Prion diseases

1. Prion Diseases

2. • Prions are abnormal forms of a cellular
protein that cause rapidly progressive
neurodegenerative disorders that may be
sporadic, familial or transmitted

3. • This group of diseases includes Creutzfeldt-
Jakob disease, Gerstmann-Sträussler-
Scheinker syndrome, fatal familial insomnia,
and kuru in humans
• Scrapie in sheep and goats;
• Mink-transmissible encephalopathy;
• Chronic wasting disease of deer and elk; and
• Bovine spongiform encephalopathy

4. • All associated with abnormal forms of a
specific protein termed prion protein (PrP).
• They are all characterized morphologically by
“spongiform change” caused by intracellular
vacuoles in neurons and glia, and clinically by
a rapidly progressive dementia

5. Pathogenesis
• Prion diseases are conceptually important
because they exemplify degenerative
disorders that are caused by “spreading” of
misfolded proteins, a remarkable
phenomenon that allows a pathogenic
protein to acquire many of the characteristics
of an infectious organism

6. • Normal PrP is a 30-kD cytoplasmic protein present in
neurons.
• Disease occurs when PrP undergoes a conformational
change from its normal α-helix-containing isoform
(PrPc) to an abnormal β-pleated sheet isoform, usually
termed PrPsc (for scrapie)
• Associated with the conformational change, PrP
acquires resistance to digestion with proteases, such as
proteinase K.

8. • Accumulation of PrPsc in neural tissue seems
to be the cause of the pathologic changes in
these diseases, but how this material induces
the development of cytoplasmic vacuoles and
eventual neuronal death is still unknown.
• Western blotting of tissue extracts after partial
digestion with proteinase K allows detection
of PrPsc, which is diagnostic.

10. • The conformational change resulting in PrPsc
may occur spontaneously at an extremely low
rate (resulting in sporadic cases) or at a higher
rate if various mutations are present in PrPc,
such as occurs in familial forms of Creutzfeldt-
Jakob disease (CJD) and in Gerstmann-
Sträussler-Scheinker syndrome (GSS) and fatal
familialinsomnia (FFI)

11. Molecular Genetics
• The gene encoding PrP, termed PRNP, shows a
high degree of conservation across species. A
variety of mutations in PRNP have been found to
underlie familial forms of prion diseases.
• In addition, a polymorphism at codon 129 that
encodes either methionine (Met) or valine (Val)
influences development of the disease:
individuals who are homozygous for either Met
or Val are overrepresented among cases of CJD
compared with the general population

12. Creutzfeldt-Jakob Disease (CJD)
• Most common prion disease
• CJD is a rare disorder that manifests clinically as a
rapidly progressive dementia
• Sporadic form of CJD has an annual incidence of
approximately 1 per 1,000,000 people and accounts for
about 90% of cases; familial forms are caused by
mutations in PRNP.
• The disease has a peak incidence in the seventh decade

13. • Well-established cases of iatrogenic
transmission, notably by corneal
transplantation, deep implantation of
electrodes in the brain, and administration of
contaminated preparations of naturally
derived human growth hormone

14. Clinical features
• The onset is marked by subtle changes in memory and
behavior followed by a rapidly progressive dementia,
often associated with pronounced involuntary jerking
muscle contractions on sudden stimulation (startle
myoclonus).
• Signs of cerebellar dysfunction, usually manifested as
ataxia, are present in a minority of affected individuals.
• The disease is uniformly fatal. The average survival is
only 7 months after the onset of symptoms

15. Variant Creutzfeldt-Jakob Disease
• Different from typical CJD in several important
respects:
– the disease affected young adults,
– behavioral disorders figured prominently in the early
stages of the disease
– neurologic syndrome progressed more slowly than in
individuals with other forms of CJD.
• Neuropathologic findings and molecular features
were similar to those of CJD

16. • Variant form of CJD was linked to exposure to bovine spongiform
encephalopathy
• Pathologically, variant CJD (vCJD) is characterized by the presence of
extensive cortical plaques surrounded by a “halo” of spongiform
change.
• No alterations in the PRNP gene are present and the disease
appears to be limited to date to codon 129 Met/Met homozygotes.
• Onset of vCJD is linked to consumption of the bovine spongiform
encephalopathy agent in contaminated foods or blood transfusion,
raising significant public health issues

18. MORPHOLOGY
• The progression of the dementia in CJD is usually so
rapid that there is little if any grossly evident brain
atrophy
• The pathognomonic finding is a spongiform
transformation of the cerebral cortex and, often, deep
gray matter structures (caudate, putamen); this
multifocal process results in the uneven formation of
small, apparently empty, microscopic vacuoles of
varying sizes within the neuropil and sometimes in the
perikaryon of neurons

19. • In advanced cases there is severe neuronal loss, reactive
gliosis, and sometimes expansion of the vacuolated areas
into cystlike spaces (“status spongiosus”).
• Inflammation is notably absent.
• Electron microscopy shows the vacuoles to be membrane-
bound and located within the cytoplasm of neuronal
processes.
• Kuru plaques are extracellular deposits of aggregated
abnormal protein; they are Congo red- and PAS-positive
and usually occur in the cerebellum but are abundant in
the cerebral cortex in cases of vCJD

21. • In all forms of prion disease,
immunohistochemical staining demonstrates
the presence of proteinase K-resistant PrPsc in
tissue.

22. Fatal Familial Insomnia (FFI)
• Sleep disturbances characterize its initial
stages, is also caused by a specific mutation in
the PRNP gene.
• The mutation, which leads to an aspartate
substitution for asparagine at residue 178 of
PrPc

23. • In the course of the illness, which typically
lasts fewer than 3 years, affected individuals
develop other neurologic signs, such as ataxia,
autonomic disturbances, stupor, and finally
coma.
• A noninherited form of the disorder (fatal
sporadic insomnia) has also been described

24. MORPHOLOGY
• Most striking alteration is neuronal loss and
reactive gliosis in the anterior ventral and
dorsomedial nuclei of the thalamus; neuronal
loss is also prominent in the inferior olivary
nuclei.
• Proteinase K-resistant PrPsc can be detected
by immunostaining or western blotting.

25. PREVENTION AND CONTROL
• At present, there are no effective vaccines or
specific treatment available for prion diseases.
• Infection control measures are therefore the
mainstay of prevention
• A number of strategies can be adopted to
enhance surveillance.

26. • These include:
– 1. Establishment of a National Surveillance Centre
which performs neuropathological and
immunological tests for prion proteins.
– 2. Making physicians aware of monitoring and
surveillance efforts.
– 3. Autopsies should be performed in all cases of
prion diseases to confirm diagnosis.
– 4. Animals and high risk human population should
be screened.

27. • Prion diseases constitute a unique infection
control problem because they exhibit unusual
resistance to conventional chemical and physical
decontamination methods
• Summary of the recommendations made by the
Centers for Disease Control and Prevention (CDC,
Atlantaj." World Health Organization (WHO)6I
and other healthcare professionals for infection
control precautions for patients with known or
suspected CJD is given below

28. • 1. Precautions have to be taken for all patients of known or
suspected prion disease, patients with rapidly progressive dementia
and those who have received dura mater transplants or human
growth hormone injection,
• 2. No additional precautions other than standard universal safety
precautions need to be observed for these patients.
• 3. All tissue from these patients must be labelled as 'biohazard' or
'Suspected CJD' before being sent to the laboratory,
• 4. No special precautions are required for handling food utensils or
disposal of body fluids.

29. • 5. Laundry should be managed as for other blood borne pathogens.
• 6. The morgue must be notified that a patient had CJD.
• 7. Patients with suspected or known prion disease should not serve
as donors for organs, tissues or blood components.
• 8, Infection control professionals must be notified of all patients
with a known or suspected prion disease, They must also be
informed when such patients are scheduled to undergo any invasive
procedure where personnel or instruments will be exposed to
infectious material.

30. Decontamination of contaminated
medical devices
• Tissues such as brain, spinal cord and eyes are
high risk tissues
• Tissues and fluids such as CSF, kidney, liver,
spleen, lung and lymph nodes are low risk
tissues

31. • Devices contaminated with low risk tissues
can be cleaned and disinfected or sterilized by
use of conventional protocols of heat or
chemical sterilization or high level disinfection

32. • Devices contaminated with high risk tissues
must be cleaned and sterilized by autoclaving
at 134°C for ~18 minutes in a prevaccum
sterilizer or at 121-132 °C for 1 hour in a
gravity displacement sterilizer.
• Devices that cannot be cleaned must be
discarded. Neurosurgical instruments used in
such cases could be disposable.

33. • Non-critical equipment contaminated with
high risk tissue should be cleaned and
disinfected with 1:10 sodium hypochlorite (i.e.
bleach) or 1N sodium hydroxide depending on
material compatibility
• Contaminated environmental surfaces must
be cleaned and disinfected with 1:10 sodium
hypochlorite

34. • Environmental surfaces contaminated with these
tissues require to be disinfected as for standard blood-
contaminated surfaces.
• In the case of a percutaneous exposure to CSF or brain
tissue of an infected person-although scientifically
unproven-the wound should be rinsed with 0.5%
sodium hypochlorite for several minutes and then
washed with soap and water.
• Mucous membrane exposure should be managed by
irrigating thoroughly with saline for several minutes

35. Recent Developments Toward
Diagnostic Tests

36. Summary