VARIANT CJD

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VARIANT CJD

• AN UPDATE
• DR. HESTER WARD
• National CJD Surveillance Centre
• Edinburgh, UK
• h.ward_at_ed.ac.uk

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UK frequency of CJD

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Variant CJD

• UK
• 114 definite probable cases
• 89 definite cases- confirmed neuropathologically
• 14 probable cases- died- no post mortem
• 1 probable case- died- awaiting post mortem
• 10 probable cases- alive
• FRANCE 3 definite 2 alive probable cases
• REPUBLIC OF IRELAND 1 definite case

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Variant CJD

• AGE
• Median age at onset 26 years (range 12 - 74
  years)
• Median age at death 28 years (range 14 - 74
  years)
• GENDER 60 males 54 females
• DURATION OF ILLNES
• Median 13 months (range 6 - 39 months)
• GENETICS All tested MM at codon 129 (n 97)

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Courtesy of Nick Andrews, PHLS Statistics Unit,
London
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Geographical distribution of places of residence
at onset of symptoms of vCJD cases (n93)
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Variant CJD - GEOGRAPHY
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Variant CJD - GEOGRAPHY
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Variant CJD - GEOGRAPHY
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Variant CJD- GEOGRAPHY

• Dietary Nutritional Survey of British Adults
• 1986 - 1987
• 2197 adults aged 16 to 64 years
• weighed, 7 day dietary records
• Household Food consumption Expenditure Report
• 1984 - 1986
• 20, 000 households
• One week records of all foods entering home for
  consumption

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Scatterplot of cumulative, age-standardised vCJD
incidence against weekly consumption of other
meat and meat products (grams) by region
(Household Food Consumption and Expenditure
1988)

• of cumulative, age-standardised vCJD incidence
  against weekly consumption of other meat and meat
  products (grams) by region (dietary data from
  Household Food Consumption and Expenditure1988)

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GEOGRAPHICALLY ASSOCIATED CASES (GACs) of vCJD
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Geographically associated cases

• Definition
• 2 or more cases of probable or definite vCJD
  where preliminary investigations suggest there is
  an association between the cases because of
• a) Geographical proximity of residence at some
  time, either now or in the past
• b) Other link with the same geographic area, eg.
  attending the same school or work place or
  attending functions in the same area.

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The Leicester cluster

• 5 cases of variant CJD lived in Leicestershire
  (population 870, 000)
• Cumulative incidence
• UK 1.5/ million Leicester 5.7/ million
• 4/5 from Charnwood (142, 000) 28.2 / million
• Kulldorffs method- spatial scan statistic-
• Leicestershire- most likely cluster (plt0.004)
• No other significant clusters
• (Cousens et al. Lancet 2001 357 1002- 1007)

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The Leicester cluster

• 4/5 were reported to have bought meat from
  butchers who processed whole carcass beasts
  split the heads to remove the brains for
  commercial purposes
• Hypothesis- cases bought meat from butchers that
  split heads
• Tested - control study- matched each case to 6
  community controls
• OR 15 (1.6- 139)

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The Leicester cluster

• If true minimal incubation- between 10- 16years
• Does this explain other cases in UK in other
  countries?
• BUT
• Bias
• Interview with butchers
• Brain- where did it go?- food chain..

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Variant CJD- RISK FACTORS

• TO DATE from case control study
• No evidence of increased risk of CJD associated
  with diet, surgery or occupation (although,
  some differences in diet between cases
  controls)
• BUT- rare disease, recall bias, surrogate
  witnesses, small numbers, control recruitment

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Size of the vCJD epidemic- predictions

• 1997 Cousens et al. Nature 385 197-198 (n14
  vCJD)
• 75- 80, 000
• Back calculation
• MM genotype
• 2000 Ghani et al. Nature 406 583- 584 (n
  55 vCJD)
• 63- 136 000
• Scenario analysis (gt 5 million combinations of
  parameters)
• MM genotype
• lt 2 cases vCJD per infectious bovine

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Size of the epidemic- predictions

• 2001 Huillard dAignaux et al. Science 294
  1792- 1931 (n 82)
• Clinical cases hundreds - few thousands
• Infected individuals hundreds - millions, but
  long mean incubation period so die from
  competing causes
• Close to peak of epidemic
• Back calculation- calc. number infected based on
  assumptions of when infected incubation pd
• Exposure cut off- 1996
• MM genotype
• ? not reassuring re. potential secondary spread

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Size of the epidemic- predictions

• 2001 Valleron et al. Science 294 1726- 1728
  (n97)
• Total number of cases 205 (upper limit 403)
• Mean incubation pd 16.7 yrs (12- 23)
• Peak 2000/ 2001
• Bimodal age distribution
• Age at diagnosis age at infection incubation
  time.
• Assuming age of infection parallels BSE
  epidemic- incubation pd calc using deconvolution
  technique.
• Exposure cut off 1990
• Exponential decrease in susceptibility gt15 years
  of age

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Size of the epidemic- predictions

• 2002 Ferguson et al. Nature 9 January 2002 DOI
  10.1038/nature 709
• Predictions of future cases of vCJD based on BSE
  infection of British sheep
• Bovine BSE only Upper 95 CIs 50 000- 100 000
  vCJD cases
• Bovine ovine BSE Upper 95 CIs 150, 000 vCJD
  cases (BSE endemic in national flock)
• Past exposure to BSE in UK majority from cattle
• On- going exposure to BSE sheep greater than
  cattle- reduce risk up to 90- ? age at slaughter
  ? SRM controls
• Many assumptions epidemiology based on scrapie
  experimental BSE in sheep, tissue infectivity
  during incubation

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Size of the epidemic- predictions

• Conclusions
• Much uncertainty, esp incubation period, risk
  from sheep
• Only based on MM genotypes (40 of population)
• ? not necessarily reassuring if considering
  secondary spread

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Transfusion Medicine Epidemiology Review (TMER)

• Joint project between National Blood Service
  NCJDSU
• AIM to investigate whether any evidence that
  CJD, including vCJD, may be transmitted via blood
  supply

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TMER- vCJD

• TMER
• All definite probable cases vCJD- reported to
  transfusion service of relevant country (England,
  Wales, Scotland Northern Ireland)
• If a donor- trace fate of all donations-
  recipient details passed to NCJDSU
• Reverse TMER
• vCJD cases ( matched controls) who have received
  blood transfusions- details passed to BTS
• Details of donors passed back to NCJDSU

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TMER- vCJD

• RESULTS (April 2001)
• (n 87 vCJD cases)
• TMER
• 8 cases vCJD were blood donors- 22 recipients
  between 1981- 1999
• None have developed CJD to date- 9 have died
  from other causes
• None have registered as blood donors

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TMER- vCJD

• Reverse TMER
• 4 cases of vCJD received blood components (117- 1
  case 103 of these)
• 111 donors- none have developed CJD to date

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National CJD Surveillance Unit, UK

• Director Neuropathology- Professor J.
  Ironside
• Neurology-
• Professor R.G. Will Dr. R. Knight
• Protein Biochemistry-
• Dr. M. Head

• Genetics- Mr. M. Bishop
• CSF Biochemistry-
• Dr. A. Green
• Epidemiology-
• Dr. H. Ward
• Care co-ordinator-
• Dr. B. Weller

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• Blood transmission studies on going
• Tests of CJD
• Blood/ urine
• Screening vs. diagnostic

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• DIAGNOSTIC CRITERIA FOR vCJD
• I A Progressive neuropsychiatric disorder
• B Duration of illness gt 6 months
• C Routine investigations do not suggest an
  alternative diagnosis
• D No history of potential iatrogenic exposure
• E No evidence of a familial form of TSE
• II A Early psychiatric symptomsa
• B Persistent painful sensory symptomsb
• C Ataxia
• D Myoclonus or chorea or dystonia
• E Dementia
• III A EEG does not show the typical appearance of
  sporadic CJD c
• (or no EEG performed)

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• DEFINITE I A and neuropathological confirmation
  of vCJD
• (spongiform change and extensive PrP
  deposition with florid plaques, throughout
  the cerebrum and cerebellum)
• PROBABLE I and 4/5 of II and III A and III B
• OR
• I and IV Ad
• POSSIBLE I and 4/5 of II and III A
• a depression, anxiety, apathy, withdrawal,
  delusions.
• b this includes both frank pain and/or
  dysaesthesia.
• c generalised triphasic periodic complexes at
  approximately one per second.
• d tonsil biopsy is not recommended routinely,
  nor in cases with EEG appearances typical of
  sporadic CJD, but may be useful in suspect cases
  in which the clinical features are compatible
  with vCJD and MRI does not show bilateral
  pulvinar high signal.
• e spongiform change and extensive PrP deposition
  with florid plaques, throughout the cerebrum
• and cerebellum.