This document discusses prion diseases, also known as transmissible spongiform encephalopathies (TSEs). It notes that TSEs have long incubation periods and progressive clinical courses. They can be caused by conventional or unconventional agents and include diseases like Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Prions, the infectious agents responsible for TSEs, are abnormal forms of proteins that can induce normal proteins to also take the abnormal form. They are resistant to heat, chemicals, and radiation. Diagnosis of prion diseases is difficult due to a lack of immune response or signs of infection. Currently, there

1. Dr. Rahi kiran
SR I
Neurology
1

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.

3. In Animals
 Scrapie
 Transmissible Mink Encephalopathy (TME)
 Chronic Wasting Disease of Mule deer (CWD)
 Bovine Spongiform Encephalopathy (BSE)

4. In Humans
 Creutzfeldt -Jacob Disease (CJD)
 Gerstmann-Straussler-Scheinker Syndrome (GSS)
 Fatal Familial Insomnia (FFI)
 kuru

5.  Animals/Humans suffer
 Sheep – Scrape Visna Maedi
 Incubation months to years
 CNS involvement,
 Genetic Predisposition.
 Absence of Immune response.
 Fatal Terminal Illness. 5

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

7. 7Dr.T.V.Rao MD

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
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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

11. Dr.T.V.Rao MD 11

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)
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19. Human transmission - Spongiform Encephalopathy.
1 Idiopathic
2 Familial
3 Acquired
85%
14%
1%
Sporadic Genetic Acquired
Genetic CJD
Fatal familial insomnia
Gerstmann-Sträussler-ScheinkerKuru
Iatrogenic CJD
Variant CJD

20.  Due to autosomal dominant mutation of PrP
 Inherited – at least 10-15% of total human TSE cases
 fCJD, FFI, GSS
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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.
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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.
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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
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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)
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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

33. vCJD
gCJD
sCJD
Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007

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
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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

53. COMPOUND
 Quinacrine
 Pentosan polysulphate
 Doxycycline
 no effect
 may have effect in vCJD
 verdict is unclear
OUTCOME

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
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