2014-04-10 Grand Rounds, Department of Neurology, Lehigh Valley Health Network

1. Brian S. Appleby, M.D.
Associate Professor
Departments of Neurology, Psychiatry, & Pathology
University Hospitals Case Medical Center
Diagnosis and Management of
Creutzfeldt-Jakob Disease

2. Objectives
I. Understand key elements of diagnosing CJD
II. Demonstrate strategies for managing
patients with CJD
III. Demonstrate knowledge regarding CJD risks

3. Disclosures
• Honoraria from CJD Foundation
• Salary from FDA for TSEAC
• Research materials from FDA
• Off-label uses of:
– Quinacrine
– Pentosan Polysulphate
– Doxycycline
– Various medications for symptomatic treatment

4. What is a prion?
• proteinaceous and infectious
• -ion (infectious, e.g. virion)
• No nucleic acid
• Non-degradable by typical sterilization

5. Soto C, Trends Biochem Sci 2006

6. Etiologies
Genetic CJD
Fatal familial insomnia
Gerstmann-Sträussler-Scheinker
Kuru
Iatrogenic CJD
Variant CJD

7. Age at Onset
vCJD
gCJD
sCJD
Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007

8. Adapted from: Appleby BS, Arch Neurol 2009

9. Epidemiology
• 1 new case per million individuals per year
across the entire population (all ages)
• 1/10,000 US deaths per year
• OH=10.5 million people
– 10.5 new cases/yr
– ~2.5 cases living past one year
– Would not be unusual to have 13 active cases in
OH
Holman RC, PLoS ONE 2010

10. Definitive Diagnosis
H & E Staining
Immunohistochemistry

11. Probable sCJD
At least two clinical signs:
1.Dementia
2.Cerebellar or visual symptoms
3.Pyramidal or extrapyramidal symptoms
4.Akinetic mutism
At least one of the following:
1.PSWCs on EEG
2.14-3-3 in CSF and disease duration < 2 years
3.High signal abnormalities in basal ganglia or at least two
cortical regions (temporal, parietal, or occipital) on
DWI/FLAIR sequences on brain MRI
Zerr I, et al. Brain 2009

12. Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWCs)

13. MRI (DWI/FLAIR)

14. Hamlin C, Neurology 2012

15. Real-Time Quaking-Induced Conversion (RT-QuIC)
PrPc
PrPc
PrPc PrPSc
PrPSc
PrPSc
Sample
PrPSc

16. McGuire LI, Ann Neurol 2012

17. RT-QuIC: Highly Specific
UK Japan Australia
RT-QuIC 14-3-3 RT-QuIC 14-3-3 RT-QuIC 14-3-3
Sensitivity 89% 94% 83% 72% 88% 88%
Specificity 99% 65% 100% 86% 100% 71%
Atarashi R, Nat Med 2011 & McGuire LI, Ann Neurol 2012
CSF Samples from sCJD Cases

18. NPDPSC Reports
• CSF tau ≥ 1150pg/mL -> prion disease highly likely
• CSF tau ≥ 500pg/mL -> RT-QuIC analyses
– If RT-QuIC (+) -> prion disease
– If RT-QuIC (-) -> does not rule out prion disease
• Need to look at clinical suspicion and results of other
biomarkers
www.cjdsurveillance.com

19. Genetic Prion Disease
Kovács GG, J Neurol 2002

20. Acquired Prion Disease
• Kuru
• Iatrogenic CJD (iCJD)
• Variant CJD (vCJD)

21. Kuru

22. Iatrogenic CJD
Brown P, Neurology 2006

23. http://www.cjd.ed.ac.uk/documents/worldfigs.pdf

24. vCJD Characteristics
Will RG, Lancet 1996

25. Pulvinar Sign
Zeidler M, Lancet 2000

26. BSE
1980’s
MM
MV
Creutzfeldt-Jakob Disease in the UK, 20th Annual Report, 2011

27. Chronic Wasting Disease (CWD)

28. www.cwd-info.org

29. Experimental Treatments
• Quinacrine and other tricyclic compounds
• Pentosan polysulphate (PPS)
• Doxycycline

30. Quinacrine
1. 30 sCJD/2vCJD, no sig diff in survival time (Haik
S, Neurology, 2004)
2. PRION-1 (UK), 45 sCJD/2 iCJD, 18 vCJD, 42
gCJD, no sig diff in survival time (Collinge J, Lancet
Neurol, 2009)
3. UCSF, no sig diff in survival time (Geshwind MD,
Neurology 2013)

31. Individuals with less impairment and better functioning chose quinacrine
Individuals with more impairment and less functioning declined quinacrine
Only 2 of 107 subjects chose randomization
Collinge J et al, Lancet Neurol 2009

32. Doh-ura K, J Virol 2004

33. “On the basis of the available evidence, the
best possible outcome that could be expected
after treatment with intraventricular PPS is that
there may be some temporary slowing or
halting of the disease progression. However,
there is little likelihood of significant clinical
improvement. Nor is there a likelihood of
permanent halting of disease progression.”
CJD Support Network Newsletter, March 2004

34. Doxycycline
• French study-no difference in survival time
(Brandel J-P, Prion 2013, Banff, Canada)
• Italian study-reportedly negative
• German study-possible slight prolongation of
survival time in codon 129 MM (Zerr I, Prion 2008,
Madrid, Spain)
• Italian study: prophylactic use in FFI carriers

35. Future Clinical Trials
• UK MRC: monoclonal Ab against PrPc in
symptomatic prion disease (date TBD)

36. CARE AND MANAGEMENT

37. Goals

38. Intervals of Care
I. Pre-clinical/Presentation Phase
II. Diagnostic Phase
III. Caring Phase

39. Preclinical/Presentation Phase
• Initial interactions with primary medical
doctor
• At risk individuals should identify
“physician champions”
Kranitz FJ & Simpson DM. CNS Neurol Disord Drug Targets 2009

40. Diagnosis Phase
• Discuss process with patient and family
• Don’t forget about present needs
• Refer to organizations and clinicians familiar
with the illness
• Discharge planning (before discharge)
• Must establish a “key worker”
Douglas M, Patients with nvCJD and their families 1999

41. Caring Phase
• Frequent reassessment/symptomatic
treatment
• Limit visits to few individuals of short
durations
• Assess caregiver requirements
• Hospice/Respite care

42. Symptomatic Treatment
Symptom Suggested Treatment
Psychosis/Agitation Low potency neuroleptics (e.g., quetiapine)
Myoclonus/Hyperstartle Long acting benzodiazepines (e.g., diazepam)
Anticonvulsants (e.g., valproic acid)
Seizures Anticonvulsants
Dystonia/Contractures Passive movement
Long acting benzodiazepines, Botulinum toxin injections
Constipation Bowel regimen (e.g., dulcolax)
Dysphagia/Rumination Thickener, cueing
Behavioral/Environmental changes first
Start low and go slow
Re-evaluate frequently

43. Afterwards
• Arrange requested post-mortems prior to
death (www.cjdsurveillance.com)
• Frequent check-ins with family/caregivers
• If postmortem performed, communicate
results (in person if possible)
• Encourage contact as needed

44. Risk Assessment

45. Routine Clinical Care
• Standard Precautions Only
• No need for gowns, masks, isolation, etc.
• Consider the family

46. Surgery/Equipment
• WHO. WHO consultation on TSE in relation to
biological and pharmaceutical products. Geneva,
Switzerland; 2003
• WHO. WHO guidelines on tissue infectivity
distribution in TSE. Geneva, Switzerland; 2005
• Transfusion Medicine Epidemiological Review
(TMER) (
http://www.cjd.ed.ac.uk/TMER/TMER.htm)

47. Resources
www.cjdfoundation.org
www.cjdsurveillance.com
CDC, http://www.cdc.gov/ncidod/dvrd/prions
Monthly CJD Support Groups through Cleveland
& NY Alz Assoc and CJD Foundation
bsa35@case.edu

48. Current Studies
• Blood and urine bioassay study with FDA
• Factors affecting initial diagnoses of prion
disease
• Art therapy in prion disease
• Brain FDG-PET scans in prion disease

49. Summary
• Diagnosing CJD can be difficult and frustrating
• Getting a proper diagnosis and managing the
care of a patient with CJD is stressful, but very
doable, and extremely rewarding
• Care and management of patients with prion
disease is supportive and entails several disease
specific interventions

50. Thank You
• Patients and families
• CJD Foundation
• National Prion Disease Pathology Surveillance
Center
• CJD Support Group Network (Australia)
• UH-CMC Brain Health and Memory Center
• Alzheimer’s Association
• Dr. Paul Brown, Florence Kranitz, Deana Simpson