Antemortem diagnosis of variant Creutzfeldt-Jakob disease

Antemortem diagnosis of variant Creutzfeldt-Jakob disease

COMMENTARY unlikely to reflect a novel or unique disease. A major feature, however, of Fukuda and colleagues’ study was the construction of a case-de...

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COMMENTARY

unlikely to reflect a novel or unique disease. A major feature, however, of Fukuda and colleagues’ study was the construction of a case-definition of a chronic multisystem illness among the veterans by incorporation of the key elements that the researchers had found to be most predictive of illness. The researchers then compared the results of physical examinations and extensive laboratory investigations of veterans who met these criteria with those of veterans who did not, and they found that a unique Gulf War syndrome could not be delineated. The cumulative studies now confirm that there is no unique Gulf War syndrome. Although the possibility of some still unappreciated environmental factor cannot be dismissed entirely, the Gulf War seems to differ from others only in a quantitative sense and in the intensity of public discourse about it. There were highly prevalent exposures that, together with the fear of injury and death from unseen nuclear, chemical, and biological weapons, made service in the Gulf War more hazardous than the mere “body count” would suggest. Perhaps it was the very lack of mutilation and death in that war that permitted the true physical and emotional costs of battle to be revealed. On the assumption that these conclusions are correct, there are limited means of preventing chronic illness in future wars. Unless those wars are to be fought solely by machines, the human cost of warfare will remain high. The troops must be prepared both physically and emotionally for combat, be provided with routine health surveillance afterwards, and be given a commitment for all necessary care for war-related illness. Military scientists also need to undertake prospective studies to define the pre-existing attributes of an individual and the experiences that contribute most to the risk of long psychological illnesses. The outcomes of such studies will undoubtedly benefit the victims of similar illnesses among the larger civilian population.

Stephen E Straus Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA 1

Lewis T. The soldier’s heart and the effort syndrome, 2nd edn. London: Shaw, 1940. 2 Grant RT. Observations on the after-histories of men suffering from the effort syndrome. Heart 1925; 12: 121–42. 3 Wood P. Da Costa’s syndrome (or effort syndrome): the mechanisms of somatic manifestations: BMJ 1941; i: 805–11. 4 Wood P. Aetiology of Da Costa’s syndrome. BMJ 1941; i: 845–51. 5 Da Costa JM. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci 1871; 121: 17–52. 6 DeFraites RF, Wanat ER, Norwood AE, Williams S, Cowen D, Callahan T. Investigation of a suspected outbreak of an unknown disease among veterans of operation Desert Shield/Storm, 123rd Army Reserve Command, Fort Benjamin Harrison, Indiana, April 1992. Washington, DC: Walter Reed Army Institute of Research, 1992. 7 Office of the Under Secretary of Defense for Acquisition and Technology. Report of the Defense Science Board Task Force on Persian Gulf War Health Effects. Washington, DC. June, 1994. 8 Health Consequences of Service during the Persian Gulf War: Recommendations for research and information systems. Washington DC: National Academy Press, 1996. 9 Rook G, Zumla A. Gulf War syndrome: is it due to a systemic shift in cytokine balance towards a Th2 profile? Lancet 1997; 349: 1831–33. 10 Fukuda K, Nisenbaum R, Stewart G, et al. Chronic multisystem illness affecting Air Force veterans of the Gulf War. JAMA 1998; 280: 981–88.

THE LANCET • Vol 353 • January 16, 1999

Antemortem diagnosis of variant Creutzfeldt-Jakob disease See page 183 Since the first report of a case of variant CreutzfeldtJakob disease in 1996, there have been a further 33 cases in the UK and one in France. How many more individuals harbour the disease in a latent state is unknown. To date there has been no reliable screen for presymptomatic individuals. However, in this issue of The Lancet, A F Hill and co-workers describe a study that is a follow-up on their previous report of proteaseresistant prion protein (PrPSc) in a necropsy sample from the tonsil of an individual affected by variant CJD.1 They show that the PrPSc in the tonsil is specific for variant CJD. Prion diseases are associated with the conversion of a normal cellular protein, the prion protein, from a protease-sensitive to a protease-insensitive form.2 CJD, occurs in sporadic, inherited, or acquired forms. Variant CJD has been associated with the bovine spongiform encephalopathy (BSE) epidemic. The association was based on the molecular phenotype of the proteaseresistant prion protein found in affected individuals and its transmission to animals.3,4 In the study reported today, Hill and colleagues examined lymphoreticular tissue obtained at necropsy from patients with prion disease and from neurological and non-neurological controls, as well as tonsil biopsy samples from patients with suspected prion disease. In lymphoreticular tissue PrPSc was detected only in samples from individuals with confirmed variant CJD. It was also detected from tonsil biopsy samples from all eight patients whose disease turned out to be variant CJD. It was not detected in samples from patients with other forms of prion diseases, including iatrogenic and inherited CJD. The detection of PrPSc in tonsil tissue of individuals with variant CJD represents, so far, the only means of diagnosing specific prion disease before death without a brain biopsy. The PrPSc found in the tonsil had a different pattern of glycosylation from that found in the brain. The investigators designate the two types 4t and 4, respectively. However, there is controversy over the molecular typing of PrPSc.5,6 The investigators suggest that the altered glycosylation pattern may be tissue specific, but did not compare the glycosylation pattern of the normal prion protein derived from brain with that from the tonsil, to find out whether the pattern is the same as that found in PrPSc. The role of the glycans in determining prion strains is unknown. Thus, perhaps the most interesting question is whether the disease transmitted by type 4 differs from that transmitted by 4t. If it does, the difference in glycosylation might be important for specification of strain characteristics. Although unproven, there has been a suggestion that variant CJD occurs through the ingestion of BSEcontaminated beef. Presumably, the prion is transmitted from the gut to the brain. On the basis of animal studies, this transmission seems to occur via the lymphoreticular system, so PrPSc would be expected to be present in the lymphoreticular system, including the tonsil, before symptoms occur. In scrapie, the prion disease that affects sheep, PrPSc has been observed in the tonsil during the incubation phase.7 PrPSc has also been detected in an appendix removed 8 months before the

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onset of symptoms in a patient with variant CJD.8 Thus, Hill and colleagues’ study seems to open up prospects for widespread screening for latent variant CJD. However, the population of the UK is unlikely to be willing to undergo this type of screening procedure. Nor could the cost of screening be justified, since there is no treatment for the disease. This point does not, however, diminish the value of this screening procedure for risk estimates based on archival tonsil and appendix samples. Although this type of screening may result in an underestimate, such as whether PrPSc is detectable early after exposure to an infectious source, collection of data is an important first step in the assessment of the potential exposure of the UK population to the agent that causes variant CJD. Furthermore, this situation emphasises the need for a sensitive non-invasive test for the disease. The detection of potentially infectious prions in the tonsil and appendix also ushers in a new set of concerns for the medical community. Although the concentration of infectious prions is expected to be lower in these tissues than in the brain, the opportunity for iatrogenic transmission from appendicectomies or tonsillectomies should not be overlooked. This possibility is particularly important in prion-related diseases because of the welldocumented difficulty in inactivating the prion. Perhaps the adoption of universal precautions, based on the assumption that the material is infectious until proven otherwise, would be the most prudent course.

Robert B Petersen Depar tment of Pathology, Case Western Reser ve University, Cleveland, OH 44106-2622, USA 1

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Hill AF, Zeidler M, Ironside J, Collinge J. Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy. Lancet 1997; 349: 99–100. Prusiner SB. Prions. Proc Natl Acad Sci USA 1998; 95: 13363–83. Bruce ME, Will RG, Ironside JW, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 1997; 389: 498–501. Hill AF, Desbruslais M, Joiner S, Sidle KCL, Gowland I, Collinge J. The same prion strain causes vCJD and BSE. Nature 1997; 389: 448–50. Parchi P, Capellari S, Chen SG, et al. Typing prion isoforms. Nature 1997; 386: 232–33. Collinge J, Hill AF, Sidle KCL, Ironside J. Typing prion isoforms; reply. Nature 1997; 386: 233–34. Schreuder BE, van Keulen LJ, Vromans ME, Langeveld JP, Smits MA. Tonsillar biopsy and PrPSc detection in the preclinical diagnosis of scrapie. Vet Rec 1998; 142: 564-68. Hilton DA, Fathers E, Edwards P, Ironside JW, Zajicek J. Prion immunoreactivity in appendix before clinical onset of variant Creutzfeldt-Jakob disease. Lancet 1998; 352: 703–04.

The information wars Doctors today cannot escape the cult of information. The idea that several years at medical school, a postgraduate diploma or two, and a lifetime subscription to a medical journal will last a doctor out until it is time to exchange stethoscope for golf clubs has long withered. Not only do doctors need to worry about the research evidence on which they base their clinical decisions, but also they need to immerse themselves in ever more abstruse and competing collections of data. Elizabeth McGlynn and colleagues1 from RAND Health, a US agency that aims to “improve policy and decision making through research and analysis”, have lately tried to make sense of this bewildering mass of material in a book for “stakeholders” in health care. 164

They have attempted to design a framework that integrates information from medical records, laboratories, radiology departments, welfare and insurance files, consumer surveys, employment documents, health-policy initiatives, environmental assessments, registries, census data, and pharmaceutical reports, together with input from economists, statisticians, computer programmers, “psychometricians”, and, somewhat mysteriously, “organizational behaviorists”. Their purpose is driven by a genuine need, although the busy clinician may think that the back of rationality is being broken by the carthorse of common sense. Still, technology can help the information-challenged doctor. Computer-based clinical-decision support systems can improve aspects of medical practice,2 although finding information is commonly hampered by poor search methods.3 Publishers are moving quickly to put their content on-line and medical journals in particular are working hard to devise new ways to present their material to a much broader, web-based readership.4 Pressure is also building for commercial publishers to face up to a shift in power towards authors and researchers because of expansion of the internet. Some companies still believe that they can charge high prices for journals and retain copyright control over what they see as their intellectual property. Many scientists strongly disagree,5 and commercial science publishing is under sharp attack.6 A war against these publishers is under way. The explosion in quantity of information and diversity of access to it has also led to a debate about how clinicians use evidence. For instance, we now have, at the very least, evidence-based,7 interpretive,8 and narrative-based medicines.9 One technique has come to exemplify the simmering tensions over evidence between clinicians and methodologists—namely, the systematic review and its quantitative counterpart, the meta-analysis. Last week, the second Symposium on Systematic Reviews took place in Oxford, UK. This meeting has already established itself as one of the leading international multidisciplinary conferences on the use of evidence in medicine. The conflicts over systematic reviews were most powerfully brought to public attention last year by the Cochrane Injuries Group. Its systematic review indicated that “for every 17 critically ill patients treated with albumin there is one additional death”.10 This conclusion caused an outcry. The group was accused of a “lack of clinical insight”, “ignorance and incomprehension”, using “irrelevant data”, and not taking account “of the purpose, design, or specific end points of the studies”.11 By contrast, Iain Chalmers, director of the UK Cochrane Centre, commented that, “I would attempt to sue anyone who had given me an infusion of albumin”.11 The positions taken by these protagonists could not have been more extreme. Another information war is being fought. Is the systematic review and meta-analysis now fatally wounded? Research presented at last week’s symposium provided justifiable cause for concern. Measuring quality of studies (design, conduct, consistency of results, and clinical relevance) included in systematic reviews is essential, yet there is no clarity about how to do it (Alessandro Liberati, Italy). Randomised and non-

THE LANCET • Vol 353 • January 16, 1999