Creutzfeldt-Jakob Disease Diagnosis

  • Diagnosis

    Creutzfeldt-Jakob Disease (CJD) is a degenerative, invariably fatal brain disease that destroys mind and body. Creutzfeldt-Jakob Disease (CJD) is characterized by rapid mental deterioration (dementia) accompanied by a loss of coordination, and involuntary, irregular jerking movements of the body (myoclonus). Symptoms vary considerably, but typically at first include difficulty sleeping, decreased appetite, dizziness, confusion, and behavior changes. Eventually, the patient loses the ability to speak or move, and enters a coma. Death usually results from a bodily disease such as pneumonia, which occurs as a result of being bedridden. Death normally occurs within one year of the onset of symptoms, and frequently occurs within two to six months.

    Fortunately, CJD is extremely rare. Worldwide, CJD affects about one person in every million per year. In the U.S., there are about 200 cases annually. The low random incidence of CJD suggests that it is not a contagious disease. Indeed, relatives of afflicted individuals have lived for years in the same household without getting the disease, and they appear to be no more at risk for CJD than the general population.

    Even though CJD is extremely rare, because of its apparent connection with bovine spongiform encephalopathy (BSE), or “mad-cow disease,” it has received a great deal of media attention in the last few years. However, only one type of CJD, known as new-variant CJD (nvCJD), is thought to be linked to BSE.

    There are four different types of CJD. Before the discovery of nvCJD in 1996, CJD was thought to exist only in three forms: sporadic, familial, and iatrogenic. These three forms of CJD occur most often in people who are 60 to 70 years of age.

    • Sporadic CJD occurs for no known reason, and accounts for 85% to 90% of all cases.
    • The familial form, which is associated with an inherited gene mutation, accounts for 5% to 15% of cases. Familial CJD generally manifests at an earlier age, and takes longer to develop than sporadic CJD
    • Iatrogenic is the third form, accounting for less than 1% of all cases. This type can result from accidental transmission of the disease during a medical procedure such as cornea transplantation or treatment with human growth hormone. Because of the way it spreads, the iatrogenic form of CJD can affect people of any age. Moreover, the time between exposure to the disease-causing agent and the start of symptoms (called the incubation period) can be several decades
    • New variant CJD (nvCJD). In 1996, a fourth type of CJD called new variant CJD (nvCJD) was discovered in the United Kingdom. In contrast to traditional forms of the disease, nvCJD affects younger patients; more than half of those affected are younger than 30. Although a link has not been firmly proven, nvCJD seems to result from eating BSE-infected beef. As of 2005, one case of nvCJD has been diagnosed in the U.S., with 165 probably cases worldwide. It is important to note that nvCJD accounts for less than 1% of CJD cases worldwide.

    The cause of the most common form of CJD—sporadic CJD—is unknown. Sporadic CJD accounts for more than 85% of CJD cases, but scientists do not know why it occurs. It is thought that a specific protein found in the brain converts to an abnormally folded form. This abnormal protein (called a prion) then acts as a template for further protein misfolding. Abnormal protein builds up and destroys brain tissue, resulting in the symptoms of CJD

    Familial—or inherited—CJD results from a defect in genetic coding. A mutation in the PRNP gene causes 5% to 15% of CJD cases. The prevalence of this form of CJD among certain groups such as Chileans, Czechoslovakians, and Libyan Jews suggests that it may be inherited.

    Iatrogenic, or infectious, CJD is the unintended result of medical procedures such as a corneal transplantation, grafts of the dura mater (the outmost membrane covering the spinal cord and brain), deep-brain electrode implantation, or treatment with human growth hormone. While tragic, accidental transmission of CJD during medical treatment is extremely rare; approximately 250 cases have been reported worldwide to date. Most of the cases are associated with the use of human growth hormone and pituitary gonadotropin therapy. The resulting CJD seems to have an incubation period of 4 to 30 years. More than 70 cases have been reported after dura mater grafts (for example, the use of spinal membrane to repair a punctured eardrum), with all of the graft material having come from the same manufacturer. There have been no confirmed cases of CJD as a result of blood transfusions.

    A recent new variant CJD (nvCJD) outbreak in the United Kingdom seems to be linked to a deadly brain disease in cattle similar to CJD. This variant in cattle is known scientifically as bovine spongiform encephalopathy (BSE), but has been dubbed “mad-cow disease” by the media Table 01. BSE was discovered in Great Britain in 1995, and is thought to have been caused by the use of cattle feed containing ground meat and bone meal from sheep infected with a prion disease (like BSE and CJD) found only in sheep, called scrapie. Although the link has not been firmly proven, recent evidence suggests that nvCJD is caused by eating beef infected with BSE.

    Table 1.  Types of Creutzfeld-Jakob Disease

    Type Percentage of cases Presumed cause
    Sporadic 85-90 Prion mutation for unknown reason
    Familial or inherited 5-15 Inherited defect in genetic coding
    Iatrogenic or infectious <1 Infection by contaminated instruments during surgical procedures, transplantation or graft of contaminated tissue, or treatment with hGH or PGT
    New variant <1 Possibly caused by eating BSE-infected beef
    Kuru Among Fore people of New Guinea only Ritualistic cannibalism

    HGH: human growth hormone; PGT:pituitary gonadotropin therapy; BSE: bovine spongiform encephalopathy.

    Most patients with CJD first show vague, non-specific physical and mental symptoms. This phase is followed by rapidly progressive dementia accompanied by motor disturbances such as loss of coordination and muscle jerking known as myoclonus. However, the symptoms of CJD vary widely in different patients. Early in CJD, most patients experience some combination of the following symptoms:

    • Difficulty sleeping
    • Decreased appetite
    • Depression
    • Failing memory
    • Behavior or personality changes
    • Impaired judgment
    • Strange physical sensations
    • Visual disturbances
    • Lack of coordination
    • Involuntary movements, especially muscle jerking known as myoclonus

    With time, patients rapidly lose their ability to think clearly and carry out daily activities. Involuntary muscle jerking known as myoclonus can occur at any point in the disease, although it is most common in the middle or late stages. Patients may develop additional symptoms such as weakness in the arms or legs, blindness, and seizures.

    As the disease progresses, mental deterioration becomes so pronounced that patients can no longer perform daily activities. In the final stages, the patient loses all mental and physical function, and ultimately lapses into a coma. Patients usually die from an infection or other bodily illness (e.g., pneumonia) because the dementia prevents them from communicating their symptoms.

    The symptoms of nvCJD differ somewhat from those of the other forms of the disease. Patients with nvCJD are more likely to experience depression, anxiety, and other psychiatric symptoms, as well as sensory abnormalities. As the disease progresses, patients lose coordination, and experience involuntary muscle jerking (myoclonus) and other motor problems seen in the other forms of CJD. Unlike in these other forms, patients may not show dementia until late in the course of the disease. While symptoms of memory loss, reduced mental capability, and agitation can also occur in other dementias, such as Alzheimer's or Huntington's diseases, CJD causes a more rapid deterioration of a person's abilities than all other types of dementia.

    The most common form of CJD—sporadic CJD—has no proven risk factors. However, a new study indicates a possible connection between frequency of surgical operations and living or working on a farm. A 1999 study from Australia (published in the British medical journal The Lancet) raised the possibility that the risk for sporadic CJD increases with the number of surgical operations one has in one's lifetime. The study also suggested that people who have lived or worked on farms for 10 years or more may also be at higher risk. Additional studies are needed to confirm these and other potential risk factors for sporadic CJD.

    People with a family history of CJD have an increased risk of developing familial CJD. A person who has only a single known family member with CJD may not be at increased risk for familial CJD—the likelihood is that the case represents an isolated occurrence. Moreover, simply living with a person with CJD does not increase one’s risk of contracting the disorder. However, in an extremely small number of families, CJD appears in multiple generations. Members of such families have a greater risk of developing CJD than the general population

    People most at risk for infectious CJD are those who received brain dura mater transplants or growth hormone taken from human pituitary glands in the 1980s. Since the link between CJD and human growth hormone was discovered, growth hormone is no longer harvested from human pituitary glands. There are also reported cases of CJD transmission through corneal transplants. However, cornea donors have been routinely screened for CJD risk since 1980, and cornea transplantation is no longer considered to be a significant risk factor.

    When considering a diagnosis of CJD, a doctor will look for rapid-onset dementia, muscle jerking, a lack of coordination, and a pattern of periodic electrical bursts on an electroencephalogram (EEG), which is a record of the brain’s electrical activity. Unfortunately, doctors have a hard time diagnosing CJD because traditional laboratory tests cannot detect the disease. Doctors have to diagnose CJD by ruling out other types of rapidly progressing dementia such as encephalitis or chronic meningitis. Computerized tomography (CAT scans) and magnetic resonance imaging (MRI) of the brain are done to check for problems such as stroke or brain tumor.

    One helpful test for diagnosing CJD is the electroencephalogram (EEG), which produces a record of electrical activity of the brain. In patients with CJD, the EEG often shows a characteristic abnormal pattern of brain waves in periodic bursts. However, the EEG cannot be used to make a definite diagnosis of CJD. Not all patients with CJD—especially those with nvCJD—show the characteristic abnormal EEG pattern. Nevertheless, the abnormal pattern strongly indicates CJD if the patient also has dementia and muscle jerking.

    Recently, scientists at the National Institutes of Neurological Disease and Stroke developed a test of cerebrospinal fluid that can aid in the diagnosis of CJD. The test detects a specific protein in cerebrospinal fluid, which is the fluid that bathes the brain and spinal cord. Some studies have shown that this protein is elevated in the cerebrospinal fluid of over 90% of patients with suspected CJD. Nevertheless, many patients with CJD (especially familial and nvCJD) do not have increased levels of the protein, and the protein may be increased in the cerebrospinal fluid of patients with many other neurological conditions besides CJD.

    If the patient has a family history of CJD, a genetic test may help confirm the diagnosis. The genetic test is most helpful in the diagnosis of CJD for patients with a family history of the disease. Although scientists have identified many different gene mutations in patients with family histories of CJD, genetic testing cannot identify a mutation in all patients with familial CJD.

    No one suspected of having CJD should donate blood, tissues, or organs. At this time, it is not entirely clear how likely it is that patients receiving blood or donated parts from individuals with CJD will get the disease. Until more conclusive evidence is obtained, it is best for patients with suspected CJD not to donate blood, tissues, or organs.

  • Prevention and Screening

    No one suspected of having CJD should donate blood, tissues, or organs. At this time, it is not entirely clear how likely it is that patients receiving blood or donated parts from individuals with CJD will get the disease. Until more conclusive evidence is obtained, it is best for patients with suspected CJD not to donate blood, tissues, or organs.

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