|Biopsy of the tonsil in variant CJD. Prion protein immunostaining.|
Early: memory problems, behavioral changes, poor coordination, visual disturbances|
Later: dementia, involuntary movements, blindness, weakness, coma
|Usual onset||Around 60|
|Types||Sporadic, hereditary, acquired|
|Diagnostic method||After ruling out other possible causes|
|Differential diagnosis||Encephalitis, chronic meningitis, Huntington’s disease, Alzheimer's disease|
|Prognosis||Fatal, 90% die within a year of diagnosis|
|Frequency||1 per million per year|
Creutzfeldt–Jakob disease (CJD) is a universally fatal brain disorder. Early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. Later dementia, involuntary movements, blindness, weakness, and coma occur. About 90% of people die within a year of diagnosis.
CJD is believed to be 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).
- 1 Signs and symptoms
- 2 Cause
- 3 Diagnosis
- 4 Treatment
- 5 Outcomes
- 6 Epidemiology
- 7 History
- 8 Research
- 9 See also
- 10 References
- 11 External links
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.
Transmissible spongiform encephalopathy diseases 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."
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 patient.
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.
As of 2018 evidence suggest that while there may be prions in the blood of individuals with vCJD, this is not the case in individuals with sporadic CJD.
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 patients with sporadic CJD, particularly in the later stages.
- Cerebrospinal fluid 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 PrPScin CSF samples of CJD patients. 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[update], screening tests to identify infected asymptomatic individuals, such as blood donors, are not yet available, though methods have been proposed and evaluated.
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 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
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 patients 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.
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.
|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 fluid attenuated inversion recovery (FLAIR) MRI. Also posterior thalami 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|
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.
The condition is universally fatal, though cases where people live up to 2.5 years have been described.
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.
- 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 patients 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.
The Lancet in 2006 suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea. The reasoning behind the claim is that kuru was possibly transmitted through cannibalism in Papua New Guinea when family members would eat the body of a dead relative as a sign of mourning. In the 1950s, cannibalism was banned in Papua New Guinea. In the late 20th century, however, kuru reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 20 to 50 years. A critique to this theory is that while mortuary cannibalism was banned in Papua New Guinea in the 1950s, that does not necessarily mean that the practice ended. Fifteen years later Jared Diamond was informed by Papuans that the practice continued. Kuru may have passed to the Fore people through the preparation of the dead body for burial.
These researchers noticed a genetic variation in some kuru patients that has been known to promote long incubation periods. They have also proposed that individuals having contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for bovine spongiform encephalopathy (BSE). This means that there may be many more vCJD patients with longer incubation periods, which may surface many years later.
In 1997, a number of people from Kentucky developed CJD. It was discovered that all the victims had consumed squirrel brains, although a coincidental relationship between the disease and this dietary practice may have been involved. In 2008, UK scientists expressed concern over the possibility of a second wave of human cases due to the wide exposure and long incubation of some cases of vCJD.
Prion protein is detectable in lymphoid and appendix tissue up to two years before the onset of neurological symptoms in vCJD. Large scale studies in the UK have yielded an estimated prevalence of 493 per million, higher than the actual number of reported cases. This finding indicates a large number of asymptomatic cases and the need to monitor.
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 patients 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.
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".
There have been ten cases of healthcare-acquired CJD 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 CJD deaths in Australia.
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.
In 1988, there was a confirmed death from CJD of a person from Manchester, New Hampshire. Massachusetts General Hospital believed the patient acquired the disease from a surgical instrument at a podiatrist's office. In September 2013, another patient in Manchester was posthumously determined to have died of the disease. The patient 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 patients 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.
- 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 CJD patients.
- Pentosan polysulphate (PPS) was thought to slow the progression disease, and may have contributed to the longer than expected survival of the seven patients 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 patients 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.
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