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

5.77 During the quarter to 30 September 1995 four further cases of CJD in people under the age of 50 had been referred to the CJDSU. ¹ We will refer to them as F, G, H and I. ² A further seven cases were to be referred in the quarter to 31 December 1995. We refer to them as J, K, L, M, N, O and P.

5.78 At SEAC's special 21st meeting of 4 October 1995, Dr Will summarised recent sporadic cases of CJD in young people. There were currently two cases in teenagers, a 19-year-old and a 17-year-old. The case in the 17-year-old had unusual pathology, although this could be related to age. There were also other cases in their 30s and 40s, which was unusual. However, although this was a change from usual experience, it was difficult to relate to BSE. ³ The 19-year-old and 17-year-old were cases D and E respectively. Dr Will has informed the Inquiry that the other cases he had in mind were F, G and H.

5.79 One of the cases referred in the December quarter was J. This patient, aged 29, was referred to the CJDSU after a brain biopsy at another hospital. ⁴ Following a review of the biopsy results for this case on 18 October 1995, Dr Will noted that one of the neuropathological features common to all three cases (D, E, and J), was plaque deposition. He considered that these three cases were unusual, because only about 10 per cent of cases of sporadic CJD had plaque deposition. However, he did not consider that there was sufficient evidence to identify these three cases as neuropathologically distinct at that stage. ⁵ Further information on the formation of plaques is given in vol. 2: Science.

5.80 On 26 October 1995, Mr Lister (DH) minuted the Private Secretary to Baroness Cumberlege, with copies to the CMO and other DH officials, as well as Mr Render at MAFF. ⁶ This minute enclosed proof copies of letters which were to be published in The Lancet the following day. The letters concerned the cases of D and E. He noted that the 17-year-old whom the press first alleged had CJD nearly two years previously was still in a coma and the cause of her illness remained uncertain. This was case A. Mr Lister added that the CJD Surveillance Unit was investigating a confirmed case of CJD in a 29-year-old from London. The patient was still alive, and the diagnosis had been confirmed by brain biopsy. The patient in question was J. ⁷ Mr Lister's minute also noted a probable case of CJD in a 38-year-old woman which had attracted media attention. This case was G. ⁸

5.81 On 28 October 1995, cases D and E (the two suspect CJD cases in teenagers described earlier) were reported in The Lancet. The case report for E indicated that the diagnosis had been confirmed by brain biopsy and was entitled 'Sporadic CJD in a 16-year-old in the UK'. It continued:

A 16-year-old girl was first seen in September 1994. In March 1994, she injured her right foot during a fall and subsequently developed right-sided lower lumbar backache and numbness in the fingertips and face. In August 1994, she developed slurred speech, poor balance, clumsiness of her limbs, and urinary frequency. ⁹

5.82 The report on D also referred to sporadic CJD in the title and stated:

An 18-year-old male was initially referred to a psychiatrist with suspected depression. He gave a 6 month history of deterioration of memory, complaining that he had 'gone nutty' . . . There was no family history of dementing or ataxic illness and no history of exposure to human pituitary-derived hormone, neurosurgical procedures, or tissue grafting. For a period of 8 years he visited his aunt's farm annually and would have drunk unpasteurised milk and been exposed to cows. No cases of bovine spongiform encephalopathy (BSE) have been reported in this herd. ¹⁰

5.83 The report on D concluded 'However, it is unlikely that CJD and particularly cases with a typical clinical presentation and histology would have been previously missed in teenagers.' ¹¹

5.84 An update on the CJD situation was listed as agenda item 7 for SEAC's 22nd meeting on 23 November 1995. This was not reached because of lack of time. ¹²

5.85 In late 1995, Dr Will and others at the CJDSU considered the possibility that the identification of these three confirmed young cases of CJD (D, E and J) might be due to ascertainment bias:

In 1994, the incidence of CJD in England and Wales was double that of earlier study periods, including the period 1980-84, during which a similar prospective surveillance study of CJD, using similar methodology, had been undertaken (see 4th Annual Report of the CJDSU). This rise in incidence was judged to be 'most likely related to improved ascertainment of cases' and that '. . . the major influence on the increased incidence of cases is an increased number of cases of CJD in those aged 75 and over . . .'. There was a possibility that a similar bias in ascertainment may have occurred in younger age groups. ¹³

5.86 Also in late 1995, Dr Will considered the possibility that young cases of CJD might in the past have been misclassified as subacute sclerosing panencephalitis (SSPE) - a chronic progressive illness seen in children a few years after measles infection and usually considered a slow virus disease. The possibility of misdiagnosis of such cases as SSPE had been raised by a survey of SSPE in Poland, in which three young cases of CJD, including one teenager, had been identified. On 19 December, in the light of this possibility, Dr Will reviewed the SSPE register held by the PHLS to identify any cases of suspect SSPE, not subsequently confirmed, that might have a phenotype compatible with CJD. No such cases were identified. ¹⁴

5.87 In written evidence to the Inquiry, Dr Will listed other factors that were influencing his views in late 1995:

The post-mortem rate in suspect cases of CJD since 1990 had increased from approximately 50 per cent [of suspect cases] in the 1980-84 study to over 70 per cent from 1990 and there was, therefore, an increased chance of identifying atypical cases.

Through a review of all cases of suspect CJD since 1970, in which an alternative diagnosis had been confirmed neuropathologically, a case aged 16 years from 1980 was identified. This case had originally been identified as CJD after neuropathological examination, but this diagnosis was later retracted, perhaps because CJD was thought to be an unlikely diagnosis in a patient in this age group.

The hospital notes of one of the three young cases identified in the UK in 1995 included the statement 'First slides of the biopsy do not suggest any striking diagnosis - await more specific stains'. The diagnosis of CJD was supported by slides stained immunocytochemically for PrP, a technique developed in the 1990s and not available in previous study periods. This may have improved case ascertainment in the 1990s and this led us to re-examining and immunostaining tissues from past cases of CJD in the younger age groups. ¹⁵

The hospital notes referred to were those for case J.

5.88 In his evidence to the Inquiry, Dr Will noted that by 14 December 1995 ten suspect cases of CJD in patients aged less than 50 years had been referred to the CJDSU (cases D, E, F, G, H, J, K, L, M and O). ¹⁶ He also noted that by 31 December 1995 only three of these cases had been confirmed neuropathologically as CJD (cases D, E and J), but none had been classified as new variant CJD because the clinicopathological phenotype had not been recognised at that time. He cautioned that it was important to note that some of these ten suspect cases were not finally confirmed as cases of new variant CJD. Dr Will has also informed the Inquiry that on 15 December 1995 a further case in an individual under 50 was referred to the CJDSU after a neuropathologist diagnosed GSS. This was Case P. ¹⁷

5.89 A further three referrals of suspect CJD cases aged less than 50 years were made in the period from January to 20 March 1996. We refer to these cases as Q,R and S. Dr Will explained in a statement to the Inquiry that during this time there were two main issues, with sub-issues, that needed consideration in order to assess the significance of the cases:

1. To what extent are these cases different and new?
   
   
   1. is there a novel clinical phenotype?
   2. is there a novel neuropathological phenotype?
   3. are these cases linked to mutations [in the prion genes]?
   4. is there ascertainment bias or increased efficiency of surveillance?
2. To what extent might these cases be linked to BSE?
   
   
   1. are these cases in the UK distinct from previous experience?
   2. are these cases only occurring in the UK? ¹⁸

5.90 When asked about this during his oral evidence to the Inquiry, he confirmed that affirmative answers to points (i.) (a) and (b) would suggest that cases were 'different and new'. Conversely, if (i.) (c) and (d) were true, it would suggest cases were due to factors that had been around in the past, eg, cases linked to prion gene mutations. ¹⁹

5.91 We set out below how Dr Will's assessment of these issues changed from early January to 20 March 1996, and how by 8 March he and Dr Ironside concluded they had sufficient evidence to be confident that they had identified and characterised a new variant of CJD. Later in March, it became apparent that this new variant was restricted to the UK, consistent with a causal link to BSE.

5.92 On 4 January 1996, the diagnosis of CJD was confirmed by neuropathology in two more of the ten suspect cases identified in paragraph 5.89 above. These were patients K (aged 29 years at death) and H (aged 30 years at death). ²⁰ The histological appearances were judged to be unusual by the CJDSU and extensive plaque deposition was detected. The possibility of a genetic form of human prion disease was raised in these cases as they featured plaque formation, a feature in some cases of hereditary prion disease.

5.93 Dr Will updated SEAC on CJD surveillance results at their 23rd meeting on 5 January 1996. ²¹ He 'reaffirmed that the incidence of CJD in dairy farmers in Europe showed an excess over the incidence for the population as a whole'. He confirmed that a 52-year-old abattoir worker from York was suspected of having CJD. The patient had worked mainly as a stockman in a mixed abattoir for 18 months in the late 1980s, and had occasionally pithed animals but had much less exposure than other abattoir workers. Dr Will believed that the patient was no more than a suspect at that stage.

5.94 The minutes of the meeting record that Professor Smith commented on this case:

He [Professor Smith] felt that it was not possible to come to any conclusions on the basis of this case alone even if CJD is confirmed. Nevertheless, taking into consideration the affected farmers as well, and even though the abattoir worker was in an apparently relatively low risk category, the 'box' of 'at risk' occupations was getting full compared to expectation on pure chance and could not be dismissed. ²²

5.95 At this meeting, Dr Will also reviewed the age distribution of cases at the meeting. He continued to have no concern about the incidence of disease in those aged over 30 but the number of cases under 30 was worrying. He then went on to list the four definite and one possible case under 30. ²³ The definite cases were D, E, J and K . The possible case, a 29-year-old who was still alive, was L.

5.96 Dr Will told SEAC that there were two confirmed cases in patients between 30 and 40 years old. The minutes record that Dr Will also mentioned 'a 35-year-old suspect, who now looks unlike CJD'. ²⁴ The two confirmed cases were H and G, while the 35-year-old suspect was O.

5.97 The minutes noted that although Dr Will was not 'unduly concerned at the overall number of CJD suspect cases that had occurred in the under-30 age bracket, what he did find worrying was that all cases had occurred over a very short period'. ²⁵ Dr Will has added in written evidence to the Inquiry that he is confident that there was a more extended discussion than that recorded and that this included 'some of the caveats to the interpretation of the data available 5.1.1996'. ²⁶

5.98 By the time of the SEAC meeting on 5 January there had been 14 referrals of suspect cases of CJD in patients under 50 years of age to the CJDSU. ²⁷ Diagnosis of CJD had been confirmed in four of these cases at death (cases, D, H, K and G) and by biopsy in two cases (E and J). ²⁸ In his statement, Dr Will considered that by 5 January 1996, the scientific criteria on which these cases could be judged to be significant were fulfilled as follows:

1. 1. is there a novel clinical phenotype?: not identified;
   2. is there a novel pathological phenotype?: not identified;
   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;
2. 1. are these cases in the UK distinct from previous experience?: not identified;
   2. are these cases only occurring in the UK?: unknown.

5.99 We now turn to developments at the CJDSU during January 1996 leading up to the identification later that month of a possible novel clinical and pathological phenotype in some confirmed CJD cases in patients under 50 years of age.

5.100 On 8 January 1996, the CJDSU confirmed the diagnosis, by neuropathology, of CJD in two further cases (cases L and M) bringing the total number of confirmed cases to eight - comprising cases D, E, G, H, J, K, L and M. Dr Will wrote to the clinicians responsible for the two latest patients noting the possibility of a genetic form of CJD as the histological appearances were unusual for sporadic CJD. He also commented on the importance of genetic analysis in these cases. ²⁹

5.101 In early 1996, Dr Will contacted Professor Hofman, who coordinated the European surveillance project on CJD, to request information from participating countries on young cases of CJD, amongst other things. ³⁰ The CJDSU received this information later in January. The information showed that from 1993 to 1 February 1996 there were five deaths from sporadic CJD in continental Europe in the age range 20 to 39. Dr Will told us that 'this data indicated that the age distribution of young sporadic CJD in continental Europe was similar to the age distribution of young cases in the UK, with the exception of the two cases in teenagers'. ³¹ When Dr Will gave oral evidence, he qualified this statement:

There is an important qualification, and that is in the European surveillance system we are talking about a relatively and much larger population than the UK and a more prolonged study period in which these cases have been identified. So the comparison is not exact and we have to be aware of that. The only point I was trying to make is we did at that stage know that there were cases in the younger age group which had been identified in the European surveillance system, although I must stress not in teenagers at the time. ³²

5.102 Towards the end of January, Dr Will and Dr Ironside were becoming increasingly concerned about the number of cases of CJD in the younger age groups and the short time period in which the cases had been identified. Dr Will told us:

Concern about the presence of plaques on neuropathological examination in all the confirmed cases to date was heightened by previous work from the unit, which had indicated a significant excess of plaques in association with a valine or heterozygous [prion protein] genotype. At this stage we were aware that three of the young cases were methionine homozygotes and that these were not associated with [prion protein] mutations. ³³

5.103 Summary tables were produced by Dr Martin Zeidler of the CJDSU on 16 and 29 January 1996, on the clinical, investigative and pathological data on suspect or confirmed cases aged less than 50 years. ³⁴ The results from these tables are shown at Annex 2. Dr Will told us that around this time:

. . . (neither my colleagues nor I can recall the exact date) by the examination of summarised clinical and pathological data we identified what we believed might be a common clinical phenotype, which was linked to plaque deposition neuropathologically. This phenotype included, in addition to young age at death, a relatively prolonged duration of illness in relation to sporadic CJD, early psychiatric symptoms, prominent ataxia and the absence of the characteristic EEG appearance seen in sporadic CJD . . . ³⁵

It is important to stress that the identification of this 'novel' phenotype was tentative at this stage. Each component of the phenotype can occur in sporadic CJD. Some of the cases on which the putative phenotype was based were suspect and at that stage unconfirmed and one of these cases was subsequently discovered to have an insert mutation of [the prion protein gene]. There was the possibility that the cases had a heterogeneous aetiology, with some cases sporadic and some genetic. The latter issue was the subject of intense discussion, which continued over subsequent weeks. We believed that genetic analysis was essential to determine whether some of the cases were mutation-associated . . . ³⁶

[The] review of historical data on the clinical phenotype of young cases of CJD led to the identification of some cases with a similar phenotype to that proposed in the recent young cases. For example, in the 1970-79 study of CJD the following cases of sporadic CJD were identified:

1. A patient aged 34 years presenting with depression and seen by a psychiatrist. Total illness duration 8 months. EEG typical.
2. A patient aged 35 years presenting with emotional lability and who developed ataxia. Total illness duration 23 months. EEG showed slow activity.
3. A patient aged 28 years presenting with depression and seen by a psychiatrist. Total illness duration 22 months. EEG showed some triphasic complexes. ³⁷

5.104 Dr Will explained, in written evidence to the Inquiry, the views he held at the end of January 1996:

I had become increasingly concerned about the young cases of CJD, but there was insufficient scientific evidence to reach a conclusion about the novelty of these cases, nor to reach a judgement about whether these cases might be causally linked to BSE. The interpretation of the neuropathological findings was of critical importance and I asked Dr Ironside for his opinion. Dr Ironside said that there clearly were very unusual pathological features in these cases, but that it would be premature to conclude that these cases were linked to BSE on the basis of the neuropathological findings alone.

5.105 Reflecting these developments, Dr Will set out in written evidence his assessment as of 1 February 1996 of the extent to which some of the scientific criteria were met. We describe this below, and give a comparison for each criterion where the position had changed since 5 January:

i.
1. is there a novel clinical phenotype?: possible (compared with 'not identified' on 5 January);
2. is there a novel pathological phenotype?: possible (compared with 'not identified' on 5 January);
3. are these cases linked to PRNP mutations?: 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?: possible (compared with 'not identified' on 5 January);
2. are these cases only occurring in the UK?: unknown. ³⁸

5.106 At the 24th meeting of SEAC on 1 February 1996, Dr Will reported on the CJDSU findings in the young cases of CJD. ³⁹ By this time, five cases [cases D, E, J, K, L] of CJD under the age of 30 had been confirmed by neuropathology, three of whom were dead [D, K, L] and two alive [E, J]. However, genetic screening for mutations was incomplete, so familial CJD could not be ruled out. He also referred to two cases of confirmed CJD in the 30-39-year-old age bracket [cases H and G] bringing the total to seven cases confirmed in patients under 40 years of age. In addition, he referred to a further patient P who was in the 30-39 age group with a pathology suggestive of Gerstmann-Sträussler Syndrome (GSS) and a further confirmed case of CJD in a 41-year-old [case M]. The minutes of the meeting record:

In all of the cases mentioned above (except the GSS case and the one case where results are incomplete) there was extensive plaque formation in the cerebral cortex, cerebellum and spinal cord. An extensive and unusual pattern of PrP deposition was an unexpected finding. Dr Will reported Dr Ironside's view that it is premature to decide that these cases are linked with BSE. Cerebellar and spinal cord plaques are evident in hGH cases. ⁴⁰

5.107 In written evidence to the Inquiry, Dr Will clarified what was known at that time about the neuropathology of the cases:

I am recorded as saying in paragraph 21 [of the minutes of the SEAC meeting] that 'In all of the cases mentioned above there was extensive plaque formation in the cerebral cortex, cerebellum and spinal cord.' I regret that I had not previously recognised that this statement is inaccurate and I cannot recall whether the error is in what I said or what I am recorded to have said. By 1.2.1996, seven cases of what was subsequently recognised as new variant CJD had been confirmed neuropathologically. In two of these cases the neuropathological confirmation was by brain biopsy and, at that stage, information on regional neuropathology, including spinal cord, cannot have been available. With the assistance of the neuropathology staff at CJDSU I have identified that on 1.2.1996 full regional neuropathology was available in three cases and minimal regional data, excluding spinal cord, was available in a further two cases, although at that stage the neuropathological phenotype of nvCJD had not be identified. ⁴¹

5.108 The minutes of SEAC's 24th meeting also record that:

Dr Will reiterated that the crucial issue is not simply the young age or pathology of recent cases but the short time scale in which five cases in individuals under 30 years of age had occurred. The dates of onset of symptoms of the cases were February 94, May 94, June 94, January 95 and April 95 although they were not reported to the CSU in that order. He advised SEAC that definitive genetic data on these five cases would soon be available and that he intended to publish the clinico/pathological data together with that of cases under 40 years of age. Details of the third young case will also soon be published. Dr Will agreed to let SEAC see an agreed proof copy of the paper. This would not be for amendment by SEAC and must remain confidential. It was agreed that a statement from SEAC should be prepared before the paper was published. ⁴²

5.109 In written evidence to the Inquiry, Dr Will expanded on the discussions at the meeting in relation to this:

In my view it was essential that the descriptive information on these cases was published, although this would almost certainly not have been possible until the genetic data was available. The short time scale in which five young cases of CJD aged less that 30 years had been identified was clearly a matter of concern, but I did not at that time believe there was sufficient clinical, pathological or epidemiological evidence to indicate that we had identified a novel clinicopathological phenotype of CJD. The reasons for this view are indicated above and included the possibility of ascertainment bias, the data on young cases identified in continental Europe and concerns about improvement in neuropathological diagnosis following the introduction of modern [biochemical] techniques. Although not minuted, I believe that some of these issues were discussed at SEAC. ⁴³

5.110 The minutes also record that, Professor (now Sir) John Pattison, Chairman of SEAC, concluded that:

The unusual data on young cases is of greater concern than the cases in farmers which appeared to be classical sporadic cases with typical pathology. He repeated the need to look at young people in other countries. If these patients shared the unusual pathology it would be comforting. It could be that CJD in young cases was different because of the age of the patient. ⁴⁴

5.111 At the meeting Dr Will emphasised the urgency of strain typing of these cases of CJD. ⁴⁵ In written evidence Dr Will expanded on his reasons:

. . . I had been concerned since the early years of the project that the identification of small numbers of atypical cases of CJD might be very difficult to interpret from an epidemiological perspective, particularly if there were ascertainment bias in comparison to previous study periods. It was, in my view, essential to obtain information from laboratory strain typing studies on these young cases as this might be crucial to an evaluation of whether or not these cases were linked to BSE. ⁴⁶

5.112 In oral evidence he added:

What I am really saying there is it is extraordinarily difficult to assess small numbers of cases when you are carrying out a national surveillance project. It is a very difficult thing to do. Therefore, the issue of having further scientific evidence in relation to these cases was critically important. And if I may say, in the end it was critically important in providing very strong evidence that links BSE to the occurrence of new variant CJD. ⁴⁷

5.113 The minutes of the SEAC meeting also record that Dr Will described recent developments in relation to sporadic CJD:

. . . Recent findings suggested that there are two subsets of sporadic CJD: those with an extended duration of illness with plaques in the spinal cord and cerebellum and those with a short duration of illness which do not show such plaques. Dr Will said there were no apparent environmental factors identified, except that 5 of the 9 spinal cord positive cases had had abdominal surgery, in three cases in the 1950s/60s. None of the spinal cord negative cases had had abdominal surgery. ⁴⁸

5.114 In written evidence Dr Will explained why he had presented this information:

In paragraph 21 [of the SEAC minutes] reference is made to a description I gave of two subsets of sporadic CJD, differentiated by the presence or absence of PrP staining in the spinal cord. The reason I presented this data was in order to ensure that SEAC were fully informed about recent developments that might be of concern. It is important [to] stress that this data on spinal cord neuropathology related to sporadic CJD and not new variant CJD. ⁴⁹

5.115 Dr Will emphasised this point at his oral hearing:

Just to be completely clear about this, this is nothing to do with new variant CJD. And the reason it was presented was because I felt, at the meeting, that SEAC should have access to all the information that we had that might be a cause for concern. ⁵⁰