| Creutzfeldt–Jakob disease | |
|---|---|
| Other names | Classic Creutzfeldt–Jakob disease |
 | |
| MRI of sporadic CJD | |
| Pronunciation | |
| Specialty | Neurology |
| Symptoms | Early: memory problems, behavioral changes, poor coordination, visual disturbances Later: dementia, involuntary movements, blindness, weakness, coma |
| Usual onset | Around 60 |
| Types | Sporadic, hereditary, acquired |
| Causes | Prion |
| Diagnostic method | After ruling out other possible causes |
| Differential diagnosis | Encephalitis, chronic meningitis, Huntington’s disease, Alzheimer's disease |
| Treatment | Supportive care |
| Prognosis | Universally fatal; 70% die within a year of diagnosis |
| Frequency | 1 per million per year |
Creutzfeldt–Jakob disease (CJD), also known as classic Creutzfeldt–Jakob disease, is a fatal degenerative brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later dementia, involuntary movements, blindness, weakness, and coma occur. About 70% of people die within a year of diagnosis.
CJD is caused by a protein known as a prion. Infectious prions are misfolded proteins that can cause normally folded proteins to become misfolded. Most cases occur spontaneously, while about 7.5% of cases are inherited from a person's parents in an autosomal dominant manner. Exposure to brain or spinal tissue from an infected person may also result in spread. There is no evidence that it can spread between people via normal contact or blood transfusions. Diagnosis involves ruling out other potential causes. An electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis.
There is no specific treatment. Opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements. CJD affects about one per million people per year. Onset is typically around 60 years of age. The condition was first described in 1920. It is classified as a type of transmissible spongiform encephalopathy. CJD is different from bovine spongiform encephalopathy (mad cow disease) and variant Creutzfeldt–Jakob disease (vCJD).
Signs and symptoms
The first symptom of CJD is usually rapidly progressive dementia, leading to memory loss, personality changes, and hallucinations. Myoclonus (jerky movements) typically occurs in 90% of cases, but may be absent at initial onset. Other frequently occurring features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. This is accompanied by physical problems such as speech impairment, balance and coordination dysfunction (ataxia), changes in gait, rigid posture. In most people with CJD, these symptoms are accompanied by involuntary movements and the appearance of an atypical, diagnostic electroencephalogram tracing. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks. Most victims die six months after initial symptoms appear, often of pneumonia due to impaired coughing reflexes. About 15% of people with CJD survive for two or more years.
The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion protein molecules forming amyloids. When brain tissue from a person with CJD is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word "spongiform" in "transmissible spongiform encephalopathies" refers to the sponge-like appearance of the brain tissue.
Cause
CJD, is a type of transmissible spongiform encephalopathy (TSE), which are caused by prions.
Prions are proteins that occur normally in neurons of the central
nervous system (CNS). These proteins, once misfolded, are thought to
affect signaling processes, damaging neurons and resulting in
degeneration that causes the spongiform appearance in the affected
brain.
The CJD prion is dangerous because it promotes refolding of native prion protein into the diseased state. The number of misfolded protein molecules will increase exponentially and the process leads to a large quantity of insoluble protein in affected cells.
This mass of misfolded proteins disrupts neuronal cell function and
causes cell death. Mutations in the gene for the prion protein can cause
a misfolding of the dominantly alpha helical regions into beta pleated
sheets. This change in conformation disables the ability of the protein
to undergo digestion. Once the prion is transmitted, the defective
proteins invade the brain and induce other prion protein molecules to
misfold in a self-sustaining feedback loop. These neurodegenerative diseases are commonly called prion diseases.
People can also develop CJD because they carry a mutation of the gene that codes for the prion protein (PRNP).
This occurs in only 5–10% of all CJD cases. In sporadic cases the
misfolding of the prion protein probably occurs as a natural,
spontaneous process. An EU study determined that "87% of cases were sporadic, 8% genetic, 5% iatrogenic and less than 1% variant."
Transmission
MRI of iCJD because of growth hormone
The defective protein can be transmitted by contaminated harvested human brain products, corneal grafts, dural grafts, or electrode implants and human growth hormone.
It can be familial (fCJD); or it may appear without risk factors (sporadic form: sCJD). In the familial form, a mutation has occurred in the gene for PrP, PRNP, in that family. All types of CJD are transmissible irrespective of how they occur in the person.
It is thought that humans can contract the disease by consuming
material from animals infected with the bovine form of the disease.
Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, once found primarily among women and children of the Fore people in Papua New Guinea.
While the men of the tribe ate the body of the deceased and rarely
contracted the disease, the women and children, who ate the less
desirable body parts, including the brain, were eight times more likely
than men to contract kuru from infected tissue.
Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention
recommend that instrumentation used in such cases be immediately
destroyed after use; short of destruction, it is recommended that heat
and chemical decontamination be used in combination to process
instruments that come in contact with high-infectivity tissues. No cases
of iatrogenic transmission of CJD have been reported subsequent to the
adoption of current sterilization procedures, or since 1976. Copper-hydrogen peroxide has been suggested as an alternative to the current recommendation of sodium hydroxide or sodium hypochlorite. Thermal depolymerization
also destroys prions in infected organic and inorganic matter, since
the process chemically attacks protein at the molecular level, although
more effective and practical methods involve destruction by combinations
of detergents and enzymes similar to biological washing powders.
Blood products
As
of 2018, evidence suggests that while there may be prions in the blood
of individuals with vCJD, this is not the case in individuals with
sporadic CJD.
Diagnosis
Testing
for CJD has historically been problematic, due to nonspecific nature of
early symptoms and difficulty in safely obtaining brain tissue for
confirmation. The diagnosis may initially be suspected in a person with
rapidly progressing dementia, particularly when they are also found with
the characteristic medical signs and symptoms such as involuntary muscle jerking, difficulty with coordination/balance and walking, and visual disturbances. Further testing can support the diagnosis and may include:
- Electroencephalography – may have characteristic generalized periodic sharp wave pattern. Periodic sharp wave complexes develop in half of the people with sporadic CJD, particularly in the later stages.
- Cerebrospinal fluid (CSF) analysis for elevated levels of 14-3-3 protein could be supportive in the diagnosis of sCJD. However, a positive result should not be regarded as sufficient for the diagnosis. The Real-Time Quaking-Induced Conversion (RT-QuIC) assay has a diagnostic sensitivity of more than 80% and a specificity approaching 100%, tested in detecting PrPSc in CSF samples of people with CJD. It is therefore suggested as a high-value diagnostic method for the disease.
- MRI of the brain – often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.
In recent years, studies have shown that the tumour marker Neuron-specific enolase
(NSE) is often elevated in CJD cases; however, its diagnostic utility
is seen primarily when combined with a test for the 14-3-3 protein. As of 2010,
screening tests to identify infected asymptomatic individuals, such as
blood donors, are not yet available, though methods have been proposed
and evaluated.
Imaging
Imaging
of the brain may be performed during medical evaluation, both to rule
out other causes and to obtain supportive evidence for diagnosis.
Imaging findings are variable in their appearance, and also variable in
sensitivity and specificity. While imaging plays a lesser role in diagnosis of CJD, characteristic findings on brain MRI in some cases may precede onset of clinical manifestations.
Brain MRI is most useful imaging modality for changes related to
CJD. Of the MRI sequences, diffuse-weighted imaging sequences are most
sensitive. Characteristic findings are as follows:
- Focal or diffuse diffusion-restriction involving the cerebral cortex and/or basal ganglia. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies. The most iconic and striking cortical abnormality has been called "cortical ribboning" or "cortical ribbon sign" due to hyperintensities resembling ribbons appearing in the cortex on MRI. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.
- Varying degree of symmetric T2 hyperintense signal changes in the basal ganglia (i.e., caudate and putamen), and to a lesser extent globus pallidus and occipital cortex.
- Cerebellar atrophy
Histopathology
Spongiform change in CJD
Testing of tissue remains the most definitive way of confirming the
diagnosis of CJD, although it must be recognized that even biopsy is not
always conclusive.
In one-third of people with sporadic CJD, deposits of "prion protein (scrapie)," PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbour significant amounts of PrPSc; however, biopsy
of brain tissue is the definitive diagnostic test for all other forms
of prion disease. Due to its invasiveness, biopsy will not be done if
clinical suspicion is sufficiently high or low. A negative biopsy does
not rule out CJD, since it may predominate in a specific part of the
brain.
The classic histologic appearance is spongiform change in the gray matter: the presence of many round vacuoles from one to 50 micrometers in the neuropil, in all six cortical layers in the cerebral cortex or with diffuse involvement of the cerebellar molecular layer. These vacuoles appear glassy or eosinophilic and may coalesce. Neuronal loss and gliosis are also seen. Plaques of amyloid-like material can be seen in the neocortex in some cases of CJD.
However, extra-neuronal vacuolization can also be seen in other disease states. Diffuse cortical vacuolization occurs in Alzheimer's disease, and superficial cortical vacuolization occurs in ischemia and frontotemporal dementia. These vacuoles appear clear and punched-out. Larger vacuoles encircling neurons, vessels, and glia are a possible processing artifact.
Classification
Types of CJD include:
- Sporadic (sCJD), caused by the spontaneous misfolding of prion-protein in an individual. This accounts for 85% of cases of CJD.
- Familial (fCJD), caused by an inherited mutation in the prion-protein gene. This accounts for the majority of the other 15% of cases of CJD.
- Acquired CJD, caused by contamination with tissue from an infected person, usually as the result of a medical procedure (iatrogenic CJD). Medical procedures that are associated with the spread of this form of CJD include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants. Variant Creutzfeldt–Jakob disease (vCJD) is a type of acquired CJD potentially acquired from bovine spongiform encephalopathy or caused by consuming food contaminated with prions.
| Characteristic | Classic CJD | Variant CJD |
|---|---|---|
| Median age at death | 68 years | 28 years |
| Median duration of illness | 4–5 months | 13–14 months |
| Clinical signs and symptoms | Dementia; early neurologic signs | Prominent psychiatric/behavioral symptoms; painful dysesthesias; delayed neurologic signs |
| Periodic sharp waves on electroencephalogram | Often present | Often absent |
| Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI | Often present | Often absent |
| Pulvinar sign-bilateral high signal intensities on axial FLAIR MRI. Also posterior thalamic involvement on sagittal T2 sequences | Not reported | Present in >75% of cases |
| Immunohistochemical analysis of brain tissue | Variable accumulation. | Marked accumulation of protease-resistant prion protein |
| Presence of agent in lymphoid tissue | Not readily detected | Readily detected |
| Increased glycoform ratio on immunoblot analysis of protease-resistant prion protein | Not reported | Marked accumulation of protease-resistant prion protein |
| Presence of amyloid plaques in brain tissue | May be present | May be present |
Treatment
As of 2015 there was no cure for CJD. Some of the symptoms like twitching can be managed, but otherwise treatment is palliative care.
Psychiatric symptoms like anxiety and depression can be treated with
sedatives and antidepressants. Myoclonic jerks can be handled with
clonazepam or sodium valproate. Opiates can help in pain. Seizures are very uncommon and can be treated with antiepileptic drugs.
Prognosis
The condition is universally fatal. As of 1981 people are not known to
have lived longer than 2.5 years after the onset of CJD symptoms.
Epidemiology
Although CJD is the most common human prion disease, it is still believed to be rare, estimated to occur in about one out of every one million people every year. However, an autopsy study published in 1989 and others suggest that between 3–13% of people diagnosed with Alzheimer's were actually misdiagnosed and instead had CJD.
Presumably, those afflicted have become infected through
prion-contaminated beef from cattle with subclinical atypical BSE
(bovine spongiform encephalopathy), which has a very long incubation
period. CJD usually affects people aged 45–75, most commonly appearing
in people between the ages of 60–65. The exception to this is the more
recently recognised 'variant' CJD (vCJD), which occurs in younger
people.
CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC:
- CJD occurs worldwide at a rate of about 1 case per million population per year.
- On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million people in the United States.
- In the United States, CJD deaths among people younger than 30 years of age are extremely rare (fewer than five deaths per billion per year).
- The disease is found most frequently in people 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.
- In more than 85% of cases, the duration of CJD is less than 1 year (median: four months) after onset of symptoms.
History
The disease was first described by German neurologist Hans Gerhard Creutzfeldt in 1920 and shortly afterward by Alfons Maria Jakob,
giving it the name Creutzfeldt–Jakob. Some of the clinical findings
described in their first papers do not match current criteria for
Creutzfeldt–Jakob disease, and it has been speculated that at least two
of the people in initial studies were suffering from a different
ailment. An early description of familial CJD stems from the German psychiatrist and neurologist Friedrich Meggendorfer (1880–1953).
A study published in 1997 counted more than 100 cases worldwide of
transmissible CJD and new cases continued to appear at the time.
The first report of suspected iatrogenic
CJD was published in 1974. Animal experiments showed that corneas of
infected animals could transmit CJD, and the causative agent spreads
along visual pathways. A second case of CJD associated with a corneal
transplant was reported without details. In 1977, CJD transmission
caused by silver electrodes previously used in the brain of a person
with CJD was first reported. Transmission occurred despite
decontamination of the electrodes with ethanol and formaldehyde.
Retrospective studies identified four other cases likely of similar
cause. The rate of transmission from a single contaminated instrument is
unknown, although it is not 100%. In some cases, the exposure occurred
weeks after the instruments were used on a person with CJD. In the 1980s it was discovered that Lyodura,
a dura mater transplant product was shown to transmit Creutzfeldt–Jakob
disease from the donor to the recipient. This led to the product being
banned in Canada but it was used in other countries as Japan until 1993.
A review article published in 1979 indicated that 25 dura mater
cases had occurred by that date in Australia, Canada, Germany, Italy,
Japan, New Zealand, Spain, the United Kingdom, and the United States.
By 1985, a series of case reports in the United States showed that when injected, cadaver-extracted pituitary human growth hormone could transmit CJD to humans.
In 1992, it was recognized that human gonadotropin administered by injection could also transmit CJD from person to person.
Stanley B. Prusiner of the University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 "for his discovery of Prions—a new biological principle of infection". However, Yale University neuropathologist Laura Manuelidis
has challenged the prion protein (PrP) explanation for the disease. In
January 2007, she and her colleagues reported that they had found a virus-like
particle in naturally and experimentally infected animals. "The high
infectivity of comparable, isolated virus-like particles that show no
intrinsic PrP by antibody labeling, combined with their loss of
infectivity when nucleic acid–protein complexes are disrupted, make it
likely that these 25-nm particles are the causal TSE virions".
Australia
There
have been ten cases of healthcare-acquired CJD (iatrogenic or ICJD) in
Australia. They consist of five deaths following treatment with
pituitary extract hormone for either infertility or short stature, with
no further cases since 1991. The five other deaths were caused by dura
grafting during brain surgery, where the covering of the brain was
repaired. There have been no other known healthcare-acquired ICJD deaths
in Australia.
However, the wife of Australian Reporter Mike Willesee died of the sporadic form of the disease in December 2006.
New Zealand
A case was reported in 1989 in a 25-year-old man from New Zealand, who also received dura mater transplant. Five New Zealanders have been confirmed to have died of the sporadic form of Creutzfeldt–Jakob disease (CJD) in 2012.
United States
In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire. Massachusetts General Hospital believed the person acquired the disease from a surgical instrument at a podiatrist's office.
In September 2013, another person in Manchester was posthumously
determined to have died of the disease. The person had undergone brain
surgery at Catholic Medical Center
three months before his death, and a surgical probe used in the
procedure was subsequently reused in other operations. Public health
officials identified thirteen people at three hospitals who may have
been exposed to the disease through the contaminated probe, but said the
risk of anyone's contracting CJD is "extremely low." In January 2015, former speaker of the Utah House of Representatives Rebecca D. Lockhart died of the disease within a few weeks of diagnosis. John Carroll, former editor of The Baltimore Sun and Los Angeles Times, died of CJD in Kentucky in June 2015, after having been diagnosed in January. American actress Barbara Tarbuck (General Hospital, American Horror Story) died of the disease on December 26, 2016.
Research
Diagnosis
- In 2010, a team from New York described detection of PrPSc in sheep's blood, even when initially present at only one part in one hundred billion (10−11) in sheep's brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay (SOFIA) and some specific antibodies against PrPSc. The technique allowed improved detection and testing time for PrPSc.
- In 2014, a human study showed a nasal brushing method that can accurately detect PrP in the olfactory epithelial of people with CJD.
Treatment
- Pentosan polysulphate (PPS) was thought to slow the progression of the disease, and may have contributed to the longer than expected survival of the seven people studied. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 people with PPS finds no proof of efficacy because of the lack of accepted objective criteria.
- Use of RNA interference to slow the progression of scrapie has been studied in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years.
- Both amphotericin B and doxorubicin have been investigated as treatments for CJD, but as yet there is no strong evidence that either drug is effective in stopping the disease. Further study has been taken with other medical drugs, but none are effective. However, anticonvulsants and anxiolytic agents, such as valproate or a benzodiazepine, may be administered to relieve associated symptoms.
- Quinacrine, a medicine originally created for malaria, has been evaluated as a treatment for CJD. The efficacy of quinacrine was assessed in a rigorous clinical trial in the UK and the results were published in Lancet Neurology, and concluded that quinacrine had no measurable effect on the clinical course of CJD.
- Astemizole, a medication approved for human use, has been found to have anti-prion activity and may lead to a treatment for Creutzfeldt–Jakob disease.
