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From: TSS ()
Subject: Re: Neuropathology of variant CJD James W. Ironside 2002
Date: August 12, 2005 at 1:28 pm PST

CJD FARMERS WIFE 1989

http://www.bseinquiry.gov.uk/files/yb/1989/10/13007001.pdf

http://www.bseinquiry.gov.uk/files/yb/1989/10/13003001.pdf

20 year old died from sCJD in USA in 1980 and a 16 year
old in 1981. A 19 year old died from sCJD in
France in 1985. There is no evidence of an iatrogenic
cause for those cases....

http://www.bseinquiry.gov.uk/files/yb/1995/10/04004001.pdf

CJD in 3 farmer a cause for concern

http://www.bseinquiry.gov.uk/files/yb/1995/01/00002001.pdf


cjd in farmer who has had a case of BSE in his beef suckler herd.
Three previous cjd cases have been confirmed in dairy farmers whose herds had had cases of BSE...


http://www.bseinquiry.gov.uk/files/yb/1995/10/00005001.pdf


cover-up of 4th farm worker ???

http://www.bseinquiry.gov.uk/files/yb/1995/10/23006001.pdf

http://www.bseinquiry.gov.uk/files/yb/1995/10/20006001.pdf

CONFIRMATION OF CJD IN FOURTH FARMER

http://www.bseinquiry.gov.uk/files/yb/1995/11/03008001.pdf

now story changes from;

SEAC concluded that, if the fourth case were confirmed, it would be
worrying, especially as all four farmers with CJD would have had BSE
cases on their farms.

to;

This is not unexpected...

was another farmer expected?

http://www.bseinquiry.gov.uk/files/yb/1995/11/13010001.pdf

4th farmer, and 1st teenager

http://www.bseinquiry.gov.uk/files/yb/1996/02/27003001.pdf

2. snip...
Over a 5 year period, which is the time period on which the advice
from Professor Smith and Dr. Gore was based, and assuming a
population of 120,000 dairy farm workers, and an annual incidence
of 1 per million cases of CJD in the general population, a
DAIRY FARM WORKER IS 5 TIMES MORE LIKELY THAN
an individual in the general population to develop CJD. Using the
actual current annual incidence of CJD in the UK of 0.7 per
million, this figure becomes 7.5 TIMES.

3. You will recall that the advice provided by Professor Smith in
1993 and by Dr. Gore this month used the sub-population of dairy
farm workers who had had a case of BSE on their farms -
63,000, which is approximately half the number of dairy farm
workers - as a denominator. If the above sums are repeated using
this denominator population, taking an annual incidence in the general
population of 1 per million the observed rate in this sub-population
is 10 TIMES, and taking an annual incidence of 0.7 per million,
IT IS 15 TIMES (THE ''WORST CASE'' SCENARIO) than
that in the general population...

http://www.bseinquiry.gov.uk/files/yb/1995/01/31004001.pdf


SEAC have reviewed the situation following the confirmation of CJD in a fourth farmer in whose herd a case of Bovine Spongiform Encephalopathy (BSE) was diagnosed. They have concluded that although there is a stitistical excess of CJD cases in cattle farmers, compared with the general population, the absolute risk of contracting CJD, even for cattle farmers, is extremely low at about 2 cases per million per year...

http://www.bseinquiry.gov.uk/files/yb/1995/12/05018001.pdf

The Committee has recently considered the cases of CJD in teenagers in the UK. They advised that it was not possible to draw any conclusions, as confirmed cases of CJD have been found in the same group in other countries...

http://www.bseinquiry.gov.uk/files/yb/1995/12/07017001.pdf

CONFINDENTIAL
SUSPECT CASE OF CJD IN AN ABATTOIR WORKER

http://www.bseinquiry.gov.uk/files/yb/1995/12/22007001.pdf


TABLE CJD YOUNG CASES 13/11/95

(check out clinical features etc...tss)

http://www.bseinquiry.gov.uk/files/yb/1995/11/13011001.pdf

SPORADIC CJD TABLE

http://www.bseinquiry.gov.uk/files/yb/1996/03/04003001.pdf

Dr J E Bell and Dr J W Ironside Pathology Reports from CJD Surveillance Unit

http://www.bseinquiry.gov.uk/files/yb/1996/01/04011001.pdf


http://www.bseinquiry.gov.uk/files/yb/1996/01/04011001.pdf

cjd 28 year old 1981

http://www.bseinquiry.gov.uk/files/yb/1996/01/11010001.pdf

unusual cjd

http://www.bseinquiry.gov.uk/files/yb/1996/01/12009001.pdf

FURTHER TWO INCIDENCE OF CJD AROUND DEVIZES

http://www.bseinquiry.gov.uk/files/yb/1995/11/01023001.pdf

PATHOLOGICAL REPORT

http://www.bseinquiry.gov.uk/files/yb/1996/02/26005001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/02/26006001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/03/05004001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/03/20051001.pdf

31 year old male cjd some parkinsonian features

http://www.bseinquiry.gov.uk/files/yb/1996/03/22018001.pdf

Professor John Collinge very concerned about BSE in sheep

http://www.bseinquiry.gov.uk/files/yb/1996/03/26001001.pdf

CJD INQUEST RESTRICTED

http://www.bseinquiry.gov.uk/files/yb/1996/02/06009001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/02/06016001.pdf

CJD 27 YEAR OLD POLISH WOMAN

http://www.bseinquiry.gov.uk/files/yb/1996/03/06003001.pdf

NEW Information: Bob Wills and associateds at SEAC meeting on Friday reported indentifying a new (amyloid plaque-rich) type of CJD disease (clinically and pathologically) occuring in under fourty years olds over the last two (check accuracy of this time period - at one stage someone quoted six months on friday but I am not clear why according to the data) years. This could be called 'atypical CJD (A. CJD) ...

http://www.bseinquiry.gov.uk/files/yb/1996/03/08007001.pdf


http://www.bseinquiry.gov.uk/files/yb/1996/03/13006001.pdf

SEAC and 10 cases of CJD under age 42

http://www.bseinquiry.gov.uk/files/yb/1996/03/20018001.pdf

DOH still in denial

http://www.bseinquiry.gov.uk/files/yb/1996/03/20020001.pdf

unavoidable accumulation of cases

http://www.bseinquiry.gov.uk/files/yb/1996/04/29001001.pdf


term new variant CJD was born

http://www.bseinquiry.gov.uk/files/yb/1996/04/02001001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/04/02001001.pdf

http://www.bseinquiry.gov.uk/files/yb/1996/07/01001001.pdf


cjd cases uk 1985 - 1996

http://www.bseinquiry.gov.uk/files/yb/1996/06/26005001.pdf

cjd surveillance unit 4th annual report

Q1 How do you explain a 50% increase in cases of sporadic CJD in one year (from 35 in 1993 to 53 in 1994) and a 100% increase since 1990 (26 cases)? (answer same old BSeee...tss)

snip...

A4 WE do not propose to make cjd reportable.

snip...

Q5 The report reveals a strong statistical association between a lifetime history of eating venison and the risk of developing CJD. There was a similar association with venison last year. IS venison safe to eat?

A5 Venison is perfectly safe to eat. ...

snip...

Q7 The report draws attention to statistical associations with other meats lamb, beef, brain, and sweetbreads. Are you concerned about these?

A 7: These associations, all of which were much less strong than venison, leave us with the same problems of interpretation.

snip...

CJD in teenagers
Q16: How many cases of sporadic CJO in teenagers have occurred in the UK?

A16: The recent case of CJD in a 19 year old is the first confirmed case of
sporadic CJD in a teenager in the UK.

Q17: What about Vicky Rimmer? Doesn't she also have CJD?

A17: There has been no confirmation that this patient is suffering from CJD.

Q18: Given that you cannot explain why a 19-year old should die from CJD, isn't
it possibleMikely that BSE is the cause?

A18; There is absolutely no evidence to support a link between this case and BSE:

- although the cause of most cases of CJD is unknown, there is no scientific
evidence to link the disease with meat eating;

- sporadic CJD in young people is extremely rare, but it is by no means
unique. In 1981, a 16 year old died from CJD in the US, a 20 year old died
in 1980 also in the US, and a 19 year old died from the disease in France in
1985. Creutzfeldt's first patient in 1920 was aged 23. There is no
evidence of an iatrogenic cause for those cases nor, of course, was BSE a
factor. It does therefore seem that there are rare cases where CJD is found
in younger age groups than would normally be expected.

- a further case in a 16 year old girl occurred in Canada, but the onset o1
disease was no later than 1986 (when the first cases of BSE were being
reported in the UK). Although the girl was born in the UK, there is no
reason to make a connection with BSE.

96/10.05/1.9


http://www.bseinquiry.gov.uk/files/yb/1996/10/05001001.pdf


TSS

----- Original Message -----
From: "Terry S. Singeltary Sr."
To:
Sent: Thursday, August 11, 2005 10:19 PM
Subject: Neuropathology of variant CJD James W. Ironside 2002


##################### Bovine Spongiform Encephalopathy #####################

Acta Neurobiol. Exp. 2002, 62: 175-182

Correspondence should be

addressed to J.W. Ironside, Email:

J.W.Ironside@ed.ac.uk

Neuropathology of variant

Creutzfeldt-Jakob disease

James W. Ironside, Mark W. Head, Linda McCardle and

Richard Knight

National Creutzfeldt-Jakob Disease Surveillance Unit, University of

Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom

Abstract. The clinical, neuropathological genetic and biochemical features of

variant Creutzfeldt-Jakob disease (vCJD) are compared to the 926 other cases

of suspected CJD referred to the National CJD Surveillance Unit laboratory

from 1990-2001. Histological studies of the central nervous system, lymphoid

tissues and other organs were accompanied by immunocytochemistry for

prion protein (PrP); Western blot analysis of PrP

RES

was performed on frozen

brain tissue. The pathology of vCJD showed relatively uniform morphological

and immunocytochemical characteristics, with PrP accumulation in lymphoid

tissues, but not in other non-neural tissues. PrP

RES

accumulation in vCJD

showed a uniform glycotype pattern distinct from sporadic CJD. All cases of

vCJD were methionine homozygotes at codon 129 of the PrP gene. In view of

the spread of bovine spongiform encephalopathy in Europe and Japan,

continuing surveillance is required for all forms of CJD, with histological and

biochemical analysis of suspected cases to allow an accurate laboratory

diagnosis.

Key words: variant CJD, prion, PrP, BSE, immunocytochemistry, Western

blot, neuropathology

INTRODUCTION

Surveillance of Creutzfeldt-Jakob disease (CJD) was

reinstated in the UK in 1990 in light of the epidemic of

bovine spongiform encephalopathy in cattle and its possible

consequences for humans. Identification of a new

variant form of Creutzfeldt-Jakob disease (vCJD) in 1996

was based on neuropathological and clinical features in a

series of 10 patients (Will et al. 1996) in the UK. At present,

116 cases of vCJD in the UK, six cases in France, one

in Italy and one in Ireland have been identified. All patients

who have undergone analysis of the prion protein

gene (PRNP) were homozygous for methionine at the

polymorphic codon 129. Since the identification of vCJD

in 1996, the evidence for a causal relationship between

vCJD and BSE has been considerably strengthened by

the results of experimental strain typing and biochemical

studies of the disease –associated form of the prion protein

(PrPRES) in wild-type and transgenic mice (Collinge

et al. 1996, Bruce et al. 1997, Scott et al. 2000). Since it is

likely that human exposure to BSE has occurred across

Europe in all prion protein genotypes in the population,

the development of criteria to detect a BSE-related disease

is clearly important for surveillance purposes.

Neuropathological examination is mandatory for the

confirmation of a diagnosis of vCJD(WHO 1996). The

original neuropathological criteria for vCJD are reviewed

in relation to the widening age range of vCJD

patients, with particular attention to the differentiation

of vCJD from other forms of CJD (Will et al. 2000).

These criteria have been applied to all suspected cases of

CJD referred to the National CJD Surveillance Unit up

to the end of 2001, in whom detailed clinical and genetic

data are available.

METHODS

Since 1990, neuropathological review of all cases of

CJD in the United Kingdom has been undertaken at the

National CJD Surveillance Unit. Since the project began,

926 cases of suspected CJD have been examined.

Brain biopsy is seldom performed as a primary investigation

in cases of CJD, and the diagnosis is usually confirmed

after autopsy. Brain tissue from autopsy cases

were fixed in formalin for a minimum of three weeks

prior to brain dissection. The brains were sampled extensively,

including material from the frontal, parietal,

temporal and occipital cortex, the hippocampus, hypothalamus,

thalamus, basal ganglia, midbrain, pons, medulla

and spinal cord (when available). Other organs

were examined histologically if material was available.

All tissue blocks were immersed in 96% formic acid

for one hour prior to routine processing. Sections were

cut at 5 m and stained by conventional histological

techniques and by immunocytochemistry for PrP using

monoclonal antibodies which recognise different PrP

epitopes in a standardised validated technique (Bell et

al. 1997) (see Table I).

Biochemical Analysis

Frozen brain tissue was stored at –80oC and investigated

for the presence of protease-resistant PrP (PrPRES)

by Western blotting as previously described (Ironside et

al. 2000). Briefly, 10% brain homogenates were subjected

to limited proteolysis by digestion with

ProteinaseK(BDH). Electrophoresis was performed on

a 12%T acrylamide SDS-PAGE mini-gel format

(Bio-Rad Laboratories) and proteins transferred to

Hybond ECL membranes (Amersham Parmacia

Biotech). The anti-PrP monoclonal antibody 3F4

(Senetek) was used at a 1:10,000 dilution. Detection

employed ECL+ reagents and Hyperfilm ECL

(Amersham Pharmacia Biotech). PrPRES was visualised

by the inclusion of streptavidin peroxidase at a dilution

of 1:1,500 in the secondary incubation. The molecular

weight was estimated by reference to biotinylated ECL

176 J.W. Ironside

Table I

Details of antibodies used for immunocytochemistry

Antibody Source Dilution Incubation

PrP (KG9) TSE Resource Centre Compton, UK 1:50 overnight at room temperature

PrP (3F4) Senetek, USA 1:2000 overnight at room temperature

PrP (6H4) Prionics, Switzerland 1:3000 overnight at room temperature

molecular weight markers (Amersham Pharmacia

Biotech.).

RESULTS

Pathology of vCJD cases

The clinical and neuropathological features of vCJD

cases in theUKare summarised in Tables II and III. The

brain weight in most cases was within the normal ranges

for age. However, in cases with a lengthy clinical history

(>18 months) there was evidence of cerebellar atrophy

(particularly involving the vermis), with a corresponding

reduction in myelinated axons in the white matter.

Cerebral cortical atrophy was identified in patients who

had survived for 28 months and over. Incidental findings

in vCJD include a small right temporal cavernous

angioma and a small focus of chronic inflammation

within the brainstem in the absence of a widespread

encephalomyelitis.

Spongiform change was focally distributed within

the cerebral cortex in vCJD, particularly in the occipital

and inferior frontal regions. Extensive confluent

spongiform change was not a prominent feature in the

cerebral cortex (in comparison to cases of sporadic

CJD). The hippocampus was relatively spared. In cerebellar

cortex, spongiform change was a prominent feature

in the hemispheres and vermis with no particular

anatomical predilection. Extensive spongiform change

was always present in the caudate nucleus and putamen.

In the thalamus, focal spongiform change involved

many of the anterior and medial nuclei, often in the absence

of plaques. In the hypothalamus, spongiform

change was most evident in the paraventricular and

supraoptic nuclei. Spongiform change was also detected

in the periaqueductal grey matter of the midbrain and the

pontine nuclei, but was not present in either the medulla

or spinal cord.

Table II

Clinical diagnostic criteria for vCJD

I A Progressive neuropsychiatric disorder

B Duration of illness > 6 months

C Routine investigations do not suggest an

alternative diagnosis

D No history of potential iatrogenic exposure

E No evidence of a familial form of TSE

II A Early psychiatric symptomsa

B Persistent painful sensory symptomsb

C Ataxia

D Myoclonus or chorea or dystonia

E Dementia

III A EEG does not show the typical appearance of

sporadic CJDc (or no EEG performed)

B Bilateral pulvinar high signal on MRI scan

IV A Positive tonsil biopsyd

DEFINITE: I A and neuropathological

confirmation of vCJDe

PROBABLE: I and 4/5 of II and III A and III B

OR

I and IV Ad

POSSIBLE I and 4/5 of II and III A

a, depression, anxiety, apathy, withdrawal, delusions; b,

this includes both frank pain and/or dysaesthesia; c, generalised

triphasic periodic complexes at approximately one per

second; d, tonsil biopsy is not recommended routinely, nor in

cases withEEGappearances typical of sporadic CJD, but may

be useful in suspect cases in which the clinical features are

compatible with vCJD and MRI does not show bilateral

pulvinar high signal.

Table III

Diagnostic neuropathological features of vCJD

Cerebral and

cerebellar cortex:

Multiple florid plaques in H&E

sections

Numerous small cluster plaques in

PrP stained sections

Amorphous pericellular and

perivascular PrP accumulation

Caudate nucleus

and putamen:

Severe spongiform change

Perineuronal and axonal PrP

accumulation

Posterior thalamic

nuclei and

midbrain:

Marked astrocytosis and neuronal

loss

Brainstem and

spinal cord:

Reticular and perineuronal PrP

accumulation in grey matter

PrPRES accumulation in lymphoid tissues throughout the

body

Predominance of di-glycosylated PrPRES in central

nervous system and lymphoid tissues

vCJD neuropathology 177

f e

Fig. 1. a, a typical florid plaque in the cerebral cortex (centre) comprises an eosinophilic core with a pale radial periphery, surrounded

by spongiform change. Haematoxylin and eosin; b, low magnification view of PrP immunocytochemistry in the cerebral

cortex in vCJD. In addition to the staining of plaques, multiple amorphous deposits are located around neurones and blood

vessels.KG9antibody; c, immunocytochemistry for PrP in the cerebellar cortex shows large numbers of plaques, particularly in

the granular layer (bottom) with numerous amorphous perineuronal deposits in the granular layer (top). 3F4 antibody; d, PrP deposition

in the basal ganglia shows no plaque structures, but there is perineuronal staining and a linear decoration of axons.KG9

antibody; e, folicular dendritic cells and tingible body macrophages within the germinal centre of a tonsil from a patient with

vCJD stain strongly for PrP. KG9 antibody; f, positive punctate staining for PrP in the spinal dorsal root ganglia in vCJD. As

well as the punctate ganglion cell staining, some satellite cells also appear to be positive. KG9 antibody.

b a

d c

178 J.W. Ironside

In the dorsomedial and posterior regions of the

thalamus there was severe and extensive neuronal loss

with marked astrocytosis (Zeidler et al. 2000). The distribution

of astrocytosis did not relate to the presence of

amyloid plaques or spongiform change. In the midbrain,

severe neuronal loss and astrocytosis occurred in the

colliculi and the periaqueductal grey matter. Neuronal

loss in the cerebral cortex was most evident in the primary

visual cortex, with accompanying astrocytosis.

The neuronal populations in the hippocampus were relatively

well-preserved. All layers of the cerebellar cortex

suffered neuronal loss, particularly the granular cell

layer. In cases with a lengthy clinical course, there was

severe neuronal loss in the cerebral and cerebellar cortex

with marked astrocytosis, consistent with the macroscopic

finding of atrophy in these structures. Neuronal

loss and astrocytosis were not prominent in the pontine

nuclei, but were identified in the inferior olivary nuclei

in the medulla.

Florid plaques were identified on haematoxylin and

eosin stains in all autopsy cases of variant CJD. As previously

reported (Ironside et al. 1996, Ironside 1998),

these structures comprise an eosinophilic central core

with radiating fibrils which are surrounded by a rim or

corona of spongiform change (Fig. 1a). Florid plaques

were most numerous in the occipital cortex, particularly

at the bases of sulci, but were present in all cerebral

lobes in all cortical layers. In the cerebellum, florid

plaques were most easily identified in the molecular

layer, but were also present as aggregates in the granular

layer.Noevidence of an amyloid angiopathy was identified.

Immunocytochemistry

Immunocytochemistry for PrP showed strong staining

of the florid plaques in the grey matter in all areas of

the cerebral and cerebellar cortex, and also revealed numerous

smaller plaques arranged in irregular clusters

(Figs. 1b, c). In addition, there was widespread deposition

of PrP in a pericellular distribution, apparently

around small neurones and astrocytes (Fig. 1d). These

deposits were not visualised on routine stained preparations

but some could be identified on Gallyas silver impregnation.

In the basal ganglia and thalamus, there was

a linear and perineuronal pattern of PrP accumulation

(Fig. 1d), in marked contrast with the lower levels of PrP

accumulation in cases of sporadic CJD which were

methionine homozygotes at codon 129 in the PrP gene.

In the hippocampus, the cornu ammonis showed little

PrP deposition, but there was a dense accumulation in

the dentate fascia and the subiculum. Synaptic and

neuronal positivity was also present in the midbrain,

pons and medulla, particularly in the pontine nuclei. In

the spinal cord, PrP positivity was present in the grey

matter regions at all levels, particularly in the substantia

gelatinosa. No PrP immunoreactivity was detected in

the dura mater. Spinal dorsal root ganglia stained positively

for PrP (Fig. 1f).

Non-CNS tissues

The commonest immediate cause of death in the

vCJD patients was bronchopneumonia. Occasional

cases exhibited mild fatty change in the liver. Routine

morphological analysis of the peripheral nerves revealed

no evidence of a neuropathy. Positive staining

for PrP was identified (as previously reported) in

follicular dendritic cells within germinal centres of the

tonsil (Fig. 1e), appendix, spleen and lymph nodes from

the cervical, mediastinal, para-aortic and mesenteric regions

(Hilton et al. 1999, Ironside et al. 2000). Positive

staining for PrP was also identified in follicular dendritic

cells in Peyer’s patches in the ileum, although

marked autolysis prevented detailed analysis. PrP

immunocytochemistry in other organs (the heart, lung,

skeletal muscle, salivary gland, oesophagus, stomach,

liver, gall bladder, pancreas, kidney, adrenal gland, thyroid

gland, parathyroid gland, bladder, testes, and pelvic

organs (vagina, cervix, uterus, Fallopian tubes and ovaries)

and skin) was all negative in vCJD. In sporadic

CJD, all lymphoid tissues, and other organs showed no

immunoreactivity for PrP.

Biochemistry

In agreement with Parchi et al. (Parchi et al. 1997,

Parchi et al. 1999a) we have only observed the presence

of either one of two different mobility variants in case of

sporadic CJD: the first having a non-glycosylated

PrPRES of ~21 kDa and termed type 1, and the other of

~19 kDa termed type 2 (Fig. 2, lanes B and C). In our experience,

the PrPRES isoform pattern from patients with

vCJD is closely similar in terms of mobility to the type 2

isoform seen in sporadic CJD. However, as described

previously (Collinge et al. 1996, Parchi et al. 1997, Ironside

et al. 2000) vCJD samples do show a glycoform

profile characterised by the predominance of

vCJD neuropathology 179

di-glycosylated PrPRES, termed type 2B (Parchi et al

1997) (Fig. 2, lane D). The diagnostic use of this type 2B

glycoform pattern is clear since we have found this characteristic

hyperglycosylation in every case of vCJD and

have not yet encountered it in any other case of CJD as

defined by clinical and pathological criteria. Some atypical

cases of sporadic CJD have exhibited clinical features

which initially resembled those of vCJD.

However, on Western blot analysis, none of these atypical

cases show the characteristic type 2B glycosylation

pattern of vCJD.

Comparison of vCJD cases with other cases of CJD

diagnosed in the UK since 1990 showed no major overlap

in terms of neuropathological or biochemical features.

Furthermore, only cases of vCJD have PrPRES

detectable in lymphoid tissues, with a predominance of

the di-glycosylated form of PrPRES in Western blots after

proteaseKdigestion. The laboratory diagnostic features

of vCJD are summarised in Table III.

DISCUSSION

Laboratory studies in vCJD have helped define

neuropathological and biochemical features which are

characteristic and allow a clear distinction from other

forms of CJD. The uniformity of these features is in

marked contrast to sporadic CJD (the main differential

diagnosis), and is consistent with a single strain of

causal agent, namely BSE. The significance of the florid

plaque as a neuropathological hallmark of vCJD is also

confirmed. Florid plaques are not unique to vCJD, and

were first described in transmissions of Icelandic scrapie

to mice (Fraser 1979). They also occur in chronic

wasting disease (Williams et al. 1993), a disorder which

appears unrelated to BSE. Since the initial description of

florid plaques in vCJD, similar lesions were identified in

the brains of macaques following experimental

intracerebral transmission of BSE (Lasmezas et al.

1996). Florid plaques have been recently reported in

small numbers in occasional cases of iatrogenic CJD in

dura mater graft recipients in Japan; however, these iatrogenic

cases do not exhibit any of the other distinguishing

neuropathological features of vCJD (Schimizu et al.

1999). The small cluster plaques in the cerebral and cerebellar

cortex visible on PrP immunocytochemistry

may be a more specific pathological marker for vCJD,

and have not been reported to occur in any other form of

human prion disease. The amyloid plaques occurring in

kuru can be distinguished easily from florid plaques by

their restricted distribution in the cerebral cortex and

cerebellum, their generally smaller size, and the absence

of surrounding spongiform change (McLean et al.

1997).

Ultrastructural studies of florid plaques in vCJD have

revealed a close accumulation of amyloid fibrils in the

central core. One recent study has also revealed neuritic

dystrophy around florid plaques in the cerebellum

(Liberski et al. 2000). This interesting observation requires

further study, since neuritic dystrophy is not evident

on light microscopy (and is not associated with

positive staining for phosphorylated tau). The association

between amyloid plaques and dystrophic neurites in

vCJD is similar to that in Alzheimer’s disease, highlighting

the potential similarities in mechanisms of degeneration

in these disorders.

The pattern of thalamic neuronal loss and gliosis in

vCJD (Zeidler et al. 2000) is distinct from the thalamic

lesions in both fatal familial insomnia (Gambetti et al.

1995) and sporadic fatal insomnia (Mastrianni et al.

1999), which focus on the anterior and medial thalamic

nuclei. The clinical significance of this observation is of

potential interest in relation to the sensory abnormalities

experienced by patients with vCJD, which do not occur

in neuroanatomical dermatomes and may therefore represent

thalamic pain. Furthermore, this pathological

Fig. 2. A, western blot analysis of protease resistant prion protein

(PrPRES) in post-mortem cerebral cortex from patients

without Creutzfeldt-Jakob disease; B, C, with sporadic

Creutzfeldt-Jakob disease, or D, with variant

Creutzfeldt-Jakob disease. PrPRES is absent from the control

case (A) but is present in the cases of Creutzfeldt-Jakob disease

(B, C, D). The PrPRES isotype found in sporadic

Creutzfeldt-Jakob disease has either a 21 kDa non-

-glycosylated PrPRES (B) or a 19 kDa non-glycosylated

isoform with the predominance of the diglycosylated isoform

(marked with an asterisk in D).

180 J.W. Ironside

finding correlates with the anatomical distribution of the

"pulvinar sign" on MRI in vCJD (Zeidler et al. 2000).

The epidemiological features of vCJD indicate that a

dietary route of exposure is the most likely route of exposure

to the BSE agent in the cases identified so far

(Will et al. 1996), particularly in a cluster of 5 cases

identified in a 4 year period in a rural region of England.

However, the identification of other routes of exposure

to BSE in future cases cannot be excluded and is part of

an ongoing case-control study. In the limited data available

on kuru (another acquired human prion disease

which was probably transmitted by the oral route),

codon 129 genotype did not appear to exert a major influence

on the clinical or neuropathological features of

the disease in one series (McLean 1997), although in another

larger series it was suggested that kuru plaques

were more evident (but not exclusively present) in individuals

who were valine homozygotes or heterozygotes

at codon 129 (Cervenakova et al. 1999)

Our experience suggests that a characteristic PrPRES

glycoform ratio can usefully distinguish between vCJD

and sporadic CJD as reported previously (Collinge et al.

1996, Parchi et al. 1997, Ironside et al. 2000); however,

a glycoform pattern similar to that of vCJD is known to

characterise fatal familial insomnia (Parchi et al. 1995,

Telling et al. 1996) andGSS(Parchi et al. 1999b) and we

have recently made a similar finding in an unusual

Dutch case of sporadic CJD (Head et al. 2001). It is

questionable whether this pattern will be conserved in

patients with "human BSE" who are valine homozygotes

or heterozygotes at codon 129, although transmission

studies using transgenic "humanised" mice suggest

that it might (Hill et al. 1997). The presence of PrPRES in

the lymphoreticular system (Hilton et al. 1999, Hill et al.

1999) might similarly be a useful diagnostic criterion,

although studies of scrapie in sheep have suggested that

the distribution of PrPRES in lymphoid tissues is dependent

on the host PRNP genotype. It should also be noted

that the overall levels of both of PrPRES and infectivity in

the lymphoreticular system are significantly lower than

in the CNS in vCJD (Bruce et al. 2001, Wadsworth et al.

2001), requiring increased sensitivity in the Western

blotting assay and careful assessment by PrP

immunocytochemistry. An integrated approach to the

post-mortem diagnosis of vCJD, relying on a combination

of histology, immunohistochemistry, PrP gene sequencing

and PrPRES analysis. As more cases of BSE

and vCJD are identified in an increasing number of

countries, detailed laboratory investigation of all suspected

CJD cases is required in order to maintain

vigilance concerning the effects of the BSE agent in

man.

ACKNOWLEDGEMENTS

This study would not have been possible without the

generous co-operation of all the neuropathologists and

neurologists in the United Kingdom. We thank Ms BA

Mackenzie for preparation of the manuscript. The National

CJD Surveillance Unit is funded by the Department

of Health and the Scottish Executive Department

of Health. We are grateful to the TSE Resource Centre,

Compton, for supplying the KG9 antibody and to Dr B

Oesch, Prionics, Switzerland, for supplying the 6H4 antibody.

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of truncated prion protein fragments correlate with distinct

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P., DeArmond S.J., Prusiner S.B. (2000) Compelling

transgenetic evidence of transmission of bovine

spongiform encephalopathy prions to humans. Proc. Natl.

Acad. Sci. USA. 96: 15137-15142.

Shimizu S., Hoshi K., Muramoto T., Homma M., Ironside

J.W., Kuzuhara S., Sato T., Yamamoto T., Kitamoto T.

(1999) Creutzfeldt-Jakob disease with florid-type plaques

after cadaveric dura mater grafting. Arch. Neurol. 56:

357-362.

Telling G.C., Parchi P., DeArmond S.J., Cortelli P.,

Montagna P., Gabizon R., Mastrianni J., Lugaresi E.,

Gambetti P., Prusiner S.B. (1996) Evidence for the conformation

of the pathologic isoform of the prion protein enciphering

and propagating prion diversity. Science 274:

2079-2082.

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Desbruslais M., Luthert P.J., Collinge J. (2001) Tissue distribution

of protease resistant prion protein in variant

Creutzfeldt-Jakob disease using a highly sensitive

immunoblotting assay. Lancet 358: 171-180.

Will R.G., Ironside J.W., Zeidler M., Cousens S.N., Estibeiro

K., Alperovitch A., Poser S., Pocchiari M., Hofman A.,

Smith P.G. (1996) A new variant of Creutzfeldt-Jakob disease

in the UK. Lancet 347: 921-925.

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J.W., Cousens S.N., Mackenzie J., Esitbeiro K., Green

A.J.E., Knight R.S.G. (2000) Diagnosis of new variant

Creutzfeldt-Jakob disease. Ann. Neurol. 47: 575-582.

World Health Organisation (1996) In: Report of aWHOconsultation

on clinical and neuropathological characteristics

of the new variant of CJD and other human and animal

transmissible spongiform encephalopathies. Geneva:

World Health Organisation..

Zeidler M., Sellar R.J., Colie D.A., Knight R., Stewart G.,

Macleod M.A., Ironside J.W., Cousens S., Colchester

A.F.C., Hadley D.M., Will R.G. (2000) The pulvinar sign

on magnetic resonance imaging in variant

Creutzfeldt-Jakob disease. Lancet 355: 1412-1418.

Received 8 July 2002, accepted 20 July 2002

182 J.W. Ironside

http://www.nencki.gov.pl/pdf/an/vol62/iron.pdf

1

The BSE Inquiry / Statement No 210

CJD Surveillance Unit

(not scheduled to give evidence)

STATEMENT FROM THE CJDSU TO THE BSE INQUIRY

1. This Statement is presented in order to clarify some issues discussed at the time of our attendance

at the Inquiry on 3rd June 1998. This Statement addresses the following issues :

A. The difficulty of clinical diagnosis of new variant CJD prior to the announcement on the

20th of March 1996 and the effect this had on surveillance.

B. The policy of the Unit in relation to obtaining consent for post-mortem.

C. The difficulties of informing the families of victims of nvCJD of the imminent

announcement relating to these cases made on March 20th 1996.

D. The efforts made by the CJDSU to provide support and information to the families of cases

of CJD since the inception of the CJD Surveillance Unit in 1990 and details of activities

directly related to the relatives of nvCJD families after March 20th 1996.

2

A. The difficulty of clinical diagnosis of new variant CJD prior to the announcement on the

20th of March 1996 and the effect this had on surveillance

2. Since the start of the CJD Surveillance project in 1990 the methodology for case ascertainment of

cases of suspect CJD has been to ask targetted professional groups and particularly neurologists, to

refer any "suspect" case of CJD to the Surveillance Unit. This usually involves direct telephone

contact with the Unit, but suspect cases have also been identified from other sources including

death certificates and requests for advice or information. At the time of each referral a standard

form is completed and a decision is made about whether to request permission to visit the hospital

in order to obtain relevant information directly. An essential component of this process is to obtain

permission to interview relatives of the suspect case. Since the start of the project it has been the

policy of the Unit that it is essential to obtain permission from the consultant responsible for the

case before a visit to the hospital can take place and that the relatives of any suspect case should

know about the potential diagnosis of CJD prior to the visit from the CJDSU and that the relatives

should be informed of the function of the CJDSU and the purpose of the visit.

3. With some referrals, particularly those not made directly by neurologists, the suspicion of the

diagnosis of CJD may be insubstantial and in some cases, including those directly referred by

neurologists, it may be necessary to wait for the results of investigation or the evolution of the

clinical illness before the diagnosis of CJD can be considered as a real possibility. In these

circumstances the decision may be made to defer a visit from the CJDSU, often because it is not

felt justifiable by the responsible clinician to raise the possibility of the diagnosis of CJD with the

relatives of the patient (or in some cases the patient themselves). It is not good medical practice to

discuss hypothetical diagnoses with patients or relatives if there are no substantial grounds for a

particular diagnosis. With CJD of all forms, even the suspicion of this diagnosis can cause major

distress, at least in part because of the extensive public concerns about this condition. In many

suspect cases referred to the Unit the decision not to visit at the time of the first referral has been

vindicated by the subsequent diagnosis of an alternative condition or because the patient recovered.

4. The clinical features of new variant CJD are relatively distinct from classical CJD. The duration

of illness is longer, the early clinical features are atypical for CJD, the electroencephalogram does

not show the "typical" appearance so often seen in classical CJD and the mean age of death is

about 40 years less than classical CJD. It is quite understandable that (prior to March 1996)

neurologists might not suspect the diagnosis of CJD in a patient aged less than 50 years with

predominantly psychiatric features and with a normal or "atypical" EEG. The diagnosis of CJD

was raised as a possibility in some of the early cases of new variant CJD, but the decision to notify

the CJD Surveillance Unit must have been difficult, because the clinical features of these cases

were different from previous experience in CJD. Some clinicians took the understandable view that

CJD was not a likely diagnosis and the involvement of the CJDSU was not appropriate,

particularly if this might cause distress and potentially unnecessary distress to the relatives of

patients who were having to cope with a terminal illness of a child or spouse. It is of note that the

first three cases of new variant CJD underwent brain biopsy prior to referral to this Unit and two of

these cases were promptly referred to the CJDSU when the diagnosis of CJD was confirmed.

5. On the 21st of March 1996 all neurologists in the United Kingdom were circulated with a letter

from the Unit describing the clinical and pathological features of new variant CJD. The

neurological community was thereby informed of the novel clinical pathological phenotype. Since

the 21st of March 1996, all cases of new variant CJD have been referred to the CJDSU and the

referring hospital visited with the permission of the responsible clinician and the patient’s relatives.

3

B. The policy of the Unit in relation to obtaining consent for post-mortem

6. The CJDSU was funded as a research unit to study the epidemiology of CJD. The methodology of

the study involved a visit by a research registrar to referring hospitals to obtain relevant

information in order that any change in the characteristics of CJD that might be attributable to BSE

could be identified. This methodology involved the clinical examination of suspect cases and an

interview with the relatives of these cases. As was stated in the original grant application, an

important consideration from the start of the study was that the opportunity to discuss CJD in detail

with someone knowledgeable in the subject might be of benefit to the relatives of patients with

CJD. It has also been a primary imperative of the CJDSU not to interfere with the relationship

between the relatives of patients and the responsible clinicians. This is an issue which was (and is)

discussed in detail with all the research registrars who have worked on the CJD project.

7. The boundary between provision of information and perception of interference in clinical care is

delicate and it is to the credit of all the research registrars who have worked in the Unit and to the

neurological community that problems have only very rarely arisen.

8. Since the start of the project the view of the CJDSU has been that the research registrars should not

raise the issue of post-mortem with the relatives of patients unless specifically asked. It may for

example be particularly inappropriate to discuss post-mortem if patients are seen early in the

clinical course. It has been our view that the issue of permission for post-mortem is a matter that

should be discussed between the responsible clinician and the relatives. Although, if asked, the

registrars have discussed the importance of post-mortem in the confirmation of diagnosis, consent

for the post-mortem has not been a matter for the research registrars. We have encouraged

clinicians to request post-mortem but we have always firmly believed that the final decision about

post-mortem was a matter for the families to decide after discussion with the responsible clinicians.

9. The CJDSU has acted as a reference centre for the examination of neuropathological and other

tissue and staff at the Unit have carried out post-mortems in suspect cases. These post-mortems

have been carried out at the request of a Coroner or Procurator Fiscal or with a Consent Form for

Post-Mortem signed by a relative. Some centres carry out their own examination of post-mortem

tissue and may supply tissue blocks or slides for examination at the CJDSU.

10. The results of histological examination of brain tissue are supplied to the referring pathologist

and/or clinician or to the Coroner/Procurator Fiscal. Since the start of the project it has been the

view of the CJDSU that the provision of post-mortem results to relatives should primarily be the

responsibility of the referring clinician. We have sometimes been asked directly by relatives for the

results of post-mortem findings and have provided these results, usually in the form of an

explanatory letter and with the post-mortem report itself, if requested.

11. The system for reviewing neuropathology of CJD which was established in the UK has been of

great importance to the scientific study of this disease and was of critical importance to the

identification of new variant CJD. However the CJDSU was set up as a research project and we

have tried to avoid interference with the relationships between clinicians and the relatives of

patients. Consent for post-mortem and the provision of the results of post-mortem have not been

the direct responsibility of the CJDSU.

4

announcement relating to these cases made on March 20th 1996

12. The CJDSU has viewed the provision of information and support to relatives of patients with CJD

as a matter of great importance since the start of the project. Details of the activities of the CJDSU

in relation to this issue are described in Part D of this Statement.

13. The details of the process of the identification of new variant CJD have already been provided to

the Inquiry. On March the 8th 1996 evidence was presented at the SEAC committee by Dr

Ironside and Dr Will which raised the possibility that a new form of CJD had been discovered

which might be causally linked to BSE. Further information was requested by the SEAC

committee. Dr Ironside and Dr Will discussed the research findings with senior figures in

neuropathology and neurology and further information was provided as requested to SEAC at a

meeting on March the 16th 1996. At this meeting it was indicated that an announcement of these

findings would be made, but there was no indication as to when this was to happen. My

recollection of the meeting was that the announcement was not imminent.

14. On March the 17th and 18th Dr Will and Dr Ironside were attending a scientific meeting in Paris.

If they had known there was going to be an imminent announcement of the research findings they

would not have attended this meeting. In the late morning of March the 18th a telephone call was

received from the Department of Health suggesting that Dr Will should return to London for a

further SEAC meeting. On the afternoon of the 18th of March Dr Will and Dr Ironside returned to

the United Kingdom.

15. On the morning of March the 19th, Dr Will discussed the research findings with a senior

neurologist in London. The issue of informing the relatives was the first matter discussed at this

meeting and it was agreed as a first priority that the families of the cases of the new form of CJD

should be informed of the research findings prior to any public announcement. In the afternoon of

March the 19th Dr Will attended a SEAC meeting but had to leave before the end of the meeting in

order to catch the last flight back to Edinburgh. No date for any announcement was suggested

during the time Dr Will was at the SEAC meeting. Dr Will arrived in Edinburgh about 10 p.m.

and shortly afterwards received a telephone call from a media representative requesting involvement

in a radio programme the following morning to discuss the details of the new cases of CJD as these

were to be announced the following afternoon. This development was completely unexpected.

16. First thing the following morning, Dr Will requested Dr Zeidler, the Research Registrar, to contact

all the neurologists who had been responsible for the care of the individual cases of new variant

CJD to inform them of the situation and to ask whether they would prefer to inform the relatives

directly or whether they would prefer Dr Zeidler to inform the relatives. As stated above, an

important policy of the CJDSU has been not to interfere with the relationship between the relatives

and responsible clinicians and it was felt essential the decision about the means of informing the

relatives should be taken in collaboration with the responsible clinicians. Dr Zeidler contacted all

but one of the responsible clinicians and most of the patient’s families were able to be contacted

and informed prior to the announcement that afternoon. It is a matter of great regret to the CJDSU

if some of the relatives of these cases were not informed about the research findings prior to the

public announcement. The CJDSU has always regarded the provision of information and support

to the relatives of people with CJD as a primary objective (see point 4). The CJDSU were not able

to inform all the relatives prior to the announcement because the fact of the imminent

announcement was only known to the Unit the night before the announcement and there was

insufficient available time on the morning of March the 29th 1996 to ensure that all the relatives of

cases of new variant CJD had been informed.

5

D. The efforts made by the CJDSU to provide support and information to the families of

cases of CJD since the inception of the CJD Surveillance Unit in 1990 and details of

activities directly related to the relatives of nvCJD families after March 20th 1996

17. Although primarily a Research Unit the CJDSU has regarded the provision and support of the

relatives of patients with CJD as an important priority. This is referred to in Dr Will’s original

Statement paragraphs 28 to 33.

18. There has always been something of a dilemma between the need to provide a source of information

for relatives of patients who have died of Creutzfeldt-Jakob disease and the importance of not

interfering in the relationship between the relatives and clinicians. There has also been an

imperative not to intrude on relatives who may not wish to be involved with further information and

support. This issue was discussed by the CJD Support Network and it was decided in 1996 to

forward a letter to the general practitioners of past patients with CJD in order to give the GP the

opportunity to judge whether it were appropriate to forward a letter regarding the Support Network

on to individual families. Copies of the documents that were drawn up in February 1996 are

enclosed and these letters were sent to a number of past patients with CJD including cases that

subsequently turned out to be new variant CJD (Annex 1).

19. On March the 20th 1996 the CJD Support Network were contacted in order to inform them of the

facts of the recent research on the young patients with CJD. A draft statement was corrected by the

CJDSU and returned immediately to the Alzheimer’s Disease Society. Enclosed are copies of the

documents which were published by the Alzheimer’s Disease Society on behalf of the CJD Support

Network on March the 21st 1996 (Annex 2). On the 26th of April 1996 there was a meeting of the

committee of the CJD Support Network which included two relatives of a patient who had died of

new variant CJD. Concern was expressed about the way the news broke about the discovery of the

new strain of CJD and Dr Will who was a committee member explained the situation and the

decision that had been made by the Support Group on the 10th of June 1994 that, after the initial

hospital contact, the CJD Surveillance Unit would not contact individual relatives directly, but

would do so through their clinicians or through the Support Network. Since 1992 the CJD

Surveillance Unit has provided each suspect case with an information booklet with the name and

address of the CJD Unit in order that any questions or concerns may be discussed with staff at the

Unit after the original hospital visit. The CJD Surveillance Unit was in contact with some relatives

of the new variant cases after the initial visit and as a policy had tried to provide as much

information to these relatives as requested. It was not however the policy of the Unit to contact

individuals without permission following the initial contact during the hospital visit.

20. In April 1996 following a visit by relatives of a patient with new variant CJD to the Unit in

Edinburgh, a request was made that all the new variant CJD cases identified up until that time

should be circularised in order to inform them that a group of relatives had been set up and that a

meeting was to be arranged later in the year for a representative of the CJDSU to address the

assembled relatives. In the light of previous policy, a draft letter was drawn up, a copy of which I

enclose (Annex 3) which was sent to responsible clinicians who had been caring for the individual

cases of new variant CJD. The decision about whether to forward this on to the individual families,

as before was one that had to be made by clinicians who were directly involved with the care of

these families. The difficulty of the situation is referred to in the draft letter that was to be sent to

clinicians. In the second last paragraph this stated "We have of course been in contact with the

families of the recent CJD cases and it is clear that in at least two cases currently there is no wish

6

for contact with any outside agency."

21. At the request of the new variant families, a meeting was arranged in Birmingham, funded by the

CJDSU to allow the families to discuss directly various issues regarding the research findings of

the CJDSU. This meeting was held on the 6th of July 1996.

22. Subsequently there has been extensive communication between the new variant CJD families and

the CJDSU. We have made every attempt to keep the families informed of research developments

and have sent them pre-publication copies of a number of papers including:

· "Cerebrospinal-fluid test for new-variant Creutzfeldt-Jakob disease" published in the Lancet

· "Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent" published

in Nature

· "Predicting the CJD epidemic in humans" published in Nature

· "New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests" published

in the Lancet

· "New variant Creutzfeldt-Jakob disease: psychiatric features" published in the Lancet

· "Molecular analysis of prion stain variation and the aetiology of "new variant" CJD" published

in Nature

23. Members of the CJDSU have attended the inaugural meeting of the Human BSE Foundation and a

subsequent meeting in December 1997 and have also provided information at the Annual General

Meetings of the CJD Support Network, during which the opportunity has been taken to have

conversations with new variant families to explain any questions about this condition. There is

extensive correspondence held at the CJDSU relating to these contacts. We believe we have done

everything possible to try and provide information and support to the families of the victims of

human BSE within the limits of available resources at the Unit and with the ethical constraint of not

interfering in patient care.

Professor R G Will

Dr J W Ironside

October 1998

7

Issued on behalf of the witness by:

The BSE Inquiry Press Office

6th Floor Hercules House

Hercules Road

London SE1 7DU

Tel: 0171 261 8377 / 8383

Fax: 0171 803 0893

Website: http://www.bse.org.uk

email: inquiry@bse.org.uk

http://www.bseinquiry.gov.uk/files/ws/s210.pdf

PDF] The BSE Inquiry / Statement No 60 Dr James Ironside (scheduled to ...
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[PDF] The BSE Inquiry / Statement No 60A Dr James Ironside Issued 15/12/1999
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TSS

TSS


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