CC: cjdvoice@yahoogroups.comTHE LANCET • Vol 363 • June 19, 2004 • www.thelancet.com 2013
Identification of possible animal origins of
prion disease in human beings
The transmissible spongiform encephalopathies (TSE or
prion diseases) are fatal transmissible neurodegenerative
diseases of mammals that include sporadic and variant
Creutzfeldt-Jakob disease (sCJD and vCJD,
respectively) in human beings, bovine spongiform
encephalopathy (BSE or mad-cow disease) in cattle, and
scrapie in sheep. Definitive diagnosis of a TSE infection
largely depends on the detection of abnormal prion protein
(PrPSc), a conformational isoform of normal mammalian
prion protein (PrPC). PrPSc accumulates mainly in tissues of
the central nervous and lymphoreticular systems. Different
strains of TSE agent are defined by several properties of
brain-derived protease-digested PrPSc—eg, size, glycosylation,
and conformation—and by in-vivo phenotypes such
as neuropathology, disease incubation times, and patterns
of PrPSc accumulation (figure).1–6 These criteria have been
used with epidemiological data to link vCJD to BSE, and to
identify a single strain of TSE agent as probably responsible
for both diseases.4,7,8
Cristina Casalone and colleagues’ report1 is the latest in a
flurry of studies2,3 that challenge the conclusion that there is
only one strain of BSE. These investigators analysed PrPSc
from the brains of cattle with BSE. An atypical form of the
disease was identified (bovine amyloidotic spongiform
encephalopathy or BASE) that had PrPSc molecules with
different biochemical properties and distribution patterns
within the brain compared with typical cases of BSE
(figure). A further comparison6 of BASE with sCJD in
people revealed that, at least in terms of PrPSc characteristics,
BASE was similar to a particular type of sCJD—
sCJD(MV2) (figure). These researchers conclude not only
that BASE is a new strain of BSE, but also that characteristics
of human and animal PrPSc could help to identify
potential risk factors for disease in individuals with sCJD of
unknown origin.
For personal use. Only reproduce with permission from The Lancet
Publishing Group.
Determining whether or not some cases of sCJD are a
consequence of exposure to animal TSE diseases is very
important epidemiologically given concerns that animal
TSE diseases other than BSE might also cause disease in
human beings.9 As such, Casalone and colleagues’ study
brings to the forefront a long standing question within the
TSE community: can we trace the origin of some sCJD
cases to an animal source based solely on PrPSc characteristics?
In view of the strong link between vCJD and
BSE,4,7,8 the similarity of their PrPSc molecules,5 and the
assumption that PrPSc encodes strain phenotypes, the notion
seems plausible.
However, use of PrPSc characteristics as markers for
tracking transmission of TSE disease between species
depends on those characteristics remaining invariant for any
given TSE strain. There is no question that biologically
cloned or carefully characterised TSE strains maintain their
strain-specific phenotypes when passaged in defined mouse
strains.10 Unfortunately there is also no question that these
phenotypes can change in unpredictable ways once defined
TSE strains are put into different mouse strains or species.10
Such transmissions often yield new neuropathologies or
PrPSc that is different from the original PrPSc,11,12 or absent
altogether.13,14 Thus, once a TSE strain has crossed a
transmission barrier, nothing is certain. In view of this
uncertainty, assuming that cross-species similarities in PrPSc
characteristics are indicative of a common TSE strain is
rather like assuming that two identically wrapped boxes
with the same shape and size must have identical contents.
Far from being invariant, key characteristics of PrPSc,
such as size and glycosylation, can be easily altered by
changing the sequence of PrPC,11,12 its glycosylation state,15
or the infected cell type.15,16 Ironically, BSE is one of the best
examples of how PrPSc characteristics do not necessarily
predict in-vivo phenotypes once a species barrier has been
crossed. Although PrPSc molecules in all animal species
infected with BSE look similar,5 neuropathologically BSE in
cattle is different from vCJD in people4,8 or even BSE in
other mammalian species.8 Such results strongly suggest
that, independent of PrPSc, the infected host plays a large
part in determining the final TSE disease phenotype. Thus
careful transmission studies and meticulous neuropathological
analysis, with defined mouse strains, are
essential for identification of TSE strains.
The rarity of TSE diseases and their extremely long
incubation times make identification of possible exogenous
sources of infection for human sCJD
difficult.17 This situation will probably
remain unchanged until we have a better
understanding of how TSE strain phenotypes
are controlled. The data reported by
Casalone and colleagues1 and others2,3 reemphasise
the importance of BSE testing
to look not only for new strains that could
pose a danger to human beings but also to
understand the pathogenesis of BSE in
cattle. However, as Casalone and colleagues
rightfully state, caution is dictated
when only similarities between PrPSc
molecules are used to conclude that TSE
diseases in different species are related.
COMMENTARY
Atypical BSE BSE
BASE France Japan vCJD sCJD(MV2) sCJD(MM1)
Phenotype
Size (kDa) ~20 ~20 ~19 ~19 ~20–21 ~21 ND
Yes Yes Yes ND No path No No Plaques
28 59 66 ~2 11, 15 8, 10, 15 ~5 Age (years)
Common Rare Rare ND ND ND Rare Peripheral tissue
involvement
CJD
Glycosylation
Di
Mono
None
PrPsc
Characteristics of different BSE and CJD isolates
˜=approximate. Strains of TSE are defined in part by biochemical
properties of PrPSc
(glycosylation and size), pattern of PrPSc deposition in brain
(plaques), average age of disease
onset, and involvement of peripheral tissues, such as spleen and lymph
nodes. These
characteristics are shown for typical BSE and atypical BSE cases from
cattle in Italy (BASE),1
France,2 and Japan,3 and for three different human CJD strains, vCJD4,5
sCJD(MV2),6 and
sCJD(MM1).6 Glycosylation: Di=diglycosylated, Mono=monoglycosylated,
None=unglycosylated.
Height and intensity of bar (black=highest, light grey=lowest) indicate
relative abundance of
each band for given strain. Size: size of unglycosylated PrPSc in kDa.
ND=not done, No path=no
BSE-associated pathology in brain. Data are adapted and simplified from
references indicated.
We have no conflict of interest to declare.
*Suzette A Priola, Ina Vorberg
Laboratory of Persistent Viral Diseases, Rocky
Mountain Laboratories, National Institute of Allergy
and Infectious Diseases,
National Institutes of Health, Hamilton, MT 59840,
USA (SAP); and Institute of Virology, Technical
University of Munich, Munich, Germany (IV)
(e-mail: spriola@niaid.nih.gov)
1 Casalone C, Zanusso G, Acutis P, et al. Identification of a
second bovine amyloidotic spongiform encephalopathy:
molecular similarities with sporadic Creutzfeldt-Jakob disease.
Proc Natl Acad Sci USA 2004; 101: 3065–70.
2 Biacabe A-G, Laplanche JL, Ryder S, Baron T. Distinct
molecular phenotypes in bovine prion diseases. EMBO Rep
2004; 5: 110–14.
3 Yamakawa Y, Hagiwara K, Nohtomi K, et al. Atypical
proteinase K-resistant prion protein (PrPres) observed in an
apparently healthy 23-month-old Holstein steer. Jpn J Infect Dis
2003; 56: 221–22.
4 Will RG, Ironside JW, Zeidler M, et al. A new variant of
Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921–25.
5 Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF.
Molecular analysis of prion strain variation and the aetiology
of “new variant” CJD. Nature 1996; 383: 685–90.
6 Parchi P, Giese A, Capellari S, et al. Classification of sporadic
Creutzfeldt-Jakob disease based on molecular and phenotypic
analysis of 300 subjects. Ann Neurol 1999; 46: 224–33.
7 Hill AF, Desbruslais M, Joiner S, et al. The same prion strain
causes vCJD and BSE. Nature 1997; 389: 448–50.
8 Bruce ME, Will RG, Ironside JW, et al. Transmissions to
mice indicate that ‘new variant’ CJD is caused by the BSE
agent. Nature 1997; 389: 498–501.
9 Lasmezas CI, Fournier JG, Nouvel V, et al. Adaptation of the
bovine spongiform encephalopathy agent to primates and
comparison with Creutzfeldt-Jakob disease: implications for
human health. Proc Natl Acad Sci USA 2001; 98: 4142–47.
10 Bruce ME. Strain typing studies of scrapie and BSE. In:
Baker H, Ridley RM, eds. Methods in molecular medicine:
prion diseases. Ottawa: Humana Press, 1996: 223–36.
11 Barron RM, Thomson V, Jamieson E, et al. Changing a single
amino acid in the N-terminus of murine PrP alters TSE
incubation time across three species barriers. EMBO J 2001;
20: 5070–78.
12 Asante EA, Linehan JM, Desbruslais M, et al. BSE prions
propagate as either variant CJD-like or sporadic CJD-like prion
strains in transgenic mice expressing human prion protein.
EMBO J 2002; 21: 6358–66.
13 Manson JC, Jamieson E, Baybutt H, et al. A single amino acid
alteration (101L) introduced into murine PrP dramatically alters
incubation time of transmissible spongiform encephalopathy.
EMBO J 1999; 18: 6855–64.
14 Lasmezas CI, Deslys JP, Robain O, et al. Transmission of the
BSE agent to mice in the absence of detectable abnormal prion
protein. Science 1997; 275: 402–05.
15 Vorberg I, Priola SA. Molecular basis of scrapie strain glycoform
variation. J Biol Chem 2002; 277: 36775–81.
16 Birkett CR, Hennion RM, Bembridge DA, et al. Scrapie strains
maintain biological phenotypes on propagation in a cell line in
culture. EMBO J 2001; 20: 3351–58.
17 Belay ED, Gambetti P, Schonberger LB, et al. Creutzfeldt-Jakob
disease in unusually young patients who consumed venison.
Arch Neurol 2001; 58: 1673–78.
2014 THE LANCET • Vol 363 • June 19, 2004 • www.thelancet.com
==================================================TSS
Asante/Collinge et al, that BSE transmission to the 129-methionine
genotype can lead to an alternate phenotype that is indistinguishable
from type 2 PrPSc, the commonest _sporadic_ CJD;
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm
BASE in cattle in Italy of Identification of a
second bovine amyloidotic spongiform encephalopathy: Molecular
similarities with sporadic
Creutzfeldt-Jakob disease
http://www.pnas.org/cgi/content/abstract/0305777101v1
THE findings from Corinne Ida Lasmézas*, [dagger] , Jean-Guy Fournier*,
Virginie Nouvel*,
Hermann Boe*, Domíníque Marcé*, François Lamoury*, Nicolas Kopp [Dagger
] , Jean-Jacques Hauw§, James Ironside¶, Moira Bruce [||] , Dominique
Dormont*, and Jean-Philippe Deslys* et al, that The agent responsible
for French iatrogenic growth hormone-linked CJD taken as a control is
very different from vCJD but is similar to that found in one case of
sporadic CJD and one sheep scrapie isolate;
http://www.pnas.org/cgi/content/full/041490898v1
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob
disease in the United States
http://www.neurology.org/cgi/eletters/60/2/176#535
LANCET INFECTIOUS DISEASE JOURNAL
Volume 3, Number 8 01 August 2003
Newsdesk
Tracking spongiform encephalopathies in North America
Xavier Bosch
My name is Terry S Singeltary Sr, and I live in Bacliff, Texas. I lost
my mom to hvCJD (Heidenhain variant CJD) and have been searching for
answers ever since. What I have found is that we have not been told the
truth. CWD in deer and elk is a small portion of a much bigger problem.
49-year-old Singeltary is one of a number of people who have remained
largely unsatisfied after being told that a close relative died from a
rapidly progressive dementia compatible with spontaneous
Creutzfeldt-Jakob disease (CJD). So he decided to gather hundreds of
documents on transmissible spongiform encephalopathies (TSE) and
realised that if Britons could get variant CJD from bovine spongiform
encephalopathy (BSE), Americans might get a similar disorder from
chronic wasting disease (CWD)the relative of mad cow disease seen among
deer and elk in the USA. Although his feverish search did not lead him
to the smoking gun linking CWD to a similar disease in North American
people, it did uncover a largely disappointing situation.
Singeltary was greatly demoralised at the few attempts to monitor the
occurrence of CJD and CWD in the USA. Only a few states have made CJD
reportable. Human and animal TSEs should be reportable nationwide and
internationally , he complained in a letter to the Journal of the
American Medical Association (JAMA 2003; 285: 733). I hope that the CDC
does not continue to expect us to still believe that the 85% plus of all
CJD cases which are sporadic are all spontaneous, without route or source.
Until recently, CWD was thought to be confined to the wild in a small
region in Colorado. But since early 2002, it has been reported in other
areas, including Wisconsin, South Dakota, and the Canadian province of
Saskatchewan. Indeed, the occurrence of CWD in states that were not
endemic previously increased concern about a widespread outbreak and
possible transmission to people and cattle.
To date, experimental studies have proven that the CWD agent can be
transmitted to cattle by intracerebral inoculation and that it can cross
the mucous membranes of the digestive tract to initiate infection in
lymphoid tissue before invasion of the central nervous system. Yet the
plausibility of CWD spreading to people has remained elusive.
Part of the problem seems to stem from the US surveillance system. CJD
is only reported in those areas known to be endemic foci of CWD.
Moreover, US authorities have been criticised for not having performed
enough prionic tests in farm deer and elk.
Although in November last year the US Food and Drug Administration
issued a directive to state public-health and agriculture officials
prohibiting material from CWD-positive animals from being used as an
ingredient in feed for any animal species, epidemiological control and
research in the USA has been quite different from the situation in the
UK and Europe regarding BSE.
Getting data on TSEs in the USA from the government is like pulling
teeth , Singeltary argues. You get it when they want you to have it,
and only what they want you to have.
Norman Foster, director of the Cognitive Disorders Clinic at the
University of Michigan (Ann Arbor, MI, USA), says that current
surveillance of prion disease in people in the USA is inadequate to
detect whether CWD is occurring in human beings ; adding that, the
cases that we know about are reassuring, because they do not suggest the
appearance of a new variant of CJD in the USA or atypical features in
patients that might be exposed to CWD. However, until we establish a
system that identifies and analyses a high proportion of suspected prion
disease cases we will not know for sure . The USA should develop a
system modelled on that established in the UK, he points out.
Ali Samii, a neurologist at Seattle VA Medical Center who recently
reported the cases of three hunterstwo of whom were friendswho died
from pathologically confirmed CJD, says that at present there are
insufficient data to claim transmission of CWD into humans ; adding that
[only] by asking [the questions of venison consumption and deer/elk
hunting] in every case can we collect suspect cases and look into the
plausibility of transmission further . Samii argues that by making both
doctors and hunters more aware of the possibility of prions spreading
through eating venison, doctors treating hunters with dementia can
consider a possible prion disease, and doctors treating CJD patients
will know to ask whether they ate venison.
CDC spokesman Ermias Belay says that the CDC will not be investigating
the [Samii] cases because there is no evidence that the men ate
CWD-infected meat . He notes that although the likelihood of CWD
jumping the species barrier to infect humans cannot be ruled out 100%
and that [we] cannot be 100% sure that CWD does not exist in humans&
the data seeking evidence of CWD transmission to humans have been very
limited .
http://infection.thelancet.com/journal/journal.isa
>>> he complained in a letter to the Journal of the American Medical
>>
>>
>>
Association (JAMA 2003; 285: 733). I hope that the CDC does not
continue to expect us to still believe that the 85% plus of all CJD
cases which are sporadic are all spontaneous, without route or source. <<<
actually, that quote was from a more recent article in the Journal of
Neurology (see below), not the JAMA article...
Full Text
Diagnosis and Reporting of Creutzfeldt-Jakob Disease
Singeltary, Sr et al. JAMA.2001; 285: 733-734.
http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama
BRITISH MEDICAL JOURNAL
SOMETHING TO CHEW ON
BMJ
http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2
BMJ
http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1
THE PATHOLOGICAL PROTEIN
BY Philip Yam
CHAPTER 14 Laying Odds Are prion diseases more prevalent than we
thought? Researchers and government officials badly underestimated the
threat that mad cow disease posed when it first appeared in Britain.
They didn't think bovine spongifbrm encephalopathy was a zoonosisan
animal disease that can sicken people. The 1996 news that BSE could
infect humans with a new form of Creutzfeldt-Jakob disease stunned the
world. It also got some biomedical researchers wondering whether
sporadic CJD may really be a manifestation of a zoonotic sickness. Might
it be caused by the ingestion of prions, as variant CJD is? Revisiting
Sporadic CJD It's not hard to get Terry Singeltary going. "I have my
conspiracy theo- ries," admitted the 49-year-old Texan.1 Singeltary is
probably the nation's most relentless consumer advocate when it comes to
issues in prion diseases. He has helped families learn about the
sickness and coordinated efforts with support groups such as CJD Voice
and the CJD Foundation. He has also connected with others who are
critical of the American way of handling the threat of prion diseases.
Such critics include Consumers Union's Michael Hansen, journalist John
Stauber, and Thomas Pringle, who used to run the voluminous www.mad-
cow.orgWeb site. These three lend their expertise to newspaper and
magazine stories about prion diseases, and they usually argue that 223
224 CHAPTER 14 prions represent more of a threat than people realize,
and that the gov- ernment has responded poorly to the dangers because it
is more con- cerned about protecting the beef industry than people's
health. Singeltary has similar inclinations, but unlike these men, he
doesn't have the professional credentials behind him. He is an 11-grade
dropout, a machinist who retired because of a neck injury sustained at
work. But you might not know that from the vast stores of information in
his mind and on his hard drive. Over the years, he has provided unac-
knowledged help to reporters around the globe, passing on files to such
big-time players as The New Tork Times, Newsweek, and USA Today. His
networking with journalists, activists, and concerned citizens has
helped medical authorities make contact with suspected CJD victims. He
has kept scientists informed with his almost daily posting of news items
and research abstracts on electronic newsgroups, including the bulletin
board on www.vegsource.com and the BSE-listserv run out of the
University of Karlsruhe, Germany. His combative, blunt, opinion- ated
style sometimes borders on obsessive ranting that earns praise from some
officials and researchers but infuriates othersespecially when he
repeats his conviction that "the government has lied to us, the feed
industry has lied to usall over a buck." As evidence, Singeltary cites
the USDA's testing approach, which targets downer cows and examined
19,900 of them in 2002. To him, the USDA should test 1 mil- lion cattle,
because the incidence of BSE may be as low as one in a mil- lion, as it
was in some European countries. That the U.S. does not, he thinks, is a
sign that the government is really not interested in finding mad cows
because of fears of an economic disaster. Singeltary got into the field
of transmissible spongiform encepha- lopathy in 1997, just after his
mother died of sporadic CJD. She had an especially aggressive
versionthe Heidenhain variantthat first causes the patient to go blind
and then to deteriorate rapidly She died just ten weeks after her
symptoms began. Singeltary, who said he had watched his grandparents die
of cancer, considered her death by CJD to be much, much worse: "It's
something you never forget." Her uncon- trollable muscle twitching
became so bad "that it took three of us to hold her one time,"
Singeltary recalled. "She did everything but levitate in bed and spin
her head." Doctors originally diagnosed Alzheimer's disease, but a
postmortem neuropathological exam demanded by Singeltary revealed the
true nature other death. Laying Odds 225 Classifying a disease as
"sporadic" is another way for doctors to say they don't know the cause.
Normal prion proteins just turn rogue in the brain for no apparent
reason. The term "sporadic" is often particularly hard for the victims'
families to accept, especially when the patient was previously in robust
health. Maybe it was something in the water, they wonder, or in the air,
or something they atethe same questions CJD researchers tried to answer
decades ago. The names "sporadic CJD" and "variant CJD" also confuse the
public and raise suspicions that U.S. authorities are hiding something
when they say there have been no native variant CJD cases in the
country. Singeltary suspected an environmental cause in his mother's
demise a feeling reinforced a year later when a neighbor died of spo-
radic CJD. For years, the neighbor had been taking nutritional supple-
ments that contained cow brain extracts. Researchers from the National
Institutes of Health collected samples of the supplement, Singeltary
recounted, and inoculated suspensions into mice. The mice remained
healthywhich only means that those supplement samples tested were
prion-free. Scientists have made several attempts during the past few
decades to find a connection between sporadic CJD and the environment.
Often, these studies take the form of asking family members about CJD
vic- timstheir diet, occupation, medical history, hobbies, pets, and
so forthand comparing them with non-CJD subjects. Such case-control CJD
studies have produced some intriguingand sometimes contra-
dictoryresults. In 1985, Carleton Gajdusek and his NIH colleagues
reported a correlation between CJD and eating a lot of roast pork, ham,
hot dogs, and lamb, as well as rare meats and raw oysters.2 Yet they
also recognized that the findings were preliminary and that more studies
were needed. Following up, Robert Will of the U.K. National CJD
Surveillance Unit and others pooled this data with those from two other
case-con- trol studies on CJD (one from Japan and one from the U.K.). In
particu- lar, they figured the so-called odds ratiocalculated by
dividing the fre- quency of a possible factor in the patient group by
the frequency of the factor in the control group. An odds ratio greater
than I means that the factor may be significant. In their study, Will
and his collaborators found an increase of CJD in people who have worked
as health profes- sionals (odds ratio of 1.5) and people who have had
contact with cows 226 CHAPTER 14 (1.7) and sheep (1.6). Unfortunately,
those connections were not statisti- cally significant: The numbers of
pooled patients (117) and control sub- jects (333) were so small that
the researchers felt the odds ratios needed to reach 2.5 to 8 (depending
on the assumptions) before they could be deemed statistically
significant. The only statistically significant corre- lations they
found were between CJD and a family history of either CJD (19.1) or
other psychotic disease (9.9), although the latter might simply be
correlated because psychotic disease may be an early symp- tom of
undiagnosed CJD.3 In contrast with earlier findings, the team concluded
that there was no association between sporadic CJD and the consumption
of organ meats, including brains (0.6). Although these case-control
studies shed a certain amount of light on potential risk factors for
CJD, it's impossible to draw firm conclu- sions. Obtaining data that
produces statistically meaningful results can be difficult because of
the rarity of CJD and hence the shortage of sub- jects. Human memory is
quite fragile, too, so patients' families may not accurately recall the
lifestyle and dietary habits of their loved ones over the course of a
decade or more. Consequently, researchers must cope with data that
probably contain significant biases. In a review paper on CJD, Joe Gibbs
of the NIH and Richard T.Johnson of Johns Hopkins University concluded
that "the absence of geographic differences in incidence is more
convincing evidence against major dietary factors, since large
populations eschew pork and some consume no meat or meat products."A CJD
study of lifelong vegetarians, they proposed, could produce some
interesting data.4 The inconclusive results of case-control studies do
not completely rule out the environment as a possible cause of CJD. "Dr.
Prusiner's theory does fit much of the data of spontaneous generation of
[mal- formed] PrP somewhere in the brain," Will remarkedthat is, the
idea that sporadic CJD just happens by itself falls within the realm of
the prion theory. Still, "it's very odd, if you look at all the forms of
human prion diseases there are, all of them are transmissible in the
laboratory and could be due to some sort of infectious agent."5 One of
the great difficulties, he explained, is that "given that this is a
disease of an extraordinarily long incubation period, are we really
confident that we can exclude childhood exposure that is transmitted
from person to person, as people move around? It's difficult to be sure
about that." There might a "carrier state" that leaves people healthy
yet still able to Laying Odds 227 infect others. If so, "you would never
be able to identify what's causing the spread of the disease," concluded
Will, who hasn't stopped looking for a possible environmental link. He
has some preliminary data based on studies that trace CJD victims' lives
well before the time symptoms beganup to 70 years; they suggest some
degree of geographic cluster- ing, but no obvious candidates for a
source of infection. A Case for Undercounting The difficulty in
establishing causal links in sporadic prion diseasesif there are any in
the first placeunderlines the importance of thorough surveillance. The
U.K. has an active program, and when a victim of CJD is reported, one of
Robert Will's colleagues visits and questions the victim's family. "No
one has looked for CJD systematically in the U.S.," the NIH's Paul Brown
noted. "Ever."6 The U.S., through the Centers for Disease Control and
Prevention, has generally maintained a more passive system, collecting
information from death certificates from the National Center for Health
Statistics. Because CJD is invariably fatal, mortality data is
considered to be an effective means of tabulating cases. The CDC
assessed the accuracy of such data by comparing the numbers with figures
garnered through an active search in 1996: Teams covering five regions
of the U.S. contacted the specialists involved and reviewed medical
records for CJD cases between 1991 and 1995. Comparing the actively
garnered data with the death certificate infor- mation showed that "we
miss about 14 percent," said CDC epidemiolo- gist Lawrence Schonberger.
"That's improving. Doctors are becoming more knowledgeable," thanks to
increased scientific and media atten- tion given to prion diseases.7 The
active surveillance study of 1996, however, only looked at cases in
which physicians attributed the deaths to CJD. Misdiagnosed patients or
patients who never saw a neurologist were not tabulated thus CJD may be
grossly underreported. Many neurological ailments share symptoms,
especially early on. According to various studies, autopsies have found
that CJD is misdiagnosed as other ills, such as dementia or Alzheimer's
disease, 5 to 13 percent of the time. The CDC finds that around 50,000
Americans die from Alzheimer's each year 228 CHAPTER 14 (about 4 million
have the disease, according to the Alzheimer's Association). Therefore,
one could argue that thousands of CJD cases are being missed. (On the
flip side, CJD could be mistakenly diagnosed as Alzheimer's disease or
dementia, but the number of CJD patients is so small that they wouldn't
dramatically skew the statistics for other neurological ills.) In part
to address the issue of misdiagnosis, CJD families have asked the CDC to
place the disease on the national list of officially notifiable
illnesses, which tends to include more contagious conditions such as
AIDS, tuberculosis, hepatitis, and viral forms of encephalitis.
Currently, only some states impose this requirement. CDC officials have
discounted the utility of such an approach, arguing that it would
duplicate the mortality data, which is more accurate than early diag-
noses of CJD, anyway. Moreover, mandatory reporting of CJD cases does
not necessarily guarantee the end to missed cases.8 One clue suggests
that the passive system is undercounting CJD in the U.S.: racial
difference. The number of black CJD victims is about 38 percent that of
white victims. Rather than sporadic CJD being a one- in-a-million
lottery, it's more like one-in-2.5-million for African- Americans.
Access to medical care might be one reason. Schonberger recounted that
the CDC had asked other countries with substantial black populations to
submit CJD figures for comparison but found that the surveillance in
those countries was inadequate. "We haven't been able to find any
comparable literature on this issue, so it's still up in the air,"
Schonberger said. On the other hand, Alzheimer's disease is more common
among black people than whites, with an estimated higher prevalence
ranging from 14 percent to almost 100 percent, according to a February
2002 report by the Alzheimer's Association. Are some black CJD cases
being misdiagnosed as Alzheimer's? Answering critics like Terry
Singeltary, who feels that the U.S. under- counts CJD, Schonberger
conceded that the current surveillance system has errors but stated that
most of the errors will be confined to the older population. As
Schonberger pointed out, no doctor would misdiagnose a 30-year-old CJD
patient as having Alzheimer's. The average age of the first 100 variant
CJD victims was 29; should the epidemiology of vCJD changeif older
people start coming down with itthen there would be problems. "The
adequacy of our overall CJD surveillance would be Laying Odds 229
greatly reduced should the proportion of older individuals affected by
variant CJD substantially increase," Schonberger explained.9 To date,
only brain autopsies can confirm CJD. To encourage the necessary
neuropathological studies, in 1997 the CDC helped establish the National
Prion Disease Pathology Surveillance Center at Case Western Reserve
University, under the directorship of Pierluigi Gambetti. But the number
of brains examined has fallen far short of the number of CJD cases in
the U.S.: Gambetti's lab, which receives brains based on referrals from
local physicians and families, looked at only 99 sporadic CJD cases in
2000 and 138 in 2001, when about 300 each year are expected. "I'm very
unhappy with the numbers," Gambetti lamented. "European countries see
100 or 90 percent of all the cases suspected. We see 30 to 40
percent."10 Most families don't think about having an autopsy done
(which can cost upward of $1,500 if the hospitals don't pick up the
tab), and mem- bers of the support group CJD Voice have said they were
too distraught to think of shipping a loved one's brain by Federal
Express to Gambetti's lab. (For accurate analyses of brain tissue, the
autopsy must be performed within 72 hours of death, assuming the body
has been kept refrigerated.) Moreover, physicians often do not suggest
an autopsy, perhaps because of liability fears should the postmortem
reveal that the original diagnosis was wrong. Gambetti has been work-
ing on establishing a network that would enable postmortems to be done
near where the deceased person lived and without cost to the family. He
is also working on advertising the existence of his surveil- lance
center, via meetings and letters to neurologists, pathologists, and
other specialists. Gambetti is also attempting to combat what he termed
"hysteria" over the potential for infection that has pathologists
irrationally shunning CJD cases while they willingly conduct arguably
riskier AIDS autopsies. "In order to make people aware, you have to keep
informing them over and over and over," he said. Money is the main
reason why the U.S. lags behind Europe in terms of surveillance. To
adequately survey the 290 U.S. million residents, "you need a lot of
money," Robert Will explained. "There was a CJD meeting of families in
America in which poor old Larry {Schonberger] got attacked fairly
vigorously because there wasn't proper surveillance. You could only do
proper surveillance if you have adequate resources. 230 CHAPTER 14
That's the bottom line. We're very fortunate in the U.K.; we have very
generous resources for CJD surveillance." Moreover, the U.K. makes
feline spongifbrm encephalopathy an offi- cially notifiable disease.
Domestic cats proved to be good sentinel ani- mals because they dine on
the meat not fit for human consumption the parts more likely to harbor
prion infectivity. In the U.S., FSE isn't federally notifiable. And
while the USDA says it has sent educational material to private
veterinarians and works with vet schools,21 it's not clear just how many
vets can spot FSE, which has never been reported in the U.S. Certainly,
not many cat postmortems are done. The only active portion of the U.S.
CJD surveillance system are the follow-up investigations conducted for
victims of CJD under 55 years of age. It began in 1996, when young
people in the U.K. started succumb- ing to variant CJD. Victims under 30
years of age especially arouse interest, because such cases could
indicate an infection from the envi- ronment. Except for the variant CJD
case in Florida, the CDC has clas- sified all of these more youthful
cases of CJD as having either sporadic or familial origins. One such age
cluster involved the three venison eaters that the CDC tried
unsuccessfully to link to the deer-and-elk borne chronic wasting
disease. A second grouping occurred in 2002 in a pair of Michigan men.
The twoone 26 years old, the other 28 did not know each other but
lived in neighboring counties in Michigan and went to the same hospi-
tal for diagnosis.12 The CDC's investigation turned up nothing that
suggested a new form of CJD had emerged. But the increased frequency of
young CJD cases is disturbing. In the 18-year period between 1979 and
1996, the U.S. had 12 cases in patients under 30, and only one of them
had the sporadic form of CJD. (The other cases resulted from heredity or
from transmission via contami- nated growth hormone or dura mater
grafts.13) Between 1997 and 2001, five people under 30 died of sporadic
CJD: the three venison eaters and the two Michigan patients. That
represents a substantial blip of five young cases in five years, as
opposed to only one case in 18 years. Physicians at the University of
Michigan Health System who examined the two Michigan men concluded: As a
result of our findings, we feel that sporadic CJD may be more common
than previously thought, that it may occur in younger indi- Laying Odds
231 viduals than currently perceived, and that some cases may go undiag-
nosed due to insufficient testing. . . . We recommend that physicians
everywhere begin to consider CJD in rapidly progressive neurological
decline of unknown causes in people under 30 years of age, and that
brain biopsy and autopsy with genetic and prion analysis be performed in
all such cases.14 Pathologically, the recent bout of young casualties in
the U.S. appears to be no different from CJD already seen in America.
Yet theoretically it may have come from a new source of infection, based
on an unex- pected result announced in late November 2002. John Collinge
of the British Medical Research Council's Prion Unit found that not all
trans- genic mice infected with BSE prions developed the
neuropathological and molecular characteristics of variant CJD; some of
the mice instead generated the molecular features of sporadic CJD.
Therefore, some CJD cases classified as sporadic may have actually been
caused by BSE prions, Collinge hypothesized.15 So far, the epidemiology
of CJD in the U.K. does not bear out that suppositionthere has been no
substantial uptick in sporadic CJD as would be expected if BSE could
paint more than one pathological picture. But the preliminary study,
taken at face value, could be seen as evidence that something infectious
is happening in the cases of young, sporadic CJD victims in the U.S.
Another mouse study, reported in March 2002, fueled concern that prion
infections may be more common than previously thought.16 Stanley
Prusiner's lab found that mice infected with mouse prions accu- mulated
PrPSc in their skeletal muscles, mostly in those in the hind limbs. In
some mice, each gram of muscle contained some 10 million infectious
doseson par with that in the brain in other experiments involving
intracerebral inoculation. To some CJD researchers, this find- ing
suggested that muscle meat from cows might not be safe, after all, and
that the measures taken in Europe to protect the food supply banning
high-risk cow partsmay not be enough. Although this study may seem
alarming, its implications are not as sweeping as they may appear. Only
a minority of results in mouse stud- ies end up having a direct analog
in humans. The skeletal muscle discov- ery warrants further examination,
but it would be premature to alter food policies. Prions are different
for each species, and accumulation of prions varies from species to
species and from disease to disease. Furthermore, BSE cattle muscle has
failed to sicken mice in bioassay 232 CHAPTER 14 work, suggesting that
little or no infectious prions lurk there. What such findings truly
reveal is that prion diseases are complicated and still mysterious, and
trying to quantify the risks for human health is fraught with
uncertainties...snip...284 pages...thanks Philip...TSS The Pathological
Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases,
Philip Yam Philip Yam News Editor Scientific American www.sciam.com
http://www.thepathologicalprotein.com/
NEW SCIENTIST MAGAZINE 4/02/01
NEW SCIENTIST EDITORIAL PAGE 3
MAD SHEEP DISEASE?
IF THERE is one categorical pronouncement you
can safely make about prion diseases like BSE
or CJD, it is that one should not make
categorical pronouncements. "British beef is
safe" and "there is no BSE in Germany" come
to mind. Now there are two more: "scrapie is
safe", and "people don't catch sporadic CJD".
Scrapie is the most widespread prion
disease, infecting untold numbers of
sheep worldwide. Sporadic CJD is the
old-fashioned pre-BSE kind that is supposed
to happen spontaneously in unlucky people.
But a surprise observation in France suggests
some sCJD cases--though by no means all--may
be linked to scrapie after all (see p 4).
For years, British authorities asserted that
BSE was harmless because it was a form of
scrapie. In fact, the only evidence scrapie
is safe is some broad-brush epidemiology, good
as far as it goes but unable to reveal
occasional risks for some people from some
sheep. Alarm bells should have rung in 1980
when researchers gave monkeys scrapie by
feeding them infected brains. But that
research, like so much other work on
prion diseases, was never followed up.
We still have little idea what BSE does
in pigs and chickens. The Queniborough
vCJD outbreak (see p 5) would be easier
to understand if we knew how much brain
we must eat to be infected. As for scrapie,
it shouldn't take a chance finding to
tell us that there may be dangerous sheep
out there.
Suspect symptoms
What if you can catch old-fashioned CJD by
eating meat from a sheep infected with
scrapie?
Exclusive from New Scientist magazine
Four years ago, Terry Singeltary watched his
mother die horribly from a degenerative brain disease.................
full text url follows
By Debora MacKenzie
Suspect Symptoms
http://www.newscientist.com/hottopics/bse/suspectsymptoms.jsp
if url dead, go here for 'SUSPECT SYMPTOMS'
http://www.organicconsumers.org/meat/scrapiecjd.cfm
USA
Loch in der Mauer
Die BSE-Angst erreicht Amerika: Trotz strikter Auflagen gelangte in
Texas verbotenes Tiermehl ins Rinderfutter - die Kontrollen der
Aufsichtsbehörden sind lax.
Hier klicken!
So funktioniert es: Artikel kaufen
http://www.spiegel.de/spiegel/0,1518,119306,00.html
TSS
