Prion disease: A Rare Phenomena


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Prion disease: A Rare Phenomena

  1. 1. Prion Disease: A Rare Neurological Phenomenon Brian S. Appleby, M.D. Associate Professor Department of Neurology University Hospitals Case Medical Center
  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 • No relevant financial disclosures • 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 sCJD vCJD gCJD 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 Immunohistochemistry H & E Staining
  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. Diagnostic Test Comparison Satoh K, Dement Geriatr Cog Disord 2007
  15. 15. Genetic Prion Disease Kovács GG, J Neurol 2002
  16. 16. Acquired Prion Disease • Kuru • Iatrogenic CJD (iCJD) • Variant CJD (vCJD)
  17. 17. Kuru
  18. 18. Iatrogenic CJD Brown P, Neurology 2006
  19. 19.
  20. 20. vCJD Characteristics Will RG, Lancet 1996
  21. 21. Pulvinar Sign Zeidler M, Lancet 2000
  22. 22. MM MV BSE 1980’s Creutzfeldt-Jakob Disease in the UK, 20th Annual Report, 2011
  23. 23. Chronic Wasting Disease (CWD)
  24. 24. Experimental Treatments • Quinacrine and other tricyclic compounds • Pentosan polysulphate (PPS) • Doxycycline
  25. 25. 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)
  26. 26. 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
  27. 27. Doh-ura K, J Virol 2004
  28. 28. “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
  29. 29. 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
  30. 30. Future Clinical Trials • UK MRC: monoclonal Ab against PrPc in symptomatic prion disease (date TBD)
  32. 32. Goals
  33. 33. Intervals of Care I. Pre-clinical/Presentation Phase II. Diagnostic Phase III. Caring Phase
  34. 34. 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
  35. 35. 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
  36. 36. Caring Phase • Frequent reassessment/symptomatic treatment • Limit visits to few individuals of short durations • Assess caregiver requirements • Hospice/Respite care
  37. 37. 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
  38. 38. Afterwards • Arrange requested post-mortems prior to death ( • Frequent check-ins with family/caregivers • If postmortem performed, communicate results (in person if possible) • Encourage contact as needed
  39. 39. Risk Assessment
  40. 40. Routine Clinical Care • Standard Precautions Only • No need for gowns, masks, isolation, etc. • Consider the family
  41. 41. 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) (
  42. 42. Resources CDC, Monthly CJD Support Group through Cleveland Alz Assoc and CJD Foundation Myself:
  43. 43. Current Studies • Blood and urine bioassay study with FDA • Factors affecting initial diagnoses of prion disease • Art therapy in prion disease • Future study looking at non-invasive diagnostic test using RT-QuIC (detects actual prion protein, very specific to diagnosis)
  44. 44. Case #1 • • • • 57 y.o. AAM professional, h/o 3 TBI’s Some short term memory problems x 3 months More distractible, still working full time MMSE=24/30 (-1 calculation, -3 orientation, -2 recall) • mild left upper extremity dysmetria
  45. 45. Case #2 • 61 y.o. WF from St. Maarten’s Island with a history of alcohol abuse • 2 mo. h/o ataxia, apathy, myoclonus, and cognitive impairment • Vitamin B12=249, folate=8.6, MCV=98
  46. 46. Exam General: Vacant look, utilization behavior Speech: Dysarthric, apraxic, latent Thought Content: Appeared to be responding to visual hallucinations MMSE: 12/30 Motor: Mild rigidity UE (L>R), myoclonus Gait: Ataxic, requires 2 person assist, dysmetria (L>R)
  47. 47. Brain MRI (DWI)
  48. 48. 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
  49. 49. 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 • Staff at Foley Eldercare Center • Dr. Paul Brown, Florence Kranitz, Deana Simpson