# Presentation: 520485

## VARIANT CJD

- AN UPDATE
- DR. HESTER WARD
- National CJD Surveillance Centre
- Edinburgh, UK
*h.ward@ed.ac.uk*

## UK frequency of CJD

## 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)

## Slide 5

## Slide 6

## Slide 7

## Courtesy of Nick Andrews, PHLS Statistics Unit, London

## Geographical distribution of places of residence at onset of symptoms of vCJD cases (n=93)

## Variant CJD - GEOGRAPHY

## Variant CJD - GEOGRAPHY

## Variant CJD - GEOGRAPHY

## 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

## Slide 14

## Slide 15

## 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) **

## GEOGRAPHICALLY ASSOCIATED CASES (GACs) of vCJD

## 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/ million
- 4/5 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- 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

## 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

## Slide 33

## 
Blood transmission studies: on going

Tests of CJD
	Blood/ urine
	Screening vs. diagnostic

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

## 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

- 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 cerebrum
	and cerebellum.

- 				(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.