To: BSE-L@uni-karlsruhe.de
CJD screening may miss thousands of cases
By Steve Mitchell
UPI Medical Correspondent
Published 7/21/2003 3:00 PM
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WASHINGTON, July 21 (UPI) -- The federal government's monitoring system
for cases of Creutzfeldt-Jakob disease, a fatal human brain illness,
could be missing tens of thousands of victims, scientists and consumer
advocates have told United Press International.
Creutzfeldt-Jakob disease or CJD can be caused by eating beef
contaminated with mad cow disease, but the critics assert without a
better tracking system it might be impossible to determine whether any
CJD cases are due to mad cow or obtain an accurate picture of the
prevalence of the disorder in the United States.
Beginning in the late 1990s, more than 100 people contracted CJD in the
United Kingdom and several European countries after eating beef infected
with bovine spongiform encephalopathy -- the clinical name for mad cow
disease.
No case of mad cow has ever been detected in U.S. cattle and the Centers
for Disease Control and Prevention's monitoring system has never
detected a case of CJD due to eating contaminated American beef.
Nevertheless, critics say, the CDC's system misses many cases of the
disease, which currently is untreatable and is always fatal.
The first symptoms of CJD typically include memory loss and difficulty
keeping balance and walking. As the disease destroys the brain, patients
rapidly progress in a matter of months to difficulty with movement, an
inability to talk and swallow and, finally, death.
Spontaneously-occurring or sporadic CJD is a rare disorder. Only about
300 cases appear nationwide each year, but several studies have
suggested the disorder might be more common than thought and as many as
tens of thousands of cases might be going unrecognized.
Clusters of CJD have been reported in various areas of the United States
-- Pennsylvania in 1993, Florida in 1994, Oregon in 1996, New York in
1999-2000 and Texas in 1996. In addition, several people in New Jersey
developed CJD in recent years, including a 56 year old woman who died on
May 31, 2003. Although in some instances, a mad cow link was suspected,
all of the cases ultimately were classified as sporadic.
People who develop CJD from eating mad-cow-contaminated beef have been
thought to develop a specific form of the disorder called variant CJD.
But new research, released last December, indicates the mad cow pathogen
can cause both sporadic CJD and the variant form.
"Now people are beginning to realize that because something looks like
sporadic CJD they can't necessarily conclude that it's not linked to
(mad cow disease)," said Laura Manuelidis, section chief of surgery in
the neuropathology department at Yale University, who conducted a 1989
study that found 13 percent of Alzheimer's patients actually had CJD.
Several studies, including Manuelidis', have found that autopsies reveal
3 percent to 13 percent of patients diagnosed with Alzheimer's or
dementia actually suffered from CJD. Those numbers might sound low, but
there are 4 million Alzheimer's cases and hundreds of thousands of
dementia cases in the United States. A small percentage of those cases
could add up to 120,000 or more CJD victims going undetected and not
included in official statistics.
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.
The CDC says the annual rate of CJD in the United States is one case per
million people, but the above studies suggest the true prevalence of CJD
is not known, Manuelidis told UPI.
Diagnosing CJD or Alzheimer's is difficult because no test exists that
can identify either disease in a living patient with certainty. So
physicians must rely on the patient's symptoms to determine which
illness might be present. Sometimes, however, the symptoms of one
disease can appear similar to the other disorder. The only way to
determine the disease conclusively is to perform an autopsy on the brain
after death.
Unfortunately, although autopsies once were performed on approximately
half of all corpses, the frequency has dropped to 15 percent or less in
the United States. The National Center for Health Statistics -- a branch
of the CDC -- stopped collecting autopsy data in 1995.
"If we don't do autopsies and we don't look at people's brains ... we
have no idea about what is the general prevalence of these kinds of
infections and (whether) it is changing," Manuelidis said.
At the same time autopsies have been declining, the number of deaths
attributed to Alzheimer's has increased more than 50-fold since 1979,
going from 857 deaths then to nearly 50,000 in 2000. Though it is
unlikely the dramatic increase in Alzheimer's is due entirely to
misdiagnosed CJD cases, it "could explain some of the increase we've
seen," Manuelidis said.
"Neurodegenerative disease and Alzheimer's disease have become a
wastebasket" for mental illness in the elderly that is difficult to
diagnose conclusively, she said. "In other words, what people call
Alzheimer's now is more broad than what people used to call it, and that
has the possibility of encompassing more diseases -- including CJD."
The autopsy studies that found undiagnosed CJD cases raise the question
of whether the United States "already has an undetected epidemic here,"
Jeff Nelson, director of vegsource.com, a vegetarian advocacy Web site,
told UPI.
"What's the source of that?" Nelson asked. "Could it be the same source
of encephalitis we saw in minks?"
Nelson referred to an outbreak of a mad-cow-type disorder in minks in
Wisconsin in the 1980s. The origin was traced back to the animals' diet,
which included parts of so-called downer cattle -- sick cows that are
unable to stand, which often indicates a neurological disease, including
mad cow. The mink disease raised concerns about whether U.S. cattle were
carrying a mad-cow-like pathogen even prior to the U.K. epidemic that
began in 1986.
Andrew Monjan, chief of the neuropsychology of aging program at the
National Institute of Aging -- part of the National Institutes of Health
in Bethesda, Md. -- acknowledged there has been an increase in U.S.
Alzheimer's cases. However, he told UPI, this probably is due to the
aging of the population -- as people grow older, they develop a higher
risk of developing Alzheimer's.
"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.
So far, the CDC has refused to impose a national requirement that
physicians and hospitals report cases of the disease. The agency has not
chosen to make CJD a reportable disease because "making it reportable is
not necessarily directly helpful in surveillance because in some states
where it's reportable you may not get the physician to report it," said
Dr. Ermias Belay, CDC's medical epidemiologist working on CJD.
Instead, the agency relies on other methods, including death
certificates and urging physicians to send suspicious cases to the
National Prion Disease Pathology Surveillance Center at Case Western
Reserve University in Cleveland, which is funded by the CDC. However,
because autopsies generally are not done, if a CJD case is misdiagnosed
as Alzheimer's or dementia, a correct diagnosis might never be
determined and therefore the cause of death listed on a death
certificate might be inaccurate.
Belay told UPI he discounted this possibility. It is unlikely to happen,
he said, because it is easy to distinguish CJD from Alzheimer's -- the
two conditions display different symptoms.
Manuelidis disagreed. It can be quite difficult to determine accurately
if a patient has CJD, as evidenced by her study, in which respected and
competent neurologists and psychiatrists at Yale originally diagnosed
patients with Alzheimer's, yet were wrong at least 13 percent of the
time. Another study conducted at the University of Pennsylvania, which
found 6 percent of dementia patients actually were suffering from CJD,
supports the difficulty in distinguishing the illnesses correctly.
The U. Penn. researchers concluded: "These results show that in patients
with a clinical diagnosis of dementia, the etiology (cause) cannot be
accurately predicted during life."
In addition, the NPDPSC sees less than half of all the CJD cases each
year, so the CDC's investigational system not only is missing many of
the misdiagnosed CJD cases, it also is not conducting autopsies on most
of the detected cases.
Belay said the CDC follows up on all cases of CJD that occur in people
under age 55, as these could be linked to variant -- mad-cow-related --
CJD. But so far, all have turned out to be sporadic forms of the
disease. About 30 cases of the disorder occur each year in the United
States in this age group, while the remaining 270 or so are older.
The case of Carrie Mahan -- a Philadelphia woman who developed a brain
disorder that appeared to be CJD and died from it in 2000 at the age of
29 -- illustrates just how difficult it can be to diagnose the disease.
Mahan's physician, Dr. Peter Crinos of the University of Pennsylvania
Medical Center, ruled out other disorders and felt certain the young
woman had died of CJD, a concern that raised the possibility of a link
to mad cow disease because of her young age. When neuropathologist
Nicholas Gonatas, who had seen CJD before, examined Mahan's brain after
her death, he, likewise, was confident he detected the microscopic,
sponge-like holes caused by the disease. But when he sent brain samples
to the NPDPSC, the results came back negative. Gonatas, convinced the
surveillance center's finding was erroneous, sent off two more samples,
only to have them both come back negative.
Subsequent research, however, has shown the test used by the
surveillance center cannot rule out CJD, said Crinos, an assistant
professor of neurology.
"There's no question that Carrie had a spongiform encephalopathy,"
Crinos said, but added although it appeared to be CJD, it is difficult
if not impossible to say if it was due to mad cow disease.
Crinos told UPI until the CDC implements a better tracking system, a lot
of questions will remain about CJD and cases like Carrie Mahan's. One
central question: Why are cases of what is presumed to be a rare disease
popping up in clusters in certain areas of the country? Crinos said the
clustering suggests an environmental or food-borne cause, but so far,
"No one knows the answer to that."
Copyright © 2001-2003 United Press International
http://www.upi.com/view.cfm?StoryID=20030721-102924-4786r
WHAT ABOUT THOSE DEATH CERTIFICATES THAT ARE SUPPOSE
TO BE SO RELIABLE (per CDC et al);
THE EPIDEMIOLOGY OF CJD RG WILL 1984 (182 PAGES) & CJD ...
snip...
Localised areas with high incidence of CJD have been described in England,
Hungary, Czechoslovakia, ''U.S.A.'', and Italy, but in the absence of a
comparison with the national incidence, these ''CLUSTERS'' may well have
been
discovered by chance...[hense, the reason USA still refuses to have _NO_ CJD
Questionnaire...TSS]
snip...
HOWEVER, detailed _questioning of patients, relatives and subsequent
investigation_ (which the USA still refused to do in 2003...TSS)
revealed some remarkable coincidences. (or where they that coincidental?tss)
One patient, a dentist, had for many years daily passed the residence of
another patient, the husband of a hairdresser who worked in the family
home. The
dentist's wife used the hairdresser on occasions but the patient himself
had never
entered the salon. Interestingly the dentist himself had possible
contact with
other cases (vide infra) and a close acquaintance, another dentist,
worked in a
small town in Essex in which two further cases of CJD had occurred. In a
different
part of the country a district nurse who died of possible CJD may have
tended a patient dying of CJD seven years before she herself died of the
condition.
The nurse's daughter lived in a nearby city within 30 yards of the house
of another
patient. Detailed investigation of other cases revealed close proximity
to other
cases but no definite contact. Intensive questioning of surviving
relatives and other
witnesses was limited for FEAR OF CAUSING UNNECESSARY ALARM OR DISTRESS...
snip...
One patient who had previously worked on a farm died of CJD, but he had
workded with cattle, a species not known to be susceptible to natural
scrapie, and had no contact with sheep. [wrong...tss]
snip...
(Masters et al., 1979b) concluded that 'in familial clusters of CJD, the
virus is more likely to have gained access to the host through some form
of common environmental contamination than by vertical transmission'.
snip...
One reason for this was the _inaccuracy_ in coding of cases correctly
certified as CJD Coding is carried out by staff who are not medically
qualified
and it is not surprising that coding errors occur in the processing of large
numbers of certificates. In 1982, 12,000 certificates per week were
processed at
the office of population censuses and surveys bu 15 coders and 6
checkers (Alderson et
al., 1983). The occurrence of both inter- and intra-observer coding errors
has been described (Curb et al., 1983) and the _inaccuracies_ of BOTH
certification and coding discovered in this study _support_ the
introduction of a more
accurate system of death certificates and a more detailed and specific
coding system...
snip...
http://www.bseinquiry.gov.uk/files/mb/m26/tab01.pdf
AS implied in the Inset 25 we must not _ASSUME_ that
transmission of BSE to other species will invariably
present pathology typical of a scrapie-like disease.
snip...
http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf
ALSO;
FDA Mulls Blood Risk of Canadian Mad Cow
July 21, 2003
- STEVE MITCHELL, Medical Correspondent
United Press International
WASHINGTON, Jul 21, 2003 (United Press International via COMTEX) -- A
recent report of a Canadian case of mad cow disease has prompted the
Food and Drug Administration to ask U.S. blood banks to assess how many
donors they would lose if the agency banned people who had spent a
substantial amount of time in Canada from donating blood.
The concern is variant Creutzfeldt-Jakob disease, a fatal brain illness
humans can acquire from eating beef infected with mad cow disease, could
be unwittingly transmitted via blood transfusions. The potential for
this to occur in the United States was raised in late May when Canadian
authorities reported a cow in the province of Alberta had tested
positive for mad cow disease.
Dr. Jay Epstein, director of the FDA's office of blood research and
review, speaking at a meeting of the agency's transmissible spongiform
encephalopathies advisory committee, said the agency had requested blood
banks conduct residential travel surveys to estimate the number of
donors that would be lost if restrictions were imposed on people who had
lived or spent time in Canada. Several blood organizations have signaled
their support for this, he noted.
"This discussion actually started...when the Canadian cow was discovered
(May 20)," Dr. Louis Katz, president of America's Blood Centers, a
network of blood banks located in 46 U.S. states and Quebec, Canada,
told United Press International.
Since then, "people at FDA and people at blood centers have been
discussing what information we want and how best to collect it," he said.
One concern is a Canadian ban could drastically limit the number of
people who could donate, as "a substantial number of people,"
particularly in the northern and mid-western states, have spent a
substantial amount of time in Canada, Katz said. He noted they do not
yet have a good estimate of the number of donors a Canadian ban would
affect.
Epstein, speaking via FDA spokeswoman Lenore Gelb, emphasized the agency
is not currently considering putting a Canadian restriction in place.
"Our current thinking is the available data do not support a change in
policy at this time," he said. The FDA wants to have the data on the
impact of such a ban "just in case."
If anyone were infected with vCJD by Canadian beef, it could be years
before cases are detected as people can carry the illness for 10 years
or more before symptoms develop.
If the agency thought it was prudent to restrict people who had spent a
lengthy amount of time in Canada from donating blood, they first would
put the question to one of their advisory committees, Gelb said.
No case of CJD has ever been conclusively linked to a blood transfusion
but studies in animals have shown it is theoretically possible to
transmit the disease via blood, according to the World Health
Organization. For that reason, the FDA has banned people who spent three
months or more in the United Kingdom or five years or more in Europe
from donating blood in the United States. Beginning in the mid-1990s,
more than 100 people in the United Kingdom and several individuals in
various European countries contracted vCJD after eating beef tainted
with mad cow disease.
All of those infected with vCJD eventually die from the brain-wasting
disease as there is no treatment.
"Until more scientific information about blood safety is available or a
test is found to diagnose people who may carry vCJD, the main way to
lower the theoretical risk of vCJD in blood is through deferral of
donors who might have eaten contaminated beef products," the FDA said in
a statement posted on its Web site.
The agency estimated deferring the U.K. and European donors reduces the
risk by 90 percent, while not unduly limiting the blood supply.
So far, blood banks have not begun issuing a survey, Katz said. It would
be fairly easy to collect information on how much time donors have spent
in Canada, but the blood banks are considering whether it would be
appropriate to collect similar information for other countries so they
do not have to repeat the survey every time a country reports its first
case of mad cow disease.
If the FDA decides to impose restrictions on donors who have spent time
in Canada, Katz said he would expect it to be in accord with European
restrictions and require that people had spent a considerable amount of
time there, such as five years, due to the low-risk of a single case of
mad cow disease.
In the meantime, Katz said the blood supply is safe with regard to vCJD.
"The precautionary measures we've taken in the U.S. are adequate," he said.
Other deadly risks of blood transfusions, such as being given the wrong
blood type, are much bigger concerns than vCJD, he said.
The ideal situation would be to have a test that could screen blood
donations for vCJD, but Katz said that remains years away. By the time a
reliable test is developed the outbreak of vCJD in the United Kingdom
might have nearly disappeared and there could be no real use for a
screening test, he said.
Copyright 2003 by United Press International.
http://magazines.ivillage.com/goodhousekeeping/hb/news/article/0,,comtex_2003_07_21_up_0000-4845-bc-us-madcow-cjd-blood~ew~xml,00.html
Greetings,
SO, if the new findings from Asante/Collinge et al plays out to be true,
the price of poker will go up for sure in relations to the blood supply.
how many of the type 2 PrPSc (commonest sporadic CJD) will be from
BSE or other animal related TSEs i.e. CWD and whatever TSE is
documented in the USA cattle, whenever they decide to make it official;
Evidence That Transmissible Mink Encephalopathy
Results from Feeding Infected Cattle
R.F. Marsh* and G.R. Hartsough
http://www.bseinquiry.gov.uk/files/mb/m09/tab05.pdf
PDF]Freas, William TSS SUBMISSION
File Format: PDF/Adobe Acrobat -
Page 1. J Freas, William From: Sent: To: Subject: Terry S. Singeltary
Sr. [flounder@wt.net] Monday, January 08,200l 3:03 PM freas ...
snip...
I am beginning to think that the endless attempt to track down and ban,
potential
victims from known BSE Countries from giving blood will be futile. You would
have to ban everyone on the Globe eventually?
snip...
http://www.fda.gov/ohrms/dockets/ac/01/slides/3681s2_09.pdf
STUDY DESIGN AND METHODS: BSE was passaged through macaque monkeys and
then adapted to the prosimian microcebe (Microcebus murinus ). Brain
homogenate and buffy coat from an affected microcebe were separately
inoculated intracerebrally into three healthy microcebes (two animals
received brain and one received buffy coat).
RESULTS: All three inoculated microcebes became ill after incubation
periods of 16 to 18 months. Clinical, histopathologic, and
immunocytologic features were similar in each of the recipients.
CONCLUSION: Buffy coat from a symptomatic microcebe infected 17 months
earlier with BSE contained the infectious agent. This observation
represents the first documented transmission of BSE from the blood of an
experimentally infected primate, which in view of rodent buffy coat
infectivity precedents and the known host range of BSE is neither
unexpected nor cause for alarm.
http://www.blackwell-synergy.com/servlet/useragent?func=synergy&synergyAction=showAbstract&doi=10.1046/j.1537-2995.2002.00098.x
Transmission of prion diseases by blood transfusion
Nora Hunter,1 James Foster,1 Angela Chong,1 Sandra McCutcheon,2 David
Parnham,1 Samantha Eaton,1 Calum MacKenzie1 and Fiona Houston2
see full text;
http://www.socgenmicrobiol.org.uk/JGVDirect/18580/18580ft.pdf
http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm
NOW, besides all the ruminant SRMs that are still fed to cattle in the
USA in 2003,
what have we here, the USA also feeds them massive amounts of blood
products;
FIRST LIFE FORMULA A supplement for growing calves. I First Life
Formula is a unique combination of innovative calf supplements. ...
FIRST LIFE FORMULA includes PORCINE PLASMA AND
BOVINE SERUM for added immune protection and improved calf
performance......
Ingredients-- SPRAY DRIED ANIMAL PLASMA, SPRAY DRIED
BOVINE SERUM, LECITHIN BLEND....snip...CRUDE PROTEIN,
MINIMUM 55.0 %...snip///
http://www.accelgen.com/wn_FirstLifeFormula.html
TSS
-------- Original Message --------
Subject: Re: re-CJD screening may miss thousands of cases (see comments)
Date: Mon, 28 Jul 2003 15:56:22 -0500
From: "Terry S. Singeltary Sr."
Reply-To: Bovine Spongiform Encephalopathy
To: BSE-L@uni-karlsruhe.de
References: <3F1D5345.7070304@wt.net>
Greetings,
thought some might find interest in the data in this article on
clustering of
CJD and other topics of interest (a very horny French Foreign
Legionnaire?) ;
Is there evidence for exogenous risk factors in the aetiology and spread
of Creutzfeldt-Jakob disease?
SNIP...
The median age of death is 65 years. Below the age of 40, the incidence
is extremely low, but increases steadily, reaching a peak of
approximately 2/million/year in the 60–69 group. Most retrospective
studies have demonstrated that disease incidence drops steadily after
the age of 70. However, the most recent UK CJD Surveillance Report11
and a study
in Italy12
both show that the greatest relative increase in mortality has occurred
in those aged 70 years and above.
Clusters of cases
Something which is difficult to reconcile with the hypothesis that the
initial event in spCJD is a spontaneous conformational change in PrP, in
the absence of exogenous factors, is the existence of apparent clusters
of cases. There have been at least eight of these reported19,
25,
36–
39
and one for
vCJD.
Libyan Jews
A countrywide search for CJD in Israel uncovered 29 cases with onset
between 1963–72.25
The
incidence in various ethnic groups varied from 0.4 to 1.9 per million,
except among Jewish immigrants from Libya, among whom the incidence was
31.3 per million. The eating of lightly cooked sheep brain, a delicacy
amongst Mediterranean Jews, was at first postulated to be responsible,
but the incidence of CJD amongst other ethnic groups with the same
dietary habits was only 1–2 cases per million of the population.
Subsequently a genetic mutation at codon 200 of the prion protein gene
(PRNP) has been discovered in this ethnic group40
and would
explain this increased rate of disease seen. The accepted view is that
this mutation predisposes an individual to spontaneous transformation of
the normal soluble prion protein into the abnormal insoluble isoform.
This hypothesis is supported by the experimental observation that
transgenic mice carrying one of the mutations associated with
Gerstmann-Straussler-Scheinker disease (GSS), a rare hereditable human
prion disease, also spontaneously develop a spongiform encephalopathy.41
However,
could this mutation have its effect by predisposing to susceptibility to
an environmental cofactor? A more recent study by Zilber42
attempted
to answer this question. They argue that a direct answer could be
obtained by studying, either the incidence of CJD among the non-Jewish
population in Libya (same environment as the Libyan immigrants to Israel
but different ethnic group) or the incidence of CJD among Israeli born
Jewish population of Libyan ancestry (different environment but same
ethnic origin). Unfortunately little epidemiological data exist about
the incidence of CJD in Libya, and most of the cases, who emigrated to
Israel in 1949 and their children, born in Israel, are still too young
for epidemiological study. Instead, they tested their environmental
hypothesis indirectly. They made the assumption that the probability of
becoming infected would increase with length of stay in Libya if there
were an environmental risk factor. They found no indication of any
difference in probability of CJD by age at immigration.
The codon 200 mutation is not confined to Libyan Jews. It has been found
in families affected by familial CJD in Slovakia,43
Chile,44
America and
Japan,45
countries with very different cultures. This suggests that an
environmental cofactor would have to be ubiquitous. Also the codon 200
mutation does not automatically predict development of clinical disease.
Low degrees of disease penetrance (as low as 56% carrying the mutation44
) also
suggest that other genes or environmental factors may contribute to the
expression of disease in these mutation positive families.
The English clusters
Matthews described three geographical clusters in England. The first
concerned a small rural community in the Midlands and involved three
cases. Case 1, a woman of 46, died in 1964 and 4 years later, case 2, a
woman of 34, died of CJD. Case 2 had regularly spent time at her
sister's residence 2 km from the first case. Case 1 probably met case 2,
but this remains unconfirmed. In 1971, case 3, a 54-year-old man died of
CJD. He had lived in the same village as the sister of case 2 during the
1960s.
The second cluster involved five cases with onsets between 1969 and 1973
in four towns/villages in eastern England (separated by no more than 20
km), of whom at least three had lived locally since 1960. No definite
contact between cases could be established.
The third cluster described a patient who died of confirmed CJD in 1965.
In 1968, a patient who lived within 250 m also died of the disease.
Although they shared the same General Practitioner, their medical
records had been destroyed, and no further information was available. In
1980, a patient who lived midway between the two previous patients and
within sight of both houses died of pathologically-proven CJD. This last
patient had been a dentist from 1950–77, and used his house as a
surgery. Although the dental records have been examined, they were
incomplete and did not include records of either of the previous two
patients.39
An Italian cluster
Eleven cases of CJD occurred in and around Parma, Italy, between 1975
and 1979. Of the 11 cases, five were farmers. Case 1 was a man aged 50
who had been born into a farming family. From 1936–9, he had lived in
Ethiopia, and from 1940 to 1946 in Libya. Since then he had been a lorry
driver. He had been otherwise fit, except for contracting malaria at age
30, and having surgery in Libya for a strangulated hernia. Case 2 was a
miller who lived in the country 10 km from Parma. Cases 3, 4 and 5 were
described as small landowners and farmers. Case 4 had a gastrectomy in
1960. Case 6 was a blacksmith, and had previous surgery for carcinoma of
the lip. No details are given for case 7. Case 8 lived permanently in
Parma but had spent two short holidays in the same village where case 3
had lived. Case 9 had been a farmer, and cases 10 and 11 had both been
housewives, although the latter had at one time been a cook.38
No
spatio-temporal analysis was attempted and no conclusions can be drawn.
The Chilean cluster
A cluster in Chile, involving four cases of histologically-proven CJD in
three farmers and one housewife, occurred in 1982–3. The four lived in
small rural communities situated within a 20-km radius of the town of
Chillian. They were unrelated and did not know each other. Their life
long dietary habits are of interest, but uncertain relevance. They all
consumed uncooked sheep blood and poorly-cooked sheep blood and brain.
Although the existence of clusters might be said to constitute
persuasive evidence for an exogenous environmental factor in the
aetiology of CJD, it must be remembered that some clustering may occur
by chance and that ascertainment of a first case may predispose to
ascertainment of further cases.46
Case-to-case transmission in humans: case reports and series in which
spread through everyday human contact is suggested
There are six reports in which this possible mode of transmission is
considered. The most recent is that of a couple from the USA who had
been married for 30 years.47
The husband
died at age 53. He had no relevant family history, but had had a rotator
cuff repair one year before disease onset. His wife developed symptoms
four and half years after her husband's death. She was morbidly obese
and had had a previous hysterectomy, hernia repair and cholecystectomy.
Both occasionally ate brains in the form of ‘kizka’, a type of sausage.
Immunocytochemistry confirmed pathogenic prion protein deposition in
brain tissue from both husband and wife. Full sequencing of the open
reading frame of the PRNP failed to demonstrate any pathogenic
mutations. Another suspected conjugal case has recently been shown not
to be CJD. The histopathological specimens did not stain for prion
protein despite the microscopic appearance of spongiform change.48
Sporadic CJD has been described in two co-workers who shared a school
wing for 9 months.49
The first
was a 48-year-old Californian-born man of Hispanic American descent who
had had a traumatic leg amputation at age 23, but was otherwise well.
The second was a 48-year-old Chilean-born male who had a blood
transfusion 6 months before onset of symptoms, and was known to eat
lambs' brains. The first patient developed symptoms 5 months after the
last contact with his colleague and was confirmed to have spCJD 2 months
after this. The second patient developed symptoms months later and died
9 months after the last contact with his colleague.
An English woman, who died of CJD, histologically confirmed at post
mortem, was known to have contact with several affected members of a
family with familial CJD and was related to them by marriage.39
She had
known one of the family, who later died of CJD and had afternoon tea
with her at family gatherings, twice a year, for 20 years, as well as
visiting in her final illness. The woman herself died 12 years later.
There is another similar case of probable CJD, reported in a Chilean
woman who died 13 years after contact with a family with familial CJD.
No details of contact are given. A third case of death from CJD in
someone related in marriage to a family with familial CJD has been
reported in France, in a Tunisian family. No details are given with
regards to family history or contact.21
What is
notable about these last three incidents of supposed infection by social
contact is that all have occurred in association with familial CJD.
Although these patients were not known to have been genetically related
to their spouses, the possibility that they came from the same gene pool
cannot be dismissed.
Iatrogenic case-to-case transmission in humans: case reports and series
in which iatrogenic transmission has been proposed
It is clear that CJD can be transmitted from person to person by
injecting or implanting CJD infected instruments, tissue extracts and
organs.50–
52
Several
points relevant to a wider understanding of the epidemiology arise. (i)
The time from inoculation to disease onset is dependent on the route of
entry, the shortest incubation being approximately 16 months, in the
case of implantation of cerebral electrodes and recipients of corneal
grafts. By contrast, the longest incubation time is 30 years following
subcutaneous and intramuscular injection of growth hormone extract and
of gonadotrophins. These incubation times call into question some of the
proposed case-to-case transmission scenarios (above). (ii) The route of
transmission predicts the clinical appearance. Those infected directly
into the central nervous system develop a global dementia, whereas those
infected peripherally develop a progressive cerebellar syndrome. The
genotype of the prion gene does not explain this difference. That the
peripheral route of infection presents as a cerebellar syndrome would
support the view that vCJD is acquired peripherally by, for example,
diet, as cerebellar signs are an early prominent feature of vCJD but not
of spCJD.
Blood transfusion
The infectivity of blood for TSEs in animals is well described.53,
54
In
experimental scrapie, serum from infected sheep has transmitted the
disease to mice following intracerebral inoculation. Rat-to-rat
transmission has been demonstrated, also following inoculation of serum
intracerebrally. Infected mouse whole blood has been used to infect
previously healthy mice via the intracerebral route. Experimental CJD in
a guinea pig has transmitted to other guinea pigs by inoculation of
buffy coat (leukocytes and platelets) by the intracerebral,
intramuscular, intraperitoneal and subcutaneous routes, and inoculation
of infected mouse buffy coat by the intraperitoneal route has caused
disease in healthy mice.
Nevertheless, attempts to transmit CJD by infusing units of blood from
patients with CJD to the chimpanzee have failed.55
Although
experimentally difficult, transmission of spCJD and human
growth-hormone-related iatrogenic CJD to mouse, hamster and guinea pig,
by buffy coat and whole blood, has been demonstrated on four separate
occasions,53
but only
after intracerebral injection. This suggests that transmission from
human to human, via blood and blood products, is difficult but
theoretically possible. A number of case reports have suggested that
transmission by the transfusion of blood or a blood product has occurred
in humans.
In Australia,56
Klein
reported on four patients who had died of CJD in the early 1990s. None
had a history of familial CJD or had received human pituitary growth
hormone (hGH) or gonadotropin (hPG), but each had received a blood
transfusion 5 years before onset of symptoms. Unlike other reported
cases of blood-transfusion-related CJD cases, all presented with
symptoms of CJD suggestive of infection by the peripheral route—a
cerebellar syndrome in the absence of early dementia. Concern was raised
that these patients may have received blood from 1500 women who had
received pituitary gonadtrophin for infertility, three of whom have
already died of CJD ascribed to CJD-contaminated hPG. Of these three
women, two are known to have been regular blood donors.
There is only a single confirmed case of spCJD who is known to have
received albumin from a donor with confirmed CJD.57
This was a
69-year-old Canadian man who received 3 units of albumin during surgery
for a triple-coronary-artery bypass graft. The patient became
symptomatic 8 to 10 months post transfusion, and died one year later.
One case-control study has examined blood transfusion in spCJD.
Esmonde58
identified 202 definite and probable UK cases of spCJD between 1980–4
and 1990–2. Twenty-one patients had received blood, and 29 had donated
blood. This frequency of blood transfusion or donation did not differ
from that in age- and sex-matched controls. The clinical features in
patients with a history of blood transfusion were similar to those with
a history of classical spCJD and clearly distinct from CJD in recipients
of human growth hormone. However since spCJD is a rare disease and the
number of potentially infected units of blood is small, any difference
in the rate of receipt of transfusions between cases and controls will
be small. Thus a case-control study would have to be very large to
detect such a small difference.
Dietary factors: case reports and series compatible with the dietary
route of infection
Several case reports and series have reported an apparent increase in
the prevalence of CJD in populations of people who eat sheep or wild
animal brains. There has been one case report of definite CJD in a Dutch
man who ate occasional sheep brain and an annual feast of hog brain,59
and a case
series of four patients from North America who all ate squirrel and
other animal brains, including goat.60
A more
recent case series obtained a history of eating squirrel brains in all
five patients with probable or definite CJD seen over 3.5 years in a
neurocognitive clinic in Western Kentucky, USA.61
There are,
however, two reports of CJD in vegetarians. Matthews described a case in
a 62-year-old lifelong vegetarian.62
Although
she had never eaten meat, meat products or offal, she had handled raw
meat, preparing food for her husband. A study of seen patients from
India63
revealed that two cases had been vegetarians, but no further details are
given.
Zoonotic transmission: case reports and series compatible with infection
from animals
CJD and scrapie exist together in many countries, but the incidence of
CJD in countries where there is no scrapie, such as Australia, New
Zealand and Chile, (Table 2
) is no
different from that in scrapie-endemic countries.
In France, a detailed study looking at regional distribution of CJD and
scrapie infected flocks found no relationship.64
Nevertheless as CJD is rare, the incubation period may be very long, and
both human and animal populations may be very mobile, thus any
reassurance would have to be qualified.
A recent case of an Italian man and his cat65
is of
interest. A 60-year-old man developed CJD in November 1993 and died 3
months later. His cat developed a neurological disease at the same time,
and was killed at the time of her owner's death. Strain typing suggested
that the man was a case of sporadic CJD. The cat had the same strain,
distinct from the feline spongiform encephalopathy (FSE) strain,
described in the UK in the early 1990s.66
Zoonotic
transmission would require that the cat had infected her owner whilst
pre-symptomatic. A common source for both cat and man would seem more
probable. The circumstances would be hard to explain without an
exogenous source of disease.
Matthews67
described definite or probable CJD in four patients all of whom kept
ferrets for pets. One of the cases, who had also kept ferrets 30 years
previously, had definitely been bitten by a ferret 2 years before
disease onset. After his death, the ferret was killed and examined
histologically but no spongiform change was found. In addition the brain
of the ferret was inoculated into four species of monkey and one cat,
all of whom remained well. No such studies were performed with the other
cases.
Finally, Brown68
mentions
two cases of CJD in patients who, a year before diagnosis, had hip
replacements from goats as well as a case who had been a member of the
French Foreign Legion and had had sexual relations with a goat.
Occupational exposure: observations from case reports and series
Case reports and series focus on two main occupational groups; health
professionals and those who are exposed to farm animals, in particular
sheep and cattle.
There are at least 26 reports of sporadic CJD in health-care workers
world-wide.69–
71
These
include seven physicians, including a neurologist and head of an
intensive care unit, two neurosurgeons, an orthopaedic surgeon and a
pathologist, three dentists, a dental surgeon, nine nurses, three
nursing assistants and two histopathology technicians. Clinical details
are available for six of the cases.
Berger70
describes a 58-year-old physician who died of definite CJD and who, 20
years previously, had frequently performed autopsies. Weber71
described a
case in a 55-year-old orthopaedic surgeon who died of definite CJD. The
clinical picture was suggestive of a peripheral route of infection.
Twenty years previously, he had handled both sheep and human dura mater.
The specimens of dura mater were later sent to a company that sold dura
mater preparations that subsequently transmitted CJD on six occasions.
His wife did not remember any definite injury during the time he was
working with dura mater. Schoene72
reported a
case with an atypical clinical presentation including necrotizing
cutaneous lesions with vasculitis in a 54-year-old neurosurgeon, which
was later confirmed, as CJD, by experimental transmission. There was no
definite history of exposure to any case of CJD. In a case in a
pathologist,73
he is known
to have performed over 14 000 autopsies, but it is not known if any of
them were cases of CJD. There is no information on the dentists or
nurses. One of the two histopathology technicians had been a
neuropathology technician for 22 years74
and had
come into contact with two cases of CJD, 16 and 11 years before the
onset of her disease. The other technician75
had been
exposed to animal and human brain.
A wide range of occupations have been reported among cases of sporadic
CJD.6, 21
Several
case series quote an excess number of farmers and farmers' wives.24,
30
In an
Italian study,24
the
incidence was three times the expected. An analysis of epidemiological
surveillance data in the UK from 1970–9616
revealed a
statistically significant excess of cases among dairy farm workers and
their spouses and among people with greater degrees of contact with live
cattle infected with BSE. No such excess was found in abattoir workers
butchers or meat cutters.
Case-control studies
Case control studies are the time-honoured way of studying rare
diseases. To date there have been seven case-control studies of spCJD in
humans...
SNIP...
FULL TEXT;
http://qjmed.oupjournals.org/cgi/content/full/93/9/617#R25
Terry S. Singeltary Sr. wrote:
> CJD screening may miss thousands of cases
>
