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From: TSS ()
Subject: MONTHLY CREUTZFELDT JAKOB DISEASE STATISTICS March 08, 2005 UK (SPORADIC CJD INCREASING)
Date: March 8, 2005 at 2:24 pm PST
-------- Original Message --------
Subject: [CJDVoice] MONTHLY CREUTZFELDT JAKOB DISEASE STATISTICS March 08, 2005
Date: Tue, 08 Mar 2005 08:56:15 -0600
From: "Terry S. Singeltary Sr."
Reply-To: cjdvoice@YAHOOGROUPS.COM
To: CJDVOICE
Date: March 08, 2005 Time: 13:15
MONTHLY CREUTZFELDT JAKOB DISEASE STATISTICS The Department of Health is today issuing the latest information about
the numbers of known cases of Creutzfeldt Jakob disease. This includes
cases of variant Creutzfeldt Jakob disease (vCJD) - the form of the
disease thought to be linked to BSE. The position is as follows: Definite and probable CJD cases in the UK: As at 7 March 2005 Summary of vCJD cases Deaths Deaths from definite vCJD (confirmed): 106 Deaths from probable vCJD (without neuropathological confirmation): 42 Deaths from probable vCJD (neuropathological confirmation pending): 1 Number of deaths from definite or probable vCJD (as above): 149 Alive Number of probable vCJD cases still alive: 5 Total number of definite or probable vCJD (dead and alive): 154 CREUTZFELDT-JAKOB DISEASE IN THE UK
By Calendar Year REFERRALS OF SUSPECT CJD / DEATHS OF DEFINITE AND PROBABLE CJD Year ReferralsYear Sporadic Iatrogenic Familial GSS vCJD Total Deaths
1990 [53] 1990 28 5 0 0 - 33 1991 75 1991 32 1 3 0 - 36 1992 96 1992 45
2 5 1 - 53 1993 78 1993 37 4 3 2 - 46 1994 118 1994 53 1 4 3 - 61 1995
87 1995 35 4 2 3 3 47 1996 134 1996 40 4 2 4 10 60 1997 161 1997 60 6 4
1 10 81 1998 154 1998 63 3 3 2 18 89 1999 170 1999 62 6 2 0 15 85 2000
178 2000 50 1 2 1 28 82 2001 179 2001 58 4 3 2 20 87 2002 163 2002 72 0
4 1 17 94 2003 162 2003 77 5 4 2 18 106 2004 112 2004 47 1 2 1 9 60
2005* 18 2005 5 0 0 1 1 7 Total 1938 Total 764 47 43 24 149 1027 Ref(s)
Deaths * As at 4 March 2005 Summary of vCJD cases Deaths
Deaths from definite vCJD (confirmed): 106
Deaths from probable vCJD (without neuropathological confirmation): 42
Deaths from probable vCJD (neuropathological confirmation pending): 1
Number of deaths from definite or probable vCJD (as above): 149 Alive
Number of definite/probable vCJD cases still alive: 5 Total number of definite or probable vCJD (dead and alive): 154 The next table will be published on Monday 4th April 2005 Referrals: a simple count of all the cases which have been referred to
the National CJD Surveillance Unit for further investigation in the year
in question. CJD may be no more than suspected; about half the cases
referred in the past have turned out not to be CJD. Cases are notified
to the Unit from a variety of sources including neurologists,
neuropathologists, neurophysiologists, general physicians,
psychiatrists, electroencephalogram (EEG) departments etc. As a safety
net, death certificates coded under the specific rubrics 046.1 and 331.9
in the 9th ICD Revisions are obtained from the Office for National
Statistics in England and Wales, the General Register Office for
Scotland and the General Register Office for Northern Ireland. Deaths: All columns show the number of deaths that have occurred in
definite and probable cases of all types of CJD and GSS in the year
shown. The figures include both cases referred to the Unit for
investigation while the patient was still alive and those where CJD was
only discovered post mortem (including a few cases picked up by the Unit
from death certificates). There is therefore no read across from these
columns to the referrals column. The figures will be subject to
retrospective adjustment as diagnoses are confirmed. Definite cases: this refers to the diagnostic status of cases. In
definite cases the diagnosis will have been pathologically confirmed, in
most cases by post mortem examination of brain tissue (rarely it may be
possible to establish a definite diagnosis by brain biopsy while the
patient is still alive). Probable vCJD cases: are those who fulfil the 'probable' criteria set
out in the Annex and are either still alive, or have died and await post
mortem pathological confirmation. Those still alive will always be shown
within the current year's figures. Sporadic: Classic CJD cases with typical EEG and brain pathology.
Sporadic cases appear to occur spontaneously with no identifiable cause
and account for 85% of all cases. Probable sporadic: Cases with a history of rapidly progressive dementia,
typical EEG and at least two of the following clinical features;
myoclonus, visual or cerebellar signs,
pyramidal/extrapyramidalsigns or akinetic mutism. Iatrogenic: where infection with classic CJD has occurred accidentally
as the result of a medical procedure. All UK cases have resulted from
treatment with human derived pituitary growth hormones or from grafts
using dura mater (a membrane lining the skull). Familial: cases occurring in families associated with mutations in the
PrP gene (10 - 15% of cases). GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare
inherited autosomal dominant disease, typified by chronic progressive
ataxia and terminal dementia. The clinical duration is from 2 to 10
years, much longer than for CJD. vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered
by the National CJD Surveillance Unit and reported in The Lancet on 6
April 1996. This is characterised clinically by a progressive
neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or
chorea) without the typical EEG appearance of CJD. Neuropathology shows
marked spongiform change and extensive florid plaques throughout the brain. Definite vCJD cases still alive: These will be cases where the diagnosis
has been pathologically confirmed (by brain biopsy). ANNEX
DIAGNOSTIC CRITERIA FOR VARIANT CJD 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 II A) EARLY PSYCHIATRIC SYMPTOMS *
B) PERSISTENT PAINFUL SENSORY SYMPTOMS **
C) ATAXIA
D) MYOCLONUS OR CHOREA OR DYSTONIA
E) DEMENTIA III A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC CJD *** (OR
NO EEG PERFORMED)
B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN IV A) POSITIVE TONSIL BIOPSY DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and
NEUROPATHOLOGICAL CONFIRMATION OF vCJD **** PROBABLE: I and 4/5 OF II and III A and III B or I and IV A * depression, anxiety, apathy, withdrawal, delusions. ** this includes both frank pain and/ or unpleasant dysaesthesia *** generalised triphasic periodic complexes at approximately one per second ****spongiform change and extensive PrP deposition with florid plaques,
throughout the cerebrum and cerebellum. http://www.wired-gov.net/WGLaunch.aspx?ARTCL=30334tss -------- Original Message --------
Subject: Re: [CJDVoice] MONTHLY CREUTZFELDT JAKOB DISEASE STATISTICS March 08, 2005
Date: Tue, 08 Mar 2005 16:21:56 -0600
From: "Terry S. Singeltary Sr."
Reply-To: cjdvoice@YAHOOGROUPS.COM
To: cjdvoice@YAHOOGROUPS.COM
References: <422DBD0F.2090208@wt.net>
PB DAZED AND CONFUSED OR JUST PROTECTING HIS PENSION,
because i just cannot believe he is this stupid ;
> Paul Brown, a CJD expert at the National Institutes of Health in
> Bethesda, Md., said the findings do not pose a concern for humans.
>
> "Were it not for the fact that diagnosed cases of sporadic CJD in the
> U.K. have not increased in the past 10 years, it would have worrisome
> implications," Brown told UPI. "As it stands, it does not, because if
> the proposition is that we're misdiagnosing (mad cow) in humans as
> sporadic CJD, it stands to reason that there would be more cases of
> sporadic in the U.K., where most of this is happening, and there isn't.
>
> "Nor for that matter is there in Italy or in most other countries in
> Europe," he added.
>
> http://www.upi.com/view.cfm?StoryID=20040216-043819-7124r
PLEASE NOTE DRAMTIC INCREASE IN SPORADIC CJD IN
DOCUMENTED BSE COUNTRIES ;
COUNTRY...1993...2002
FRANCE......35....108 GERMANY.....21+....80 ITALY.......27.....80 http://www.eurocjd.ed.ac.uk/sporadic.htm ALSO, DRAMATIC INCREASE IN SPORADIC CJD IN SWITZERLAND Mad Cow: Linked to thousands of CJD cases? By Steve Mitchell
United Press International
Published 12/29/2003 9:50 AM snip... > Experiences in England and Switzerland -- two countries that
> discovered mad cow disease in their cattle -- have heightened concerns
> about the possibility some cases of sporadic CJD are due to consuming
> mad-cow-tainted beef. Both countries have reported increases in
> sporadic CJD since mad cow was first detected in British herds in 1986.
>
> Switzerland discovered last year its CJD rate was twice that of any
> other country in the world. Switzerland had been seeing about eight to
> 11 cases per year from 1997 to 2000. Then the incidence more than
> doubled, to 19 cases in 2001 and 18 cases in 2002.
> snip... > "There's been no change in the number of CJD cases in the country and
> there has been clearly a tracking of the unusual cases of CJD" that
> could be due to mad cow disease, Monjan said. However, Terry
> Singletary, coordinator of CJD Watch -- an organization founded to
> track CJD cases -- says efforts to track the disease have been close
> to nonexistent. For example, only 12 states require such reports.
> Therefore, many cases might be going undetected, unreported or
> misdiagnosed.
>
> If more states made CJD a reportable illness, there would be more
> clusters detected across the United States, said Singletary, who
> became involved with CJD advocacy after his mother died from a form of
> CJD known as Heidenhain variant. In the 18-year period between 1979
> and 1996, he noted, the country saw a jump from one case of sporadic
> CJD in people under the age of 30 -- a warning sign for a link to mad
> cow because nearly all of the U.K. victims were 30 years of age or
> younger -- to five cases in five years between 1997 and 2001. "That
> represents a substantial blip," he told UPI.
>
> Singletary also said there have been increases in sporadic CJD in
> France, Germany and Italy, all of which have detected mad cow disease
> in their cattle.
> http://www.upi.com/view.cfm?StoryID=20030721-102924-4786r Mouse model sheds new light on human prion disease New findings from Professor John Collinge and his MRC Prion Unit team
have increased our understanding of human prion diseases, for example
Creutzfeldt-Jacob disease (CJD) which destroys the brain. Their work
also raises new research questions about susceptibility to exposure to
the infective agent that causes bovine spongiform encephalopathy (BSE),
a similar brain disease that affects cows. The research is published in
the 28 November 2002 edition of the European Molecular Biology
Organisation journal. In order to study human susceptibility to BSE and the species barrier
between cattle and humans, Professor Collinges team has developed mice
which have the human form of prion protein the infectious protein, or
prion, commonly believed to cause spongiform encephalopathies. The mice
show remarkably similar damage to that seen in people, indicating that
these mice are a good model of the human disease. This means we can see
how prions from BSE and human new variant CJD (vCJD) which is believed
to be caused by BSE prion infection act on the mice to mimic human
patterns of the disease. The experiments confirmed earlier findings that the BSE and vCJD prions
are closely similar. However, the scientists were surprised to see that
while some of the mice developed a disease pattern closely similar to
human vCJD, others produced a pattern like a form of sporadic
(classical) CJD. Sporadic CJD simply refers to a form of CJD with no
known cause (such as genetic mutation or accidental exposure to prions).
It has always been possible that it may have multiple causes. These data
suggest that some cases of apparently sporadic CJD in the UK and
elsewhere where people have been exposed to BSE prions may in fact be
caused by BSE. Professor John Collinge said We are not saying that all or even most
cases of sporadic CJD are as a result of BSE exposure, but some more
recent cases may be the incidence of sporadic CJD has shown an upward
trend in the UK over the last decade. While most of this apparent
increase may be because doctors are now more aware of CJD and better at
diagnosing it, serious consideration should be given to a proportion of
this rise being BSE-related. Switzerland, which has had a substantial
BSE epidemic, has noted a sharp recent increase in sporadic CJD. While few of the mice inoculated with BSE or vCJD prions showed clinical
signs of disease, which might have suggested a good species barrier,
closer examination revealed that many of the mice were in fact infected.
This finding of a sub-clinical form of prion disease has been
recognised before by this research group and now also seems relevant to
BSE infection. Further work in the paper argues that it is the genetic makeup of the
mice which determines whether BSE infection makes them produce the type
4 prion strain (as seen in variant CJD in humans) or the type 2 strain
(as seen in sporadic CJD in humans). http://www.mrc.ac.uk/index/public-interest/public-bse_and_sporadic_cjd.htm For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 757
Human prion disases are devastating and incurable, but
are very rare. Fears that the bovine spongiform
encephalopathy epizootic would lead to a large epidemic
of its presumed human counterpart, variant Creutzfeldt-
Jakob disease (vCJD), have not been realised. Yet a
feeling of uncertainty prevails in the general public and in
the biomedical world. The lack of data on the prevalence
of asymptomatic carriers of vCJD compounds this
uncertainty. In addition to this problem, Switzerland is
currently faced with another issue of major public concern:
a recent rise in the incidence of CJD. Here we examine the
plausibility of several scenarios that may account for the
increase in CJD incidence, including ascertainment bias
due to improved reporting of CJD, iatrogenic transmission,
and transmission of a prion zoonosis. In addition, we
present the design and current status of a Swiss
population-wide study of subclinical vCJD prevalence.
Lancet Neurol 2003; 2: 75763
Prion diseases, or transmissible spongiform encephalopathies
(TSEs), are a group of neurodegenerative disorders
affecting many species, including sheep, cattle, deer, and
human beings.1,2 All these diseases have an aetiological trait
in common: the only identified component of the infectious
agent is PrPSc, a modified form of a normal cellular protein
termed PrPC.35 The most common human TSE is
Creutzfeldt-Jakob disease (CJD), of which there are four
types: sporadic, familial, iatrogenic, and variant (s, f, i, and
vCJD respectively). sCJD is very rare, and seems to be evenly
distributed worldwide; in all countries that carry out
surveillance, incidences of about 0·41·8 cases per 1 million
people per year are reported.6 The aetiology of sCJD is
unknown: no exogenous or endogenous causes have been
identified. Familial forms are transmitted as autosomal
dominant traits, and cosegregate with mutations in the gene
that encodes the prion protein, PRNP.7 Instead, iatrogenic
cases are attributed to neurosurgical intervention,
transplantation of tissues, or administration of hormones
derived from dead people who had undiagnosed TSEs.
Biochemical and histopathological evidence suggests that
vCJD represents transmission of bovine spongiform
encephalopathy (BSE) prions to human beings.810 The
incidence of vCJD in the UK has been rising each year from
1996 to 2001,11 which has evoked fears of a future, large
epidemic. Since the year 2001, however, the incidence of vCJD
in the UK seems to be stabilising and may actually be falling. It
might be too early to draw any far-reaching conclusions, but
as each month passes without a substantial rise in the number
of cases, hope increases that perhaps the total number of
people who develop vCJD will not grow much more.12
Incidence of CJD in Switzerland
In Switzerland, CJD has been a statutory notifiable disease
since December 1987. A national reference centre for prion
diseases, NRPE (Nationales Referenzzentrum für Prionen-
Erkrankungen), was established in 1995 at the Institute of
Neuropathology of the University Hospital of Zurich. NRPE
conducts CJD surveillance, including clinical assessment of
patients, biopsies, autopsies, as well as biochemical and
genetic analyses on cases in which a human prion disease is
suspected.13 Between 1996 and 2000, the number of patients
diagnosed with CJD ranged from eight to 11 yearly,
corresponding to an incidence of 1·31·4 people per million
per year (figure 1). However, in 2001 there were 19
definite or probable cases and one possible case of
CJD.14 The numbers for 2002 (19 definite or probable )
seem to suggest that CJD incidence in Switzerland may be
stabilising at a high level, the yearly incidence for 2001 and
2002 being 2·6 people per million per year (figure 1).
Preliminary data for JanuaryAugust 2003 indicate that the
incidence is not decreasing (http://www.eurocjd.ed.ac.uk).
The definite diagnosis of CJD can only be made by
analysis of CNS tissue, before or after death. A potential
problem is represented by probable CJD cases, which are
diagnosed solely on the basis of clinical symptoms, and for
which no histopathological or biochemical confirmation is
available. Such probable CJD cases significantly contribute
to mortality statistics in those countries that diagnose CJD
based on surrogate markers such as high concentrations of
protein 14-3-3 in CSF.15 In the Swiss collective, diagnosis was
confirmed in frozen and paraffin embedded brain tissue in
95% of cases in 2001 and 2002.
Personal view Human prion diseases
MG and AA are at the Institute of Neuropathology and National
Reference Center for Prion Diseases and PMO is at the Department
of Otorhinolaryngology, University Hospital Zurich; TL is at the
Department of Otorhinolaryngology, Kantonsspital and JOG is at the
Institute of Pathology, Kantonsspital, Luzern; AG is at the
Department of Otorhinolaryngology, Kantonsspital and WW is at the
Institute of Pathology, Kantonsspital, Chur; GH is at the Department
of Otorhinolaryngology, University Hospital and HM is at the Institute
of Pathology, University Hospital, Basel; MP is at the Department of
Otorhinolaryngology, and BS is at the Institute of Pathology,
Kantonsspital, Aarau; Switzerland.
Correspondence: Prof Adriano Aguzzi, Institute of Neuropathology,
University Hospital of Zurich, Schmelzbergstrasse 12,
CH-8091 Zurich. Tel +41 1 255 2107; fax +41 1 25 54402;
email adriano@pathol.unizh.ch
Human prion diseases: epidemiology and
integrated risk assessment
Markus Glatzel, Peter M Ott, Thomas Linder, Jan O Gebbers, Arnold Gmür,
Werner Wüst, Gerhard Huber,
Holger Moch, Michael Podvinec, Bernhard Stamm, and Adriano Aguzzi
For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 758
1 year after our first report of this phenomenon,14 we still
lack any obvious explanation for the observed increase in
CJD incidence in Switzerland. Five scenarios are possible: a
mere statistical fluctuation; improved ascertainment of CJD;
genetically determined clusters of fCJD; clusters of
iatrogenic transmission; and transmission of an as yet
unknown prion zoonosis to human beings. As discussed in
the final part of this article, investigation of this situation
requires a vigorous interdisciplinary effort by
neuropathologists, molecular biologists, epidemiologists,
pathologists, andmaybe somewhat surprisingly
otorhinolaryngologists.
Statistical fluctuations and ascertainment bias
Could the surge in the number of people with CJD in
Switzerland represent a simple statistical fluctuation? This
possibility represents the best-case scenario, and there is no
method that would allow formal exclusion. However,
statistical analysis at the end of 2001 indicated that the
observed rise in incidence of CJD was unlikely to occur
stochastically (p=0·007, assuming a Poisson distribution).
The stabilisation of the high incidence since 2002 helps rule
out the random-fluctuation hypothesis as its sole cause.
Alternatively, the rise may be due to an ascertainment
bias over previous years (eg, because of increased awareness
of prion diseases among health professionals and within the
general population), which may lead to more frequent
detection of CJD in patients who would have otherwise been
misdiagnosed. Several arguments support this possibility,
including the fact that the rise in referrals is loosely
associated with the introduction of the 14-3-3 test as a
screening tool for CJD. Similar effects have been observed in
other countries.16 Some European countries have
experienced an increase in the median age of patients with
CJD, which is believed to reflect the heightened intensity of
CJD surveillance and better recognition of CJD in elderly
demented patients who otherwise might have been
diagnosed with more prevalent forms of dementia.17
Moreover, CJD can imitate dementing illnesses that are
prevalent in residents of nursing homes. Therefore, any
increase in diagnostic sophistication is likely to produce a
rise in CJD diagnoses in this group of patients. Yet, none of
the patients with confirmed CJD in
2001 and 2002 were in nursing homes
when the diagnosis was first
suspected.
As a counter argument, we found
that the current average age of Swiss
patients with CJD does not differ from
that of previous years, when CJD
incidence was similar to that of other
countries. This observation is one
argument against the possibility that
ascertainment bias can explain the
recent rise in incidence.
Finally, the awareness-bias
hypothesis would postulate that the
Swiss surveillance system uncovers the
true average incidence of sCJD, of
around 2·6 per million per year or more. If that were true, all
countries but Switzerland would underreport an excess of
50%. Although this poor detection in other countries is
possible, postulation that the Swiss system is so much better
than others at recognising patients with CJD is somewhat
presumptuous. In both Switzerland and Austria, for
example, CJD surveillance is funded by generous
governmental grants and is done by a network of
experienced neuropathologists. However, there is no CJD
surge in Austria (http://www.eurocjd.ed.ac.uk), despite the
fact that the size and age structure of the population, the
quality of the healthcare system, and even the resources per
million inhabitants allocated to CJD surveillance are not
obviously different between Switzerland and Austria (Dr
Jesús de Pedro Cuesta, personal communication). Finally,
owing to the Rokitansky legislation in Austria, which
requires that every person who dies in a hospital has an
autopsy, the general autopsy rate is even higher than that of
Switzerland. The entirety of these observations suggests that
the increase in Swiss CJD incidence may not be due to an
allegedly superior sensitivity of the Swiss surveillance system.
Genetics
One or several foci of genetically determined TSEs could
contribute to the rise in incidence of CJD in Switzerland.
Small presumed CJD epidemics in the past (eg, among
Libyan Jewish people), have eventually been traced to
inherited pathogenetic mutations of the PRNP gene.18 To
date all fCJD cases have been shown to cosegregate with
PRNP mutations; however, this mutation was detected in
only one of the Swiss patients of 2001 and 2002, which is in
agreement with reports of pathogenetic PRNP mutations in
1015% of all CJD cases.
However, prion genetics is a rapidly developing subject
and genetic susceptibility markers and modifiers are not
necessarily limited to polymorphisms in the PRNP locus.
What these additional modifiers could be is unclear;
controversy has recently arisen about the possible protective
effect of MHC allelotypes in vCJD. A study claimed that a
certain HLA type may serve as protective factor for the
development of vCJD,19 but a follow-up study reached
diametrically opposite conclusions.20 Yet whether the MHC
Personal view Human prion diseases
Number of patients
0
5
10
15
20
25
Incidence (patients/million/year)
0
0·5
1·0
1·5
2·0
2·5
3·0
1996 1997 1998 1999 2000 2001 2002
Figure 1. The epidemiology of CJD in Switzerland since 1996. Number of
newly diagnosed cases of
definite and probable CJD (bars) and incidence per million people per
year (diamonds) in
Switzerland from 1996 to 2002. There is a sharp rise in CJD incidence in
Switzerland in 2001 and
2002.
For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 759
allele in question represents a risk
modifier or not, there can be little
doubt that endogenous genetic
modifiers do indeed modulate the risk
of prion infection after exposure to the
agent. A large percentage of the
European population may have been
exposed to BSE infectious agents, and
animal experiments indicate that the
infectious dose for oral cross-species
transmission of BSE is low (about 500
mg of brain tissue represent one
infectious dose in sheep).21 Moreover,
because only about 140 human beings
have contracted vCJD, susceptibility is
almost certainly controlled by
endogenous or exogenous factors in
addition to the mere size of the
inoculum.22 Because certain genetic
profiles, other than the known
pathogenetic mutations in PRNP,
predispose for the development of
TSEs, further genetic analysis of the
Swiss patients with CJD may be
justified.
Refinements in the technologies
available for detection of PrPSc have
prompted us to study the distribution
of the disease-associated prion protein
in extracerebral organs of the Swiss
patients with CJD. These studies have
found that extraneuronal PrPSc is
detectable much more commonly than
previously thought: about a third of
patients investigated displayed PrPSc in
their skeletal muscle, and another third
(partly overlapping) had PrPSc in
lymphoid organs.23 At present, whether these findings are
universally valid for patients with CJD or whether they are
specific to the Swiss patients with CJD, is unknown. If the
findings are unique to Switzerland, the abnormal peripheral
pathogenesis of CJD in Swiss patients might point to a
specific aetiology.
Iatrogenic and zoonotic transmission
There is a fourth hypothesis, that a significant proportion of
the cases is caused by some form of iatrogenic transmission.
This hypothesis cannot be dismissed: indeed there have been
studies suggesting that a proportion of allegedly sporadic
CJD cases may actually be iatrogenic.24 According to the
official notification forms, none of the patients were exposed
to any of the known iatrogenic risk factors. However, the
sensitivity of this method is unsatisfactory. Therefore we
have initiated an in-depth retrospective survey, which
encompasses a review of each patients clinical records as
well as structured interviews of relatives with questionnaires
developed by the National CJD Surveillance Unit in
Edinburgh (www.cjd.ed.ac.uk). Over 200 individual
variables are being assessed. The results of this survey might
shed light on possible risk factors that were shared by subsets
of Swiss patients who have died of CJD.
The publication of the data of the shift in Swiss CJD
epidemiology triggered, particularly in the popular press,
far-reaching speculations that Swiss CJD may be related to a
prion epizootic, such as BSE, scrapie, or chronic wasting
disease. In fact, Switzerland has reported the largest number
of BSE cases among continental European countries between
1991 and 1999 (415 cases of BSE since 1990).25 The first
diagnosed case of BSE, as well as the peak of the epidemic,
hit Switzerland four years after the UK (figure 2).26,27
The Swiss population may have been exposed to BSEtainted
bovine materials before the ban of specific bovine
risk material from the human food chain, which was
implemented in late 1990, after the first case of BSE was
recognised. vCJD was first reported in the UK in 1996.
Assuming that the incubation period of vCJD is similar in
the UK and in Switzerland, one might have expected cases of
vCJD to appear in Switzerland around 2000. However, BSE
is thought to cause vCJD rather than sCJD,810 and all clinical,
genetic, histopathological, and biochemical data of the
recent CJD cases clearly indicate that no Swiss case fulfils the
Personal view Human prion diseases
2000
4000
Cases of BSE/month
0
1985 1987 1989 1991 1993 1995 1999 2001 1997
Cases of BSE/year
0
40
20
60
80
Voluntary test
Active surveillance
Clinical cases
1990
1991
1992
1993
1994
1995
1996
2001
2002
2000
1998
1999
1997
UK
Switzerland
Figure 2. Comparison between the incidences of BSE in the United
Kingdom26 and in Switzerland27
since the disease was first diagnosed (1986 in the UK and 1990 in
Switzerland). BSE has been
eradicated in neither country, but the incidence has been steadily
decreasing since its peaks in 1992
(UK) and 1995 (Switzerland). Even accounting for the smaller size of the
bovine and human
populations in Switzerland, the extent of the Swiss epizootic has been
much smaller than that of
BSE in the UK. The apparently trimodal course of the epizootic in
Switzerland reflects increased
detection of cases owing to the introduction of an active surveillance
programme in 1999 and of
voluntary testing programmes by most large retailers in 2001.
For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 760
diagnostic criteria of vCJD. Although the diagnostic criteria
for vCJD established by the WHO are firm,28 there is little
reason to believe that vCJD is the only possible clinical
manifestation of human infection with an animal prion
disease. Moreover, recent studies in genetically modified
mice have raised questions as to whether vCJD cases may be
erroneously classified as sCJD on account of their PrPSc types
as assessed by western blotting.29 Finally, BSE may have
infected human beings in the UK through routes different
from those that may have possibly been at work in Swiss
BSE, maybe because slaughtering procedures, eating habits,
or the enforcement of regulatory measures differ between
the two countries. If so, the disease phenotype in human
beings in Switzerland might be different from that identified
in the UK. Analogously, hamsters and mice fed or inoculated
peripherally with prions accumulate PrPSc in different sites of
the CNS than mice inoculated intracerebrally.30,31
Could the Swiss patients with CJD have developed the
disease as a result of BSE transmission after one or more
serial passages through species other than cattle (eg, sheep)
or through a prion zoonosis other than BSE? At present,
there is no evidence for such a possibility. Indeed, regulatory
measures aimed to prevent the entry of bovine CNS tissue
into human and animal food chains were implemented in
Switzerland several years before other continental European
countries.32
In sheep, scrapie cannot be easily distinguished from
BSE.33 Scrapie is very rare in Switzerland (only seven cases
were reported in the past 10 years), although cases of scrapie
may be underreported. Sheep and lamb is rarely consumed
in Switzerland and about 50% of that is Swiss; the remainder
is primarily imported from Australia and New Zealand
(Dagmar Heim, personal communication). Chronic wasting
disease of deer and elk is prevalent in various regions of
North America but has never been reported in Europe.
Therefore, chronic wasting disease seems to be an unlikely
cause of CJD in Switzerland. As a qualification, it is
important to realise that surveillance data on TSEs in
European game animals are incomplete at best.
The UK cases of vCJD are likely to be primary
transmissions from cattle. However, experimental
transmission studies show that TSE strain characteristics can
change upon serial passages after the original primary
transmission.34 Therefore, horizontal vCJD transmission
among human beings could present with a different
phenotype than vCJD. Nevertheless, this scenario is unlikely
to account for the high CJD incidence in Switzerland,
because no vCJD cases have been recorded in Switzerland.
As a result of the surge in CJD incidence, we have
initiated a study that characterises current cases of CJD and
tests factors that could explain such a development. The
study uses classic methods as well as new, up-to-date strain
typing tools.
Assessment of subclinical-vCJD prevalence in
Switzerland
vCJD has claimed over 130 lives in the past 7 years.
Although most cases have been reported in the UK, other
European and non-European countries including France,
Italy, and Canada have also been hit by vCJD. It is of direct
practical relevance whether subclinical vCJD exists in
countries with vCJD cases and maybe in BSE-exposed
countries that seem to have been spared from vCJD so far. A
quantitative answer to that question could be used to reduce
the uncertainty about the future size of the epidemic and will
put health authorities in a position to assess whether the
current measures taken to prevent the horizontal spread of
vCJD (ie, through medical interventions) are sufficient.
In vCJD, significant amounts of pathological prion
protein can be detected in lymphoid tissue at preclinical
stages of the disease; the detection of pathological prion
protein in lymphoid tissues of non-demented individuals is
therefore a potential marker for vCJD in asymptomatic
people.35,36 Conventional methods of PrPSc detection by
western blotting and immunohistochemistry do not reveal
its presence in lymphoid tissues of patients with sCJD.
Although more sensitive methods based on detecting PrPSc
before dementia develops may have positive results also in
lymphoid tissue.23
The Swiss Federal Office of Public health has mandated
the NRPE to do a study aimed at quantification of the
prevalence of subclinical carriers of vCJD-prions in
Switzerland. However, the detection of people that might
eventually develop a progressive, lethal dementia with no
effective treatment invariably poses several ethical questions.
To accommodate these issues, a working group that includes
members with expertise in law, ethics, epidemiology, and
basic research was set up with the goal to design an
appropriate study protocol. For the successful completion of
this study, several critical factors need to be respected. In
order to use highly sensitive and specific methods, tissues to
be tested need to be collected under native (non-fixed)
conditions. A statistically sound statement can only be made
if the size of the sampled population is large enough for a
Personal view Human prion diseases
Probability of detecting
one or more infections
0
0·5
0·6
0·7
0·8
0·9
0·1
0·2
0·3
0·4
1·0
10 000 1 10 100 1000
Prevalence per million
500
1000
2000
5000
10 000
Figure 3. Influence of sample size on the probability of the detection of
positive samples as a function of actual vCJD prevalence. The probability
to detect a given prevalence of vCJD can only be considered adequate if
the sampled pool is above 10 000 (ie, if the vCJD prevalence is about
100/106 inhabitants, the probability of detecting one or more samples
containing disease-associated prion protein is about 0·7).
For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 761
reasonable power of analysis: in view
of the size of the Swiss population
(about 7 million), this requires
sampling of at least 10 000 people
(figure 3). Finally, ethical issues, such
as patients rights and public
information policy, need to be taken
into account.
In order to satisfy both ethical and
scientific criteria, we decided to do a
cross-sectional, linked anonymised
prevalence study. Here we discuss the
details of the study design, with
particular focus on its bioethical
implications.
All samples to be studied originate
from leftovers of lymphoid tissue
taken for diagnostic procedures and
were obtained from tonsillectomies
and autopsies. Therefore, there is no
need to remove tissues for the specific
purpose of the study, which greatly
facilitates sample collection.
Nevertheless, patients rights were
analysed in detail and taken to the
furthest possible degree of
consideration. It was deemed essential
that donors understand how the
samples will be used, and how this
research might affect their interests.
Donors may opt out of the study at
any time. The patients must sign a
consent form detailing these points
before the study of samples can proceed.
Potential donors are informed
that there will be no link between
donor data and study results as long as
no samples containing pathological
prion protein are detected. However,
should prion-positive samples occur,
the Federal Office of Public Health
would inform the public about this
fact. Starting from that moment,
an officially announced neutral
institution would be set up to offer
information and counselling to people
who donated samples.
An unlinked anonymous prevalence
study for vCJD was launched
in the UK: the prevalence data
generated by that study contain only
minimal demographic information (such as breakdown of
age into only one of two groups), and no provisions were
taken to allow for allocation of test results to individual
donors. There is a lot to be said in favour of the UK study
design in terms of economy and avoidance of very involved
and entangled questions of bioethics. On the other hand, in
the light of the vast advances that are being accomplished in
prion research,3739 newly developed therapeutic40 or
prophylactic4144 options may become available in the future.
In such case, it might be unethical not to be able to inform
donors who tested positive. Conversely, not to undertake
efforts to ensure the safety of the general public in the
(admittedly very unlikely) case of a very high prevalence of
subclinical vCJD would also be unethical. Therefore, it was
decided to maintain a link between the tonsillectomy
samples and the patients from whom they were obtained,
Personal view Human prion diseases
No
Autopsy Tonsillectomy
Information of putative
participants
Donors have the right to:
withdraw sample from
study
retrieve information
on donated sample
(under defined
circumstances)
Post-mortem
approved?
Yes No
Excluded from study
Yes
No
Written
consent
from
donor?
Neutral custodian
for donor data
Included in study
Assessment of sample
No >4 lymphoid
follicles?
Yes
Included in study
Immunohistochemical
biochemical detection
of PrPSc
Identification of
donors tested
positive
Unlinked
anonymised study
No Samples
tested
positive?
Yes
Study design working
group assesses the
situation
Under defined
circumstances,
donors tested
positive can
be identified
Circumstances
fulfilled?
Unlinked
anonymised study
Yes
Figure 4. Trial profile of the study of the prevalence of vCJD in the
Swiss population. Samples
obtained through autopsies and samples obtained from patients having
routine tonsillectomies are
being assessed. Tonsillectomy samples are only included if consent is
given. Withdrawal from the
study is possible throughout the entire study period.
For personal use. Only reproduce with permission from The Lancet.
References
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THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 762
which will enable future identification of individuals
enrolled in the study if needed. The information to establish
this link is deposited in the safeguard of a neutral warden:
the Swiss Academy of Medical Sciences agreed to fulfil this
custodial role.
The study design described above puts the investigators
in a unique position. Depending on the study outcome and
on the development of therapies that may influence prion
diseases, several possible outcomes are conceivable
(figure 4). There are two principal outcomes of this study.
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The Swiss investigation into the possible presence of
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Conclusions
In terms of human prion diseases, Switzerland is facing two
key problems. First, the incidence of sCJD during the last
2 years is more than twice as high as that of other countries
doing CJD surveillance. This problem is being addressed by
research into epidemiology and by basic research.
The second key problem, which affects Switzerland and
other countries with significant exposure to BSE, is the
absolute lack of epidemiological data on subclinical vCJD
infection in the population. Human prion diseases have
incubation times that are unparalleled by any other
infectious disease, and people who have vCJD prions but are
clinically unidentifiable might cause further spread of prion
infections in human beings. Hence, there is a crucial and
urgent need for statistically sound epidemiological data on
the prevalence of vCJD. How to assess vCJD prevalence in
the face of its unique disease kinetics, while simultaneously
safeguarding the rights of study participants, is a formidable
challenge that has preoccupied epidemiologists, ethicists,
and public health officials, and has paralysed efforts towards
this goal in several countries. The Swiss medical community
has initiated a study to determine vCJD prevalence that has
the potential to satisfy epidemiologists, ethicists, and public
health officials. Bioethical issues and patients rights are
becoming more important even in epidemiological studies
that do not, at first, seem to have ethically problematic
components. With this in mind, the proposed study design
may, if proven feasible in practical and economical terms,
have some potential for representing a new useful paradigm
for future studies of disease epidemiology beyond human
prion diseases.
Acknowledgments
We thank all referring physicians, Azra Ghani for help with statistical
analyses, Colette Rogivue for help with the study design, Lorenz
Amsler for epidemiological data, Thomas Blättler for clinical
surveillance of CJD and Mauri Peltola for dedicated technical help.
The biochemical analyses of tonsils were made possible through a
generous infrastructural grant from the University Hospital of Zurich.
The NRPE is funded by the Swiss Federal Office of Public Health.
Strain typing analyses are funded by a joint grant to AA and MG of the
Swiss National Foundation (NFP38+) and the Swiss Federal Offices of
Public Health and of Veterinary Affairs.
Authors contributions
PMO, TL, JG, AG, WW, GH, HM, MP, and BS contributed to the
section describing the prevalence study and MG and AA planned and
wrote the review.
Conflict of interest
We have no conflict of interest.
Role of the funding source
No funding body had a role in the preparation of this manuscript or
the decision to submit it for publication.
Personal view Human prion diseases
Search strategy and selection criteria
Data for this review were identified by searches of Medline with
the search terms prion and Creutzfeldt-Jakob and from the
reference lists from relevant articles. Articles published until
June 2003 were included. Only papers published in English
and German were reviewed.
For personal use. Only reproduce with permission from The Lancet.
THE LANCET Neurology Vol 2 December 2003 http://neurology.thelancet.com 763
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Personal view Human prion diseasesTSS Terry S. Singeltary Sr. wrote: > Date: March 08, 2005 Time: 13:15
>
> MONTHLY CREUTZFELDT JAKOB DISEASE STATISTICS snip...end...TSS
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