE. We will investigate the epidemiology of the disease along with the unique clinicopathological and biochemical phenotype associated with vCJD cases. Additionally, this review will examine the impact vCJD has had on public health in the UK and the ongoing concerns raised by this rare group of disorders.

Prion Infectivity and PrPBSE in the Peripheral and Central Nervous System of Cattle 8 Months Post Oral BSE Challenge

After oral exposure of cattle with classical bovine spongiform encephalopathy (C-BSE), the infectious agent ascends from the gut to the central nervous system (CNS) primarily via the autonomic nervous system. However, the timeline of this progression has thus far remained widely undetermined. Previous studies were focused on later time points after oral exposure of animals that were already 4 to 6 months old when challenged. In contrast, in this present study, we have orally inoculated 4 to 6 weeks old unweaned calves with high doses of BSE to identify any possible BSE infectivity and/or PrPBSE in peripheral nervous tissues during the first eight months post-inoculation (mpi). For the detection of BSE infectivity, we used a bovine PrP transgenic mouse bioassay, while PrPBSE depositions were analyzed by immunohistochemistry (IHC) and by protein misfolding cyclic amplification (PMCA). We were able to show that as early as 8 mpi the thoracic spinal cord as well as the parasympathetic nodal ganglion of these animals contained PrPBSE and BSE infectivity. This shows that the centripetal prion spread starts early after challenge at least in this age group, which represents an essential piece of information for the risk assessments for food, feed, and pharmaceutical products produced from young calves.