The Kuru Epidemic
Introduction
Kuru is a human spongiform encephalopathy, widely regarded to be caused by a prion molecule.1-7 Prion molecules are endogenous mammalian proteins that have been misfolded such that the tertiary structure is markedly different; more stable and pathogenic. Prion molecules can first arise via genetic influences, sporadic misfolding, or through environmental exposure. They self-propagate when they touch another protein in the healthy formation and subsequently misfold it into the prion shape.1
Kuru is part of the class of human transmissible prion diseases. Some prion encephalopathies are shown to be acquired through oral ingestion; for example, beef infected with Mad Cow Disease4. Exposure can also occur through modern “cannibalism” practices such as organ transplantation or use of cadaver-derived hormone products.4 The discovery that Creutzfeldt-Jakob disease (CJD) can be caused by dietary exposure to bovine spongiform encephalopathy4 led to increased interest in the kuru epidemic. Historically, the Fore linguistic group in Papua New Guinea practiced mortuary cannibalism—feasts were held to honor the peoples' deceased by consuming their flesh. It was believed that their souls would persist in the bodies of the living; the cannibalistic practice was one of great respect.2-7
The first instance of kuru was likely a result of cannibalism (transumption) of a sporadically CJD-infected individual2-3,5-6. Kuru is always fatal and women and young children bore the majority of the disease burden. At the peak of the epidemic, kuru was the top killer of women in the Fore.2 Prevalence peaked in the late 1950s and steadily declined after cannibalism was outlawed in the area.2-5 The surveillance of kuru supplied significant information about incubation times, genetics, and the molecular biology of prion transmissible encephalopathies.
Diagnosis and Symptoms
Kuru is characterized as a progressive cerebellar ataxic syndrome.2-7 Objective signs of motor coordination deficits in walking and other voluntary movement lead to a clinical kuru diagnosis, which always ends with death. “Recoveries” sometimes rumored about in the local community proved to be cases of malaria or other debilitating fevers. The clinical experience of a case of kuru starts with general joint pain and headache,2,4 followed by a progression through three more distinct states, as follows:
Ambulatory:
The first stage of kuru initially has no outward signs of illness and is usually self-diagnosed when the sufferer begins to experience slurred speech or double vision. Unsteadiness when walking or standing progresses to ataxia of the gait. Patients in this state will exhibit a broad step when walking in attempt to stabilize trunk tremors. Movement accentuates the tremor. Attempts to stand with feet together result in toe clawing for balance, especially characteristic of kuru. Severe depression can occur and the sufferer becomes withdrawn. As the illness progresses, photophobia can occur and chills may present even when warm. After an average of eight months, the loss of ambulation leads to the sedentary stage.4
Sedentary:
The second stage of disease is marked by the loss of the ability to walk. When supported, attempted ambulation leads to reeling instability. The arms fling and their steppage is high, attempting balance restoration. Reflexes become exaggerated, yet muscle tone decreases. Rhythmic muscular spasms are common. Notably, the patient experiences exaggerated mood changes. The presentation of inappropriate laughter and euphoria earned kuru the nickname of ‘Laughing Death.’ The moribund stage starts with the loss of ability to sit unsupported, after an average of 2-3 months.4
Recumbent/Moribund:
Muscle weakness, urinary and fecal incontinence, and low muscle tone and weakness occur in the final stage of illness. Dementia develops and patients may exhibit some primitive reflexes. Sufferers usually die after 1-3 months from secondary infections like pneumonia, although this stage can be prolonged and lead to death when vital centers in the brain are impacted.4
Descriptive Epidemiology
The epidemiological study of kuru is unique in that every case of the disease was included in the study.2As such, measurements of frequency describe the data in its entirety with no sampling. The Fore linguistic group in the Eastern Highlands Province in Papua New Guinea--and the neighboring groups in which they intermarried--were the only populations affected by the kuru epidemic2-7. According to native verbal history, the first kuru appearance happened in a village just northwest of the Fore around 19005 and was believed to have occurred after the transumption of a person with spontaneous CJD. The disease propagated with each following mortuary feast. Around 1920, kuru appeared at the North Fore border4 and made its way southward from the 20s to 40s.6
Cultural practices had a major influence on who was impacted by the kuru epidemic in the Fore. Mortuary feast rituals were mainly the responsibility of women as it was believed that their wombs were capable of carrying and releasing the disembodied spirits of the deceased. Male children stayed with their mothers until around 7 years of age and ate whatever their mothers gave them. As a result, 98% of all kuru cases were in adult women or children of both sexes. Kuru is always fatal and was the most common cause of death among women.2,4-6 At the peak, there were three men for every one woman in the South. Notably, the Fore practice of hunting down and killing the male “sorcerers” believed to be the cause of kuru had a minor balancing effect on gender-based mortality comparisons.7
The Australian outlawing of cannibalism in the 50s led to child cases of kuru ceasing in children born after 1960. Following this landmark, the average age of kuru patients increased every year. Fore prevalence decreased in the North before the South, due to the South illicitly practicing mortuary feasts throughout the 50s. Notably, kuru incidence in various linguistic groups north of the Fore dropped to zero shortly after cases appeared. This is best explained by the quick change in mortuary feast rules in those villages that occurred after kuru appeared. The 1940s and 1950s marked the maximum incidence rate of the disease,4-6reaching a mortality rate of 35 per 1,000 in the Fore population of 12,000. Mortality began to fall in 1960. By 1987, the North Fore was completely absent of kuru and overall kuru mortality decreased to 3-12 deaths per year. 3 Eleven patients died between mid-1996 and 2004, and 2 died between 2005 and 2009. Surveillance ended in 2012.5
Kuru incubation time ranges from 1 year to 50 or more. Surveillance followed all 11 cases of kuru between 1996 and 2004, each with childhood exposure to mortuary feasts. The minimum incubation for those patients was calculated to be between 34-41 years. Notably, 8 of 10 patients possessed a specific gene variant encoding the protein involved in prion disease. This gene seemed to confer partial resistance to kuru, leading to delayed disease in those patients4-6. A population-based genetic study was performed using banked brain tissue samples and showed that the variant was seen in historical cases with incubations of 20 or more years. The people with the original gene were more likely to have died quickly from kuru.6
Further genetic study mapped the epidemic over prevalence changes of the genotypic variation. Those with the original gene died out entirely by 1959. Some elderly women with multiple mortuary feast exposures had the genetic variant and survived with an absence of the disease entirely. This demonstrates a strong selective pressure that occurred in the Fore population for the variant expression of the prion protein. Ethnic groups across the world express this genetic variation at some level, implying that prehistoric humans may have suffered a number of prion epidemics with cannibalistic etiologies in unrecorded history.4-6
Conclusion
The kuru epidemic led directly to the discovery of the infectious prion molecule2,4, marking a monumental change in medical understanding of protein conformational disorders. It also provided a unique opportunity to study the entirety of a disease course, following each and every case until the epidemic’s end. The impact of anthropological and cultural changes on disease outbreaks were elegantly demonstrated in the 55 years of kuru surveillance. Kuru was not eradicated by any scientific or medical means, but rather by the cessation of a very specific cultural practice.
References
1. Prusiner SB, Scott MR, DeArmond SJ, et al. Prion protein biology. Cell. May 1998;93:337-348.
2. Alpers MP. The epidemiology of kuru: monitoring the epidemic from its peak to its end. Philos Trans R Soc Lond B Biol Sci. Nov 27 2008;363(1510):3707-3713. doi: 10.1098/rstb.2008.0071
3. Alpers MP; Kuru Surveillance Team. The epidemiology of kuru in the period 1987 to 1995. CDI. Dec 2005;29(4):391-399.
4. Collinge J, Whitfield JT, McKintosh E, et al. A clinical study of kuru patients with long incubation periods at the end of the epidemic in Papua New Guinea. Phil Trans R Soc B. Nov 2008;363:3725-3739. doi: 10.1098/rstb.2008.0068
5. Whitfield JT, Pako WH, Collinge J, et al. Cultural factors that affected the spatial and temporal epidemiology of kuru. R Soc Open Sci. Jan 2017;4(1):160789. doi: 10.1098/rsos.160789
6. Liberski PP, Sikorska B, Lindenbaum S, et al. Kuru: genes, cannibals, and neuropathology. Journal of Neuropathology & Experimental Neurology. Feb 2012;71(2):92-103. doi: 10.1097/NEN.0b013e3182444efd
7. Liberski PP, Brown P. Kuru: its ramifications after fifty years. Experimental Gerontology. Jan-Feb 2009;44(1-2):63-69. doi: 10.1016/j.exger.2008.05.010