#########Worrying rise in Swiss CJD
'Incidence of Creutzfeldt-Jakob disease (CJD) in Switzerland increased
two-fold in 2001'
Sporadic CJD (sCJD) is evenly distributed worldwide with an incidence of
around one in a million people. However, this rate doubled in 2001 and
data from the first quarter of 2002 show that it continues to rise.
Markus Glatzel and colleagues sequenced the entire PRNP reading frame in
25 of the 27 patients with a definite diagnosis of CJD in 2001-02. One
PRNP allele had a mutation associated with hereditary dominant CJD, but
all the other alleles were wild-type. Glycotype analysis of the
disease-associated prion protein in 26 patients showed that none had the
type associated with bovine spongiform encephalopathy and variant CJD
(vCJD). The rise in disease could be accounted for by improved
reporting, iatrogenic transmission, or transmission of a prion zoonosis.
http://www.thelancet.com/journal/vol360/iss9327/full/llan.360.9327.talking_points.21754.5
Volume 360, Number 9327 13 July 2002
Incidence of Creutzfeldt-Jakob disease in Switzerland
Markus Glatzel, Colette Rogivue, Azra Ghani, Johannes R Streffer, Lorenz
Amsler, Adriano Aguzzi
The incidence of Creutzfeldt-Jakob disease (CJD) in Switzerland
increased two-fold in 2001, and figures from the first quarter of 2002
indicate that it continues to rise. Neither age at onset nor duration of
disease were different from previous years. Genetic analysis of the 27
reported cases revealed only one disease-associated mutation in the
prion gene. None of the recognised risk factors for acquired CJD were
reported on the offical notification forms. Glycotype profiling,
histopathology, and immunohistochemistry indicate that none of the cases
fulfilled the definition of variant CJD, which is thought to be caused
by bovine prions. Several scenarios could account for the increase in
CJD, including improved reporting, iatrogenic transmission, and
transmission of a prion zoonosis.
Lancet 2002; 360: 139-141
Sporadic Creutzfeldt-Jakob disease (sCJD) is evenly distributed
worldwide, with an incidence of about one in a million per year. In
Switzerland, however, the incidence rate has risen over the past 2 years.
We assessed data from 1996 to the first quarter of 2002 recorded by the
Swiss National Reference Centre for Prion Diseases and by the Federal
Office of Public Health, to which all instances of CJD are reported.
Diagnosis was confirmed on frozen and paraffin embedded brain tissue in
95% (n=19) of patients in 2001 and in 100% (n=7) in 2002. Of the 26
instances of CJD confirmed in these 2 years, 15 were in men and 11 in
women. The mean age at death was 67·2 years (range 48-83; figure 1).
Median disease duration was 3·1 months (1·3-11·0), according to official
declaration forms.
[02let_6093_1]
Figure 1: Epidemiology of CJD in Switzerland since 1996
*Data available to March, 2002. +One patient from outside Switzerland
excluded. Number of individuals reported and diagnosed with CJD and
incidence rates (upper), and age of death of patients with definite or
probable CJD (lower). In the lower panel: black dots=individual
patients; black lines within boxes=medians; boxes encompass 25th and
75th percentiles of distribution.
We did genetic analysis on all but two of the individuals diagnosed with
definite CJD in 2001 and 2002 by sequencing the entire PRNP reading
frame, and assigned results to individuals whenever permission was
obtained to do so. One PRNP allele had a mutation associated with
hereditary dominant CJD (PRNP E200K); all other sequenced alleles had
wild-type sequences. Codon 129 of PRNP encodes methionine (M) or valine
(V). Homozygosity for either allele is over-represented in sCJD, and all
patients with vCJD to date have been homozygous for methionine.1 In the
Swiss patients of 2001-2002, M/M was the most common allelic variant
(n=19), followed by V/V (n=5) and M/V (n=1); a similar pattern to that
noted in a large German sCJD collective.2
The disease-associated prion protein3 PrPSc can be resolved
biochemically into three bands, the relative intensity (glycotype) of
which represents a marker for the classification of CJD.4 We therefore
investigated the glycotype profile of PrPSc of every patient, except
one, referred in 2001 and 2002 (figure 2). Briefly, brain tissue was
homogenised in 2% sarcosyl with a RiboLyser (Hybaid, Ashford, UK),
digested with proteinase K (20 mg/L) for 30 min at 47°C,
electrophoresed, blotted, probed with antibody 3F4 (1/20 000, Signet,
Denham, USA), and developed by enhanced chemiluminescence (Amersham,
Chesham, UK). We then quantified unglycosylated, monoglycosylated, and
diglycosylated PrPSc with a Kodak image station 440 (Kodak, Wellesley, USA).
[02let_6093_2]
Figure 2: Glycotype analysis of PrPSc (upper) and biochemical and
histopathological analysis of a representative individual with CJD (lower)
A The triangular plot correlates the intensities of the diglycosylated,
monoglycosylated, and unglycosylated bands of PrPSc. Swiss cases of
2001/02 cluster around control sCJD.
B Western blot analysis of a Swiss patient with CJD, showing proteinase
K (Pk) resistant PrPSc in frontal cortex and cerebellum; unglycosylated
PrPSc is visible at about 21 kDa (type 1 or 2), whereas the positive
control (left two lanes) shows a PrPSc core fragment of about 19 kDa
(type 3).
C-F Spongiform changes (C and E=haematoxylin eosin staining) and
synaptic pattern of PrP deposition (Dand F; immunostain for PrP) in
frontal cortex (C, D) and cerebellum (Eand F). Scale bar=50 µm.
17 patients were classified as type 1 or type 2, nine cases were type 3,
but none were type 4, which is common to bovine spongiform
encephalopathy (BSE) and vCJD.4 Four patients had predominantly synaptic
cortical PrP depositions. We noted synaptic and patchy-perivacuolar
patterns of PrP deposition in 14 patients; six of these showed
additional plaque-like PrP deposits; four had strictly synaptic PrP
(figure 2). One patient had predominantly plaque-like PrP
immunoreactivity. Cortical florid PrP plaques characteristic of vCJD
were not observed.
Between 1997 and 2000, between 11 and 27 individuals who lived in
Switzerland were reported to the centre each year with suspected CJD, of
which between eight and 11 (42-73%) were subsequently diagnosed with the
disease, according to internationally accepted diagnostic criteria
(http://www.eurocjd.ed.ac.uk ). In 2001, 29 instances of suspected CJD
were reported (18 definite, one probable, one possible, and nine
non-CJD). In the first quarter of 2002, eight instances of CJD were
reported, of which seven were confirmed as CJD (figure 1). An eighth
patient with definite CJD lived in a principality affiliated to
Switzerland and is not included in the Swiss statistics and statistical
analyses. The diagnostic accuracy among referrals was 66% in 2001 and
88% in 2002. Hence, CJD accounted for 2·7 deaths per million in 2001
and, on the basis of the first quarter, 3·9 deaths per million in 2002
(figure 1).
The relatively large number of individuals with CJD in 2001, compared
with previous years, is unlikely to be due to chance fluctuation
(Poisson probability 0·004, assuming constant incidence), and the
quarterly incidence data are better fit by an increasing exponential
trend than by assuming constant incidence (figure 1, p=0·02).
The rise in incidence of CJD in Switzerland over the past 2 years could
be a result of ascertainment bias--ie, increased awareness of the
disease might have led to enhanced detection of CJD in patients who
would have otherwise been misdiagnosed.
In Switzerland the mere suspicion, rather than the diagnosis, of CJD
became statutorily notifiable in March, 1999. This change in the law was
followed by an immediate increase in the number of referrals, but not of
confirmed CJD diagnoses, in the year 2000 (figure 1). Yet the average
age of Swiss patients diagnosed in 2001-02 does not differ from that of
patients diagnosed in previous years (figure 1), whereas in several
other countries an increase in age was noted, which might indicate more
frequent recognition of CJD in elderly demented patients caused by an
increase in surveillance activities. CJD can imitate dementing illnesses
prevalent among residents in nursing homes; any increase in diagnostic
sophistication could produce a rise in CJD diagnoses in this subgroup.
However, it is noteworthy that only one of 27 patients diagnosed in
2001-02 was a nursing home resident when their diagnosis was first
suspected.
Finally, the ascertainment bias hypothesis would postulate that the true
average incidence of sCJD is three or more per million per year,
indicating that all countries other than Switzerland are under-reporting
by more than 50% the number of CJD patients diagnosed every year. This
suggestion is not very plausible. In Austria, for example, where the
population size, age structure, and the quality of health care are
similar to Switzerland, no rise in incidence of CJD has been reported
(http://www.eurocjd.ed.ac.uk).
Genetic inheritance of CJD is unlikely to have contributed to the rise
in mortality from this disease, since familial instances of CJD
co-segregate with PRNP mutations, and we detected only one such mutation
in the Swiss collective. Furthermore, there seems to be no familial
association between individuals with CJD diagnosed between 2001 and 2002.
A subset of cases might be due to some form of iatrogenic transmission.
Results of studies5 suggest that a proportion of allegedly sporadic
cases might actually be iatrogenic. However, according to the official
notification forms, none of the patients had been exposed to any of the
known iatrogenic risk factors.
A final possible explanation is that CJD in Switzerland is related to a
prion epizootic. Between 1995 and 1998, Switzerland reported a larger
incidence of BSE than did all other continental European countries (415
cases between 1990 and 2002). Exposure to BSE-infected products might
have mainly taken place before high-risk bovine food products were
banned from the human food chain in 1990. However, BSE is thought to
cause vCJD rather than sCJD, yet all evidence indicates that none of the
Swiss cases fulfil the diagnosis criteria of vCJD. Swiss CJD may be
related to BSE if the strain of Swiss BSE prion differs from the strain
of BSE prevalent in the UK. Available data, though limited, suggest that
this is not the case. Alternatively, BSE might have infected people in
the UK through routes different from those operational in Switzerland.
If so, the disease phenotype in human beings in Switzerland might be
different from that identified in the UK.
At present there is no evidence that the Swiss CJD cases might result
from transmission of BSE to people after one or more serial passages
through species other than cattle. Scrapie is exceedingly rare in
Switzerland: only seven cases have been reported in the past 10 years.
Chronic wasting disease of deer has not been reported in Europe,
although surveillance data on transmissible spongiform encephalopathies
in European game are incomplete.
In summary, we report a worrying development in the incidence of CJD in
Switzerland. All recognised clinical and molecular markers combine to
indicate that none of the Swiss patients developed vCJD. The elucidation
of the underlying chain of events is a national research priority, and
might uncover previously unrecognised modes of prion infection.
Contributors
M Glatzel and L Amsler obtained cases and handled samples; M Glatzel and
C Rogivue designed the study; A Ghani did statistical analysis and J
Streffer did genetic analysis; and A Aguzzi was the principal
investigator. All authors were involved in writing the manuscript.
Conflict of interest statement
None declared.
Acknowledgments
We thank all referring physicians; Charles Weissmann and Neil Mabbott
for discussions; Jesús de Pedro Cuesta for socioeconomical analyses;
Jonathan Wadsworth for provision of vCJD tissue; and Mauri Peltola for
technical help. This work was supported by the Kanton of Zurich and by
grants from the European Union. The Swiss Reference Center for Prion
Diseases is funded by the Swiss Federal Office of Public Health. CJD
surveillance in Switzerland is done as part of the EU Concerted Action
on the Epidemiology of CJD funded through the EU.
1 Will RG, Zeidler M, Stewart GE, et al. Diagnosis of new variant
Creutzfeldt-Jakob disease. Ann Neurol 2000; 47: 575-82. [PubMed]
2 Windl O, Giese A, Schulz-Schaeffer W, et al. Molecular genetics of
human prion diseases in Germany. Hum Genet 1999; 105: 244-52. [PubMed]
3 Aguzzi A, Weissmann C. Prion research: the next frontiers. Nature
1997; 389: 795-98. [PubMed]
4 Hill AF, Desbruslais M, Joiner S, et al. The same prion strain causes
vCJD and BSE. Nature 1997; 389: 448-50. [PubMed]
5 Collins S, Law MG, Fletcher A, Boyd A, Kaldor J, Masters CL. Surgical
treatment and risk of sporadic Creutzfeldt-Jakob disease: a case-control
study. Lancet 1999; 353: 693-97. [Text]
Institute of Neuropathology and National Reference Center for Prion
Diseases, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland (M Glatzel
MD, Prof A Aguzzi MD); Federal Office of Public Health, Division of
Epidemiology and Infectious Diseases, Bern, Switzerland (C Rogivue DVM,
L Amsler MD) ; Department of Infectious Disease Epidemiology, Faculty of
Medicine, Imperial College of Science, Technology and Medicine, London,
UK (A Ghani PhD); and Division of Psychiatry Research, University of
Zurich, Zurich, Switzerland (J Streffer MD)
Correspondence to: Prof Adriano Aguzzi (e-mail:adriano@pathol.unizh.ch)
http://www.thelancet.com/journal/vol360/iss9327/full/llan.360.9327.original_research.21709.1
Swiss CJD rise raises alarm
BSE-related brain disease could emerge in different form.
12 July 2002
HELEN PEARSON
Cows are thought to have caused a rise in variant, not sporadic CJD.
© alamy
The number of people dying from sporadic Creutzfeldt-Jakob disease (CJD)
has risen sharply in Switzerland. The finding is raising fears that 'mad
cow disease' could have spread to humans in another form1.
In Britain, a cattle epidemic of BSE is thought to have triggered a
brain disease called variant CJD in some people who ate infected meat
products. Variant CJD strikes young people.
Four years after Britain's BSE outbreak, Swiss cattle were also hit by a
BSE epidemic, which peaked in 1996. Now Swiss epidemiologists have
recorded an alarming rise in apparent cases of sporadic CJD, a different
form of the disease that affects those over 60.
Each year between 1997 and 2000, 8 to 11 of Switzerland's 6.5 million
people developed CJD. In 2001, 19 cases were reported; 7 were reported
in the first quarter of 2002. This is around four times higher than the
reported incidence anywhere else, including Britain.
There are many possible reasons for the climb - including a simple
statistical variation or improved disease reporting. The most alarming
possibility is that BSE has passed into humans and caused sporadic CJD.
At present, it is impossible for scientists to judge if this has occurred.
Blip or climb?
The hike may be a random statistical blip - in which case next year's
figures may fall. Fluctuations have occurred in the UK sporadic CJD
figures over the past few years. "I'm still hoping the numbers will go
down," says the researcher who led the study, Adriano Aguzzi of the
Institute of Neuropathology and National Reference Center for Human
Prion Diseases in Zurich.
Increased awareness of the disease may have produced more diagnoses
Roy Anderson
Imperial College London
Epidemiologist Roy Anderson of Imperial College of Science, Technology
and Medicine, London, says his "preferred option" is a reporting bias:
that an increased awareness of the disease amongst doctors and the
public has produced more diagnoses.
But Aguzzi thinks that over-reporting is unlikely. He points out that
other countries - Britain, Austria and Germany - who spend as much on
CJD surveillance have not reported similar sharp increases.
The infectious prion protein that causes CJD could also have been
transmitted from one patient to another via surgical instruments, blood
transfusions or some other medical procedure. "It's a distinct
possibility," says Aguzzi. Whether this is so would become clear through
scrutiny of clinical records.
Worst-case scenario
If BSE is the cause of Swiss sporadic CJD - the worst-case scenario -
researchers have to work out how the cattle disease can cause two
different forms of the human disease: variant CJD in Britain and
elsewhere in Europe, and sporadic CJD in Switzerland.
This could be explained if British and Swiss cattle harboured different
strains of the infectious prion protein - but preliminary experiments
suggest that they are the same.
Alternatively, Swiss CJD could have leapt to humans through the
injection of vaccines or medicines produced using serum made from cows,
suggests Cornelia van Duijn of the European collaborative group on CJD
incidence at the Erasmus University Medical School in Rotterdam, The
Netherlands. Finding the source of the disease has "got to be priority
number one for Europe", she says.
Researchers now hope to establish whether sporadic CJD came from BSE.
They will use 'strain typing': infecting mice with the prions causing
the two diseases and seeing if the symptoms match up. "It's the best way
to establish or exclude any suspected link," says Moira Bruce of the
Institute for Animal Health Neuropathogenesis Unit in Edinburgh, UK.
These experiments will take at least a year.
References
* Glatzel, M. et al. Sharply increased Creutzfeld-Jakob disease
mortality in Switzerland. Lancet , 360, 139 - 141, (2002).
http://www.nature.com/nsu/020708/020708-18.html
TOTAL CASES OF SPORADIC CJD (DEATHS)
http://www.eurocjd.ed.ac.uk/sporadic.htm
as i have said all along, the 85%+ of all CJDs, did not
just happen spontaneously, as most officials would want
you to believe. there are routes and there are sources.
we must focus on all Human TSEs, not just the 'chosen ones'
nv/vCJD. if we ignore all Human TSEs, except the nv/v CJD,
then we _loose_. there are over 20 strains of Scrapie.
from what science has said so far, BSE came from one of those
strains;
Possibility of BSE being cause of variant CJD is indeed biologically
plausible
EDITOR [---] Venters argued against bovine spongiform encephalopathy
(BSE) causing variant Creutzfeldt-Jakob disease.1 In fact, the
biological plausibility of this being the cause, the strength of the
epidemiological association, and the experiments indicating that the
same prion is involved are all good.
Incubation periods for BSE are proportional to the life expectancy of
the animal affected. The disease's incubation period is 18% of a cow's
life expectancy and would be expected to about double when crossing to
another species [---] that is, to 36% of 70 years in humans. Thus the
incidence of a disease due to BSE in humans would be predicted to peak
in 2014. A few human cases would be seen before 2000 and none early in
the 1990s. Small outbreaks would be expected early in the epidemic
before they become lost among a high background prevalence.2 The pattern
of variant Creutzfeldt-Jakob disease cases fits this.
Everyone in the United Kingdom has eaten on average over 50 meals of the
tissues of cattle infected with BSE; this figure would be lower in other
countries. The novelty of variant Creutzfeldt-Jakob disease is not now
questioned as it is different from kuru on histopathological grounds and
scrapie prion (PrPsc) biochemistry. No similar cases before 1995 have
been found.3
BSE infects a different range of animals from scrapie and infected all
the species inoculated experimentally except chickens and hamsters. It
is reasonable that it might infect humans. When fed BSE, 25% of sheep,
33% of goats, 50% of kudu, 100% of mice, and 100% of mink died.
Calculating this percentage for humans is difficult as it is early in
the epidemic.2
BSE prion doses to which humans may have been exposed might well cause
large numbers to become infected despite the inefficiency of the oral
route. Beef exported from the United Kingdom to France was mainly older
animals, specific tissues, and calves. This means that there was a
relatively high dose of prions per meal in France, and this fits the
number of cases of variant Creutzfeldt-Jakob disease seen there.2 Why
younger people are apparently becoming infected is not clear, but this
does not mean that BSE is not the cause.
Identical pathology and PrPsc glycoforms are produced in mice when
variant Creutzfeldt-Jakob disease, BSE, or feline spongiform
encephalopathy is inoculated. This is exceptional evidence that the same
prion is the cause.4 PrPsc associated with BSE will alter human normal
prion protein to the abnormal form in vitro,5 but it is not surprising
that transgenic mice expressing human prion protein did not become
infected easily with BSE.
Steve Dealler, consultant in medical microbiology.
Burnley General Hospital, Burnley BB10 2PQ deal@airtime.co.uk
1. Venters GA. New variant Creutzfeldt-Jakob disease: the epidemic that
never was. BMJ 2001; 323: 858-861[Full Text].
2. Dealler SF. Should young UK cattle be considered free of BSE or is it
endemic? Br Food J 2001; 103: 264-280.
3. McLean CA, Ironside JW, Alpers MP, Brown PW, Cervenakova L, Anderson
RM, et al. Comparative neuropathology of kuru with the new variant of
Creutzfeldt-Jakob disease: evidence for strain of agent predominating
over genotype of host. Brain Pathol 1998; 8: 429-437[Medline].
4. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, et
al. Transmissions to mice indicate that `new variant' CJD is caused by
the BSE agent. Nature 1997; 389: 498-501[Medline].
5. Raymond GJ, Hope J, Kocisko DA, Priola SA, Raymond LD, Bossers A, et
al. Molecular assessment of the potential transmissibilities of BSE and
scrapie to humans. Nature 1997; 388: 285-288[Medline].
http://bmj.com/cgi/content/full/325/7355/102
so why can't another form of TSE come from another
strain of Scrapie, or from TSE in deer and elk, why is this
so hard to believe? it's already been proven in the USA in the
lab, that USA scrapies can cause TSE in USA cattle. the late
Dr. Richard Marsh also proved that some strain of TSE has been
in the USA cattle for some time.
absence of evidence is not evidence of absence.
you can call it what you want, paint it whatever color you want,
but a cover-up is just that, a cover-up. they have been _documented_
in the past, don't think it cannot happen again.
sporadic CJDs 85%+ are _not_ a happen-stance of bad luck or spontaneous
happening. if politicians continue to insists they are, i would like
one of them to prove it. if they would take half the time of trying to
find source and route, as they do insisting it's just a happen-stance of
bad luck, and half the time and money on research of sporadic CJDs as
they do with the infamous nv/v CJD, instead of trying to totally
alienate the sCJDs from the nv/v CJDs, we would be much further ahead
in science.
just my opinion for today...
TSS
########### http://mailhost.rz.uni-karlsruhe.de/warc/bse-l.html ############
