Testing for<unk>  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<unk>  may have characteristic generalized periodic sharp wave pattern. Periodic sharp wave complexes develop in half of the people with sporadic<unk> , 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<unk> . It is therefore suggested as a high-value diagnostic method for the disease. * MRI of the brain<unk>  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<unk>  cases; however, its diagnostic utility is seen primarily when combined with a test for the 14-3-3 protein. , 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<unk> , 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<unk> . 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 suffering from<unk>  will normally have hypometabolism on FDG PET. Histopathology Spongiform change in<unk>  Testing of tissue remains the most definitive way of confirming the diagnosis of<unk> , although it must be recognized that even biopsy is not always conclusive. In one-third of people with sporadic<unk> , 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<unk> , 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<unk> . 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<unk>  include: * Sporadic (sCJD), caused by the spontaneous misfolding of prion-protein in an individual. This accounts for 85% of cases of<unk> . * Familial (fCJD), caused by an inherited mutation in the prion-protein gene. This accounts for the majority of the other 15% of cases of<unk> . * Acquired<unk> , caused by contamination with tissue from an infected person, usually as the result of a medical procedure (iatrogenic<unk> . Medical procedures that are associated with the spread of this form of<unk>  include blood transfusion from the infected person, use of human-derived pituitary growth hormones, gonadotropin hormone therapy, and corneal and meningeal transplants. Variant<unk>  (vCJD) is a type of acquired<unk>  potentially acquired from bovine spongiform encephalopathy or caused by consuming food contaminated with prions. +Clinical and pathologic characteristics Characteristic Classic<unk>  Variant<unk>  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
Creutzfeldt–Jakob disease
Anti-Hu associated encephalitis
Powassan encephalitis
Kuru (disease)  Kuru  1
Saint Louis encephalitis
Variant Creutzfeldt–Jakob disease  Variant Creutzfeldt–Jakob disease  1
Autoimmune encephalitis
Viliuisk encephalomyelitis