View
220
Download
0
Embed Size (px)
Citation preview
VARIANT CJD
AN UPDATE
DR. HESTER WARD
National CJD Surveillance Centre
Edinburgh, UK
UK frequency of CJD
SINCE1985
< 1994n= 360
> 1995n= 513
Classicalsporadic
88% 67%
Geneticfamilial
7% 6%
Iatrogenic* 5% 5%
(new)Variant
--- 22%
* human growth hormone, human gonadotrophin, neurosurgery, depthelectrodes, corneal transplant, dura mater
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
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)
vCJD ONSETS/YEAR- DEFINITE & PROBABLE
CASES (n=114)
05
101520253035
1994 1995 1996 1997 1998 1999 2000 2001
YEAR
NU
MB
ER
OF
CA
SE
S
vCJD DEATHS by YEAR- DEFINITE & PROBABLE CASES (n=104)
0
5
10
15
20
25
30
1995 1996 1997 1998 1999 2000 2001 2002
Courtesy of Nick Andrews, PHLS Statistics Unit, London
Quarter/Year
Inci
dence
02
46
810
12
o
oo o
o
o
o o
o
o
o
o
o
o
o
o
o
o o
o
o
o
o
o
o
oo
o
o o o
e
ee e
e
e
e e
e
e
e
e
e
e
e
e
e
e e
e
e
e
e
e
e
e e
e
e
ee
2/94 4/94 2/95 4/95 2/96 4/96 2/97 4/97 2/98 4/98 2/99 4/99 2/00 4/00 2/01 4/01
Figure1: Observed (-o-) and expected (-e-) quarterly incidence of vCJD onsets
Fitted underlying trend* (___) is given with its 95% confidence limits (...)
* includes adjustment for delay from onset to diagnosis
Variant CJD - GEOGRAPHYDistribution of 51 variant CJD cases by region of residence in 1991
Standard region Population aged 16-54 at the1991 census (%)
Number (rate/million) ofvCJD cases
Scotland 2,684,004 ( 9) 8 (2.98)
Northern 1,592,257 ( 5) 5 (3.14)
North-West 3,293,814 (11) 6 (1.82)
Yorkshire & Humberside 2,567,630 ( 9) 7 (2.73)
Wales 1,461,006 ( 5) 2 (1.37)
West Midlands 2,749,699 ( 9) 1 (0.36)
East Midlands 2,121,678 ( 7) 4 (1.89)
East Anglia 1,072,018 ( 4) 1 (0.93)
South-West 2,379,370 ( 8) 3 (1.26)
South-East 9,469,745 (32) 14 (1.48)
Total 29,393,174 (100) 51 (1.74)
Variant CJD - GEOGRAPHY
Standard region Population (millions)aged 10 years andabove at the 1991census (%)
Number (rate/million) ofvCJD cases
“North” (North West,Yorkshire & Humberside,Northern, Scotland)
16.6 (35) 26 (1.57)
“South” (South West, SouthEast, Wales, West Midlands,East Midlands, East Anglia)
31.2 (65) 25 (0.80)
Total 47.8 (100) 51 (1.94)
Variant CJD - GEOGRAPHY
Number (rate/million) of vCJD cases by place ofresidence at 1st January 1991
Region Population aged10 years andabove at the1991 census First 51 cases Subsequent
casesTotal
“North” (NorthWest, Yorks &Humbs, Northern,Scotland)
16.6 million 26 (1.57) 19 (1.14) 45 (2.71)
“South” (SouthWest, South East,Wales, WestMidlands, EastMidlands, EastAnglia)
31.2 million 25 (0.80) 21 (0.67) 46 (1.47)
Total (age/sexadjusted rate ratio)
47.8 million 51 (1.94) 40 (1.66) 91 (1.81)
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
Regional variations in weekly quantities of foods consumed (grams) measured in theperiod 1986-1987
Type of food Mean quantity per person in grams by region
Scotland Northern,North West,
Yorks &Humbs
East Midlands,East Anglia,
WestMidlands,
South Westand Wales
South East
Beef and veal 351 342 319 362
Burgers and kebabs 170 166 139 205
Sausages 147 136 142 143
Meat pies and pastries 251 284 243 237
Other meat products 170 201 197 215
Total 1089 1129 1040 1162
Data from the Nutritional Survey of British Adults
Regional variations in weekly quantities of foodsbrought into the home (grams) measured inthe period 1984-1986
Scotland North Yorks &Humbs
NorthWest
EastMids
WestMids
SouthWest
SouthEast/East
Anglia
Wales
Carcasemeat
325 362 359 377 373 392 395 382 355
Bacon 102 119 113 121 110 122 89 88 113
Poultry 158 192 174 199 175 212 196 205 191
Othermeat andmeatproducts
455 456 369 408 367 376 362 338 339
Total 1040 1129 1015 1105 1025 1102 1042 1013 998
Data from Household Food Consumption and Expenditure:1988
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 Expenditure:1988)
vC
JD
sta
nd
ard
ise
d c
um
. in
cid
.
Other meat/meat products(grams)300 350 400 450
0
50
100
150
200
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.
The Leicester cluster
5 cases of variant CJD lived in Leicestershire (population 870, 000)
Cumulative incidence: UK 1.5/ million Leicester 5.7/ million4/5 from Charnwood (142, 000): 28.2 / million
Kulldorff’s method- spatial scan statistic-Leicestershire- most likely cluster (p<0.004)No other significant clusters
(Cousens et al. Lancet 2001; 357: 1002- 1007)
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)
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…..
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
Size of the vCJD epidemic- predictions
1997: Cousens et al. Nature; 385: 197-198 (n=14 vCJD)
75- 80, 000
Back calculation
MM genotype
2000: Ghani et al. Nature; 406: 583- 584 (n= 55 vCJD)
63- 136 000
Scenario analysis (> 5 million combinations of parameters)
MM genotype
< 2 cases vCJD per infectious bovine
Size of the epidemic- predictions
2001: Huillard d’Aignaux 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
Size of the epidemic- predictions
2001: Valleron et al. Science 294: 1726- 1728 (n=97)• 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 >15 years of age
Size of the epidemic- predictions2002: 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
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
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
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
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
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
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
DIAGNOSTIC CRITERIA FOR vCJD
I A Progressive neuropsychiatric disorder
B Duration of illness > 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)
B Bilateral pulvinar high signal on MRI scan
IV A Positive tonsil biopsyd
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 cerebrumand cerebellum.