1. Transmissible Spongiform Encephalopathies Ryan Maddox, MPH Creutzfeldt-Jakob Disease Surveillance Unit Division of Viral and Rickettsial Diseases National Center for Infectious Diseases Centers for Disease Control and Prevention

2. Abbreviations TSE – Transmissible Spongiform Encephalopathy (prion disease) CJD – Creutzfeldt-Jakob Disease vCJD – Variant Creutzfeldt-Jakob Disease BSE – Bovine Spongiform Encephalopathy (“mad cow” disease) CWD – Chronic Wasting Disease

3. Transmissible Spongiform Encephalopathies (TSEs): Neurodegenerative diseases Rapidly progressive, always fatal Affect humans and animals Long incubation periods Brain, spinal cord, and adjacent tissues are considered infectious Prion theory widely accepted

4. TSEs are further characterized by: Absence of immune response Neuropathology may include: –Spongiform changes –Reactive gliosis –Neuronal loss –Amyloid plaques –No inflammatory reaction

5. Human TSEs Kuru Creutzfeldt-Jakob Disease (CJD) Variant Creutzfeldt-Jakob Disease (vCJD) Gerstmann-Sträussler Scheinker Syndrome (GSS) Fatal Familial Insomnia (FFI)

6. Animal TSEs Scrapie Bovine Spongiform Encephalopathy (BSE) Chronic Wasting Disease (CWD)

7. Creutzfeldt-Jakob Disease (CJD) Occurs worldwide Annual incidence (U.S.): ~1 case per million population Median age at death (U.S.): 68 years

8. CJD – Clinical Features Patients usually present with dementia, visual problems, or cerebellar dysfunction Subsequent neurologic signs include myoclonus, tremors, and rigidity Neurologic signs deteriorate very rapidly  akinetic mutism

9. CJD – More Features Rapidly progressive - over 50% of CJD patients die within 6 months and 85-90% within 12 months of illness onset (median illness duration: 4 months) CJD occurs in three different forms: – sporadic – familial – iatrogenic

10. Sporadic CJD About 85% of CJD patients No recognizable mode of transmission identified May be caused by: Age-related somatic mutation of the prion protein gene Error in production of the normal prion protein

11. Familial CJD About 10-15% of CJD patients Autosomal dominant inheritance Associated with prion protein gene abnormalities Usually a family history of CJD is present

12. Iatrogenic CJD <1% of CJD patients Transmission through: –Human Growth Hormone –Dura Mater Graft Lyodura –Cornea transplantation –Use of neurosurgical instruments and EEG depth electrodes

13. CJD Transmission Not contagious Not transmitted through casual contact or airborne particles

14. CJD Transmission CJD does not appear to be transmissible through blood –Follow-up of recipients of blood from donors subsequently diagnosed with CJD –Investigation of CJD cases with history of receipt of blood products

15. CJD - Diagnosis Clinical course highly suggestive –Patient’s age –Rapidly progressive disease –Family history EEG: diagnostic picture in 75% of patients CSF test to identify protein 14-3-3 Genetic studies Neuropathology required for confirmation

16. Bovine Spongiform Encephalopathy (BSE) First recognized among cattle in the United Kingdom in 1986 Cases may have occurred in the early 1980s Peaked in 1992-1993: 36,682 cases reported in 1992 alone As of June 1, 2005, 180,800 total cases in Great Britain

17. BSE is no longer confined to U.K. Many other countries in Europe have reported cases –As of July 21, 2005, 945 total cases in France, 963 in Portugal, 569 in Spain, 458 in Switzerland, and 363 in Germany Japan has reported 19 cases, and Israel reported its first case in 2002

18. BSE in North America In 2003, BSE cases were reported in Canada and the United States (cow was from Canada) Two cases reported in Canada in January, 2005: –Both cows from Alberta –One cow born October 1996, other one March, 1998 (after 1997 ruminant feed ban)

19. BSE in North America June 24, 2005 – USDA announces BSE case in United States –did not enter food supply

20. BSE in the United Kingdom: Possible Causes The practice of feeding cattle rendered animal parts was implicated Rendered material was from either: –Scrapie infected sheep –Cattle with spontaneous BSE In the early 1980s, rendering practices changed which might have facilitated transmission

21. BSE: U.K. Government Actions BSE made notifiable - 1988 Ruminant feed ban - 1988 Specified bovine offal ban – 1989 –Brain, spinal cord, and other high risk tissues excluded from human food Nationwide CJD surveillance in 1990 Cattle >30 months prevented from entering human or animal food chain - 1996

22. U.K. CJD Surveillance Detected 10 CJD patients with: –Unusual clinical presentation Young age: Median, 28 years (Range 16-39) Psychiatric presentation followed by cerebellar symptoms Non-diagnostic, abnormal EEG Prolonged duration of illness (Median: 14 months)

23. U.K. CJD Surveillance (2) Unique neuropathology –Spongiform changes most evident in the basal ganglia and thalamus –Widespread kuru-type plaques in the cerebellum and cerebrum The plaques had pale periphery and were surrounded by spongiform lesions

24. U.K. CJD Surveillance (3) U.K. surveillance unit reported that the 10 cases represented a distinct new entity, variant CJD (vCJD), based on: –The unique clinicopathological features –Absence of any known CJD risk factors –Absence of genetic abnormalities –Absence of similar cases in other countries

25. Variant Creutzfeldt-Jakob Disease (vCJD) U.K. government announced that the BSE agent may have spread to humans (probably through consumption of contaminated beef and beef products) –Cluster in 10 young patients –Unique to the U.K. –Consistent incubation period (9 years after BSE outbreak) –No other plausible explanation

26. Evidence for BSE-vCJD Link Epidemiological evidence –Geographic clustering in the United Kingdom –Absence of vCJD cases in BSE-free countries Laboratory evidence –Experimental study using macaques –Western blot analysis of infecting prions –Experimental study using panels of inbred and cross-bred mice

27. Variant CJD is different from CJD Variant CJD patients tend to be much younger, present with behavioral or sensory problems, have a delayed onset of neurologic signs, and tend to have a longer duration of illness Pathology differs between vCJD and CJD

28. USDA and FDA USDA and FDA have taken measures to prevent the introduction of BSE into the U.S. –Importation of ruminants from BSE-endemic countries banned, and certain cattle products restricted (1989) –Importation of live ruminants and most ruminant products from all of Europe prohibited (1997) –Mammalian-to ruminant feed ban in the U.S. (1997)

29. USDA Surveillance USDA tests high-risk animals 176,468 cattle tested in 2004 www.usda.gov

30. FDA Regulations Prohibited use of cattle materials at highest risk of BSE in human food, including dietary supplements, and cosmetics (2004) High risk includes –Material from non-ambulatory, disabled cattle –Material from organs of cattle >= 30 months –Mechanically separated material

31. 107 deaths from definite vCJD + 43 deaths from probable vCJD (no neuropathological confirmation) = 150 6 patients with probable vCJD alive; 156 vCJD cases total (definite/probable, dead/alive) Data from http://www.cjd.ed.ac.uk/figures.htm

32. Data from http://invs.sante.fr/publications/mcj/donnees_mcj.html

33. Variant CJD Around the World Cases have also been reported from Canada (1), Ireland (2), Italy (1), Japan (1), The Netherlands (1), Portugal (1), Saudi Arabia (1), and the United States (1) One of the Irish cases, the Canadian case, Japanese case, and the U.S. case were believed to have been exposed to the BSE agent in the United Kingdom

34. CDC CJD surveillance Conducted active surveillance in 5 areas Periodic review of national cause-of-death data Potential cases (iatrogenic, vCJD, etc.) reported by doctors and state public health departments Ongoing review of clinical and pathologic records of CJD decedents aged <55 years Collaboration with National Prion Disease Pathology Surveillance Center (NPDPSC) in Cleveland, Ohio Collaborative surveillance of special groups

35. Blood Some potential donors deferred –American Red Cross defers from donating: anyone in U.K. for 3 months since 1980 or any European country for 5 years since 1980 Blood shortage vs. potentially unsafe blood

36. vCJD Blood-Associated Cases So far, 2 of 48 recipients of blood components from donors who later died of vCJD have evidence of bloodborne transmission –Case 1: Donor developed vCJD >3 years after donation; recipient developed vCJD 6.5 years after transfusion –Case 2: Donor developed vCJD 18 months after donation; recipient (methionine/valine) had subclinical infection

37. Chronic Wasting Disease (CWD) Known natural hosts: deer (Odocoileus species) and Rocky Mountain elk Clinical symptoms –Weight loss –Behavioral changes –Excessive salivation –Difficulty swallowing

38. CWD Most animals die within several months of onset Wide range of ages affected May be highly transmissible within a population, but mode of transmission is not fully understood –Direct: animal-to-animal contact –Indirect: causative agent in environment

39. Chronic Wasting Disease Among Free-Ranging Deer and Elk by County, United States

40. CWD transmissible to humans? Belay ED, Maddox RA, Williams ES, Miller MW, Gambetti P, Schonberger LB. Chronic wasting disease and potential transmission to humans. Emerg Infect Dis 2004;10:977-84. Investigation of “clusters” of CJD cases Collaborative project with Wyoming

41. CaseAgeYearCodon 129Western BlotFinal diagnosisEndemic? 1252001MVType 1GSS 102Yes 2262001MMType 2CJDNo 3282002nd GSS 102No 4281997MMndCJDNo 5282000MVType 1CJDNo 6301999VVType 1CJDNo 7542002VVType 2CJDNo 8551999MMType 1CJDNo 9612000MMType 1CJDYes 10632002VVType 1CJDNo 11642002MMType 1CJDYes 12662001MMType 1CJDNo

42. Is CWD affecting humans? Unique pathology among suspect cases? More human TSE cases in endemic areas? Common genetics among suspect cases? History of exposure to deer and elk with CWD?

43. For more on prion diseases: www.cjdsurveillance.com –Information on National Prion Disease Pathology Surveillance Center (NPDPSC) –established by CDC and AANP –NPDPSC provides free, state-of-the-art diagnostic testing www.cdc.gov/ncidod/diseases/cjd/cjd/htm –Links to various prion disease articles and sites

44. Acknowledgements CDC Dr. Larry Schonberger Dr. Ermias Belay Dr. Jim Sejvar Mr. Bob Holman Mr. Aaron Curns NPDPSC Dr. Pierluigi Gambetti Ms. Carrie Harris State health department personnel