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From: TSS ()
Subject: Re: TSE Conference Agenda Agenda for 26 - 29 June 2006, Renaissance Penta Vienna, Austria
Date: May 9, 2006 at 11:10 am PST

In Reply to: Re: TSE Conference Agenda Agenda for 26 - 29 June 2006, Renaissance Penta Vienna, Austria posted by TSS on May 7, 2006 at 8:24 am:



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

Date: April 19, 2006 at 4:56 pm PST


Dura mater-associated Creutzfeldt–Jakob disease:

experience from surveillance in the UK

C A Heath, R A Barker, T F G Esmonde, P Harvey, R Roberts, P Trend, MWHead, C Smith, J E Bell,

J W Ironside, R G Will, R S G Knight

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

J Neurol Neurosurg Psychiatry 2006;000:1–4. doi: 10.1136/jnnp.2005.073395

Between 1970 and 2003, seven cases of human dura materassociated

Creutzfeldt–Jakob disease (CJD) were identified in

the UK. Furthermore, we identified a case of CJD in a porcine

dura graft recipient. The mean incubation period of the

human dura mater cases was 93 (range 45–177) months.

The clinico-pathological features of the cases are described

and compared with cases previously reported in the world


Creutzfeldt–Jakob disease (CJD) exists in four clinical

forms: sporadic, genetic, iatrogenic and variant. The

cause of sporadic CJD, the most common form worldwide,

is unknown and case–control studies have failed to

identify any consistent risk factor, although two studies have

implicated previous surgical interventions.1 2 Genetic forms of

the disease are associated with underlying mutations of the

prion protein gene (PRNP), which are generally considered to

be directly causative.Mutations, however, possibly increase

liability to some, as of yet unrecognised, source of infection.

The two remaining forms of CJD are acquired. Variant CJD is

considered to be caused by bovine spongiform encephalopathy,

3–5 through contaminated food products; iatrogenic CJD

results from the inadvertent transmission of CJD during the

course of medical or surgical treatment. The two most

numerically significant instances of iatrogenic CJD resulted

from treatment with cadaveric human growth hormone and

the use of dura mater grafts in surgery. Corneal grafts, depth

electrodes and neurosurgical instruments have also rarely

been implicated.6 7

The first report of dura mater-associated CJD was

published in 1987,8 with a more detailed report appearing

the following year;9 to date, 164 cases have been recognised

worldwide (P Brown, personal communication) ; . This paper

reports and describes the seven cases of human dura mater

graft-associated CJD identified during surveillance in the UK

and also, for the first time, reports a case of CJD in a porcine

dura graft recipient.


CJD surveillance in the UK has been undertaken in four


N A retrospective review was carried out in England and

Wales from 1970 to 1979.

N A prospective study was carried out in England and Wales

from 1980 to 1984.

N A retrospective review was conducted in UK to cover the

period from 1985 to 1990.

N A prospective surveillance was instituted in the UK in 1990

and continues.

The methodology of the National CJD Surveillance Unit

has been described in previous publications.10 11


Human dura mater

During the period between 1970 and 2003, seven cases of

human dura mater-associated CJD were identified in the UK.

Table 1 shows the basic demographic features. The latent

period between surgery and the onset of CJD ranged from 45

to 177 (mean: 93) months. The mean age at surgery was

33 years, with a mean age at onset of 41 years.

Lyodura (B Braun Melsungen, Germany) < , a particular

brand of human dura mater, was implicated in six of the

seven cases (the manufacturer of the dura graft implicated in

case I is unknown).

The six cases associated with Lyodura were exposed to the

presumed source of ‘‘infection’’ between 1983 and 1987, with

the first recognised case in the UK exposed to human dura

mater in 1969.

A detailed account of both clinical and investigative

features is available online. In four cases, the clinical

phenotype at onset appears to correlate with the site of graft

placement or underlying parenchymal damage (cases II, III, V

and VI). For example—in case II, the initial illness presentation

included a right visual field defect; a left hemisphere

tumour was also diagnosed. The subsequent CJD began with

a right visual field disturbance and progressed with signs

indicating the involvement of the left hemisphere. Some of

the cases were investigated before the widespread availability

of MRI, and therefore MRI was only available in only four of

the seven cases. None of the cases showed the characteristic

radiological features of human prion disease14 with postsurgical

change being the most commonly recognised

abnormality. Despite all seven cases having at least one

electroencephalogram during the course of investigation,

only three of the seven cases showed the ‘‘typical’’ features.

Autopsy was carried out in five of our seven cases. In

general, the neuropathology was characterised by widespread

spongiform change accompanied by variable neuronal loss

and gliosis. Western blot analysis for PrPres was carried out in

three cases (cases II, VI and VII). The mobility and glycoform

ratio of the PrPres is indistinguishable from those of the type 1

PrPres, identified in cases of sporadic CJD, and is distinct from

type 2B, PrPres identified in variant CJD.

Porcine dura mater

We believe the identification of CJD in a porcine graft

recipient to be the first such report worldwide (table 1,case

VIII). The recipient underwent excision of a right fronto-

Rev 7.51n/W (Jan 20 2003)

Journal of Neurology, Neurosurgery, and Psychiatry jn73395 Module 4 3/4/06 07:25:26 Topics:

Abbreviations: CJD, Creytzfeldt–Jakob disease

Case V received two dura grafts, is assumed that the first graft was

responsible for transmission.


parietal meningioma in 1988 and a zenoderm graft was used

to repair the dura. The recipient presented with headaches,

ataxia and cognitive decline after 134 months. Investigative

features were consistent sporadic CJD, with a typical

electroencephalogram was identified, and pathological confirmation

was obtained. Autopsy showed spongiform change

in the frontal and temporal cortex, with similar features

identified in the basal ganglia, thalamus and cerebellum.

Immunocytochemistry for PrP showed widespread accumulation

and western blot analysis showed the type 1 isoform.


Human dura mater is a rare, but important source of

transmission of human prion disease, with only seven cases

recognised in a 33-year period. Surveillance systems worldwide

have identified 164 cases of CJD in people previously

exposed to human dura mater. Prevalence is particularly high

in Japan and probably reflects neurosurgical practice, with an

estimated 20 000 grafts used each year.15 The overall risk of

CJD associated with human dura grafts in the UK is

unknown because an accurate estimation of human dura

graft use and thus a denominator for calculation of risk is not

available. The estimated risk after exposure in Japan has

been estimated to be approximately 1 per 2000 patients

treated between 1979 and 2000 and approximately 1 per 1000

between 1983 and 1987.16 Neurosurgical practice in Japan,

with widespread use of dura mater, may be different from

other countries throughout the industrialised world and

therefore it would seem unreasonable to extrapolate any

estimated risk from these data. If neurosurgical practices in

the UK were more akin to those in Australia, then a

subsequent study by Brooke and co-workers would help

provide additional information pertaining to estimated risk.

By using information from the Australian CJD Surveillance

system, Brooke and co-workers estimated the risk associated

with exposure to human dura mater to be approximately 1

per 500 patients treated between 1978 and 2003.17 Clearly, the

risk of developing CJD in this patient population is

considerably higher than we would expect by chance.

The human dura mater implicated in the transmission of

CJD was processed, almost exclusively, by B Braun

Melsungen in Germany and traded under the name

Lyodura. Over 100 Japanese cases, and all but one of the

UK cases (the source of the first case identified in the UK is

unknown), have been associated with this particular product

and only rarely has dura processed by other manufacturers

been associated with transmission.18 19 Although the first case

in the UK was exposed to potentially infectious dura in 1969,

a disproportionately large number of cases were exposed

between 1983 and 1987 (80% of those identified worldwide

and six of the seven cases in the UK). Interestingly, the

apparent reduction in the number of cases post-1987

coincided with the introduction of stringent donor selection

criteria and also the introduction of sodium hydroxide

immersion techniques in the manufacturing process.

We found no temporal or geographical association between

any of the dura-associated cases, or any other case of CJD

identified in the UK, despite potential contamination of

neurosurgical instruments.

It has been proposed that clinical features at onset are

dependent on the site of graft placement or underlying

parenchymal damage20–22 and our findings may support such

a proposition. The explanation for this observation is unclear.

We, could, however, speculate that the pathological process

starts within a region adjacent to the graft and that this is

reflected in the early clinical features. This proposition may

also be supported by findings obtained at autopsy, with

severe pathological changes identified adjacent to graft

placement in three cases. Overall, the pathology is consistent

for that previously described in dura mater-associated

CJD.9 18 We did not identify either ‘‘kuru-type’’ or florid PrP

plaques. The florid PrP plaques were previously noted in

limited distribution in a small number of dural graftassociated

iatrogenic CJD cases in Japan.21 23 24

We believe case VIII represents the first reported case of

CJD in a person previously exposed to a graft from a nonhuman

source. The age at onset, duration of illness, clinical

and investigative features were similar to a typical case of

sporadic CJD. Furthermore, the pathological features were

also considered characteristic of sporadic CJD, with type 1

PrPres identified. Neither finding can definitively exclude the

possibility of transmission of a yet unidentified pathogen. As

natural transmissible spongiform encephalopathies are,

however, as yet unrecognised in pigs, despite experimental

transmission in animal models,25 a chance association seems

the most plausible explanation.


We thank Jan MacKenzie for all her help in producing this

manuscript. We also thank our colleagues within the European

Rev 7.51n/W (Jan 20 2003)

Journal of Neurology, Neurosurgery, and Psychiatry jn73395 Module 4 3/4/06 07:25:26 Topics:

Table 1 UK case details—human dura mater

Case Surgical procedure Dura Year of surgery Year of death Incubation period (Months)

Duration of illness


I, Esmonde et al12 Suboccipital craniotomy and C1/2

laminectomy for cerebellar ectopia and


? 1969 1979 104* 6

II, Esmonde et al12 Excision of a left temporal cortex


L 1983 1991 93* 5*

III Repair surgical leak after acoustic

neuroma excision

L 1985 1989 51 2

IV, Willison et al13 Posterior fossa decompression and

cervical laminectomy for cerebellar

ectopia or syringomyelia

L 1985 1989 45* 4

V Excision of a left parietal cortex


1) L 1985 1993 1) 86 11

2) L 1986 2) 79

VI Excision of a cerebellar astrocytoma L 1986 1997 103 33

VII Excision of a eosinophilic granuloma

right frontal region skull

L 1987 2003 177 5

Porcine Dura Graft:

VIII Excision of a right frontoparietal


P 1988 2000 134 3

*Revised from previously published figures.

L, Lyodura; P, Porcine dura.

2 Heath, Barker, Esmonde, et al

surveillance programme for updated information, particularly

Pascual Sanchez Jaun, and neurological colleagues throughout UK,

particularly Dr Graham Lennox, for assistance with this manuscript.

Finally, we thank our colleagues at the NCJDSU, particularly Alison

Green, for carrying out CSF analysis, David Summers for advice on

neuroimaging, and also Hester Ward and Katy Murray for comments

on the manuscript.

Authors’ affiliations

. . . . . . . . . . . . . . . . . . . . .

C A Heath, M W Head, C Smith, J E Bell, J W Ironside, R G Will,

R S G Knight, National CJD Surveillance Unit, University of Edinburgh,

Edinburgh, UK

R A Barker, Cambridge Centre for Brain Repair, University of

Cambridge, Cambridge, UK

T F G Esmonde, Royal Victoria Hospital, Belfast, UK

P Harvey, Harley Street, London, UK

R Roberts, Ninewells Hospital, Dundee, UK

P Trend, The Royal Surrey County Hospital, Surrey, UK

Competing interests: None.

Correspondence to: Dr R S G Knight, National CJD Surveillance Unit,

Bryan Matthews Building, Western General Hospital, Edinburgh EH4

2XU, UK;

Received 7 June 2005

Revised version received 23 August 2005

Accepted for publication 24 August 2005


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23 Takashima S, Tateishi J, Taguchi Y, et al. Creutzfeldt-Jakob disease with florid

plaques after cadaveric dural graft in a Japanese woman. Lancet


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Rev 7.51n/W (Jan 20 2003)

Journal of Neurology, Neurosurgery, and Psychiatry jn73395 Module 4 3/4/06 07:25:29 Topics:

Dura mater-associated CJD 3

Authors Queries

Journal: Journal of Neurology, Neurosurgery, and Psychiatry

Paper: jn73395

Title: Dura mater-associated Creutzfeldt–Jakob disease: experience from surveillance in the UK

Dear Author

During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend to these

matters and return this form with your proof. Many thanks for your assistance



Query Remarks

1 Please provide the year for P

Brown, personal communication

2 Please provide the town of the

manufacturer B Braun Melsungen

3 Please provide the date and the

location of the proceedings in

reference 10

Rev 7.51n/W (Jan 20 2003)

Journal of Neurology, Neurosurgery, and Psychiatry jn73395 Module 4 3/4/06 07:25:29 Topics:

4 Heath, Barker, Esmonde, et al


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