Volume 8: Variant CJD
5. Emergence of variant CJD
Evolution of knowledge leading to the identification of new variant CJD and the hypothesis of causal link with BSE between late 1995 and early March 1996
Results of statistical analysis of CJD in young cases
Dr Will's presentation at the Parliamentary Food and Health Forum on 20 February 1996
Dr Will's comments on an MLC briefing paper on 23 February 1996
Further developments in knowledge from late February 1996

Results of statistical analysis of CJD in young cases

5.116 On 5 February 1996, Dr Sheila Gore (MRC Biostatistics Unit in Cambridge) wrote to Dr Will about the results of her statistical analysis of CJD incidence. ¹ Her letter (written on the basis of information supplied at a time when four sporadic CJD cases had been diagnosed in individuals aged under 40) included the following:

Thank you very much for the data on age and farming occupation of sporadic CJD cases diagnosed in the UK in the 5 year period 1985-89. Since about 21 million persons in UK are aged 15-39 years, the three sporadic CJD cases (aged 35, 36, 38) diagnosed under 40 in 1985-89 give an estimated sporadic CJD incidence of 0.0286 per million person-years in this age group. Since 1 May 1990, the four sporadic CJD cases diagnosed under 40 (two teenagers, 29, 30) may be compared to 3.6 expected in six years [0.0286*6*21=3.6] based on the 1985-89 cases and the probabilities of observing 4 or more cases {also 5+, 6+, 7+, 8+, 9 or more} are 0.48 {0.29, 0.16, 0.07, 0.03, 0.012} in the context of this expectation.

Please note that I have taken no formal account of the fact that the four 1990s cases are younger than the three 1985-89 cases. Nonetheless, the newly available age-specific UK data for 1985-89 are somewhat reassuring that 4 cases diagnosed under age 40 since 1 May 1990 are not out of line with expectation based on the earlier quinquennium. It would be further reassuring if data were adduced from your EC collaboration as follows: number of persons in country aged 15-29 and aged 30-39, number of months of active CJD surveillance, number and ages of sporadic CJD cases diagnosed at ages under 40 during those months. ²

5.117 After commenting on data on farming occupation, Dr Gore concluded:

. . . Thus the 1985-89 farming occupational cases accord with the 1990s estimated age-appropriate sporadic CJD incidence for this occupational group as derived from UK-wide age-specific incidences of sporadic CJD. ³

Dr Will's presentation at the Parliamentary Food and Health Forum on 20 February 1996

5.118 On 20 February 1996, Dr Will made a presentation at a meeting called by the Parliamentary Food and Health Forum to discuss the relationship between BSE and CJD. Dr Dealler, a medical microbiologist, was the other invited speaker at the meeting. ⁴ In evidence to the Inquiry Dr Will set out an assessment, as at the date of this meeting, of the extent to which the scientific criteria had been met (in relation to judging the significance of the cases). ⁵ This assessment did not differ from his assessment of 1 February (see above).

5.119 The report of the meeting recorded that:

Dr Will opened by saying that the theoretical risk of BSE to the human population was judged to be remote by the Southwood Committee in 1989, and this view was supported by the World Health Organisation, the European Community and other organisations. Although the cause of sporadic Creutzfeldt-Jakob Disease (CJD) was not known, the available evidence virtually precluded scrapie in sheep as a source of human disease. Dr Will said there was, however, a theoretical possibility that the BSE agent might be more pathogenic to man than was scrapie, and a series of legislative measures have been taken to minimise any potential risk to the human population in the UK. He said that current evidence did not suggest any definite change in the pattern of CJD that could be attributable to BSE, but it would be many years before such a change could finally be excluded . . .

Dr Will explained that there had been a slight increase in CJD in the 1970s, which levelled off only to increase again in the 1990s. Evidence suggests that this increase may have been due to improved ascertainment in the elderly. Parallel surveillance of CJD has also been taking place in the European Union and, in the period 1993-94, the incidence had been similar to that in the UK. This surveillance had shown no change in CJD which could be attributed to BSE.

Dr Will went on to say that there was no overall change in the age-specific incidence of CJD in the UK, and that the incidence of CJD amongst farmers showed no mechanism for the transference of BSE. He added that it was difficult to conclude what was happening amongst diary farmers, and that research was underway.

Dr Will said that while current information was reassuring, any risk to man from BSE might not be evident for some years, although there was currently no proof of a link between CJD and BSE. ⁶

Dr Will's comments on an MLC briefing paper on 23 February 1996

5.120 On 12 February 1996, Mr Mike Skinner of DH (Health Aspects of the Environment and Food Division) sent an MLC briefing paper on BSE to Dr Will, Professor Pattison and Professor Collinge, and requested their views on it. The paper had been sent by Mr Don Curry (Chairman of the MLC) to Dr Eileen Rubery of DH on 3 January. ⁷ The briefing paper stated:

British beef is safe to eat. The existence of BSE in cattle and the similar disease in humans, CJD (Creutzfeldt Jakob Disease) does not imply any link between the two . . .

The most eminent scientists who are involved in studying and seeking to understand the disease do not believe that there is a significant risk to humans. They include: Professor John Pattison, Dean of University College Medical School and Chairman of the independent Spongiform Encephalopathy Advisory Committee; Dr Robert Will, Head of the CJD Surveillance Unit and a world authority on this disease; Dr Richard Kimberlin, a world authority on scrapie and similar diseases.

The Spongiform Encephalopathy Advisory Committee has itself found no evidence to suggest that there is an emerging CJD epidemic. The Chief Medical Officer, Dr Kenneth Calman, is satisfied that 'there is no scientific evidence of a link between meat eating and CJD and that beef and other meats are safe to eat'. The international scientists in the World Health Organisation and the European Union have also examined the evidence and believe that beef and beef products are safe to eat. ⁸

5.121 On 18 January 1996, Dr Rubery had responded to Mr Curry stating that 'as regards the safety of beef your paper is in line with current Government advice'. ⁹ She also pointed out that the quote from the CMO should have read 'I continue to be satisfied that there is currently no scientific evidence of a link between meat eating and the development of CJD and that beef and other meats are safe to eat'. Mr Skinner had summarised Dr Rubery's response in the letters he sent on 12 February. ¹⁰

5.122 On 23 February 1996, Dr Will replied to Mr Skinner. He said:

My view is that there is a remote theoretical risk that BSE in cattle might cause disease in humans. The risk from beef and beef products is likely to be negligible provided statutory measures are fully enforced. I would also agree with the statement that there is currently no scientific evidence that BSE can be transmitted to humans or that eating beef causes CJD. ¹¹

5.123 When giving oral evidence to the Inquiry, Professor Will was asked whether the words 'a remote theoretical risk' were the right words to have used when at the beginning of February the data available had led him to think it was possible there had been a change in the disease phenotype. Professor Will explained:

I think this is with hindsight. I think you are saying we now know that these cases were significant. At the time we could not be sure about that at all. And you know, I have tried to go through in this statement the various issues that we had to consider that were confounding factors. Of course these applied throughout this time, the issue of ascertainment bias, etc. So my own feeling is that at that time I had not reached a stage at which there was sufficient evidence to make a scientific judgement that there had been a change. ¹²

Further developments in knowledge from late February 1996

5.124 On 26 February 1996, the CJDSU obtained the full regional neuropathology results on three cases of CJD (L, M and J), and in addition, during that same week, a further case was confirmed by neuropathology (case I, identified in January as 'possible'), bringing the total number of post-1994 confirmed cases of spongiform encephalopathy in people under 50 years old to ten (D, E, G, H, I, J, K, L, M and P ¹³). ¹⁴ In evidence to the Inquiry, Dr Will commented about the significance of these detailed results:

The suspicion of a novel neuropathological phenotype was strongly supported and review of the available pathology in previous cases indicated that all the cases shared a common pathology. Neuropathological re-examination of historical young cases was completed by late February with the exception of the 16-year-old case from 1980. None showed the pathology of the recent young cases. ¹⁵

5.125 After reviewing the clinical data on the confirmed cases, Dr Will and other colleagues at the CJDSU were further persuaded that the cases in young people shared an unusual clinical phenotype. On 1 March 1996, Dr Will became more confident about this assessment in young people after he had reviewed a patient with suspect CJD whom he had previously seen in early February. In evidence to the Inquiry he said:

The clinical evolution in this case was entirely consistent with the clinical phenotype that we had identified. This was of a major importance in the development of my views about the validity of the proposed clinical phenotype in the young cases. I had not previously seen a similar case of CJD and in general terms it is very much easier to be confident about a clinical phenotype from direct experience. ¹⁶

5.126 Dr Will explained in his statement his assessment as of 1 March 1996 of the extent to which some of the scientific criteria were met (in relation to judging the significance of the cases). We set this out with an indication of how the position had changed compared with the position at 1 February:

i.
1. is there a novel clinical phenotype?: probable (compared with 'possible' on 1 February);
2. is there a novel pathological phenotype?: probable (compared with 'possible' on 1 February);
3. are these cases linked to PRNP mutation?: no mutation identified in three cases;
4. is there ascertainment bias or increased efficiency of surveillance?: probable;

ii.
1. are these cases in the UK distinct from previous experience?: probable (compared with 'possible on 1 February);
2. are these cases only occurring in the UK?: unknown. ¹⁷

5.127 Shortly after the evidence for a novel neuropathological phenotype was established, further genetic information on the cases came to light. Hitherto it had been established that three (D, E and J) of the confirmed cases did not have a genetic basis because mutations of the prion protein gene associated with familial forms of CJD had not been identified. On 4 March 1996, Dr Will received preliminary results from the prion protein gene analysis in four additional cases in people under 50 years. Prion protein gene mutations associated with familial forms of CJD were not identified in three (H, K and M) of these four cases. The fourth case (G) was found to have an insertional mutation of the prion protein gene. These results and the earlier genetic analysis of three of the cases, indicated that six of the confirmed cases of CJD in people under 50 did not have a genetic basis - they were not associated with the familial forms of CJD.

5.128 In early March, Dr Will received the results of the inquiries he had made during February of colleagues in other countries, asking for information on specific cases of CJD aged less than 30 years identified from the world literature. Some of the cases in this age group in other countries had a relatively prolonged illness duration and some an unusual clinical onset, but in only one case were plaques described in the neuropathology. ¹⁸ Dr Will's inquiries into four of these cases confirmed that:

Plaques had not been identified on neuropathological examination in three cases of CJD aged 14, 16 and 20 years from the USA and Canada.

. . . the single case of sporadic CJD that we had identified in the world literature aged less than 30 years with plaque deposition was probably a hereditary form of human prion disease. ¹⁹

5.129 As a result of these developments in relation to genetics and the cases of CJD in patients in other countries, Dr Will explained in his statement that by 8 March 1996, his assessment of the extent to which some of the scientific criteria were met (in relation to judging the significance of the cases) had changed compared with the position at 1 March:

i.
1. is there a novel clinical phenotype?: probable;
2. is there a novel pathological phenotype?: probable;
3. are these cases linked to PRNP mutations?: no mutation identified in six cases (compared with three cases on 1 March);
4. is there ascertainment bias or increased efficiency of surveillance?: probable;

ii.
1. are these cases in the UK distinct from previous experience?: probable;
2. are these cases only occurring in the UK?: possible (compared with 'unknown' on 1 March). ²⁰

5.130 Dr Will explained further in his statement:

By early March we had concluded that there was sufficient evidence to be confident that we had identified and characterised a novel clinicopathological phenotype of CJD . . . It is important to stress that although we believed we had identified a new form of CJD, novel clinicopathological variants of CJD had been identified in the past both in the UK and in other countries. In order to indicate a link between BSE and 'new variant CJD' it was essential to determine whether similar cases were occurring in other countries. ²¹

5.131 Dr Will and Dr Ironside presented a paper summarising their findings at the 25th SEAC meeting on 8 March 1996. ²² The paper entitled 'Human TSE Epidemiology - The Emerging Picture' described the identification of a subset of CJD with an early age of onset, long duration of illness, no prion protein gene mutations, 'florid' plaques throughout the brain and extensive prion protein deposition. ²³

5.132 Dr Will reported further on the two subsets of sporadic CJD. The CJDSU had found that:

There appeared to be two distinct subsets of sporadic CJD cases. The first with extended duration of illness with plaques in the brain and spinal cord, and the second with a short duration of illness which did not show these features. The presence of plaques in the spinal cord might be related to the extended duration of illness which allowed time for centrifugal spread of PrP down the spinal cord . . . The pathology in the sporadic cases in young people was different to the two subsets mentioned above. ²⁴

5.133 Dr Will also reported that the UK cases had been compared with the 17 cases in patients under 30 years of age that had been found world wide since 1965. ²⁵ The clinical features and the duration of the illness were variable in these 17 cases, there was no genetic information available, and in all but one case (thought to be hereditary) there were no plaques recorded. They had concluded that the cases in young people in the UK with their unique pathology and similar clinical features 'could be' a new form of CJD.

5.134 By this time, 8 confirmed cases of the new phenotype had been identified (D, E, H, I, J, K, L, and M). ²⁶ All were aged under 50. In addition, one case had undergone a biopsy that was negative but had clinical symptoms of CJD (O) and post-mortem and neuropathology results were awaited for two further patients, cases R and S. The minutes from the SEAC meeting record that:

Dr Will and Dr Ironside were of the opinion that the young cases in the UK with their unique pathology and similar clinical features could be a new form of CJD. They intended to publish the findings in a peer-reviewed journal such as The Lancet as soon as possible. They preferred for the findings to be kept confidential until then, but would be prepared for them to be made public now should the Committee and Government consider that necessary. ²⁷

5.135 Much discussion followed this presentation. Members of SEAC queried whether these cases had only been identified because of improved case identification and whether this new form of CJD could have been present, but unidentified, in the population for some time. Dr Will and Dr Ironside did not believe that this was the case as awareness of CJD had been growing in neurologists over a number of years, identification had been based on neuropathology, and the pathology was very different to that in young cases outside the UK. Referral bias, due to increased awareness of CJD, was considered. ²⁸ However, the increase in CJD awareness should have also caused referral bias in other countries and as similar young cases had not been seen in other countries, referral bias as an explanation of the increase of young CJD cases was ruled out.

5.136 The minutes record that Professor Pattison (Chairman) closed the discussion by confirming that:

. . . the Committee would keep the information confidential pending publication of the paper by Dr Will and Dr Ironside. He would inform the Chief Medical Officer and the Chief Veterinary Officer of the findings and SEAC's concerns. It would be for Ministers to decide whether or not they should be put into the public domain now. ²⁹

5.137 On 13 March 1996, the diagnosis of new variant CJD was confirmed by brain biopsy in the case Dr Will had seen on 1 March 1996, a 31-year-old (case S). This brought the total number of confirmed (non-familial) CJD cases in young people to nine. ³⁰ In his statement to the Inquiry, Dr Will said that 'review of the results of inquiry on risk factors for CJD had not shown any common or recognised risk factor for the development of CJD in these young cases'. ³¹

5.138 On the same day, the neuropathological findings in the 16-year-old case who died in 1980 became available. These findings showed an appearance consistent with sporadic CJD. No plaques were identified, even with biochemical staining for prion protein. ³²

5.139 Dr Will told us that during March evidence became available to indicate that the novel phenotype of CJD was restricted to the UK, suggesting a link with BSE:

In March 1996 I contacted my colleagues in the European surveillance system and requested further details on the young cases that had been identified in participating countries. I requested details of the clinical characteristics during disease evolution, the results of EEG examination and details of the neuropathological appearances, if available. My colleagues kindly responded promptly and it became apparent that none of the young cases in continental Europe had the clinical and pathological phenotype of the young cases in the UK. This evidence indicated that the novel phenotype of CJD was restricted to the UK, consistent with a causal link with BSE. ³³

5.140 An emergency meeting of SEAC was held on 16 March 1996 to discuss the new variant CJD cases in detail. ³⁴ Dr Will reiterated the description of the new variant of CJD and the CJDSU had identified: early age of onset, initial presentation with psychiatric or behavioural problems, long incubation period, ³⁵ abnormal EEG, distinct histopathology with large plaques. He also presented full details of all the 'variant' CJD cases including the newly identified ninth case. ³⁶

5.141 Dr Will reported on the CJDSU analysis of archival CJD cases. All cases under the age of 40 had been examined in detail and no evidence of the unusual characteristics of the variant form of CJD had been detected. He also referred to the literature search of young cases of CJD from around the world. Again none of the unusual characteristics of this variant form of CJD had been detected. Therefore, Dr Will concluded that 'the new variant form of CJD was a distinct form which was partly age related, notably having an excess of cases in people under 30'. ³⁷

5.142 The minutes of this SEAC meeting also record that the CJDSU pathological material had been reviewed by three other pathologists, all with experience of spongiform encephalopathies and their independent view was that 'this was a distinct entity unlike any previously seen form of CJD'. ³⁸

5.143 The genetic analysis of six of the nine cases was discussed. ³⁹ Complete DNA sequencing of the prion protein gene had been performed in the six cases and no mutations had been detected, thereby ruling out familial CJD. Geographical spread and the medical histories of the cases were discussed but no common factor between the cases could be identified.

5.144 In conclusion, the Committee agreed that this new variant of CJD was a distinct entity, although it was uncertain whether it was a new form of the disease or represented clustering linked to a new risk factor. ⁴⁰ It was agreed that 'they must take very seriously the possibility that this new risk factor was BSE, although it was noted that the data did not allow this conclusion to be drawn firmly'.

5.145 On 19 March 1996, the 28th meeting of SEAC was convened in response to a request from the Government for advice on the significance of the findings about a new form of CJD and to provide recommendations for any action. ⁴¹ The minutes record that the intention was for SEAC to provide this advice by early the following day for discussion by the Cabinet in preparation for Ministerial statements. ⁴² Further details of the deliberations at the meeting on the adequacy of control measures at that time to protect animal and public health, and SEAC's advice to the Government are given in vol.6: Human Health, 1989-96 and in vol.11: Scientists after Southwood.

5.146 Dr Will reported to the meeting that a tenth case of the new form of CJD had been confirmed post-mortem in a 20-year-old (case R). He added that the genetic analysis of seven out of the ten cases would be completed on the following day. Whilst there was so far no evidence of a genetic mutation, Professor Collinge commented 'that there was only a small possibility that the genetic sequencing would provide any information to change the view SEAC had reached at its meeting on the 16 March'. ⁴³

5.147 The following day SEAC resumed the meeting to continue their discussions of the options for additional measures and to decide on the Committee's advice about the risk to human health from eating beef. ⁴⁴ Their discussions and recommendations are described in vol. 6: Human Health, 1989-96.

5.148 As a result of these developments, Dr Will confirmed in his statement that by 20 March 1996, his assessment of the extent to which some of the scientific criteria were met (in relation to judging the significance of the cases) had changed compared with the position at 8 March:

i.
1. is there a novel clinical phenotype?: probable;
2. is there a novel pathological phenotype?: probable;
3. are these cases linked to PRNP mutations?: no mutation identified in six cases (compared with three cases on 1 March);
4. is there ascertainment bias or increased efficiency of surveillance?: probable;

ii.
1. are these cases in the UK distinct from previous experience?: probable;
2. are these cases only occurring in the UK?: probable (compared with 'possible' on 8 March). ⁴⁵