Kuru disease is a neurological disorder that affected the Fore tribe of Papua New Guinea. The Fore tribe performed a ritual practice of endocannibalism, eating the deceased body of a relative, which has led to the spread of kuru disease. This disease is known as a prion disease or transmissible spongiform encephalopathies (TSE) (Collinge et al., 2008). To help better understand this fatal disease, the etiology, pathophysiology, signs and symptoms, diagnostic tests, types of treatment, and complication of heart failure will be discussed in this paper.
The first case of kuru was found in the early 1900's and first studied in the 1950's. (Collinge et al., 2008). This disease primarily affected women and children because of how the body was distributed during the feast. When the body was eaten, the spirit would remain in the wombs of the females, to keep it from harming other family members. Also, the brain was a delicacy and believed that it helped with the growth of young children, leading to the transmission and spread of the disease (Whitfield, Pako, Collinge, & Alpers, 2008).
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Kuru Signs & Symptoms
Headache and pain in the limbs and joints are some of the early signs of kuru. The progression of symptoms can be described in three clinical stages. The ambulatory stage is the first stage and lasts about eight months. It includes unsteady gait, tremors, slurred speech, sensitivity to light, and double vision. The symptoms worsen as the disease progresses and patients become withdrawn, developing depression. The second stage is called the sedentary stage and lasts approximately three months. During this stage, the patient can no longer walk due to severe tremors, and involuntary muscle movements. Feelings of happiness with outbursts of laughter, have led the disease to be called "laughing death". The terminal stage is the final stage of kuru and begins when the patient is unable to sit without support, lasting under two months. Some symptoms include difficulty swallowing causing malnutrition, urinary and bowel incontinence, dementia, respiratory failure, heart failure, and infection later causing death (Collinge et al., 2008).
The motor system consists of the cerebral cortex, basal ganglia, thalamus, cerebellum, brains stem, and spinal cord; all of which are involved in controls of movement. The cerebellum and basal ganglia will be the focus for this essay, as it will help to explain the signs and symptoms of kuru disease.
The cerebellum is composed of external grey matter and internal white matter. Close to the fourth ventricle of the cerebellum is called the deep cerebellar nuclei. To send information to the motor cortex, cells from the cerebellar cortex and deep nuclei interact with axons using thalamic relay. The motor cortex then sends signals to the cerebellum, to tell it that a movement has been made. Movements are smooth and include the limbs, trunk, head, larynx, and eyes. To help the body perform continuous movement, the cerebellum sends signals back and forth to the motor system, using the proprioceptor input with the vesticular system. Also, the cerebellum allows the body to tell its movements when to stop at an exact position, called dampening of muscle movement (Hannon, Pooler, & Porth, 2010).
The basal ganglia are made up of grey matter and consist of the caudate, nucleus, putamen, and globus pallidus. It is responsible for controlled movements that provide arm- swinging during walking. These connections are made by the motor cortex to provide smooth and precise movements. Damages to the basal ganglia and cerebellum can lead to involuntary movements, lack of coordination and balance (Hannon, Pooler, & Porth, 2010).
In 1982, Stanley Prusiner determined that the infectious agent causing TSE was composed of only protein. Some concepts suggested that the agent was a slow virus due to its long incubation period; the agent did not contain a nucleic acid due to its ability of ionizing radiation; and the agent was a small basic protein. Also the agent was resistant to procedures like changes in pH, nucleases, and ultraviolet irradiation. Treatments that denature proteins, such as digestion with proteinase K or trypsin, chemical modification with diethylpyrocarbonate, and treatment with sodium dodecyl sulfate reduces the agents' effect. These observations led Prusiner to describe the agent as "prion" and found that it contained sialoglycoprotein which is known as prion protein (PrP) (Gains & LeBlanc, 2007).
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The prion diseases or transmissible spongiform encephalopathies affect both animals and humans. Types of animal prion diseases include bovine spongiform encephalopathy (BSE), also known as mad cow disease, and scrapie which affect sheep and goats. Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia and kuru are types of human prion diseases (Collinge et al., 2008). The main characteristic is the post-translational process of converting a normal cellular prion protein (PrPC) to an abnormal isoform (PrPSc). Human prion diseases can be acquired through dietary exposure and infection by prion-infected tissues. The disease process can be inherited by mutations of the human prion protein gene (PRNP) or by unknown exposure to an infectious agent called sporadic (Bradner et al., 2008).
The central nervous system is where prion infection takes place. Characteristics of kuru symptoms can be seen with cerebellar ataxia and dementia. Also, found within the cerebellum are amyloid plaques, which is the degradation of neurons in the brain. These plaques contain amyloid fibrils composed of PrP63 and astrocytic and microglial processes. The lysosomes collect the prion protein (PrP), resulting in the removal of excess PrP, rather than producing PrP (Gains & LeBlanc, 2007).
Transmission of the kuru disease is by cannibalism, via oral route. The infectious agent is absorbed in the gastrointestinal tract, where it is transported to the spleen. In the spleen the infectious agent invades follicular dendritic cells which are the site for PrPSc deposition. As the FDCs mature, cytokines are released by B lymphocytes, which help in the transmission of the agent and inhibit neuroinvasion. The agent enters the sympathetic nerve from the FDCs and spread to the CNS. Also, neuroinvasion can occur via the vagal nerve to the dorsal motor, leading to the transmission of acquired prion diseases. PrPC is found within the cytoplasm, attached to the outer cell surface, and at synaptic areas in neurons, which act in cell metabolism and synaptic transmission (Gains & LeBlanc, 2007).
The following diagnostic tests for prion disease include electoencephalogram (EEG), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and lumbar puncture. An EEG can illustrate abnormal electrical activity in sharp and slow wave complexes. The MRI and MRS images can show high signals in parts of the brain such as striatum, cerebral cortex, and thalamus. A lumbar puncture can test for the presence of the 14-3-3 protein in the cerebral spinal fluid, using western blot (Lodi et al., 2009). In order to accurately diagnose prion diseases, biopsy of the brain and spinal cord are performed post-mortem, using immunohistochemistry and immunoblotting (Brandner et al., 2008). Brain biopsy is an accurate way to diagnosis kuru disease. The importance of performing this diagnostic test will help support research in the prevention and treatment of incurable diseases.
In the study done by Brandner et al. (2008), the brain and peripheral tissues were examined on an infected patient with kuru disease in 2003.
The Ventana imunohistochemical staining machine was used to analyze brain and peripheral tissues with anti-glial fibrillary acidic protein, rabbit polyclonal antiserum and anti-PrP monoclonal antibody ICSM 35. Next, the tissue was placed in 10% formol saline and incubated in 98% formic acid. After 1 day, tissue samples were embedded with graded alcohols and paraffin wax, then sliced into 4mm sections, placed in 98% formic acid for 5 min and then boiled for 20 min (Bradner et al., 2008).
Next Bradner et al. (2008), examines the "abnormal PrP accumulation using anti-PrP monoclonal ICSM 35 followed by a biotinylated anti-mouse IgG secondary antibody and an avidin-biotin horseradish peroxidase conjugate before development with 3Ì ,3-diaminobenzedine tetrachloride as the chromogen. Haematoxylin was used as the counter stain. Haematoxylin and eosin staining of serial sections was performed using conventional methods".
Brain and peripheral tissues were prepared as 10% w/v homogenates in Dulbecco's sterile phosphate buffered saline lacking CaÂ²+ and MgÂ²+ ions using Duall tissue grinders. Brain homogenate was analysed, before or after proteinase K digestion (50 Âµg mlË‰Â¹ final protease concentration, 1 hour, 37° C), by immunoblotting with anti-PrP monoclonal antibody 3F4 using high sensitivity enhanced chemiluminescence. Peripheral tissue homogenate was analysed by sodium phosphotungstic acid precipitation of PrPSc, proteinase K digestion and immunoblotting with anti-PrP monoclonal antibody 3F4 using high sensitivity enhanced chemiluminescence, as described previously (Brandner et al., 2008).
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Findings of the brain biopsy showed concentrated spongiosis and abnormal PrP in the grey matter, than in the white matter. The caudate nucleus and thalamus were greatly affected by spongiosis, neuronal loss, synaptic and plaque deposition PrP. The unaffected parts of the brain included the cerebral cortex, hippocampus, and spinal cord. The peripheral tissues that showed undetectable amounts of abnormal PrP deposition included the heart, lung, muscle, thymus, dura, and cranial nerves. Also, no PrPSc was found in the spleen or distal ileum (Bradner et al., 2008).
Prion diseases are fatal and there is no effective treatment or cure (Korth, May, Cohen, & Prusiner, 2001). There are several experimental treatments and therapeutic strategies that have slowed the progression of this disease. Treatments include passive immunization with anti-PrP antibodies, which prevent progression of peripheral prion infection; and transgenic knockout of neuronal PrPC to prevent development of disease. It is important to begin treatment in the early stages and before loss of neurons occur for effective treatment (Trevitt & Collinge, 2006).
According to Korth, May, Cohen, & Prusiner (2001), quinacrine and chlorpromazine, which are antimalarial and antipsychotic drugs, can be used to treat humans with prion disease. The blood-brain barrier does not allow molecules to enter the CNS. These drugs are able to pass the blood-brain barrier and slow down PrPSc formation. The antipsychotic drug chlorpromazine has the potential to treat people with prion disease and will be discussed further.
Antipsychotic drugs are used to treat mental illness like depression and schizophrenia. Chlorpromazine belongs to one of the largest groups of antipsychotic drugs called phenothiazines. The purpose of antipsychotic drugs is to block dopamine receptors in the brain, causing the concentration of dopamine in the CNS to decrease. Dopamine binds postsynaptically to the limbic system and basal ganglia, areas in which are connected to emotion, cognitive function and motor function. This causes the drugs to produce therapeutic and toxic effects due to the dopamine being blocked. Also, antipsychotics can block serotonin receptors along with dopamine receptors, and inhibit neurotransmitters in the gastrointestinal tract causing this drug to act as an antiemetic drug, to relieve nausea and vomiting.
Chlorpromazine or brand name Thorazine is given orally and intramuscular at a dose of 25-500 mg/day. Contraindications of the drug include drug allergy to phenothiazines, comatose state, and alcohol withdrawl. Side effects include drowsiness, blurred vision, and involuntary movements (Lilley, Harrington, & Snyder, 2004).
Complication of Kuru
Heart failure (HF) is a complex syndrome that can result from any cardiac disorder that reduces the ability of the heart to pump blood. Some common causes of heart failure include hypertension, coronary artery disease, and valvular heart disease. In 2004, heart failure has been diagnosed in 400, 000 Canadians and is associated with high morbidity and mortality rates among the elderly. Decreased cardiac output and increased body fluid volume are signs of heart failure. If heart failure is detected early, treatment measures can be taken to delay the progression of disease. The New York Heart Association (NYHA) Functional Classification describes the progression of heart failure and is used to group patients into four classifications (Hannon, Pooler, & Porth, 2010)
According to Hannon, Pooler, & Porth (2010), when the heart begins to fail the body tries to compensate using mechanisms such as Frank-Starling's Law, the sympathetic nervous system, the renin-angiotensin-aldosterone system, natriuretic peptides, endothelins, ventricular remodeling, and inflammatory mediators. These compensatory mechanisms maintain cardiac output and contribute to the disease process of heart failure. For the purpose of this essay, the sympathetic nervous system will be discussed because it is an essential part in the disease process due to the decrease in cardiac output.
Sympathetic Nervous System Stimulation
As the heart begins to fail, the decreased cardiac output and reduced systemic blood pressure activate baro
Brain natriuretic peptide (BNP)
Angiotensin II receptor blockers