Bovine Spongiform Encephalopathy and Other Transmissible Spongiform Encephalopathies

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Bovine Spongiform Encephalopathy and Other
Transmissible Spongiform Encephalopathies

• James J. Sejvar, MD
• Division of Viral and Rickettsial Diseases
• Centers for Disease Control and Prevention

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Bovine Spongiform Encephalopathy

• The risk of transmission of BSE to humans
  appears remote. It is most unlikely that BSE
  will have any implication on human health
• Report of the Working Party on Bovine Spongiform
  Encephalopathy, Ministry of Health, UK, Feb. 27,
  1989

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Transmissible Spongiform Encephalopathies (TSEs)

• Subacute, transmissible neurodegenerative
  diseases
• Affect both animals and humans
• Distinctive clinical and pathologic features
• Due to unconventional, novel transmissible
  agentprion hypothesis

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Prion Hypothesis

• Prionproteinaceous infectious particle
• Normal protein (PrPc) encoded on short arm of
  chromosome 20 expressed in high concentrations
  in nervous tissue
• Role of normal PrPc unclearcell signaling?
• In normal state, non-pathogenic
• Abnormal form of prion protein (PrPsc) is
  pathogenicmay form by
• Spontaneous (stochastic) conversion
• Genetic mutation
• Conversion of normal PrPc

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PrPc and PrPsc
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PrPc PrPsc Conversion
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Prions as Transmissible Agents

• Protein as etiology of infection
• Transmissibility demonstrated
• Unique characteristics for transmissible agent
• Both transmissible and inherited
• Extremely long incubation period (years)
• Resistant to physical/chemical sterilization
• Invariably fatal

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TSEs Pathology

• Unifying feature of all TSEs is underlying
  neuropathology
• Predominantly gray matter
• Neuronal loss
• Gliosis
• Spongiform changes
• Absence of inflammatory reaction

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Spongiform Changes

• Normal Cortex CJD Cortex

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TSEs Animals

• Scrapiesheep, goats
• Bovine Spongiform Encephalopathy (BSE) cattle
• Chronic Wasting Disease (CWD)deer, elk
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Spongiform encephalopathy of captive ungulates

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TSEs Humans

• Sporadic
• Creutzfeldt-Jakob disease (CJD)
• Acquired
• Iatrogenic CJD (neurosurgical instruments, dura
  mater grafts)
• Kuru
• Variant CJD (vCJD)
• Familial (genetic)
• Familial CJD
• Gerstman-Straussler-Scheinker Syndrome (GSS)
• Fatal Familial Insomnia (FFI)

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BSE--Recognition

• Late 1985cattle in disparate locations in UK
  dying of strange neurologic illness
• Insidious onset
• Motor/coordination difficulties
• Wasting
• Aggression toward other cattle and humans
• Death
• Mainly in dairy, rather than beef, cattle
• Differences in feeding practices
• Meat-and-bone meal in dairy cattle

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BSE

• 1986-- Neuropathological examination microscopic
  vacuoles and fibrils similar to scrapie described
• UK Ministry of Agriculture Report in Nov 1987new
  disease strongly resembled unconventional
  encephalopathies in sheep, humans
• Bovine Spongiform Encephalopathy coined

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BSE Epidemic

• Explosive epidemic
• Peaked at 37,000 cases per annum in 1992
• Etiologyunclear
• Spontaneous TSE?
• Species barrier passage of scrapie?
• Perpetuation due to feeding of meat-and-bone meal
  (contaminated with neural tissue)
• 1988-1989 Feed ban enacted

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Confirmed Cases of BSE in UK in Animals Born
After Ban on Meat-and-Bone Meal in Feed
As of 30 June 2004
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Spread of BSE Epidemic

• 1990domestic BSE detected in Switzerland,
  imported cases in Portugal
• By end of 1999 7 other EU countries with
  domestic BSE
• Between Jan 2000 and Oct 2002 11 additional EU
  countries
• 2001 BSE detected in Japan
• 2002 BSE detected in Israel
• 2003
• BSE detected in Canadian cow
• Dec 2003 detected in cow in Washington state-
  imported from Canada

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BSE and Variant CJD

• 1990heightened surveillance for CJD in the UK in
  light of BSE epidemic
• 1990 1997 207 patients with CJD identified
• 10 patients found to have features very different
  than classic CJD

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Classic Creutzfeldt-Jakob Disease

• Prototypical TSE in humans
• Incidence of about 1 per million population per
  year worldwide
• Median age at onset 68 years
• Rapidly progressive dementia
• Early dementing symptoms
• Development of movement disorders, characteristic
  EEG changes
• Progression to akinetic mutism, eventually death
• Median interval between diagnosis and death 6
  months survival longer than a year unusual

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New Variant CJD

• Young age at onset
• Prominent early behavioral features psychosis,
  depression
• Prominent early sensory abnormalities
• Movement disorders late
• Longer duration of illness
• Distinct neuropathologypresence of florid
  plaques, similar to that of BSE

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Percent distribution of non-iatrogenic UK vCJD
and US CJD deaths, by age group, 1995-2003

Excludes blood transfusion-associated vCJD and
pituitary hormone- or dural graft-associated
CJD UK vCJD deaths, including UK-related
nonresident cases, 1995-2003 (Will, RG personal
communication, 2004) US CJD deaths, 1995- 2001.
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BSE and vCJD

• 1997association between new form of CJD and BSE
  proposed
• Occurrence about 9 years following BSE epidemic
  matched general incubation period for CJD
• Cases occurring only in areas with BSE
• Similarities in molecular markerssame prion
  strain as in BSE, similar neuropathology
• Transmission studies in transgenic mice, macaque
  monkeys

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BSE and vCJD

• Oral route of transmission of BSE agent in vCJD
  hypothesized
• Ingestion of beef products contaminated with
  neural tissue containing BSE agent
• No single food item associated with vCJD
• Specified Risk Material (SRM)tissues thought to
  present greatest risk
• Brain/spinal cord/dorsal ganglia
• Eyes
• Distal ileum

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vCJD Worldwide

• As of November 2004
• 151 cases in UK
• 8 cases in France
• 1 case in Italy
• 1 case in Ireland
• 1 case in Canada
• 1 case in US

Cases in Ireland, Canada, US belived to be
acquired in UK
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Deaths of Definite and Probable vCJD, UK, 1995 -
2004
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so, vCJD epidemic appears to be on downward
curve, BUT

• 20042 cases of apparent transmission of vCJD
  through blood transfusion reported in UK
• Development of vCJD neuropathology in person with
  atypical genotype
• ?? Second wave of vCJD cases?

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BSE in the United States

• Since 1997, ban on feeding US cattle
  meat-and-bone meal
• Upon identification of BSE cow in 2003,
  additional measures proposed
• downer cattle excluded from human consumption
• Ban on SRM from animals gt30 months of age from
  human consumption
• Ban on mechanically-separated meat
• Screening of subset of at-risk cattle (USDA
  enhanced surveillance)

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CJD Surveillance in the United States

• Since 1996enhanced surveillance for CJD by CDC
• Review of national mortality data to assess for
  unusual trends
• Active investigation of CJD decedents aged lt55
  years
• Establishment of National Prion Disease Pathology
  Surveillance Center
• Increase rates of autopsies among suspected CJD
  cases in US

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Chronic Wasting Disease

• TSE of deer, elk
• First identified among mule deer in late 1960s
  near Fort Collins, CO
• Wasting, anorexia, listlessness, death
• 1978recognized as a spongiform encephalopathy
• Since 1960swider spread throughout states in
  West, Midwest, Canada

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CWD

• Unlike BSEefficient spread from infected to
  uninfected animals
• Directly after exposure or indirectly from
  occupied pasture
• Exact mechanism of spread unclear
• May be efficiently spread between different
  species
• Potential spread to humans consuming meat from
  animals unknown

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Summary

• BSE epidemic diminished in the UK, but emerging
  at lower levels in other countries
• Risk of transmission of BSE agent to humans
  small, but not zero
• Species barrier
• Implementation of feed bans
• Emergence of BSE, CWD highlights the possible
  emergence of other TSEs
• Underscores need for continued surveillance of
  possible human and animal disease

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Questions?