What is Creutzfeldt-Jakob disease?
• Creutzfeldt-Jakob disease (CJD) is a rapidly
progressive, invariably fatal
neurodegenerative disorder believed to be
caused by an abnormal isoform of a cellular
glycoprotein known as the prion protein. CJD
occurs worldwide and the estimated annual
incidence in many countries, including the
United States, has been reported to be about
one case per million population.
• Nonspecific prodromal symptoms occur in about a third of patients with
CJD and may include fatigue, sleep disturbance, weight loss, headache,
anxiety, vertigo, malaise, and ill-defined pain. Most patients with CJD
present with deficits in higher cortical function. These deficits almost
always progress over weeks or months to a state of profound dementia
characterized by memory loss, impaired judgment, and a decline in
virtually all aspects of intellectual function. A few patients present with
either visual impairment or cerebellar gait and coordination deficits.
Frequently the cerebellar deficits are rapidly followed by progressive
dementia. Visual problems often begin with blurred vision and diminished
acuity, rapidly followed by dementia.
• Other symptoms and signs include extrapyramidal dysfunction manifested
as rigidity, masklike facies, or (less commonly) choreoathetoid
movements; pyramidal signs (usually mild); seizures (usually major motor)
and, less commonly, hypoesthesia; supranuclear gaze palsy; optic atrophy;
and vegetative signs such as changes in weight, temperature, sweating, or
• Most patients (90%) with CJD exhibit myoclonus that
appears at various times throughout the illness. Unlike
other involuntary movements, myoclonus persists
during sleep. Startle myoclonus elicited by loud sounds
or bright lights is frequent. It is important to stress that
myoclonus is neither specific nor confined to CJD and
tends to occur later in the course of CJD. Dementia
with myoclonus can also be due to Alzheimer's disease
(AD), dementia with Lewy bodies, corticobasal
degeneration, cryptococcal encephalitis, or the
myoclonic epilepsy disorder Unverricht-Lundborg
• The constellation of dementia, myoclonus, and periodic electrical bursts in
an afebrile 60-year-old patient generally indicates CJD. Clinical
abnormalities in CJD are confined to the CNS. Fever, elevated
sedimentation rate, leukocytosis in blood, or a pleocytosis in cerebrospinal
fluid (CSF) should alert the physician to another etiology to explain the
patient's CNS dysfunction.
• Variations in the typical course appear in inherited and transmitted forms
of the disease. fCJD has an earlier mean age of onset than sCJD. In GSS
disease, ataxia is usually a prominent and presenting feature, with
dementia occurring late in the disease course. GSS disease typically
presents earlier than CJD (mean age 43 years) and is typically more slowly
progressive than CJD; death usually occurs within 5 years of onset. FFI is
characterized by insomnia and dysautonomia; dementia occurs only in the
terminal phase of the illness. Rare sporadic cases have been identified.
vCJD has an unusual clinical course, with a prominent psychiatric
prodrome that may include visual hallucinations and early ataxia, while
frank dementia is usually a late sign of vCJD.
• The only specific diagnostic tests for CJD and other human prion diseases
measure PrPSc. The most widely used method involves limited proteolysis
that generates PrP 27-30, which is detected by immunoassay after
denaturation. The conformation-dependent immunoassay (CDI) is based
on immunoreactive epitopes that are exposed in PrPC but buried in PrPSc.
In humans, the diagnosis of CJD can be established by brain biopsy if PrPSc
is detected. If no attempt is made to measure PrPSc, but the constellation
of pathologic changes frequently found in CJD is seen in a brain biopsy,
then the diagnosis is reasonably secure (see "Neuropathology," above).
The high sensitivity and specificity of cortical ribboning and basal ganglia
hyperintensity on FLAIR and diffusion-weighted MRI for the diagnosis of
CJD have greatly diminished the need for brain biopsy in patients with
suspected CJD. Because PrPSc is not uniformly distributed throughout the
CNS, the apparent absence of PrPSc in a limited sample such as a biopsy
does not rule out prion disease. At autopsy, sufficient brain samples
should be taken for both PrPSc immunoassay, preferably by CDI, and
immunohistochemistry of tissue sections.
• T2-weighted (FLAIR) MRI showing hyperintensity in the cortex in a patient with sporadic
CJD. This so-called "cortical ribboning" along with increased intensity in the basal ganglia on
T2 or diffusion-weighted imaging can aid in the diagnosis of CJD.
Care of Cjd Patients
• Although CJD should not be considered either contagious or
communicable, it is transmissible. The risk of accidental inoculation by
aerosols is very small; nonetheless, procedures producing aerosols should
be performed in certified biosafety cabinets. Biosafety level 2 practices,
containment equipment, and facilities are recommended by the Centers
for Disease Control and Prevention and the National Institutes of Health.
The primary problem in caring for patients with CJD is the inadvertent
infection of health care workers by needle and stab wounds.
Electroencephalographic and electromyographic needles should not be
reused after studies on patients with CJD have been performed.
• There is no reason for pathologists or other morgue employees to resist
performing autopsies on patients whose clinical diagnosis was CJD.
Standard microbiologic practices outlined here, along with specific
recommendations for decontamination, seem to be adequate precautions
for the care of patients with CJD and the handling of infected specimens.
Prevention and Therapeutics
• There is no known effective therapy for preventing or treating CJD. The finding
that phenothiazines and acridines inhibit PrPSc formation in cultured cells led to
clinical studies of quinacrine in CJD patients. Unfortunately, quinacrine failed to
slow the rate of cognitive decline in CJD, possibly because therapeutic
concentrations in the brain were not achieved. Although inhibition of the P-
glycoprotein (Pgp) transport system resulted in substantially increased quinacrine
levels in the brains of mice, the prion incubation times were not extended by
treatment with the drug. Whether such an approach can be used to treat CJD
remains to be established.
• Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc from
cultured cells. Additionally, such antibodies in mice, either administered by
injection or produced from a transgene, have been shown to prevent prion disease
when prions are introduced by a peripheral route, such as intraperitoneal
inoculation. Unfortunately, the antibodies were ineffective in mice inoculated
intracerebrally with prions. Several drugs, including pentosan polysulfate as well as
porphyrin and phenylhydrazine derivatives, delay the onset of disease in animals
inoculated intracerebrally with prions if the drugs are given intracerebrally
beginning soon after inoculation.