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From: TSS (
Date: October 18, 2004 at 6:32 am PST

-------- Original Message --------
Date: Mon, 18 Oct 2004 08:35:53 -0500
From: "Terry S. Singeltary Sr."
To: Bovine Spongiform Encephalopathy

Date: October 18, 2004 Time: 12:15


The twelfth annual report of the National Creutzfeldt-Jakob Disease
Surveillance Unit was published today. The report looks back over the
period from May 1990 when the Unit was set up to 31 December 2003. The
report outlines the Unit's work in the clinical surveillance of
sporadic, variant (vCJD) and iatrogenic CJD.

Details of a case-controlled study on potential risk factors for variant
and sporadic CJD, the Unit's laboratory activities, and the work of the
National Care Team in arranging care packages for CJD cases and
providing advice on all forms of CJD to parents, their families and
professional carers are also included.

Issues highlighted in the report are:

- 145 cases of definite or probable vCJD had been identified in the UK
up to 31 December 2003, with 139 deaths reported. Analysis of the
incidence of vCJD onsets and deaths from January 1994 to December 2003
provides statistically significant evidence that the epidemic may have
reached a peak or a plateau.

The identification of a first case of vCJD associated with blood

- The incidence of vCJD across the UK continues to show a "North -
South" difference, although slightly less than previously reported, with
a higher incidence being maintained in the North of the UK. The
underlying reason for this finding is not clear.

- It remains the case that the only statistically significant geographic
cluster of vCJD cases in the UK was in Leicestershire. This cluster was
first identified in July 2000. All geographically associated cases of
vCJD are considered for investigation according to a protocol which
involves the NCJDSU, the Health Protection Agency, The Scottish Centre
for Infection and Environmental Health (SCIEH), and local public health

- There is no evidence of any difference between the UK and other
European countries in the incidence of sporadic CJD, nor any significant
variation in recorded mortality within the UK.

Notes for Editors

The NCJDSU is jointly funded by the Department of Health and the
Scottish Executive Health Department.

The report is available on the NCJDSU website at

Creutzfeldt-Jakob Disease Surveillance in the UK

Twelfth Annual Report 2003

The National CJD Surveillance Unit, Western General Hospital, Edinburgh,


Department of Infectious and Tropical Diseases, London School of Hygiene
and Tropical Medicine, Keppel Street, London, WC1E 7HT

Summary | Clinical
Case-Control Study
Laboratory Activities
National Care Team
| Staff


The national surveillance programme for Creutzfeldt-Jakob disease (CJD)
in the UK was initiated in May 1990. In 1999, the National CJD
Surveillance Unit (NCJDSU) became a WHO Collaborative Centre for
Reference and Research on the Surveillance and Epidemiology of Human
Transmissible Spongiform Encephalopathies (TSEs). In September 2001 the
National Care Team was formed, comprising 2 care co-ordinators, a
neurologist (part-time) and a secretary. The National Care Team is based
within the NCJDSU and was formed in response to concerns regarding the
care of CJD patients.

The information provided in this twelfth report continues to provide
evidence of a high level of case ascertainment. Detailed clinical and
epidemiological information has been obtained for the great majority of
patients. The methodology of the case-control study for risk factors of
CJD has been altered in an attempt to overcome some logistic problems in
its conduct. The post mortem rate for patients with suspected CJD is
high, although there is ongoing evidence that this rate continues to
decline, in line with autopsy rates in the UK. This is reflected in the
reduced number of brain specimens examined in the neuropathology
laboratory this year, particularly for variant CJD.

In 1990-2003 mortality rates from sporadic CJD in England, Scotland,
Wales and Northern Ireland were, respectively, 0.86, 0.84, 1.08 and
0.57/million/year. The difference between the rates in each country is
not statistically significant (p>0.2). These rates are comparable to
those observed in other countries in Europe and elsewhere in the world,
including countries which are free of BSE. There was some variation in
the observed mortality rates between the different regions within the UK
but this variation is not statistically significant (p>0.2). The highest
and lowest mortality rates from sporadic CJD were observed in the South
West (SMR=129) and Northern Ireland (SMR=79).

Up to 31 December 2003, there have been 139 deaths from definite or
probable variant CJD (vCJD) in the UK. Of these, 104 were confirmed by
neuropathology. The clinical, neuropathological and epidemiological
features of all these cases of vCJD are remarkably uniform and
consistent with our previous descriptions. Analysis of the incidence of
vCJD onsets and deaths from January 1994 to December 2003 shows evidence
that the epidemic may have reached a peak or a plateau. While this is an
encouraging finding, incidence of vCJD may increase again, particularly
if different genetic subgroups are found to be affected.

Risk factors for the development of vCJD include age, residence in the
UK and methionine homozygosity at codon 129 of the prion protein gene -
123 cases of vCJD with available genetic analysis have all been
methionine homozygotes. The incidence of vCJD across the UK continues to
show a "North-South" difference (though slightly less than previously
reported), with a higher incidence being maintained in the North of the
UK. The underlying reason for this finding is not clear. The only
statistically significant geographic cluster of vCJD cases in the UK was
in Leicestershire. All geographically associated cases of vCJD are
considered for investigation according to a protocol which involves the
NCJDSU, colleagues at the HPA, SCIEH and local public health physicians.

The activities of the NCJDSU are strengthened by collaboration in other
surveillance projects, including the Transfusion Medicine Epidemiology
Review and the study of Progressive Intellectual and Neurological
Deterioration in Children. The collaboration of our colleagues in these
projects is greatly appreciated; the effectiveness of this collaboration
allowed the identification in 2003 of a case of variant CJD associated
with blood transfusion. The success of the National CJD Surveillance
Project continues to depend on the extraordinary level of co-operation
from the neuroscience community and other medical and paramedical staff
throughout the UK. We are particularly grateful to the relatives of
patients for their help with this study.


The national surveillance of CJD in the UK was initiated in May 1990 in
response to a recommendation in the Report of the Working Party on
Bovine Spongiform Encephalopathy (Southwood Committee). The surveillance
is funded by the Department of Health and by the Scottish Executive
Health Department. The initial aim of the NCJDSU was to identify any
change in the pattern of CJD that might be attributable to the emergence
of bovine spongiform encephalopathy (BSE). Such a change was recognised
in 1996 when vCJD was first described. The NCJDSU now aims to monitor
characteristics of CJD, specifically sporadic CJD and variant CJD, to
identify trends in incidence rates and to study risk factors for the
development of disease. This report documents the findings in relation
to UK cases of sporadic, familial, iatrogenic and variant CJD referred
up to 31st December 2003 (with data ascertained up to 14th April 2004).
Data from England and Wales include retrospective data from 1970; for
Scotland and Northern Ireland, retrospective data are available from 1985.

2.1 Sporadic Creutzfeldt-Jakob Disease

Between 1st January 1970 and 31st December 2003, 1107 cases of sporadic
CJD were identified in the UK, of which 11 cases were still alive on
31st December 2003. Two further cases were identified in Jersey but they
were not included in the following UK analyses. Of these UK cases, 848
(77%) were classified as definite cases with the remainder classed as
probable. Figure 1a shows
the number of deaths each year from sporadic CJD for the UK between 1985
and 2003, Figure 1b shows
similar data for England and Wales between 1970 and 2003 and Figure 1c
shows the number of
deaths from sporadic CJD in Scotland and Northern Ireland between 1985
and 2003. In England and Wales the number of deaths identified each year
has increased from an average of about 10 per year at the beginning of
the 1970s, to about 40 per year in the 1990s. A similar phenomenon has
been observed in other European countries and this probably largely
reflects improved case ascertainment. Over the shorter time period for
which data are available for Scotland and Northern Ireland there is no
clear secular trend. Over the period 1990-2003 the average crude annual
mortality rates from sporadic CJD per million population were 0.86 in
England, 1.08 in Wales, 0.84 in Scotland and 0.57 in Northern Ireland,
as shown in Table 1 . When
account is taken of age and sex, the variation in recorded mortality
between the different countries is not statistically significant (p > 0.2).

Figure 2a , Figure 2b
and Figure 2c
show average annual age-
and sex-specific mortality rates over the time periods 1970-89, 1990-95
and 1996-03, respectively. The median ages of cases at death during
these time periods were 64, 66 and 67 years, respectively. In all three
time periods, the mortality rates below 40 years of age were extremely
low (<0.2/million/year). Thereafter, in all three periods, the mortality
rates increased until the ages of 60-74 years and then declined. The
decline in mortality rate in the older age groups was more marked prior
to 1990. The mortality rate in those over 75 years of age was 2.78
cases/million/year in 1996-03, 2.11 cases/million/year in 1990-95 and
0.38 cases/million/year in 1970-89. This might be explained by an
increase in case ascertainment in the elderly over time. Another feature
over the time period studied is a change in the sex ratio, affecting
particularly older cases, with a male excess after 1996, was examined in
the 2001 annual report. The explanation for this trend remains unclear.

An analysis of age specific trends from 1970 to 2003 (Figure 3
) shows there has been an
increase in recorded mortality over time in all age groups, but that the
greatest relative increase has occurred in those aged 70 years and
above. Currently the mortality rate in this age group is similar to that
in the age group 60-69 years. The temporal increases in mortality are
statistically significant in all age groups (p=0.004, p=0.003, p<0.001,
p<0.001 for age groups 40-49, 50-59, 60-69 and >= 70 years
respectively). These observations are consistent with improved case
ascertainment in all ages, but with the greatest increase occurring in
the elderly.

Table 2 presents, by 2-year
period, the numbers of deaths underlying these trends. These data
emphasise the very small numbers of cases of sporadic CJD occurring in
individuals aged less than 50 years. They show clearly the substantial
increase in the numbers of deaths identified among those aged 70 years
and above, from around one per year in England and Wales in the early
1970s to around 25 per year in the UK in recent years.

Age- and sex- standardised mortality ratios (SMRs) for the 11 standard
regions of the UK for the period 1st January 1990 to 31st December 2003
were calculated (Figure 4
). After adjusting for the
age/sex distribution of the population, the variation in mortality rates
between the different regions is not statistically significant (p>0.2).
Regions of relatively high mortality are South West (SMR=129), Wales
(SMR=117) and East Anglia (SMR=114). Low mortality rates were observed
in Northern Ireland (SMR=79), West Midlands (SMR=83) and East Midlands
(SMR=87). The SMRs for the other five regions all lay between 93 and
100. The highest SMR (129 in South West) arose from 82 cases observed
compared with 64 expected, an excess of about 1.4 cases every year
compared to the national average. In Wales and East Anglia the total
numbers of excess cases were approximately 6 and 4 respectively.

2.2 Variant Creutzfeldt-Jakob Disease

Up to 31st December 2003, 145 cases of definite or probable vCJD had
been identified in the UK (104 definite, 35 probable who did not undergo
post mortem and 6 probable cases still alive). Sixty-three (43%) of the
145 cases were women. The median age at onset of disease was 26 years
and the median age at death 28 years (compared with 66 years for the
median age at onset and 67 years for the median age at death for
sporadic CJD). The youngest case was aged 12 years at onset while the
oldest case was aged 74 years. The age- and sex-specific mortality rates
for vCJD over the time period 1 May 1995 to 31 December 2003 are shown
in Figure 5 . The median
duration of illness from the onset of first symptoms to death was 14
months (range 6-39). The comparable duration of illness for cases of
sporadic CJD was 4 months (range 1 to 74) during the period 1990-2003.

Incidence of vCJD onsets and deaths from January 1994 - December 2003

Each quarter the data on diagnosed cases of vCJD are reviewed in order
to investigate trends in the underlying rate at which onsets and deaths
are occurring. The following analysis reviews the data to the end of
December 2003 by which time there was a total of 145 cases of which 139
had died. The data were grouped into quarters and modelled using Poisson
regression. Models were fitted with either exponential or
quadratic-exponential time parameters.



The incidence of onsets by quarter was analysed with Poisson models
using polynomials (constant, exponential, quadratic exponential). When
modelling the incidence of onsets over time, delay to diagnosis, and the
fact that this delay may be shortening over time because of new
diagnostic methods, must be taken into account. Consequently the data
were cross-classified by quarter of onset and number of quarters delay
from onset to diagnosis, and the delay from onset to diagnosis modelled
using a gamma distribution with a mean that can vary over time.


After grouping deaths by quarter the incidence of deaths were modelled
by Poisson regression using polynomials. Most deaths are reported
quickly so an adjustment for reporting delay is not necessary. So far
the age at death has not increased as might have been expected, assuming
that most exposure to BSE ceased in the early 1990s. In order to examine
this further the cases were stratified by quarter of death and birth
cohort (pre1970, 1970s and 1980s). Trends in deaths over time were
compared between these cohorts.

Also, to investigate further whether the epidemic has reached a peak, an
alternative model was considered using annual data in which incidence
rises to a plateau and then remains constant.

Results for Onsets

Since vCJD was first identified, the average interval between the onset
of first symptoms and the diagnosis of vCJD has decreased. The mean
delay to diagnosis is estimated to have reduced by an average of 5% per
year and is currently estimated at 10 months.

Figure 6a shows the
observed and expected number of onsets and the estimated trend (assuming
exponential growth) with 95% confidence intervals (CIs). This model
estimates that the number of onsets have increased by 9% per year since
1994 (95% CI 1.3-16). The estimated incidence in the current quarter is
6.1 cases per quarter.

A separate model including a quadratic trend showed significant evidence
of a better fit (p=0.001 for quadratic term). Figure 6b
shows the quadratic model
fitted to the data. The quadratic model is consistent with an epidemic
that has reached a peak and this model gives an estimated current
incidence of 2.5 onsets per quarter. If the quadratic model is assumed
to be correct then the peak is estimated to have occurred in September
1999 with a 95% CI for the time of the peak from December 1998 to June 2001.

Predicted onsets by the end of December 2003

Based upon the exponential model, the total number of cases with onset
by December 2003 is 165 (145 already diagnosed plus 20 not yet
diagnosed) with a 95% prediction interval of 158 to 174. Based on the
quadratic model, however, the estimated total number of cases with onset
by December 2003 is 155 (145 already diagnosed plus 10 not yet
diagnosed) with a 95% CI of 150 to 162.

Results for Deaths

All deaths combined

Figure 7a shows the
observed numbers of deaths by quarter with the exponential model fitted.
The annual number of deaths has increased by an estimated 13% per year,
(95% CI 5-20). Based on this model the estimate of the current quarterly
incidence of deaths is 6.2.

The model that included a quadratic term provides a better fit to the
data (p=0.0003) indicating strong evidence of a departure from a
constant exponential increase. Figure 7b
shows the data with the
fitted quadratic trend. This model estimates that the current quarterly
incidence of deaths is 3.5. If the quadratic model is assumed to be
correct then the peak is estimated to have occurred in December 2000
with a 95% CI for the time of the peak from March 2000 to August 2002.

An alternative model in which the incidence of deaths rises to a plateau
was also fitted to the annual data (Figure 7c
). This model, which gave
an estimate for the plateau at 19.5 deaths per year (4.9 per quarter),
fitted the observed incidence of deaths as well as the quadratic model
with neither model showing evidence of lack of fit. Therefore it is not
possible to distinguish between a trend that has reached a peak and one
that has reached a plateau.

Predictions for deaths in 2004

From the model with an increasing exponential trend, the predicted
total number of deaths for 2004 is 27 with a 95% prediction interval of
16 to 39. However the model with the quadratic term predicts a total of
11 deaths for 2004 with a 95% prediction interval of 4 to 19. The
plateau model predicts a total of 19 deaths for 2004 with a 95%
prediction interval of 10 to 29.

Assessment of predictions made at the end of December 2002

The exponential model predicted 28 deaths for 2003 with a 95% prediction
interval of 16-40, whereas the quadratic model predicted 13 deaths with
a 95% prediction interval of 5-23. The observed number of deaths was 18.
Although this is within both prediction intervals it is closer to the
prediction by the quadratic model.

Deaths by cohort

The age at death has so far remained stable, contrary to what may be
expected given that most exposure to BSE is presumed to have ceased in
the the early 1990s. This finding is consistent with, for example,
varying age-specific susceptibility or exposure or possibly different
incubation periods by age. To examine this in more detail the epidemic
curves (quadratic model) are compared in those born before 1970 with
those born in the 1970s and the 1980s. This analysis revealed evidence
of differences between cohorts in the shape of the fitted curves
(p<0.001). The main difference is that in the 1980s cohort no deaths
were seen prior to 1999. Figure 8a
, Figure 8b
and Figure 8c
shows the fitted
quadratic epidemic curves for each of the cohorts. The data are
compatible with the shapes of the curves in the pre-1970s cohort and the
1970s cohort being the same (p=0.15). Note that in the 1980s cohort the
confidence intervals are very wide due to small numbers and it is
unclear in this cohort whether or not the trend is still exponential.


There is statistical evidence (p=0.001 for death, p=0.0003 for disease
onset) that the epidemic is no longer increasing exponentially.
Furthermore estimates from quadratic models fitted to the incidence
suggest that the epidemic may have reached a peak. Estimates for the
time of this peak are September 1999 (95% CI: December 1998 - June 2001)
for disease onset and December 2000 (95% CI: March 2000 - August 2002)
for deaths. Although these models suggest a peak may have been reached,
analysis of the annual number of deaths indicates that an alternative
model with an increase to a plateau of 19 deaths per year rather than a
peak is also consistent with the data. That the epidemic may have
reached and passed one peak does not exclude the possibility of further
peaks in the future.

For the purposes of short-term predictions the model used is important;
predictions are best made based on the quadratic model or plateau model
rather than the exponential model which has a poor fit. The quadratic
models estimate the current incidence of onsets to be 2.5 per quarter
and deaths to be 3.5 per quarter with 11 deaths predicted for 2004 (95%
prediction interval 4 to 19). The plateau model estimates the current
incidence of deaths to be 4.9 per quarter with 19 deaths for 2004 (95%
prediction interval 10 to 29). A plateau model has not as yet been
fitted to the onsets data.

An analysis of deaths by birth cohort (pre 1970, 1970s, 1980s) indicates
that the shape of the epidemic differs between cohorts, mainly due to
the fact that deaths of individuals born in the 1980s only occurred from
1999 onwards.

Geographical distribution of variant CJD

Figure 9 shows the
geographical distribution, by place of residence at onset, of 143 cases
of vCJD in the UK for whom a residential address at onset is available.
For one case the address at onset is known only at county level and for
a further case residential address at onset is not known. Cases have
been widely spread throughout the UK. Table 3
presents data on the
geographical distribution, by county of residence at onset, of the cases
who had died by 31 December 2003 (for whom information on place of
residence at onset was available) along with the crude mortality rate
per million population per annum of each standard region.

Table 4 shows cumulative
regional rates of vCJD based on cases’ place of residence in 1991,
rather than at onset, and the population aged 10 years and above
resident at that time. We originally performed an analysis of the first
51 cases, distinguishing two areas. The “North” comprised four standard
regions: Scotland, North, Yorkshire and Humberside, North West. The
“South” comprised the remaining 6 regions: Wales, West Midlands, East
Midlands, East Anglia, South West, South East.

Age- and sex-standardised "incidence" ratios (SIRs) based on cases'
place of residence in 1991 are shown in Figure 10
for the 11 standard
regions of Great Britain.

Table 5 shows the
distribution of cases between the “North” and the “South” according to
place of residence in 1991, for those cases included in the initial
analysis (51) and for all cases. The excess of cases previously
identified in the “North” (rate ratio controlling for age and sex =
1.94; 95% c.i. 1.12, 3.36) has been largely maintained in subsequent
cases with, overall, a rate ratio controlling for age and sex of 1.60
(95% c.i. 1.15, 2.23) i.e. individuals living in the "North" in 1991 are
about one and a half times more likely to have developed vCJD than
individuals who were living in the "South" in 1991. The overall rate
ratio is slightly less than that estimated last year (1.65), based on
125 cases.

Northern cases were slightly older at onset than southern cases (median
of 26.5 years versus 24.5 years; p=0.5), a similar proportion were male
(56% versus 54% of southern cases; p=0.8).

Geographically Associated Cases of variant CJD

Geographically associated cases of vCJD are defined by two or more cases
of probable or definite vCJD with a geographical association, either
through proximity of residence or through another link with the same
location (occupational, educational or social/recreational). By the end
of December 2003 a total of thirteen investigations into geographically
associated cases of vCJD had been opened in the UK. Those in eleven
localities were concluded and in two were ongoing. The Leicestershire
cluster of five cases remains the only statistically significant cluster
of cases of vCJD in the UK to date. None of the concluded investigations
have revealed any suggestion of possible iatrogenic transmission. No
evidence emerged from these investigations in any of the areas apart
from Leicestershire of bovine heads being split or brains removed by
local butchers in their shops during the relevant time period.

2.3 Iatrogenic Creutzfeldt-Jakob Disease

Since 1970, up to 31st December 2003, 51 cases of CJD attributable to
iatrogenic exposure have been identified, 7 in individuals receiving
dura mater implants, 43 in individuals who had received human-derived
growth hormone (hGH) and one in a recipient of human gonadotrophin (hGN)
(Figure 11 ).

The mean age at death of the hGH /hGN group was 30 years (with a range
of 20-45 years) and for the dura mater cases 42 years (range 27-59 years).

The first identified iatrogenic case was a dura mater recipient who died
in 1979. The first hGH-related death occurred in 1985. Since 1985 in the
UK, human pituitary-derived hormones have been replaced by synthetic

2.4 Transfusion Medicine Epidemiology Review

The Transfusion Medicine Epidemiology Review (TMER) is a collaborative
project between the UK NCJDSU and UK Blood Services (UKBS). The main
purpose is to investigate whether there is any evidence that CJD or vCJD
may have been transmitted via the blood supply.


vCJD cases(definite and probables) are notified to the UKBS by NCJDSU; a
search establishes whether any have acted as donors. Donation records
are checked and all components traced through hospital records. Details
of all identified recipients are forwarded to NCJDSU for subsequent

In the reverse procedure, patients with vCJD reported to have received
blood transfusions are identified by NCJDSU and notified to UKBS.
Details of transfusions are traced through hospital records and relevant
blood donors identified. The identity of donors is notified to NCJDSU
for subsequent checking.


Twenty-seven vCJD cases were reported to have been blood donors, of whom
18 have been traced at blood centres. Components from 15 of these
individuals were actually issued to hospitals. It has been established
that 49 components were transfused to named recipients (with 3 units
discarded and 6 hospitals unable to trace component fate). One of these
recipients was identified as developing symptoms of vCJD 6.5 years after
receiving a transfusion of red cells donated 3.5 years before the donor
developed symptoms of vCJD (Llewlyn et al. Possible transmission of
variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 2004;
363: 417-421).

In the reverse study, 9 vCJD cases were reported to have received blood
transfusions. Checks revealed that 2 were not transfused, 2 had
transfusions which predated available records and 5 had records of
transfusion which could be traced. These 5 individuals had received 122
components of blood (with one patient given 103 components), which have
been traced to 120 named donors (including the vCJD donor described
above). The donors of two components are not traceable.


These findings raise the possibility of a transfusion transmitted case
of vCJD. Infection in the recipient could have been due to past dietary
exposure to the BSE agent. However, the age of the patient was well
beyond that of most vCJD cases, and the chance of observing a case of
vCJD in a recipient in the absence of transfusion transmitted infection
is about 1 in 15 000 to 1 in 30 000.

(Collaborators on this project: Dr P.E. Hewitt and Dr C.A. Llewelyn).

2.5 Study of Progressive Intellectual & Neurological Deterioration

The aim of this project is to use the mechanism of the British
Paediatric Surveillance Unit to identify all cases of progressive
intellectual and neurological deterioration in children in the UK,
particularly those with features suggestive of vCJD. All cases are
discussed by an Expert Neurological Advisory Group of six paediatric
neurologists which allocates the cases to a diagnostic category. (see
reference: Verity CM, Nicoll A, Will RG, Devereux G, Stellitano L.
Variant Creutzfeldt-Jakob disease in UK children: a national
surveillance study. Lancet 2000; 356: 1224-1227).

After almost 7 years surveillance, 1711 patients with suspected PIND
have been reported. The Expert Group has discussed 1204 cases, of which
696 have a confirmed underlying cause other than vCJD, being categorised
into 112 known neurodegenerative diseases. Among them were six cases of
vCJD; four definite and two probable. Three were reported in 1999, one
in 2000 and 2 in mid-2001. One girl was aged 12 at onset - the youngest
case of vCJD identified to date.

(Collaborators: Dr C. Verity, Dr A. Nicoll, Ms G. Devereux).


Since May 1990, a case-control study of CJD has been carried out in the
UK to investigate potential risk factors for variant and sporadic CJD.
Patients themselves are usually too unwell to answer questions when they
are seen by members of the Unit. Therefore, relatives of patients with
suspected CJD are asked to be interviewed using a standard
questionnaire, which includes a wide range of questions relating to
possible risk factors for CJD, including residential, occupational,
dietary and medical histories. To maximise the study's validity, it is
important that this interview takes place as early as possible, that is,
as soon as a person is suspected as having CJD. We are indebted to the
families of those with suspected CJD, who agree to be interviewed at
often an extremely difficult time in their lives.

Each type of control group used in a case-control study has advantages
and disadvantages in terms of suitability as controls, practicalities of
recruitment and cost. Since 1990 there have been variations of control
recruitment for the CJD risk factor study:-

1990-1997: For each suspect case, an age- and sex-matched patient at the
same hospital was identified as a control.

1998-2002: With the diagnosis of the first cases of variant CJD, it was
decided that in addition to hospital controls for variant cases, and
instead of hospital controls for sporadic cases, community controls
would be recruited, matched for sex and age, through general medical
practices (one control for each sporadic case and up to 4 controls for
each variant case). Community controls are more suitable than hospital
controls for the investigation of potential medical risk factors.
However, from the start difficulties were encountered arising from the
complex process of recruitment of general practice based controls. Of
particular concern was the low response rate to the initial letter from
the GP to the potential control. With a low response rate, the results
from the study would be hard to interpret because of the potential for
selection bias. Therefore, a revised strategy for control recruitment
was devised.

2002 to date: Hospital controls continue to be recruited for variant
cases. Recruitment of community controls from general practices ceased
and was replaced by two new control groups. The first are general
population controls, who were recruited using the services of the
National Centre for Social Research, which is the largest independent
social research institute in Britain. The second new group of controls
are friends nominated by relatives of cases. That is, relatives of cases
are asked to nominate a friend who would agree to be interviewed about a
relative of theirs (the control), who is age- and sex-matched to the
case. The degree of relative between control and 'friend' is matched to
that between the case and their relative. Consent of the control is
sought before the 'friend' is interviewed.

Table 6 and Table 7
shows the response rate for
controls recruited through general practices and those nominated by
relatives of cases. The latter has achieved an overall success rate of
control recruitment for variant cases of 50% and for sporadic cases of
55%. Seventy-four hospital controls have been recruited for variant
cases. To recruit general population controls the National Centre for
Social Research selected 4400 addresses in total; 385 of which were
non-residential addresses and considered 'ineligible'. Of the remaining
4015 addresses, 2148 were ineligible because they either did not have an
adult of the right age, there was no household member with a living
relative or there was no household member resident in the UK between
1980 and 1996. From 1867 eligible addresses, 1065 controls were
recruited (57%). 87% (924) of relatives were interviewed, giving a final
percentage of 49% for achieved interviews at eligible addresses.

Data from cases and controls recruited from hospitals, general practices
and by the National Centre for Social Research are being analysed
currently and will be published when completed. The recruitment of
hospital controls for variant cases and relative nominated controls for
sporadic and variant cases continues. GP and dental records are being
traced for controls that have given consent and potential medical,
surgical and dental risk factors will be compared where possible with
those of cases.


Laboratory investigations are part of the internationally-agreed
diagnostic criteria for CJD, both during life (CSF protein analysis and
PrP genetic studies) and post-mortem (neuropathology and protein
studies). The NCJDSU has facilities to perform all of these
investigations, which aid the timely and accurate diagnosis of all forms
of CJD and are essential for surveillance purposes.

4.1 Neuropathology - Statement of Progress

The neuropathology laboratory in the NCJDSU continues to maintain a high
workload in terms of diagnostic and research activities, including the
work of the protein laboratory. The laboratory maintains close links
with other neuropathology centres across the UK and overseas with
scientific, medical, technical and student visitors over the past year
for specialist training purposes. The laboratory has continued its major
role in the National Retrospective Review of CJD and Related Disorders
and in the retrospective study to detect abnormal PrP in anonymised
specimens of appendix and tonsil tissue. The laboratory has developed
the PET blot technique for the detection of protease-resistant PrP in
paraffin sections; this has been of immense diagnostic value,
particularly for cerebral biopsy specimens and cases where there is no
frozen tissue available for Western blot analysis. Since 2001 the
autopsy rates for sporadic and variant CJD have declined, in keeping
with national trends which have been markedly influenced by the outcome
of the Alder Hey inquiry. This continues to influence the number of
cases examined in 2003, but the figures for both sporadic and variant
CJD are increased in relation to comparable figures for 2002. As before,
the laboratory continues to act as a source of information to a wide
range of professionals involved in health and safety issues relating to
CJD. We are most grateful to all neuropathologists, general pathologists
and their technical, secretarial and autopsy room staff for their
continuing support of the NCJDSU. We are also grateful to the relatives
of patients with CJD for allowing us to study this group of devastating

4.2 Surveillance and Workload during 2003

A detailed breakdown of laboratory activities is summarised in Table 8
. These demonstrate that the
total number of cases referred to the laboratory from the UK has
increased in comparison with the previous year, with increases in the
numbers of both sporadic and variant CJD cases. Neuropathological
referrals are made from pathologists in the UK and overseas. These
include cases where a preliminary histological diagnosis of CJD has been
made, cases which have undergone autopsy but no histological examination
has been undertaken in a patient with suspected CJD, and cases where a
diagnosis of CJD is thought unlikely, but no specific histological
diagnosis has been made. The latter are usually referred to help the
exclusion of CJD from the differential diagnosis. Material from
DH-funded research projects is also referred to the NCJDSU, particularly
in the UK Haemophilia Study (director: Professor Christine Lee, Royal
Free Hospital, London). In contrast to last year, the most frequent
alternative diagnoses for sporadic CJD is dementia with Lewy bodies,
closely followed by Alzheimer's disease. The pathological features of
variant CJD cases have been reviewed (see publications list). This has
indicated that the neuropathological phenotype of variant CJD has
remained relatively constant over the past 8 years, in terms of the
changes occurring in the central nervous system and in peripheral
tissues, particularly lymphoid tissues. The neuropathological features
of the case of variant CJD associated with blood transfusion were
closely similar to other cases of variant CJD investigated in the

The laboratory is a major contributor to the World Health Organisation
TSE Diagnostics Working Group, and continues to act as an international
reference centre for the diagnosis of CJD.

4.3 Protein Laboratory

CNS Tissues

Prion protein isotyping is carried out as a routine diagnostic test on
all suspected cases of CJD where fresh brain tissue is received by the
NCJDSU. Small quantities of cerebral cortex are homogenized, treated
with proteases and the size and abundance of the three PrPres glycoforms
determined by Western blot analysis. The prion protein isotype is
classified as type 1 if the nonglycosylated form has a molecular weight
of ~21kDa or type 2 if the nonglycosylated form has a molecular weight
of ~19kDa. The suffix B is used to denote a PrPres isotype where the
diglycosylated band predominates. The remaining type 2 cases where the
diglycosylated band does not predominate are termed type 2A. The type 2B
isotype has previously found to be characteristic of variant CJD (Figure
12 ).

A total of 57 UK cases with frozen tissue were received and analysed in
2003, representing a 50% increase in the number of cases referred for
analysis in 2001 and 2002. The results of these analyses are shown in
Table 9. When the sporadic
and variant cases are sub-classified according to the PrPres type and
the PRNP codon129 genotype, the following results were obtained (Table
10 ).

Four requests for Western blot analysis were also received from non-UK
referrals. Three of these were found to have detectable PrPres in CNS
specimens, while the fourth was a PrPres negative tonsil biopsy.

Methodological Note: Previously all Western analysis has used the
SDS-PAGE and Western transfer method described in Ironside et al (2000)
which was itself based on that described in Collinge et al (1996). This
year the hand-poured Bio-Rad gel format was replaced with pre-cast
NuPAGE 10% Bis-Tris gels (Invitrogen Corporation, Paisley, UK) which
were run and transferred according to the manufacturer's instructions.
Sample preparation and post-transfer steps remained unaltered.

The results of a long-term study of the PrPres type and PRNP codon 129
in the UK sporadic CJD population (Head et al, in press) allow us to
compare this year's data with that from the period 1991-2002. The
results are broadly similar but show an apparent under-representation of
MM1, MM2, VV2 subtypes and an over-representation of MV1, MV2 and VV1
subtypes (Figure 13 )
which may reflect random variation occurring in these small groupings.

The presence of PrPres in peripheral tissues, particularly in the
lymphoreticular system, has been thought to be a defining feature of
variant CJD. Our Western blot and immunohistochemical studies confirm
this and have been published recently in The American Journal of
Pathology (Head et al 2004). Two further articles describing the
presence and distribution of PrPres in the eye (Head et al 2003a) and in
the oral cavity (Head et al 2003b) have also been published. The Western
blot results are shown in condensed form in Table 11
along with results from a
more recent article on the central nervous system (Head et al, Ann
Neurol, in press).

These observations are unlikely to be definitive since PrPSc detection
methods of increased sensitivity continue to be developed and applied by
us and by others. It can therefore be expected that the tissue
distribution of PrPSc (and by inference infectivity) in variant CJD will
widen and secondly that lower levels of PrPSc in peripheral tissue in
sporadic CJD may also be found.

4.4 Brain banking activities

The bank of fixed and frozen tissues in the surveillance unit was used
extensively in 2003 for diagnostic and collaborative research purposes
with colleagues in the UK and overseas. A brain bank manager was
appointed in 2002, who has primary responsibility for this unique
resource. The activities of the Bank comply with current guidelines from
MRC and the Royal College of Pathologists. The Bank and its activities
are overseen by the Tissue Management Group established by the
Department of Health.

4.5 Molecular Genetics

Familial CJD

Sixty-two cases of familial CJD (excluding cases of GSS) have been
identified since 1970 by the NCJDSU (these data are incomplete as formal
investigation of familial CJD in the UK is undertaken by the National
Prion Clinic in London). Of the 62 cases, 57 were resident in England
and 5 were resident in Wales. Twelve cases are still alive. Thirty-three
of the cases had insertions in the coding region of the PrP gene, 15
carried the mutation at codon 200 (Glu-Lys), 2 at codon 178 (Asp-Asn,
both with methionine at codon 129, ie FFI), one at codon 117 (Ala-Val)
and one at codon 210 (Val-Ile). Ten were identified as familial on the
basis of relatives known to have had CJD. The mean age at death was 55
years (range 31 - 77 years).

Codon 129 distribution in sporadic CJD

The distribution of codon 129 genotypes in sporadic CJD has been
analysed since the inception of the Unit in 1990. The overall
distribution of codon 129 genotypes in sporadic CJD is 66% MM, 17% MV,
17% VV) (see Table 12 ).
There appears to be evidence (p=0.022) of a change in the codon 129
distribution in sporadic CJD between the periods 1990-1995 and
1996-2003. The explanation for this remains unclear and is being
investigated further. It should be noted that not all cases are
genotyped (data available on 63%) and, therefore, the codon 129
distribution may reflect selection bias.

Codon 129 distribution in vCJD

All cases for whom genetic data are available (123) were methionine
homozygotes at codon 129 of the PrP gene.

The genetic laboratory undertakes genetic analysis on a national and
international basis.

4.6 CSF 14-3-3 and other brain-specific proteins

The laboratory received 283 CSF samples from January 2003 - December
2003. Of these, 111 were from patients who were referred to the NCJDSU
as suspect cases of CJD and 152 were from patients who did not have
clinical features to merit formal referral as a suspect case of CJD, but
in whom the diagnosis remained a possibility. These are termed "CSF only
referrals". The remaining CSF samples were sent to the laboratory from
hospitals outside the United Kingdom. The origin and numbers of these
samples is given in Table 13.

The number of CSF-only referrals have increased by 55% whilst the number
of CSF samples from patients referred to the NCJDSU have increased by
21%. The numbers of CSF samples referred from non-UK countries have
halved as Sweden has established a CSF 14-3-3 diagnostic service in

CSF 14-3-3 results in CSF samples received from CJD patient

Of the 111 CSF samples from patients referred to the NCJDSU with
suspected CJD, five were blood-stained and unsuitable for 14-3-3
analysis. The CSF 14-3-3 results in the remaining 106 patients are shown
in Table 14 .

Two patients with definite sporadic CJD had a negative CSF 14-3-3. The
clinical course in one was atypical and the disease duration was 42
months. The codon 129 genotype was MV and neuropathological examination
showed the presence of protease-resistant PrP with a type 2A isoform.
The second patient is still alive 13 months after onset.

Three of the 31 patients with probable sporadic CJD are still alive,
seven patients have died and are awaiting neuropathological examination
and the remaining 21 patients have died without neuropathological
confirmation of sporadic CJD. Of the patients who died without
neuropathological confirmation of sporadic CJD, four had EEG traces that
were considered typical for sporadic CJD whilst 14 had either EEG traces
that were not considered typical or EEG traces that were not reviewed by
the NCJDSU. Three EEGs are awaiting review. Therefore 14 of the 21
patients with probable sporadic CJD who died without neuropathological
confirmation have been classified as probable on the basis of the 14-3-3
result without independent EEG support.

There were 15 patients who were referred as suspect cases of CJD who had
a positive 14-3-3 but were not diagnosed with CJD. In seven patients the
diagnosis of CJD remains a possibility (one patient has died without
undergoing post mortem and 6 cases are still under review). Of the
remaining 8 cases, 3 had Alzheimer's disease, 2 patients improved, one
patient had vasculitis, one patient had central pontine myelinolysis and
one patient had Lewy body dementia.

Of the 12 patients with probable variant CJD (a classification made
independent of 14-3-3), six were positive for 14-3-3.

The sensitivity, specificity, positive and negative predictive values
for CSF 14-3-3 in the diagnosis of sporadic and variant CJD are given in
Table 15 .

CSF 14-3-3 in CSF only referrals

One hundred and fifty-two CSF samples were received as CSF only
referrals and constituted 50% of the total number of samples received.
As seven CSF sample was blood-stained only 145 were available for
analysis. Twenty-three of the 145 CSF samples analysed for CSF 14-3-3
were positive. The diagnoses these cases are given in Table 16

In addition to the above samples, a set of 19 serial CSF samples were
received from a patient undergoing pentosan polysulphate treatment.


The presence of 14-3-3 in the CSF in 14 patients with clinical features
of sporadic CJD who died without post mortem and without typical EEG
changes, has enabled these patients to be classified as probable
sporadic CJD. Without CSF 14-3-3 analysis these patients would have
remained as possible cases of sporadic CJD and would not have entered
into the annual sporadic CJD figures. As sporadic CJD is a rare disease
these 14 cases constitute a significant proportion, approximately 25%,
of the annual number of cases.

The number of CSF samples received have increased, with the largest
increase being samples received from patients without enough signs or
symptoms to be considered a suspect case of CJD. This suggests that CSF
14-3-3 is increasingly being used as a screening test for CJD.

The specificity of 14-3-3 for sporadic CJD has decreased. There are
three possibilities for this, one is that this is a chance occurrence,
secondly that a change in the analytical and interpretative process has
increased the number of false positives detected. There have been no
such changes and there is no concomitant increase in the detection of
false positives in patients with suspected variant CJD. Thirdly it is
possible that the population of patients with suspected sporadic CJD has
changed with an increasing number of patients with conditions other than
CJD that are associated with positive 14-3-3 being referred to the unit
as suspect sporadic cases. This situation will be closely monitored over
the next year.


The National CJD Care team is based within the National CJD Surveillance
Unit and was formed in response to concerns regarding the care of CJD
patients. An initial National Care Co-ordinator post was established in
February 2000 and in September 2001 the National CJD Care Team was
formed. Since March 2003 the team consists of two co-ordinators and a

The role of the National CJD Care Team is to provide advice on all forms
of CJD to the patients, their family and professional carers, including
information on the clinical features, diagnostic procedures and
prognosis. The National Care Co-ordinators are available to assist with
co-ordination of care locally, by providing the necessary education and
support to local health professionals involved in care of CJD patients.
They are available to visit patients and their families and will provide
advice on specific management issues such as symptom control. The team
are supported by neurologists within the unit.

When a referral has been made to the NCJDSU of a suspect case of CJD,
the co-ordinator makes direct contact with the family and offers the
opportunity to meet and to assist with care interevention. Referrals are
also made to the Care Team from the National Prion Clinic at St. Mary's
Hospital and Leah Davidson, who co-ordinates the care of iatrogenic CJD
cases. Once contact is made, the co-ordinator can meet with the patient
and family on a regular basis, depending on need, to provide support and
to assist with co-ordination of local health and social care
professions. Post bereavement support is offered to the family after the
patient dies or assistance given with accessing more specialised

The National CJD Care Team is in close liaison with the Department of
Health and provides access to the CJD Care Package, which is a sum of
money available to assist local authorities with the care of CJD
patients. The National CJD Care Team is also responsible for management
of the CJD Advice Network. This is a group of Health and Social Services
Professionals who have had experience of working with CJD and are
available to share their experience and provide advice with other
professionals. Audit is performed on contacts made to the Network and
members will be kept up to date with recent developments within CJD with
a six monthly newsletter.

From the establishment of the first National Care Co-ordinator post
until 31st December 2003, the co-ordinators have been in conact with,
and/or provided access to care funds, to 67 variant cases, 62 sporadic
cases, 14 familial cases and 6 iatrogenic cases. The Care Team is
currently involved with 8 variant cases, 9 sporadic cases and 9 familial
cases. The number of variant CJD cases has remained constant over the
last 2 years, however increased referrals of sporadic, familial and
iatrogenic patients have led to an increased workload for the care team
and to increased expenditure from the CJD Care Fund.

The National Care Co-ordinators undertook 267 patient visits and case
conferences during 2003 compared to 194 in 2002 (Table 17
and Table 18
). In addition, 35 teaching
sessions were provided to professionals involved in the provision of
care to CJD patients. A further 17 talks/teaching sessions were provided
to various organisations/conferences.

Expenditure from the National CJD Care Fund has increased and to the end
of December 2003 a total of £630,653 has been spent, comprising £322,575
in 2003 compared with £243,476 in 2002 and £64,602 in 2001. A breakdown
of expenditure during 2003 is shown in Table 19.

There is a difference in expenditure between the different disease
subtypes which reflects the variability of their progression. With
familial/genetic CJD cases generally having a much longer duration, this
enables local services to plan ahead for the patients' changing needs.
However, in relation to sporadic CJD cases, by the time the
co-ordinators are referred patients with this disease subtype, they are
usually in the advanced stages of the condition and will have a much
shorter prognosis.



Andrews NJ, Farrington CP, Ward HJT, Cousens SN, Smith PG,
Molesworth AM, Knight RSG, Ironside JW, Will RG. Deaths from
variant Creutzfeldt-Jakob disease in the UK. Lancet 2003;361:751-752.


Armstrong RA, Cairns NJ, Ironside JW, Lantos PL. Does the
neuropathology of human patients with variant Creutzfeldt-Jakob
disease reflect haematogenous spread of the disease? Neurosci Lett
2003; 348: 37-40.


Armstrong RA, Lantos PL, Ironside JW, Cairns NJ. Differences in
the density and spatial distribution of florid and diffuse plaques
in variant Creutzfeldt-Jakob disease (vCJD). Clin Neuropathol
2003; 22: 209-214.


Armstrong RA, Lantos PL, Ironside JW, Cairns NJ. Spatial
correlation between the vacuolation, prion protein deposition and
surviving neurones in patients with variant Creutzfeldt-Jakob
disease (vCJD). J Neural Transm 2003; 110: 1303-1311.


Barr J, Harris N, Chapman K, Head MW, Fraser J. A proteomics
(SELDI) approach to disease markers for TSEs. International
Conference on Transmissible Spongiform Encephalopathies Book of
Abstracts, 49. 2003.


Barron R, Jamieson E, Thomson V, Melton D, Will R, Ironside JW,
Manson J. The 101 L mutation in murine PrP can alter transmission
across three species barriers. In: Fraser JR (ed): Recent Progress
in Transmissible Spongiform Encephalopathies. Neuropathol and Appl
Neurobiol 2003; 29(5): 208. (abstract)


Bird SM, Will RG. Dedication, yet uncertainty. Statistical Methods
in Medical Research 2003;12:175-176.


Bishop MT, Will RG, Aitchson L, Baybutt H, Gall E, Hart P, Tuzi N,
Manson JC. Novel gene targeted transgenic mice as models for codon
129 disease association in Creutzfeldt-Jakob disease. Munich
Conference, 2003 (abstract).


Boelle P-Y, Thomas G, Valleron A-J, Cesbron J-Y, Will R. Modelling
the epidemic of variant Creutzfeldt-Jakob disease in the UK based
on age characteristics: updated, detailed analysis. Statistical
Methods in Medical Research 2003;12:221-233.


Brandel J-P, Preece M, Brown P, Croes E, Laplanche J-L, Agid Y,
Will R, Alperovitch A. Distribution of codon 129 genotype in human
growth hormone-treated CJD patients in France and the UK. Lancet


Brown P, Bradley R, Detwiler L, Dormont D, Hunter N, Wells GAH,
Wilesmith J, Will R, Williams E. Transmissible spongiform
encephalopathy as a zoonotic disease. Brussels, 2003.


Budka H, Head MW, Ironside JW, Gambetti P, Parchi P, Zeidler M,
Tagliavini F. Sporadic Creutzfeldt-Jakob disease. In: Dickson DW
(ed). Neurodegeneration: The Molecular Pathology of Dementia and
Movement Disorders. Basel, ISN Neuropath Press; 2003, pp287-297.


Collie DA, Summers DM, Sellar RJ, Ironside JW, Cooper S, Zeidler
M, Knight R, Will RG. Diagnosing variant Creutzfeldt-Jakob disease
with the pulvinar sign: MR imaging findings in 86
neuropathologically confirmed cases. Am J Neuroradiol


Cousens S, Everington D, Ward HJT, Huillard J, Will RG, Smith PG.
The geographical distribution of variant Creutzfeldt-Jakob disease
in the UK: what can we learn from it? Statistical Methods in
Medical Research 2003;12:235-246.


Cousens SN, Ward HJT, Everington D, Will RG, Smith PG. The
geographical distribution of vCJD in Great Britain. In: Fraser JR
(ed): Recent Progress in Transmissible Spongiform
Encephalopathies. Neuropathol and Appl Neurobiol 2003; 29(5): 208.


Everington D, Ward HJT, Cousens SN, Will RG. Population density
and variant Creutzfeldt-Jakob disease (CJD). International
Conference on Transmissible Spongiform Encephalopathies Book of
Abstracts, 61. 2003.


Fagge TF, Barclay GR. Analysis of PrP expression in blood of CJD
patients by DELFIA and flow cytometry. Munich Conference, 2003


Fraser E, McDonagh AM, Head M, Bishop M, Ironside JW, Mann DM.
Neuronal and astrocytic responses involving the serotonergic
system in human spongiform encephalopathies. Neuropathol and Appl
Neurobiol 2003; 29(5): 482-295.


Green AJE, Knight RSG, Ironside JW. Cerebrospinal fluid Tau
protein as a diagnostic test for variant Creutzeldt-Jakob disease.
International Conference on Transmissible Spongiform
Encephalopathies Book of Abstracts, 45. 2003.


Green AJE, Sivtseva TM, Al'bina PD, Osakovsky VL, Vladimirtsev VA,
Zeidler M, Knight RS, Plaonov FA, Shatunov A, Alekseev VP,
Krivosshapkin VG, Masters CL, Gajdusek DC, Goldfarb LG. Viliuisk
encephalomyelitis: intrathecal synthesis of oligoclonal IgG. J
Neuro Sciences 2003;212:69-73.


Head MW, Ritchie D, McLoughlin V, Ironside JW. Investigation of
PrPres in dental tissues in vaiant CJD. Br Dent J 2003; 195(6):


Head MW, Bunn TJR, Bishop M, Knight R, Will R, Ironside JW.
Heterogeneity in the abnormal prion protein isoforms in the brains
of sporadic but not variant Creutzfeldt-Jakob disease patients.
Conference . 2003.


Head MW, Northcott V, Rennison K, Ritchie D, McCardle L, Bunn TJR,
McLennan NF, Ironside JW, Tullo AB, Bonshek RE. Prion protein
accumulation in eyes of patients with sporadic and variant
Creutzfeldt-Jakob disease. Investigative Ophthalmology & Visual
Science 2003; 44(1): 342-346.


Hill AF, Joiner S, Wadsworth JDF, Sidle KCL, Bell JE, Budka H,
Ironside JW, Collinge J. Molecular classification of sporadic
Creutzfeldt-Jakob disease. Brain 2003;126:1333-1346.


Hilton DA, Ironside JW. Screening for variant Creutzfeldt-Jakob
disease. JNNP 2003;74(6):828-829.


Ironside JW. The spectrum of safety : variant Creutzfeldt-Jakob
disease in the United Kingdom. Semin Hematol 2003; 40 (Suppl 3):


Ironside JW. Variant Creutzfeldt-Jakob disease. Vet Res Comm 2003;
27 (Suppl 1): 11-13.


Ironside JW, Head MW, Will RG. Variant Creutzfeldt-Jakob disease;
In: Dickson DW (ed): Neurodegeneration: The Molecular Pathology of
Dementia and Movement Disorders. Basel, ISN Neuropath Press pp


Ironside JW, Head MW. Variant Creutzfeldt-Jakob disease and its
transmission by blood. J Thromb Haemost 2003; 1: 1479-1486.


Ironside JW. What is to be gained from the study of human
transmissible spongiform encephalopathies? In: Fraser JR (ed):
Recent Progress in Transmissible Spongiform Encephalopathies.
Neuropathol and Appl Neurobiol 2003; 29(5): 207 (abstract)


Kapur N, Abbott P, Lowman A, Will RG. The neuropsychological
profile associated with variant Creutzfeldt-Jakob disease. Brain
2003; 126(12): 2693-2702.


Knight R. Variant CJD: the present position and future
possibilities. Int J Pediatric Otorhinolaryngology 2003;67S1:S81-S84.


Knight R, Will B. Prion Diseases; in: Caplan LR, Dichgans J,
Diener HC, Kennard C (eds). Neurological Disorders: Course and
Treatment. USA, Academic Press pp 707-720.


Korth C, Kaneko K, Groth D, Heye N, Telling G, Mastrianni J,
Parchi P, Gambetti P, Will R, Ironside J, Tremblay P, DeArmond SJ,
Prusiner SB. Abbreviated incubation times for human prions in mice
expressing a chimeric mouse-human prion protein transgene. PNAS
2003;100 (8):4784-4789.


Kovacs GG, Koperek O, Ritchie D, Ironside JW, Wick G, Budka H. Do
mobile cells contribute to prion transport? In: Fraser JR (ed):
Recent Progress in Transmissible Spongiform Encephalopathies.
Neuropathol and Appl Neurobiol 2003; 29(5): 207. (abstract)


Lim R, Dhillon B, Kurian KM, Aspinall PA, Fernie K, Ironside JW.
Retention of corneal epithelial cells following Goldmann
tonometry: implications for CJD risk. Br J Ophthalmol


Manson J, Barron RM, Baybutt H, Tuzi NL, Jamieson E, Gall E,
Aitchison L, Thomson V, McConnell I, Moore R, Melton DW, Ironside
J, Will R. Targeting the PrP gene. International Conference on
Transmissible Spongiform Encephalopathies Book of Abstracts, 52.


McCormack J, Baybutt H, Everington D, Will R, Ironside J, Manson
J. Polymorphism in the regulatory regions of the PRNP gene
associated with susceptibility to CJD. International Conference on
Transmissible Spongiform Encephalopathies Book of Abstracts, 51.


Molesworth AM, Gill ON, Ward H, Everington D, Cousens S.
Investigating geographically associated cases of variant
Creutzfeldt-Jakob disease in the United Kingdom. Health Protection
Agency Inaugral Conference, Warwick, September 2003.


Nurmi MH, Bishop M, Strain L, Brett F, McGuigan C, Hutchinson M,
Farrell M, Tilvis R, Erkkila S, Simell O, Knight R, Haltia M. The
normal population distribution of PRNP codon 129 polymorphism.
Acta Neurol Scand 2003; 108: 374-378.


Lowman A, Everington D, Ward H, Will RG. Medical and surgical
interventions in the first 100 cases of variant Creutzfeldt-Jakob
disease in the UK - a risk factor for the development of the
disease. Association of British Neurologists, 2003.


Paramithiotis E, Pinard M, Lawton T, LaBoissiere S, Leathers VL,
Wen-Quan Z, Estey LA, Lamontgne J, Lehto MT, Kondejewski LJ,
Francoeur GP, Papadopoulous M, Haghighat A, Spatz SJ, Head M, Will
R, Ironside J, O'Rourke K, Tonelli Q, Ledebur HC, Chakrabartty A,
Cashman NR. A prion protein epitope selective for the
pathologically misfolded conformation. Nature Medicine 2003.


Pepys MB, Bybee A, Booth DR, Bishop MT, Will RG, Little AM,
Prokupek B, Madrigal JA. MHC typing in variant Creutzfeldt-Jakob
disease. Lancet 2003;361:487-489.


Petzold A, Jenkins R, Watt HC, Green AJE, Thompson EJ, Keir G, Fox
NC, Rossor MN. Cerebrospinal fluid S100B correlates with brain
atrophy in Alzheimer's disease. Neurosci Lett 2003; 336: 167-170.


Petzold A, Keir G, Green AJE, Giovanonni G, Thompson EJ. A
specific ELISA for measuring neurofilament heavy chain
phosphoforms. J Immunol Methods 2003; 278(102): 179-190.


Richard M, Biacabe A-G, Streichenberger N, Ironside JW, Mohr M,
Kopp N, Perret-Liaudet A. Immunohistochemical localization of
14.3.3 zeta protein in amyloid plaques in human spongiform
encephalopathies. Acta Neuropathol (Berl) 2003; 105(3): 296-302.


Ritchie D, Ironside J. Advances in the immunodetection of prion
protein in peripheral tissues of variant CJD. International
Conference on Transmissible Spongiform Encephalopathies Book of
Abstracts, 45. 2003.


Satoh K, Muramoto T. Tanaka T, Kitamoto N, Ironside JW, Nagashima
K, Yamada M, Sato T, Mohri S, Kitamoto T. Association of an 11-12
kDa protease-resistant prion protein fragment with subtypes of
dura graft-associated Creutzfeldt-Jakob disease and other prion
diseases. J Gen Virol 2003; 84: 2885-2993.


Smith AJ, Bagg J, Ironside JW, Will RG, Scully C. Prions and oral
cavity. J Dent Res 2003;82(10):769-775.


Taguchi Y, Mohri S, Ironside JW, Muramoto T, Kitamoto T. Humanized
knock-in mice expressing chimeric prion protein showed varied
susceptibility to different human prions. Am J Pathol 2003; 163:


Ward H, Cousens S, Everington D, Lowman A, Smith-Bathgate B,
Leitch M, Cooper S, Knight R, Smith P, Will R. Vaccines and
Creutzfeldt-Jakob disease (CJD). International Conference on
Transmissible Spongiform Encephalopathies Book of Abstracts, 57.


Ward HJ, Head MW, Will RG, Ironside JW. Variant Creutzfeldt-Jakob
disease. Clin Lab Med 2003;23(1):87-108.


Ward HJT, Everington D, Sanchez-Juan P, Smith A, Cooper S, Heath
C, Knight RSG, Will RG. Secondary transmission of variant
Creutzfeldt-Jakob disease? International Prion Conference, Munich


Weller B, Knight R, Will R. An overview of the care issues for
Creutzfeldt-Jakob disease. European J Palliative Care 2003;10(1):5-8.


Will RG. Human prion diseases; in: Warrell DA, Cox TM, Firth JD,
Benz EJJ (eds): Oxford Textbook of Medicine. Oxford, Oxford
University Press pp 1046-1053.


Will RG. The biology and epidemiology of variant Creutzfeldt-Jakob
disease. Bulletin et Memoires de l'Academie Royale de Medicine de
Belgique 2003;158:250-257.


Will RG. Variant Creutzfeldt-Jakob disease and bovine spongiform
encephalopathy: current status; in: Ragaini R (ed): International
Seminar on Nuclear War and Planetary Emergencies - 27th Session -
2002. Singapore, World Scientific Publishing Co Pte Ltd pp 668-673.


Will RG, Knight RSG, Spencer MD. Neuropsychiatric aspects of
variant Creutzfeldt-Jakob disease.; in: Ragaini R (ed):
International Seminar on Nuclear War and Planetary Emergencies -
27th Session - 2002. Singapore, World Scientific Publishing Co.
Pte. Ltd. pp 674-682.


Will RG. Progress with Prions. Transfusion Medicine 2003; 13(1):
2. (abstract)


Will RG. Variant CJD - what are the risks? In: Fraser JR (ed):
Recent Progress in Transmissible Spongiform Encephalopathies.
Neuropathol and Appl Neurobiol 2003; 29(5): 208. (abstract).


Will RG. Acquired prion disease: iatrogenic CJD, variant CJD,
kuru. Br Med Bull 2003; 66: 255-265.


Staff based at the National CJD Surveillance Unit, Western General
Hospital, Edinburgh

Professor JW Ironside

Professor RG Will

Dr RSG Knight

Professor JE Bell, Dr C Smith

Dr H Ward

Dr C Butler

Dr S Cooper

Dr C Heath

Mrs B Smith-Bathgate

Ms M Leitch

Mr G McLean, Ms F Barnett

Dr MW Head

Dr A Green

Mr M Bishop

Ms J Mackenzie

Mr A Hunter

Ms D Everington

Mr N Attwood

Ms D Ritchie

Mrs L McCardle

Mrs M Le Grice, Ms S Lowrie, Mrs M Nicol

Ms C-A Mackenzie

Ms L Taylor, Ms V Jones

Ms J Esteve, Ms H Yule

Ms C Goodall

Ms K Connolly

Ms E Kouverianou

Mrs V McLoughlin

Ms P Lorenco

Dr M Jones

Ms K Forrest, Ms A Honeyman

Ms S Smith, Ms A Roberts

Mrs S Macdonald

Ms A Davies, Ms K Sewell

Staff funded by Other Sources

Ms T Lindsay (BIOMED2)

Mrs C Donaldson (BIOMED2)

Mr T Fagge (CSO)

Dr A Peden (EU)

Director, NCJDSU

Consultant Neurologist

Consultant Neurologist

Honorary Consultants in Neuropathology

Consultant Epidemiologist

Clinical Research Fellow

Research Registrar

Research Registrar

Nurse Practitioner

Research Nurse

National Care Co-Ordinators

Senior Research Fellow

Senior Clinical Scientist

Molecular Biologist

Study Co-Ordinator

Business Manager


Database Manager

Research Assistant

Chief Biomedical Scientist

Senior Biomedical Scientists

Tissue Bank Manager

Research Technicians

Research Technicians

Research Technician

Research Technician

Research Technician

Laboratory Technician

Research Associate

Postdoctoral Research Fellow

Secretariat - Neuropathology

Secretariat - Clinical

Secretariat - Care Team

Secretariat - Case-control study

European Study Co-Ordinator


Research Associate

Postdoctoral Research Fellow

Epidemiological and Statistical Support, London School of Hygiene
and Tropical Medicine

Professor P Smith

Professor S Cousens

Epidemiologist, Department of Infectious and Tropical Diseases

Statistician, Department of Infectious and Tropical Diseases


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