Pathogenesis of the central

nervous system infection

Dr. Yordan Khaedir, PhD

Dr. T. Mirawati Sudiro, PhD
Dept. Microbiology
Faculty of Medicine University of Indonesia
 Central nervous system (CNS)
Brain and Spinal Cord

Peripheral nervous system (PNS)

Nerves that transfer commands between CNS,
muscles, and glands
Sensory nerves carry signals towards the CNS
Motor nerves carry signal away from the CNS
Mixed nerves carry signal both toward and
away from CNS

Defenses:
* Meninges
* Cerebrospinal fluid
* Bone casing
* Blood brain barrier
* Immunologically privileged
 The impact of infection on the host depends very much
on the tissue involved
The CNS is vulnerable to slight damage -- can be fatal
Disease can be caused by :

- Effects on neural cell membrane --- abnormal

passage of nerve impulse
- Tissue oedema
Vasogenic oedema (caused by albumin in
CSF)
Toxigenic oedema
- Effects on small blood vessels circulatory
changes anoxia or necrosis
- Immunopathological factors
- Toxins
- Abscess
 Portals of Infections of the CNS
1. Hematogenous spread
most common
Usually via arterial route
Can enter retrogradely (veins)
2. Direct implantation
most often is traumatic
Iatrogenic (rare) via lumbar puncture
Congenital (meningomyelocele)
3. Local extension (secondary to established infections)
Most often from mastoid and frontal sinuses, infected tooth,
etc
4. PNS to CNS
Viruses : rabies, herpes zoster
 CSF
Direct spread
from adjacent Cerebral blood
vessel
structure (e.g.
mastoid)
Choroid
flexus blood
vessel
Ventricle

Ependymal
cells

Nerve ending

Meningeal blood vessel

The main routes to the brain

From: Struthers et al. Clinical Bacteriology

 ASEPTIC MENINGITIS SYNDROME
Causes :
Viral (eg. enteroviruses, HSV, HIV) meningitis
Tuberculous meningitis
Amebic meningitis
Brain abcess
Cotiguous sinusitis, otitis
Epidural abcess
Fungal meningitis
Infectious endocarditis
Lyme disease
Syphilic meningitis
Vertebral osteomyelitis
Chemical menginitis
Cyst-related meningitis
Drug-induced meningitis (eg. Ibuprofen, sulfa-trimetoprim)
Leptospiral meningitis
Neoplastic meningitis
Etc
More common Bacterial infection

Tuberculous meningitis

Bacterial meningitis
Streptococcus pneumoniae
Haemophilus influenzae
Neisseria meningitidis
Escherichia coli K1
Streptococcus agalactiae (Group B)
Listeria monocytogenes
Staphylococcus aureus
Brain abscess
Anaerobes (e.g. Bacteroides, Porphyromonas and
Prevotella spp)
Streptococci (e.g. Streptococcus anginosus)
Coliform
Staphylococcus

Ventriculo-peritoneal shunt infection

Coagulase-negative staphylococcus
Staphylococcus aureus
Corynebacteria
Coliform
Pseudomonas aeruginosa

Toxin and immune-mediated disorders

Clostridium botulinum
Clostridium tetani
Campylobacter spp.
Bacterial invasion
Meningococcal meningitis

1. Entry into
cerebrospinal fluid

2. Immune
response
Stimulation
 3. Margination of
neutrophils

4. Entry of neutrophils
and albumin
into CSF
5. The last stage entry of neutrophils and albumin into CSF
now CSF contains bacteria, neutrophils, and
protein in significant quantities
 Pathophysiology of bacterial meningitis
Bacterial attachment & colonisation

Local invasion

Bacteremia

Choroid flexus epithel and vascular endothel

Vascular
Cell injury and meningeal invasion
thrombosis
Increased BBB Bacterial replication & inflamation in the CSF
permiability
CSF outflow resistance
Increased Cerebral vasculitis
Hydrocephalus
CSF prot
Vasogenic edema Cytotoxic edema Interstitial edema Cerebral infraction

Decreased blood flow Increased intracranial pressure

Cerebral hypoxia Encephalopathy

Decrease CSF glucose Anaerobic glycolysis Increased CSF lactate CSF acidosis
 Brain Abscess
Bacteria enter the brain tissue
(from infected embolus lodged in a small vessel, cerebritis)

Inflammatory response to control bacterial growth

Abscess, covered in a collagen capsule, fibroblast

 Clostridium tetani : TETANUS

Gram stain,
drumstick

Peritrichous flagella, obligate anaerobe

Toxigenic and non-toxigenic strain
Toxin : Tetanospasmin (lethal dose 130g) and
tetanolysin
 Pathogenesis

Trauma to host tissue contamination with

C. tetani
Tissue damage oxidation-reduction potential
growth is initiated
Organism is confined to the necrotic tissue and
elaborate the lethal toxin that invades
systemically
Incubation period : infectious dose and the site
of the wound (4-5 days many weeks)
 Clostridium tetani : TETANUS

Toxin binds to receptors on the presynaptic

membranes of motor neurons retrograde
axonal transport system spinal cord and
brain stem. It blocks release of inhibitory
glycine and -aminobutiric acid, and the motor
neuron is not inhibited spasms of voluntary
muscles hyperreflexia, spastic paralysis.
 Clostridium botulinum : BOTULISM
A strain produces only one of seven similar neurotoxin
types
Pathogenesis :
Food Poisoning
ingestion of toxin in improperly preserved food
Wound Botulism
growth of C.botulinum in the necrotic tissue of a
wound
Infant Botulism
organism grows and produces toxin in the
intestinal of infants
 C. botulinum toxin
The toxin travels through the blood and
lymphatic system and fixed to cranial and
peripheral nerves

It binds to receptor sites at

the neuromuscular junctions
of parasympathetic nerves

It interferes with the release of

acethylcholine, a transmitter substance

It prevents impulses from passing

from motor nerves to
parasympathetic nerves
 Clostridium botulisme : BOTULISM

Toxin muscle paralysis, cranial descending,

symmetric paralysis of motor nerves flaccid paralysis

Symptoms : begins 18-24 hours after ingestion

Cranial nerves problems with eyesight, hearing,

speech
Descending paralysis with critical involvement of
the respiratory tree
Death: respiratory/cardiac failure (type A, E, B)
Mode of action of botulism toxin
 Viral Spread of virus in the body
Replication at the site of infection

Primary viremia

Replication sites

(From : Jawetz Medical Microbiology)

Secondary viremia

Replication sites

Transmission to other host

 Pathogenesis CNS Viral Infections

Steps required to establish an viral infection of neuron:

1. Enter the neuron at the axon, sensory terminal, or cell

body, depending on the site of infection
2. Transport the virus particle or subviral particle toward
the cell body of the neuron, where replication occurs
3. Replicate the genome
4. Assemble virus particle
Neural spread
Viral entry into the CNS by olfactory route
Olfactory neuron cell bodies are in the olfactory epithelia and their axon
terminals are in synaptic contact with olfactory bulb neurons

From SJ Flint, et al. Principles of Virology : Molecular Biology,

Pathogenesis and Control, 2000
Viruses
Pathogenesis of enterovirus infection
Spread of poliovirus in the body
Pathogenesis of Rabies
Intrauterine viral infection causing
defects in nervous system

Rubella virus
Herpes simplex virus (HSV-1, HSV-2)
Cytomegalovirus
 FUNGAL CENTRAL NERVOUS SYSTEM
INFECTION

Mucosal colonization blood stream

spread in the CSF blood-brain barrier

High number of microorganisms local energy

metabolism switch to anaerobic glycolysis

lactate concentration CSF glucose

 Inflammation local irritation abnormal
neuronal
activity
Pus collection, subsequent fibrosis around brainstem
interference with cranial nerve function
Focal pus collection (brain abscess)
intracranial pressure
Different microorganisms are more likely to cause
CNS infection in patients with immunocompromised
defence e.g. Cryptococus neoformans
 FUNGAL INFECTIONS THAT MAY BE MANIFEST
AS CHRONIC MENINGITIS OR BRAIN ABSCESS

Cryptococcus neoformans
Coccidioides immitis
Histoplasma capsulatum
Candida albicans
Blastomyces dermatitidis*
* Disease manifest as brain abscess
 CRYPTOCOCCUS NEOFORMANS
CNS infection mainly in immunocompromised patients,
hematogenous from lung to meninges expanding
intracerebral mass neurological defect

Acute meningitis (rare):

acute inflammation of leptomeninges

Chronic meningitis:
cranial nerve palsies and other neurological
complications

Brain abscess

Meningoencephalitis
 Further reading

C Mims, et al. Medical Microbiology 3rd ed. Mosby,

Edinburgh, 2004, 323-341.

JK Struthers and RP Western. Clinical Bacteriology,

ASM Press, Washington DC, 2003, 115-128

SJ Flint, et al. Principles of Virology : Molecular

Biology, Pathogenesis and Control, ASM Press,
Washington DC, 2000, 595-628.