prion disease: a rare phenomena
TRANSCRIPT
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Brian S. Appleby, M.D.Associate Professor
Department of NeurologyUniversity Hospitals Case Medical Center
Prion Disease: A Rare Neurological Phenomenon
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Objectives
I. Understand key elements of diagnosing CJDII. Demonstrate strategies for managing
patients with CJDIII. Demonstrate knowledge regarding CJD risks
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Disclosures
• No relevant financial disclosures• Off-label uses of:– Quinacrine– Pentosan Polysulphate– Doxycycline– Various medications for symptomatic treatment
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What is a prion?
• proteinaceous and infectious• -ion (infectious, e.g. virion)• No nucleic acid• Non-degradable by typical sterilization
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Soto C, Trends Biochem Sci 2006
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EtiologiesGenetic CJDFatal familial insomniaGerstmann-Sträussler-Scheinker
KuruIatrogenic CJDVariant CJD
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Age at Onset
vCJDgCJD
sCJD
Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007
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Adapted from: Appleby BS, Arch Neurol 2009
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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
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Definitive Diagnosis
H & E StainingImmunohistochemistry
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Probable sCJDAt least two clinical signs:1.Dementia2.Cerebellar or visual symptoms3.Pyramidal or extrapyramidal symptoms4.Akinetic mutism
At least one of the following:1.PSWCs on EEG2.14-3-3 in CSF and disease duration < 2 years3.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
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Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWCs)
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MRI (DWI/FLAIR)
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Diagnostic Test Comparison
Satoh K, Dement Geriatr Cog Disord 2007
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Genetic Prion Disease
Kovács GG, J Neurol 2002
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Acquired Prion Disease
• Kuru• Iatrogenic CJD (iCJD)• Variant CJD (vCJD)
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Kuru
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Iatrogenic CJD
Brown P, Neurology 2006
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http://www.cjd.ed.ac.uk/vcjdworld.htm
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vCJD Characteristics
Will RG, Lancet 1996
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Pulvinar Sign
Zeidler M, Lancet 2000
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BSE1980’s
MMMV
Creutzfeldt-Jakob Disease in the UK, 20th Annual Report, 2011
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Chronic Wasting Disease (CWD)
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Experimental Treatments
• Quinacrine and other tricyclic compounds• Pentosan polysulphate (PPS)• Doxycycline
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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)
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Individuals with less impairment and better functioning chose quinacrineIndividuals with more impairment and less functioning declined quinacrine
Only 2 of 107 subjects chose randomization
Collinge J et al, Lancet Neurol 2009
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Doh-ura K, J Virol 2004
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“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
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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
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Future Clinical Trials
• UK MRC: monoclonal Ab against PrPc in symptomatic prion disease (date TBD)
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CARE AND MANAGEMENT
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Goals
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Intervals of CareI. Pre-clinical/Presentation PhaseII. Diagnostic PhaseIII. Caring Phase
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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
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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
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Caring Phase
• Frequent reassessment/symptomatic treatment
• Limit visits to few individuals of short durations
• Assess caregiver requirements• Hospice/Respite care
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Symptomatic TreatmentSymptom 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 firstStart low and go slow
Re-evaluate frequently
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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
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Risk Assessment
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Routine Clinical Care• Standard Precautions Only• No need for gowns, masks, isolation, etc.• Consider the family
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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)
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Resources
www.cjdfoundation.orgwww.cjdsurveillance.comCDC, http://www.cdc.gov/ncidod/dvrd/prionsMonthly CJD Support Group through Cleveland Alz Assoc and CJD FoundationMyself: [email protected]
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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)
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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
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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
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ExamGeneral: Vacant look, utilization behaviorSpeech: Dysarthric, apraxic, latent Thought Content: Appeared to be responding to visual hallucinationsMMSE: 12/30Motor: Mild rigidity UE (L>R), myoclonusGait: Ataxic, requires 2 person assist, dysmetria (L>R)
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Brain MRI (DWI)
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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
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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