MOST INTERESTING TOPIC IN NEUROLOGY/MEDICINE

1. PRION DISEASES
DR SRIRAMA ANJANEYULU
RESIDENT,NEUROLOGY
KING GEORGE HOSPITAL,VIZAG

2. INTRODUCTION
• Prions-infectious proteins causing
degenerative CNS disease.
• Rapidly progressing dementia.
• Myoclonus.
• Death.
• 50-75 yrs(17-93).

3. PRION STRUCTURE

5. PRION CONCEPTS
• Infectious pathogens devoid of nucleic acid.
• Manifest s as infectious ,genetic and sporadic.
• Prion diseases results from accumalution of
PrP sc which differs from its precursor Pr P c.
• PrP sc exists in different conformations-
disease phenotype.

6. SPECTRUM

7. EPIDEMIOLOGY
• Sporadic-85%
• Inherited-15%
• Infectious-<1%
• World wide-1 in mn population.

8. PRION TERMINOLOGY

9. PRION PROTEIN ISOFORMS

13. PATHOGENESIS
• Limited proteolysis of Pr P sc----PrP 27-30
(smaller protease resitant ).
• Polymerizes into amyloid.
• Deposition of Prion rods and amyloid
filaments.

16. SPORADIC AND INHERITED PRION
Initiation of prion disease
• Somatic mutation.
• Crossing of activation barrier.
• PrP sc may present at lower levels in normal
cells with unknown function.
• Imbalance between production and clearing
Pr P sc.

17. SPECIES BARRIER
• Transmission between species is less efficient .
• Differences in amino acid sequences of PrP c.
• 28 between human-mouse.
• 2 between human chimpanzee.
• Complex interactions with prion associated
proteins- protein X .

18. INFECTIOUS PRION
Iatrogenic CJD.
• Corneal transplants.
• Contaminated EEG electrodes.
• Surgical procedures.
• hGH ,gonadotropins.
Variant CJD.
• Consumption of contaminated beef.

19. NEUROPATHOLOGY
• Vacuolar changes in grey matter.
• Spongiform degeneration and astrocytic gliosis and lack of an
inflammatory response.
• Vacuoles are 5-25 micro m ( cross sections of swollen dendritic and
axonal process).
• Spongiform changes –cerebral cortex,putamen,thalamus and
molecular layer of cerebellum.(sporadic,familial,iotrogenic)
• Heidenhein- visual cortex
• Brownell-Oppenheimer- cerebellar
• Stern –Garcin- basal ganglia and thalmus
• V CJD –florid plaques. highest spongiosis.
• GSS-severe amyloidosis.
• FFI-neuronal loss and atrophy of AV&MD thalamus ,spongiosis of
cerebral cortex.
• Kuru-highest neuronal dropout in cerebellum followed by medial
temporal lobe,basal ganglia and thalmus.

21. CLINICAL FEATURES
SPORADIC CJD
• 45-75 yrs,mean-67 yrs.
• Core features-rapidly progressive multidomain
dementia with myoclonus.
• Addl.features-cerebellar ataxia,extra pyramidal
signs,pyramidal signs and cortical blindness.
• Clinical course-days-yrs,avg-7 months.
• Type 1 banding----20-21 KDa .
• Type 2---------------18-19 KDa .
• Six subclasses depending on M/V genotype at 129
codon.{MM1,MV1(most common types),
VV1,MM2,MV2,VV2}.

22. CJD
IATROGENIC CJD-
• IP- 6-7 yrs.
FAMILIAL CJD-
• AD,variable penetrance,early onset ,slow
progression,F/H +.
VARIANT CJD-
• Transmission of BSE to humans.
• Mean age of death-29 yrs.psychiatric symptoms
(anxiety ,depression and withdrawal), rarely psychosis.
• Dementia,ataxia,chorea,dystonia and myoclonus
follows.

23. DIAGNOSTIC CRITERIA

26. GERSTMANN-STRUSSLER-SCHEINKER
SYNDROME
• Slowest inherited prion disease,ataxia,dysarthria
followed by dementia.
• Parkinsonism features .
• Gaze palsy,deafness,cortical blindness,extensor
plantar.
• Myoclonus rare.
• Early age, slow progression.
• Difficult differentiate from SCA,MSA,early PD.
• Analysis for mutations in PRNP gene definite
diagnosis.

27. FFI &sFI
• Age of onset-20-72.avg-49 yrs.
• Course—6 months to 3 yrs.
• Progressive intractable insomnia and symptoms
of sympathetic overactivity .
• HTN,tachycardia,hyperthermia,hyperhydrosis.
• Tremor ,ataxia,hyperreflexia and myoclonus.
• Dementia –mild .
• Disorientation,confusion ,complex hallucinations.
• Endocrine abnormalities.PRL,ACTH,GH.

28. KURU
• Kuru-fore language-trembling associated with fear or cold.
• Women and children of fore people of New Guinea.
• Ritualistic cannibalism.
• Progressive cerebellar ataxia.
• 3 phases.
• 1-initial phase-ambulant with minimal truncal
ataxia,dysarthria and tremor.
• 2-sedentary phase-loss of ambulation due to ataxia
choreoathetosis,worsening of tremor and mood instability.
• 3-terminal phase-generalized hyperreflexia,progression of
dysarthria and dysphagia.
• Muscle strength and sensorium normal.
• Down hill course within 12 months from onset.

29. DIAGNOSIS
• Brain biopsy histology with western blot analysis of
proteinase K treated brain homogenate.
• iqPCR as one of the choice methods for PrPres
detection in brain surgical biopsy and autopsy
specimens.
• CSF ---14-3-3 protein and tau protein.
• Sensitivity 94% and specificity ---93% in s CJD.
• Less sensitive in v CJD&f CJD, rarely elevated in GSS,not
in FFI.
• False positive in acute
stroke,MS,encephalitis,AD.FTD,HAD.

33. DIFFERENTIALS
• AD.
• FTD.
• CBD.
• DLB.
• Thyroid.
• Syphilis.
• B12 def.
• Lymphoma,meningitis and encephalitis (HSV)

38. CARE OF CJD PTS
• Although CJD should not be considered either
a contagious or communicable disease, it is
transmissible.
• The risk of accidental inoculation by aerosols
is very small.
• Procedures producing aerosols should be
performed in certified biosafety cabinets.
• Inadvertent infection of health care workers
by needle and stab wounds.

39. DECONTAMINATION
• Autoclaving at 132C for 5 h or treatment with
2 N NaOH for several hours is recommended
for sterilization of prions.
• Treating CJD-contaminated materials once
with 1 N NaOH at room temperature, this
procedure may be inadequate.

40. TREATMENT
• Antipsychotics,BZD,L-dopa,amantadine.
• Congo red ,amphoterecin B - tired,found
ineffective.
• Quinacrine under clinical trials.
• Short peptide homologs to Pr P c to interact with
PrP sc and act as beta sheet breakers.
• Drugs inhibiting conversion .
• Splenectomy –prolong incubation period.
• Immunization with recombinant Pr P.

41. Thank you