More on BSE/vCJD
Authors: A J Beale
Journal: Journal of the Royal Society of Medicine (2001)

Since the topic was considered here in May1, various reports have offered further enlightenment. Also, on 18 September the Spongiform Encephalopathy Advisory Committee (SEAC) held a meeting open to the public, and on 2 October the RSM's Section of Pathology discussed the threat posed by variant Creutzfeldt—Jakob disease (vCJD) in areas such as surgery, ophthalmology, blood transfusion and dentistry.

The epidemic of BSE in British cattle is still declining much as expected, and the numbers of cases in the UK next year may well fall below those in France. The disease seems to be under good control, and, with enforcement of the ban on meat-and-bone meal (MBM) and removal of potentially contaminated material from the food chain, British beef is for practical purposes safe at last.

At the SEAC meeting Gabriel Horn, Emeritus Professor of Zoology at Cambridge, presented his team's report on the origin of BSE (available on [www.defra.gov.uk./animalh/bse ]). He put forward the suggestion that BSE occurred in Britain because we were unique in feeding calves in dairy herds from the day of birth, or shortly thereafter, with a ‘starter ration’ made with MBM (open to contamination by scrapie) as well as milk substitute. The starter ration was pioneered in Australia—a country essentially free from scrapie. The relevance of the starter ration is supported by the higher incidence of BSE in dairy herds than in beef suckler herds; also, calves seem much more susceptible than adult cows. Horn observes that the question of increased susceptibility can be resolved by direct experiment. His report also discusses whether BSE originated in cattle or resulted from passage of scrapie across the species barrier from sheep to cattle. This question remains unresolved, as does the related question of whether BSE has reinfected sheep, via MBM fed to them after lambing. Horn thinks that the changes in the rendering process that took place in the early 1970s could have been just sufficient to raise the scrapie infectivity of the MBM to a level at which it could cross the species barrier, especially in young calves.

The pathogenesis of spongiform encephalopathies depends on the conversion of normal cellular prion protein PrPc to the pathological proteinase resistant form PrPsc, and here some progress has been made. Thus it seems that changes in the metal-ion occupancy of the protein are crucial. PrPc contains 1-4 copper atoms per molecule of protein that confers superoxide dismutase activity. Replacement of copper by manganese leads to a loss of enzyme activity and, after a short delay, to proteinase resistance2. Lately this work has been extended3 to the study of brains from patients with sporadic Creutzfeldt—Jakob disease (sCJD) in the USA. In these brains copper was found to have been replaced by manganese, and overall the content of manganese was increased tenfold. Moreover, metal-ion occupancy varied between different forms of sCJD. This work needs to be confirmed and extended to the study of vCJD. It is important because it opens the way to new diagnostic procedures (e.g. by magnetic resonance) and possibly to treatment with specific chelators.

Another development of great theoretical and practical importance is the technique of protein misfolding cyclic amplification4. This entails mixing of PrPc (as normal hamster brain homogenate) with a small amount of PrPsc (as diluted scrapie infected brain homogenate), incubation at 37°C for 1 hour and sonication, the process then being repeated. The result is progressive amplification of the conversion of PrPc to PrPsc. It will be of great interest to see whether the resultant PrPsc is transmissible in animals. If it is, the way will be open to dissect the components of brain homogenate for their ability to confer transmissibility. The technique has obvious applications to diagnosis, especially if PrPsc from lymphoid tissue can be used. An accurate sensitive laboratory method of diagnosis that can be performed on non-central-nervous tissue is one of the most urgent needs. Ignorance of the likely extent of the disease in the population makes planning particularly daunting—as was made plain at the RSM meeting, which aired such matters as what you do when you discover that a patient with proven vCJD has been a blood donor or had an appendicectomy in your hospital. Dilemmas of this sort are discussed in a consultation document drawn up by the CJD Incidents Panel set up by SEAC and the Advisory Committee on Dangerous Pathogens [www.doh.gov.uk/CJD/consultation ]. One thing we did learn at the Section of Pathology meeting was how to kill prions. There are now four publications agreeing that 2M sodium hydroxide at 121°C for 30 minutes will do the job. Some grades of stainless steel will stand the conditions but not much else.

Efforts to use histological methods on tonsils and appendices removed at operation, retrospectively and then prospectively as a surveillance method, are underway, but no news has emerged since the first 3000 or so tests were reported (all negative)5. The prospective studies are hindered by the fall in tonsillectomies that followed the Department of Health's advice to use disposable instruments for such operations. What we need is a simpler blood-based test, not only to help epidemiologists assess the likely size of the outbreak but also for detecting infected blood donations and removing them from the supply, as has been effectively done for other infectious agents. The consultation document considers the implications of a test for epidemiological surveillance that confers no benefit, and perhaps harm, to the people tested. At present the assumptions6 that have to be made to estimate the likely size of the epidemic, by mathematical modelling, inspire little confidence in the predictions. More data are needed, especially about the prevalence of the agent in the population and the incubation period. At this point a proposal from Venters7 deserves mention—that vCJD is not a new disease but an artifact of increased surveillance. The error, he suggests, will be shown when cases still occur long after the risk from eating beef has disappeared. This possibility is acknowledged by the National Surveillance Centre and SEAC but rejected on the grounds that the clinical and neuropathological picture is distinctive and a particular prion strain is involved.

What every patient and doctor wants most is a cure. Much work is in progress to find a treatment, with the spotlight on two existing drugs—quinacrine (an antimalarial) and chlorpromazine (an antipsychotic). These drugs inhibit the formation of PrPsc in mouse brain cell cultures; no in-vivo work has been reported. The Department of Health has asked the Medical Research Council to design a trial to evaluate the efficacy of quinacrine and any side-effects. This is a challenging task when in-vivo data are lacking and the number of living patients is too small for a conventional controlled trial. Other approaches to treatment include monoclonal antibodies to PrPsc, and the beta sheet breakers (normal PrP has alpha helices of peptides and the pathological form has beta sheets). In the long term, unfortunately, there will probably be no shortage of patients in whom to try these treatments.