Download CNS Infections III

Micribiology: CNS Infections (Holland)
DNA VIRUSES AND CNS INFECTIONS:
Herpesvirus:

Herpesvirus Infections of the CNS:
HSV Encephalitis:
o Basics: most common form of sporadic fatal encephalitis in aduse
o Pathogenesis: focal encephalopathy, most often affecting the temporal lobe
o Symptoms: fever, altered consciousness and behavior, severe headache, disordered thinking, LOC
o Mortality: very high if not treated
o Treatment: Acyclovir and other anti-herpesviral drugs (reduce mortality)

Note: many patients do NOT regain full mental function (long term sequelae) even with
treatment
Herpes B Virus (Cercopithecine Herpesvirus 1) Infections:
o Basics: monkey virus
o Transmission: infected animals secrete virus in saliva and other bodily secretions (may not appear
sick); therefore, transmitted by bite or contact of secretions with mucous membranes
o Mortality: highly pathogenic for humans with high frequency of fatal encephalitis
o Treatment: high doses of acyclovir/ganciclovir (but often also long term sequelae)
VZV Infections:
o Complications of Varicella:

Encephalitis (most common of these but still fairly uncommon)

Transient cerebellar ataxia (usually self-limiting)

Aseptic meningitis (rare)

Transverse myelitis (rare; infection of the spinal cord)
o Complications of Zoster:

Encephalitis
o Congenital Varicella:

Mental retardation

Cerebral atrophy

Non-CNS abnormalities
Congenital CMV Infections:
o Mechanism: transplacental transmission of CMV during primary infection of mother
o Presentation:

Some (~10%) Present with Signs at Birth:
 Intrauterine growth retardation
 Hepatosplenomegaly
 Microcephaly (long term neurological issues)
 Many develop long term sequelae: mental retardation, seizures, blindness,
deafness, or death

The rest are asymptomatic at birth: have a significant probability (10-15%) of developing
hearing and vision problems, as well as intellectual impairment
Polyomavirus:

Human Polyomavirus:
Basics:
o Family: Papoviridae
o Subfamily: Polyomavirinae
Types Endemic in Humans:
o JC Virus: asymptomatic in most cases, but can be associated with mild URI

Associated with Progressive Multifocal Leukoencephalopathy (PML)
o BK Virus: may cause a mild URI

Associated with polymavirus nephropathy in renal transplant patients

Associated with hemorrhagic cystitis in bone marrow transplant patients
Newly Discovered:
o KI Virus
o WU Virus
o MCV (Merkel Cell Virus)

Animal Polyomaviruses:
Polymavirus: mouse virus that causes multiple types of tumors in mice


SV40: monkey virus closely related to JCV and BKV; reported to have been isolated from some human tumors
(although role in human cancer is controversial)
Characteristic of Polyomavirus:
Structure: nonenveloped icosahedral
Genome: circular, dsDNA
Replication: in the nucleus; highly dependent on cellular enzymes for DNA replication and gene expression
JC Virus:
Basics: prevalent word-wide with 50-75% of adults being seropositive
Transmission: mode unknown
Primary Infections: frequently asymptomatic (may be associated with mild URI)
Progressive Multifocal Leukoencephalopathy in Immunocompromise:
o Clinical Features:

Initial Symptoms: usually indicate focal cerebral involvement (personality changes,
intellectual development, loss of motor skills, sensory loss)
 Less Frequently: symptoms may indicate cerebellar or brain stem involvement
(difficulty speaking, swallowing, ataxia)

Rapid Progression: death occurs within 2-12 months

Treatment: generally not treatable; rare remissions may occur, associated with correction of
immunodeficiency
o Pathogenesis:

Pathological changes may occur in the cerebrum, cerebellum or brain stem

Lesions characterized by loss of myelin
 Cerebrum: this typically occurs in the subcortical regions (deep white matter) as
opposed to the cerebral cortex and gray matter, which appear normal

Loss of myelin is due to virus replication in oligodendrocytes

Little to no inflammation*
o Diagnosis:

Suspicion: should be suspected in immunocompromised patients with progressive
development of neurological deficits

Imaging: MRI/CT for lesions in subcortical and deep white matter

PCR: detection of JCV in CSF

Brain Biopsy: verify presence of JCV and eliminate other infections that may imitate PML (ie.
Toxoplasma gondii, Cryptococcus neoformans, Mycobacterium tuberculosis
TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHIES:

TSE Basics:
Basics: invariably fatal neurodegenerative diseases
Infectious Agent: prion (infectious protein)
Transmission of TSE: ingestion or inoculation
Spontaneous Occurrence of TSE: sporadic or familial

Basic Characteristics:
Clinical:
o Impaired cognitive function
o Ataxia
o Progressive degeneration of neurological function leading to death
Histological:
o Spongiform degeneration
o Amyloid plaques
o Activated astrocytes and microglial cells
Molecular:
o Accumulation of an abnormal, protease-resistant form of PRNP gene product
o PRNP Gene:

Present in all vertebrates

PrPc (cellular) or PrPsen (protease sensitive) is the normal form

PrPsc (scrapie) or PrPres (protease resistance) is the abnormal form
o PrPc vs. PrPsc: both have the same amino acid sequence but different conformations

PrPc: membrane bound glycoprotein with high alpha-helix content

PrPsc: primarily beta-sheet configuration

Characteristics of Human TSEs:
Prion Disease
sCJD
Major Symptoms
Dementia
Ataxia
Myoclonus
Visual problems
Similar to sCJD
Major CNS Target
Cerebrum
6 month
Similar to sCJD
Cerebrum
26
(12-74)
14 months
(6-24 months)
Cerebrum
Gerstmann-StrausslerScheinker Syndrome (GSS)
50-60
5-6 years
(3 months-13 yr)
Fatal Familial Insomnia (FFI)
Only affects a few families
50
(20-63)
13-15 months
(6-42 months)
Psychiatric symptoms
Neurological deficits
Cognitive decline
Cerebellar dysfunction
Ataxia
Nystagmus
Dysarthria
Insomnia
Autonomic disorders
fCJD
Mutation in PRNP gene leads
to predisposition
iCJD
Due to medical procedure or
neurosurgery instruments
vCJD


Age at Onset
55-70
(17-83)
Disease Duration
6 months
(1-35 months)
50-60
6 months
(2-41 months)
Any age
Cerebrum
Cerebellum
Thalamic
involvment
Creutzfeldt-Jakob Disease (CJD):
Basics: most common TSE affecting humans
Forms:
o Sporadic (sCJD): no identified cause
o Familial (fCJD): autosomal dominant mutations in PRNP, leading to predisposition
o Iatrogenic (iCJD): neurosurgery, transplantation, brain-derived hormones (ie. hGH from cadavers)
o Variant (vCJD): thought to be caused by transmission of BSE to humans
Neuropathology:
o Spongiform degeneration
o Astrocytosis
o Cerebral atrophy
o Neuronal vacuolization (neurons killed)
o Amyloid plaques
o Lack of inflammation (due to the fact that there is NO immune response mounted)
Molecular Aspects of Prions:
Prion Replication Models:
o Refolding Model: exposure of PrPc to PrPsc converts PrPc to PrPsc (exposure of normal to abnormal
converts normal to more abnormal)

PrPc does not spontaneously convert to PrPsc (or vice vers)

Exception: hereditary TSE disease (mutant forms of PrPc may spontaneously convert)
o Seeding (Nucleation) Model: PrPc and PrPsc are in equilibrium with eachother (balance strongly favors
PrPc)

PrPsc slowly form aggregates (since rate is so low, it almost never happens spontaneously)

In this model, there is a little PrPsc around all the time
Prion Strain Variation:
o Prions derived from different sources exhibit different properties : variation in disease symptoms and
pathology

Localization: cerebrum vs. cerebellum

Disease time course

Extend of amyloid protein deposition

Ease of crossing species barriers
o Variation at the molecular level:

Prion conformation

Extent of glycosylation



PRNP Gene:
Genotype Influences Susceptibility to Disease:
o PRNP Codon 129: can be MM, MV, or VV

Normal Population: most are MV

Sporadic CJD: most are MM

Variant CJD: all are MM
Mutations in PRNP Gene:
o Pathogenic octarepeat insertions can be deleted and may segregate with a neurogenenerative disorder
Bovine Spongiform Encephalitis (Mad Cow Disease):
Origin Theories:
o BSE comes from a Scrapie (TSE of sheep):

Previously thought to be non-transmissible to other animals

Sheep and cattle waste parts used to make meat and bone meal added to animal feed, which
may have transferred disease to cattle through feed (crossing “species barrier”)
o BSE comes from spontaneous conformational shift of bovine PrP: which then spread to other cattle
through contaminated feed
vCJD and BSE:
vCJD may originate from BSE:
o Early clinical onset and neuropathology distinct from other forms of CJD
o Protease Fingerprinting shows vCJD prions resemble BSE prions, not classical CJD prions (strongly
suggests transmission from cattle)
Full scope of human outbreak hard to estimate:
o Best Case: a few hundred cases

This is the prediction of BSE is hard to transmit to humans

Current cases would mostly result from those infected at the peak of the BSE epidemic in
cattle (ie. only a few were infected when exposure was highest- can expect a decrease in
number of cases)
o Worst Case: several tens of thousands of cases

This is the prediction if current cases were infected at the beginning of BSE epidemic (before
exposure was the highest- therefore, in the next few years, you would expect the number of
cases to increase)