Slow viral or prion diseases of the central nervous system

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Slow viral or prion diseases of the central
nervous system
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Slow viral diseases of the central nervous system

• tempo of clinical disease
• protracted incubation period
• (may also be protracted course of disease)
• multiple neurological symptoms

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SLOW INFECTIONS IN HUMANS

• VIRUSES
• SV40-like viruses (PML)
• measles virus (SSPE)
• rubella virus (PRP)
• ATYPICAL AGENTS
• Kuru,
• Creutzfeld-Jakob disease (CJD)
• (new) variant CJD disease (vCJDnvCJD)

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Progressive multifocal leukoencephalopathy

• Polyoma virus family, SV40-like (JC virus etc)
• progressive, usually fatal, associated with
  immune suppression
• HAART may prolong life in AIDS patients
• but little effect on PML incidence
• typically non inflammatory
• but can get an inflammatory response in the brain
  after HAART treatment (immune reconstitution
  inflammatory syndrome)
• demyelination (oligodendrocytes infected)

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SYMPTOMS

• weakness
• speech problems
• cognitive problems
• headaches
• gait problems
• visual problems
• sensory loss
• seizures

http//library.med.utah.edu/WebPath/TUTORIAL/AIDS/
AIDS076.html
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Progressive multifocal leukoencephalopathy

• reactivation of latent infection
• 70-80 population are seropositive
• associated with immunosuppression
• 1979 1.5 per 10,000,000 population
• 2004 1 in 20 AIDS patients

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BK virus (polyoma)

• Associated with urinary tract infections in
  immunosuppression
• Possibly contributory factor in prostate cancer???

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MEASLES VIRUS

• paramyxovirus family (morbillivirus genus)
• sub-acute sclerosing panencephalitis
• inflammatory disease
• defective virus
• 1-10 yrs after initial infection
• early infection with measles is a risk factor
• rare complication of measles (7-70 cases per
  1,000,000 cases measles)
• vaccine protects against SSPE

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RUBELLA VIRUS

• togavirus family (rubrivirus genus)
• progressive rubella panencephalitis
• inflammatory disease
• years after initial infection
• congenital / very early infections
• very very rare

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transmissible subacute spongiform encephalopathies
transmissible cerebral amyloidoses

• prion diseases

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TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES (TSEs,
TRANSMISSIBLE CEREBRAL AMYLOIDOSES, PRION
DISEASES)

• human
• Kuru
• Creutzfeldt-Jakob disease (CJD)
• Gerstmann-Straussler-Scheinker syndrome (GSS)
• fatal familial insomnia (FFI)
• variant CJD (human BSE)
• animal
• scrapie (sheep and goats)
• bovine spongiform encephalopathy (BSE)
• transmissible mink encephalopathy
• etc

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ATYPICAL AGENTS

• atypical viruses
• atypical agents
• prions

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ATYPICAL AGENTS

• SIMILAR TO VIRUSES
• small
• filterable
• need host cells
• no machinery for energy generation or protein
  synthesis

• DIFFERENT FROM VIRUSES
• no detectable virions in infected tissues
• no detectable virions in purified infectious
  material
• if nucleic acid is present, very small
• very resistant to inactivation

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• RESISTANT TO OR ONLY PARTIALLY INACTIVATED BY
• formaldehyde
• ethanol
• glutaraldehyde
• ultraviolet and ionizing irradiation
• non-ionic detergents
• INACTIVATED BY
• autoclaving (121C for one hour) (gt standard)
• 5 sodium hypochlorite
• sodium hydroxide
• proteases, urea, other protein denaturants

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purified infectious material

• protein present (PrP)
• proteases inactivate
• nucleic acid controversial
• but little or none

PRION
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PRION DISEASE

• CNS
• LONG INCUBATION
• SLOW COURSE OF
• DISEASE (FATAL)
• SPONGIFORM
• ENCEPHALOPATHY
• VACUOLATION OF NEURONS
• FIBRILLAR AGGREGATES, AMYLOID-TYPE MATERIAL (form
  plaques)
• RARE IN MAN

http//www.cdc.gov/ncidod/dvrd/cjd/ (Ermias
Belay)
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PRION PROTEIN (PrP)(host cell gene)
PrP or PrPC alpha-helical protease sensitive
PrPRES or PrPSC beta-pleated sheet protease
resistant
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PrP


PrPSC
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WHY ARE DIFFERENT PRION DISEASES DIFFERENT?

• SEEMS MORE THAN ONE CONFORMATION FOR THE PrPSC
  FORM

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PrP
1


PrPSC
PrP
2


disease caused by conformation 1 may differ from
that caused by conformation 2
PrPSC
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WHY ARE PRION DISEASES SOMETIMES INHERITED?

• MUTATIONS IN THE PrP GENE CAN INCREASE THE CHANCE
  OF PrPSC FORMATION

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germline mutation 1 INHERITED
germline mutation 2 INHERITED
disease caused by germline mutation 1 may differ
from that caused by germline mutation 2
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SCRAPIE

• sheep
• loss of muscular control
• wasting
• glial proliferation
• vacuolation of neurons
• amyloid plaques
• abnormal properties infectious material
• does not seem to cross sheep/human species barrier

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KURU

• human disease
• tremors, ataxia, weakness
• dementia, death
• amyloid plaques
• spongiform changes
• transmission contact with infectious material

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CREUTZFELDT-JAKOB DISEASE

• spongiform appearance of brain at autopsy
• dementia, myoclonus, ataxia
• 16-80, usually 50-70
• Median age at death in US68 yrs
• 10 familial
• also sporadic form
• also acquired form (eg. iatrogenic CJD)
• several hundred deaths in US per year

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CREUTZFELDT-JAKOB DISEASEclassical form

• no evidence for direct person to person
  transmission
• blood
• milk
• other body fluids
• intimate social contact

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CREUTZFELDT-JAKOB DISEASE

• iatrogenic CJD
• human cadaver growth hormone
• human cadaver gonadotropin
• dural mater grafts
• corneal transplantation
• neurosurgical instruments
• stereotactic EEG electrodes

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variant CJD (vCJD)

• patients younger at presentation, more protracted
  course of disease
• median age at death for UK vCJD patients28 yrs
• often patients present with psychiatric symptoms
• BSE connection
• seems bovine/human barrier is easier to cross
  than sheep/human barrier
• distinctive pathological appearance
• distinctive properties of the PrPres
• agent is in some peripheral tissues
• lymphoid tissues
• 2 probable cases where transmitted by blood
• future?
• two cases in US both had spent time in UK

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Belay et al (2005) Emerging Infectious Diseases
www.cdc.gov/eid 11 1351
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CDC/ Teresa Hammett , Photo Credit Sherif Zaki
MD PhD Wun-Ju Shieh MD PhD MPH
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Amino acid 129 Met or Val?- both variants found
in the human population

• Britain
• 37 of the UK population is MM
• 100 of clinical vCJD cases are MM
• Are MV, VV immune to vCJD, or will they develop
  vCJD later on?
• 83 of sporadic CJD cases are MM
• Britain, France, Japan
• excess of VV in growth hormone recipients with
  iatrogenic CJD
• does heterozygosity (M/V) offer some protection?

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OTHER HUMAN PRION DISEASES

• Gerstmann-Sträussler-Scheinker syndrome (GSS)
  (familial)
• motor
• sometimes regarded as subclass of CJD
• fatal familial insomnia (FFI)
• circadian rhythm problems
• hypothalamus

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IMMUNE RESPONSE

• no inflammatory response
• no interferon induction
• no antibody response
• no cell-mediated response

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TREATMENT

• invariably fatal
• attempts at drug therapy disappointing
• blood brain barrier

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DIAGNOSIS

• CLINICAL PICTURE, EEG, MRI (vCJD)
• USUALLY CONFIRMED POST-MORTEM
• NOW HAVE ANTIBODIES RAISED IN RECOMBINANT MICE
• can use on biopsy of brain (or peripheral
  lymphoid tissue in vCJD)

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PLAQUES

• PrP
• NOT THE SAME AS IN ALZHEIMERS

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http//www.cdc.gov/ncidod/dvrd/vcjd/
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The Times (London)
Dura mater - used in brain surgery
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Belay, E. http//www.cdc.gov/ncidod/dvrd/vcjd/char
t_percent_vcjd_cjd_deaths.htm