1. Second case of variant CJD in Canada: case report and implications for assessment of geographic risk Michael B. Coulthart, PhD Director, Canadian CJD Surveillance System Public Health Agency of Canada US FDA TSE Advisory Committee Gaithersburg, MD Aug 1, 2011

2. Outline CJD surveillance in Canada Case report Interpretation and policy decisions - qualitative risk profile (individual) - blood safety measures (deferral)

3. CJD Surveillance in Canada

4. Mandate, approach and objectives Blood Safety (1998, 2001); BSE (2004, 2006, 2009) Prion diseases nationally and provincially reportable Comprehensive case registry: features, causes Support: clinicians, pathologists, hospitals, families - laboratory services, consultation, education Detailed family interviews conducted routinely Epidemiology: incidence, subtyping, etiology Analysis/response: classic CJD; vCJD; ?human CWD

5. Referrals and cases 1999–June 30 2011 Sporadic: 423 92% Genetic: 33 7% Iatrogenic: 4 Variant: 2 250300 patient files opened per year: full+partial referrals } ~1% Definite, probable cases included

6. vCJD (2002) vCJD (2011)

7. Sporadic CJD mortality, EUROCJD 1999-2009 Data: http://www.eurocjd.ed.ac.uk/sporadic.htm

8. Main conclusions Prospective CJD surveillance conducted continuously over period of primary concern for Canada (1998present) All etiologic types observed, in “expected” proportions Mortality rate steady across time and space Findings consistent with those of other expert CJD surveillance systems internationally Acquired human prion disease detected (total 6 cases) - zoonotic (vCJD, 2 cases) - iatrogenic (dura mater, 4 cases) Canada’s CJD surveillance methods and data are technically sufficient to address question of presence/absence of domestically acquired vCJD

9. Case report

10. Clinical profile 24 yomale; ~1-yr hx of neurological problems: - psychiatric prodrome (Jan 2010) - movement disorder (July 2010) - rapid cognitive decline (Sept 2010) - aphasia; ataxia; profound cognitive deficits; involuntary movements; painful dysaesthesias (Jan 2011) Negative or inconclusive: - family history of similar problems - various routine laboratory investigations

11. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive for pathologic PrP - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (1/6)

12. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive for pathologic PrP - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (2/6)

13. Magnetic Resonance Imaging (DWI) Pulvinar nucleus Cortical ribboning Head of caudate Putamen Dorsomedial nucleus

14. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive for pathologic PrP - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (3/6)

15. CSF 14-3-3 protein immunoblot: Negative (below cutoff) PS Primary Mab: SC-165714-3-3 diagnostic accuracy in Canada (sporadic CJD): Sensitivity: 88% Specificity: 72%

16. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive for pathologic PrP - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (4/6)

17. PRNP sequencing: 129M/M; 219E/K Strand 1 Strand 2

18. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive for pathologic PrP - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (5/6)

19. Tonsil biopsy, immunohistochemistry: Positive (Courtesy Dr. Gerard Jansen, Ottawa Hospital) PrP

20. EEG (Nov 2010): - generalized slowing (nonspecific) T2/FLAIR MRI (Nov 2010): - cortical ribboning - hockey stick sign (?)  probable vCJD (slightly atypical)? CSF 14-3-3 (Jan 2011): - negative (below cutoff) PRNP gene sequencing (Feb 2011): - no mutations  genetic prion disease excluded - 129M/M; 219E/K  sporadic CJD nearly excluded Bx examination palatine tonsil (Feb 2011): - immunohistochemistry: positive - PrP immunoblot: positive for PrP-res (Type 2B/4t)  “highly” probable vCJD (lack only neuropathology) Supporting investigations (6/6)

21. Tonsil biopsy, immunoblot: Positive; PrP-res Type 4t Primary MAb: 3F4

22. History: residence, travel, medical, dietary Residence: - Saudi Arabia (19861999) - United Arab Emirates, Bangladesh, USA (19992010) - Canada (2010present) Travel: - UK and Europe: total ~7 weeks 19952009 - Canada: 1 week 2008 - Bangladesh: 48 weeks annually 19862010 Medical: - No history of blood receipt/donation, surgery Dietary: - non-vegetarian (regular beef consumption) - bovine, goat brain (locally purchased, Saudi Arabia)

23. Interpretation and policy decisions

24. Exposure risk profile I. Factors to consider Possible routes of exposure: - beef consumption: known risk factor - blood transfusion: known risk factor - surgery: theoretical risk factor Residence history (broad sense  includes travel): - country: index of exposure risk - duration: index of exposure risk - dates: index of exposure risk : can estimate incubation time - surveillance and epidemiology of BSE and CJD - importation of beef, live bovines and bovine materials - control/safety measures (feed bans; SRM removal) Availability of data Relative risk scale: highmoderatelownear-zerounknown

25. Exposure risk profile II. Route and data Foodborne exposure highly probable - consumed beef regularly - brain included in traditional diet - no history of transfusion or surgery Detailed historical data available (family interview) - residence history - dietary history - medical history

26. Exposure risk profile III. Canada and USA Canada: risk near zero - 2008 (1 week) - residence 2010present * clinical onset pre-dated 2010 arrival - surveillance systems for BSE and CJD - low BSE case numbers; no known non-imported vCJD - ruminant feed ban 1997 - SRM regulations 2003 - enhanced feed ban 2007 USA: risk near zero - 20072009 (2 years) - surveillance systems for BSE and CJD - low BSE case numbers; no known non-imported vCJD - control/safety measures very similar to Canada’s

27. Exposure risk profile IV. UK and Europe UK: risk low - 1995 (2 weeks); 2009 (4 weeks) - surveillance systems for BSE and CJD - highest number of reported BSE cases - highest number of non-imported vCJD cases - reinforced feed ban 1996 France: risk near zero - 2002 (1 week) * no beef consumed during visit - surveillance systems for BSE and CJD - fourth-highest number of reported BSE cases - second-highest number of non-imported vCJD cases - reinforced feed ban 2001

28. Bangladesh, UAE: risk unknown - Bangladesh: 19862010 (total 5.57 years) - UAE: 19992010 (total ~4.5 years) - no public data on surveillance - no public data on control/safety measures - data on bovine imports? Saudi Arabia: risk moderate - 19861999 (total 1112 years) - would imply incubation period ~1123 years - no systematic data on surveillance, but * 2 other vCJD cases reported in Saudi residents - no public data on control/safety measures - known importation of UK beef and live bovines pre-1991 (Sanchez-Juan et al. 2007) Exposure risk profile V. Other countries

29. Precautionary approach (Krever Commission 1997): i) safety transcends other considerations ii) complete understanding of hazard and evidence of harm are not prerequisites for action iii) probability of occurrence, severity of consequences and potential future risks must all be considered iv) costs, risks and benefits must be balanced Policy I. Guiding principles

30. Data suggest an undocumented source of human exposure to BSE in Saudi Arabia - three vCJD cases in Saudi residents; similar risk profiles - domestic exposure most probable explanation - unknown potential for ongoing exposure (in region?) Canadian vCJD patient would not have been deferred from blood donation on existing criteria (safety gap) Argument for consistency of donor deferral policy - cf. vCJD numbers in other deferred countries: NL (3); IT (2); PT (2); DE (0); CH (0); AT (0) Change in donor deferral policy (March 29 2011): >6 mo residence in Saudi Arabia 19801996 First mandatory change in geographic deferral since 2001 Acceptable impact on donor base (rapid recovery) Policy II. Rationale and implementation

31. 13 years of surveillance data strongly indicate that Canada has not experienced domestically acquired vCJD Diagnoses of all 3 Saudi Arabian vCJD patients supported by clinical, paraclinical, laboratory evidence Risk profiles are similar for all three cases Most prominent risk factor: - residence in a country (Saudi Arabia) that imported UK beef during period of highest human exposure risk Evidence points toward an undocumented source of human exposure to BSE in Saudi Arabia Safety gap required mitigation For Canada, the precautionary principle and supporting criteria led to a decision to expand the scope of blood donor deferral Summary

32. Contributions: Case investigation Clinical neurology (University of Toronto) Dr. Nicolas Phielipp Dr. Anthony Lang Dr. David Morgenthau Pathology (University of Ottawa) Dr. Gerard Jansen Blood safety policy (Health Canada) Dr. Peter Ganz Biochemical and genetic analyses (PHAC) Dr. Michael Coulthart Epidemiological data (PHAC) Jennifer Kruse

33. Canadian CJD Surveillance System Senior Investigators Michael Coulthart (PHAC)Gerard Jansen (U of Ottawa) Clinical Coordination (PHAC) Rolande D’AmourJennifer Kruse Elina Olsen Stacy Sabourin Chantal Berubé-Brault Epidemiology/Data Management (PHAC) Dr. Zheng Wang Tim ConnollyZiad Saab Laboratory (PHAC; U of Ottawa) Debby Godal Kristen AveryShannon Hiebert Laura Landry Lisa PodhorodeckiAngela Sloan Rebekah Van BruggenRob Vendramelli Olga AgahEric LabelleLouise Pelletier

34. Acknowledgements Professor Robert Will (University of Edinburgh) Professor Richard Knight (University of Edinburgh) Dr. Lawrence Schonberger (US CDC) Dr. Neil Cashman (University of British Columbia) Dr. Maura Ricketts (Canadian Medical Association) Dr. Catherine Bergeron (University of Toronto) Dr. Antonio Giulivi (Ottawa Hospital) Dr. David Asher (US FDA) Dr. Luisa Gregori (US FDA)