Brian S. Appleby, M.D.Associate Professor

Department of NeurologyUniversity Hospitals Case Medical Center

Prion Disease: A Rare Neurological Phenomenon

Objectives

I. Understand key elements of diagnosing CJDII. Demonstrate strategies for managing

patients with CJDIII. Demonstrate knowledge regarding CJD risks

Disclosures

• No relevant financial disclosures• Off-label uses of:– Quinacrine– Pentosan Polysulphate– Doxycycline– Various medications for symptomatic treatment

What is a prion?

• 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

Adapted from: Appleby BS, Arch Neurol 2009

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

Definitive Diagnosis

H & E StainingImmunohistochemistry

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 (PSWCs)

MRI (DWI/FLAIR)

Diagnostic Test Comparison

Satoh K, Dement Geriatr Cog Disord 2007

Genetic Prion Disease

Kovács GG, J Neurol 2002

Acquired Prion Disease

• Kuru• Iatrogenic CJD (iCJD)• Variant CJD (vCJD)

Kuru

Iatrogenic CJD

Brown P, Neurology 2006

http://www.cjd.ed.ac.uk/vcjdworld.htm

vCJD Characteristics

Will RG, Lancet 1996

Pulvinar Sign

Zeidler M, Lancet 2000

BSE1980’s

MMMV

Creutzfeldt-Jakob Disease in the UK, 20th Annual Report, 2011

Chronic Wasting Disease (CWD)

Experimental Treatments

• Quinacrine and other tricyclic compounds• Pentosan polysulphate (PPS)• Doxycycline

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)

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

Doh-ura K, J Virol 2004

“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

• 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

Future Clinical Trials

• UK MRC: monoclonal Ab against PrPc in symptomatic prion disease (date TBD)

CARE AND MANAGEMENT

Goals

Intervals of CareI. Pre-clinical/Presentation PhaseII. Diagnostic PhaseIII. 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 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

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)

Resources

www.cjdfoundation.orgwww.cjdsurveillance.comCDC, http://www.cdc.gov/ncidod/dvrd/prionsMonthly CJD Support Group through Cleveland Alz Assoc and CJD FoundationMyself: bsa35@case.edu

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)

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

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

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)

Brain MRI (DWI)

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

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