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Creutzfeldt-Jakob Disease in Unusually Young Patients Who Consumed Venison
Ermias D. Belay, MD;
Pierluigi Gambetti, MD;
Lawrence B. Schonberger, MD;
Piero Parchi, MD;
Douglas R. Lyon, MD;
Sabina Capellari, MD;
Jennifer H. McQuiston, DVM;
Kristy Bradley, DVM;
Gerrie Dowdle, MSPH;
J. Michael Crutcher, MD;
Craig R. Nichols, MPA
Arch Neurol. 2001;58:1673-1678.
ABSTRACT
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Background Creutzfeldt-Jakob disease (CJD) in humans and chronic wasting disease
(CWD) in deer and elk occur in the United States. Recent reports of 3 unusually
young patients with CJD who regularly consumed deer or elk meat created concern
about the possible zoonotic transmission of CWD.
Objective To examine the possible transmission of CWD to humans.
Patients Three unusually young patients (aged 28, 28, and 30 years) with CJD
in the United States during 1997-2000.
Methods We reviewed medical records and interviewed family members and state
wildlife and agriculture officials. Brain tissue samples were tested using
histopathologic, immunohistochemical, immunoblot, or prion protein gene analyses.
Main Outcome Measures Presence or absence of established CJD risk factors, deer and elk hunting
in CWD-endemic areas, and comparison of the evidence for the 3 patients with
that of a zoonotic link between new variant CJD and bovine spongiform encephalopathy.
Results None of the patients had established CJD risk factors or a history of
travel to Europe. Two patients hunted game animals and 1 was a daughter of
a hunter. Unlike patients with new variant CJD, the 3 patients did not have
a unique neuropathologic manifestation, clinicopathologic homogeneity, uniformity
in the codon 129 of the prion protein gene, or prion characteristics different
from those of classic variants.
Conclusions Although the occurrence of 3 unusually young patients with CJD who consumed
venison suggested a possible relationship with CWD, our follow-up investigation
found no strong evidence for a causal link. Ongoing CJD surveillance remains
important for continuing to assess the risk, if any, of CWD transmission to
humans.
INTRODUCTION
CREUTZFELDT-Jakob disease (CJD) is a rapidly progressive, invariably
fatal neurodegenerative disorder classified as a transmissible spongiform
encephalopathy.1 This disease, like other transmissible
spongiform encephalopathies, is believed to be caused by the accumulation
in neurons of an abnormal isoform of a membrane glycoprotein known as the prion protein. Creutzfeldt-Jakob disease occurs at an estimated
annual incidence of approximately 1 case per million population. In the United
States, the disease primarily affects persons aged 55 to 75 years (median
age at death, 68 years).1, 2 Creutzfeldt-Jakob
disease occurs sporadically, without any recognizable pattern of transmission,
in approximately 85% of patients and as an inherited disease in 5% to 15%
of patients. Iatrogenic transmission of the CJD agent has been reported in
more than 250 patients worldwide through the use of contaminated cadaveric
human growth hormone, neurosurgical equipment, and dura mater and corneal
grafts.1, 3, 4 Sporadic
CJD has recently been further characterized and subdivided into 5 distinct
variants by correlating the clinical and pathologic phenotypes with the genotype
at the polymorphic codon 129 of the prion protein gene (PRNP) and the size of the protease-resistant prion protein (PrP-res)
fragment.5 The presence of these variants underscores
the heterogeneity of sporadic CJD.
In 1996, a new variant form of CJD (nvCJD) in unusually young patients
(median age at onset, 28 years) with a previously unrecognized distinct clinicopathologic
profile was reported in the United Kingdom.1, 6, 7
Strong laboratory and epidemiologic evidence indicates that nvCJD is causally
linked to an outbreak of bovine spongiform encephalopathy (BSE).7
The presumed transmission of BSE to humans through food consumption causing
nvCJD has focused attention on the possibility that chronic wasting disease
(CWD) in deer and elk could be transmitted in a similar way.
Chronic wasting disease was first recognized in 1967 in captive deer
at wildlife research facilities in Colorado. Subsequently, its occurrence
in free-ranging deer (Odocoileus species) and elk
(Cervus elaphus) was reported in Colorado and Wyoming.
Results of random preclinical testing of harvested animals indicated that
CWD occurs almost exclusively in a contiguous 38 137-km2 area
in northeastern Colorado and southeastern Wyoming.8, 9, 10
The overall CWD prevalence in mule deer in the endemic area during 1996-1999
was 4.9%; the prevalence in elk was less than 1%.10
Chronic wasting disease in free-ranging deer or elk has not been detected
in more than 10 states outside of the endemic areas in which surveys have
been conducted, except for 1 CWD-positive deer from southwestern Nebraska,
a few kilometers across the border from the known CWD-endemic areas of Colorado
and Wyoming. Occurrence of CWD in privately owned captive elk herds has been
reported in Colorado, Nebraska, Oklahoma, Montana, South Dakota, and Saskatchewan.8, 9
To explore the possible zoonotic transmission of the CWD agent, we investigated
3 unusually young patients with CJD who were reported to have regularly consumed
deer or elk meat. We summarize the clinical, epidemiologic, and laboratory
findings and present the available evidence regarding a possible causal link
between CWD and CJD in these patients.
PATIENTS AND METHODS
Patients were identified via the ongoing nationwide CJD surveillance
conducted by the Centers for Disease Control and Prevention (CDC), Atlanta,
Ga. This surveillance includes review of passively reported CJD cases, analysis
of national mortality data, follow-up investigation of patients younger than
55 years with CJD, and review of cases evaluated at the National Prion Disease
Pathology Surveillance Center, Cleveland, Ohio. This center was established
in 1997 by the American Association of Neuropathologists in collaboration
with the CDC to facilitate neuropathologic surveillance of human transmissible
spongiform encephalopathies in the United States. We reviewed clinical records
of the patients to assess their illness presentation, laboratory findings,
and disease progression. We determined the presence or absence of established
CJD risk factors, travel history, details of hunting practices, and food consumption
histories by interviewing close family members. We focused on possible exposures
to deer or elk meat originating from the known CWD-endemic areas of Colorado
and Wyoming. The Animal and Plant Health Inspection Service, US Department
of Agriculture, Riverdale, Md, in cooperation with state wildlife and agriculture
officials, collected hunter-harvested deer and elk brain samples from areas
where the patients or their families were reported to have hunted deer or
elk to evaluate the presence or absence of CWD in these areas. These brain
samples were tested by immunohistochemistry at the National Veterinary Services
Laboratories, Animal and Plant Health Inspection Service, US Department of
Agriculture, Ames, Iowa.
Fixed cortical sections of the brain obtained at autopsy and a blood
sample were available for testing for patient 1; fixed and unfixed brain tissue
samples obtained at biopsy and autopsy were available for patient 2; and fixed
and unfixed brain tissue samples obtained at biopsy were available for patient
3. Tissue samples were examined at the National Prion Disease Pathology Surveillance
Center. Histopathologic and immunohistochemical examinations and sequencing
of the open reading frame of the PRNP were performed
on tissue samples from all 3 patients. Immunoblotting of the PrP-res fragment
was done for patients 2 and 3 but not for patient 1 because frozen brain tissue
samples were unavailable. Immunohistochemical and immunoblot analyses were
performed using the monoclonal antibody 3F4 to prion protein residues 109-112.
The laboratory methods used in the histopathologic, immunohistochemical, immunoblot,
and genetic analyses have been described elsewhere.5, 11
Cerebrospinal fluid examination for the presence of the 14-3-3 protein was
performed for patients 2 and 3 according to methods described by Hsich et
al.12
RESULTS
Between January 1, 1997, and May 31, 2000, 2 patients with CJD aged
28 years and 1 aged 30 years with a history of venison consumption were reported
to the CDC (Table 1). None of
the patients had established CJD risk factors, such as a family history of
CJD, receipt of human growth hormone or dura mater or corneal grafts, or a
previous neurosurgical procedure. In addition, none of the patients had traveled
to Europe. Two patients were hunters and regularly consumed game meat. The
third patient was not a hunter but consumed venison from game animals hunted
by family members. Comparison of key evidence for a possible causal link between
the 3 patients' illness and CWD with that of patients with nvCJD and BSE in
the United Kingdom is shown in Table 2.
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Table 1. Selected Clinical and Laboratory Findings in 3 Unusually Young
Patients With CJD Who Had a History of Regular Venison Consumption, United
States*
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Table 2. Comparison of Key Evidence Supporting a Causal Link Between
BSE and nvCJD in the United Kingdom With That of CWD and Unusually Young Patients
With CJD in the United States*
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PATIENT 1
In early 1997, a 28-year-old woman was examined several times in an
emergency department for abnormal mental status, weakness, and unsteady gait.
She also developed ataxia, dyskinesia, and marked dysarthria. The patient's
condition gradually deteriorated, and she was admitted to a community hospital
in March 1997. On admission, the patient had lethargia, athetoid and choreoform
movements, constant lip smacking, possible hallucination, and increased muscle
tone. After hospital admission, she developed primitive frontal release signs
and episodic focal seizures. The electroencephalogram showed a severely abnormal
tracing with diffuse, slow triphasic waves. The computed tomographic scan
and magnetic resonance image of the brain did not reveal any abnormality.
A brain biopsy performed to evaluate a suspected CJD diagnosis showed only
gliosis. The patient died in June 1997, almost 4 months after the onset of
illness.
Histologic examination of brain tissue samples obtained at autopsy showed
widespread spongiform degeneration involving the cerebral cortex. The spongiosis
was associated with astrogliosis and moderate loss of neurons. The lesions
seemed to be more prominent in the frontal lobe and in the entorhinal cortex.
The basal ganglia; the thalamus, especially the mediodorsal nucleus; the tectum
of the midbrain and pons; the substantia nigra; and the molecular layer of
the cerebellar cortex all showed spongiosis and astrogliosis. Immunohistochemical
examination for prion protein residues demonstrated a strong and consistent
"synaptic" or "punctate" pattern of immunostaining in the cerebral cortex.
Rarely, the immunostaining showed a preferential perineuronal distribution
that involved both cell body and processes. Analysis of the PRNP indicated a Met/Met homozygosity at the
polymorphic codon 129 and absence of genetic mutations.
The patient's mother indicated that the patient had worked as a cashier
at different department stores and a fast food restaurant. She had undergone
tonsillar surgery at age 5 years. Her regular diet included consumption of
beef, pork, and chicken several times a week. She might have consumed lamb
or mutton once every several years. In addition, the patient consumed deer
meat between ages 1 and 6 years. The deer were harvested mostly from Maine
by the patient's father but occasionally from New Jersey by other family members.
The deer carcasses were usually prepared by a custom processor. The patient
primarily consumed the deer meat as steaks and ground meat mixed into sauce.
At about 6 years of age, the patient had also consumed elk meat provided by
a family friend as a gift on 2 different occasions. Although the origin of
the elk could not be clearly ascertained, a family member reported that it
was likely harvested in Wyoming. The patient was also reported to have occasionally
consumed meat from squirrel, bear, and rabbits. No consumption of brain or
organ meat from domesticated or game animals was reported.
PATIENT 2
In September 1998, a 29-year-old man was examined at a university hospital
for progressive cognitive difficulties. His illness began in May 1998, when
he experienced difficulty completing his travel expenses after a routine business
trip. The patient became increasingly forgetful, with inability to recall
his wife's name, his own home telephone number, and names of long-time family
friends. In August 1998 the patient resigned from his job because of the cognitive
problems. Subsequently, he developed behavioral problems and difficulties
with speech, writing, naming objects, and dressing without assistance. The
patient was ambulatory without imbalance but had dysmetria, tremors, and occasional
myoclonus. Findings from the initial 2 electroencephalograms, the computed
tomographic scan, and cerebral angiographic studies were normal. The magnetic
resonance image showed cerebral atrophy without any other abnormalities. Single-photon
emission computed tomographic imaging of the brain revealed a nonspecific,
asymmetric, diminished perfusion over the left parietal lobe. Results of initial
cerebrospinal fluid analysis for 14-3-3 protein were negative in November
1998. A brain biopsy performed in November 1998 showed diffuse spongiform
encephalopathy consistent with CJD. The patient died at age 30 years in March
1999, almost 10 months after the onset of illness.
Histologic examination of the brain tissue samples obtained at autopsy
showed prominent spongiform degeneration and gliosis with possible neuronal
loss in the cerebral cortex and basal ganglia. In contrast, the cerebellum
showed virtually no pathologic changes. The spongiosis often displayed a laminar
distribution that affected the deep cortical regions. Neurons that were moderately
ballooned were occasionally seen in the cerebral cortex. The pattern of prion
protein immunostaining was exclusively "synaptic" in the cerebral cortex and
basal ganglia, whereas the cerebellum was virtually unstained. Analysis of
the PRNP indicated that the patient was homozygous
for valine at the polymorphic codon 129. No PRNP
mutation was detected. Immunoblot analysis showed that the PrP-res fragment
migrated to 21 kd, corresponding to the prion protein type 1.
His past occupations included working as a stock boy in a grocery store
and recently as a salesperson. The patient had undergone a hernia repair during
infancy and tonsillar surgery at approximately 10 years of age. His regular
diet included consumption of beef many times a week and pork several times
a week. He occasionally ate mutton and cow brain, approximately once every
several years. The patient was described as a regular hunter, hunting almost
every year since 1985. He was reported to have hunted deer and elk in many
areas, almost always in Utah. He did, however, hunt an elk in the southwestern
part of Wyoming in 1995 and was part of a team that hunted deer around Williams
Lake, British Columbia, in 1989. The patient usually field dressed the carcasses
himself and took them to a particular plant for custom processing. In addition,
the family has many times received gifts of deer and elk meat from the patient's
brother, who regularly hunted in Utah. The family usually ate the deer and
elk meat as steak, ground meat, and jerky almost once a month. Moreover, the
patient regularly ate liver from deer and elk but not other organ meat, including
brain, from any game animals.
PATIENT 3
In December 1998, a 27-year-old man began experiencing difficulty finding
his hometown and lapses in memory while performing his duties as a truck driver.
During the next month, the patient became increasingly forgetful, constantly
asking for directions and instructions on how to operate the truck. He started
to exhibit impulsive and impatient behavior, the inability to dress properly,
difficulty finding words, and confusion. He also developed myoclonus and sleep
disturbances. The electroencephalographic tracing was abnormal but nondiagnostic.
The magnetic resonance image of the brain showed diffuse cortical hyperintensity
with an unusual but nonspecific pattern. Findings from the cerebrospinal fluid
14-3-3 immunoassay were positive. Histopathologic examination of the cerebral
cortical tissue samples obtained at biopsy revealed widespread spongiform
degeneration associated with astrogliosis and a possible loss of neurons.
Analysis of the PRNP indicated a Met/Val heterozygosity at codon 129 and absence of PRNP mutations. Immunoblot analysis showed that the PrP-res fragment
migrated to 21 kd, in the polyacrylamide gel corresponding to the prion protein
type 1. The patient died in April 2000 at age 28 years, almost 15 months after
the onset of illness. No autopsy was performed.
His occupations included driving a truck locally and spreading fertilizers.
Since 1993 he had also been assisting his father-in-law in raising beef cattle.
The patient had no history of surgical procedures. His regular diet included
consumption of beef, pork, and chicken several times a week. No consumption
of lamb or mutton was reported. The patient was described as an "avid hunter,"
hunting deer regularly since age 13 years, and frequently harvested at least
1 deer annually. Almost all his deer hunting took place exclusively in 2 very
localized areas within 2 counties close to his hometown. The patient usually
field dressed the deer carcasses himself and took them to a particular plant
for custom processing. During the previous 6 years, the patient and his family
had reportedly consumed only ground venison almost once a month. During his
childhood, the patient also consumed deer meat harvested by his father. The
patient's wife reported no consumption of deer or elk meat originating from
either Colorado or Wyoming. However, the custom processing plant where the
patient regularly took the deer carcasses for processing also processed approximately
20 elk from Colorado every year. The exact geographic origin in Colorado of
these elk could not be ascertained. No consumption of brain or other organs
from domesticated or game animals was reported. On the basis of hunter survey
data obtained from the local Department of Wildlife Conservation, the patient's
hunting practices were typical of other game animal hunters in the area. Analysis
of the 1998 hunter licensing data estimated that approximately 24% of families
and approximately 17% of households in the state might include a licensed
hunter.
COMMENT
In the United States, the occurrence of CJD in persons 30 years or younger
is rare. During 1979-1996, only 12 CJD cases in this young age group were
reported to the CDC. The occurrence of CJD in unusually young patients is
generally regarded as a warning signal for an exogenous source of infection.
Eight of the 12 US CJD cases in persons 30 years or younger resulted from
the use of contaminated human growth hormone or dura mater grafts. After surveillance
for young patients with CJD was increased in 1996 owing to concern about nvCJD,
the 3 young patients described in this study constituted all but 1 of the
sporadic CJD cases in persons 30 years or younger reported in the United States
through May 31, 2000. The fourth unusually young patient with CJD was homozygous
for valine and predominantly had cerebellar dysfunction and an illness duration
of approximately 5 years; the patient was not a hunter and did not have a
history of venison consumption. Nevertheless, the occurrence since 1996 of
the 3 patients described in this study created concern about a possible zoonotic
transmission of CWD primarily because of their unusually young age, absence
of established CJD risk factors, and frequent consumption of deer or elk meat.
In the United Kingdom, the occurrence of a cluster of 10 unusually young
patients with CJD (median age, 28 years) during 1994-1995 prompted investigators
to explore the possible transmission to humans of the BSE agent that was causing
a widespread epidemic in cattle in the United Kingdom for more than 10 years.6 The UK government's conclusion that the illness in
these unusually young patients might have been causally linked to BSE was
later strengthened by additional epidemiologic and laboratory evidence.1 These key lines of evidence supporting a causal link
between BSE and nvCJD in the United Kingdom were compared with those of a
possible link between CWD and CJD in the 3 young US patients (Table 2). The nvCJD was notable for a definite increase of the disease
in unusually young patients. Through February 2001, 57 (67%) of 85 patients
with nvCJD died at 30 years or younger in the United Kingdom (R. G. Will,
MD, oral communication, February 2001).13 In
contrast, no definite increase of unusually young patients with CJD was documented
in the United States despite increased surveillance for young patients with
CJD since 1996. Among the nvCJD cases, a unique but uniform neuropathologic
profile was reported, including spongiform lesions most evident in the basal
ganglia and the presence of multiple plaques characterized by a halo of surrounding
spongiform lesions, resembling the "florid" plaques described in experimental
transmission of Icelandic scrapie in mice.14
In contrast, the neuropathologic manifestation in the 3 US young patients
was not different from that previously documented for patients with sporadic
CJD.5 In patients with nvCJD, the immunoblot
characteristics of the PrP-res fragment were distinct from those of PrP-res
obtained from patients with sporadic CJD. In at least 2 of the patients we
investigated (patients 2 and 3), however, the PrP-res fragment was shown to
have the type 1 immunoblot pattern similar to that reported in about 71% of
patients with sporadic CJD.5 All the reported
patients with nvCJD had Met/Met homozygosity at codon
129 of the PRNP, whereas each of the 3 patients in
our study had the different polymorphisms at codon 129 (Table 1).
On the basis of a sporadic CJD classification scheme developed by Parchi
et al,5 patients 2 and 3 would have been classified
into 2 distinct groups, VV1 and MM1/MV1 variants, respectively. Patient 1
had Met/Met homozygosity at the polymorphic codon
129, but the immunoblot was not performed because of lack of frozen brain
tissue samples. However, the CJD phenotype in this patient was consistent
with that of the MM1/MV1 variant. The MM1/MV1 variant is the most common and
represents approximately 70% of sporadic CJD cases. In comparison, the VV1
variant represents approximately 1% of sporadic CJD cases. Because of the
similar characteristics between patients with the VV1 variant and patient
2, we explored the possibility that the 4 other patients with this variant
reported to date might have also hunted game animals or consumed venison.
Three of the cases were reported in Germany and the fourth was in the United
States (H. A. Kretzschmar, MD, written communication, August 2000).15 None of the 4 patients were game animal hunters,
and 2 of the 4 had no history of venison consumption.
The most frequent exposure to game animals in all 3 patients was consumption
of deer meat. However, none of the deer consumed by the patients originated
from the CWD-endemic areas of Wyoming and Colorado. In addition, immunohistochemical
analysis identified no CWD among 1037 hunter-harvested deer and elk brain
samples collected during the 1999 hunting season from the areas where the
deer meat consumed by patient 1 (299 deer samples), patient 2 (404 deer and
196 elk samples), and patient 3 (138 deer samples) originated (L. A. Detwiler,
DVM, e-mail communication, April 2000). Although our investigation did not
document exposure to game animals specifically from the CWD-endemic counties
of Wyoming and Colorado, patients 1 and 2 had a history of possible or recent
exposure, respectively, to elk meat from Wyoming. The elk meat consumed by
patient 1 and her family on 2 different occasions when the patient was aged
approximately 6 years was reported to have possibly been harvested by a family
friend from Wyoming. The Wyoming origin of the elk was based on a vague recollection
by the patient's mother, and we were unable to trace and independently verify
the origin by interviewing the family friend. The elk meat consumed by patient
2 and his family was reportedly harvested by the patient from southwestern
Wyoming during the 1995 hunting season. However, the exposure to elk meat
in 1995 implies an incubation period of less than 3 years, which seems to
be too short for the oral route of exposure. In addition, no cases of CWD
were reported in the southwestern part of Wyoming where the patient hunted
the elk.10 For patient 3, the only plausible
exposure to deer or elk meat from CWD-endemic states that our investigation
uncovered was the possibility that his deer meat could have been contaminated
at the custom processing plant with elk meat harvested from Colorado and processed
in the same plant. It remains uncertain whether any of the elk processed in
the plant were infected or originated from Colorado counties known to have
endemic CWD.
Although the occurrence of CJD in 3 unusually young persons who regularly
consumed deer and elk meat and had no known CJD risk factors suggested a possible
link to CWD, our investigation found no strong evidence for a causal association
between CWD and CJD. None of these patients had a definite history of consumption
of deer or elk meat obtained from the CWD-endemic areas. In addition, the
lack of homogeneity in the polymorphic codon 129 of the PRNP and phenotypic expression of the disease suggest that a causal
link between CWD and CJD in the 3 patients is unlikely. Rather, the results
of our investigation indicate that the association of the 3 unusually young
CJD cases with game animal hunting or venison consumption was more likely
coincidental than causal. Venison consumption is not uncommon in the United
States. In a survey conducted by the American Red Cross and other blood banking
establishments, 40% of US blood donors reported consumption of deer or elk
meat obtained from the wild.16 On the basis
of such a prevalence of venison consumption, a history of consumption of deer
or elk meat in 3 of the 4 patients with sporadic CJD 30 years or younger reported
in the United States after March 1996, when surveillance for young patients
with CJD was increased, could reasonably have occurred by chance alone. Nevertheless,
to further assess the possibility that the CWD agent might occasionally cause
disease in humans, additional laboratory studies could be helpful, including
molecular characterization and strain typing of the agents causing CWD in
deer and elk and CJD in potentially exposed patients. Ongoing national surveillance
of CJD will remain important for continuing to assess the risk, if any, of
CWD transmission to humans.
AUTHOR INFORMATION
Accepted for publication March 22, 2001.
This study was supported in part by grant AG 14359 from the National
Institutes of Health, Bethesda, Md; grant CCU 515004 from the CDC; and the
Britton Fund, Cleveland.
We thank John O'Connor for editorial assistance; Monica Colucci, MD,
and Shu Chen, PhD, for assisting in immunoblot analysis; Aaron Curns, MPH,
for statistical consultation; and family members of the patients for their
collaboration in providing detailed information about the patients. We also
thank the Oklahoma Department of Wildlife Conservation, Oklahoma City, for
providing information on hunter-harvest surveys and hunter license information
and the Florida Department of Health, Tallahassee, for facilitating our investigation.
From the Division of Viral and Rickettsial Diseases, National Center
for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta,
Ga (Drs Belay, Schonberger, and McQuiston); the National Prion Disease Pathology
Surveillance Center, Division of Neuropathology, Institute of Pathology, Case
Western Reserve University, Cleveland, Ohio (Drs Gambetti, Parchi, and Capellari);
the Utah Department of Health, Salt Lake City (Dr Lyon, Ms Dowdle, and Mr
Nichols); and the Oklahoma State Department of Health, Oklahoma City (Drs
Bradley and Crutcher).
Corresponding author and reprints: Ermias D. Belay, MD, Centers for
Disease Control and Prevention, Mailstop A-39, 1600 Clifton Rd, Atlanta, GA
30333.
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Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
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