2. Diseases have a prolonged incubation period and a protracted
progressive clinical course.
Slow virus diseases may be caused by conventional viruses or
unconventional (atypical) agents.
Diseases caused by conventional viruses include; PML, SSPE,
and AIDS dementia complex.
6. 6
Prions lack nucleic acid and
propagate by transmission
of protein misfolding.
The nature of prions and
their unique mode of
transmission present
challenges for early
diagnosis of prion disease
8. Feed that has an infected prion causes the infection in the cattle
The prions are concentrated in the brain and spinal cord of these
animals
There is no evidence that it is concentrated in the muscle mass of
cattle, and they are considered safe as long as they are not in
contact with the brain and spinal cord during the slaughter
process
8
9. Prions are single molecules containing about 250 amino acids
They are abnormal variants of normal proteins
Prions have the ability to convert the normal forms that they
come into contact with into abnormal forms
No antibiotics can cure disease caused by prions
They are not typical of a prokaryotic organism or a eukaryotic
organism
10. All that is present in this pathogen is the protein PrPSc, the
mutation of PrPC
PrPSc is resistant to any form of digestion
Prions are non immunogens and do not induce an immune
response
Prions are not easy to decompose biologically
They are resistant to high temperatures & disinfectants
12. Other researchers:
1. prion-like properties to a mechanism involved in maintaining memory
2. involvement with the immune system
3. function in circadian rhythm and sleep regulation
(Mice in which PrPc copy is knocked out have altered sleep/wake cycles and circadian rhythm)
Some researchers speculate that prions are not needed for “routine”
functions but somehow enable the nervous system to “fine-tune” itself at
the cellular level
13. • For a prion (PrPSc) to infect a host, the host must have a
recognizable cellular form (PrPc) of that prion
• the closer the phylogenetic relationship between the host and
the recipient, the greater the chance for infection, and the
more rapidly symptoms occur
• Level of accumulation of prion does not necessarily correspond
to level of disease
14. Vacuolation of neurons and formation of amyloid- containing plaques
and fibrils.
Proliferation and hypertrophy of astrocytes and fusion of neurons and
adjacent glial cells.
Prions reach high concentrations in the brain and can be isolated from
tissues other than the brain but only the brain shows any pathology.
No inflammation or immune response is generated to the agent.
15. vacuole
Source: UC Davis School of Veterinary Medicine
Brain Damage from Spongiform
Encephalopathy
16. ▪ PrPC PrPSC
Solubility
▪ Soluble Non soluble
Structure
▪ Alpha-helical Beta-sheeted
Multimerisation state
▪ Monomeric Multimeric
Infectivity
▪ Non infectious Infectious
Susceptibility to Proteinase K
▪ Susceptible Resistant
17. In fatal familial insomnia (FFI) –
thalamus- unable to sleep.
In Creutzfeldt-Jakob disease -
cerebral cortex.
In kuru and GSS, accumulates in
cerebellum.
18. Human
Creuzfeldt and Jacob Disease –
CJD
Gerstmann-Strasussler – GSS
Fatal Familial Insomnia –FFI
Kuru
Animal
•Scrapie (sheep and goats)
•Transmissible mink encephalopathy
•Bovine spongiform encephalopathy
(BSE; mad cow disease)
•Chronic wasting disease (mule,
deer, and elk)
18
20. Due to autosomal dominant mutation of PrP
Inherited – at least 10-15% of total human TSE cases
fCJD, FFI, GSS
20
21. Prion-related diseases are relentlessly progressive and invariably
lead to death.
The mean duration of sporadic CJD is 8 months.
vCJD has a slightly longer course, with a mean duration of 14
months.
Familial CJD has a mean duration of 26 months,
GSS has the longest course, about 60 months.
22. Sporadic CJD occurs throughout the world in people of all
races and typically has similar features.
Familial CJD, can have distinct features in an ethnic group
(familial CJD in the Libyan Jewish population associated with a codon 200 mutation
has features of a peripheral neuropathy in addition to the more typical
manifestations of CJD.)
vCJD has been limited to Europe, with almost all cases
occurring in the United Kingdom.
23. AGE
The mean age of onset of sporadic CJD
is 62 years, range can be broad – 17 to
83 yrs
vCJD occurs in younger patients, with
a mean age of onset of 28 years.
Familial CJD, GSS, and FFI have mean
ages of onset ranging from 45-49
years.
SEX
No sex preponderance is known .
But, women had a greater tendency
than men to develop kuru
(because it was part of the ritual cannibalism for
women to eat the brains and neural tissue has
the highest dose of PrPSc).
24. Kuru is a disease of man.
It is transmitted by cannibalism in Fore people in Papua/New
Guinea.
No one born since these practices ceased has acquired Kuru.
There is no evidence for transmission to fetus, transmission via
milk or intimate social contact.
24
25. cerebellar ataxia and a shivering-like tremor. Headache, joint
pain, then 6-12 weeks later, difficulty walking, then death
usually within 12 months, always within 2 years
The disease has three phases, ambulant, sedentary, and
terminal.
Emotional liability leading to outbursts of pathologic laughter
is frequent; sometimes appearing in the first stage of the
disease
Kuru
26. Smiling and laughter are terminated slowly (laughing death, a
journalistic synonym). Nearly true euphoria may be observed.
Terminally, patients develop incontinence, dysphagia with thirst and
starvation, flaccidity, mutism and unresponsiveness.
Kuru
27. Kuru: shivering or trembling
in Fore tribe of New Guinea , who used to eat dead human body.
Women and children are high risk.
27
28. FFI is a disease of man that results in progressive untreatable
insomnia, loss of circadian rhythm, endocrine disorders,
dysautonomia, motor disorders, and dementia.
It seems that the hypothalamus function is the target.
brain MRI is usually normal
FDG-PET imaging reveals thalamic and cingulate
hypometabolism,
29. slowly progressive limb and truncal ataxia, as well as
dementia.
neuropathology of GSS is remarkable in that extensive and
invariable amyloid deposition and NFTs occurs
Death occurs 3-8 years following presentation
30. When cattle brains and other
cattle byproducts infected with
BSE are ingested by humans,
there is a risk of developing the
Creutzfeldt-Jakob Disease
30
31. 1/ 1 million
most common human prion disease is CJD, about 85% of all
human prion disease
10% of CJD cases have amyloid plaques.
Ten percent of cases of CJD are familial (AD)
31
32. CJD is classified into 2 forms: Classic CJD & Variant CJD
Classic CJD can be transmitted to other species, however other animals
cannot carry it.
Sub classified into: Sporadic CJD and Iatrogenic CJD
Sporadic CJD - >85% of Classic CJD cases
Most common between 50 – 75 years
Characterized by rapidly increasing dementia
Iatrogenic CJD - < 5% Classic CJD cases
Transmission of prion via medications & surgical equipment
34. Almost all patients with sporadic CJD develop myoclonic jerks
that involve either the entire body or a limb.
These can occur spontaneously or can be precipitated by
auditory or tactile stimulation.
sCJD - 40% of patients rapidly progressive cognitive impairment,
40% with cerebellar dysfunction,
20% with a combination of both.
35. sporadic CJD
onset is subacute with agitated or depressed behavioral change.
rarely with aggressive, but never violent, behavior.
Commonly, there is an inability to find words, perform simple
arithmetic or write correctly.
Two thirds of cases have ataxic gait at onset, vertigo and nystagmus,
there is trunk and limb ataxia, tremors or dysarthria.
36. Progression to global dementia leading to mutism, cerebellar
incoordination, myoclonus, and marked progressive motor dysfunction
follow.
May be transmitted by corneal transplants, dura matter transplants,
infected neurological electrodes and ingestion of diseased nervous
tissue.
Jews of Libyan origin have a high incidence of CJD which was linked to
consumption of sheep eye balls.
37. At least two clinical signs:
1. Dementia
2. Cerebellar or visual symptoms
3. Pyramidal or extrapyramidal symptoms
4. Akinetic mutism
At least one of the following:
1. PSWCs on EEG
2. 14-3-3 in CSF and disease duration < 2 years
3. 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
38. Definite CJD
Characteristic neuropathology
Protease-resistant PrP by Western blot
Possible CJD
Progressive dementia
Atypical findings on EEG or EEG not available
At least 2 of the following - Myoclonus, visual impairment,
cerebellar signs, pyramidal or extrapyramidal signs, or
akinetic mutism
Duration less than 2 year
39. Reported in the UK in patients who are younger (frequently under 40).
vCJD has a distinctive neuropathological appearance and more PrPSC
deposits than typical CJD.
There has been considerable concern that this might be associated
with exposure to BSE-contaminated beef.
Some believe it is more common than what was believed (1/10.000 or
more at death).
40. The first 10 cases of variant CJD were observed in 1996, ten years after the
outbreak of BSE in the UK
Young infected 12-74 years
Psychiatric & sensory symptoms
Accumulation of Pr psc - Amyloid plaques - With Spongiform chains
Acquired by oral route - Possible transmission of variant CJD
40
41. 41
CJD causes fatal degradation of brain tissue
The symptoms include loss of expressiveness, muscular tremble,
spasm, impaired muscle coordination, loss of memory & dementia
vCJD patients also display unusual psychiatric problems
There is no cure for CJD
The condition of the patient deteriorates, finally resulting in death
Clinical Symptoms
42. sporadic CJD variant CJD
age 55-70 19-39
presenting
features
dementia,
myoclonus
Behavioral, ataxia,
dysesthesia(sensory &
psychiatric)
course rapidly progressive prolonged
cerebellar 40% 100%
PrP banding pattern Type 1, Type 2 Type 4 (BSE like)
43. viral encephalitis
Diffuse Lewy body disease
Chronic meningitis
Dementia as a paraneoplastic syndrome
Dementia in motor neuron disease
Limbic encephalitis (and other paraneoplastic syndromes)
Hashimoto encephalopathy (or Steroid-responsive encephalopathy
associated with autoimmune thyroiditis [SREAT])
FTD
ADC
44. laboratory tests as for dementia
CBC count, serum chemistry panel, LFT, ESR, thyroid function,
B-12 levels and folate levels
tests for neurosyphilis. anti-thyroperoxidase, paraneoplastic
syndrome Igs,
45. • High signal abnormality in basal
ganglia
• High signal abnormality in ≥ 2
cortical regions
• Temporal
• Parietal
• Occipital
• 91% sensitive, 95% specific,
Frontal
Zerr I et al, Brain 2009
46. which refers to increased
signal in the putamen and
head of the caudate nucleus
resembling a hockey stick,
47. Zeidler M, Lancet 2000
corresponds to a usually bilaterally
increased signal in the pulvinar thalamic
nuclei. This has been found especially in
patients with vCJD.
48. In a few patients, has been performed in which regional
hypometabolism of glucose was noted that correlated with the
neuropathologic lesions found at autopsy.
49. PSWC – Sn 67%, Sp 87%
Repeated > 90
In vCJD, EEG does not show the typical changes observed in
sporadic CJD, and findings often are normal.
50. CSF is typically normal in sporadic CJD, although the CSF
protein may be elevated slightly (but never >100 mg/dL).
CSF for the 14-3-3 protein. The sensitivity and specificity of
this test – 52 & 76%.
51. similar to a PCR reaction for amplifying nucleic acid.
high specificity (~98%–100%) , moderate sensitivity (~80%–
87%)
52. During life, a probable diagnosis is based on the clinical
picture.
EEG - supportive evidence in some cases.
The final diagnosis is usually made from post-mortem
examination of the brain. A brain biopsy can be used.
Serology is of no use since the patient does not show an
immunological response. 52
54. UK MRC: monoclonal Ab against PrPc in symptomatic prion
disease
55. 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 Thickener, cueing
Behavioral/Environmental changes first
Start low and go slow
Re-evaluate frequently
56. Standard Precautions Only
No need for gowns, masks, isolation, etc.
Consider the family
57. Diagnosing CJD can be difficult.
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
58. At Present, there is no Cure for the
Creutzfeldt-Jakob Disease
Prevention is the only available
option
58
