CJD Overview Bob Will, National CJD Surveillance Unit, Edinburgh, UK

Associazione Italiana Encefalopatie da Prion

Milano 3 Ottobre 2009

Hans Creutzfeldt Alfons JakobHans Creutzfeldt Alfons Jakob

Science 1968

Questions

• What is the origin of infection in CJD?• Is there a link to scrapie in sheep?• What are the clinical and pathological

characteristics of CJD?• What are the epidemiological characteristics

of CJD?

SYSTEMATIC STUDIES OF CJD WORLDWIDECountry Period Incidence:

cases/million Country Period Incidence:

cases/million

Austria 1969-1985 1986-1994 1995-2001

0.18 0.67 1.15

Italy 1958-1971 1993-2001

0.05 1.10

Australia 1970-1980 1987-1996 1997-2001

0.66 1.07 1.39

Japan 1975-1977 1985-1996

0.45 0.58

Chile 1955-1972 1973-1977 1978-1983

0.10 0.31 0.69

Netherlands New Zealand

1993-2001 1989-1989

1.00

0.88 Czechoslovakia 1972-1986 0.66 Slovakia 1993-2001 1.17

France 1968-1977 1978-1982 1993-2001

0.34 0.58 1.52

Switzerland

1995-2001

1.50

Germany

1979-1990 1993a-2001

0.31 1.14

UK 1964-1973 1970-1979 1980-1984 1985-1989 1993-2001

0.09 0.31 0.47 0.46 0.99

Israel 1963-1972 1963-1987

0.75 0.91

US 1973-1977 1983-1990b 1991-1998b

0.26 1.10 1.10

a Extrapolated from part-year data b Age-adjusted to the standard US projected 2000 population

DISTRIBUTION OF SPORADICCJD IN THE UK: 1990-2002

AUTHOR METHOD RISK FACTORS

Bobowick et al. (1973) 38 “selected” cases; healthy controls. None.

Kondo & Kuroiwa (1982) Population study: 60 cases, healthy controls

trauma in males.

Kondo (1985) 88 autopsied cases; autopsied controls

organ resection.

Davanipour et al (1985) 26 cases; 40 controls trauma or surgery to head or neck;

other trauma; surgery needing sutures; tonometry

Davanipour et al (1985) 26 cases; 40 controls roast pork, ham, underdone meat, hot dogs.

Davanipour et al (1985) 26 cases; 40 controls contact with fish, rabbits, squirrels.

Harries-Jones et al (1980) 92 cases; 184 controls Herpes Zoster; keeping cats; contact with pets other than cats/dogs; dementia in family

Van Duijn et al (1998) 405 cases; 405 controls consumption of raw meat; consumption of brain; frequent exposure to leather products, exposure to fertilizer consisting of hoof and horn.

Collins et al (1999) 241 cases; 784 controls number of surgical procedures; residence or employment on a farm or market garden.

Ward et al (2002) 326 cases; 326 controls surgery, especially in females; ear piercing, psychiatric consultation.

SIGNIFICANT RISK FACTORS IN CONTROLLED STUDIES

HUMAN TSEs (Prion diseasesHUMAN TSEs (Prion diseases

DISEASE CAUSE

Sporadic Creutzfeldt-Jakob disease (CJD)

Unknown

Iatrogenic CJD Kuru

Human to human transmission

Variant CJD Transmission of BSE to humans

Familial CJD Gerstmann-Straussler syndrome Fatal Familial Insomnia

Mutations of prion protein gene

SPORADIC CJD : EEGPERIODIC TRIPHASIC DISCHARGES

• 60-80% SENSITIVITY(TESTING POLICY)

• ? SPECIFICITY (? 74%)(CONTEXT DEPENDENT)

• ‘SUBJECTIVITY’ OF REPORTING

NO EEG CRITERIA PROSPECTIVELY VALIDATED IN LARGE NUMBERS OF CASES

CSF Analysis

Dr Alison Green, The National CJD Surveillance Unit ECDC funded meeting, 10 th March 2009

sCJD AD vCJD SpCJD

14-3-3 Western Blot

MRI brain scan in sporadic CJD

MRI brain scan in variant CJD

FIGURE 2

Sporadic CJD0.00 - 0.500.51 - 1.001.01 - 1.50

Genetic CJD0.00 - 0.100.11 - 0.150.16 - 0.80

Iatrogenic CJD0.01 - 0.050.070.17

0.00 Variant CJD0.000.050.20

MORTALITY RATES PER COUNTRY - (EUROCJD) 1993-2000)

IATROGENIC CREUTZFELDT-JAKOB DISEASE WORLDWIDE

Mode of infection

No. of patients

Agent entry

into brain

Mean incubation period (range)

Clinical signs on presentation

Corneal transplant 2 Optic nerve 18, 320 mo Dementia, cerebellar

Stereotactic EEG 2 Intra-cerebral 16, 20 mo Dementia, cerebellar

Neurosurgery 4 Intra-cerebral 17 mo (12-28) Visual/dementia/cerebellar

Dura mater graft 209 Cerebellar surface 11 yr (1.5-23) Cerebellar (visual, dementia)

Growth hormone 203 Hematogenous(?) 15 yr (4-36) Cerebellar

Gonadotrophin 4 Hematogenous (?) 13 yr (12-16) Cerebellar

Blood transfusion 3 (+1) Hematogenous 6.5, 7.5, 8.5 yr Sensory, psychiatric

DURA MATER CASES WORLDWIDE SHOWN BY YEAR OF OPERATION AND YEAR OF ONSET OF SYMPTOMS FOR CJD

0

2

4

6

8

10

12

14

16

18

20

69 - - - 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96

Year

Operation Onset

Mean incubation period from operation to onset of symptoms: 6.8 years (range 1-16)

THE HUMAN PRION PROTEIN GENE Mutations and polymorphisms

• Clinical diagnosis

• Screening of family members

• Pre-natal testing

• Influence on phenotype

‘BSE posed the greatest political and economic challenge to the EU since its foundation’

The specified bovine offal ban UK Dec 1989/ Jan1990

The UK BSE epidemic

DIFFERENCES BETWEEN SPORADICAND VARIANT CJDDIFFERENCES BETWEEN SPORADICAND VARIANT CJD

SPORADIC CJD VARIANT CJD

Mean age at death 66 years 29 years

Median duration of illness

4 months 13 months

Thalamic MRI high signal

Caudate/Putamen 60%

Pulvinar

90%

EEG "Typical" 70% "Typical" 0%

Neuropathology Plaques

10%

Florid plaques 100%

0

20

40

60

80

100

120

140

160

180

15-1

9

20-2

4

25-2

9

30-3

4

35-3

9

40-4

4

45-4

9

50-5

4

55-5

9

60-6

4

65-6

9

70-7

4

75-7

9

80-8

4

85-8

9

90+

sCJD vCJD

AGE AT DEATH FOR SPORADIC CJD CASES AND vCJD CASES BY 5-YEAR AGE GROUP

Age Group

Nu

mb

er o

f ca

ses

ResultsTemporal distribution of vCJD cases in France and UK

10 0 0

1 1 1 20

2

7

4 4

0

810 11

14

17

29

24

16

13

4

9

5

20

0

5

10

15

20

25

30

35

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007

year of onset

num

ber o

f cas

es

vCJD in France

vCJD in UK

According to the year of onset, the number of vCJD cases in France reached a peak of incidence in 2004, five years after the peak observed in the UK in 1999

YEAR OF ONSET OF ILLNESS OF vCJD WORLDWIDE Year

Onset

UK France Ireland Italy USA Canada Saudi Arabia

Japan Nether-lands

Portugal

Spain

1994 8 1

1995 10

1996 11

1997 14

1998 17 1

1999 29 1 1

2000 24 1

2001 17 2 1 1 1 1

2002 14

2003 5 2 1

2004 9 7 2 1 1 1

2005 5 4 1 1 1

2006 3 4 1 1 1

2007 1 3

2008 2 2 1

Total 169 25 4 1 3 1 1 1 3 2 5

CHARACTERISTICS OF TSEs

• Prolonged incubation periods.• Uniformly fatal neurological diseases.• Causal agents (prions) resistant to

sterilisation.• No serological test for infection.• Infection may be present in tissues (LRS)

during the incubation period.

0

10

20

30

40

50

60

70

80

9096-1

96-3

97-1

97-3

98-1

98-3

99-1

99-3

00-1

00-3

01-1

01-3

02-1

02-3

03-1

03-3

04-1

04-3

05-1

05-3

06-1

06-3

07-1

Donation (RBC)Donoronset

Donordeath

vCJD case(Case 1)

vCJD case(Case 3)

Transfusion to recipient

Donation 1 (RBC)Donoronset

Donordeath

Recipientonset

Recipientdeath

Transfusion to recipient Recipientonset

Recipientdeath

Pre-clinical infection(Case 2)

Donoronset

DonordeathDonation (RBC)

RBC=red blood cells

Transfusion to recipient Recipient death

Years shown by quarter

vCJD case(Case 4)

Donation 2 (RBC)

Transfusion to recipient

Donoronset

Donordeath

Recipientonset

Recipientdeath

There is no evidence of transmission of any form of CJD through:

• Social contact• Treating minor injuries• Occupational contact• Maternal transmission• Sexual transmission• General surgery

Number of Reported BSE cases,vCJD Deaths (Probable & Definite) and vCJD Onsets

in the EC & the UK 1988-2008

0

5

10

15

20

25

30

35

40

1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008

Year

No

. BS

E c

ases

('0

00s)

0

5

10

15

20

25

30

35

40

45

50

No

. vC

JD d

eath

s UK BSE cases('000s)

UK vCJD deaths

EC BSE cases(x 100)

EC vCJD deaths

EUROCJD & NEUROCJDJoint MeetingLake Garda, Italy May 2003