NR AMNP
AU Will,R.G.; Zeidler,M.
TI Diagnosing Creutzfeldt-Jakob disease - case identification depends on neurological and neuropathological assessment
QU British Medical Journal 1996 Oct 5; 313(7061): 833-4
PT editorial
VT
Central to the identification and classification of patients with Creutzfeldt-Jakob disease (CJD) is the application of standardised diagnostic criteria based on accumulated data on the clinical and pathological features of the disease. Typically, patients present clinically with rapidly progressive dementia and myoclonus associated with various focal neurological signs. The diagnosis is confirmed by identifying characteristic neuropathological features, which include spongiform change, astrocytic gliosis, and neuronal loss. Diagnostic criteria originally proposed in 1979(1) have been validated by the "gold standard" of experimental transmissibility in primates.(2) This indicates that the clinical diagnosis is highly accurate, particularly if there is a characteristic appearance on an electroencephalogram.
However, not all cases are straightforward: about 10% of patients have a protracted clinical course, which makes the distinction from Alzheimer's disease difficult(3); 20-40% of patients do not exhibit a typical electroencephalogram(4); and unusual clinical phenotypes occur in patients with genetic and iatrogenic forms of the disease.(4) Updated diagnostic criteria have been published, including new definitions for "familial" and iatrogenic Creutzfeldt-Jakob disease,(5) but case ascertainment in the small proportion of atypical cases depends on review of a wide spectrum of suspect cases and a high necropsy rate.
Since 1990 in Britain, the criterion for referral to the National Creutzfeldt-Jakob Disease Surveillance Unit has been any suspected case, and about 70% of these cases will go to necropsy. About half of all suspect cases fulfil criteria for definite or probable Creutzfeldt-Jakob disease,(6) reflecting a high level of cooperation from the neurological community in referring any case in which the diagnosis is raised even as a possibility.
Crucial to case ascertainment is the targeting of professional groups who are likely to diagnose patients with Creutzfeldt-Jakob disease. In Britain since 1980, and more recently in other European countries, targeted groups have included neurologists, neurophysiologists, and neuropathologists. Although classic Creutzfeldt-Jakob disease usually presents with rapidly progressive dementia, in about 10% of cases the initial clinical symptom is behavioural disturbance or personality change, often resulting in psychiatric referral. An important assumption in epidemiological surveys is that such patients will be referred for a neurological opinion once neurological deterioration develops. This has been borne out in the British study(7) and also in a study in France.(8)
There has always been concern that elderly patients might be missed, and the significant increase in the incidence of Creutzfeldt-Jakob disease in Britain since 1996 is largely due to an increase in the number of cases in patients aged over 75, probably reflecting better case ascertainment in this group. On the other hand, death certificates mentioning Creutzfeldt-Jakob disease have been used in Britain as a safety net for case identification; and since 1990, two thirds of certified cases have fulfilled the diagnostic criteria for Creutzfeldt-Jakob disease, of which only a small minority had not been seen by a neurologist.(4) In Germany, where there is a tradition of joint training in neurology and psychiatry, 1436 departments of neurology, psychiatry, and rehabilitation have been asked to notify cases of Creutzfeldt-Jakob disease. However, the overall incidence in Germany is similar to that in Britain,(9) where clinical referral has largely depended on targeting about 400 neurologists.
The identification of a new variant of Creutzfeldt-Jakob disease in Britain(10) has been possible only through the cooperation of neurologists and neuropathologists and the availability of comparative information from parallel surveillance projects in Europe, coordinated through the European Community's BIOMED 1 research programme. Psychiatric symptoms are a component of the early clinical phenotype of the new variant disease, and in a recent survey only three out of 10 psychiatrists in one British city were aware of the surveillance project.(11) This is hardly surprising as psychiatrists have not been asked to notify cases of Creutzfeldt-Jakob disease in Britain, but it is pertinent to consider whether the system of case ascertainment should be extended to psychiatrists. Review of psychiatric histories in patients with the new variant disease Suggests that there is no specific psychiatric phenotype and that distinction from common psychiatric diagnoses such as depression may be impossible.
In all the cases of new variant disease, the psychiatric symptoms were superseded after a period of some months by progressive and devastating neurological dysfunction including ataxia, cognitive impairment, and involuntary movements-terminating in severe neurological dysfunction and death. Although 11 out of the 12 cases were seen by a psychiatrist, only six patients were initially admitted to hospital under the care of a psychiatrist, and these were promptly referred to a neurologist when the neurological syndrome developed. On current evidence a clinical diagnosis of new variant Creutzfeldt-Jakob disease cannot be made during the psychiatric phase of the illness, and identifying these cases depends on the evolution of neurological signs and in particular on neuropathological examination.
Early diagnosis of new variant disease was made in three cases by brain biopsy, which showed numerous cortical plaques surrounded by spongiform change. However, it is difficult to recommend biopsy as a routine diagnostic tool in view of the risk of complications (such as extradural haematoma or brain abscess), the possibility of sampling an area of brain unaffected by the pathological process, the need to destroy the neurosurgical instruments, and the low chances of the result altering management of the patient. There is an urgent need for an early non-surgical diagnostic test.
Last week saw the publication of details of a new test for Creutzfeldt-Jakob disease, based on immunoassay of 14-3-3 protein in the cerebrospinal fluid, which promises high sensitivity and specificity. (12) The test would be of particular value if it allowed accurate diagnosis at an early stage in the clinical course and in atypical cases of the disease, but this remains to be established. "Blind" testing of samples of cerebrospinal fluid from British patients with classic and new variant Creutzfeldt-Jakob disease, done in collaboration with research groups in the United States, has provided promising results, but a specific test for new variant disease is not yet available. Until this is possible the diagnosis of new variant disease will depend on clinical assessment and in particular on the evolution of neurological signs. Confirmation depends on the apparently characteristic neuropathological appearances.
The crucial issue of whether new variant disease is causally linked to bovine spongiform encephalopathy (BSE) may be answered only by continuing epidemiological research, including comparative studies of the incidence in countries with different incidences of bovine spongiform encephalopathy. The methodologies of these studies must be adapted to improve case recognition of new variant Creutzfeldt-Jakob disease, but surveillance will become unmanageable if reference centres are flooded with referrals of patients who turn out not to have the disease. Because new variant disease occurs in younger patients, including teenagers, it is essential to consider extending surveillance to the paediatric population, and lessons drawn from surveillance of classic Creutzfeldt-Jakob disease in elderly people suggest that we should also be alert for new variant disease in this age group. The methods of Britain's Creutzfeldt-Jakob disease surveillance system must adapt to changing circumstances, but case identification still depends primarily on neurological and neuropathological assessment.
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8 Brown P, Cathala F. Creutzfeldt-Jakob disease in France. In: slow transmissible diseases of the nervous system. Vol 1. San Diego, CA: Academic Press, 1979:213-27.
9 Delasnerie-Laupretre N, Poser S, Pocchiari M, Wientjens D P W M, Will R G. Creutzfeldt-Jakob disease in Europe. Lancet 1995;346:598.
10 Will R G, Ironside J W, Zeidler M, Cousens S N, Estibeiro K, Alperovitch A et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921-5.
11 Franks A, Schweiger M. Half of physicians are unaware of surveillance system for Creutzfeldt-Jakob disease. BMJ 1996;312:1358
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ZR 12
MH Creutzfeldt-Jakob Syndrome/*diagnosis; Diagnostic Services; Human
AD ROBERT WILL Consultant neurologist, MARTIN ZEIDLER Research fellow, National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Edinburgh ER4 2XU
SP englisch
PO England
OR Prion-Krankheiten 8