Emerging problems in prion disease

Vincent Dodelet, BSc;* Maura Ricketts, MD, MHSc, FRCPC;~ Neil R. Cashman, MD*

Canadian Medical Association Journal 1996; 155: 549-551

[résumé]

From *the Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal Que., and ~the Division of Blood-borne Pathogens, Bureau of Infectious Diseases, Laboratory Centre for Disease Control, Health Protection Branch, Health Canada, Ottawa, Ont.

Paper reprints may be obtained from: Dr. Neil R. Cashman, Montreal Neurological Institute and Hospital, 3801 University St., Montreal QC H3A 2B4. Other correspondence to mailing address or to 514 398-7371 (fax) or mdnc@musica.mcgill.ca

© 1996 Canadian Medical Association (text and abstract/résumé)

See also:
  • Article: Creutzfeld-Jakob disease latest unknown in struggle to restore faith in blood supply [full text / en bref]

    Abstract

    The authors comment on the report by Drs. Chris MacKnight and Kenneth Rockwood (see pages 529 to 536 of this issue [full text]) on the implications for Canadian physicians of human prion diseases. They argue that there is reason for concern about the possible crossover of bovine spongiform encephalopathy to humans in the form of a variant of Creutzfeldt-Jakob disease (CJD) recently identified in the United Kingdom. A second emerging issue is the potential for the causative agent of CJD to be transmitted through donated blood and tissue. Although the epidemiologic evidence suggests that this risk is remote, current national and international initiatives to increase surveillance for new cases of CJD are timely.

    Résumé

     Les auteurs commentent le rapport des Drs Chris MacKnight et Kenneth Rockwood (voir pages 529 à 536 du présent numéro [full text / résumé]) au sujet des répercussions pour les médecins du Canada des maladies à prions chez les êtres humains. Ils soutiennent qu'il y a lieu de craindre que l'encéphalopathie spongiforme bovine passe chez les êtres humains sous forme d'une variante de la maladie de Creutzfeldt-Jakob identifiée récemment au Royaume-Uni. Une deuxième grande question se pose, soit la transmission possible de l'agent pathogène de la maladie de Creutzfeldt-Jakob par don de sang et de tissus. Même si les données probantes épidémiologiques indiquent que ce risque est mince, les initiatives nationales et internationales en cours qui visent à resserrer la surveillance des nouveaux cas de maladie de Creutzfeldt-Jakob tombent à point.

    What do Canadian physicians need to know about prion disease? In this issue (see pages 529 to 536 [full text / résumé]), Drs. Chris MacKnight and Kenneth Rockwood ably review two emerging problems in this field.1 The first is bovine spongiform encephalopathy (BSE) and its potential crossover to humans. The second is the realization that Creutzfeldt-Jakob disease (CJD) may be transmissible through blood and blood products.

    Prion diseases

    The prion diseases are a group of rapidly progressive, fatal and untreatable neurodegenerative syndromes characterized by the accumulation in the brain of a protease-resistant protein that is the main (or only) macromolecule of the transmissible agent. The human prion diseases include CJD, kuru, Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. With the recent inclusion of familial progressive subcortical gliosis and a subset of inherited thalamic dementias under the heading of prion diseases, it appears likely that the spectrum of human prion-disorder phenotypes will continue to expand.

    The transmissible agent of the prion diseases is like nothing else in biology: a "life form" that does not contain nucleic acid. Infectivity appears to reside in the prion protein designated PrPSc -- the abnormal, protease-resistant isoform of a normal cellular membrane protein designated PrPC. Dr. Stanley B. Prusiner of the University of California at San Francisco has long contended that changes in conformation underlie the dramatic differences in the properties of the two isoforms; by abnormal molecular folding, PrPSc acquires protease resistance and a "catalytic" ability to recruit more conformational copies of itself from PrPC.2 PrPSc-catalyzed conversion of PrPC to PrPSc has been reported in a cell-free system,2 supporting the "protein-only" hypothesis of prion infectivity.

    BSE and variant CJD

    The prototypical prion disease of animals is scrapie, which has been long recognized in sheep and goats as a common and economically important disorder. As MacKnight and Rockwood note, BSE has given rise to considerable economic and political turmoil in the United Kingdom, and now may also present a serious concern for human health in the form of variant CJD. Since 1988, when BSE was first recognized as a novel prion disorder,3 the disease has developed in more than 150 000 cattle. At the peak of the epidemic in 1993 approximately 700 cattle were newly affected each week. The epidemic has been linked to changes in the rendering of carcasses for use as protein supplements to feed meal, suggesting that inadequately inactivated scrapie agent from sheep, cattle or both was the initial cause. Although the rate of diagnosed disease has decreased as a consequence of legislation banning the feeding of ruminant offal to livestock, about 200 new cases still occur weekly in the United Kingdom.

    In April 1996 a team coordinated by Dr. Robert G. Will of the National CJD Surveillance Unit, Edinburgh, published a report in The Lancet describing 10 cases of a new variant of CJD in the United Kingdom that may be linked to the BSE epidemic.4 The variant is distinguished from conventional CJD by the relatively low age of patients at onset and by its clinical course: nine of the patients presented with behavioural changes initially interpreted as psychiatric disease, whereas conventional CJD almost always begins with dementia or ataxia. The neuropathological features of these cases -- characterized by an abundance of unusual amyloid plaques haloed by prominent spongiform changes -- was also atypical. Recently, experimental transmission of the BSE agent to macaques was accomplished; the affected brain tissue exhibited neuropathological features virtually identical to human variant CJD.5 These reports strongly suggest that something new in the history of medicine has occurred -- namely, the development of a novel human strain of CJD. It is unclear how many people will ultimately be affected.

    CJD and the safety of the blood supply

    An important issue discussed by MacKnight and Rockwood is the potential risk that blood and blood products may become contaminated by the causative agent of CJD. The Canadian Red Cross Society has recently withdrawn potentially tainted blood products worth almost $12 million provided by donors in whom CJD subsequently developed.

    Should we worry about prion contamination of the blood supply? Perhaps the most compelling cause for concern is the bizarre nature of the agent itself: as a protease-resistant protein, PrPSc displays an incredible resistance to many procedures that inactivate conventional infectious agents. Moreover, prion replication is supported in solid organs related to the body's blood supply, such as the spleen and the lymph nodes. Indeed, the spleen is the first organ to support a high level of prion replication in rodents, although it is surpassed by the brain in the final stages of the disease. In animals, scrapie can be transmitted though blood elements, particularly white blood cells. Because the expression of PrPC is a prerequisite for the propagation of PrPSc, blood cells that express PrPC -- lymphocytes and monocytes -- may harbour and distribute infectious proteins in the body.6

    Conversely, what is the evidence favouring the safety of the blood supply? Most important is the fact that the causative agent of CJD, unlike HIV and other emerging agents, is not new. Thus, we can be comforted by the absence of a single recorded case of CJD among people with hemophilia and the absence of CJD outbreaks among recipients of multiple transfusions or people who abuse injection drugs. The transmission of CJD to recipients of cadaveric pituitary hormones7 provides a "positive control" for our ability to detect such outbreaks. Other arguments militating against undue concern include the finding in animal studies that the prion agent is present in very low titre in peripheral blood and that peripheral inoculation (such as by transfusion) is a very inefficient route of transmission. Finally, a small case-control study performed in Britain revealed no risk for the subsequent development of CJD associated with receiving blood.8

    In view of the theoretical risk of bloodborne transmission of CJD, Health Canada has recommended that the following groups of people not donate blood: all people with CJD; first-degree relatives of CJD patients with familial disease (determined by genetic testing, by identifying two or more first-degree relatives with CJD or, if there is no information, by a precautionary assumption of familial disease); recipients of products derived from human pituitary glands; and recipients of corneal or dura-mater grafts.

    Participants at a conference held in Toronto in June 1996 organized by the Laboratory Centre for Disease Control (LCDC) and the McGill Centre for Medicine, Ethics and Law reviewed and discussed the evidence regarding the transmissibility of CJD through blood and blood products. They agreed that precautions should continue to be implemented at their current level but made no recommendations for more stringent restrictions. Regarding notification of the recipients of potentially contaminated blood products, the participants agreed that patients have the right to be able to determine if they may be at risk from CJD and that public consultation was necessary.

    Future directions

    How can we confront the emerging problems posed by prion diseases? The facts necessary for truly informed decisions are still lacking. To address the issue of the risk of transmission of CJD through blood, blood products and organ or tissue transplants, the Division of Blood-borne Pathogens of the Bureau of Infectious Diseases, LCDC, will initiate an enhanced surveillance system for CJD throughout Canada. Cases will be reported to the surveillance system by specialists in neurology, neuropathology and geriatrics. Through record review, interview, genetic sequencing and neuropathological examination, extensive information about every person suspected of having CJD will be collected and compared with data from a control population to ascertain the relative risk of CJD associated with exposure to blood and blood products. In addition, Canada has been invited to participate in European Concerted Action on CJD, an international surveillance program for variant CJD coordinated by investigators in Edinburgh.

    As physicians, we should cultivate particular alertness to atypical neurologic illnesses and obtain travel and food histories from patients with unusual syndromes. Variant CJD may present as an entirely novel neurodegenerative syndrome resembling, for example, motor neuron disease or parkinsonism. Basic research should be fostered to find ways to detect and neutralize the agent in blood and blood products, and development of clinical therapies should be encouraged for the currently untreatable prion diseases of humans and animals. It is crucial that clinicians, scientists and other investigators continue to conduct and participate in studies that will address these critical issues.

    References

    1. Prusiner SB. Molecular biology of prion diseases. Science 1991; 252: 1515-22.
    2. Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, et al. Cell-free formation of protease-resistant prion protein. Nature 1994; 370: 471-4.
    3. Hope J, Reekie LJ, Hunter N, Multhaup G, Beyreuther K, White H, et al. Fibrils from brains of cows with new cattle disease contain scrapie-associated protein. Nature 1988; 336: 390-2.
    4. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-5.
    5. Lasmézas CI, Deslys JP, Demaimay R, Adjou KT, Lamoury F, Dormont D, et al. BSE transmission to macaques. Nature 1996; 381: 743-4.
    6. Cashman NR, Loertscher R, Nalbantoglu J, Shaw I, Kascsak RJ, Bolton DC, et al. Cellular isoform of the scrapie agent protein participates in lymphocyte activation. Cell 1990; 61: 185-92.
    7. Brown P, Gajdusek DC, Gibbs CJ, et al. Potential epidemic of Creutzfeldt-Jakob disease from human growth hormone therapy. N Engl J Med 1985; 313: 728-31.
    8. Esmonde TFG, Will RG, Slattery JM, et al. Creutzfeldt-Jakob disease and blood transfusion. Lancet 1993; 341: 205-7.
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