Transmissible Spongiform
Encephalopathies
Ryan Maddox, MPH
Creutzfeldt-Jakob Disease Surveillance Unit
Division of Viral and Rickettsial Diseases
National Center for Infectious Diseases
Centers for Disease Control and Prevention
Abbreviations
• TSE – Transmissible Spongiform
Encephalopathy (prion disease)
• CJD – Creutzfeldt-Jakob Disease
• vCJD – Variant Creutzfeldt-Jakob Disease
• BSE – Bovine Spongiform Encephalopathy
(“mad cow” disease)
• CWD – Chronic Wasting Disease
Transmissible Spongiform
Encephalopathies (TSEs):
•
•
•
•
•
Neurodegenerative diseases
Rapidly progressive, always fatal
Affect humans and animals
Long incubation periods
Brain, spinal cord, and adjacent tissues are
considered infectious
• Prion theory widely accepted
TSEs are further characterized
by:
• Absence of immune response
• Neuropathology may include:
–
–
–
–
–
Spongiform changes
Reactive gliosis
Neuronal loss
Amyloid plaques
No inflammatory reaction
Human TSEs
•
•
•
•
Kuru
Creutzfeldt-Jakob Disease (CJD)
Variant Creutzfeldt-Jakob Disease (vCJD)
Gerstmann-Sträussler Scheinker Syndrome
(GSS)
• Fatal Familial Insomnia (FFI)
Animal TSEs
• Scrapie
• Bovine Spongiform Encephalopathy (BSE)
• Chronic Wasting Disease (CWD)
Creutzfeldt-Jakob Disease (CJD)
• Occurs worldwide
• Annual incidence (U.S.): ~1 case per
million population
• Median age at death (U.S.): 68 years
CJD – Clinical Features
• Patients usually present with dementia,
visual problems, or cerebellar dysfunction
• Subsequent neurologic signs include
myoclonus, tremors, and rigidity
• Neurologic signs deteriorate very rapidly 
akinetic mutism
CJD – More Features
• Rapidly progressive - over 50% of CJD
patients die within 6 months and 85-90%
within 12 months of illness onset (median
illness duration: 4 months)
• CJD occurs in three different forms:
– sporadic
– familial
– iatrogenic
Sporadic CJD
• About 85% of CJD patients
• No recognizable mode of transmission
identified
• May be caused by:
• Age-related somatic mutation of the prion
protein gene
• Error in production of the normal prion
protein
Familial CJD
• About 10-15% of CJD patients
• Autosomal dominant inheritance
• Associated with prion protein gene
abnormalities
• Usually a family history of CJD is present
Iatrogenic CJD
• <1% of CJD patients
• Transmission through:
– Human Growth Hormone
– Dura Mater Graft
• Lyodura
– Cornea transplantation
– Use of neurosurgical instruments and EEG
depth electrodes
CJD Transmission
• Not contagious
• Not transmitted through casual contact or
airborne particles
CJD Transmission
• CJD does not appear to be transmissible
through blood
– Follow-up of recipients of blood from donors
subsequently diagnosed with CJD
– Investigation of CJD cases with history of
receipt of blood products
CJD - Diagnosis
• Clinical course highly suggestive
– Patient’s age
– Rapidly progressive disease
– Family history
•
•
•
•
EEG: diagnostic picture in 75% of patients
CSF test to identify protein 14-3-3
Genetic studies
Neuropathology required for confirmation
Bovine Spongiform
Encephalopathy (BSE)
• First recognized among cattle in the United
Kingdom in 1986
• Cases may have occurred in the early 1980s
• Peaked in 1992-1993: 36,682 cases reported
in 1992 alone
• As of June 1, 2005, 180,800 total cases in
Great Britain
BSE is no longer confined to
U.K.
• Many other countries in Europe have
reported cases
– As of July 21, 2005, 945 total cases in France,
963 in Portugal, 569 in Spain, 458 in
Switzerland, and 363 in Germany
• Japan has reported 19 cases, and Israel
reported its first case in 2002
BSE in North America
• In 2003, BSE cases were reported in
Canada and the United States (cow was
from Canada)
• Two cases reported in Canada in January,
2005:
– Both cows from Alberta
– One cow born October 1996, other one March,
1998 (after 1997 ruminant feed ban)
BSE in North America
• June 24, 2005 – USDA announces BSE case
in United States
– did not enter food supply
BSE in the United Kingdom:
Possible Causes
• The practice of feeding cattle rendered
animal parts was implicated
• Rendered material was from either:
– Scrapie infected sheep
– Cattle with spontaneous BSE
• In the early 1980s, rendering practices
changed which might have facilitated
transmission
BSE: U.K. Government Actions
• BSE made notifiable - 1988
• Ruminant feed ban - 1988
• Specified bovine offal ban – 1989
– Brain, spinal cord, and other high risk tissues
excluded from human food
• Nationwide CJD surveillance in 1990
• Cattle >30 months prevented from entering
human or animal food chain - 1996
U.K. CJD Surveillance
• Detected 10 CJD patients with:
– Unusual clinical presentation
• Young age: Median, 28 years (Range 16-39)
• Psychiatric presentation followed by
cerebellar symptoms
• Non-diagnostic, abnormal EEG
• Prolonged duration of illness (Median: 14
months)
U.K. CJD Surveillance (2)
• Unique neuropathology
– Spongiform changes most evident in the basal
ganglia and thalamus
– Widespread kuru-type plaques in the
cerebellum and cerebrum
• The plaques had pale periphery and were
surrounded by spongiform lesions
U.K. CJD Surveillance (3)
• U.K. surveillance unit reported that the 10
cases represented a distinct new entity,
variant CJD (vCJD), based on:
–
–
–
–
The unique clinicopathological features
Absence of any known CJD risk factors
Absence of genetic abnormalities
Absence of similar cases in other countries
Variant Creutzfeldt-Jakob
Disease (vCJD)
• U.K. government announced that the BSE
agent may have spread to humans (probably
through consumption of contaminated beef
and beef products)
– Cluster in 10 young patients
– Unique to the U.K.
– Consistent incubation period (9 years after BSE
outbreak)
– No other plausible explanation
Evidence for BSE-vCJD Link
• Epidemiological evidence
– Geographic clustering in the United Kingdom
– Absence of vCJD cases in BSE-free countries
• Laboratory evidence
– Experimental study using macaques
– Western blot analysis of infecting prions
– Experimental study using panels of inbred and
cross-bred mice
Variant CJD is different from
CJD
• Variant CJD patients tend to be much
younger, present with behavioral or sensory
problems, have a delayed onset of
neurologic signs, and tend to have a longer
duration of illness
• Pathology differs between vCJD and CJD
USDA and FDA
• USDA and FDA have taken measures to prevent
the introduction of BSE into the U.S.
– Importation of ruminants from BSE-endemic countries
banned, and certain cattle products restricted (1989)
– Importation of live ruminants and most ruminant
products from all of Europe prohibited (1997)
– Mammalian-to ruminant feed ban in the U.S. (1997)
USDA Surveillance
• USDA tests high-risk animals
• 176,468 cattle tested in 2004
• www.usda.gov
FDA Regulations
• Prohibited use of cattle materials at highest
risk of BSE in human food, including
dietary supplements, and cosmetics (2004)
• High risk includes
– Material from non-ambulatory, disabled cattle
– Material from organs of cattle >= 30 months
– Mechanically separated material
Variant CJD deaths in the United
Kingdom, 1995-July 1, 2005
30
Deaths
25
20
15
10
5
0
1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year of Death
Deaths (confirmed or probable vCJD)
Probable case - patient still living
107 deaths from definite vCJD + 43 deaths from probable vCJD (no neuropathological confirmation) = 150
6 patients with probable vCJD alive; 156 vCJD cases total (definite/probable, dead/alive)
Data from http://www.cjd.ed.ac.uk/figures.htm
Variant CJD deaths in France, 1996 July 4, 2005
Deaths
6
4
2
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005
Year of Death
Probable case - Patient still living
Deaths (confirmed or probable vCJD)
Data from http://invs.sante.fr/publications/mcj/donnees_mcj.html
Variant CJD Around the World
• Cases have also been reported from Canada
(1), Ireland (2), Italy (1), Japan (1), The
Netherlands (1), Portugal (1), Saudi Arabia
(1), and the United States (1)
• One of the Irish cases, the Canadian case,
Japanese case, and the U.S. case were
believed to have been exposed to the BSE
agent in the United Kingdom
CDC CJD surveillance
• Conducted active surveillance in 5 areas
• Periodic review of national cause-of-death data
• Potential cases (iatrogenic, vCJD, etc.) reported by
doctors and state public health departments
• Ongoing review of clinical and pathologic records
of CJD decedents aged <55 years
• Collaboration with National Prion Disease
Pathology Surveillance Center (NPDPSC) in
Cleveland, Ohio
• Collaborative surveillance of special groups
Blood
• Some potential donors deferred
– American Red Cross defers from donating:
anyone in U.K. for 3 months since 1980 or any
European country for 5 years since 1980
• Blood shortage vs. potentially unsafe blood
vCJD Blood-Associated Cases
• So far, 2 of 48 recipients of blood components
from donors who later died of vCJD have
evidence of bloodborne transmission
– Case 1: Donor developed vCJD >3 years after donation;
recipient developed vCJD 6.5 years after transfusion
– Case 2: Donor developed vCJD 18 months after
donation; recipient (methionine/valine) had subclinical
infection
Chronic Wasting Disease
(CWD)
• Known natural hosts: deer (Odocoileus
species) and Rocky Mountain elk
• Clinical symptoms
–
–
–
–
Weight loss
Behavioral changes
Excessive salivation
Difficulty swallowing
CWD
• Most animals die within several months of
onset
• Wide range of ages affected
• May be highly transmissible within a
population, but mode of transmission is not
fully understood
– Direct: animal-to-animal contact
– Indirect: causative agent in environment
Chronic Wasting Disease Among Free-Ranging Deer
and Elk by County, United States
CWD transmissible to humans?
• Belay ED, Maddox RA, Williams ES,
Miller MW, Gambetti P, Schonberger LB.
Chronic wasting disease and potential
transmission to humans. Emerg Infect Dis
2004;10:977-84.
• Investigation of “clusters” of CJD cases
• Collaborative project with Wyoming
Case
Age
Year
Codon 129
Western Blot
Final diagnosis Endemic?
1
2
3
4
5
6
7
8
9
10
11
12
25
26
28
28
28
30
54
55
61
63
64
66
2001
2001
2002
1997
2000
1999
2002
1999
2000
2002
2002
2001
MV
MM
nd
MM
MV
VV
VV
MM
MM
VV
MM
MM
Type 1
Type 2
nd
nd
Type 1
Type 1
Type 2
Type 1
Type 1
Type 1
Type 1
Type 1
GSS 102
CJD
GSS 102
CJD
CJD
CJD
CJD
CJD
CJD
CJD
CJD
CJD
Yes
No
No
No
No
No
No
No
Yes
No
Yes
No
Is CWD affecting humans?
•
•
•
•
Unique pathology among suspect cases?
More human TSE cases in endemic areas?
Common genetics among suspect cases?
History of exposure to deer and elk with
CWD?
For more on prion diseases:
• www.cjdsurveillance.com
– Information on National Prion Disease
Pathology Surveillance Center (NPDPSC)
– established by CDC and AANP
– NPDPSC provides free, state-of-the-art
diagnostic testing
• www.cdc.gov/ncidod/diseases/cjd/cjd/htm
– Links to various prion disease articles and sites
Acknowledgements
CDC
• Dr. Larry Schonberger
• Dr. Ermias Belay
• Dr. Jim Sejvar
• Mr. Bob Holman
• Mr. Aaron Curns
NPDPSC
• Dr. Pierluigi Gambetti
• Ms. Carrie Harris
State health department personnel