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.

In 2009, researchers at the Medical Research Council discovered a naturally occurring variant of a prion protein in a population from Papua New Guinea that confers strong resistance to kuru. In the study, which began in 1996, researchers assessed over 3,000 people from the affected and surrounding Eastern Highland populations, and identified a variation in the prion protein G127. G127 polymorphism is the result of a missense mutation, and is highly geographically restricted to regions where the kuru epidemic was the most widespread. Researchers believe that the PrnP variant occurred very recently, estimating that the most recent common ancestor lived 10 generations ago.

Of the discovery, Professor John Collinge, director of the MRC’s Prion Unit at University College London, has stated that:The findings of the study could help researchers better understand and develop treatments for other related prion diseases, such as Creutzfeldt-Jakob disease and Alzheimer’s disease.

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.

The tests used for detecting BSE vary considerably, as do the regulations in various jurisdictions for when, and which cattle, must be tested. For instance in the EU, the cattle tested are older (30 months or older), while many cattle are slaughtered younger than that. At the opposite end of the scale, Japan tests all cattle at the time of slaughter. Tests are also difficult, as the altered prion protein has very low levels in blood or urine, and no other signal has been found. Newer tests are faster, more sensitive, and cheaper, so future figures possibly may be more comprehensive. Even so, currently the only reliable test is examination of tissues during a necropsy.

As for vCJD in humans, autopsy tests are not always done, so those figures, too, are likely to be too low, but probably by a lesser fraction. In the United Kingdom, anyone with possible vCJD symptoms must be reported to the Creutzfeldt–Jakob Disease Surveillance Unit. In the United States, the CDC has refused to impose a national requirement that physicians and hospitals report cases of the disease. Instead, the agency relies on other methods, including death certificates and urging physicians to send suspicious cases to the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University in Cleveland, which is funded by the CDC.

To control potential transmission of vCJD within the United States, the American Red Cross has established strict restrictions on individuals' eligibility to donate blood. Individuals who have spent a cumulative time of 3 months or more in the United Kingdom between 1980 and 1996, or a cumulative time of 5 years or more from 1980 to present in any combination of countries in Europe, are prohibited from donating blood.

The condition is fatal. Cases where people live up to 2.5 years have been described.

In the U.S., the FDA has banned import of any donor sperm, motivated by a risk of Creutzfeldt–Jakob disease, inhibiting the once popular import of Scandinavian sperm. Despite this the scientific consensus is that the risk is negligible, as there is no evidence Creutzfeldt–Jakob is sexually transmitted.

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.

This hypothesis postulates that an infectious viral agent is the cause of the disease. Evidence for this hypothesis is as follows:

Every infectious agent is different, but in general, slow viruses:

Additionally, the immune system seems to plays a limited role, or no role, in protection from these slow viruses. This may be in part because the host has acclimated to the virus, or more likely because the host must be immunocompromised in order for many of these slow virus infections to emerge, so the immune system is at a disadvantage from the start.

A slow virus is a virus, or a viruslike agent, etiologically associated with a disease, having a long incubation period of months to years and then a gradual onset of symptoms which progress slowly but irreversibly and terminate in a severe compromised state or, more commonly, death.

A slow virus disease is a disease that, after an extended period of latency, follows a slow, progressive course spanning months to years, frequently involving the central nervous system and ultimately leading to death. Examples include the Visna-Maedi virus, in the genus Lentivirus (family Retroviridae), that causes encephalitis and chronic pneumonitis in sheep, and subacute sclerosing panencephalitis which is apparently caused by the measles virus, as well as Paget's Disease of Bone (Osteitis Deformans) which is associated with paramyxoviridae, especially RSV and Rubeola (Measles).

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.

There are other diseases involving the mammalian prion protein. Some are transmissible (TSEs, including FFI) such as kuru, bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cows, and chronic wasting disease in American deer and American elk in some areas of the United States and Canada, as well as Creutzfeldt–Jakob disease (CJD). Until recently, prion diseases were only thought to be transmissible via direct contact with infected tissue, such as from eating infected tissue, transfusion, or transplantation; new research now suggests that prion diseases can be transmitted via aerosols, but that the general public is not at risk of airborne infection.

There are many types of encephalopathy. Some examples include:

- Mitochondrial encephalopathy: Metabolic disorder caused by dysfunction of mitochondrial DNA. Can affect many body systems, particularly the brain and nervous system.

- Glycine encephalopathy: A genetic metabolic disorder involving excess production of glycine.

- Hepatic encephalopathy: Arising from advanced cirrhosis of the liver.

- Hypoxic ischemic encephalopathy: Permanent or transitory encephalopathy arising from severely reduced oxygen delivery to the brain.

- Static encephalopathy: Unchanging, or permanent, brain damage.

- Uremic encephalopathy: Arising from high levels of toxins normally cleared by the kidneys—rare where dialysis is readily available.

- Wernicke's encephalopathy: Arising from thiamine (B) deficiency, usually in the setting of alcoholism.

- Hashimoto's encephalopathy: Arising from an auto-immune disorder.

- Hypertensive encephalopathy: Arising from acutely increased blood pressure.

- Chronic traumatic encephalopathy: Progressive degenerative disease associated with multiple concussions and other forms of brain injury.

- Lyme encephalopathy: Arising from Lyme disease bacteria, including "Borrelia burgdorferi".

- Toxic encephalopathy: A form of encephalopathy caused by chemicals, often resulting in permanent brain damage.

- Toxic-Metabolic encephalopathy: A catch-all for brain dysfunction caused by infection, organ failure, or intoxication.

- Transmissible spongiform encephalopathy: A collection of diseases all caused by prions, and characterized by "spongy" brain tissue (riddled with holes), impaired locomotion or coordination, and a 100% mortality rate. Includes bovine spongiform encephalopathy (mad cow disease), scrapie, and kuru among others.

- Neonatal encephalopathy (hypoxic-ischemic encephalopathy): An obstetric form, often occurring due to lack of oxygen in bloodflow to brain-tissue of the fetus during labour or delivery.

- Salmonella encephalopathy: A form of encephalopathy caused by food poisoning (especially out of peanuts and rotten meat) often resulting in permanent brain damage and nervous system disorders.

- Encephalomyopathy: A combination of encephalopathy and myopathy. Causes may include mitochondrial disease (particularly MELAS) or chronic hypophosphatemia, as may occur in cystinosis.

- Creutzfeldt–Jakob disease (CJD; transmissible spongiform encephalopathy).

- HIV encephalopathy (encephalopathy associated with HIV infection and AIDS, characterized by atrophy and ill-defined white matter hyperintensity).

- Sepsis-associated encephalopathy (this type can occur in the setting of apparent sepsis, trauma, severe burns, or trauma, even without clear identification of an infection).

- Epileptic encephalopathies:

- Early infantile epileptic encephalopathy (acquired or congenital abnormal cortical development).

- Early myoclonic epileptic encephalopathy (possibly due to metabolic disorders).

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.

In medicine and medical anthropology, a culture-bound syndrome, culture-specific syndrome, or folk illness is a combination of psychiatric and somatic symptoms that are considered to be a recognizable disease only within a specific society or culture. There are no objective biochemical or structural alterations of body organs or functions, and the disease is not recognized in other cultures. The term "culture-bound syndrome" was included in the fourth version of the "Diagnostic and Statistical Manual of Mental Disorders" (American Psychiatric Association, 1994) which also includes a list of the most common culture-bound conditions (DSM-IV: Appendix I). Counterpart within the framework of ICD-10 () are the "culture-specific disorders" defined in Annex 2 of the "Diagnostic criteria for research".

More broadly, an epidemic that can be attributed to cultural behavior patterns or suggestion is sometimes referred to as a behavioral epidemic. As in the cases of drug or alcohol abuse or smoking, transmission can be determined by communal reinforcement as well as by person-to-person interactions. On etiological grounds, it can be difficult to distinguish the causal contribution of culture in disease from other environmental factors such as toxicity.

A culture-specific syndrome is characterized by:

1. categorization as a disease in the culture (i.e., not a voluntary behaviour or false claim);

2. widespread familiarity in the culture;

3. complete lack of familiarity or misunderstanding of the condition to people in other cultures;

4. no objectively demonstrable biochemical or tissue abnormalities (signs);

5. the condition is usually recognized and treated by the folk medicine of the culture.

Some culture-specific syndromes involve somatic symptoms (pain or disturbed function of a body part), while others are purely behavioral. Some culture-bound syndromes appear with similar features in several cultures, but with locally specific traits, such as penis panics.

A culture-specific syndrome is not the same as a geographically localized disease with specific, identifiable, causal tissue abnormalities, such as kuru or sleeping sickness, or genetic conditions limited to certain populations. It is possible that a condition originally assumed to be a culture-bound behavioral syndrome is found to have a biological cause; from a medical perspective it would then be redefined into another nosological category.