Bovine Spongiform
Encephalopathy and Other
Transmissible Spongiform
Encephalopathies
James J. Sejvar, MD
Division of Viral and Rickettsial Diseases
Centers for Disease Control and Prevention
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
Transmissible Spongiform
Encephalopathies (TSEs)
• Subacute, transmissible neurodegenerative
diseases
• Affect both animals and humans
• Distinctive clinical and pathologic features
• Due to unconventional, novel transmissible
agent—prion hypothesis
Prion Hypothesis
• Prion—proteinaceous infectious particle
• Normal protein (PrPc) encoded on short arm of
chromosome 20; expressed in high concentrations
in nervous tissue
– Role of normal PrPc unclear—cell signaling?
– In normal state, non-pathogenic
• Abnormal form of prion protein (PrPsc) is
pathogenic—may form by:
– Spontaneous (stochastic) conversion
– Genetic mutation
– Conversion of normal PrPc
PrPc and PrPsc
PrPc – PrPsc ―Conversion‖
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
TSEs: Pathology
• Unifying feature of all TSEs is underlying
neuropathology
– Predominantly gray matter
– Neuronal loss
– Gliosis
– Spongiform changes
– Absence of inflammatory reaction
Spongiform Changes
Normal Cortex CJD Cortex
TSEs: Animals
• Scrapie—sheep, goats
• Bovine Spongiform Encephalopathy (BSE) –cattle
• Chronic Wasting Disease (CWD)—deer, elk
• Transmissible mink encephalopathy
• Feline spongiform encephalopathy
• Spongiform encephalopathy of captive ungulates
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)
BSE--Recognition
• Late 1985—cattle 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
BSE
• 1986-- Neuropathological examination:
microscopic vacuoles and fibrils similar to
scrapie described
• UK Ministry of Agriculture Report in Nov
1987—new disease strongly resembled
unconventional encephalopathies in sheep,
humans
– ―Bovine Spongiform Encephalopathy‖ coined
BSE Epidemic
• Explosive epidemic
• Peaked at 37,000 cases per annum in 1992
• Etiology—unclear
– 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
Confirmed Cases of BSE in UK in Animals Born
After Ban on Meat-and-Bone Meal in Feed*
1988 1989 1990 1991 1992 1993 1994 1995
Great Britain 11978 12736 5737 4741 3475 2933 2089 1035
N. Ireland N/A 102 68 50 43 63 87 117
1996 1997 1998 1999 2000 2001 2002 2003
Great Britain 58 35 19 7 0 0 0 0
N. Ireland 27 5 2 3 0 0 0 0
*As of 30 June 2004
Spread of BSE Epidemic
• 1990—domestic 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
BSE and Variant CJD
• 1990—heightened 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
―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
―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 neuropathology—presence of ―florid
plaques‖, similar to that of BSE
Percent distribution of non-iatrogenic# UK vCJD and
US CJD deaths, by age group, 1995-2003
30 UK vCJD* (n=140)
US CJD** (n=1,816)
25
20
Percent
15
10
5
0
+
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90
Five-year age group at death
# 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.
BSE and vCJD
• 1997—association 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 markers—same prion
strain as in BSE, similar neuropathology
– Transmission studies in transgenic mice,
macaque monkeys
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
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
Deaths of Definite and Probable
vCJD, UK, 1995 - 2004
30
25
20
15 # Deaths
10
5
0
93
94
95
96
97
98
99
00
01
02
03
04
19
19
19
19
19
19
19
20
20
20
20
20
…so, vCJD epidemic appears to be
on downward curve, BUT
• 2004—2 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?
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 >30 months of age from
human consumption
– Ban on mechanically-separated meat
– Screening of subset of at-risk cattle (USDA
enhanced surveillance)
CJD Surveillance in the United
States
• Since 1996—enhanced surveillance for CJD by
CDC
• Review of national mortality data to assess for
unusual trends
• Active investigation of CJD decedents aged <55
years
• Establishment of National Prion Disease
Pathology Surveillance Center
– Increase rates of autopsies among suspected
CJD cases in US
Chronic Wasting Disease
• TSE of deer, elk
• First identified among mule deer in late 1960s
near Fort Collins, CO
– Wasting, anorexia, listlessness, death
• 1978—recognized as a spongiform
encephalopathy
• Since 1960s—wider spread throughout states in
West, Midwest, Canada
CWD
• Unlike BSE—efficient 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
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
Questions?