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!