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BMJ No 7131 Volume 316
Editorial Saturday 21 February 1998
Early identification of variant Creutzfeldt-Jakob disease
Some promising approaches but no clear answers yet
See Paper, p 577 and Paper, p 593Unequivocal evidence now exists that the variant form of Creutzfeldt-Jakob disease is caused by the same strain of agent as bovine spongiform encephalopathy and that this strain differs from other strains isolated from cases of classic sporadic Creutzfeldt-Jakob disease.(1,2) At present definitive diagnosis of either form of the disease is possible only after death, but clinicians are under great pressure to distinguish between the two forms and in particular to be able to identify cases of variant Creutzfeldt-Jakob disease as early as possible.
Exposure of the human population in Britain to the agent causing variant Creutzfeldt-Jakob disease is likely to have occurred in the 1980s through beef products affected by bovine spongiform encephalopathy. Although it is reassuring that there have been only 24 cases of variant Creutzfeldt-Jakob disease (23 in Britain and 1 in France) and that the number of new cases did not increase in the last year, it is impossible to predict how many people are now incubating the variant form of disease. As well as concern over the size of any possible "epidemic" there is also the remote possibility that the level of infectivity outside the nervous system is higher in variant Creutzfeldt-Jakob disease than in the sporadic disease. Preliminary data have shown that necropsy samples of tonsils from patients with variant Creutzfeldt-Jakob disease are loaded with the pathological conformer of the PrP protein,(3) while those of patients with sporadic disease are not.(4) This may increase the risk of accidental transmission by medical procedures. In particular, concern exists about plasma derived products because they are prepared from huge pools, with the chance of including blood from potentially infected donors. Batches of plasma derived products can be withdrawn if a donor is subsequently suspected of having Creutzfeldt-Jakob disease, particularly of the variant form. For all these reasons we need a method of early identification of cases of variant Creutzfeldt-Jakob disease.
From the meticulous work of the Creutzfeldt-Jakob disease Surveillance Unit(5-7) we learn that so far the variant form of disease affects teenagers or young adults (all patients were under 40 years at clinical onset except one who was 48). Usually they present with severe depression (or other psychiatric disorders)(7) or sensory disturbances (disaesthesia or paraesthesia), or both.(5,6) These early and non-specific clinical signs may last several months and most patients turn out not to have either form of Creutzfeldt-Jakob disease.(6) Later during the course of the disease more characteristic clinical signs evolve: dementia, cerebellar and various focal neurological signs, myoclonus or other involuntary movements, and, finally, akinetic mutism.(5,6) The young age, the relatively long clinical course (over a year), the persistent sensory disturbances, an upgaze paresis, and the absence of typical periodic electroencephalographic signs suggest variant rather than sporadic disease.(5,6)
Help may come from neuroimaging techniques. In this issue de Silva and colleagues(8) report reduced brain cortical perfusion in two cases of variant Creutzfeldt-Jakob disease by single photon emission computed tomography (SPECT) analysis. Although this finding is non-specific, it may help to raise the suspicion of disease in young adults presenting with psychiatric disorders where all other routine investigations have been useless. Another promising procedure is cranial magnetic resonance imaging. Although it may give negative results, four patients with variant Creutzfeldt-Jakob disease (3 British and 1 French) had strong signals in the posterior thalamus on T2 weighted images.(6-9) This pattern looks to be specific to variant Creutzfeldt-Jakob disease and, if confirmed, may prove to be the best procedure for differentiating between the two forms of Creutzfeldt-Jakob disease.
The presence of protein 14-3-3 in the cerebrospinal fluid without any other cytochemical abnormalities strongly reinforces the diagnosis of Creutzfeldt-Jakob disease, but this test is equally positive in variant and sporadic disease.(10) Genetic analysis of the PrP gene is important to exclude the familial form of the disease, which may present at a younger age and with a longer duration than sporadic Creutzfeldt-Jakob disease.(11) Also, all cases of variant Creutzfeldt-Jakob disease but only about 70% of sporadic cases are methionine homozygous at the polymorphic codon 129 of the PrP gene.(5,6) At present we can not predict whether heterozygous or valine homozygous subjects at codon 129 are susceptible to variant Creutzfeldt-Jakob disease and, if so, which is the clinical picture that they will eventually develop.
Definite diagnosis of all forms of Creutzfeldt-Jakob disease is still possible only by histological examination of the brain, and the only procedures capable of distinguishing between the variant and sporadic forms of the disease are evaluation of neuropathological lesions(5,6) or PrP glycotyping on western blot.(12) Nevertheless brain or tonsil biopsies cannot be recommended as a routine procedure in view of the poor benefit for the patient, the risk of contaminating the operating room, and the need to destroy surgical instruments. A simple but specific blood test is badly needed.
Some hope for such a test come from the report of Otto et al, who report in this issue that patients with Creutzfeldt-Jakob disease have a median serum concentration of the brain specific S100 protein higher than that of controls (p 577).(13) Unfortunately the range of values in these patients is wide and overlaps with those in several other neurological disorders, including other dementing illnesses, making the test not very useful for diagnosis in individual patients. Nevertheless, the test is promising and should be quickly validated in a large cohort of patients with Creutzfeldt-Jakob disease and other neurological diseases, a task that should be easily achieved through the European Union collaborative study group for Creutzfeldt-Jakob disease surveillance. Other possibilities for a blood test may come from the recent development of a monoclonal antibody that specifically recognises the pathological conformer of PrP(14) and from the identification that, among the various cells in the blood, only the differentiated B lymphocytes play a crucial role in the pathogenesis of the disease.(15)
Maurizio Pocchiari
Professor of virology
Istituto Superiore di Sanita,
00161 Rome,
Italy
References
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Suttie A, et al. Transmissions to mice indicate that "new variant"
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Collinge J, et al. The same prion strain causes vCJD and BSE.
Nature 1997;389:448-50.
3 Hill A F, Zeidler M, Ironside J, Collinge J. Diagnosis of new
variant Creutzfeldt-Jakob disease by tonsil biopsy.
Lancet 1997;349:99-100.
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7 Zeidler M, Johnstone E C, Bamber R W, Dickens C M, Fisher C J,
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8 de Silva R, Patterson J, Hadley D, Russell A, Turner M,
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9 Chazot G, Broussolle E, Lapras C I, Blattler T, Aguzzi A, Kopp
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11 Pocchiari M. Prions and related neurological diseases.
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12 Collinge J, Sidle K C, Meads J, Ironside J, Hill A F. Molecular
analysis of prion strain variation and the aetiology of "new
variant." Nature 1996;383:685-90.
13 Otto M, Wiltfang J, Schütz E, Zerr I, Otto A, Pfahlberg A, et
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protein in serum: prospective case-control study. BMJ
1998;316:577-82.
14 Korth C, Stierli B, Streit P, Moser M, Schaller O, Fischer R,
et al. Prion (PrPSc) specific epitope defined by a monoclonal antibody.
Nature 1997;390:74-7.
15 Klein M A, Frigg R, Flechsig E, Raeber A J, Kalinke U, Bluethmann
H, et al. A crucial role for B cells in neuroinvasive scrapie.
Nature 1997;390:687-90.
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