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The fundamentals of variant Creutzfeldt-Jakob disease.

Abstract: Since the discovery of a variant form of Creutzfeldt-Jakob disease (vCJD), the human form of bovine spongiform encephalopathy, researchers have been persistent in their search for the way in which this disease manifests itself in humans. Like all other forms of CJD, vCJD is a prion disease, or transmissible spongiform encephalopathy. The differences from other forms of CJD are its manifestation and the population at risk. Diagnosing the disease remains a problem because true diagnosis can be determined only by postmortem evaluation. Because there is no treatment for vCJD or any form of CJD, palliative care is the foundation of care. Nurses should know the risks of the disease and understand its pathogenesis not only to explain modes of transmission to families but also to be able to protect themselves. Researchers are currently investigating a genetic link as well as the immunological relationship of this disease in hopes of providing more answers related to transmissibility, incubation, and risk for the disease.

The dairy industry in the United Kingdom took a serious hit in 1985, when bovine spongiform encephalopathy (BSE) was discovered in the cattle population (Painter, 2000). Nicknamed "mad cow disease" for the behavior displayed by the cows as the disease progressed, the Department of Health in the United Kingdom assured its citizens that this was a serious epidemic to the farmers, but not a disease transmissible to humans (Weihl & Roos, 1999). In 1995, this belief was found to be incorrect. The disease manifested in humans is called variant Creutzfeldt-Jakob disease (vCJD), because it closely resembles the prion disease, Creutzfeldt-Jakob disease (Narang, 2001). This new variant form was discovered and linked to the ingestion of offal, ground upparts of the brain, spinal cord, nerves, and other nervous tissue often found in hot dogs, sausage, deli meats, potted meats, and other processed meat sources (Weihl & Roos). Since 1995, 110 cases of vCJD have been reported (Balter, 2001). As small as the numbers are, vCJD has displayed many crucial differences from "classic" forms of CJD and investigators continue to research the pathology of vCJD. The pathophysiology of vCJD, expected alterations in the neurons and brain tissue, implications for practice, and the implications for research are discussed in this article.

Background

Understanding the origin of vCJD begins at its classification as a prion disease. Prion diseases are a group of transmissible, subacute neurodegenerative diseases with distinctive clinical and pathophysiological features (Weihl & Roos, 1999). Prion diseases are also known as transmissible (subacute) spongiform encephalopathies (TSE or SSE; Johnson & Gibbs, 1998). A prion is a small, proteinaceous, infectious particle that can resist sources used to kill other pathogens or denature proteins (Weihl & Roos). Prion diseases are classified in both human and animal forms. Human prion diseases are divided into subgroups: sporadic or iatrogenic, acquired, and familial or genetic (Weihl & Roos). Variant CJD is currently classified in the subgroup acquired human prion disease, but may be reclassified as researchers learn more about its transmission (Weihl & Roos).

In 1995, as the epidemic of BSE in cattle was in decline, a CJD-like disease was appearing more frequently and with new manifestations in a younger human population (Brown, 2001). Epidemiologically, these cases were appearing in the same countries stricken by BSE (MacKnight, 2001). It was determined in 1997 that this new form of CJD shared the same biological and molecular features as BSE (Collinge, 1999). The link between vCJD and BSE was very alarming to the farming communities and to human beef consumers. Scientists studying BSE theorized that the origin of the disease was from scrapie, the transmissible spongiform encephalopathy that occurs in sheep that had now been transmitted to cows (Brown). In 1994, it was also theorized that the transmission of the disease from one species to another could allow the disease to manifest itself in additional species (Brown). For example, scrapie, a transmissible spongiform encephalopathy found in sheep, is not able to manifest itself in humans. According to the theory, once the prion in its new and altered form had become infectious to cattle, it could also be transmitted to a human population (Brown).

Expected Cellular and Genetic Alterations

Prions are found naturally in humans and their function remains unclear. It is known that prions are involved with neuronal development and function, as well as in prevention of cell death (MacKnight, 2001). Prions have characteristics that make them unique from other pathogens, leaving them in a class of their own (Weihl & Roos, 1999). The closest biological entity in likeness would be the virus because of the similarity in proteinaceous makeup, but the lack of nucleic acid associated with a prion defines the pathogen (Weihl & Roos). The normal prion form is the Pr[P.sup.C], while the abnormal form of the prion is the Pr[P.sup.SC] (Collinge, 1999).

Because prions lack nucleic acid, this pathogen is difficult to kill. Prions can withstand irradiation, formalin (liquid containing 37% formaldehyde), and heat inactivation at temperatures that would kill most microbes (Weihl & Roos). Protein chemistry is the basis of the prion theory. Few hypotheses of prion replication have been offered. The prion theory suggests that a prion is able to replicate without nucleic acid (Weihl & Roos, 1999), while an alternative theory suggests the Pr[P.sup.SC] has some undetectable amount of nucleic acid associated with it to aid in its reproduction (Knight, 1999). The uncertainty of prion function and the lack of nucleic acid make an understanding of prion replication difficult. Another component of the prion theory is that prions cannot be inactivated in vivo (Weihl & Roos). The ability of the prion to resist inactivation is due to nervous tissue's inability to modify the proteinaceous material and the prion's lack of nucleic acid. At temperatures that would normally denature nucleic acids, the protein structure of the prion remains intact, leaving the prion capable of infection (Weihl & Roos).

The transformation of Pr[P.sup.C] to Pr[P.sup.SC] is different for each subgroup of CJD. The Pr[P.sup.C] is full of a-helical structure, while the Pr[P.sup.SC] primarily comprises b-pleated sheets Collinge, 1999). In vCJD, the Pr[P.sup.C] acts as a substrate for conversion to Pr[P.sup.SC] once it is introduced into a human (Weihl & Roos, 1999). Another interesting finding in the biochemical makeup of vCJD is the genetic link. All the people who have had vCJD are homozygous for methionine at codon 129 in the human prion gene (PRNP) (Brown, 2001). The two assumptions about this fact are that only this particular genotype is susceptible to vCJD or that other genotypes have a longer period of incubation and are at risk of developing this disease in years to come (Brown).

Pathophysiology

Prions responsible for vCJD deposit and replicate in neurological tissues. The accumulation of prions in neurological tissue causes the death of these cells, leaving large vacuoles in the brain tissue over time (Knight, 1999). Johnson & Gibbs (1998) postulated that the infection begins with the ingestion of offal. Bovine nervous tissue, retina, trigeminal and paraspinal ganglia, the distal ileum, and possibly bone marrow have been shown to be infectious (Brown, 2001). Specifically, both double negative intentional milk and muscle have not been shown not to carry the BSE or other transmissible spongiform encephalopathy (Brown, 2001). After ingestion, abnormal prion proteins (Pr[P.sup.SC]) are absorbed into the bloodstream, cross the blood-brain barrier, and are carried into the brain and other nervous tissues (Knight & Stewart, 1998). Many researchers believe that it takes only a minute quantity of the Pr[P.sup.SC] prion, once inoculated in the body, to begin the cascade of events that convert the Pr[P.sup.C] into the "misfolded" form (Coulthart & Cashman, 2001). Unique to prion diseases is the lack of inflammation in the central nervous system as a result of the depositing prions (Coulthart & Cashman). The deposition of Pr[P.sup.SC] in the brain starts a chain of events that changes the shape of the Pr[P.sup.C] into the abnormal Pr[P.sup.SC] configuration (Weihl & Roos, 1999). Accumulation of abnormal prions is associated with the disease vCJD and its infectivity. In general, the Pr[P.sup.SC] prion begins to aggregate in the neural tissues in a fashion, not well understood by researchers, that progressively leads to neurotoxicity, neurodegeneration, and death (Coulthart & Cashman). As in the classic forms of CJD, the deposition of the Pr[P.sup.SC] causes spongiform changes, neuronal loss, astrogliosis, and amyloid plaque formation (Knight). The striking difference between CJD and vCJD was the finding of distinctive florid plaques (in vCJD) that are immunoreactive Pr[P.sup.C] amyloid plaques with an eosinophilic core and a pale periphery surrounded by a spongiform change not seen in CJD (Weihl & Roos).

Spongiform, or sponge-like, accurately describes the physiologic effects of prion disease on the tissue of the brain. The physiologic mechanics of the disease are not truly understood by researchers at this time; however, postmortem autopsy has identified three factors that result in neurologic deterioration (Wallace, 1999). The first factor is the displacement of the nucleus to the side of the cell as a result of the glial swelling. The contents of the neuron then deteriorate, leaving an intact membrane still bound to outside structures and filled with membranous residuals of cellular material; this is the process of vacuolation. The second process is the formation of amyloid plaques that block the transmission of impulses across the membranes. The three theories surrounding the formation of amyloid plaques are that (a) they are the composition of the circulating prion and a macrophage that tried to attack it; (b) that local, immunological factors in the brain of an affected patient "provoke the amyloid formation," and (c) scrapie-associated fibrils in the brain of a CJD patient are unable to be properly transmitted down an axon and accumulate as a result (Wallace). Finally, the last process is astrocytosis. Astrocytosis is the abnormal growth of the astrocytes that are fibrous, supportive cells of the nervous system. These cells are star-shaped and have many branches. The normal astrocyte will become infected with the prion, grow and branch out, in turn, interfering with normal neuronal transmission (Wallace).

Clinical Manifestations

The presentation of vCJD varies in people based on how severely affected they are and which area becomes affected first. Early-stage clinical manifestations are typically cerebellar ataxia and behavioral changes. Changes such as agitation, impaired judgment, and mood swings are some behavior characteristics seen (Wallace, 1998). The onset of early psychiatric symptoms is specific to vCJD. However, the presence of psychiatric disorders can be evident in the other subgroups of CJD (Weihl & Roos, 1999). The difference is that, in vCJD, psychological symptoms present early while psychological symptoms in CJD present later, if at all (Coulthart & Cashman, 2001). Painful dysesthesias and sensory disturbances are also common symptoms seen in the early stages of vCJD (Weihl & Roos). As the disease progresses, later symptoms are spasticity and rigidity, tremors and myoclonic jerks, dysarthria, agnosias, incoordination, and sleep disturbances. Finally, the disease progresses to complete mental and physical dysfunction, epileptic seizures, and decorticate posturing (Wallace). Death occurs when degradation of brainstem and other areas of motor function has become so severe as to cause brain death and apnea (Wallace). Table 1 discusses symptoms distinctive to vCJD.

Other criteria specific to vCJD are normal electroencephalogram (EEG) studies (EEG findings are commonly abnormal in CJD), early age of onset (16 to 48 years), and a longer duration of the disease (Aminoff, Greenburg, & Simon, 1999). The typical age range for classic CJD is between 50 and 75 years (Wallace, 1999). Researchers suggest that the consumption of products containing offal, such as hot dogs and some deli meats, are eaten more frequently in younger people (Johnson & Gibbs, 1998). The average duration of classic CJD is 6 to 12 months, whereas the mean duration period in vCJD is 14 months (Aminoff et al., 1999). There is also evidence that suggests the vCJD has a longer incubation period (10-15 years) than classic forms of CJD (Wallace, 1999).

Diagnostic Criteria

Definitive diagnosis of vCJD is made only upon postmortem biopsy, although open brain biopsies are being done to detect the presence of vCJD, once other cerebellar diseases are ruled out (Wallace, 1999). Originally, open brain biopsies were not considered accurate because the tissue obtained may not be an infected tissue and the patient may indeed have the disease. Since the discovery of vCJD, methods of obtaining specimens via brain biopsy can be performed in patients who are suspected of having vCJD (Johnson & Gibbs, 1998). Table 2 presents the diagnostic criteria set forth by the World Health Organization for vCJD (MacKnight, 2001).

Even when the EEG is negative for abnormal changes, a magnetic resonance imaging scan may be abnormal, showing increased signal in the posterior portion of the thalamus on the T-2 weighted images (Weihl & Roos, 1999). Computed tomography scans have also been considered a sensitive means for imaging vCJD but render more generalized results, such as detecting abnormal areas of fluid or air and degradation of tissues (Wallace, 1999). In classic CJD, the 14-3-3 cerebrospinal fluid (CSF) test is effective for diagnosing the disease, but researchers are still trying to evaluate the effectiveness of this test in vCJD (Wallace, 1999). Also important is the complete neurological examination to detect cerebellar and cerebral cortical dysfunction (Wallace). From the abnormal results of these examinations, a foundation of differential diagnosis, including vCJD, can be made.

Differential Diagnosis

Diseases that are characterized by myoclonus and dementia typically serve as the basis for the differential diagnosis of vCJD (Ropper & Victor, 2001). Alzheimer's disease is commonly considered due to the ataxia and behavioral/personality changes seen in the disease (Ropper & Victor). A significant difference between Alzheimer's and vCJD is that in vCJD the dementia progresses in 4 to 7 months, whereas the dementia in Alzheimer's disease occurs over 4 to 7 years (Wallace, 1999). Because the symptoms of vCJD do not present the same in each patient, the differential diagnoses can shift in many directions based on patient history. The most common differential diagnoses used are AIDS dementia, Lewybody disease, Hashimoto encephalopathy, especially in the younger population, lithium intoxication, carcinomatous meningitis, limbic brainstem-cerebellar encephalitis, vascular dementia, herpes encephalitis, and, as stated, Alzheimer's disease (Ropper & Victor). These differential diagnoses are narrowed down as tests such as EEG, 14-3-3 CSF examination, and biopsies are done and results guide their exclusion or inclusion.

Implications for Practice

Early recognition of symptoms and early diagnosis remain crucial to the treatment of the patient (Wallace, 1999). The easiest, most effective, and most cost-efficient means for diagnosing vCJD is the neurological examination (Wallace). Many of the cerebellar changes are evident on examinations such as rapid alternating movement, point-to-point, Romberg, tandem walking, and other balance changes (Wallace).

Because there is no cure for this devastating disease, treatment is palliative, focusing mainly on achieving patient comfort and safety (Wallace, 1999). The practitioner's role shifts as the patient deteriorates and is no longer able to perform the activities of daffy living. The practitioner should then become a support for the family (Wallace). Sensitivity is crucial for practitioners in supporting family coping and also when discussing decision making with regard to treatment and life-sustaining interventions (Wallace).

Another important factor that practitioners need to be aware of is the inability to kill the prions, especially where surgical instruments are concerned (Weihl & Roos, 1999). This point is crucial not only for practitioners but also for the operating room staff, including the nurses, surgical technicians, sanitation staff, and surgeons. When any form of CJD is included in a differential diagnosis and a procedure is performed, instruments from that procedure are sealed and held until a diagnosis is determined. Once the diagnosis is officially CJD, the instruments are then considered biohazardous waste and are destroyed (Coulthart & Cashman, 2001; MacKnight, 2001). Further education is necessary because although most institutions accept this practice, it is not required by guidelines or regulations at this time (Brown, 2001). Also, in patients suspected of the disease, disposable equipment should be used when possible.

An important matter is mode of transmission. Understanding how a person contracts the disease helps healthcare workers protect themselves as well as alleviate potential fears regarding "catching the disease" by the family. The key point is that vCJD or CJD is believed to be bloodborne (Senior, 2001). Because this point has not been proven, the American Red Cross takes the extra precaution to not accept blood from anyone who has traveled in Europe for more than 6 months (Senior). This is the most stringent of the bans set by a blood collection agency, but they are defended by the idea that this limits the potential transmission of a devastating disease with no cure (Senior).

Another recently discovered mode of transmission has been in corneal and dural transplants. Some of the iatrogenic CJD cases (this included vCJD) have been traced to human cadaveric-derived dural homografts and corneal grafts (Lang, Hecjmann, Neundorfer, 1998). Because these iatrogenic cases make up approximately 1%-5% of the cases of CJD overall, the risk is small. However, it does stress the importance of documenting a detailed history, focusing on past surgical history, as well as documenting any European travel after 1986, which was when BSE emerged.

Implications for Research

The homozygous presence of methionine at codon 129 is the most significant genetic link so far, because cattle are also homozygous for methionine at this codon (Turner & Ludlam, 2000). In addition, two recent papers have stated that seven other genes affect the "susceptibility to prions in mice" (Balter, 2001, p. 1439). Recently, a researcher discovered that 80% of patients diagnosed with vCJD lack the human leukocyte antigen (HLA), an immune system protein antigen that helps the immune system recognize foreign invaders (Balter).

These studies have also led to the suggestion that prions must travel through lymphatic organs such as lymph nodes, spleen, and tonsils (Balter, 2001). A man diagnosed with vCJD had his appendix removed 2 years prior to his diagnosis and was found to have Pr[P.sup.SC] deposits in the lymphoid tissue of the appendix at the time of excision (Weihl & Roos, 1999). Similar Pr[P.sup.SC] deposits have also be found in the tonsils of patients with vCJD (Coulthart & Cashman, 2001). This poses the question, if we can detect the disease in the lymph tissue before the onset of symptoms, can a screening test for the disease be devised? Also, if the lymphoid tissue is affected, what is the potential transmissibility of vCJD via blood or peripheral tissues (Coulthart & Cashman, 2001)? The possibility of blood transmission, still not substantiated, sparked an international movement by many countries, including the United States, to defer blood donors who lived or visited the United Kingdon before 1995 (Brown, 2001).

Based on research reviewed for this paper, some areas of concern are the young age of the patients and the inability to determine the incubation period for vCJD. In July 1988, the use of dead cattle carcasses and bone meal in the food being ingested by the cattle was banned, and animals suspected to have the disease were killed (Turner & Ludlam, 2000). Seven years passed before the first case of vCJD was diagnosed. Because nothing was known about the incubation period of the vCJD, 10,000 or more people were originally estimated as a maximum number to develop the disease (Brown, 2001). As a result of the yearly incidence of the disease in the United Kingdom, and assuming the disease has an incubation period of 20 to 30 years, the researchers, using mathematical models, are now estimating a maximum 3,000 people will be infected with vCJD; that number decreases to 600 if the incubation period is less than 20 years (Brown). Once the incubation is better understood, either genetically or pathologically, a more accurate assumption of the incidence of vCJD can be made.

Summary

The investigation of vCJD remains very active and involves many areas of research such as infectious disease, genetics, hematology, pathology, histology, and cytology. Much is still to be learned about the pathophysiology of the disease, but what is known is enough to understand the symptomatology behind the disease and how further destruction by prions leads to the progression of the disease and eventually death. Among the important points for healthcare professionals to understand are early diagnosis and appropriate testing for the disease, ensuring the comfort of the diagnosed vCJD patient, protecting the safety of the patient, and supporting the patient and the family members while they cope mad make decisions regarding the well-being of their loved one.

Finally, the need for further research remains important because genetic aspects are not fully understood; an uncertain incubation period disrupts the ability to predict future cases; and modes of transmissibility are still a dangerous question. Further, reasons why younger populations are affected are unclear. Note that vCJD has not traveled to the United States. As research continues and more breakthroughs are discovered, the United States, as a nation, can hope to prevent this deadly disease from spreading in the country.
Table 1. Differences in New Variant Creutzfeldt-Jakob Disease Compared
to CJD

* Younger age of onset; average age of onset was 29 years (ranging from
16-48 years).

* Longer duration; average duration was approximately 16 months (ranging
from 9-38 months).

* Behavioral changes are common and early, frequently prompting a
psychiatric consultation. In addition,
painful dyesthesias can be seen as an early symptom. Ataxia is
frequently seen after the
appearance of the psychiatric changes and the sensory disturbances.

* Cases do not have the typical EEG abnormalities of CJD.

* Cases may have abnormal MRI studies, with increased signal in the
posterior thalamus on T-2
weighted images.

Note: Adapted from Weihl and Roos, 1999.

Table 2. World Health Organization Diagnostic Criteria for New Variant
Creutzfeldt-Jakob
Disease

Patients must have five of the following six symptoms:

* Early psychiatric symptoms

* Early persistent paresthesia/dysthesia

* Ataxia

* Chorea/dystonia or myoclonus

* Dementia
* Akinetic mutism

Patients should meet all the following criteria:

* Clinical duration of symptoms >6 months

* Age at onset of <50 years

* Absences of PrP gene mutation

* Electroencephalogram does not show typical periodic appearance

* Routine investigations do not suggest an alternative diagnosis

* MRI scan shows abnormal bilateral high signal from the pulvinar on
axial T-2 and/or proton density
weighted images

Note: From "Clinical Importance of Bovine Spongiform Encephalopathy, "by
C. MacKnight, 2001, Clinical Infectious
Diseases, 32, 1726-31. Copyright 2001 by the University of Chicago
Press. Reprinted with permission.


Acknowledgments

I thank Therese Richmond, PhD CRNP CS FAAN, at the University of Pennsylvania for encouraging me to submit this work for publication and mentoring me through the process.

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Date:Dec 1, 2003
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