creutzfeldt–jakob disease creutzfeldt–jakob disease creutzfeldt–jakob disease (cjd), also known as subacute spongiform encephalopathy or neurocognitive disorder due to prion disease, is an invariably fatal degenerative brain disorder. early symptoms include memory problems, behavioral changes, poor coordination, and visual disturbances. later symptoms include dementia, involuntary movements, blindness, weakness, and coma. about 70% of people die within a year of diagnosis. the name creutzfeldt–jakob disease was introduced by walther spielmeyer in 1922, after the german neurologists hans gerhard creutzfeldt and alfons maria jakob. not to be confused with variant creutzfeldt–jakob disease. creutzfeldt–jakob diseaseother namesclassic creutzfeldt–jakob diseasemagnetic resonance image of sporadic cjdpronunciationuk: /ˌkrɔɪtsfɛlt ˈjækɒb/ kroyts-felt yak-ob, us: /- ˈjɑːkoʊb/ -⁠ yah-kohb specialtyneurologysymptomsearly: memory problems, behavioral changes, poor coordination, visual disturbanceslater: dementia, involuntary movements, blindness, weakness, comacomplicationsaspiration pneumonia due to difficulty coughingusual onsetaround 60duration70% die within a year of diagnosistypessporadic (mutation), familial (heredity), iatrogenic (acquired), variant (infection)causesprionrisk factorshaving at least one living or deceased ancestor with the disease (in case of hereditary cjd)diagnostic methodbased on symptoms and medical tests after other possible causes are ruled outdifferential diagnosisencephalitis, chronic meningitis, huntington's disease, alzheimer's disease, sjögren's syndrometreatmentsupportive caremedicationfor pain relief: morphine, methadoneprognosisuniversally fatalfrequency1 per million per year cjd is caused by a type of abnormal protein known as a prion. infectious prions are misfolded proteins that can cause normally folded proteins to also become misfolded. about 85% of cases of cjd occur for unknown reasons, while about 7.5% of cases are inherited 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 sporadic cjd can spread among people via normal contact or blood transfusions, although this is possible in variant creutzfeldt–jakob disease. diagnosis involves ruling out other potential causes. an electroencephalogram, spinal tap, or magnetic resonance imaging may support the diagnosis. there is no specific treatment for cjd. opioids may be used to help with pain, while clonazepam or sodium valproate may help with involuntary movements. cjd affects about one person 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. inherited cjd accounts for about 10% of prion disease cases. sporadic 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, and rigid posture. in most people with cjd, these symptoms are accompanied by involuntary movements. the duration of the disease varies greatly, but sporadic (non-inherited) cjd can be fatal within months or even weeks. most affected people 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 are associated with the build-up of abnormal prion proteins forming in the brain. when brain tissue from a person with cjd is examined under a microscope, many tiny holes can be seen where the nerve cells have died. parts of the brain may resemble a sponge where the prions were infecting the areas of the brain. cause cjd is a type of transmissible spongiform encephalopathy (tse), which are caused by prions. prions are misfolded proteins that occur in the neurons of the central nervous system (cns). they 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 is a process that is hypothesized to occur as a result of the effects of aging on cellular machinery, explaining why the disease often appears later in life. 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 clear 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 variant form of the disease by eating food from animals infected with bovine spongiform encephalopathy (bse), the bovine form of tse also known as mad cow disease. however, it can also cause scjd in some cases. 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, who previously engaged in funerary cannibalism. while the men of the tribe ate the muscle tissue of the deceased, women and children consumed other parts, such as the brain, and were 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. 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. 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 the 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: dwmri, fdg pet and post mortem histology from a patient who presented with scjd aged 66 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 brain fdg pet-ct tends to be markedly abnormal, and is increasingly used in the investigation of dementias. patients with cjd will normally have hypometabolism on fdg pet. 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 harbor 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. clinical and pathologic characteristics characteristicclassic cjdvariant cjd median age at death68 years28 years median duration of illness4–5 months 13–14 months clinical signs and symptomsdementia; early neurologic signs prominent psychiatric/behavioral symptoms; painful dysesthesias; delayed neurologic signs