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CJD Overview Bob Will, National CJD Surveillance Unit, Edinburgh, UK Associazione Italiana Encefalopatie da Prion Milano 3 Ottobre 2009 Hans 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 WORLDWIDE Country Period Austria 1969-1985 1986-1994 1995-2001 1970-1980 1987-1996 1997-2001 1955-1972 1973-1977 1978-1983 1972-1986 0.18 0.67 1.15 0.66 1.07 1.39 0.10 0.31 0.69 0.66 1968-1977 1978-1982 1993-2001 0.34 0.58 1.52 Australia Chile Czechoslovakia France Incidence: Country cases/million Germany 1979-1990 1993a2001 0.31 1.14 Israel 1963-1972 1963-1987 0.75 0.91 Period Incidence: cases/million Italy 1958-1971 1993-2001 0.05 1.10 Japan 1975-1977 1985-1996 0.45 0.58 Netherlands 1993-2001 1.00 New Zealand Slovakia 1989-1989 1993-2001 0.88 1.17 Switzerland 1995-2001 1.50 UK 1964-1973 1970-1979 1980-1984 1985-1989 1993-2001 1973-1977 1983-1990b 1991-1998b 0.09 0.31 0.47 0.46 0.99 0.26 1.10 1.10 US a Extrapolated from part-year data b Age-adjusted to the standard US projected 2000 population DISTRIBUTION OF SPORADIC CJD IN THE UK: 1990-2002 SIGNIFICANT RISK FACTORS IN CONTROLLED STUDIES AUTHOR Bobowick et al. (1973) Kondo & Kuroiwa (1982) Kondo (1985) METHOD 38 “selected” cases; healthy controls. RISK FACTORS None. Population study: 60 cases, healthy controls trauma in males. 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. HUMAN 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 Mutations of prion protein gene Fatal Familial Insomnia SPORADIC CJD : EEG PERIODIC 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 14-3-3 Western Blot sCJD AD vCJD Dr Alison Green, The National CJD Surveillance Unit SpCJD ECDC funded meeting, 10th March 2009 MRI brain scan in sporadic CJD MRI brain scan in variant CJD MORTALITY RATES PER COUNTRY - (EUROCJD) 1993-2000) FIGURE 2 Sporadic CJD Genetic CJD 0.00 - 0.50 0.51 - 1.00 1.01 - 1.50 Iatrogenic CJD 0.00 0.01 - 0.05 0.07 0.17 0.00 - 0.10 0.11 - 0.15 0.16 - 0.80 Variant CJD 0.00 0.05 0.20 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 4 Hematogenous (?) 13 yr (12-16) Cerebellar Hematogenous 6.5, 7.5, 8.5 yr Sensory, psychiatric Gonadotrophin Blood transfusion 3 (+1) DURA MATER CASES WORLDWIDE SHOWN BY YEAR OF OPERATION AND YEAR OF ONSET OF SYMPTOMS FOR CJD 20 18 16 14 12 10 8 6 4 2 0 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 The UK BSE epidemic ‘BSE posed the greatest political and economic challenge to the EU since its foundation’ The specified bovine offal ban UK Dec 1989/ Jan1990 DIFFERENCES BETWEEN SPORADICAND VARIANT CJD SPORADIC CJD VARIANT CJD Mean age at death 66 years 29 years Median duration of illness Thalamic MRI high signal 4 months 13 months Caudate/Putamen 60% EEG "Typical" 70% Pulvinar 90% "Typical" 0% Neuropathology Plaques 10% Florid plaques 100% 180 160 140 120 100 sCJD vCJD Age Group 90+ 85-89 80-84 75-79 70-74 65-69 60-64 55-59 50-54 45-49 40-44 35-39 30-34 25-29 20-24 80 60 40 20 0 15-19 Number of cases AGE AT DEATH FOR SPORADIC CJD CASES AND vCJD CASES BY 5-YEAR AGE GROUP Results Temporal distribution of vCJD cases in France and UK 35 29 number of cases 30 24 25 20 17 vCJD in France 16 14 15 11 10 10 vCJD in UK 13 9 8 7 4 5 1 0 0 0 1995 1996 1997 1 1 1 1998 1999 2000 2 4 5 2 4 2 0 00 0 1994 2001 2002 2003 2004 2005 2006 2007 year of onset 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 1994 8 1 1995 10 1996 11 1997 14 1998 17 1 1999 29 1 2000 24 1 2001 17 2 2002 14 2003 5 2 2004 9 7 2 2005 5 4 1 2006 3 4 2007 1 2008 2 2 Total 169 25 Italy USA Canada 1 1 1 Saudi Arabia Japan Nether -lands Portugal Spain 1 1 1 1 1 1 1 1 1 1 1 3 1 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. vCJD case (Case 1) Donor onset Donation (RBC) 90 Donor death 80 Transfusion to recipient vCJD 70 case (Case 3) Recipient onset Donor onset Donation 1 (RBC) Recipient death Donor death 60 Transfusion to recipient 50 vCJD case 40 4) (Case 30 Recipient Recipient onset death Donor onset Donation 2 (RBC) Donor death Transfusion to recipient Pre-clinical infection 20 (Case 2) Donor onset Donation (RBC) Recipient onset Donor death Recipient death 10 Years shown by quarter RBC=red blood cells 07-1 06-3 06-1 05-3 05-1 04-3 04-1 03-3 03-1 02-3 02-1 01-3 01-1 Recipient death 00-3 00-1 99-3 99-1 98-3 98-1 97-3 97-1 96-3 0 96-1 Transfusion to recipient 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 40 50 35 45 30 35 25 30 20 25 15 20 15 10 10 5 5 0 0 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 Year No. vCJD deaths No. BSE cases ('000s) 40 UK BSE cases ('000s) UK vCJD deaths EC BSE cases (x 100) EC vCJD deaths EUROCJD & NEUROCJD Joint Meeting Lake Garda, Italy May 2003