eMedicine Specialties > Neurology > Neurological Infections

Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy

Author: Chitharanjan Rao, MD, DM, MRCP, DNB, Assistant Professor, Department of Neurology, University of Pittsburgh School of Medicine
Coauthor(s): 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; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Contributor Information and Disclosures

Updated: Apr 27, 2007

Introduction

Background

Bovine spongiform encephalopathy

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

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. A complete summary is available at USDA, Animal and Plant Health Inspection Service, BSE Update.

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 Media Files 1-2). 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.

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 (see Media File 2).

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 brain4,5
  • 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. See BSE Inquiry Report for the full report.

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 (see Media File 3).

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, had behavioral symptoms at onset, and had symptoms that progressed somewhat more slowly than those of 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, 201 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 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.23 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.24 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.

Recent 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.25

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.26,27,28 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 scrapielike disease.29 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.26

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.30,31,32,33 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 CJD34 , 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.35

A functional immune system is required for prion replication and transport outside the CNS.36 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.37,38 The other possible route is via blood; this was suggested by experiments showing BSE transmission from sheep to sheep by blood transfusion.39 Which of these mechanisms is the more important route of prion invasion is not known at this time.

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.40,41,42,43,44 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.26

Frequency

United States

Cases of variant CJD acquired in the United States have not been documented.

International

As of November 3, 2006, 201 definite and probable cases of variant CJD have been reported worldwide (164 in the United Kingdom; 21 in France; 4 in Ireland; 3 in the United States; 2 in the Netherlands; and 1 each in Canada, Hong Kong, Italy, Japan, Portugal, Saudi Arabia, and Spain). See The National Creutzfeldt-Jakob Disease Surveillance Unit for more information. Of these, 2 of the 4 cases from Ireland, 3 of the 3 cases from the United States, 1 of the 21 cases from France, and single cases from Canada and Japan were probably exposed to the BSE agent while a resident in the United Kingdom.
 
So far, 199 of the 201 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.45,46 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.47

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.48,49 Recent models provide more conservative estimates of 403-1000 at 95% confidence intervals.50,51

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 Media File 1). Nine new cases were reported in 2004 and another 5 in 2005. This raises the possibility that the epidemic may have peaked.52 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. Other forms of prion diseases are even rarer.

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.53 Various models suggest that variant CJD infection seems to preferentially affect young people and that the older subjects are probably more resistant.51,54

Clinical

History

The incubation period of variant CJD is not known. However, based on the assumptions that most cases of variant CJD were exposed to BSE in the 1980s and that the incidence peaked in 2000, an average incubation period of 11-12 years can be estimated. Similar conclusions can be derived from cases of variant CJD in patients from other countries, who were probably exposed to BSE during their residence in the United Kingdom. This is similar to the median incubation periods for other human CJD epidemics caused by human-to-human transmission, eg, 10-13 years in kuru55 and 12-17 years in iatrogenic CJD following intramuscular injection of human growth hormone.56 However, cases of kuru and iatrogenic CJD have been seen 40 and 38 years after exposure, respectively. Prolonged incubation periods for these conditions have been associated with heterozygosity at codon 129 of PRNP. As mentioned above, all clinical cases of variant CJD to date have been homozygous for methionine at codon 129 of PRNP.

The incubation period for secondary transmission for variant CJD by blood transfusion is probably shorter, as suggested by the development of the disease in 2 cases 6 and 8 years following blood transfusion, respectively.45,46 In the third patient with blood transfusion–related, secondarily transmitted variant CJD infection, the disease was subclinical at the time of death from an unrelated cause 5 years following the transfusion; this patient was heterozygous for Met/Val at codon 129, raising the possibility of a prolonged incubation period or the development of a permanent carrier state.47,57,58

The clinical course of variant CJD is characterized by distinct features, with psychiatric abnormalities dominating the initial course of the disease. In a large study of 100 cases59 , psychiatric symptoms preceded neurologic features in 63 cases and neurologic features preceded psychiatric features in 15. In the remaining 22 patients, both neurologic and psychiatric features were present from the beginning. Common early psychiatric features include dysphoria, withdrawal, anxiety, irritability, insomnia, and loss of interest. In a small number of cases, pain, numbness, or ataxia may be present in the early stages. These neurologic symptoms together with new-onset psychiatric symptoms in an appropriate clinical setting may raise the possibility of variant CJD; of course, cognitive impairment soon follows.

The first signs of cognitive decline are observed at a median of 5 months after the disease onset. The first neurologic deficits are usually observed 6-7 months after onset. Akinetic mutism usually develops after a median disease duration of 12 months.60,61,62,63,64,59

  • Table 1 and Table 2 in Physical list the psychiatric and neurologic features of variant CJD as they evolve. 
  • A typical case history of variant CJD is as follows: 
    • A 33-year-old male farmer and resident of the United Kingdom was referred to the neurology clinic with a 5-month history of slurred speech, clumsy upper limbs, impaired hand writing, and progressive gait problems. He also reported worsening memory for recent events, which he attributed to impaired concentration. A diagnosis of depression was made and his mood improved somewhat on selective serotonin reuptake inhibitors. He denied any visual, swallowing, or sphincter difficulties. However, he reported uncomfortable sensations in both his lower extremities. His general health had been good, and he had no previous history of neurologic disease. He had no family history of similar neurologic disease. He did not smoke, he drank occasionally, and he did not use any recreational drugs.
    • The findings upon general examination were unremarkable, other than the patient's flat affect.
    • Higher-function testing revealed that he was unable to name the day or the month, had no knowledge of current events, could not name the current British prime minister or US president, and failed at serial 7 s. He had poor 3-object registration and recall and scored 12 out of possible 30 on Mini-Mental State Examination. A formal neuropsychological evaluation showed impairment of attention span, verbal fluency, language, memory (both verbal and nonverbal), spatial skills, judgment, and insight, indicating a generalized cortical disease process.
    • Cerebellar dysarthria and brisk jaw jerk with exaggerated facial reflexes were noted. Eye movements were full in all directions. He had pyramidal tract signs but no focal weakness. He had a limb and gait ataxia but no Romberg sign. His cooperation with the sensory examination was unsatisfactory; however, pinprick was perceived equally all over.
    • His condition progressed slowly over the next few months, and approximately 9 months after presentation, he had become mute with marked spasticity of the lower limbs. He developed incontinence for bladder and bowel. Because of worsening pseudobulbar palsy, a feeding gastrostomy was placed. Fifteen months after the initial presentation, he was completely bed bound, with spontaneous eye opening and visual tracking without any verbal response. By this stage, he had developed diffuse myoclonic jerks, which could be brought on by startle stimuli. He finally succumbed to the disease after total disease duration of 24 months.
    • A detailed workup for causes of cerebellar syndromes with dementia and pyramidal signs yielded negative results. Serial EEGs showed progressive diffuse slowing. MRI of the brain in retrospect showed high–signal intensity signals in bilateral pulvinars on T2-weighted imaging. The cerebrospinal fluid (CSF) was positive for 14-3-3 protein. Genetic studies showed the patient to be homozygous for methionine at codon 129 of the PRNP gene. He also had a tonsil biopsy, which showed marked immunoreactivity to prion protein antibodies. Autopsy confirmed the diagnosis of variant CJD.

Physical

Table 1. Psychiatric Features According to Frequency and Median Time of Onset (adapted from Spencer et al, 200259 )

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Table
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
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, 200259 )

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Table
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
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


Causes

See Pathophysiology.

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References
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Further Reading

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Keywords

transmissible spongiform encephalopathies, TSE, prion diseases, prionosis, prionoses, PrP diseases, Creutzfeldt-Jakob disease, CJD, sporadic CJD, sCJD, new variant CJD, nvCJD, variant CJD, vCJD, bovine spongiform encephalopathies, BSE, mad cow disease, mad cow, mad cows, scrapie, kuru, Gerstmann-Strãussler-Scheinker disease, GSS, familial fatal insomnia, FFI, sporadic fatal insomnia, SFI, chronic wasting disease, CWD

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Contributor Information and Disclosures

Author

Chitharanjan Rao, MD, DM, MRCP, DNB, Assistant Professor, Department of Neurology, University of Pittsburgh School of Medicine
Chitharanjan Rao, MD, DM, MRCP, DNB is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association, Medical Council of India, and Royal College of Physicians
Disclosure: Nothing to disclose.

Coauthor(s)

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; Associate Program Director, Professor, Department of Neurology and Psychiatry, Associate Professor, Institute for Molecular Virology, and Department of Molecular Microbiology and Immunology, St Louis University
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology, American Paraplegia Society, and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Medical Editor

Amy A Pruitt, MD, Program Director, Assistant Professor, Department of Neurology, University of Pennsylvania
Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, University of Pittsburgh Medical Center - Shadyside, Clinical Associate Professor, Department of Neurology, University of Pittsburgh School of Medicine
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.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
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: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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