Continuing Education Activity

Kuru disease is an infectious, acquired, non-immunogenic, fatal neurodegenerative prion disease. It progresses rapidly with cerebellar and extrapyramidal signs and symptoms, with death occurring within one to two years of onset of symptoms. The end of cannibalism has put an end to this disease. This activity describes the evaluation and management of the kuru disease and highlights the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Identify the etiology of kuru disease.
• Describe the pathophysiology of kuru disease.
• Outline management options available for kuru disease.
• Explain the importance of improving care coordination amongst the interprofessional teams to enhance the delivery of care for patients affected by prion disease.

Introduction

Kuru is the prototype human prion disease first reported in publications by Dr. D. Carleton Gajdusek and Vincent Zigas in 1957 in the Fore tribes of Papua New Guinea. The word “kuru” means to tremble due to fever or cold.[1][2] It is a non-inflammatory neurodegenerative disease and is a form of transmissible spongiform encephalopathy transmitted through the act of cannibalism.[3] 

The symptoms of kuru progress rapidly with cerebellar and extrapyramidal signs and symptoms, with death occurring within one to two years of onset of symptoms. The disease is now extinct, but its discovery in the 20th century was pivotal for understanding the other prion diseases.[4][5] Other prion diseases include Creutzfeldt-Jakob disease (CJD), fatal familial insomnia (FFI), variant CJD (vCJD), and Gerstmann-Straussler-Scheinker (GSS) disease.[6][7]

Etiology

Kuru is an acquired infectious disease linked with the ritualistic practice of feeding upon the corpses of relatives as part of mourning (endocannibalism).[8] Prions are the causative agents of the disease. These are misfolded proteins lacking instructional nucleic acids.[9]

Epidemiology

Kuru was prevalent in the Eastern Highlands of Papua New Guinea in the early 1900s. The disease was confined to the Fore tribe and their neighboring linguistic groups. The infectious prion becomes enriched in the victim’s brain.

At its peak in the 1940s to the 1950s, the mortality rate in the affected villages went as high as 35/1000 population.[10] Children and women were usually more affected than men, probably because they consumed the brain as compared to the men who preferred muscles.[11] With the decrease in the practice of ritualistic cannibalism, the cases decreased rapidly after the 1950s.

An active survey in Papua New Guinea from July 1996 to June 2004, identified only 11 new cases. In some of those cases, researchers noted an incubation period of more than 50 years.[8] There are no new cases recorded recently, with the last case reported in 2005.[12]

Pathophysiology

The prion proteins (PrP) are encoded by the prion protein gene (PRNP gene).[13] PrPc is a normally folded protein, rich in alpha-helices, and undergoes complete proteolysis. The PrPSc isoform is the misfolded protein that gives rise to the disease; it is rich in beta sheets and is resistant to degradation by enzymes.[14] Thus the PrPSc aggregates and further promotes the conversion of other PrPc to PrPSc. A chain reaction is set, which results in the pathogenesis of prion disease.

As a prion is a naturally occurring protein, no immunologic or inflammatory reactions are present against it; this is probably due to the negative selection of T and B cells that recognizes the misfolded PrPSc as a self protein since it is identical to the normal PrPc protein.[15]

Individuals with homozygosity of methionine allele at codon 129 of prion protein gene (PRNP gene) were susceptible to short incubation period and early death. In contrast, ones with heterozygosity at this position were relatively resistant to the disease with longer incubation periods and delayed death.[16][17] Heterozygosity at codon 127 provides strong, and possibly complete, resistance to kuru.[16]

Histopathology

Grossly no lesions are seen on the brain. Autopsy specimens of the brain did not show any perivascular scuffing or other signs of inflammatory brain pathology.[18] 

However, microscopic studies of the brain show astrocyte proliferation and hypertrophy due to neuronal damage. Gliosis and vacuolization extending throughout the gray matter of the brain are present. The neurons were shrunken and hyperchromatic, with the dispersion of Nissl substance within the intracytoplasmic vacuoles similar to those seen in scrapie. Vacuolated "moth-eaten" neurons (striatum) and Purkinje cells (cerebellum) are also a feature. Most affected structures involved the deeper layers of the cortex, the vermis and flocculonodular lobe in the cerebellum, and the corticospinal and spinocerebellar tracts in the spinal cord.[10] 

Amyloid plaques known as "kuru plaques" are seen, which are numerous in the cerebellum, basal ganglia, thalamus, and cerebral cortex in descending order.[19][20] These amyloid plaques stain with periodic acid-Schiff, Alcian blue, and Congo red stain. Anti PrP immunocytochemistry can be useful to demonstrate prion protein accumulation in brain tissues as well.[21]

History and Physical

Kuru is an invariably fatal neurodegenerative disease. It has a predictable history as compared to other prion diseases.

Once a patient is infected, an ill-defined prodromal phase may be present that lasts a few months. Symptoms include headaches and joint pains. The knee, ankle, elbow, and wrist joint are usually involved. Abdominal pain and weight loss can also be present. Although kuru was thought to have an infectious etiology, there are no classical signs of meningitis or encephalitis like fever, convulsions, or coma.[10]

 The three discernible phases in kuru include:

1. Ambulatory phase: Presents with features of cerebellar ataxia. There is a subtle gait unsteadiness that progresses to ataxia and incoordination of the muscles of the trunk and the lower limbs. Shivering of the body or "kuru," which is exacerbated by lower temperatures, is present. Titubation and other abnormal movements of the body are presenting signs. Curling of feet and clawing of toes are observable for maintaining a balance. Patellar clonus and ankle clonus are the hallmark clinical picture. As the disease progresses, the Romberg sign may be present. Cerebellar signs such as nystagmus, dysarthria, dysmetria, and intention tremor are also reported. Individuals are also emotionally labile and may exhibit sporadic uncontrolled laughter. Hence the disease is also referred to as the "laughing disease."
2. Sedentary phase: It starts when the patient is unable to stand without support and ends when unable to sit without support. The ataxia, dysarthria, and tremor worsen during this phase. Hyperreflexia is more prominent, and plantar response is still flexor. Other symptoms include jerky eye movements, opsoclonus, and dystonia.[10]
3. Terminal stage: The patient is bedridden and may develop dysphagia and incontinence. Victims are unresponsive to their surroundings, although conscious. Exaggeration of deep and primitive reflexes is present, but the Babinski response is negative. A fixed dystonic posture with athetosis and chorea is noted. Features of dementia may also be present but not prominent as compared to other prion diseases. Terminally moribund patients usually die of pneumonia or infection of the ulcerated wounds in 9 to 24 months of the onset of disease.

The inoculation time to time of presentation of symptoms is presumed to range from 4 to 40 years, with rare cases reaching up to 50 years.[8][22][23]

Evaluation

Evaluation is mainly through history and physical examination. The characteristic progression of symptoms in the vulnerable populations leads to high suspicion of the diagnosis. There are no laboratory and imaging tests available that give a definitive diagnosis of kuru. The pathological evaluation of CNS tissue and distinct histopathological findings are diagnostic. Electroencephalogram (EEG) is abnormal, but no periodic sharp waves are present, as compared to other prion diseases.[24]

Treatment / Management

Human prion diseases are universally fatal with no treatment other than supportive treatments to this date.[25]

Differential Diagnosis

It is crucial to differentiate and rule out other forms of dementia that are treatable and reversible. Further dementia may be associated with cerebellar signs/symptoms, which can be differentiated with kuru disease by the brain and vascular imaging, appropriate blood workup, serological workup, pathological evaluation, and genetic studies. These differentials for kuru include:

• Other prion diseases
  • The most common of the prion disease is Creutzfeldt-Jakob disease (CJD), which usually presents with neurological manifestations like myoclonus and upper motor neuron signs. Also, dementia presents early in CJD as compared to kuru, where dementia may be a late manifestation.
  • Familial fatal insomnia, in contrast to kuru, presents with prominent insomnia, dysautonomia, and myoclonus.
  • Gerstmann-Straussler-Scheinker (GSS) presents with a more diverse clinical picture with cerebellar signs, spastic paraparesis, and cognitive impairment more like Alzheimer’s disease.

• Autoimmune/antibody-mediated disorders
• Alzheimer disease, frontal, temporal dementia
• Other dementia (Lewy body, vascular, unclassified)
• Encephalitis, not specified
• Infection (herpes virus, syphilis, human immunodeficiency virus, Lyme, aspergillosis of the brain)
• Neoplasm and paraneoplastic syndromes
• Metabolic disorders/toxins/metal poisoning including lithium and heavy metals

Prognosis

Kuru is universally fatal, with death typically occurring within 24 months of the onset of symptoms. The quality of life is greatly diminished, and victims are mostly dependent on their relatives in the latter half of the disease stage.

Complications

As patients with kuru deteriorate, they develop severe cerebellar and extrapyramidal signs and symptoms. The patients become moribund and bedridden.

The care of the patient relies heavily on family members who act as caregivers once they reach the third stage of the disease. The patients are malnourished, can develop decubitus ulcers with secondary infections, and aspiration pneumonia, which causes death.

Deterrence and Patient Education

The end of cannibalism has put an end to kuru disease. The last case recorded was in 2005.[12] However, it remains the first described transmissible spongiform encephalopathy unraveling the mystery of other prion diseases. Although kuru has disappeared, it remains significant for the largest outbreak of human to human transmission of prion disease transmitted through the oral route in the Eastern Highlands of Papua New Guinea.

Enhancing Healthcare Team Outcomes

Although it has been a decade since the last report of kuru disease, other prevalent prion diseases are universally fatal. The kuru disease stands as a pioneer in the discovery of infectious prion proteins, thus providing knowledge and clues to the other prion diseases.

The current data about the natural history and clinical progression of the disease, as well as its detrimental effects (death), and designing an effective therapeutic study, have all proved challenging. Researchers are studying different therapeutic approaches targeting the conversion of PrPc to PrPsc. However, no successful treatment exists to date. Thus, a collaboration for effective pooling of the therapeutic studies is necessary to unravel more about prion diseases. Establishing an early diagnosis can be the key to therapeutic success and improvement of quality of life.

Currently, the treatments focus on symptomatic improvements of the patients. This care should include interprofessional support teams, hospice care, and the family members of the patients.