Creutzfeldt-Jakob diseaseDiagnosis and Management of Prion Diseases
March 21, 2013
Brian S. Appleby, M.D.Lou Ruvo Center for Brain Health
Cleveland Clinic
Sponsored by:
Disclosures
• No relevant financial disclosures
• Off-label uses of:
• Quinacrine
• Pentosan Polysulphate
• Doxycycline
Objectives
I. Understand key elements of diagnosing CJD
II. Demonstrate strategies for managing patients with CJD
III. Demonstrate knowledge regarding CJD risks
“Pri-on”
•proteinaceous and infectious
• -ion (infectious, e.g. virion)
• No nucleic acid
• Non-degradable by typical sterilization
Soto C, Trends Biochem Sci 2006
EtiologiesGenetic CJDFatal familial insomniaGerstmann-Sträussler-Scheinker
KuruIatrogenic CJDVariant CJD
Age at Onset
vCJDgCJD
sCJD
Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007
Epidemiology
sCJD=1/1,000,000 people per year
1/10,000 deaths per year in US due to CJD
Survival Time
Adapted from: Appleby BS, Arch Neurol 2009
Definitive Diagnosis
H & E Immunohistochemistry
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
Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWC’s)
MRI (DWI/FLAIR)
All stage CJD
Early stage CJD
Satoh K, Dement Geriatr Cog Disord 2007
Kovács GG, J Neurol 2002
Genetic Prion Disease
Acquired Prion Disease
• Kuru
• Iatrogenic CJD (iCJD)
• Variant CJD (vCJD)
Kuru
Iatrogenic CJD
Brown P, Neurology 2006
227 total cases
Variant CJD
http://www.cjd.ed.ac.uk/vcjdworld.htm
vCJD Characteristics
Will RG, Lancet 1996
Pulvinar Sign
Zeidler M, Lancet 2000
Creutzfeldt-Jakob Disease in the UK, 18th Annual Report, 2009
MM
MV
BSE1980’s
Chronic Wasting Disease
Experimental Treatment
• Quinacrine and other tricyclic compounds
• Pentosan polysulphate (PPS)
• Doxycycline
Quinacrine
I. 30 sCJD/2vCJD, no sig diff in survival time (Haik S, Neurology, 2004)
II. PRION-1 (UK), 45 sCJD/2 iCJD, 18 vCJD, 42 gCJD, no sig diff in survival time (Collinge J,
Lancet Neurol, 2009)
III. UCSF, midpoint survival analyses, no sig diff btwn comparison groups (Log rank, p=0.4) (Geschwind M, 6th CJD Family Conference, 2008)
45 sCJD, 42 genetic prion disease, 18 vCJD, 2 iCJD
Quinacrine PO 1g/24hrthen
Quinacrine 100mg PO TID
Only 2 of 107 subjects chose randomization
Collinge J, Lancet Neurol 2009
“PRION-1 was essentially an observational study of patients choosing to take quinacrine or not...”
Doh-ura K, J Virol 2004
Bone I, Eur J Neurol 2008
Pentosan Polysulphate
“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
Doxycycline
Group Number of cases Median survival time
Doxycycline treated 21 292 days
Untreated 581 169 daysLog Rank test,
p<0.001
Observational study
PRNP codon 129MM, p=0.019MV, p=0.133VV, p=0.54
Zerr I, Prion 2008, Madrid, Spain
Care and Management
Goals
Education
Communication
Implementation
Intervals of Care
I. Pre-clinical/Presentation Phase
II. Diagnostic Phase
III. Caring Phase
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
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
Caring Phase
•Frequent reassessment/symptomatic treatment
•Limit visits to few individuals of short durations
•Assess caregiver requirements
•Hospice/Respite care
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 firstStart low and go slow
Re-evaluate frequently
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
Risk Assessment
Routine Clinical Care
• Standard Precautions Only
• No need for gowns, masks, isolation, etc.
• Consider the family
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)
Case• 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
Summary•Diagnosing CJD can be difficult and frustrating
•Getting a proper diagnosis and managing the care of a patient with CJD is stressful
•Care and management of patients with prion disease is supportive and entails several disease specific interventions
Thank You!
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