Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy 

  • Author: Florian P Thomas, MD, MA, PhD, Drmed; Chief Editor: Karen L Roos, MD   more...
 
Updated: Jun 21, 2010
 

Background

Bovine spongiform encephalopathy (BSE), also known as mad cow disease, and variant Creutzfeldt-Jakob disease (CJD) are related disorders. They belong to the family of diseases known as the transmissible spongiform encephalopathies (TSEs). TSEs are caused by a transmissible proteinaceous particle, which is yet to be fully characterized. Other TSEs include scrapie (a disease of sheep), feline spongiform encephalopathy, transmissible mink encephalopathy, and chronic wasting disease of deer and elk. Human forms include classic CJD, variant CJD, kuru, Gerstmann-Strãussler-Scheinker disease, familial fatal insomnia, and sporadic fatal insomnia.

Human TSEs share the following characteristics.

  • A prolonged incubation period of several years
  • A progressive debilitating neurologic syndrome that is invariably fatal
  • Pathological changes that are confined to the CNS and consist of the following 3 classic features: spongiosis, gliosis, and neuronal loss
  • A transmissible agent that does not elicit any specific immunologic response in the host and is unusually resistant to conventional inactivation procedures

Bovine spongiform encephalopathy

On December 9, 2003, a "downer" (nonambulatory and disabled) dairy cow was slaughtered in the state of Washington. Because the animal's condition was attributed to complications from calving, the meat was considered safe for human consumption by the US Department of Agriculture (USDA). Tissues such as brain, spinal cord, and small intestine, which may have a higher likelihood of containing the pathogenic agent of BSE, were removed during slaughter and sent for rendering (often to be used as nonruminant animal feed). Samples taken from this animal as a part of targeted surveillance tested positive for BSE on December 23. This was confirmed by the BSE International Reference Laboratory in Weybridge, England on December 25.

Not surprisingly, international reaction was swift. Within a week, 53 countries had imposed a ban on imports of US beef and beef products. On December 30, the USDA announced new rules banning all downer cattle from the chain of human food production and other measures (USDA News Release, Veneman Announces Additional Protection Measures to Guard Against BSE). Subsequently, the infected cow was discovered to have originated in Alberta, Canada and was imported into the United States in September of 2001.

On January 26, 2004, the US Food and Drug Administration (FDA) announced new rules to further strengthen existing protection against BSE, including banning a wide range of bovine material from human food (United States Department of Health and Human Services, Expanded "Mad Cow" Safeguards Announced To Strengthen Existing Firewalls Against BSE Transmission). On February 9, 2004, the USDA completed its investigations.

While this was the first case of BSE in the United States, worldwide, as of January 26, 2007, more than 190,000 confirmed clinical cases have been reported since 1986, and approximately 184,000 cases were from the United Kingdom alone (see images below). Additional information is available at OIE, Bovine Spongiform Encephalopathy (BSE). Based on mathematical modeling of the BSE epidemic, estimates suggest that 1-3 million cattle may have been infected with the BSE agent in the United Kingdom.[1, 2] Most of these infected animals were slaughtered for human consumption before any clinical signs of BSE were noted.

Incidence of bovine spongiform encephalopathy (BSEIncidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food. Geographic distribution of bovine spongiform encepGeographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.

Other countries where BSE has been confirmed in native-born cattle include Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Luxembourg, Liechtenstein, the Netherlands, Poland, Portugal, Slovakia, Slovenia, Switzerland, and Spain. Cases of BSE have also been confirmed in North America, 9 in Canada (one cow was imported from the United Kingdom) and 3 in the United States (2 were imported from Canada). The third case of BSE reported from the United States was in a downer cow on a farm in Alabama, and the herd of origin could not be identified in spite of a thorough investigation. See the Alabama BSE Investigation; Final Epidemiology Report, May 2006.

Further cases of BSE cases were reported in imported cattle in the Falkland Islands (imported from the United Kingdom) and Oman (imported from the United Kingdom). No documented cases have been reported from Africa, Australia, New Zealand, or South America.

Geographic distribution of bovine spongiform encepGeographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.

Approximately 5 million head of cattle have been slaughtered in the United Kingdom in an effort to halt the epidemic. The epidemic has slowed significantly, and, since 1992, the number of cases has decreased an average of 40% per year, although new cases continue to be reported. However, this preemptive slaughter has crippled the British livestock industry and has affected the tallow, gelatin, and pharmaceutical industries, all of which make bovine-derived products.[3]

The incubation period for BSE ranges from 2-8 years. Most cases in the United Kingdom have occurred in dairy cows aged 3-6 years. The clinical features include the following:

  • Changes in temperament such as nervousness or apprehensiveness
  • Aggression towards other cattle or humans
  • Kicking when being milked
  • Reluctance to cross concrete, turn corners, and enter yards or doorways
  • Head shyness with head held low
  • Abnormal posture
  • High-stepping gait, particularly of hind legs
  • Incoordination
  • Difficulty in rising or walking
  • Skin tremors
  • Decreased milk production
  • Weight loss despite good appetite

No treatment is available for BSE; the disease is relentlessly progressive until the animal dies or is destroyed. This usually occurs in 2 weeks to 6 months.

No test can detect the disease in a live animal, although in an epidemic setting, clinical features are sufficiently distinctive to provide a clinical diagnosis. Currently, 3 laboratory methods are used to confirm the diagnosis of BSE, including the following:

  • Microscopic examination of brain tissue, which shows characteristic changes, including a predominantly vacuolar spongiform change distributed uniformly throughout the brain[4, 5]
  • Immunohistochemical labeling of the disease-associated (abnormal) prion protein (PrPSc)
  • Detection of scrapie-associated fibrils (SAF) by electron microscopy

Different hypotheses are proposed regarding the origins of BSE.

The most compelling hypothesis is that BSE originated from scrapie, an endemic spongiform encephalopathy of sheep and goats that has been endemic in Europe since the mid 18th century.[6] Scrapie has since spread to most sheep-breeding countries and is widespread in the United Kingdom, where until 1988, the rendered carcasses of livestock (including sheep) were fed to ruminants and other animals as a protein-rich nutritional supplement. The epidemiologic data appear to implicate feed containing TSE-contaminated meat and bone meal, which was used as a protein source. The causative agent is suspected to be from either scrapie-affected sheep or cattle with previously unidentified TSE.[7, 8, 9, 10]

Changes in the rendering process that took place in the early 1980s, particularly the removal of a solvent extraction process that included a steam heat treatment, probably allowed the etiologic agent to survive, contaminate the protein supplement, and infect cattle. Recycling of infected bovine carcasses within the cattle population (turning the herbivorous cows into "animal cannibals") amplified the levels of the pathogen, which had become adapted to cattle, in the feeds and eventually caused a full-scale epizootic.[11] Similarly, the spread of spongiform encephalopathies in farmed mink and captive and zoo animals may have resulted from prion-contaminated feed.[12, 13]

An alternative hypothesis was proposed in the controversial final BSE inquiry report in the United Kingdom that was released October 24, 2000, suggesting that a pathogenic mutation occurred in cattle in the 1970s, with BSE occurring as a consequence of recycling of infected cattle. The report asserts that BSE cases identified from 1986-1988 were not index cases, nor were they the result of the transmission of scrapie.

Recognition of the source of infection led to several countermeasures to break the cycle of cattle reinfection, restrict the geographic spread, and eliminate the potential source of new infection. The most important step was banning ruminant feed in 1988, extending it to include the feeding of specified bovine offal. By 1992, this ban started to bring the epidemic under control.

Time course of epidemic bovine spongiform encephalTime course of epidemic bovine spongiform encephalopathy (BSE) in the United Kingdom, 1986-2000, with dates of major precautionary interventions. SBO stands for specified bovine offal (ie, brain, spinal cord, thymus, spleen, and intestines from cattle aged >6 mo). MBM stands for meat and bone meal (protein residue produced by rendering). From Brown P, Will RG, Bradley R, et al. "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution and current concerns". Emerging Infectious Diseases, 2001;7: 6-16.

Furthermore, specified risk material, which comprises brain, spinal cord, eyes, tonsils, thymus, spleen, and intestine, is removed from all foodstuffs at slaughter.[14] In addition, cattle aged 30 months or older must not be used for consumption unless they test negative for BSE, which is known as the “over-thirty-month” rule.[15]

Variant CJD

Within weeks of identification of the first case of BSE, concern was expressed about human risk.[16, 17, 18] A national TSE surveillance was instituted in Britain in 1990 despite lack of evidence of human acquisition of scrapie based on the then-speculative grounds that exposure of millions of Britons to an apparently new bovine TSE might unmask low-frequency transmission in humans. Unfortunately, this fear proved to be well founded. The first cases of variant CJD (initially called new variant CJD) were reported in 1995.[19, 20]

By 1996, 10 patients, who had distinctive clinical and neuropathologic characteristics, had been reported to the National CJD Surveillance Unit with atypical CJD-like features. Clinically, they were younger than 40 years with an average age of younger than 30 years; had behavioral symptoms, ataxia, and sensory changes early on; and progressed more slowly than in classic CJD. None had periodic complexes on EEG. Neuropathologic findings resembled those of kuru, with extensive florid plaques in which an amyloid core is surrounded by petals of spongiform change. The report concluded that this hitherto unrecognized variant of CJD was probably due to exposure to BSE.[21] So far, 215 cases of variant CJD have been described, most from the United Kingdom (see International frequency).

The risk factors for the development of variant CJD include age, residence in the United Kingdom, and methionine homozygosity at codon 129 of the prion protein gene (PRNP).[22, 23] The encoding alternatives, methionine (Met) and valine (Val), are distributed in white populations in the approximate proportions of 50% Met/Val, 40% Met/Met, and 10% Val/Val. All patients with variant CJD who have been tested have been homozygous for methionine.[24] A reduced frequency of HLA class II type DQ7 has been described in patients with variant CJD but not in those with classic CJD; this may have important implications for understanding host susceptibility to infection by BSE prions.[25] Past surgery, previous blood transfusion, or occupation have so far not been shown to be associated with increased risk, although 2 cases have been reported in patients who received blood transfusions from donors who then went on to develop variant CJD.

Experiments in transgenic mice have shown that a significant species barrier exists that restricts the transmission of BSE to humans; however, the barrier is significantly reduced for human-to-human transmission, with increasing transmission efficiency from Met/Met to Met/Val to Val/Val genotypes.[26]

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Pathophysiology

Convincing evidence now indicates that variant CJD is indeed a new disease. Epidemiologic, biological, and biochemical data favor the hypothesis that variant CJD is a BSE zoonosis, probably arising from a double-species switch from sheep scrapie to BSE and then from BSE to human variant CJD.[27, 28, 29] Interestingly, while the BSE epizootic has apparently led to other newly host-switched TSEs in domestic and large cats, sheep fed the BSE agent experimentally acquire a scrapie-like disease.[30] Such occurrences widen the scope of possible TSE species switches and back-switches and suggest that the BSE agent may be an uncharacteristically promiscuous prion.[27]

Because no occupational exposure of patients with variant CJD to cattle on farms or in abattoirs has been identified, spread is likely to occur through consumption of BSE-contaminated meat products. Whether PrPSc can be demonstrated in skeletal muscles remains controversial.[31, 32, 33, 34] However, a high-sensitivity Western blotting technique identified muscle PrPSc in 8 of the 17 patients studied, although in much lower concentrations than in the cerebral cortex, suggesting a potential role for skeletal muscle in the transmission of variant CJD[35] , Despite this evidence, the infection probably resulted from beef products contaminated by nervous tissue because neural tissues have a much higher concentration of PrPSc compared with any other peripheral tissue.

The amount of infectious agent ingested, together with host susceptibility as determined by the human genotype at PRNP codon 129, appear to play an important role in the development of variant CJD.

However, how oral consumption of BSE-contaminated beef leads to infection of the CNS is unknown. In the early preclinical stages of the disease, PrPSc can be detected in lymphoid tissues, suggesting a possible route of transmission from the gut. Prions probably cross the mucosa via transmembranous tunneling of the membranous epithelial cells (M-cells) and come in contact with the mucosa-associated lymphoid system, including Peyer patches, where accumulation is found first.[36]

A functional immune system is required for prion replication and transport outside the CNS.[37] Mechanisms of further prion transport to other compartments of the lymphoreticular system (LRS) are unclear. Prions accumulate in cells of the LRS, most prominently in the follicular dendritic cells and in sympathetic nerve endings in the LRS. Then, prions reach the CNS via splanchnic nerves at the level of the thoracic spinal cord and via parasympathetic fibers connecting with the brain.[38, 39] The other possible route is via blood; this was suggested by experiments showing BSE transmission from sheep to sheep by blood transfusion.[40] Which of these mechanisms is the more important route of prion invasion is not known at this time.

Variant CJD is known to affect the brain, lymphoreticular system, pituitary and adrenal glands, and gastrointestinal tract. A recent case report identified protease-resistant prion protein in the dura mater, liver, pancreas, kidney, ovary, uterus, and skin of a patient with variant CJD, indicating that organ involvement may actually be even more widespread.[41]

BSE and variant CJD are similar based on patterns of infectible mouse strains, incubation time, survival time, lesion distribution in the mouse brain, PrPSc gel banding patterns, and neuropathology, which are readily distinguishable from other TSEs such as scrapie and sporadic CJD.[42, 43, 44, 45, 46] Thus, despite its name, variant CJD appears to be a human variant of BSE derived from cow-to-human species switch, rather than an actual variant of human sporadic CJD.[27]

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Epidemiology

Frequency

United States

Three cases of variant CJD in the United States have been documented.

International

As of March 2010, 215 cases of variant CJD have been reported worldwide: 169 in the UK, 25 in France, 5 in Spain, 4 in Ireland, 3 in the USA and the Netherlands, 2 in Italy and Portugal, 1 in Canada, Japan, Portugal, and Saudi Arabia.[47] Several patients may have been infected in one country but moved to another one where they then became ill.

So far, the vast majority of cases of variant CJD have included documented exposure to food products in countries where BSE occurs and 2 cases have occurred secondarily as a result of exposure to blood transfusion from individuals who then developed variant CJD.[48, 49] One patient who died of an unrelated cause was found to have a subclinical infection, very likely secondary to a blood transfusion from a variant CJD–positive donor who subsequently went on to develop the disease.[50]

Whether the cases from the United Kingdom represent the beginning of an epidemic or whether the numbers will remain low or even decline is unclear. Estimates of the possible size of the epidemic have ranged from 70-136,000 cases.[51, 52] Recent models provide more conservative estimates of 403-1000 at 95% confidence intervals.[53, 54] It is reassuring that among 63,007 surgically removed tonsils, none tested positive for PrP.[55]

The number of cases peaked in 2000 at 28 and then steadied at 20 cases in 2001, 17 in 2002, and 18 in 2003 (see image below). Nine new cases were reported in 2004 and another 5 in 2005. This raises the possibility that the epidemic may have peaked.[56] Despite the optimism, uncertainty remains about the likely size of the total variant CJD epidemic because such calculations depend on assumptions, including the mean incubation period in humans or the infectious dose of BSE for humans. In contrast, sporadic CJD occurs with a uniform incidence of 1 case per million population per year, all over the world.[57] Other forms of prion diseases are even rarer.

Incidence of bovine spongiform encephalopathy (BSEIncidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food.

Mortality/Morbidity

  • Like other prion-related diseases, variant CJD is relentlessly progressive and inevitably leads to death.
  • The mean duration for variant CJD is 16 months, which is somewhat longer than sporadic CJD at 8 months.
  • The mean duration for variant CJD is shorter compared with familial CJD, which is 26 months, and Gerstmann-Strãussler-Scheinker disease, which is 60 months.

Race

Variant CJD has been mainly reported from Europe, with most cases in the United Kingdom; therefore, no particular racial predilection can be discerned.

Sex

No sex preponderance has been noted for variant CJD. Among other prionoses, only kuru is more prevalent in women, which is likely because women ate the brains as a part of ritual cannibalism and the neural tissue has the highest concentration of PrPSc.

Age

The mean age of onset of variant CJD is 29 years, with a range of 14-74 years.[58] Various models suggest that variant CJD infection seems to preferentially affect young people and that the older subjects are probably more resistant.[54, 59]

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Contributor Information and Disclosures
Author

Florian P Thomas, MD, MA, PhD, Drmed  Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Director, National MS Society Multiple Sclerosis Center; Director, Neuropathy Association Center of Excellence, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University School of Medicine

Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Neurological Association, American Paraplegia Society, Consortium of Multiple Sclerosis Centers, and National Multiple Sclerosis Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Amy A Pruitt, MD  Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Hospital of the University of Pennsylvania

Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Neil A Busis, MD  Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Karen L Roos, MD  John and Nancy Nelson Professor of Neurology, Professor of Neurological Surgery, Department of Neurology, Indiana University School of Medicine

Karen L Roos, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association

Disclosure: Nothing to disclose.

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Chitharanjan V Rao, MD, MRCP, DM to the development and writing of this article.

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Incidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food.
Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.
Time course of epidemic bovine spongiform encephalopathy (BSE) in the United Kingdom, 1986-2000, with dates of major precautionary interventions. SBO stands for specified bovine offal (ie, brain, spinal cord, thymus, spleen, and intestines from cattle aged >6 mo). MBM stands for meat and bone meal (protein residue produced by rendering). From Brown P, Will RG, Bradley R, et al. "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution and current concerns". Emerging Infectious Diseases, 2001;7: 6-16.
Normal fluid-attenuated inversion recovery (FLAIR) image at the level of the basal ganglia shows that the thalamus is normally isointense or slightly hypointense relative to putamen. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Pulvinar sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows marked symmetrical hyperintensity of the pulvinar (posterior) thalamic nuclei, and this sign is present in 100% of cases imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Axial fluid-attenuated inversion recovery (FLAIR) showing periaqueductal gray matter hyperintensity (arrow). Although not a specific sign, periaqueductal hyperintensity is observed in 83% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Hockey stick sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows symmetrical pulvinar and dorsomedial thalamic nuclear hyperintensity. This combination produces a characteristic hockey stick appearance and is present in 93% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Prion protein (PrP) accumulation in the tonsil in variant Creutzfeldt-Jakob disease within follicular dendritic cells and macrophages in a germinal center as demonstrated by PrP immunocytochemistry. From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at high magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (higher magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] )
Psychiatric FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



Dysphoria



Withdrawal



Anxiety



Irritability



Insomnia



Loss of interest



Poor memory



Impaired concentration



Disorientation



Agitation



Less common



n = 25 to < 50



Behavioral changes



Anergia



Poor performance



Tearfulness



Weight loss



Appetite change



Hypersomnia



Confusion



Hallucinations



Impaired self care



Paranoid delusions



Inappropriate affect



Rare



n < 25



Obsessive features



Losing things



Suicidal ideation



Panic attacks



Psychomotor retardation



Diurnal mood variation



Loss of confidence



Bizarre behavior



Paranoid ideation



Recognition impairment



Confabulation



Lack of emotion



Perseveration



Impaired comprehension



Change in eating preferences



Impaired use of devices



Acalculia



Table 2. Neurologic Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 2002[64] )
Neurologic FeaturesEarly Onset



< 4 mo



Later Onset



4 to < 6 mo



Late Onset



≥ 6 mo



Common



n ≥ 50



NoneGait disturbance



Slurring of speech



Hyperreflexia



Impaired coordination



Myoclonus



Incontinence



Eye features



Less common



n = 25 to < 50)



PainParesthesia



Numbness



Chorea



Extensor plantars



Dysphagia



Clonus



Hypertonia



Primitive reflexes



Rare



n < 25



Headaches



Dropping things



Sweatiness



Loss of consciousness



Tremors



Handwriting impairment



Coldness



Odd sensation



Dizziness



Cranial motor weakness



Dysdiadochokinesis



Taste disturbance



Startle response



Hypersensitivity



Peripheral motor weakness



Primitive reflexes



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