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Creutzfeldt-Jakob Disease (CJD or Jakob-Creutzfeldt Disease)
is a rapidly progressive, fatal neurodegenerative disease. It is
part of a family of diseases, called transmissible spongiform encephalopathies,
that are caused by an agent known as a “prion”, a proteinaceous
infectious particle. Prions (Pree-ons) were named and discovered
by Dr. Stanley Prusiner at UCSF, who was awarded the 1997 Nobel Prize
for this work. Prions in animals cause diseases such as bovine spongiform
encephalopathy (BSE or mad cow disease) in cattle, scrapie in sheep
and goats, and chronic wasting disease (CWD) in mule and white-tailed
deer and in Rocky Mountain elk.
Human prion diseases include:
- Creutzfeldt-Jakob
disease (CJD)
- Fatal
Familial Insomnia (FFI)
- Gerstmann-Sträussler-Scheinker
(GSS) syndrome
- Kuru
- New
Variant CJD (nvCJD or vCJD)
Prion Disease Biology
The prion protein is a normal protein found throughout the body and brain.
In prion disease, this protein has the ability to take on an abnormal three-dimensional
shape and acts as a template that facilitates the conversion of surrounding
normal prion proteins into this abnormal form. By this mechanism, abnormal
prions accumulate within the brain. The end result of this accumulation is
neuronal dysfunction followed by neuronal death and gliosis. On neuropathology
the brain shows neuronal loss, gliosis, and
a spongiform appearance with vacuoles (vacuolation)
marking sites where the prion protein has injured pre- and post-synaptic terminals.
Demographics
Prion diseases of humans come in sporadic (spontaneous), genetic (familial),
and infectious forms. Eighty-five percent of cases of prion disease are sporadic
(sCJD), up to 15% are familial (fCJD, GSS, FFI), and fewer than 1% are iatrogenic.
Familial prion disease and the genetics of prion disease are discussed in
the section below. Iatrogenic cases of CJD have been due to insufficient
decontamination of surgical instruments, corneal transplants, dura mater
grafts, and human pituitary extract treatment.[1] As a result
of the awareness of the transmissibility of prion diseases, there has been
a significant decline in iatrogenic transmission of CJD since the 1980s.[2]
Though human prion diseases are rare, they have
been a focus of public health interest since a new type of CJD,
called new variant CJD (nvCJD, variant, or vCJD) was reported
in the UK in 1996 and linked to the ingestion of beef derived
from cows with BSE. More than 120 cases of vCJD have been reported
in the U.K. thus far. One case of variant CJD has been identified
in the United States and one in Canada, however both cases lived
in the U.K. during the BSE epidemic and are thought to have contracted
their illness from exposure in the UK.
Epidemiology
Surveillance and epidemiologic studies report an annual incidence of human
prion disease to be 1 per 1 million per year. CJD occurs worldwide, although
the cases have not been reported in countries in central Africa. There is
no compelling evidence that correlates place of residence, occupation, diet,
medical history, blood transfusion or drug therapy as risk factors for CJD.
Peak incidence for sporadic CJD occurs from ages 65-69 although age can range
significantly. CJD is especially rare in patients less than 30 years old,
and there is a sharp drop in incidence over the age of 75 years. Males and
females are affected equally, although some studies have indicated that there
is a slightly higher incidence of CJD in females (52.9%).[3] Epidemiologic
studies have not resulted in an explanation for the cause of sporadic CJD.[4]
The median survival time for sCJD is 4.5 months
and 90% of patients die within one year of first symptom. [5] However,
some cases are very rapid, surviving for only a few weeks, and
others have a prolonged disease duration lasting for a few (two
to three) years.
The new variant form of CJD affects a younger
population (average affected age is 29 years) and tends to have
a longer median survival of fourteen months. No cases of variant
CJD have been reported in the United States.
Symptoms
Prion disease or sporadic CJD is considered to be the prototypic rapidly
progressive dementia.
At UCSF we refer to CJD as the “Great Mimicker.” Because CJD affects
many different areas of the brain, it causes symptoms that can occur in other
neurological diseases. Symptoms that are commonly reported with sporadic CJD
include cerebellar dysfunction and/or ataxia, pyramidal
and extrapyramidal signs,
memory loss, changes in vision, myoclonus,
language impairment, and behavioral changes. Some patients may also present
with sensory symptoms or a peripheral neuropathy. Prodromal
symptoms prior
to the first neurologic sign or symptom are common and include insomnia, headache,
anorexia, behavioral changes, and depression.
First symptom varies widely from patient to patient.
First symptoms can include, but are not limited to, memory loss
or difficulty with balance and walking, dizziness, behavioral
change, visual disturbance, and involuntary movements. While
sporadic CJD varies clinically, the rapid progression of multiple
deficits that fail to improve is an indication that the underlying
disease could be CJD.
In the advanced stages of the disease, patients
commonly develop significant difficulties in movement and become
unable to talk and swallow (dysphagia).
Diagnosis
Diagnosing CJD as early as possible is important, because the underlying cause
of the rapidly progressive dementia (Hashimoto’s Encephalopathy, for
example) may be treatable. An early diagnosis will also aid families in making
future decisions for patient care.
— (Magnetic
Resonance Imaging) We
have found MRI to be the most helpful tool for diagnosing CJD.
An MRI should include T1, T2, FLAIR, and most importantly Diffusion
Weighted (DWI) sequences for detecting the abnormalities seen
in this disease. Sedation and even general anesthesia may be
required to avoid motion artifact for those patients unable to
be still during the time of the exam.
FLAIR and particularly DWI images will typically
show abnormalities (distinct hyperintensities) in the cortex
(cortical ribboning) and basal ganglia, specifically the caudate
and putamen, and in some cases the medial and posterior thalamus.
Hyperintensity in these subcortical structures is often bilateral,
though it may be initially unilateral. These changes are best
seen on DWI. Though specific regions that show this abnormality
vary from patient to patient, we often see involvement on MRI
of the cingulate cortex, posterior parietal cortex, insula, and
heads of the caudate. Cortical ribboning and other hyperintensities
often become more extensive as the disease progresses.
Hyperintensity in the basal ganglia and cortical
ribboning are distinct imaging features of sporadic CJD. We believe
that these specific abnormalities on MRI and having ruled out
other potential diseases often obviate the need for brain biopsy.
— (Electro-Encephalogram)
The
majority (75-85%) of sporadic CJD cases will show a specific
EEG pattern which consists of slowing of brain waves and/or the
presence of periodic sharp wave complexes; these EEG abnormalities
might not occur, however, until late in the disease course. Serial
EEGs offer the greatest likelihood of identifying these signature
findings. These EEG changes are not specific to CJD, as they
are also seen in toxic/metabolic conditions such as hyponatremia
or hepatic encephalopathy, and even rarely in Alzheimer’s
disease.
The figure shows an EEG typical of sCJD, with diffuse
one-hertz triphasic waves.
— (Cerebrospinal
fluid)
Cerebrospinal
fluid examination is usually normal with the exception of mildly
elevated total CSF protein (in our experience, typically less
than 100 mg/dL). A pleocytosis should
suggest against the diagnosis of CJD and that other diseases
need to be considered. An assay for a CSF protein called the
14-3-3 test has recently been used to diagnose CJD because several
CJD surveillance studies have reported a high sensitivity and
specificity for CJD (Hsich 1996; Posner et al); however, the
utility of this test continues to be debated.
A positive result for the 14-3-3 test has been
reported to occur in many other rapidly progressive dementias
that may be included in the differential of a patient with suspected
CJD. Our experience with this test suggests that it is not uncommon
for a patient with confirmed CJD to have a negative 14-3-3 result.
In one study, soon to be published in Archives of Neurology,
we found that only 53% of definite sCJD patients referred to
UCSF had a positive 14-3-3 test.
In
cases where diagnosis is difficult, even after MRI, patients
may undergo brain biopsy for pathologic confirmation of the
abnormal prion protein. Not all hospitals are willing to carry
out this procedure because of the transmissible nature of the
prion protein. We believe it is most helpful to biopsy regions
of the brain that appear “abnormal” on MRI. There
is a possibility that the brain biopsy results for a patient
with human prion disease are negative if unaffected tissue
is removed and analyzed. In some cases, human prion disease
is not pathologically confirmed until tissue from an autopsy
is analyzed. A recent paper in the New England Journal
of Medicine suggests that abnormal prions may be detected
in nasal mucosa. [6] Future research needs
to be done to determine the sensitivity of this assay.
Many
families need a sense of closure when a loved one passes; having
a definitive diagnosis obtained by autopsy can help in this effort.
For public health and epidemiologic reasons, the U.S. Center
for Disease Control and Prevention (CDC) strongly encourages
families with patients who suffer from human prion disease to
consider autopsy for their loved one. For help in obtaining autopsy
for patients outside of UCSF contact the National
Prion Disease Pathology Surveillance Center. Patients who
participate in UCSF CJD research projects or who are UCSF patients
may have autopsy services provided by UCSF.
Treatment
There is no established treatment or cure currently approved
for this disease. Researchers at UCSF have identified compounds
that may be potential treatments for prion diseases. A treatment
trial for sporadic CJD is currently underway at UCSF and
is actively enrolling subjects. For more information about
this study, please contact the CJD study coordinators at
(415) 476-0670 or cjdstudies@memory.ucsf.edu.
Additional details can be found on our research
page or at ClinicalTrials.gov.
Genetics
Approximately 85% of prion diseases occur sporadically with etiology unknown.
However, about 10-15% of cases have a genetic (familial) basis. This familial
form of prion disease is due to mutations in the prion gene PrP on chromosome
20. Presently more than 20 mutations (alterations in the DNA sequence) in the
gene have been reported. The characteristics of the disease (phenotype) correlate
with the mutation type.
Additionally there are 7 polymorphisms (benign
changes in the DNA sequence) some of which influence the phenotype,
age of onset, and disease duration conferred by particular mutations
and cause increased susceptibility to sporadic and variant CJD.
Of particular interest is the polymorphism at codon 129. This
codon can be found as val (valine) or met (methionine). An example
of its effect on phenotype is when it is combined with a mutation
known as D178N. If the mutation is in combination with 129val,
then the phenotype is that of CJD whereas in combination with
129met, the phenotype is a fatal familial insomnia. Additionally,
if a patient has a second copy of 129val in conjunction with
the normal allele (and is, therefore, homozygous), age of onset
is younger and survival is shorter.
Familial prion disease follows an autosomal dominant
inheritance pattern. Therefore, the offspring of someone with
one of these mutations has a 50% chance of inheriting a normal
gene and a 50% chance of inheriting the mutation. Researchers
believe that most prion mutations have full penetrance (people
with the mutation will develop the disease); however, the most
common mutation, E200K, has been reported to have reduced penetrance.
In this case, prion disease might not develop before death by
other causes. Although most familial prion disease can be detected
through careful examination of family history, uncommonly these
mutations may occur de novo.
Studies have shown that as many as 60% of cases
of genetic prion disease are not known to have a family history.
It is not known what percentage of these genetic cases without
a positive family history for prion disease are due to de
novo mutations,
though the number is thought to be very small. However, careful
review of family history often revealed supposed Alzheimer’s
or Parkinson’s disease.
The clinical characteristics of familial prion
disease are usually similar to those that are sporadic. However,
age of onset is usually earlier and duration of disease is usually
longer.
When a prion mutation is found in a family, asymptomatic
relatives may be interested in their own genetic testing. Predisposition
genetic testing should occur only after extensive genetic counseling
and baseline psychological, neuropsychological, and neurological
evaluation. Learning that one carries a gene for a fatal disease
can be devastating and should be considered very carefully. Genetic
counseling is offered to all of our familial prion disease families.
Evaluation
The Memory and Aging Center has been referred over 200 cases of rapidly progressive
dementia, including prion disease, over the past year. Dr. Michael Geschwind,
a neurologist at the MAC, is specifically interested in researching and clinically
evaluating patients with a rapidly progressive dementia. If you would like
to refer a patient with a rapidly progressive
dementia, please contact Dr. Geschwind at mgeschwind@memory.ucsf.edu or
call the Clinic Coordinator at (415) 476-6880.
The Memory and Aging Center has taken on a consultative
role for cases of rapidly progressive dementia from all over
the world. If you would like, with the family’s permission,
to share medical records and test results of cases suspected
of having CJD, the MAC will review these records.
Medical records
can be faxed to the attention of Dr. Geschwind at (415)
476-4800.
Copies of the actual MRI films can be sent to:
Attention: Dr. Geschwind
UCSF Memory and Aging Center
350 Parnassus Ave., Suite 905
San Francisco, CA 94117 |
Links & Resources
For more information, go to our Creutzfeldt-Jakob Disease section of our LINKS
and RESOURCES page where we list some other helpful websites on the topic.
References
1. Prusiner, S.B.,
Genetic and infectious prion diseases. Arch Neurol,
1993. 50(11): p. 1129-53.
2. Brown, P., M. Preece, J.P. Brandel,
et al., Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology,
2000. 55(8): p. 1075-81.
3. Holman RC, K.A., Belay ED, Schonberger
LB., Creutzfeldt-Jakob disease in the United States, 1979-1994:
using national mortality data to assess the possible occurrence
of variant cases. Emerg Infect Dis, 1996. 2(4): p.
333-7.
4. Will, R.G., M.P. Alpers, D. Dormont,
L.B. Schonberger, and J. Tateishi, Chapter 12. Infectious and
Sporadic Prion Diseases, in Prion Biology and Diseases, S.B.
Prusiner, Editor. 1999, Cold Spring Harbor Laboratory Press:
Cold Spring Harbor, New York. p. 465-507.
5. Will, R.G. and W.B. Matthews, A retrospective
study of Creutzfeldt-Jakob disease in England and Wales 1970-79.
I: Clinical features. J Neurol Neurosurg Psychiatry,
1984. 47(2): p. 134-40.
6. Zanusso, G., S. Ferrari, F. Cardone,
et al., Detection of pathologic prion protein in the olfactory
epithelium in sporadic Creutzfeldt-Jakob disease. N Engl
J Med, 2003. 348(8): p. 711-9.
7. Korth, C., B.C.H. May, F.E. Cohen,
and S.B. Prusiner, Acridine and phenothiazine derivatives as
pharmacoptherapeutics for prion disease. Proc Natl Acad
Sci U S A, 2001. 98(17): p. 9836-41.
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