The diagnosis of CJD is suspected when there are typical clinical symptoms and signs such as rapidly progressing dementia with startle myoclonus. Further investigation can then be performed to support the diagnosis including

- Electroencephalography—often has characteristic generalized periodic sharp wave pattern (~80% of pts by 6 months)

- Cerebrospinal fluid analysis for 14-3-3 protein

- MRI of the brain—often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.

- Research in 2010 and 2011 identified a possible blood test for CJD. The test attempts to identify the prion responsible for the disease. However, it has not yet been demonstrated if it is able to detect the prions in early stages of the disease.

Diffusion Weighted Imaging (DWI) images are the most sensitive. 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.

Clinical testing for CJD has always been an issue. Diagnosis has been based mostly on clinical and physical examination of symptoms. 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. , screening tests to identify infected asymptomatic individuals, such as blood donors, are not yet available, though methods have been proposed and evaluated.

In 2010, a team from New York described detection of PrP even when initially present at only one part in one hundred billion (10) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay (SOFIA) and some specific antibodies against PrP. After amplifying and then concentrating any PrP, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrP could be detected in the blood of animals long before the symptoms appeared. After further development and testing, this method could be of

great value in surveillance as a blood or urine-based screening test for CJD. In 2014, a human study showed a nasal brushing method that can accurately detect PrP in the olfactory epithelial of CJD patients. .

This finding creates new opportunities for minimally invasive detection of CJD.

In one-third of patients with sporadic CJD, deposits of "prion protein (scrapie)," PrP, 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 PrP; 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 micrometres 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.

- Clinical and Pathologic Characteristics:

- An abnormal signal in the posterior thalamus on T2- and diffusion-weighted images and fluid-attenuated inversion recovery sequences on brain magnetic resonance imaging (MRI); in the appropriate clinical context, this signal is highly specific for vCJD. (Source: CDC)

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 different condition which is potentially acquired from Bovine spongiform encephalopathy or caused by consuming food contaminated with prions.

There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have an incubation period of months to decades during which there are no symptoms, even though the pathway of converting the normal brain PrP protein into the toxic, disease-related PrP form has started. At present, there is virtually no way to detect PrP reliably except by examining the brain using neuropathological and immunohistochemical methods after death. Accumulation of the abnormally folded PrP form of the PrP protein is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine. Researchers have tried to develop methods to measure PrP, but there are still no fully accepted methods for use in materials such as blood.

In 2010, a team from New York described detection of PrP even when initially present at only one part in a hundred billion (10) in brain tissue. The method combines amplification with a novel technology called Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrP. After amplifying and then concentrating any PrP, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrP could be detected in the blood of animals long before the symptoms appeared.

Recent research from the University of Toronto and Caprion Pharmaceuticals has discovered one possible avenue that might lead to quicker diagnosis, a vaccine or possibly even treatment for prion diseases. The abnormally folded proteins that cause the disease have been found to expose a side chain of amino acids that the properly folded protein does not expose. Antibodies specifically coded to this side-chain amino acid sequence have been found to stimulate an immune response to the abnormal prions and leave the normal proteins intact.

Another idea involves using custom peptide sequences. Since some research suggests prions aggregate by forming beta barrel structures, work done "in vitro" has shown that peptides made up of beta barrel-incompatible amino acids can help break up accumulations of prion.

A third idea concerns genetic therapy, whereby the gene for encoding protease-resistant protein is considered to be an error in several species, and therefore something to be inhibited.

A ban on feeding meat and bone meal to cattle has resulted in a strong reduction in cases in countries where the disease was present. In disease-free countries, control relies on import control, feeding regulations, and surveillance measures.

In UK and US slaughterhouses, the brain, spinal cord, trigeminal ganglia, intestines, eyes, and tonsils from cattle are classified as specified risk materials, and must be disposed of appropriately.

An enhanced BSE-related feed ban is in effect in both the United States and Canada to help improve prevention and elimination of BSE.

Diagnosis of BSE continues to be a practical problem. It has an incubation period of months to years, during which no symptoms are noticed, though the pathway of converting the normal brain prion protein (PrP) into the toxic, disease-related PrP form has started. At present, virtually no way is known to detect PrP reliably except by examining "post mortem" brain tissue using neuropathological and immunohistochemical methods. Accumulation of the abnormally folded PrP form of PrP is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids such as blood or urine. Researchers have tried to develop methods to measure PrP, but no methods for use in materials such as blood have been accepted fully.

The traditional method of diagnosis relies on histopathological examination of the medulla oblongata of the brain, and other tissues, "post mortem". Immunohistochemistry can be used to demonstrate prion protein accumulation.

In 2010, a team from New York described detection of PrP even when initially present at only one part in a hundred billion (10) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrP. After amplifying and then concentrating any PrP, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a microcapillary tube. This tube is placed in a specially constructed apparatus so it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrP after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artifacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could, therefore, compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrP could be detected in the blood of animals long before the symptoms appeared. After further development and testing, this method could be of great value in surveillance as a blood- or urine-based screening test for BSE.

Transmissible spongiform encephalopathies (TSE) are very rare but can reach epidemic proportions. It is very hard to map the spread of the disease due to the difficulty of identifying individual strains of the prions. This means that, if animals at one farm begin to show the disease after an outbreak on a nearby farm, it is very difficult to determine whether it is the same strain affecting both herds—suggesting transmission—or if the second outbreak came from a completely different source.

Classic Creutzfeldt-Jakob disease (CJD) was discovered in 1920. It occurs sporadically over the world but is very rare. It affects about one person per million each year. Typically, the cause is unknown for these cases. It has been found to be passed on genetically in some cases. 250 patients contracted the disease through iatrogenic transmission (from use of contaminated surgical equipment). This was before equipment sterilization was required in 1976, and there have been no other iatrogenic cases since then. In order to prevent the spread of infection, the World Health Organization created a guide to tell health care workers what to do when CJD appears and how to dispose of contaminated equipment. The Centers for Disease Control and Prevention (CDC) have been keeping surveillance on CJD cases, particularly by looking at death certificate information.

Chronic wasting disease (CWD) is a prion disease found in North America in deer and elk. The first case was identified as a fatal wasting syndrome in the 1960s. It was then recognized as a transmissible spongiform encephalopathy in 1978. Surveillance studies showed the endemic of CWD in free-ranging deer and elk spread in northeastern Colorado, southeastern Wyoming and western Nebraska. It was also discovered that CWD may have been present in a proportion of free-ranging animals decades before the initial recognition. In the United States, the discovery of CWD raised concerns about the transmission of this prion disease to humans. Many apparent cases of CJD were suspected transmission of CWD, however the evidence was lacking and not convincing.

In the 1980s and 1990s, bovine spongiform encephalopathy (BSE or "mad cow disease") spread in cattle at an epidemic rate. The total estimated number of cattle infected was approximately 750,000 between 1980 and 1996. This occurred because the cattle were fed processed remains of other cattle. Then human consumption of these infected cattle caused an outbreak of the human form CJD. There was a dramatic decline in BSE when feeding bans were put in place. On May 20, 2003, the first case of BSE was confirmed in North America. The source could not be clearly identified, but researchers suspect it came from imported BSE-infected cow meat. In the United States, the USDA created safeguards to minimize the risk of BSE exposure to humans.

Variant Creutzfeldt-Jakob disease (vCJD) was discovered in 1996 in England. There is strong evidence to suggest that vCJD was caused by the same prion as bovine spongiform encephalopathy. 231 total cases of vCJD have been reported since it was first discovered. These cases have been found in a total of 12 countries with 178 in the United Kingdom, 27 in France, 5 in Spain, 4 in Ireland, 4 in the United States, 3 in the Netherlands, 3 in Italy, 2 in Portugal, 2 in Canada, and one in Japan, Saudi Arabia, and Taiwan.

Variant Creutzfeldt–Jakob disease (vCJD) or new variant Creutzfeldt–Jakob disease (nvCJD) is a transmissible spongiform encephalopathy which was identified in 1996 by the National CJD Surveillance Unit in Edinburgh, Scotland. It is always fatal and is caused by prions, which are mis-folded proteins. Over 170 cases of vCJD have been recorded in the United Kingdom, and around 30 cases in the rest of the world. The fact that the epidemiology of the disease coincided with an epidemic of bovine spongiform encephalopathy led to the hypothesis that consumption of BSE-infected beef caused the disease. It is a different disease from Sporadic and Familial Creutzfeldt–Jakob disease, though it is believed to be caused by the same pathogenic agent, a mis-folded protein, known as a prion.

Despite the consumption of contaminated beef in the UK being reckoned to be quite high, vCJD has infected a comparatively small cohort of people. One explanation for this can be found in the genetics of patients with the disease. The human PRNP protein which is subverted in prion disease can occur with either methionine or valine at amino acid 129, without any apparent difference in normal function. Of the overall Caucasian population, about 40% have two methionine-containing alleles, 10% have two valine-containing alleles, and the other 50% are heterozygous at this position. Only a single vCJD patient tested was found to be heterozygous; most of those affected had two copies of the methionine-containing form. Additionally, for unknown reasons, those affected are generally under the age of 40. It is not yet known whether those unaffected are actually immune or only have a longer incubation period until symptoms appear.

In 1961, Australian Michael Alpers conducted extensive field studies among the Fore accompanied by anthropologist Shirley Lindenbaum. Their historical research suggested the epidemic may have originated around 1900 from a single individual who lived on the edge of Fore territory and who is thought to have spontaneously developed some form of CJD. Alpers and Lindenbaum's research conclusively demonstrated that kuru spread easily and rapidly in the Fore people due to their endocannibalistic funeral practices, in which relatives consumed the bodies of the deceased to return the "life force" of the deceased to the hamlet, a Fore societal subunit. Corpses of family members were often buried for days then exhumed once the corpses were infested with maggots at which point the corpse would be dismembered and served with the maggots as a side dish.

The sexual dimorphism evident in the infection rates — kuru was eight to nine times more prevalent in women and children than in men at its peak — is because Fore men considered consuming human flesh to weaken them in times of conflict or battle, while the women and children were more apt to eat the bodies of the deceased, including the brain, where the prion particles were particularly concentrated. Also, the strong possibility exists that it was passed on to women and children more easily because they took on the task of cleaning relatives after death and may have had open sores and cuts on their hands.

Although ingestion of the prion particles can lead to the disease, a high degree of transmission occurred if the prion particles could reach the subcutaneous tissue. With elimination of cannibalism because of Australian colonial law enforcement and the local Christian missionaries' efforts, Alpers' research showed that kuru was already declining among the Fore by the mid‑1960s. However, the mean incubation period of the disease is 14 years, and 7 cases were reported with latencies of 40 years or more for those who were most genetically resilient, continuing to appear for several more decades. Sources disagree on whether the last sufferer died in 2005 or 2009.

Kuru is a very rare, incurable neurodegenerative disorder that was formerly common among the Fore people of Papua New Guinea. Kuru is caused by the transmission of abnormally folded prion proteins, which leads to symptoms such as tremors, loss of coordination, and neurodegeneration.

The term kuru derives from the Fore word kuria or guria ("to shake"), due to the body tremors that are a classic symptom of the disease and kúru itself means "trembling". It is also known as the "laughing sickness" due to the pathologic bursts of laughter which are a symptom of the disease. It is now widely accepted that kuru was transmitted among members of the Fore tribe of Papua New Guinea via funerary cannibalism. Deceased family members were traditionally cooked and eaten, which was thought to help free the spirit of the dead. Females and children usually consumed the brain, the organ in which infectious prions were most concentrated, thus allowing for transmission of kuru. The disease was therefore more prevalent among women and children.

While the Fore people stopped eating human meat in the early 1960's, when it was first speculated to be transmitted via endocannibalism, the disease lingered due to kuru’s long incubation period of anywhere from 10 to over 50 years. The epidemic declined sharply after discarding cannibalism, from 200 deaths per year in 1957 to 1 or no deaths annually in 2005, with sources disagreeing on whether the last known kuru victim died in 2005 or 2009.

In late 1983, Italian neurologist/sleep expert Dr. Ignazio Roiter received a patient at the University of Bologna hospital's sleep institute. The man, known only as Silvano, decided in a rare moment of consciousness to be recorded for future studies and to donate his brain for research in hopes of finding a cure for future victims. As of 2017, no cure or treatment has yet been found for FFI. Gene therapy has been thus far unsuccessful. While it is not currently possible to reverse the underlying illness, there is some evidence that treatments that focus solely upon the symptoms may improve quality of life.

It has been proven that sleeping pills and barbiturates are unhelpful; on the contrary, in 74% of cases, they have been shown to worsen the clinical manifestations and hasten the course of the disease.

One of the most notable cases is that of Michael (Michel A.) Corke, a music teacher from New Lenox, Illinois (born in Watseka, Illinois). He began to have trouble sleeping before his 40th birthday in 1991; following these first signs of insomnia, his health and state of mind quickly deteriorated as his condition worsened. Eventually, sleep became completely unattainable, and he was soon admitted to University of Chicago Hospital with a misdiagnosis of clinical depression due to multiple sclerosis. Medical professionals Dr. Raymond Roos and Dr. Anthony Reder, at first unsure of the nature of his illness, initially diagnosed multiple sclerosis; in a bid to provide temporary relief in the later stages of the disease, physicians attempted to induce a coma with the use of sedatives, to no avail as his brain still failed to shut down completely. Corke died in 1993, a month after his 42nd birthday, by which time he had been completely sleep-deprived for six months.

One person was able to exceed the average survival time by nearly one year with various strategies, including vitamin therapy and meditation, using different stimulants and hypnotics, and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day. He managed to write a book and drive hundreds of miles in this time but nonetheless, over the course of his trials, the person succumbed to the classic four-stage progression of the illness.

In the late 2000s, a mouse model was made for FFI. These mice expressed a humanized version of the PrP protein that also contains the D178N FFI mutation. These mice appear to have progressively fewer and shorter periods of uninterrupted sleep, damage in the thalamus, and early deaths, similar to humans with FFI.

As of 2016, studies are investigating whether doxycycline may be able to slow or even prevent the development of the disease.

It was reported in 1998 that there were 25 families in the world known to carry the gene for FFI: eight German, five Italian, four American, two French, two Australian, two British, one Japanese, and one Austrian. In the Basque Country there were 16 family cases of the 178N mutation between 1993 and 2005 related to two families whose common origin is located in the eighteenth century. In 2011, another family was added to the list when researchers found the first man in the Netherlands with FFI. While he had lived in the Netherlands for 19 years, he was of Egyptian descent. There are other prion diseases that are similar to FFI and could be related but are missing the D178N gene mutation.

Only nine cases of sporadic fatal insomnia have ever been diagnosed . In sFI, there is no mutation in "PRNP"-prion gene in D178N, but all have methionine homozygosity at codon 129.

Blood tests, cerebrospinal fluid examination by lumbar puncture (also known as spinal tap), brain imaging studies, electroencephalography (EEG), and similar diagnostic studies may be used to differentiate the various causes of encephalopathy.

Diagnosis is frequently clinical. That is, no set of tests give the diagnosis, but the entire presentation of the illness with nonspecific test results informs the experienced clinician of the diagnosis.

Treating the underlying cause of the disorder may improve or reverse symptoms. However, in some cases, the encephalopathy may cause permanent structural changes and irreversible damage to the brain. These permanent deficits can be considered a form of stable dementia. Some encephalopathies can be fatal.

Benign fasciculation syndrome is a diagnosis of exclusion; that is, other potential causes for the twitching (mostly forms of neuropathy or motor neuron diseases such as ALS) must be ruled out before BFS can be assumed. An important diagnostic tool here is electromyography (EMG). Since BFS appears to cause no actual nerve damage (at least as seen on the EMG), patients will likely exhibit a completely normal EMG (or one where the only abnormality seen is fasciculations).

Another important step in diagnosing BFS is checking the patient for clinical weakness. Clinical weakness is often determined through a series of strength tests, such as observing the patient's ability to walk on his or her heels and toes. Resistance strength tests may include raising each leg, pushing forward and backward with the foot and/or toes, squeezing with fingers, spreading fingers apart, and pushing with or extending arms and/or hands. In each such test the test provider will apply resisting force and monitor for significant differences in strength abilities of opposing limbs or digits. If such differences are noted or the patient is unable to apply any resisting force, clinical weakness may be noted.

Lack of clinical weakness along with normal EMG results (or those with only fasciculations) largely eliminates more serious disorders from potential diagnosis.

Especially for younger persons who have only LMN sign fasciculations, "In the absence of weakness or abnormalities of thyroid function or electrolytes, individuals under 40 years can be reassured without resorting to electromyography (EMG) to avoid the small but highly damaging possibility of false-positives". "Equally, however, most subspecialists will recall a small number of cases, typically men in their 50s or 60s, in whom the latency from presentation with apparently benign fasciculations to weakness (and then clear MND) was several years. Our impression is that a clue may be that the fasciculations of MND are often abrupt and widespread at onset in an individual previously unaffected by fasciculations in youth. The site of the fasciculations, for example, those in the calves versus abdomen, has not been shown to be discriminatory for a benign disorder. There is conflicting evidence as to whether the character of fasciculations differs neurophysiologically in MND".

Another abnormality commonly found upon clinical examination is a brisk reflex action known as "hyperreflexia". Standard laboratory tests are unremarkable. According to neurologist John C. Kincaid:

The effects of myoclonus in an individual can vary depending on the form and the overall health of the individual. In severe cases, particularly those indicating an underlying disorder in the brain or nerves, movement can be extremely distorted and limit ability to normally function, such as in eating, talking, and walking. In these cases, treatment that is usually effective, such as clonazepam and sodium valproate, may instead cause adverse reaction to the drug, including increased tolerance and a greater need for increase in dosage. However, the prognosis for more simple forms of myoclonus in otherwise healthy individuals may be neutral, as the disease may cause few to no difficulties. Other times the disease starts simply, in one region of the body, and then spreads.

Research on myoclonus is supported through the National Institute of Neurological Disorders and Stroke (NINDS). The primary focus of research is on the role of neurotransmitters and receptors involved in the disease. Identifying whether or not abnormalities in these pathways cause myoclonus may help in efforts to develop drug treatments and diagnostic tests. Determining the extent that genetics play in these abnormalities may lead to potential treatments for their reversal, potentially correcting the loss of inhibition while enhancing mechanisms in the body that would compensate for their effects.

The prognosis for those suffering from diagnosed benign fasciculation syndrome is generally regarded as being good to excellent. The syndrome causes no known long-term physical damage. Patients may suffer elevated anxiety even after being diagnosed with the benign condition. Such patients are often directed towards professionals who can assist with reductions and understanding of stress/anxiety, or those who can prescribe medication to help keep anxiety under control.

Spontaneous remission has been known to occur, and in cases where anxiety is thought to be a major contributor, symptoms are typically lessened after the underlying anxiety is treated. In a 1993 study by Mayo Clinic, 121 individuals diagnosed with benign fasciculation syndrome were assessed 2–32 years (~7 years average) after diagnosis. Of those patients there were no cases of BFS progressing to a more serious illness, and 50% of the patients reported significant improvement in their symptoms at the time of the follow-up. Only 4% of the patients reported symptoms being worse than those present at the time of their diagnosis.