Variant CreutzfeldtJakob Disease: From Mad Cows to Humans

1
Variant Creutzfeldt-Jakob DiseaseFrom Mad Cows
to Humans

• USACHPPM

2
Overview of the Problem

• Mad cows in UK 1986
• Rise in CJD incidence in UK recognized in 1996
• Further investigation revealed
• Clinical and pathologic differences from CJD,
  hence variant CJD
• Connection between beef consumption and disease
• Same infectious agent in mad cows and affected
  people
• Current risk of exposure is very small
• Risk from past exposure is unknown

3
Program Goals

• Familiarize DoD and VA medical personnel with the
  history of BSE and vCJD
• Provide information about the symptoms, clinical
  course and diagnosis of vCJD
• Give guidance on management of the worried well
  and the patient with symptoms

4
History of the Spongiform Encephalopathies

• Kuru
• Scrapie
• Several others in animals
• Bovine spongiform encephalopathy (BSE aka mad cow
  disease)
• Creutzfeldt-Jakob Disease
• Variant Creutzfeldt-Jakob disease

5
History of the Spongiform Encephalopathies

• They have in common
• Rapid progression of neurologic dysfunction,
  always fatal
• Spongy degeneration of the brain tissue on
  pathology
• Long latency period between exposure to the
  disease agent and clinical disease
• Disease agent is self-replicating protein, a
  prion a proteinaceous infectious particle

6
Kuru

• Devastating neurologic disease found only in
  primitive Fore tribes of New Guinea
• Study of epidemiology in the late 1950s revealed
  slow infection nature
• Transmitted by ritualistic cannibalism
• No one born there since cannibalism ended has
  been diagnosed with it

7
Scrapie

• Neurologic disease affecting sheep
• Similar pathologically and clinically to mad cow
  disease
• Hypothesis that the agent that causes mad cow
  disease originated in the brains of diseased
  sheep used in cattle feed

8
Bovine Spongiform Encephalopathy (BSE)

• First diagnosed in cattle in the UK in 1986
• Peaking in January 1993 at 1000 new cases per
  week
• Biggest year was 1992 with 36,680 cases
• Also found in many other European countries
• None so far in US
• Caused by feed containing contaminated animal
  parts

9
BSE

• Causes spongy degeneration of the brain
• Fatal within weeks to months from onset of
  symptoms
• Incubation period is 2 to 8 years
• Infective agent is found in the brain, spinal
  cord, neural ganglia, bone marrow and ileum
• 95 of the agent is found in CNS

10
Recognition of human transmission

• Apparent increase in rare disease CJD in younger
  age group than usually seen
• Disease course somewhat different than sporadic
  CJD
• Timing consistent with usual incubation period
  for similar diseases
• Pathology and lab findings corroborate same
  pathogen in cows and people

11
CJD Recognized Forms

• Sporadic (classic) arises spontaneously with
  worldwide distribution of 1 per million
• Iatrogenic cases from cornea and dura mater
  transplants and human growth hormone use
• Familial cases due to genetic defect
• Variant CJD related to contaminated beef

12
Sporadic CJD

• Epidemiology
• Incidence
• Demographics
• Clinical course
• Diagnostic testing

13
Sporadic CJD Epidemiology

• 1 case per million population per year
• Worldwide distribution
• No clusters or other patterns to suggest
  infectious cause
• Theory of spontaneous generation of the
  self-replicating prion protein
• Most cases 50-70 years old

14
Iatrogenic CJD Epidemiology

• Latent period (from transplant source cases) is
  15 months to 30 years
• Transmission documented from dura mater grafts,
  human growth hormone and corneal transplants
• 260 cases worldwide

15
CJD Clinical Course

• Early symptoms cognitive impairment, ataxia,
  visual distortions or impaired visual acuity
• Often delirium, myoclonus, dysarthria
• Rapid deterioration from week to week with
  profound dementia and death within 6 months in
  majority of cases
• Presentation and duration depend on patient
  genotype at polymorphic codon 129 and strain of
  prion protein

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Classic CJD Diagnosis

• Diagnosis
• CSF usually normal
• Sometimes protein is mildly high
• Presence of 14-3-3 protein in 90 of cases
• Characteristic EEG findings in majority of
  patients
• CT/MRI usually normal
• Diagnosis certain only by pathology spongiform
  degeneration (with amyloid plaques in only 5-10
  of cases)

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Pathologic Differences
Normal brain
Microphotograph of a brain from a patient with
vCJD showing numerous deposits of infectious
prion protein (in brown), which are much less
conspicuous in a brain with sporadic CJD and
are not present in normal brain.
Courtesy of Dr. James Ironside, National CJD
Surveillance Center, U.K. and Dr. Pierluigi
Gambetti, National Prion Disease Pathology
Surveillance Center, Cleveland, OH.
Brain with Sporadic CJD
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Spongiform Changes in Brain of CJD Patient
An area of vacuoles that are coalescing to
microcysts are seen in the gray matter of a
patient with CJD of more prolonged duration.
This pattern, called coarse spongiosis, is seen
in about 20 of cases of sporadic CJD.
Courtesy of Edward Klatt, MD, Department of
Pathology, University of Utah
19
Variant CJD

• Epidemiology
• Incidence
• Transmission
• Latent period
• Clinical course
• Pathology
• Genetic clues
• Diagnostic testing

20
Variant CJD Epidemiology

• First cases 1996 (suggests 10 year minimum
  incubation period)
• Incubation period range is still unknown
• (ten-??? years)
• As of 3/19/01, there were 99 deaths in Europe,
  almost all in the UK
• No US cases so far, including military personnel
• Hits younger age group (average age is 29)

21
Variant CJD Clinical Course

• Initial symptoms are primarily psychiatric
• Clinical course
• longer than seen in sporadic CJD
• most greater than one year after symptom onset
• Ataxia is prominent
• Otherwise similar to sporadic CJD clinically

22
Variant CJD Pathology

• All patients have spongy degeneration (as in
  classic CJD)
• Brains of all have amyloid plaque (unusual in
  classic CJD) in daisy configuration
• Pathologic agent is confirmed the same as the BSE
  agent

23
Variant CJD Pathology

• Infectious agent is an abnormal configuration of
  a protein normally found in the brain (unknown
  purpose)
• Termed a prion self-replicating despite lack
  of nucleic acid material (no DNA or RNA)
• Appears to replicate and cause harm by causing
  the natural protein it contacts to assume the
  abnormal configuration, like crystallization

24
Amyloid Plaques and Spongiform Changes in vCJD
Note the rounded dark pink plaques, surrounded
by prominent spongiform change, that are
features of variant CJD.
Courtesy of Edward Klatt, MD, Department of
Pathology, University of Utah
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Variant CJD Genetics

• Human genotype at polymorphic codon 129 of the
  PRNP gene is involved in susceptibility
• All vCJD patients tested were homozygous for
  methionine (this genotype is found in only 40 of
  the general Caucasian population)
• Still to be answered Are the other phenotypes
  immune or do they have a longer incubation
  period?
• In sporadic CJD, genotype at this codon affects
  phenotypic expression

26
Variant CJD Diagnosis

• No specific diagnostic test before death
• Several tests are under investigation
• Research studies show suggestive findings on
  brain SPECT scan and in testing serum S100
  protein, but these findings are not specific
• EEG findings seen in classic CJD are absent in
  vCJD

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Variant CJD Possible Iatrogenic Transmission

• Possibility (not confirmed) of blood infectivity
• Possibility of surgical instrument contamination
• Prions found in tonsils of infected patients
  prior to symptom onset
• Prions found in lymphoid tissue of infected
  animals before clinical illness
• Disease agent is hard to kill
• Tissue donor as source as in classic CJD

28
vCJD Possible Iatrogenic Transmission

• No known cases of disease transmitted via surgery
  or blood
• UK is going to single-use instruments for some
  kinds of surgery (e.g. tonsillectomy)
• CDC has recommendations for decontamination
  procedures for potentially contaminated materials
  at
• www.cdc.gov/ncidod/hip/Sterile/CJD.HTM

29
Response of the British Government

• Ban on using ruminant protein for ruminant feeds
  in 1988
• Ban on use of certain bovine tissues for human
  consumption in 1989
• Ban on using brain, spinal cord and other
  specified bovine offal in feed for nonruminant
  animals and poultry in 1990
• Slaughter of all animals thought to be infected

30
Response of the British Government

• BSE in cattle was quickly controlled once the
  control measures were put into place
• Few current cases of BSE in cattle in UK, from
  peak of 36,680 in 1992 to fewer than 1500 in 2000
• Cases continue to decline

31
Response of the US Government

• In 1989 USDA prohibited importation of live
  ruminants from countries with known BSE
• In 1997 this was expanded to the rest of Europe
  and included most ruminant products
• Cattle feed restrictions since 1997
• FDA guidance since 1992 on use of bovine products
  in products including vaccines

32
Response of the US Government

• Blood donor restrictions since 8/99 from FDA FDA
  and American Red Cross are working on another
  version
• USDA has an aggressive BSE monitoring program to
  examine brains of abnormally behaving cattle no
  BSE so far
• Ongoing CJD surveillance by CDC no increase in
  sporadic CJD and no variant seen in US

33
Potential Sources of Beef for Service Members in
Europe

• Troop feeding/dining facilities
• Commissary sales
• Exchange outlets
• Local economy

34
Response of the DoD

• Since before 1980, DoD requirements specified
  removal of spinal cord and exclusion of ill or
  downer cattle in offshore beef procurement
• Since 1996 ban on procurement/sale of beef from
  UK and other BSE confirmed countries
• Since March 2000 ban on procurement of all
  European ruminant meat and meat products

35
Response of the DoD

• European Military Dining facilities have used US
  beef since before 1980
• Operational rations (MREs and tray packs) have
  always been of US origin

36
European Commissary Stores

• 1980- 1989
• 35 of beef from UK
• 65 from other European countries
• 1990-1996
• Countries north of Alps got US beef but some
  European deli items
• Countries south of Alps mostly UK beef
• 1996-2000 US beef, some European deli items
• From March 2000 all beef was from US

37
European Exchange Outlets, 1980 - Present

• 1980 - March 1996
• Food service outlets approximately 20 of
  European beef from the UK
• Hamburger franchises
• 1980-1989 pre-formed patties from the UK
• 1990 - switched to US beef or US/European mix
  ground in Germany
• March 1996 - March 2000
• Mainly beef from European countries without cases
  of BSE, some US beef
• March 2000 - Present
• US or non-European beef

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Current Opportunities for Exposure

• None from meat in the US
• None from meat on US bases
• except German Kantines and Italian Mensas
  local civilian owned and operated cafeterias on
  bases
• Very low for meat off base in Europe (CDC
  estimates lt1 per 10 billion servings)

39
Recommended Blood Donor Restrictions

• Risk is theoretical
• One animal study with sheep showed transmission
  from sheep whole blood transfusion
• No known cases of CJD (variant or classic) from
  this route

40
Recommended Blood Donor Restrictions FDA

• Permanent deferral if diagnosed with vCJD
• Indefinite deferral for diabetics who injected
  insulin derived from cattle of UK origin any time
  since 1980
• Deferral of donors residing in the UK gt 6 months
• Considering expanding to include residence in
  France, Portugal or Ireland for gt10 years

41
Recommended Blood Donor Restrictions American
Red Cross

• Indefinite deferral of donor with 6 months
  cumulative time or more in the United Kingdom
  (England, Northern Ireland, Scotland, Wales, Isle
  of Man, or the Channel Islands) between 1980 and
  1996.
• Considering expanding this to all of Europe
• Considering shortening the cumulative time in the
  UK to 3 months and cumulative time in Europe to
  one year

42
Expected Impact of the Blood Donor Restrictions

• American Red Cross collects about 50 of the
  blood in the US
• Many non-Red Cross collection sites will follow
  Red Cross deferral criteria
• If FDA and American Red Cross disagree, DoD will
  need to decide which to follow

43
Expected Impact of the Blood Donor Restrictions

• Estimated that up to 40 of active duty Army
  personnel will be ineligible to donate blood
• Blood Donor Centers locations and mission
  capability will need review
• Major donor recruitment effort will be needed to
  replace deferred donors

44
What About Vaccines?

• Bovine products are used in the manufacture of
  some vaccines
• There is no known case or other evidence of
  transmission of BSE/vCJD by this route
• FDA has established rules for procuring
  bovine-derived products from safe sources for
  vaccine development
• FDA has not suspended or withdrawn any
  US-licensed vaccines due to BSE/vCJD concerns

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What to Tell the Worried Well

• Risk even for those stationed in UK during the
  late 1980s is unknown but likely to be very low.
• Less than 100 cases reported worldwide
• There is no screening test.
• Provide fact sheet on food safety for advice on
  minimizing any ongoing risk.

46
Approach to the Symptomatic Patient

• New behavioral or psychiatric changes vCJD is
  low on list of dDx but should be kept in the back
  of your mind
• Ataxia, loss of memory or myoclonic jerks are
  symptoms that warrant further study

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For Further Assistance

• POC for clinical discussion and advice on
  evaluating patients with such symptoms is LTC
  Robert Labutta at Walter Reed
• E-mail via Outlook
• Commercial 202-782-9730
• DSN 662-9730

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Summary

• vCJD is a new progressive and fatal neurologic
  disease caused by eating meat from infected
  cattle.
• There is no reliable pre-autopsy diagnostic test
  for vCJD.
• There is no effective treatment for vCJD.
• No cases in US or military/families.
• Risk from potential past exposure is unknown.

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Summary

• Ongoing risk of exposure is very low due to
  controls.
• Risk from blood transfusion or surgical
  instrument contamination is unknown.
• Major blood donor recruitment effort will be
  needed to offset deferred donors
• Personal risk can be minimized by choosing to
  avoid beef altogether, or at least avoid
  processed beef foods such as sausages.

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For More Information

• From the CDC http//www.cdc.gov/ncidod/hip/INFECT
  /CJD.htm
• From the FDA http//www.fda.gov/oc/opacom/hottopi
  cs/bse.html
• From your very own CHPPM http//chppm-www.apgea.a
  rmy.mil/madcowdisease/
• From the US Department of Agriculture
  http//www.fsis.usda.gov/OA/topics/bse.htm