Prion Diseases

Dr Jon Simcock

Infectious diseases of the central nervous system (CNS) are well known to everyone. Infections with parasites ( e.g. hydatid disease of the brain, malaria), bacteria (e.g. meningococcus) and viruses ( e.g. herpes virus encephalitis, poliomyelitis) are common knowledge, but a peculiar infectious agent, prion protein, is generally known only in relation to bovine spongiform encephalopathy (BSE or “mad cow disease”). While infections of humans by prion proteins are uncommon, they are of intense interest, with two Nobel prizes awarded for research in this area. Studies of prion diseases have raised fundamental new questions in microbiology.

Parasites and bacteria proliferate in the body by replication of DNA and viruses multiply by either DNA or RNA: both DNA and RNA are proteins (nucleic acids) which are destroyed by heat, enzymes (proteases) and some chemicals. One prion disease, scrapie, is a disease of sheep and goats. In the 1940’s the nature of the infectious agent was baffling – it was resistant to proteases, formaldehyde and ethanol, substances which break down DNA and RNA and therefore kill bacteria and viruses. In 1982 the term prion was proposed to “denote a small proteinaceous infectious particle which is resistant to most procedures that modify nucleic acids”. Later it was shown that one form of the prion protein is a normal component of cell membranes, although its function has not yet been determined. The mechanism of conversion from the normal to the infectious form of prion protein is being intensively studied.

Prion diseases of animals include scrapie and mad cow disease (BSE). Human disease includes Creutzfeld-Jacob disease (CJD) which is fortunately rare – about one case per million people per year – and variant CJD (vCJD), the disease caused in humans infected by eating beef from BSE cattle which was contaminated with infected CNS tissue. vCJD was first reported in 1994, with a total of 161 cases reported in the UK, the number of cases declining rapidly since 2000. 18 cases have been reported from France. Hopefully, with the control of BSE, there will be very few further cases of vCJD.

The first case of BSE in the UK occurred in 1985. Over the next decade there was a massive epidemic with a total of about one million cattle being affected. The source of the infection was apparently contamination of meat-and-bone meal fed to calves, with the disease not appearing until the cattle were 4-5 years old. This long latency is typical of prion diseases. The disease was not spread from cow to cow or from cow to calf. In 1988, cattle carcasses were banned from use in cattle feed; with the 4-year incubation period, the epidemic peaked in 2002, with a rapid drop of new infections after that. Some cats, but not dogs, fed with infected pet food developed the disease.

Sporadic CJD remains an oddity – while other prion diseases are transmissible, there is no evidence of lateral or genetic transmission of sporadic CJD, which just seems to develop as a spontaneous mutation in the prion protein. However, unintentional transmission of CJD has occurred in three settings. Firstly, in 1977 transmission to two patients occurred when intracranial electrodes were used to study a patient with CJD, then re-used to study two patients with intractable epilepsy, even although the electrodes had been “sterilized” in alcohol and formaldehyde vapour after each use. Secondly, over 100 cases of CJD have occurred years after surgical transplant of dura mater (the strong fibrous covering of the brain) obtained from patients dying from CJD into other patients. (Dural grafts are performed to replace damaged dura so that the brain can be completely enclosed by this important covering, for example after removing a meningioma attached to the dura).

Thirdly, more than 130 patients have developed CJD five to as much as 30 years after receiving growth hormone made from pooled cadaveric pituitary glands. Because of the knowledge gained from the research into prion diseases in the 1980’s measures have been implemented to ensure that these iatrogenic (see below) infections no longer occur.

In New Zealand, a register of CJD has been kept for the past ten years, supervised by Prof Martin Pollock in Dunedin and Dr Andrew Chancellor in Tauranga. Neurologists are kept informed by an annual report from Prof Pollock – there were 3 cases of CJD in NZ in 2005.

Prion diseases are fortunately rare as there is no effective treatment. Unlike other infections, there is no immune response of the body to the infection by the prion proteins, so that immunization against prion disease is not possible. Disasters such as the AIDS and BSE epidemics can have an up side – stimulating research which results in an unusually rapid expansion of our knowledge of that field.

Dr Jon Simcock is a consultant neurologist and the Neurological Foundation’s Medical Adviser.

Etymology: Greek iatros physician + English -genic: induced inadvertently by a physician or surgeon or by medical treatment or diagnostic procedures