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Creutzfeld-Jakob Disease: Diagnosis and Management of Prion Diseases

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

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Creutzfeld-Jakob Disease: Diagnosis and Management of Prion Diseases

  1. 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. 2. Objectives I. Understand key elements of diagnosing CJD II. Demonstrate strategies for managing patients with CJD III. Demonstrate knowledge regarding CJD risks
  3. 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. 4. What is a prion? • proteinaceous and infectious • -ion (infectious, e.g. virion) • No nucleic acid • Non-degradable by typical sterilization
  5. 5. Soto C, Trends Biochem Sci 2006
  6. 6. Etiologies Genetic CJD Fatal familial insomnia Gerstmann-Sträussler-Scheinker Kuru Iatrogenic CJD Variant CJD
  7. 7. Age at Onset vCJD gCJD sCJD Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007
  8. 8. Adapted from: Appleby BS, Arch Neurol 2009
  9. 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. 10. Definitive Diagnosis H & E Staining Immunohistochemistry
  11. 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. 12. Electroencephalogram (EEG) Periodic sharp wave complexes (PSWCs)
  13. 13. MRI (DWI/FLAIR)
  14. 14. Hamlin C, Neurology 2012
  15. 15. Real-Time Quaking-Induced Conversion (RT-QuIC) PrPc PrPc PrPc PrPSc PrPSc PrPSc Sample PrPSc
  16. 16. McGuire LI, Ann Neurol 2012
  17. 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. 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. 19. Genetic Prion Disease Kovács GG, J Neurol 2002
  20. 20. Acquired Prion Disease • Kuru • Iatrogenic CJD (iCJD) • Variant CJD (vCJD)
  21. 21. Kuru
  22. 22. Iatrogenic CJD Brown P, Neurology 2006
  23. 23. http://www.cjd.ed.ac.uk/documents/worldfigs.pdf
  24. 24. vCJD Characteristics Will RG, Lancet 1996
  25. 25. Pulvinar Sign Zeidler M, Lancet 2000
  26. 26. BSE 1980’s MM MV Creutzfeldt-Jakob Disease in the UK, 20th Annual Report, 2011
  27. 27. Chronic Wasting Disease (CWD)
  28. 28. www.cwd-info.org
  29. 29. Experimental Treatments • Quinacrine and other tricyclic compounds • Pentosan polysulphate (PPS) • Doxycycline
  30. 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. 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. 32. Doh-ura K, J Virol 2004
  33. 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. 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. 35. Future Clinical Trials • UK MRC: monoclonal Ab against PrPc in symptomatic prion disease (date TBD)
  36. 36. CARE AND MANAGEMENT
  37. 37. Goals
  38. 38. Intervals of Care I. Pre-clinical/Presentation Phase II. Diagnostic Phase III. Caring Phase
  39. 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. 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. 41. Caring Phase • Frequent reassessment/symptomatic treatment • Limit visits to few individuals of short durations • Assess caregiver requirements • Hospice/Respite care
  42. 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. 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. 44. Risk Assessment
  45. 45. Routine Clinical Care • Standard Precautions Only • No need for gowns, masks, isolation, etc. • Consider the family
  46. 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. 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. 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. 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. 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

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