CNS Infection
Meninges and Prions
1
CNS Infection - Meninges
•
CNS infections: most are due to sepsis
•
Pathogenesis:
–
–
–
–
Hematogenous spread (most common)
Traumatic implantation
Local extension from nearby infection
Ascent of peripheral nerve
2
Meningitis
•
•
Inflammation of pia mater covering the brain
Usually due to hematogenous spread; mechanism for
bacterial meningitis:
–
–
–
Adherence of bacteria to mucosa of nasopharynx
Bacteremia
Translocation through blood-brain barrier (BBB)
•
–
–
•
Involves bacterial lysins
Bacteria in subarachnoid space attract neutrophils.
Acute meningitis
Risk factors in children
–
–
–
–
Undernutrition; otitis media
Pneumonia; immunodeficiency
Viral infection; sickle cell disease
Craniofacial abnormality
3
Viral Meningitis
•
Pathogenesis:
–
–
•
Most transmitted by fecal-oral route
Respiratory route less common
Clinical findings:
–
Fever, nuchal rigidity, headache
4
Complications of meningitis
•
•
•
•
Seizures; focal neurologic deficits
Cranial nerve palsies
Sensorineural hearing loss
Communicating and noncommunicating
hydrocephalus
5
Laboratory findings in viral meningitis
(CSF)
•
Increased CSF protein
–
•
Increased total CSF leukocyte count
–
•
Due to increased vessel permeability
Initially neutrophils but converts to
lymphocytes in 24 hours
Normal CSF glucose
6
Laboratory findings in bacterial
meningitis (CSF)
•
•
•
Increased CSF protein
Increased total CSF leukocyte count
Decreased CSF glucose
–
Usage of glucose for bacterial and fungal
growth (bacterial & fungal meningitis)
7
Chronic Meningitis
•
–
–
Tuberculous meningitis
•
•
•
–
•
•
headache, malaise, mental confusion, and
vomiting
moderate increase in cellularity of the CSF
mononuclear cells, or a mixture of
polymorphonuclear and mononuclear cells
the protein level is elevated
the glucose content typically is moderately reduced
or normal
may also lead to
well-circumscribed intraparenchymal mass
(tuberculoma)
arachnoid fibrosis (hydrocephalus)
8
TB Meningitis - Pathology
•
•
–
–
•
•
•
•
–
–
–
The subarachnoid space contains a gelatinous or
fibrinous exudate
most often at the base of the brain
obliterating the cisterns and encasing cranial nerves
There may be discrete white granules scattered over
the leptomeninges
Arteries running through the subarachnoid space may
show obliterative endarteritis
inflammatory infiltrates in their walls
marked intimal thickening
The infection may spread through the CSF to the
choroid plexuses and ependymal surface
Florid cases show well-formed granulomas
often with caseous necrosis and giant cells
Similar findings are observed in tuberculomas within
the brain
9
Chronic Meningitis
•
Meningovascular neurosyphilis
–
–
Neurosyphilis is a tertiary stage of syphilis
occurs in only about 10% of individuals with
untreated infection
–
major manifestations is meningeal, called
meningovascular neurosyphilis
–
As with other chronic infections, there can
be parenchymal disease as well
• Paretic neurosyphilis
• Tabes dorsalis
10
Meningovascular neurosyphilis
•
•
•
involving the base of the brain and sometimes
the cerebral convexities and the spinal
leptomeninges
associated obliterative endarteritis with
distinctive perivascular inflammatory reaction
rich in plasma cells and lymphocytes
cerebral gummas (mass lesions rich in plasma
cells) may also occur in relation to meninges
and extend into the brain
11
Prion Diseases
•
This group of diseases includes
–
sporadic, familial, iatrogenic and variant forms of
Creutzfeldt-Jakob disease (CJD)
several animal diseases from this group are also known
–
•
–
including scrapie in sheep and goats and bovine spongiform
encephalopathy in cattle ("mad cow" disease)
all these disorders are associated with abnormal forms of a
normal cellular protein, prion protein (PrPc)
The abnormal form of this protein can act as an infectious
agent
–
•
•
–
it propagates itself
injures the cells in which it is present
Most cases of prion disease are either
•
•
sporadic or
associated with mutations in the gene that encodes PrPc
12
Pathogenesis of Prion Diseases
•
–
–
•
•
•
•
•
–
–
–
–
Related to changes in the conformation of PrP from its native
PrPc form to an abnormal configuration called
either PrPsc (for scrapie) or PrPres (for protease resistant)
in the abnormal conformation, the prion protein becomes resistant to
protease digestion
Once formed, PrPsc can then initiate
comparable transformation of other PrPc molecules
The infectious nature of PrPsc protein
ability to propagate the pathologic conformational change
The conformational change can occur spontaneously at an
extremely low rate
sporadic cases of prion disease
If there is a mutation in the gene encoding PrPc, then the
change can occur at a higher rate
familial forms of prion disease
Accumulation of PrPsc in neural tissue causes cell injury
–
how this material leads to the development of cytoplasmic
vacuoles and eventual neuronal death is still unknown
13
Creutzfeldt-Jakob Disease
•
•
•
–
–
•
•
•
–
–
CJD is a rare but well-characterized prion disease
clinically as a rapidly progressive dementia
It is sporadic in about 85% of cases (1 per million
worlwide)
familial forms also exist
The disease has a peak incidence in the seventh
decade
There are well-established cases of iatrogenic
transmission
deep implantation electrodes
contaminated preparations of human growth hormone
Clinically, subtle changes in memory and behavior that
rapidly progress to dementia
The disease is uniformly fatal, with an average
duration of only 7 months
14
Creutzfeldt-Jakob Disease
•
•
The progression of the dementia in CJD is usually rapid
–
–
–
•
•
•
•
no or very little macroscopic evidence of brain atrophy
On microscopic examination, the pathognomonic finding is
a spongiform transformation of the cerebral cortex and deep gray
matter (caudate, putamen)
this consists of a multifocal process that results in the uneven
formation of small, apparently empty, microscopic vacuoles of varying
sizes within the neuropil and sometimes in the perikaryon of neurons
In advanced cases, there is severe neuronal loss, reactive
gliosis, and sometimes expansion of the vacuolated areas into
cystlike spaces ("status spongiosus")
No inflammatory infiltrate is present
In all forms of prion disease, immunohistochemical staining
demonstrates the presence of proteinase K-resistant PrPsc in
tissue
Western blotting of tissue extracts after partial protease
digestion allows detection of diagnostic PrPsc
15
Variant Creutzfeldt-Jakob Disease
•
–
–
–
•
•
•
–
–
–
They differed 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
The neuropathologic findings and molecular features
of these new cases were similar to those of CJD
a close relationship between the two illnesses
Multiple lines of evidence indicate that this new
disease is a consequence of exposure to
the prion disease of cattle, bovine spongiform encephalopathy
vCJD has a similar pathologic appearance with
spongiform change and absence of inflammation
there are abundant cortical amyloid plaques, surrounded by
spongiform change
16
Variant Creutzfeldt-Jakob Disease
•
–
–
–
•
•
•
–
–
–
They differed 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
The neuropathologic findings and molecular features
of these new cases were similar to those of CJD
a close relationship between the two illnesses
Multiple lines of evidence indicate that this new
disease is a consequence of exposure to
the prion disease of cattle, bovine spongiform encephalopathy
vCJD has a similar pathologic appearance with
spongiform change and absence of inflammation
there are abundant cortical amyloid plaques, surrounded by
spongiform change
17