Volume 8: Variant CJD
5.
Emergence of variant CJD
Relevant events after 20 March 1996
Update on cases of CJD in farmers
Update on suspect cases of CJD in teenagers
Future incidence of vCJD
5.149 Several differences between classical CJD and variant CJD have been identified in the course of subsequent surveillance which supported the conclusion that vCJD was a new entity. These differences are in the age of onset, the clinical symptoms, the characteristics of electroencephalogram and in the disease pathology.
- Age. The median age in classical CJD at death was 66 compared with 29 for vCJD. The median illness duration from the first symptom to death was 4 months in classical CJD but 14 months for vCJD. 1
- Clinical symptoms. With vCJD, the clinical presentation was found to be with both behavioural and psychiatric disturbances. After several weeks or months, a progressive cerebellar syndrome developed with poor gait and poor limb muscle coordination. Dementia usually occurred later in the clinical course.
- Electroencephalogram (EEG). In vCJD patients with EEG showed no abnormality, in contrast to most classic CJD patients where unusual wave patterns can be observed. 2
- Pathology. Significant differences in the neuropathology of vCJD patients were observed compared to classic CJD patients. These included 'florid plaques' in the cerebral and cerebellar cortex; abundant prion protein deposition in all brain areas with irregularly shaped deposits around neurones and blood vessels in the cerebrum and cerebellum; spongiform change most marked in basal ganglia; and severe thalamic gliosis (proliferation of the glial or supporting cell in the brain). 3 Another unique feature in vCJD patients was found to be the presence of prion protein outside the central nervous system. Unlike other forms of CJD, the prion protein accumulated in the lymphoid tissue of vCJD patients. 4
5.150 The CJDSU considered in depth the possibility of a causal link between BSE and vCJD, the main factors being:
Investigation of these factors revealed compelling evidence that vCJD is caused by BSE. (The evidence linking the two diseases is described in detail in vol. 2: Science.)
5.151 The epidemiological data gathered by the CJDSU did not however identify a specific risk factor, including a specific dietary risk factor, linking the patients as distinct from controls. 5 Such a failure to find a common dietary factor was considered to be a result of constraints in the methodology of the study rather than the absence of a link. Food questionnaires are very difficult to administer, especially for vCJD where information dating back many years was sought from the relatives of patients who might have been subject to recall bias. Even if the information was available, interpretation of the information was made difficult because it is not known which human food products are likely to be contaminated by BSE and to what level. The critical issue, in Dr Will's opinion, was whether the food products contained brain and spinal cord tissue. He considered that the major risk was most likely from products containing mechanically recovered meat. 6 (The administration of the questionnaire is an area in which it has been suggested that the PHLS could have played a role in the surveillance of CJD, given the considerable experience of the organisation in the investigation of emerging diseases. The question of PHLS involvement in CJD surveillance is discussed in Chapter 3 and paragraphs 5.171-5.173.)
Update on cases of CJD in farmers
5.152 During the period 1986-96, much attention and publicity was focussed on four cases of CJD in farmers (see above). Although those four cases were regarded as likely to be more than might be expected for the known population frequency of the disease, analysis of CJD in Europe showed the incidence of disease in farmers was similar to that in the UK. 7 In addition, the clinical and pathological features of these cases were no different to those found in classical sporadic CJD.
5.153 It is understood that since 20 March 1996, at least two further cases of sporadic CJD in a relevant occupational group have been reported to the CJDSU, one in a farmer and another in an abattoir worker. 8 Recent transmission studies in mice indicate that the causal agent in these cases has transmission characteristics (incubation period and neuropathology) which are distinct from both vCJD and BSE, and that the protein deposited in the brain in all of these cases has a glycosylation pattern distinct from the type 4 pattern observed in vCJD and BSE.
Update on suspect cases of CJD in teenagers
5.154 The four cases A, D, E and R mentioned previously have all been confirmed post-mortem as having died of CJD. Case A had a long duration of illness and the EEG did not show the classical CJD pattern, but the neuropathology was not typical of vCJD, the lymphoreticular system was not affected and there was a type 2 glycosylation pattern as found in sporadic CJD; there was no prion mutation and the genotype at codon 129 was heterozygous methionine/valine (MV). Strain typing was undertaken but the result is not yet available. In cases D, E and R the neuropathology showed florid plaques and the glycosylation pattern was reported as type 4, the type similar to BSE. Lymphoreticular tissue contained deposits of PrPSc. Prion gene mutations were not found, and the genotype at codon 129 was homozygous for methionine (MM) as in all subsequent vCJD cases with the characteristic clinical and neuropathological features described for this condition.
5.155 In his evidence to the Inquiry, Professor Will agreed that vCJD might present differently in patients with different genotypes at codon 129. 9 Patients with the genotype MM might be expected at an earlier stage of the epidemic than patients with other genotypes. At the same session, Dr Ironside noted that when BSE was transmitted to mice carrying the human PrP gene with valine at codon 129, the glycoform pattern was slightly different from the pattern found in methionine homozygotes. This new, type 5 pattern might be expected should BSE cause disease in humans with a VV or MV genotype. 10 So far, no case of CJD has been identified with a type 5 pattern and, in particular as noted above, case A was shown to have a type 2 pattern.
5.156 By 4 September 2000, the total number of definite and probable cases of vCJD was 82. Table 5.1, below, gives the numbers of these cases identified each year since 1995.
Table 5.1: Number of definite and probable cases of vCJD since 1995
a
Includes probable cases still alive and probable vCJD deaths awaiting
post-mortem results.
Source: CJD Surveillance Unit
5.157 The many variables associated with the disease (such as route of exposure, dose, incubation period, genetic susceptibility, etc) make predicting the possible number of future cases difficult. This is evidenced by the large variations in predicted numbers of cases calculated using different statistical models. Predictions on the future incidence of vCJD are discussed in detail in vol.2: Science.
1 T24 p. 5
2 T24 p. 88
3 S60 Ironside Annex 2; T24 p. 9
4 Hill, A.F., Butterworth, R.J., Joiner, S., Jackson, G., Rossor, M.N., Thomas, D.J., Frosh, A., Tolley, N., Bell, J.E., Spencer, M., King, A., Al-Sarraj, S., Ironside, J.W., Lantos, P.L. and Collinge, J. (1999) Investigation of Variant Creutzfeldt-Jakob Disease and Other Human Prion Diseases with Tonsil Biopsy Samples, The Lancet, 353, 183-9
5 T24 pp. 24-5
6 T24 p. 55
7 IBD2 tab 12 p. 23
8 M26 tab 2 p. 3
9 T24 p. 116
10 T24 p. 117
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