Variant Creutzfeldt-Jakob Disease by wpk13069

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									       Variant Creutzfeldt-Jakob Disease:
          From Mad Cows to Humans


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
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
History of the Spongiform
 Kuru
 Scrapie
 Several others in animals
 Bovine spongiform encephalopathy (BSE
  aka mad cow disease)
 Creutzfeldt-Jakob Disease
 Variant Creutzfeldt-Jakob disease
    History of the Spongiform
   They have in common:
      Rapid progression of neurologic dysfunction,
       always fatal
      Spongy degeneration of the brain tissue on
      Long latency period between exposure to the
       disease agent and clinical disease
      Disease agent is self-replicating protein, a “prion”
       – a proteinaceous infectious particle
 Devastating neurologic disease found only
  in primitive Fore tribes of New Guinea
 Study of epidemiology in the late 1950’s
  revealed slow infection nature
 Transmitted by ritualistic cannibalism
 No one born there since cannibalism ended
  has been diagnosed with it
 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
    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
 Causes spongy degeneration of the brain
 Fatal within weeks to months from onset of
 Incubation period is 2 to 8 years
 Infective agent is found in the brain, spinal
  cord, neural ganglia, bone marrow and
 95% of the agent is found in CNS
Recognition of human
 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
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
Sporadic CJD
 Epidemiology
   Incidence

   Demographics

 Clinical course
 Diagnostic testing
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
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
 260 cases worldwide
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
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
     CT/MRI usually normal

     Diagnosis certain only by pathology:
      spongiform degeneration (with amyloid plaques
      in only 5-10% of cases)
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
Spongiform Changes in Brain of
CJD Patient
                                                 An area of
                                                 that are
                                                 coalescing to
                                                 are seen in
                                                 the gray matter
                                                 of a patient with
                                                 CJD of more
                                                 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
Variant CJD
   Epidemiology:
      Incidence

      Transmission

      Latent period

   Clinical course
   Pathology
   Genetic clues
   Diagnostic testing
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)
Variant CJD: Clinical Course
 Initial symptoms are primarily psychiatric
 Clinical course
    longer than seen in sporadic CJD

    most greater than one year after symptom
 Ataxia is prominent
 Otherwise similar to sporadic CJD clinically
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
Variant CJD: Pathology
   Infectious agent is an abnormal configuration of a
    protein normally found in the brain (unknown
   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
Amyloid Plaques and
Spongiform Changes in vCJD
                                                  Note the
                                                  dark pink
                                                  by prominent
                                                  change, that
                                                   are features
                                                  of variant CJD.

    Courtesy of Edward Klatt, MD, Department of
    Pathology, University of Utah
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
   In sporadic CJD, genotype at this codon affects
    phenotypic expression
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
 EEG findings seen in classic CJD are absent
  in vCJD
Variant CJD: Possible Iatrogenic
   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
vCJD: Possible Iatrogenic
 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:
Response of the British
   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
Response of the British
 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
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
    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
Potential Sources of Beef for
Service Members in Europe
 Troop feeding/dining facilities
 Commissary sales
 Exchange outlets
 Local economy
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
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
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
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
Current Opportunities for
 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 <1 per 10 billion servings)
Recommended Blood Donor
 Risk is theoretical
 One animal study with sheep showed
  transmission from sheep whole blood
 No known cases of CJD (variant or classic)
  from this route
    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 > 6
 Considering expanding to include residence
  in France, Portugal or Ireland for >10 years
    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
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
Expected Impact of the Blood
Donor Restrictions
 Estimated that up to 40% of active duty
  Army personnel will be ineligible to donate
 Blood Donor Centers locations and mission
  capability will need review
 Major donor recruitment effort will be
  needed to replace deferred donors
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
   FDA has not suspended or withdrawn any US-
    licensed vaccines due to BSE/vCJD concerns
What to Tell the Worried Well
 Risk even for those stationed in UK during
  the late 1980’s 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.
    Approach to the Symptomatic
 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
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
 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.
   Ongoing risk of exposure is very low due to
   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.
    For More Information
   From the CDC:
   From the FDA:
   From your very own CHPPM: http://chppm-
   From the US Department of Agriculture:

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