Causes
Transmissible spongiform encephalopathy diseases are caused by prions. The diseases are thus sometimes called prion diseases. Other prion diseases include Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, as well as bovine spongiform encephalopathy (BSE) commonly known as mad cow disease, chronic wasting disease (CWD) in elk, and scrapie in sheep.
The prion that is believed to cause Creutzfeldt-Jakob exhibits at least two stable conformations. One, the native state, is water-soluble and present in healthy cells. As of 2006, its biological function is unknown. The other conformational state is very poorly water-soluble and readily forms protein aggregates.
The CJD prion is dangerous because it promotes refolding of native proteins into the diseased state. The number of misfolded protein molecules will increase exponentially[citation needed], and the process leads to a large quantity of insoluble prions in affected cells. This mass of misfolded proteins disrupts cell function and causes cell death. Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop, causing exponential spread of the prion, death within a few months, although a few patients have been known to live as long as two years.
Stanley B. Prusiner was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. For more than a decade, Yale University neuropathologist Laura Manuelidis has been challenging this explanation for the disease. In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science and reported that they have found a virus-like particle (but without finding nucleic acids so far) in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human CJD agent.
Symptoms
The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes and hallucinations. This is accompanied by physical problems such as speech impairment, jerky movements (myoclonus), balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks (Johnson, 1998). In some people, the symptoms can continue for years. In most patients, these symptoms are followed by involuntary movements and the appearance of a typical diagnostic electroencephalogram tracing.
The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion proteins. When brain tissue from a CJD patient is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word 'spongiform' in 'transmissible spongiform encephalopathies' refers to the 'spongy' appearance of the brain tissue.
The diagnosis of CJD is suspected when there are typical clinical symptoms and signs such as rapidly progressing dementia with myoclonus. Further investigation can then be performed to support the diagnosis including
- Electroencephalography - often has characteristic triphasic spikes
- 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.
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, even is stronger and constant in vCJD.
In one third of patients with sporadic CJD, deposits of "prion protein (scrapie)," PrPSc, 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 PrpSc; however, biopsy of brain tissue is the definitive diagnostic test.
- Clinical and Pathologic Characteristics:
| Characteristic | Classic CJD | Variant CJD |
| Median age at death | 68 years | 28 years |
| Median duration of illness | 4-5 months | 13-14 months |
| Clinical signs and symptoms | Dementia; early neurologic signs | Prominent psychiatric/behavioral symptoms; painful dysesthesias; delayed neurologic signs |
| Periodic sharp waves on electroencephalogram | Often present | Often absent |
| Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI | Often present | Often absent |
| "Pulvinar sign" on MRI | Not reported | Present in >75% of cases |
| Immunohistochemical analysis of brain tissue | Variable accumulation. | Marked accumulation of protease-resistant prion protein |
| Presence of agent in lymphoid tissue | Not readily detected | Readily detected |
| Increased glycoform ratio on immunoblot analysis of protease-resistant prion protein | Not reported | Marked accumulation of protease-resistant prion protein |
| Presence of amyloid plaques in brain tissue | May be present | May be present |
- An abnormal signal in the posterior thalami 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)
Treatment
As of 2007, there is no cure for CJD, a fatal disease, and the search for viable treatments continues. An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003. The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient's lateral ventricle within the brain. PPS does not seem to stop the disease from progressing, and both brain function and tissue continue to be lost. However, the treatment is alleged to slow the progression of the otherwise untreatable disease, and may have contributed to the longer than expected survival of the seven patients that were studied. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that Pentosan Polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 patients with PPS finds no proof of efficacy because of the lack of accepted objective criteria.
Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years.
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