Prion diseases neurodegenerative diseases.

1. MYSTERIOUS
PATHOGENS
Diya Saleh
Neurology Registrar

2. DEMENTIA FOR EVALUATION
• 70 yo male retired abattoir worker
• Sharp deterioration of short term memory over six months period, leading to
word forming dificulties, misplacement of personal belongings as well as
direction finding difficulties.
• MoCA score was 8/30 and his recent MMSE, done by his GP, was 20/30.
• No focal deficits, but he did have mild extra-pyramidal signs afflicting his gait
and face. There were no involuntary movements.
• Despite his comorbidities listed above, he had been quite an independent
person, both for his personal and domestic AOL.
• No recent falls, weight loss or significant behavioral symptoms

3. BACKGROUND
• Dyslipidaemia
• Diabetes Mellitus Type II
• Hypertension
• Chronic AF on Warfarin

4. MRI BRAIN

7. CSF

10. DIAGNOSIS?

12. WHAT NEXT?
CSF Protein 14-3-3
POSITIVE
BUT what does it mean?
Marker of rapid neuronal loss

13. PUBLIC HEALTH IMPLICATION?
•
Mr X has a positive 14-3-3 protein result.
•
Based on the clinical story, the MRI and this result, I will place Mr X into the CJD surveillance system. I need to
remind you that the clinical suspicion of CJD is a notifiable disease in the setting of a positive 14-33 result. As such the family ought to be notified of this, because the ANCJDR is under contract to the DoH in
Victoria, so we have notified them of this gentleman this afternoon.
•
We will need two public health Qns put to the family regarding this gentleman:
• Has he been a blood donor in the last 3 years from onset?
• Has he had any Surgery, including eye Surgery in the last 2 years, from onset?
•
The answers to these questions may trigger public health responses – so I would be grateful for
•
I will also need to conduct follow up on this gentleman for surveillance purposes, for the Vict and Commonwealth
DoH, so I will contact you (or the most appropriate consultant) in a few weeks. I will plan contact you again soon
after the EEG.
answers to these questions very soon after the Neurology appt with this gentleman, or whenever he next presents.

14. FURTHER PENDING INVESTIGATION?
PERIODIC SYNCHRONOUS BI OR TRIPHASIC SHARP WAVE

15. PRION DISEASES
NEURODEGENERATIVE DISEASES.
• CreutzfeldtJakob disease (CJD)
• Variant CreutzfeldtJakob disease (vCJD): bovine to human transmission
• Kuru (kuru = shivering): transmitted from person to person by ritual
cannibalism
• Gerstmann Straüssler Scheinker syndrome (GSS): inherited in an autosomal
dominant.
• Fatal familial insomnia (FFI)

16. BIOLOGY AND GENETICS OF PRIONS

17. BIOLOGY AND GENETICS OF PRIONS

18. BIOLOGY AND GENETICS OF PRIONS
• Dr. Stanley Prusiner coined the term "prion" in 1982
• The gene encoding the prion protein in humans is located on
the short arm of chromosome 20.
• Prions is resistant to a number of normal decontaminating
procedures.

19. THE NOBEL PRIZE IN PHYSIOLOGY OR MEDICINE 1997
Stanley B. Prusiner receiving his Nobel Prize from
the hands of His Majesty the King.

20. THE NORMAL FUNCTION OF PrPC?
• Copper homeostasis. Copper, itself, plays a role in endocytosis
and neurotransmission.
• PrPC acts as a mediator of copper superoxide dismutase
involved in the cellular response to oxidative stress
• role for in immune function

21. COMMON NEUROPATHOLOGIC FEATURES
• Neuronal loss
• proliferation of glial cells
• absence of an inflammatory response
• presence of small vacuoles within the neutrophil  a spongiform
appearance.
• The atrophy may include the deep gray structures.
In contrast to Alzheimer disease, the hippocampus is spared.

22. PRION DISEASES
COMMON FEATURES
• long incubation periods
• progress inexorably once clinical symptoms appear

23. CREUTZFELDT-JAKOB
DISEASE
• Is the most frequent of the human prion diseases
• One case of sporadic CJD occurs per 1,000,000 population per
year
• The mean age for the onset of disease is between 57 and 62
years, while patients with vCJD and iCJD tend to be much
younger
• study in Australia found that a history of multiple surgical
procedures and residence for more than 10 years on a farm
were significant risk factors for sCJD

24. CLINICAL FEATURES
• two cardinal clinical manifestations:
• Rapidly progressive mental deterioration and
• Myoclonus: especially provoked by startle, is present in more than 90
percent of patients at some point during the illness but may be absent at
presentation, even when dementia is profound
• Extrapyramidal signs
• Corticospinal tract involvement
• Death usually occurs within one year of symptom onset

25. DIFFERENTIAL DIAGNOSIS
• All other neurodegenerative dementias even when more rapidly
progressive than is usual, virtually never progresses to death
within 12 months (a timeframe that is typical for CJD):
• Alzheimer disease
• Frontotemporal dementia
• Lewy bodies, progressive supranuclear palsy, or multiple systems atrophy

26. DIAGNOSIS
• Brain biopsy: the gold standard
• MR : the most helpful, DWI: the most sensitive
• EEG: supportive but not definitive evidence for CJD.
• Periodic synchronous bi or triphasic sharp wave complexes
(PSWC): observed in 67 to 95 percent of patients with sCJD
at some time during the course of the illness. PSWCs have a
very high specificity for the diagnosis of sCJD.
• CSF 14-3-3 protein: specific, but its sensitivity can be low

27. PROBABLE DIAGNOSIS
• Progressive dementia and
• At least two out of the following four clinical features: myoclonus; visual or
cerebellar disturbance; pyramidal / extrapyramidal dysfunction; akinetic
mutism and
• Atypical EEG during an illness of any duration, and/or a positive 14-3-3 CSF
with a clinical duration to death less than two years, and/or MRI high signal
abnormalities in caudate nucleus and/or putamen on DWI or FLAIR and
• Routine investigations should not suggest an alternative diagnosis.

28. DEFINITIVE DIAGNOSIS
The previous features in combination with one or more of the following neuropathologic
findings:
•
Loss of neurons, gliosis, spongiform degeneration, or plaques positive for PrPSc on
histopathology of brain tissue
•
Positive PrPSc staining following pre-treatment of brain tissue with proteinase K to
destroy PrPC reactivity
•
Positive histo-blotting of brain tissue extracts for PrPSc after treatment with proteinase to
destroy PrPC reactivity
•
Transmission of characteristic neurodegenerative disease to experimental animals
•
Demonstration of PRNP gene mutations

29. Characteristic
Sporadic (Classic) CJD
Variant CJD
Median age at death
68 years
28 years
Median duration of illness
4-5 months
13-14 months
Clinical signs and symptoms
Dementia; early neurologic signs
Periodic sharp waves on electroencephalogram Often present
Prominent psychiatric/behavioral symptoms;
painful dyesthesiasis; delayed neurologic
signs
Often absent
"Pulvinar sign" on MRI
Present in >75% of cases
Not reported
Presence of "florid plaques" on neuropathology Rare or absent
Present in large numbers
Immunohistochemical analysis of brain tissue
Variable accumulation
Marked accumulation of protease resistance
prion protein
Presence of agent in lymphoid tissue
Not readily detected
Readily detected
Increased glycoform ratio on immunoblot
analysis of protease-resistance prion protein
Not reported
Marked accumulation of protease resistance
prion protein

30. The pulvinar sign on MRI. Bilateral hyperintensities in the pulvinar thalami (arrows) relative to
the anterior putamen.
Lippincott Williams & Wilkins et al. Neurology
2004;62:1034-1035
© 2013 American Academy of Neurology

31. HYPERINTENSITIES IN THE THALAMUS "PULVINAR SIGN" (T2-WEIGHTED AXIAL) IN VCJD